Drugs, Pregnancy & Lactation

 

The three most potent human teratogens, with the possible inclusion of some of the first antineoplastics, are isotretinoin, alcohol, and hyperglycemia.

As with all teratogens, the toxicity is dose related. For example, the risk of embryo-fetal harm from hyperglycemia increases markedly when the HbA_1c is greater than 8%. Moreover, diabetes accounts for more than 90% of the harm caused by chronic diseases. Consequently, control of glucose levels in pregnancy is critical.

Although the American College of Obstetricians and Gynecologists recommends insulin as the drug of choice for all diabetes types, oral antidiabetic agents are often used in type 2 and gestational diabetes if diet control and exercise have not been effective. Consistent with its molecular weight (5808), insulin does not cross the human placenta, at least in clinically significant amounts. In contrast, the oral agents have molecular weights ranging from 166 to 646, strongly suggesting that they will cross to the human embryo-fetus throughout pregnancy.

If these agents are used near term, there is a risk that they will cause hypoglycemia in the newborn. Changing from oral therapy to insulin is the safest course.

There are seven pharmacologic subclasses of oral antidiabetic agents: alpha-glucosidase inhibitors, biguanides, dipeptidyl peptidase-4 inhibitors, meglitinides, sulfonylureas, sodium-glucose cotransporter-2 inhibitors, and thiazolidinediones. Many of these drugs are available in combination with metformin. All of these agents are indicated as adjunct to diet and exercise for type 2 diabetes, but they also can be used for gestational diabetes. Although the human pregnancy data are very limited or nonexistent for most of these agents, none are known to cause structural defects in humans. Additional details of the exposures are available in the 11th edition of “Drugs in Pregnancy and Lactation” (2017: Wolters Kluwer).

Alpha-glucosidase inhibitors

The two agents is this subclass are acarbose (Precose) and miglitol (Glyset). The human pregnancy data with acarbose are limited, and no human pregnancy data have been found for miglitol. The animal data for both drugs suggest low risk.

Biguanides

There are substantial human pregnancy data for metformin in both type 2 and gestational diabetes. When combined with insulin, it is effective in significantly lowering the amount of insulin required to control hyperglycemia. It also may be effective when used alone. The risk of embryo-fetal harm with this drug appears to be very low or nonexistent. The animal data suggest low risk.

Dipeptidyl peptidase-4 inhibitors

There are four drugs in this subclass: alogliptin (Nesina), linagliptin (Tradjenta), saxagliptin (Onglyza), and sitagliptin (Januvia). No reports of the use of the first three drugs in human pregnancy have been found. However, the Merck Pregnancy Registries (2006-2009) described the outcomes of eight women who were exposed to sitagliptin or sitagliptin/metformin in the first trimester. The outcomes of these pregnancies were five healthy newborns, two spontaneous abortions, and one fetal death at 34 weeks’ gestation. In that case, the mother took sitagliptin and metformin separately during the first 5 weeks of gestation. The animal data for all four drugs suggest low risk.

Meglitinides

Nateglinide (Starlix) and repaglinide (Prandin) are the agents in this subclass. There is no human pregnancy data for nateglinide, but there is limited data (eight pregnancies) for repaglinide. No birth defects or other toxicity was noted in these cases. The animal data suggest low risk.

Sulfonylureas

Six drugs are included in this subclass: chlorpropamide, glimepiride (Amaryl), glipizide (Glucotrol), glyburide, tolazamide (Tolinase), and tolbutamide. These agents were among the first oral antidiabetic agents. As a result, they have the most human pregnancy data. Although birth defects were observed in newborns of mothers who had used one of these drugs, the defects were thought to be the result of uncontrolled diabetes. The animal data suggest low risk.

SGLT2 inhibitors

There are three drugs in this sodium-glucose cotransporter-2 inhibitor subclass: canagliflozin (Invokana), dapagliflozin (Farxiga), and empagliflozin (Jardiance). No reports describing the use of these drugs in human pregnancy have been located. The animal data suggest low risk.

Thiazolidinediones

Pioglitazone (Actos) and rosiglitazone (Avandia) form this subclass. There are limited human pregnancy data for both drugs. The animal data suggest moderate risk for embryo-fetal toxicity but not for structural defects.

Lactation

All of the above drugs will probably be excreted into breast milk, but the amounts are typically unknown. When they have been measured, the amounts were usually low. However, there is still a risk for hypoglycemia in a nursing infant. Combination products containing two antidiabetic agents are best avoided. The safest course is to use insulin, but, if this is not an option, then the lowest effective dose should be used. In addition, the infant’s blood glucose levels should be routinely monitored.

 

Mr. Briggs is a clinical professor of pharmacy at the University of California, San Francisco, and an adjunct professor of pharmacy at the University of Southern California, Los Angeles, as well as at Washington State University, Spokane. He coauthored “Drugs in Pregnancy and Lactation” and coedited “Diseases, Complications, and Drug Therapy in Obstetrics.” He reported having no relevant financial disclosures.

 

The three most potent human teratogens, with the possible inclusion of some of the first antineoplastics, are isotretinoin, alcohol, and hyperglycemia.

As with all teratogens, the toxicity is dose related. For example, the risk of embryo-fetal harm from hyperglycemia increases markedly when the HbA_1c is greater than 8%. Moreover, diabetes accounts for more than 90% of the harm caused by chronic diseases. Consequently, control of glucose levels in pregnancy is critical.

Although the American College of Obstetricians and Gynecologists recommends insulin as the drug of choice for all diabetes types, oral antidiabetic agents are often used in type 2 and gestational diabetes if diet control and exercise have not been effective. Consistent with its molecular weight (5808), insulin does not cross the human placenta, at least in clinically significant amounts. In contrast, the oral agents have molecular weights ranging from 166 to 646, strongly suggesting that they will cross to the human embryo-fetus throughout pregnancy.

If these agents are used near term, there is a risk that they will cause hypoglycemia in the newborn. Changing from oral therapy to insulin is the safest course.

There are seven pharmacologic subclasses of oral antidiabetic agents: alpha-glucosidase inhibitors, biguanides, dipeptidyl peptidase-4 inhibitors, meglitinides, sulfonylureas, sodium-glucose cotransporter-2 inhibitors, and thiazolidinediones. Many of these drugs are available in combination with metformin. All of these agents are indicated as adjunct to diet and exercise for type 2 diabetes, but they also can be used for gestational diabetes. Although the human pregnancy data are very limited or nonexistent for most of these agents, none are known to cause structural defects in humans. Additional details of the exposures are available in the 11th edition of “Drugs in Pregnancy and Lactation” (2017: Wolters Kluwer).

Alpha-glucosidase inhibitors

The two agents is this subclass are acarbose (Precose) and miglitol (Glyset). The human pregnancy data with acarbose are limited, and no human pregnancy data have been found for miglitol. The animal data for both drugs suggest low risk.

Biguanides

There are substantial human pregnancy data for metformin in both type 2 and gestational diabetes. When combined with insulin, it is effective in significantly lowering the amount of insulin required to control hyperglycemia. It also may be effective when used alone. The risk of embryo-fetal harm with this drug appears to be very low or nonexistent. The animal data suggest low risk.

Dipeptidyl peptidase-4 inhibitors

There are four drugs in this subclass: alogliptin (Nesina), linagliptin (Tradjenta), saxagliptin (Onglyza), and sitagliptin (Januvia). No reports of the use of the first three drugs in human pregnancy have been found. However, the Merck Pregnancy Registries (2006-2009) described the outcomes of eight women who were exposed to sitagliptin or sitagliptin/metformin in the first trimester. The outcomes of these pregnancies were five healthy newborns, two spontaneous abortions, and one fetal death at 34 weeks’ gestation. In that case, the mother took sitagliptin and metformin separately during the first 5 weeks of gestation. The animal data for all four drugs suggest low risk.

Meglitinides

Nateglinide (Starlix) and repaglinide (Prandin) are the agents in this subclass. There is no human pregnancy data for nateglinide, but there is limited data (eight pregnancies) for repaglinide. No birth defects or other toxicity was noted in these cases. The animal data suggest low risk.

Sulfonylureas

Six drugs are included in this subclass: chlorpropamide, glimepiride (Amaryl), glipizide (Glucotrol), glyburide, tolazamide (Tolinase), and tolbutamide. These agents were among the first oral antidiabetic agents. As a result, they have the most human pregnancy data. Although birth defects were observed in newborns of mothers who had used one of these drugs, the defects were thought to be the result of uncontrolled diabetes. The animal data suggest low risk.

SGLT2 inhibitors

There are three drugs in this sodium-glucose cotransporter-2 inhibitor subclass: canagliflozin (Invokana), dapagliflozin (Farxiga), and empagliflozin (Jardiance). No reports describing the use of these drugs in human pregnancy have been located. The animal data suggest low risk.

Thiazolidinediones

Pioglitazone (Actos) and rosiglitazone (Avandia) form this subclass. There are limited human pregnancy data for both drugs. The animal data suggest moderate risk for embryo-fetal toxicity but not for structural defects.

Lactation

All of the above drugs will probably be excreted into breast milk, but the amounts are typically unknown. When they have been measured, the amounts were usually low. However, there is still a risk for hypoglycemia in a nursing infant. Combination products containing two antidiabetic agents are best avoided. The safest course is to use insulin, but, if this is not an option, then the lowest effective dose should be used. In addition, the infant’s blood glucose levels should be routinely monitored.

 

Mr. Briggs is a clinical professor of pharmacy at the University of California, San Francisco, and an adjunct professor of pharmacy at the University of Southern California, Los Angeles, as well as at Washington State University, Spokane. He coauthored “Drugs in Pregnancy and Lactation” and coedited “Diseases, Complications, and Drug Therapy in Obstetrics.” He reported having no relevant financial disclosures.

 

The three most potent human teratogens, with the possible inclusion of some of the first antineoplastics, are isotretinoin, alcohol, and hyperglycemia.

As with all teratogens, the toxicity is dose related. For example, the risk of embryo-fetal harm from hyperglycemia increases markedly when the HbA_1c is greater than 8%. Moreover, diabetes accounts for more than 90% of the harm caused by chronic diseases. Consequently, control of glucose levels in pregnancy is critical.

Although the American College of Obstetricians and Gynecologists recommends insulin as the drug of choice for all diabetes types, oral antidiabetic agents are often used in type 2 and gestational diabetes if diet control and exercise have not been effective. Consistent with its molecular weight (5808), insulin does not cross the human placenta, at least in clinically significant amounts. In contrast, the oral agents have molecular weights ranging from 166 to 646, strongly suggesting that they will cross to the human embryo-fetus throughout pregnancy.

If these agents are used near term, there is a risk that they will cause hypoglycemia in the newborn. Changing from oral therapy to insulin is the safest course.

There are seven pharmacologic subclasses of oral antidiabetic agents: alpha-glucosidase inhibitors, biguanides, dipeptidyl peptidase-4 inhibitors, meglitinides, sulfonylureas, sodium-glucose cotransporter-2 inhibitors, and thiazolidinediones. Many of these drugs are available in combination with metformin. All of these agents are indicated as adjunct to diet and exercise for type 2 diabetes, but they also can be used for gestational diabetes. Although the human pregnancy data are very limited or nonexistent for most of these agents, none are known to cause structural defects in humans. Additional details of the exposures are available in the 11th edition of “Drugs in Pregnancy and Lactation” (2017: Wolters Kluwer).

Alpha-glucosidase inhibitors

The two agents is this subclass are acarbose (Precose) and miglitol (Glyset). The human pregnancy data with acarbose are limited, and no human pregnancy data have been found for miglitol. The animal data for both drugs suggest low risk.

Biguanides

There are substantial human pregnancy data for metformin in both type 2 and gestational diabetes. When combined with insulin, it is effective in significantly lowering the amount of insulin required to control hyperglycemia. It also may be effective when used alone. The risk of embryo-fetal harm with this drug appears to be very low or nonexistent. The animal data suggest low risk.

Dipeptidyl peptidase-4 inhibitors

There are four drugs in this subclass: alogliptin (Nesina), linagliptin (Tradjenta), saxagliptin (Onglyza), and sitagliptin (Januvia). No reports of the use of the first three drugs in human pregnancy have been found. However, the Merck Pregnancy Registries (2006-2009) described the outcomes of eight women who were exposed to sitagliptin or sitagliptin/metformin in the first trimester. The outcomes of these pregnancies were five healthy newborns, two spontaneous abortions, and one fetal death at 34 weeks’ gestation. In that case, the mother took sitagliptin and metformin separately during the first 5 weeks of gestation. The animal data for all four drugs suggest low risk.

Meglitinides

Nateglinide (Starlix) and repaglinide (Prandin) are the agents in this subclass. There is no human pregnancy data for nateglinide, but there is limited data (eight pregnancies) for repaglinide. No birth defects or other toxicity was noted in these cases. The animal data suggest low risk.

Sulfonylureas

Six drugs are included in this subclass: chlorpropamide, glimepiride (Amaryl), glipizide (Glucotrol), glyburide, tolazamide (Tolinase), and tolbutamide. These agents were among the first oral antidiabetic agents. As a result, they have the most human pregnancy data. Although birth defects were observed in newborns of mothers who had used one of these drugs, the defects were thought to be the result of uncontrolled diabetes. The animal data suggest low risk.

SGLT2 inhibitors

There are three drugs in this sodium-glucose cotransporter-2 inhibitor subclass: canagliflozin (Invokana), dapagliflozin (Farxiga), and empagliflozin (Jardiance). No reports describing the use of these drugs in human pregnancy have been located. The animal data suggest low risk.

Thiazolidinediones

Pioglitazone (Actos) and rosiglitazone (Avandia) form this subclass. There are limited human pregnancy data for both drugs. The animal data suggest moderate risk for embryo-fetal toxicity but not for structural defects.

Lactation

All of the above drugs will probably be excreted into breast milk, but the amounts are typically unknown. When they have been measured, the amounts were usually low. However, there is still a risk for hypoglycemia in a nursing infant. Combination products containing two antidiabetic agents are best avoided. The safest course is to use insulin, but, if this is not an option, then the lowest effective dose should be used. In addition, the infant’s blood glucose levels should be routinely monitored.

 

Mr. Briggs is a clinical professor of pharmacy at the University of California, San Francisco, and an adjunct professor of pharmacy at the University of Southern California, Los Angeles, as well as at Washington State University, Spokane. He coauthored “Drugs in Pregnancy and Lactation” and coedited “Diseases, Complications, and Drug Therapy in Obstetrics.” He reported having no relevant financial disclosures.

 

Over the last 2 decades, there has been a growing interest in establishing a rich evidence base for treatment of psychiatric illness in pregnancy and the postpartum period. It seems as if a week does not go by when we don’t find multiple publications in the scientific literature describing a new finding or confirmation or inconsistency with existing data – whether it is a small prospective cohort study or an elegant analysis of a large administrative database. The goals of these reports center on refining our knowledge of safe treatments for perinatal psychiatric disorders.

Despite these strides, my colleagues and I frequently see a divergence between recommendations in the literature and what is done clinically by those who treat women around reproductive associated psychiatric disturbance – premenstrual dysphoric disorder or psychiatric disorder during pregnancy and the postpartum period. In some cases, scientific evidence has not filtered into day to day practice and some physicians continue to follow practices that, while outdated, make intuitive sense. In other clinical situations, limited evidence is being applied too broadly or data are too sparse to clearly inform practice. Regardless of the reason, we frequently see patients in clinical situations in which we are forced to rethink the clinical rationale for advice they have received or the clinical path taken.

Here is a sample of the clinical scenarios in which we have seen inconsistencies between current practice and the best evidence in perinatal psychiatry or situations in which data are too sparse to inform the clearest clinical path.

1. Discontinuation of antidepressants proximate to conception

Despite multiple studies supporting the high risk for relapse of major depression in women on maintenance antidepressant therapy with a history of recurrent depressive illness, it is still quite common for clinicians to routinely advise women to stop antidepressants while planning a pregnancy or after documentation of a pregnancy, regardless of the severity of the underlying illness. This runs counter to data showing high rates of relapse in women who stop antidepressants proximate to conception, the safety of antidepressants in pregnancy, and the harm to the mother and fetus when depression during pregnancy is untreated.

2. Use of a lower dose of antidepressants during pregnancy

It makes intuitive sense to use the smallest dose of medicine like antidepressant during pregnancy. However, multiple studies show that, at least in nonpregnant patients, the dose that gets patients well is typically the dose that keeps them well. One of the quickest paths to relapse in depression is a reduction in the antidepressant dose after someone has gotten well. This is even more relevant in pregnant patients because pregnancy itself dilutes the plasma level of the antidepressant given the rapidly expanding plasma volume seen in pregnancy. One can debate whether clinicians should empirically increase the dose of antidepressant during pregnancy to sustain plasma level of medication, but lowering the dose of this medication proximate or during pregnancy makes little sense.

3. A switch to sertraline in pregnancy/post partum

Another scenario that my colleagues and I often see is a pregnant patient whose depression was previously well controlled with a particular antidepressant, but whose physician, once she decides to conceive or becomes pregnant, switched her to sertraline.

The idea, which has been around for a long time, is that sertraline is the safest antidepressant for pregnant women because it has robust reproductive safety data and has particularly modest amounts of medication (if detected at all) in the plasma of infants of mothers who breastfeed while using the medicine. While we certainly have more safety data on SSRIs that were manufactured earlier, as compared with antidepressants that became available later, we have now accumulated data that fails to demonstrate a clear signal for teratogenicity across many antidepressants manufactured over the last 2 decades. Identifying an antidepressant for a given patient to which she will respond can be a challenging course for the patient. Achieving euthymia and subsequently switching to sertraline or another medication may only put her at risk for recurrence of depression and its attendant morbidity.

©Purestock/Thinkstock

4. A change to a Category B label drug

This is another example of switching a patient to a potentially less effective drug in a somewhat misguided effort at finding a treatment that is safer in pregnancy. While the Food and Drug Administration’s drug category label system was a step forward, or at least a well intentioned effort to give women and their clinicians clearer insight into the reproductive safety of a medication, ultimately, the incomplete nature of the information caused the agency to transition to a new system (see the Pregnancy Labeling and Lactation Rule). Switching a woman to a category B medicine with sparse reproductive safety data instead of a category C medicine, which may not be unsafe but has raised some concerns in animal models, is not a better choice. The new labeling system is a step forward.

 

5. Discontinuation of lithium during pregnancy

Like discontinuation of antidepressants, the discontinuation of lithium during attempts to conceive in a woman whose illness has been well controlled, is associated with a high risk of relapse. In earlier work, it was sometimes recommended that discontinuation of lithium be considered after a long period of wellness. We have learned over time that this can be a risky move. Even women with a remote history of bipolar disorder appear to be at high risk of relapse when a mood stabilizer is stopped. Exquisite response to medicine does not imply less severe illness. Women who have bipolar disorder who have sustained euthymia on lithium should consider maintaining the safest possible regimen before, during, and after pregnancy despite the known small teratogenic risk associated with fetal exposure to this agent.

6. Try supplements or alternative therapies

Out of a desire to avoid any medication with incomplete reproductive safety data, some women and clinicians make the intuitive leap that “alternative treatments” can mitigate relapse in pregnancy, and they stop pharmacological treatments and switch to supplements or alternative therapies, including acupuncture, massage, or light therapy. Unfortunately, data supporting this clinical maneuver are sparse. Frequently, we see women with past histories of severe depression who have stopped antidepressants and who have started supplements as a substitute and who then relapse. Then, they try to restore euthymia with antidepressants and psychotherapy, and the road to restoration of well-being can be long.

Data on efficacy of alternative therapies continues to evolve and is an exciting and important area of research. However, where these treatments are best employed in the algorithm for treating depression in pregnancy, or at other times, has yet to be adequately defined.
 

7. Stop breastfeeding or defer antidepressant treatment

Many women continue to be counseled to either stop breastfeeding while using antidepressants or to defer treatment with antidepressants if they wish to breastfeed. Not uncommonly, we see women who are suffering from postpartum depression and who are engaged in psychotherapy but who have deferred treatment with antidepressants despite residual depressive symptoms that impair functioning. Clinicians should keep in mind that data supporting evidence of toxicity in newborns of women using antidepressants while breastfeeding are extremely sparse. Unfortunately, some women with postpartum depression are deferring treatment because they were counseled that it is not compatible with their desire to breastfeed.

8. Use of non-benzodiazepine sedative-hypnotics

Insomnia is a common problem in pregnancy, especially when coupled with comorbid anxiety, and, increasingly, it is being treated with non-benzodiazepine sedative-hypnotics. Clinicians should keep in mind that a known small risk may be better than an unknown risk. If a pregnant woman has severe insomnia, she may benefit from a low dose of a benzodiazepine, such as lorazepam or clonazepam, as opposed to a medication such as zolpidem for which reproductive safety data are particularly limited.

9. Pumping and dumping breast milk

Many women are advised to set an alarm to “pump and dump” their breast milk to minimize their baby’s exposure to antidepressants during breastfeeding. Early literature to pump and dump breast milk at peak antidepressant concentration was of great analytic and theoretical interest but has scant clinical application. As an author of many of those early publications, I can say that we never intended for women to sacrifice precious sleep to dump breast milk with the idea that limiting exposure to trace amounts of antidepressants would have beneficial effects over the long term.

10. Failure to bring up contraception use

We continue to see a 50% unplanned pregnancy rate across sociodemographic groups in the United States. This is a critical statistic because it may affect how treatment is managed. Bringing up the topic of reliable contraception prior to pregnancy allows for planned pregnancy and affords us the time to discuss treatment options and the ability to plot a more thoughtful and safe clinical course. However, often, contraception is not discussed.

One of our goals as clinicians is to, first, do no harm and that continues to be a challenge because the data in perinatal psychiatry is still inconsistent in some areas and there are evidence gaps in others. Nevertheless, our task is to take the best available data along with the patient’s wishes and knowledge of her past clinical history and to then translate that into the best care for the individual.

Dr. Cohen is the director of the Ammon-Pinizzotto Center for Women’s Mental Health at Massachusetts General Hospital in Boston, which provides information resources and conducts clinical care and research in reproductive mental health. He has been a consultant to manufacturers of psychiatric medications.

 

Over the last 2 decades, there has been a growing interest in establishing a rich evidence base for treatment of psychiatric illness in pregnancy and the postpartum period. It seems as if a week does not go by when we don’t find multiple publications in the scientific literature describing a new finding or confirmation or inconsistency with existing data – whether it is a small prospective cohort study or an elegant analysis of a large administrative database. The goals of these reports center on refining our knowledge of safe treatments for perinatal psychiatric disorders.

Despite these strides, my colleagues and I frequently see a divergence between recommendations in the literature and what is done clinically by those who treat women around reproductive associated psychiatric disturbance – premenstrual dysphoric disorder or psychiatric disorder during pregnancy and the postpartum period. In some cases, scientific evidence has not filtered into day to day practice and some physicians continue to follow practices that, while outdated, make intuitive sense. In other clinical situations, limited evidence is being applied too broadly or data are too sparse to clearly inform practice. Regardless of the reason, we frequently see patients in clinical situations in which we are forced to rethink the clinical rationale for advice they have received or the clinical path taken.

Here is a sample of the clinical scenarios in which we have seen inconsistencies between current practice and the best evidence in perinatal psychiatry or situations in which data are too sparse to inform the clearest clinical path.

1. Discontinuation of antidepressants proximate to conception

Despite multiple studies supporting the high risk for relapse of major depression in women on maintenance antidepressant therapy with a history of recurrent depressive illness, it is still quite common for clinicians to routinely advise women to stop antidepressants while planning a pregnancy or after documentation of a pregnancy, regardless of the severity of the underlying illness. This runs counter to data showing high rates of relapse in women who stop antidepressants proximate to conception, the safety of antidepressants in pregnancy, and the harm to the mother and fetus when depression during pregnancy is untreated.

2. Use of a lower dose of antidepressants during pregnancy

It makes intuitive sense to use the smallest dose of medicine like antidepressant during pregnancy. However, multiple studies show that, at least in nonpregnant patients, the dose that gets patients well is typically the dose that keeps them well. One of the quickest paths to relapse in depression is a reduction in the antidepressant dose after someone has gotten well. This is even more relevant in pregnant patients because pregnancy itself dilutes the plasma level of the antidepressant given the rapidly expanding plasma volume seen in pregnancy. One can debate whether clinicians should empirically increase the dose of antidepressant during pregnancy to sustain plasma level of medication, but lowering the dose of this medication proximate or during pregnancy makes little sense.

3. A switch to sertraline in pregnancy/post partum

Another scenario that my colleagues and I often see is a pregnant patient whose depression was previously well controlled with a particular antidepressant, but whose physician, once she decides to conceive or becomes pregnant, switched her to sertraline.

The idea, which has been around for a long time, is that sertraline is the safest antidepressant for pregnant women because it has robust reproductive safety data and has particularly modest amounts of medication (if detected at all) in the plasma of infants of mothers who breastfeed while using the medicine. While we certainly have more safety data on SSRIs that were manufactured earlier, as compared with antidepressants that became available later, we have now accumulated data that fails to demonstrate a clear signal for teratogenicity across many antidepressants manufactured over the last 2 decades. Identifying an antidepressant for a given patient to which she will respond can be a challenging course for the patient. Achieving euthymia and subsequently switching to sertraline or another medication may only put her at risk for recurrence of depression and its attendant morbidity.

©Purestock/Thinkstock

4. A change to a Category B label drug

This is another example of switching a patient to a potentially less effective drug in a somewhat misguided effort at finding a treatment that is safer in pregnancy. While the Food and Drug Administration’s drug category label system was a step forward, or at least a well intentioned effort to give women and their clinicians clearer insight into the reproductive safety of a medication, ultimately, the incomplete nature of the information caused the agency to transition to a new system (see the Pregnancy Labeling and Lactation Rule). Switching a woman to a category B medicine with sparse reproductive safety data instead of a category C medicine, which may not be unsafe but has raised some concerns in animal models, is not a better choice. The new labeling system is a step forward.

 

5. Discontinuation of lithium during pregnancy

Like discontinuation of antidepressants, the discontinuation of lithium during attempts to conceive in a woman whose illness has been well controlled, is associated with a high risk of relapse. In earlier work, it was sometimes recommended that discontinuation of lithium be considered after a long period of wellness. We have learned over time that this can be a risky move. Even women with a remote history of bipolar disorder appear to be at high risk of relapse when a mood stabilizer is stopped. Exquisite response to medicine does not imply less severe illness. Women who have bipolar disorder who have sustained euthymia on lithium should consider maintaining the safest possible regimen before, during, and after pregnancy despite the known small teratogenic risk associated with fetal exposure to this agent.

6. Try supplements or alternative therapies

Out of a desire to avoid any medication with incomplete reproductive safety data, some women and clinicians make the intuitive leap that “alternative treatments” can mitigate relapse in pregnancy, and they stop pharmacological treatments and switch to supplements or alternative therapies, including acupuncture, massage, or light therapy. Unfortunately, data supporting this clinical maneuver are sparse. Frequently, we see women with past histories of severe depression who have stopped antidepressants and who have started supplements as a substitute and who then relapse. Then, they try to restore euthymia with antidepressants and psychotherapy, and the road to restoration of well-being can be long.

Data on efficacy of alternative therapies continues to evolve and is an exciting and important area of research. However, where these treatments are best employed in the algorithm for treating depression in pregnancy, or at other times, has yet to be adequately defined.
 

7. Stop breastfeeding or defer antidepressant treatment

Many women continue to be counseled to either stop breastfeeding while using antidepressants or to defer treatment with antidepressants if they wish to breastfeed. Not uncommonly, we see women who are suffering from postpartum depression and who are engaged in psychotherapy but who have deferred treatment with antidepressants despite residual depressive symptoms that impair functioning. Clinicians should keep in mind that data supporting evidence of toxicity in newborns of women using antidepressants while breastfeeding are extremely sparse. Unfortunately, some women with postpartum depression are deferring treatment because they were counseled that it is not compatible with their desire to breastfeed.

8. Use of non-benzodiazepine sedative-hypnotics

Insomnia is a common problem in pregnancy, especially when coupled with comorbid anxiety, and, increasingly, it is being treated with non-benzodiazepine sedative-hypnotics. Clinicians should keep in mind that a known small risk may be better than an unknown risk. If a pregnant woman has severe insomnia, she may benefit from a low dose of a benzodiazepine, such as lorazepam or clonazepam, as opposed to a medication such as zolpidem for which reproductive safety data are particularly limited.

9. Pumping and dumping breast milk

Many women are advised to set an alarm to “pump and dump” their breast milk to minimize their baby’s exposure to antidepressants during breastfeeding. Early literature to pump and dump breast milk at peak antidepressant concentration was of great analytic and theoretical interest but has scant clinical application. As an author of many of those early publications, I can say that we never intended for women to sacrifice precious sleep to dump breast milk with the idea that limiting exposure to trace amounts of antidepressants would have beneficial effects over the long term.

10. Failure to bring up contraception use

We continue to see a 50% unplanned pregnancy rate across sociodemographic groups in the United States. This is a critical statistic because it may affect how treatment is managed. Bringing up the topic of reliable contraception prior to pregnancy allows for planned pregnancy and affords us the time to discuss treatment options and the ability to plot a more thoughtful and safe clinical course. However, often, contraception is not discussed.

One of our goals as clinicians is to, first, do no harm and that continues to be a challenge because the data in perinatal psychiatry is still inconsistent in some areas and there are evidence gaps in others. Nevertheless, our task is to take the best available data along with the patient’s wishes and knowledge of her past clinical history and to then translate that into the best care for the individual.

Dr. Cohen is the director of the Ammon-Pinizzotto Center for Women’s Mental Health at Massachusetts General Hospital in Boston, which provides information resources and conducts clinical care and research in reproductive mental health. He has been a consultant to manufacturers of psychiatric medications.

 

Over the last 2 decades, there has been a growing interest in establishing a rich evidence base for treatment of psychiatric illness in pregnancy and the postpartum period. It seems as if a week does not go by when we don’t find multiple publications in the scientific literature describing a new finding or confirmation or inconsistency with existing data – whether it is a small prospective cohort study or an elegant analysis of a large administrative database. The goals of these reports center on refining our knowledge of safe treatments for perinatal psychiatric disorders.

Despite these strides, my colleagues and I frequently see a divergence between recommendations in the literature and what is done clinically by those who treat women around reproductive associated psychiatric disturbance – premenstrual dysphoric disorder or psychiatric disorder during pregnancy and the postpartum period. In some cases, scientific evidence has not filtered into day to day practice and some physicians continue to follow practices that, while outdated, make intuitive sense. In other clinical situations, limited evidence is being applied too broadly or data are too sparse to clearly inform practice. Regardless of the reason, we frequently see patients in clinical situations in which we are forced to rethink the clinical rationale for advice they have received or the clinical path taken.

Here is a sample of the clinical scenarios in which we have seen inconsistencies between current practice and the best evidence in perinatal psychiatry or situations in which data are too sparse to inform the clearest clinical path.

1. Discontinuation of antidepressants proximate to conception

Despite multiple studies supporting the high risk for relapse of major depression in women on maintenance antidepressant therapy with a history of recurrent depressive illness, it is still quite common for clinicians to routinely advise women to stop antidepressants while planning a pregnancy or after documentation of a pregnancy, regardless of the severity of the underlying illness. This runs counter to data showing high rates of relapse in women who stop antidepressants proximate to conception, the safety of antidepressants in pregnancy, and the harm to the mother and fetus when depression during pregnancy is untreated.

2. Use of a lower dose of antidepressants during pregnancy

It makes intuitive sense to use the smallest dose of medicine like antidepressant during pregnancy. However, multiple studies show that, at least in nonpregnant patients, the dose that gets patients well is typically the dose that keeps them well. One of the quickest paths to relapse in depression is a reduction in the antidepressant dose after someone has gotten well. This is even more relevant in pregnant patients because pregnancy itself dilutes the plasma level of the antidepressant given the rapidly expanding plasma volume seen in pregnancy. One can debate whether clinicians should empirically increase the dose of antidepressant during pregnancy to sustain plasma level of medication, but lowering the dose of this medication proximate or during pregnancy makes little sense.

3. A switch to sertraline in pregnancy/post partum

Another scenario that my colleagues and I often see is a pregnant patient whose depression was previously well controlled with a particular antidepressant, but whose physician, once she decides to conceive or becomes pregnant, switched her to sertraline.

The idea, which has been around for a long time, is that sertraline is the safest antidepressant for pregnant women because it has robust reproductive safety data and has particularly modest amounts of medication (if detected at all) in the plasma of infants of mothers who breastfeed while using the medicine. While we certainly have more safety data on SSRIs that were manufactured earlier, as compared with antidepressants that became available later, we have now accumulated data that fails to demonstrate a clear signal for teratogenicity across many antidepressants manufactured over the last 2 decades. Identifying an antidepressant for a given patient to which she will respond can be a challenging course for the patient. Achieving euthymia and subsequently switching to sertraline or another medication may only put her at risk for recurrence of depression and its attendant morbidity.

©Purestock/Thinkstock

4. A change to a Category B label drug

This is another example of switching a patient to a potentially less effective drug in a somewhat misguided effort at finding a treatment that is safer in pregnancy. While the Food and Drug Administration’s drug category label system was a step forward, or at least a well intentioned effort to give women and their clinicians clearer insight into the reproductive safety of a medication, ultimately, the incomplete nature of the information caused the agency to transition to a new system (see the Pregnancy Labeling and Lactation Rule). Switching a woman to a category B medicine with sparse reproductive safety data instead of a category C medicine, which may not be unsafe but has raised some concerns in animal models, is not a better choice. The new labeling system is a step forward.

 

5. Discontinuation of lithium during pregnancy

Like discontinuation of antidepressants, the discontinuation of lithium during attempts to conceive in a woman whose illness has been well controlled, is associated with a high risk of relapse. In earlier work, it was sometimes recommended that discontinuation of lithium be considered after a long period of wellness. We have learned over time that this can be a risky move. Even women with a remote history of bipolar disorder appear to be at high risk of relapse when a mood stabilizer is stopped. Exquisite response to medicine does not imply less severe illness. Women who have bipolar disorder who have sustained euthymia on lithium should consider maintaining the safest possible regimen before, during, and after pregnancy despite the known small teratogenic risk associated with fetal exposure to this agent.

6. Try supplements or alternative therapies

Out of a desire to avoid any medication with incomplete reproductive safety data, some women and clinicians make the intuitive leap that “alternative treatments” can mitigate relapse in pregnancy, and they stop pharmacological treatments and switch to supplements or alternative therapies, including acupuncture, massage, or light therapy. Unfortunately, data supporting this clinical maneuver are sparse. Frequently, we see women with past histories of severe depression who have stopped antidepressants and who have started supplements as a substitute and who then relapse. Then, they try to restore euthymia with antidepressants and psychotherapy, and the road to restoration of well-being can be long.

Data on efficacy of alternative therapies continues to evolve and is an exciting and important area of research. However, where these treatments are best employed in the algorithm for treating depression in pregnancy, or at other times, has yet to be adequately defined.
 

7. Stop breastfeeding or defer antidepressant treatment

Many women continue to be counseled to either stop breastfeeding while using antidepressants or to defer treatment with antidepressants if they wish to breastfeed. Not uncommonly, we see women who are suffering from postpartum depression and who are engaged in psychotherapy but who have deferred treatment with antidepressants despite residual depressive symptoms that impair functioning. Clinicians should keep in mind that data supporting evidence of toxicity in newborns of women using antidepressants while breastfeeding are extremely sparse. Unfortunately, some women with postpartum depression are deferring treatment because they were counseled that it is not compatible with their desire to breastfeed.

8. Use of non-benzodiazepine sedative-hypnotics

Insomnia is a common problem in pregnancy, especially when coupled with comorbid anxiety, and, increasingly, it is being treated with non-benzodiazepine sedative-hypnotics. Clinicians should keep in mind that a known small risk may be better than an unknown risk. If a pregnant woman has severe insomnia, she may benefit from a low dose of a benzodiazepine, such as lorazepam or clonazepam, as opposed to a medication such as zolpidem for which reproductive safety data are particularly limited.

9. Pumping and dumping breast milk

Many women are advised to set an alarm to “pump and dump” their breast milk to minimize their baby’s exposure to antidepressants during breastfeeding. Early literature to pump and dump breast milk at peak antidepressant concentration was of great analytic and theoretical interest but has scant clinical application. As an author of many of those early publications, I can say that we never intended for women to sacrifice precious sleep to dump breast milk with the idea that limiting exposure to trace amounts of antidepressants would have beneficial effects over the long term.

10. Failure to bring up contraception use

We continue to see a 50% unplanned pregnancy rate across sociodemographic groups in the United States. This is a critical statistic because it may affect how treatment is managed. Bringing up the topic of reliable contraception prior to pregnancy allows for planned pregnancy and affords us the time to discuss treatment options and the ability to plot a more thoughtful and safe clinical course. However, often, contraception is not discussed.

One of our goals as clinicians is to, first, do no harm and that continues to be a challenge because the data in perinatal psychiatry is still inconsistent in some areas and there are evidence gaps in others. Nevertheless, our task is to take the best available data along with the patient’s wishes and knowledge of her past clinical history and to then translate that into the best care for the individual.

Dr. Cohen is the director of the Ammon-Pinizzotto Center for Women’s Mental Health at Massachusetts General Hospital in Boston, which provides information resources and conducts clinical care and research in reproductive mental health. He has been a consultant to manufacturers of psychiatric medications.

 

Hyperemesis gravidarum (HG) affects just 1%-2% of pregnant women, but it’s clinical consequences are significant, with excess vomiting and dehydration, hospitalization, and the need for intravenous fluids being common in that group. In extreme cases, repeated vomiting has led to tears in the esophagus and severe dehydration has caused acute renal failure. All of that leaves aside the obvious suffering and distress it causes for women with the condition.

While studies continue to support the long-held theory that mild-to-moderate nausea and vomiting has a protective effect in pregnancy, that does not appear to be true for HG. Rather, the medical literature shows that HG is associated with small-for-gestational-age neonates, low birth weight, higher rates of preterm birth, and lower Apgar scores at 5 minutes.

What is even more concerning is what is happening to these children developmentally. In the last few years, controlled studies have emerged looking at long-term neurological development following pregnancy with HG.

I was one of the investigators on a study that prospectively followed more than 200 women with nausea and vomiting in pregnancy from 2006 to 2012. We found that children whose mothers were hospitalized for their symptoms – 22 in all – had significantly lower IQ scores at 3.5 years to 7 years, compared with children whose mothers were not hospitalized. Verbal IQ scores were 107.2 points vs. 112.7 (P = .04), performance IQ scores were 105.6 vs. 112.3 (P = .03), and full scale IQ was 108.7 vs. 114.2 (P = .05).

The study cohort included three groups: women treated with more than four tablets per day of doxylamine/pyridoxine (Diclegis); women treated with up to four tablets per day of the drug; and women who did not receive pharmacotherapy (Obstet Gynecol. 2015. doi: 10.1097/01.AOG.0000463229.81803.1a).

Hospitalized women in the study received antiemetics about a week later, experienced more severe symptoms, and were more likely to report depression. Overall, we found that duration of hospitalization, maternal depression, and maternal IQ all were significant predictors for these outcomes. However, daily antiemetic therapy was not associated with adverse outcomes.

©monkeybusinessimages/thinkstockphotos.com

These findings led my colleagues and I to conclude that timely preventive antiemetics and depression control could help prevent hospitalization and the associated worsened outcomes in child neurodevelopment.

Another study, published the same year, found that children exposed to HG had a more than three times increased risk for a neurodevelopmental diagnosis, including attention disorders, speech and language delays, and sensory disorders. The changes were more prevalent when women experienced symptoms early in pregnancy – prior to 5 weeks of gestation (Eur J Obstet Gynecol Reprod Biol. 2015 Jun;189:79-84).

The study compared neurodevelopmental outcomes for 312 children from 203 women with HG, with 169 children from 89 unaffected mothers. The findings are similar to those of our study, despite the differences in methodologies. Both studies found that the antiemetics were not associated with adverse outcomes, but the symptoms of HG appear to be the culprit.

While more research is needed to confirm these findings, it makes sense that the nutritional deficiencies created by excess vomiting and inability to eat are having an impact on the fetus.

It also raises an important question for the ob.gyn. about when to intervene in these women. Often, clinicians take a wait-and-see approach to nausea and vomiting in pregnancy, but the developing research suggests that earlier intervention would lead to better outcomes for mother and baby. One guide to determining that preventive antiemetics are necessary is to consider whether your patient has had HG in a previous pregnancy or if her mother or sister has experienced HG.

Another consideration is treating the nutritional deficiency that develops in women whose HG symptoms persist. These women are not simply in need of fluids and electrolytes but are missing essential vitamins and proteins. This is an area where much more research is needed, but clinicians can take a proactive approach by providing team care that includes consultation with a dietitians or nutritionist.

Finally, we cannot forget that maternal depression also appears to be significant predictor of poor fetal outcomes, so providing appropriate psychiatric treatment is essential.

Dr. Koren is professor of physiology/pharmacology and pediatrics at Western University in Ontario. He is the founder of the Motherisk Program. Dr. Koren was a principal investigator in the U.S. study that resulted in the approval of Diclegis, marketed by Duchesnay USA, and has served as a consultant to Duchesnay.

 

Hyperemesis gravidarum (HG) affects just 1%-2% of pregnant women, but it’s clinical consequences are significant, with excess vomiting and dehydration, hospitalization, and the need for intravenous fluids being common in that group. In extreme cases, repeated vomiting has led to tears in the esophagus and severe dehydration has caused acute renal failure. All of that leaves aside the obvious suffering and distress it causes for women with the condition.

While studies continue to support the long-held theory that mild-to-moderate nausea and vomiting has a protective effect in pregnancy, that does not appear to be true for HG. Rather, the medical literature shows that HG is associated with small-for-gestational-age neonates, low birth weight, higher rates of preterm birth, and lower Apgar scores at 5 minutes.

What is even more concerning is what is happening to these children developmentally. In the last few years, controlled studies have emerged looking at long-term neurological development following pregnancy with HG.

I was one of the investigators on a study that prospectively followed more than 200 women with nausea and vomiting in pregnancy from 2006 to 2012. We found that children whose mothers were hospitalized for their symptoms – 22 in all – had significantly lower IQ scores at 3.5 years to 7 years, compared with children whose mothers were not hospitalized. Verbal IQ scores were 107.2 points vs. 112.7 (P = .04), performance IQ scores were 105.6 vs. 112.3 (P = .03), and full scale IQ was 108.7 vs. 114.2 (P = .05).

The study cohort included three groups: women treated with more than four tablets per day of doxylamine/pyridoxine (Diclegis); women treated with up to four tablets per day of the drug; and women who did not receive pharmacotherapy (Obstet Gynecol. 2015. doi: 10.1097/01.AOG.0000463229.81803.1a).

Hospitalized women in the study received antiemetics about a week later, experienced more severe symptoms, and were more likely to report depression. Overall, we found that duration of hospitalization, maternal depression, and maternal IQ all were significant predictors for these outcomes. However, daily antiemetic therapy was not associated with adverse outcomes.

©monkeybusinessimages/thinkstockphotos.com

These findings led my colleagues and I to conclude that timely preventive antiemetics and depression control could help prevent hospitalization and the associated worsened outcomes in child neurodevelopment.

Another study, published the same year, found that children exposed to HG had a more than three times increased risk for a neurodevelopmental diagnosis, including attention disorders, speech and language delays, and sensory disorders. The changes were more prevalent when women experienced symptoms early in pregnancy – prior to 5 weeks of gestation (Eur J Obstet Gynecol Reprod Biol. 2015 Jun;189:79-84).

The study compared neurodevelopmental outcomes for 312 children from 203 women with HG, with 169 children from 89 unaffected mothers. The findings are similar to those of our study, despite the differences in methodologies. Both studies found that the antiemetics were not associated with adverse outcomes, but the symptoms of HG appear to be the culprit.

While more research is needed to confirm these findings, it makes sense that the nutritional deficiencies created by excess vomiting and inability to eat are having an impact on the fetus.

It also raises an important question for the ob.gyn. about when to intervene in these women. Often, clinicians take a wait-and-see approach to nausea and vomiting in pregnancy, but the developing research suggests that earlier intervention would lead to better outcomes for mother and baby. One guide to determining that preventive antiemetics are necessary is to consider whether your patient has had HG in a previous pregnancy or if her mother or sister has experienced HG.

Another consideration is treating the nutritional deficiency that develops in women whose HG symptoms persist. These women are not simply in need of fluids and electrolytes but are missing essential vitamins and proteins. This is an area where much more research is needed, but clinicians can take a proactive approach by providing team care that includes consultation with a dietitians or nutritionist.

Finally, we cannot forget that maternal depression also appears to be significant predictor of poor fetal outcomes, so providing appropriate psychiatric treatment is essential.

Dr. Koren is professor of physiology/pharmacology and pediatrics at Western University in Ontario. He is the founder of the Motherisk Program. Dr. Koren was a principal investigator in the U.S. study that resulted in the approval of Diclegis, marketed by Duchesnay USA, and has served as a consultant to Duchesnay.

 

Hyperemesis gravidarum (HG) affects just 1%-2% of pregnant women, but it’s clinical consequences are significant, with excess vomiting and dehydration, hospitalization, and the need for intravenous fluids being common in that group. In extreme cases, repeated vomiting has led to tears in the esophagus and severe dehydration has caused acute renal failure. All of that leaves aside the obvious suffering and distress it causes for women with the condition.

While studies continue to support the long-held theory that mild-to-moderate nausea and vomiting has a protective effect in pregnancy, that does not appear to be true for HG. Rather, the medical literature shows that HG is associated with small-for-gestational-age neonates, low birth weight, higher rates of preterm birth, and lower Apgar scores at 5 minutes.

What is even more concerning is what is happening to these children developmentally. In the last few years, controlled studies have emerged looking at long-term neurological development following pregnancy with HG.

I was one of the investigators on a study that prospectively followed more than 200 women with nausea and vomiting in pregnancy from 2006 to 2012. We found that children whose mothers were hospitalized for their symptoms – 22 in all – had significantly lower IQ scores at 3.5 years to 7 years, compared with children whose mothers were not hospitalized. Verbal IQ scores were 107.2 points vs. 112.7 (P = .04), performance IQ scores were 105.6 vs. 112.3 (P = .03), and full scale IQ was 108.7 vs. 114.2 (P = .05).

The study cohort included three groups: women treated with more than four tablets per day of doxylamine/pyridoxine (Diclegis); women treated with up to four tablets per day of the drug; and women who did not receive pharmacotherapy (Obstet Gynecol. 2015. doi: 10.1097/01.AOG.0000463229.81803.1a).

Hospitalized women in the study received antiemetics about a week later, experienced more severe symptoms, and were more likely to report depression. Overall, we found that duration of hospitalization, maternal depression, and maternal IQ all were significant predictors for these outcomes. However, daily antiemetic therapy was not associated with adverse outcomes.

©monkeybusinessimages/thinkstockphotos.com

These findings led my colleagues and I to conclude that timely preventive antiemetics and depression control could help prevent hospitalization and the associated worsened outcomes in child neurodevelopment.

Another study, published the same year, found that children exposed to HG had a more than three times increased risk for a neurodevelopmental diagnosis, including attention disorders, speech and language delays, and sensory disorders. The changes were more prevalent when women experienced symptoms early in pregnancy – prior to 5 weeks of gestation (Eur J Obstet Gynecol Reprod Biol. 2015 Jun;189:79-84).

The study compared neurodevelopmental outcomes for 312 children from 203 women with HG, with 169 children from 89 unaffected mothers. The findings are similar to those of our study, despite the differences in methodologies. Both studies found that the antiemetics were not associated with adverse outcomes, but the symptoms of HG appear to be the culprit.

While more research is needed to confirm these findings, it makes sense that the nutritional deficiencies created by excess vomiting and inability to eat are having an impact on the fetus.

It also raises an important question for the ob.gyn. about when to intervene in these women. Often, clinicians take a wait-and-see approach to nausea and vomiting in pregnancy, but the developing research suggests that earlier intervention would lead to better outcomes for mother and baby. One guide to determining that preventive antiemetics are necessary is to consider whether your patient has had HG in a previous pregnancy or if her mother or sister has experienced HG.

Another consideration is treating the nutritional deficiency that develops in women whose HG symptoms persist. These women are not simply in need of fluids and electrolytes but are missing essential vitamins and proteins. This is an area where much more research is needed, but clinicians can take a proactive approach by providing team care that includes consultation with a dietitians or nutritionist.

Finally, we cannot forget that maternal depression also appears to be significant predictor of poor fetal outcomes, so providing appropriate psychiatric treatment is essential.

Dr. Koren is professor of physiology/pharmacology and pediatrics at Western University in Ontario. He is the founder of the Motherisk Program. Dr. Koren was a principal investigator in the U.S. study that resulted in the approval of Diclegis, marketed by Duchesnay USA, and has served as a consultant to Duchesnay.

 

Corticosteroids such as prednisone are relatively frequently administered in pregnancy for their immunosuppressive and anti-inflammatory effects. Treatment may be initiated on a short-term basis for acute conditions. Alternatively, treatment may be more or less ongoing for severe chronic diseases such as asthma or a variety of other autoimmune conditions when disease symptoms do not remit in pregnancy. However, the safety of corticosteroid use with respect to risk of specific birth defects, preterm delivery, and low birth weight has been the subject of debate over some time.

Concerns about the teratogenicity of corticosteroids were raised as early as the 1950s, based on animal studies suggesting an increased risk for oral clefts. The association between corticosteroids and oral clefts has also been observed in some human epidemiologic studies. However, results of these studies have been inconsistent.

Earlier studies that were incorporated into a meta-analysis published in 2000 suggested a 3.4-times increased odds of cleft lip with or without cleft palate following first trimester corticosteroid use (95% confidence interval, 2.0-5.7).¹ However, a 2014 update from the multisite U.S. National Birth Defects Prevention case-control study (NBDPS) demonstrated that, while data from 1997 to 2002 indicated an elevated risk for oral clefts, more recent data from 2003 to 2009 did not.² The authors speculated that typical doses of corticosteroids or duration of use in pregnancy could have declined over time as more disease modifying alternative treatments have become available for some conditions and that this could have resulted in attenuated risk estimates in recent years.

Similar to the NBDPS findings, in a large Danish cohort study covering 832,636 live births from 1996 to 2008, exposure to any corticosteroids during the first trimester was not associated with an increased risk for cleft lip or cleft palate. Only those exposed to topical corticosteroids had a higher risk of cleft lip with or without cleft palate (odds ratio, 1.45; 95% CI, 1.03-2.05).³ Another, smaller Danish study covered primiparous births from 1999 to 2009 (n = 83,043). The unadjusted odds of oral clefts following exposure to any corticosteroids (inhaled or oral) in the first trimester was null (OR, 0.4; 95% CI, 0.1-2.8).⁴

Inconsistencies across these studies, as speculated by authors of the NBDPS analysis, may result from a lack of information on the dose of drug used by the mother, the indication for its use, or any measure of the severity of the underlying maternal disease for which the corticosteroids were prescribed. It is possible that maternal disease or disease activity in and of itself is a direct cause of oral clefts or that corticosteroids are linked to increased risk for clefts through co-occurring other exposures such as smoking, alcohol, or obesity. However, these questions have yet to be answered.

With respect to other birth outcomes, a few disease-specific studies have examined birth weight or intrauterine growth restriction following corticosteroid use. In general, study findings have been reassuring. Among Danish women with Crohn’s disease, corticosteroids were not associated with reduced birth weight after adjusting for gestational age and disease activity (adjusted risk ratio, 1.1; 95% CI, 0.2-5.7).⁵ In another study of pregnant women with rheumatoid arthritis, birth weight was not associated with prednisone use after adjustment for gestational age at delivery and sex of the newborn.⁶ In a third cohort study of pregnant women with systemic lupus erythematosus, there was no a significant elevation in odds of intrauterine growth restriction following prednisone use.⁷

Several disease-specific studies have also examined corticosteroid use and risk of preterm birth. From the Danish cohort of pregnant women with Crohn’s disease, the researchers reported no association between prednisolone and preterm birth after adjustment for covariates. In contrast, in a separate Danish cohort of pregnant women with irritable bowel disease, there was an increased risk of preterm delivery following systemic corticosteroid use, compared with women without disease (adjusted hazard ratio, 6.3; 95% CI, 3.1-12.7).⁸ However, data were not available to address underlying disease severity as a possible contributing factor. Of note, among women with irritable bowel disease who did not use medication in pregnancy, there was a 50% increase in the risk of preterm birth, compared with women without disease (aHR, 1.5; 95% CI, 1.0-2.4). This suggests that the disease itself contributed to the increased risk of preterm birth.

Currently available data regarding corticosteroid use and adverse birth outcomes are generally reassuring. Recent estimates for oral clefts suggest a low elevation in risk, if any at all. This translates to a very low absolute risk for clefts, which occur in the general population in approximately 1 in 1,000 births. The clinical benefit of adequate treatment in the first trimester for inflammatory or immune-mediated diseases may far outweigh any small and tenuous risks for oral clefts.

With respect to reduced birth weight and preterm delivery, available evidence suggests either no association or that maternal disease and disease severity are driving any increased risks noted for these outcomes. Future studies of pregnancy safety for medications used to treat maternal diseases that themselves are potentially linked to adverse outcomes must incorporate appropriate measures of disease type and disease severity in the study designs.

 

Dr. Chambers is a professor of pediatrics and director of clinical research at Rady Children’s Hospital and associate director of the Clinical and Translational Research Institute at the University of California, San Diego. She is also director of MotherToBaby California, a past president of the Organization of Teratology Information Specialists, and past president of the Teratology Society. She has no relevant financial disclosures. To comment, e-mail her at obnews@frontlinemedcom.com.

References

1. Teratology. 2000 Dec;62(6):385-92.

2. Birth Defects Res A Clin Mol Teratol. 2014 Jun;100(6):499-506.

3. CMAJ. 2011 Apr 19;183(7):796-804.

4. Am J Ther. 2014 Mar-Apr;21(2):73-80.

5. Am J Gastroenterol. 2007 Jul;102(7):1406-13.

6. Arthritis Rheum. 2009 Nov;60(11):3196-206.

7. Lupus. 2010 Dec;19(14):1665-73.

8. PLoS One. 2015 Jun 17;10(6):e0129567.

 

Corticosteroids such as prednisone are relatively frequently administered in pregnancy for their immunosuppressive and anti-inflammatory effects. Treatment may be initiated on a short-term basis for acute conditions. Alternatively, treatment may be more or less ongoing for severe chronic diseases such as asthma or a variety of other autoimmune conditions when disease symptoms do not remit in pregnancy. However, the safety of corticosteroid use with respect to risk of specific birth defects, preterm delivery, and low birth weight has been the subject of debate over some time.

Concerns about the teratogenicity of corticosteroids were raised as early as the 1950s, based on animal studies suggesting an increased risk for oral clefts. The association between corticosteroids and oral clefts has also been observed in some human epidemiologic studies. However, results of these studies have been inconsistent.

Earlier studies that were incorporated into a meta-analysis published in 2000 suggested a 3.4-times increased odds of cleft lip with or without cleft palate following first trimester corticosteroid use (95% confidence interval, 2.0-5.7).¹ However, a 2014 update from the multisite U.S. National Birth Defects Prevention case-control study (NBDPS) demonstrated that, while data from 1997 to 2002 indicated an elevated risk for oral clefts, more recent data from 2003 to 2009 did not.² The authors speculated that typical doses of corticosteroids or duration of use in pregnancy could have declined over time as more disease modifying alternative treatments have become available for some conditions and that this could have resulted in attenuated risk estimates in recent years.

Similar to the NBDPS findings, in a large Danish cohort study covering 832,636 live births from 1996 to 2008, exposure to any corticosteroids during the first trimester was not associated with an increased risk for cleft lip or cleft palate. Only those exposed to topical corticosteroids had a higher risk of cleft lip with or without cleft palate (odds ratio, 1.45; 95% CI, 1.03-2.05).³ Another, smaller Danish study covered primiparous births from 1999 to 2009 (n = 83,043). The unadjusted odds of oral clefts following exposure to any corticosteroids (inhaled or oral) in the first trimester was null (OR, 0.4; 95% CI, 0.1-2.8).⁴

Inconsistencies across these studies, as speculated by authors of the NBDPS analysis, may result from a lack of information on the dose of drug used by the mother, the indication for its use, or any measure of the severity of the underlying maternal disease for which the corticosteroids were prescribed. It is possible that maternal disease or disease activity in and of itself is a direct cause of oral clefts or that corticosteroids are linked to increased risk for clefts through co-occurring other exposures such as smoking, alcohol, or obesity. However, these questions have yet to be answered.

With respect to other birth outcomes, a few disease-specific studies have examined birth weight or intrauterine growth restriction following corticosteroid use. In general, study findings have been reassuring. Among Danish women with Crohn’s disease, corticosteroids were not associated with reduced birth weight after adjusting for gestational age and disease activity (adjusted risk ratio, 1.1; 95% CI, 0.2-5.7).⁵ In another study of pregnant women with rheumatoid arthritis, birth weight was not associated with prednisone use after adjustment for gestational age at delivery and sex of the newborn.⁶ In a third cohort study of pregnant women with systemic lupus erythematosus, there was no a significant elevation in odds of intrauterine growth restriction following prednisone use.⁷

Several disease-specific studies have also examined corticosteroid use and risk of preterm birth. From the Danish cohort of pregnant women with Crohn’s disease, the researchers reported no association between prednisolone and preterm birth after adjustment for covariates. In contrast, in a separate Danish cohort of pregnant women with irritable bowel disease, there was an increased risk of preterm delivery following systemic corticosteroid use, compared with women without disease (adjusted hazard ratio, 6.3; 95% CI, 3.1-12.7).⁸ However, data were not available to address underlying disease severity as a possible contributing factor. Of note, among women with irritable bowel disease who did not use medication in pregnancy, there was a 50% increase in the risk of preterm birth, compared with women without disease (aHR, 1.5; 95% CI, 1.0-2.4). This suggests that the disease itself contributed to the increased risk of preterm birth.

Currently available data regarding corticosteroid use and adverse birth outcomes are generally reassuring. Recent estimates for oral clefts suggest a low elevation in risk, if any at all. This translates to a very low absolute risk for clefts, which occur in the general population in approximately 1 in 1,000 births. The clinical benefit of adequate treatment in the first trimester for inflammatory or immune-mediated diseases may far outweigh any small and tenuous risks for oral clefts.

With respect to reduced birth weight and preterm delivery, available evidence suggests either no association or that maternal disease and disease severity are driving any increased risks noted for these outcomes. Future studies of pregnancy safety for medications used to treat maternal diseases that themselves are potentially linked to adverse outcomes must incorporate appropriate measures of disease type and disease severity in the study designs.

 

Dr. Chambers is a professor of pediatrics and director of clinical research at Rady Children’s Hospital and associate director of the Clinical and Translational Research Institute at the University of California, San Diego. She is also director of MotherToBaby California, a past president of the Organization of Teratology Information Specialists, and past president of the Teratology Society. She has no relevant financial disclosures. To comment, e-mail her at obnews@frontlinemedcom.com.

References

1. Teratology. 2000 Dec;62(6):385-92.

2. Birth Defects Res A Clin Mol Teratol. 2014 Jun;100(6):499-506.

3. CMAJ. 2011 Apr 19;183(7):796-804.

4. Am J Ther. 2014 Mar-Apr;21(2):73-80.

5. Am J Gastroenterol. 2007 Jul;102(7):1406-13.

6. Arthritis Rheum. 2009 Nov;60(11):3196-206.

7. Lupus. 2010 Dec;19(14):1665-73.

8. PLoS One. 2015 Jun 17;10(6):e0129567.

 

Corticosteroids such as prednisone are relatively frequently administered in pregnancy for their immunosuppressive and anti-inflammatory effects. Treatment may be initiated on a short-term basis for acute conditions. Alternatively, treatment may be more or less ongoing for severe chronic diseases such as asthma or a variety of other autoimmune conditions when disease symptoms do not remit in pregnancy. However, the safety of corticosteroid use with respect to risk of specific birth defects, preterm delivery, and low birth weight has been the subject of debate over some time.

Concerns about the teratogenicity of corticosteroids were raised as early as the 1950s, based on animal studies suggesting an increased risk for oral clefts. The association between corticosteroids and oral clefts has also been observed in some human epidemiologic studies. However, results of these studies have been inconsistent.

Earlier studies that were incorporated into a meta-analysis published in 2000 suggested a 3.4-times increased odds of cleft lip with or without cleft palate following first trimester corticosteroid use (95% confidence interval, 2.0-5.7).¹ However, a 2014 update from the multisite U.S. National Birth Defects Prevention case-control study (NBDPS) demonstrated that, while data from 1997 to 2002 indicated an elevated risk for oral clefts, more recent data from 2003 to 2009 did not.² The authors speculated that typical doses of corticosteroids or duration of use in pregnancy could have declined over time as more disease modifying alternative treatments have become available for some conditions and that this could have resulted in attenuated risk estimates in recent years.

Similar to the NBDPS findings, in a large Danish cohort study covering 832,636 live births from 1996 to 2008, exposure to any corticosteroids during the first trimester was not associated with an increased risk for cleft lip or cleft palate. Only those exposed to topical corticosteroids had a higher risk of cleft lip with or without cleft palate (odds ratio, 1.45; 95% CI, 1.03-2.05).³ Another, smaller Danish study covered primiparous births from 1999 to 2009 (n = 83,043). The unadjusted odds of oral clefts following exposure to any corticosteroids (inhaled or oral) in the first trimester was null (OR, 0.4; 95% CI, 0.1-2.8).⁴

Inconsistencies across these studies, as speculated by authors of the NBDPS analysis, may result from a lack of information on the dose of drug used by the mother, the indication for its use, or any measure of the severity of the underlying maternal disease for which the corticosteroids were prescribed. It is possible that maternal disease or disease activity in and of itself is a direct cause of oral clefts or that corticosteroids are linked to increased risk for clefts through co-occurring other exposures such as smoking, alcohol, or obesity. However, these questions have yet to be answered.

With respect to other birth outcomes, a few disease-specific studies have examined birth weight or intrauterine growth restriction following corticosteroid use. In general, study findings have been reassuring. Among Danish women with Crohn’s disease, corticosteroids were not associated with reduced birth weight after adjusting for gestational age and disease activity (adjusted risk ratio, 1.1; 95% CI, 0.2-5.7).⁵ In another study of pregnant women with rheumatoid arthritis, birth weight was not associated with prednisone use after adjustment for gestational age at delivery and sex of the newborn.⁶ In a third cohort study of pregnant women with systemic lupus erythematosus, there was no a significant elevation in odds of intrauterine growth restriction following prednisone use.⁷

Several disease-specific studies have also examined corticosteroid use and risk of preterm birth. From the Danish cohort of pregnant women with Crohn’s disease, the researchers reported no association between prednisolone and preterm birth after adjustment for covariates. In contrast, in a separate Danish cohort of pregnant women with irritable bowel disease, there was an increased risk of preterm delivery following systemic corticosteroid use, compared with women without disease (adjusted hazard ratio, 6.3; 95% CI, 3.1-12.7).⁸ However, data were not available to address underlying disease severity as a possible contributing factor. Of note, among women with irritable bowel disease who did not use medication in pregnancy, there was a 50% increase in the risk of preterm birth, compared with women without disease (aHR, 1.5; 95% CI, 1.0-2.4). This suggests that the disease itself contributed to the increased risk of preterm birth.

Currently available data regarding corticosteroid use and adverse birth outcomes are generally reassuring. Recent estimates for oral clefts suggest a low elevation in risk, if any at all. This translates to a very low absolute risk for clefts, which occur in the general population in approximately 1 in 1,000 births. The clinical benefit of adequate treatment in the first trimester for inflammatory or immune-mediated diseases may far outweigh any small and tenuous risks for oral clefts.

With respect to reduced birth weight and preterm delivery, available evidence suggests either no association or that maternal disease and disease severity are driving any increased risks noted for these outcomes. Future studies of pregnancy safety for medications used to treat maternal diseases that themselves are potentially linked to adverse outcomes must incorporate appropriate measures of disease type and disease severity in the study designs.

 

Dr. Chambers is a professor of pediatrics and director of clinical research at Rady Children’s Hospital and associate director of the Clinical and Translational Research Institute at the University of California, San Diego. She is also director of MotherToBaby California, a past president of the Organization of Teratology Information Specialists, and past president of the Teratology Society. She has no relevant financial disclosures. To comment, e-mail her at obnews@frontlinemedcom.com.

References

1. Teratology. 2000 Dec;62(6):385-92.

2. Birth Defects Res A Clin Mol Teratol. 2014 Jun;100(6):499-506.

3. CMAJ. 2011 Apr 19;183(7):796-804.

4. Am J Ther. 2014 Mar-Apr;21(2):73-80.

5. Am J Gastroenterol. 2007 Jul;102(7):1406-13.

6. Arthritis Rheum. 2009 Nov;60(11):3196-206.

7. Lupus. 2010 Dec;19(14):1665-73.

8. PLoS One. 2015 Jun 17;10(6):e0129567.

 

The Food and Drug Administration approved 22 new drug products in 12 pharmacologic classes in 2016. Additionally, daclizumab (Zenapax), which was approved several years ago for prophylaxis of acute organ rejection in patients receiving renal transplants, was approved for multiple sclerosis treatment (Zinbryta) last year, and sofosbuvir (Sovaldi), which was approved in 2013 for the treatment of hepatitis C virus, is now combined with velpatasvir (Epclusa) to treat all six major forms of hepatitis C.

There are 22 drugs that can be considered novel drugs. As defined by the FDA, novel drugs have never been approved for human use. There are no human pregnancy data for any of the newly approved drugs or drug combinations. As such, it is important to consider that high molecular weight drugs that probably do not cross the placenta in the first half of pregnancy may do so in late pregnancy.

Antineoplastics

Atezolizumab (Tecentriq) is a programmed death ligand–blocking antibody that is indicated for locally advanced or metastatic urothelial carcinoma and metastatic nonsmall cell lung cancer following platinum-containing chemotherapy. Animal reproduction studies have not been conducted, but, based on its mechanism of action, fetal exposure may increase the risk of developing immune-mediated disorders or altering the normal immune response. The molecular weight is high (145,000) and the terminal half-life is long (27 days).

Olaratumab (Lartruvo) is a platelet-derived growth factor receptor– alpha-blocking antibody. It is indicated, in combination with doxorubicin, for the treatment of soft tissue sarcoma. Although the estimated elimination half-life is long (about 11 days with a range of 6-24 days), the high molecular weight (about 154,000) should limit fetal exposure, at least in the first half of pregnancy. The drug should be avoided in pregnancy, however, based on the animal data, the mechanism of action, and its combination with doxorubicin.

Rucaparib (Rubraca) is a poly (adenosine diphosphate–ribose) polymerase inhibitor indicated for the treatment of ovarian cancer. The drug could cause human fetal harm based on the animal data, mechanism of action, relatively low molecular weight (about 556), and terminal half-life (17 hours).

Venetoclax (Venclexta) is a B-cell lymphoma 2 inhibitor indicated for the treatment of chronic lymphocytic leukemia. Although the animal data, molecular weight (about 868), and elimination half-life (about 26 hours) suggest embryo-fetal risk, the high plasma protein binding (99.9%) should limit the amount crossing the placenta.

Anti-infectives

There are two new monoclonal antibodies in this class. Bezlotoxumab (Zinplava) is used to reduce recurrence of Clostridium difficile. Animal reproduction studies have not been conducted. As the molecular weight is about 148,000, the drug will not cross the placenta, at least not in the first half of pregnancy. However, the drug has a long elimination half-life (about 19 days), so, depending on when it was given, it could cross in late pregnancy. Obiltoxaximab (Anthim), administered as a single IV dose, is indicated for the treatment of inhaled anthrax due to Bacillus anthracis. No fetal harm was observed in animal reproduction studies. The high molecular weight (about 148,000) suggests that the drug will not cross to the embryo and/or fetus, at least not in the first part of pregnancy.

Elbasvir/Grazoprevir (Zepatier) is indicated for the treatment of chronic hepatitis C virus genotype 1 or 4. Animal reproduction studies found no evidence of adverse developmental outcomes. The molecular weights of the two components are about 882 and 767, respectively. Both are extensively bound to plasma proteins, 99.9% and 98.8%, respectively, and the terminal half-lives are 24 and 31 hours. Thus, the product appears to be low risk if used in human pregnancy. However, it is contraindicated if given with ribavirin.

moodboard/Thinkstock

Velpatasvir/Sofosbuvir (Epclusa) is indicated for the treatment of chronic hepatitis C virus genotypes 1-6. No significant effects were found on embryo-fetal growth or pre- and postnatal development in animals with either drug. The molecular weights were about 883 and 529, respectively, whereas plasma protein binding was greater than 99.5% and 61%-65%, respectively. The median terminal half-lives were 15 and 0.5 hours, respectively. Taken in sum, the human embryo-fetal risk with this drug combination appears to be low.

Central nervous system agents

Brivaracetam (Briviact) is an anticonvulsant used to treat partial-onset seizures. Animal reproduction studies suggest moderate risk. The molecular weight (about 212), low plasma protein binding (less than or equal to 20%), and terminal plasma half-life of about 9 hours suggest that the drug will cross the placenta. The manufacturer recommends that the drug should be used in pregnancy only if the potential benefit justifies the potential risk to the embryo/fetus.

 

Pimavanserin (Nuplazid) is an atypical antipsychotic indicated for the treatment of hallucinations and delusions associated with Parkinson’s disease psychosis. Reproduction studies in animals suggest low risk. The molecular weight of the free base (about 428) and the long mean plasma half-lives of the parent drug and active metabolite (57 and 200 hours) suggest that the drug will cross the placenta. However, the high plasma protein binding (about 95%) may limit the exposure. Nevertheless, avoiding the period of organogenesis appears to be best.

Dermatologic agents

Crisaborole (Eucrisa) is indicated for topical treatment of mild to moderate atopic dermatitis. In 33 pediatric subjects (aged 2-17 years) who applied the ointment twice daily for 8 days, low amounts were absorbed systemically with plasma concentrations in the nanogram/milliliter range. Plasma protein binding was 97%. With oral formulations of the drug, animal reproduction studies suggest low risk. Taken in sum, the human pregnancy risk appears to be low.

Ixekizumab (Taltz) is a humanized interleukin-17A antagonist, administered subcutaneously, that is indicated for the treatment of adults with moderate to severe plaque psoriasis. The drug did not cause developmental toxicity in monkeys. The molecular weight for the drug’s protein backbone is 146,158, and the mean elimination half-life was 13 days. The human embryo-fetal risk in the first half of pregnancy appears to be low.

Diagnostic agents

Fluciclovine F 18 (Axumin) is a radioactive diagnostic agent indicated for positron emission tomography imaging in men with suspected prostate cancer. Since the agent is only used in men, there are no human or animal pregnancy data.

Gallium GA 68 dotatate injection, a diagnostic imaging agent to detect rare neuroendocrine tumors, is not yet on the market.

Endocrine/metabolic agents

Lixisenatide (Adlyxin) is a glucagon-like–peptide-1 receptor agonist that is administered subcutaneously. It is indicated as an adjunct to diet and exercise to improve glycemic control in type 2 diabetes. The drug was teratogenic in two animal species. The molecular weight is about 4,859, and the mean terminal half-life was about 3 hours. Since tight control of glucose levels in type 2 diabetes is required during pregnancy, insulin is the treatment of choice. Consequently, lixisenatide should not be used during pregnancy.

Gastrointestinal agents

Obeticholic acid (Ocaliva) is a farnesoid X receptor agonist that is given orally for the treatment of primary biliary cholangitis, in combination with ursodiol, or ursodeoxycholic acid. I have classified ursodiol as compatible in pregnancy in the 10th edition of “Drugs in Pregnancy and Lactation” (2011: Wolters Kluwer Health). The animal reproduction data for both drugs suggest low risk. Based on the molecular weight of obeticholic (about 421), the drug will probably cross to the embryo/fetus, but the high plasma protein binding (greater than 99%) may limit exposure. The elimination half-life is apparently unknown.

Hematologic agents

Defibrotide sodium (Defitelio), given as an intravenous infusion, is an oligonucleotide mixture. It is indicated for the treatment of hepatic veno-occlusive disease, also known as sinusoidal obstruction syndrome, with renal or pulmonary dysfunction following hematopoietic stem-cell transplantation. Animal reproduction studies in two species suggest risk. The mean molecular weight is 13,000-20,000. Plasma protein binding is an average 93%, and the elimination half-life is less than 2 hours. It is doubtful if the drug crosses the placenta, especially in the first half of pregnancy. If possible, avoid the drug in the second half of pregnancy.

Immunologics

Two indications have been approved for daclizumab. The first was in 2005 for the prophylaxis of acute organ rejection of renal transplants (Zenapax), and the second was in 2016 for the treatment of relapsing forms of multiple sclerosis (Zinbryta). Reproduction studies in monkeys with Zinbryta can be classified as low risk. The molecular weight (about 144,000) suggests that the drug will not cross the placenta, at least in the first half of pregnancy. However, depending on when the drug is given, the long elimination half-life of 21 days might allow the drug to cross in late pregnancy. Regardless, if the perceived maternal benefit exceeds the potential embryo-fetal risk, the drug should not be withheld because of pregnancy.

Muscular disorder agents

Eteplirsen (Exondys 51) is an antisense oligonucleotide that is given intravenously. It is indicated for the treatment of Duchenne muscular dystrophy in patients who have a confirmed mutation of the related gene, which is amenable to exon 51 skipping. There are no animal reproduction data. The molecular weight is about 10,306. This suggests that the drug will not cross the placenta, at least in the first half of pregnancy. The elimination half-life is 3-4 hours, and the plasma concentration 24 hours after a dose was 0.07% of the peak plasma concentration. The drug is given once weekly, and waiting for 24 hours or slightly longer after a dose should reduce the exposure, if any, of the embryo-fetus during the first half of pregnancy.

 

Nusinersen (Spinraza), a survival motor neuron 2 directed–antisense oligonucleotide, is given as an intrathecal dose. It is indicated for the treatment of spinal muscular atrophy. Subcutaneous doses in two animal species caused no developmental toxicity. The molecular weight of 7,501 suggests that the drug will not cross the human placenta, at least not in the first half of pregnancy. The mean terminal elimination half-life in cerebrospinal fluid was 135-177 days and 63-87 days in plasma.

Ophthalmic agents

Lifitegrast (Xiidra) is an ophthalmic solution of a lymphocyte function-associated–antigen-1 antagonist. It is indicated for the treatment of the signs and symptoms of dry eye disease. The animal reproduction data suggest low risk. The molecular weight is about 616, suggesting that the drug would cross the placenta. However, in a Phase III trial conducted before FDA approval, 47 patients with dry eye disease were given 1 drop twice daily for periods up to 360 days. Nine patients (19%) had plasma predose (trough) concentrations above 0.5 ng/mL, the lower limit of quantitation. Trough plasma concentrations in these patients ranged from 0.55 ng/mL to 3.74 ng/mL. These amounts do not appear to represent an embryo-fetal risk.

Respiratory agents

Reslizumab (Cinqair), an interleukin-5 antagonist monoclonal antibody, is given intravenously. It is indicated for add-on maintenance treatment of severe asthma in patients with an eosinophilic phenotype. Animal data in two species suggest low risk. The molecular weight is about 147,000, and the elimination half-life is about 24 days. This suggests that exposure of the embryo and fetus will be minimal, at least in the first half of pregnancy. The maternal benefit appears to outweigh the unknown embryo-fetal risk.

Lactation

None of the above drugs have been studied during breastfeeding. Many drugs, regardless of their molecular weight, will cross into milk in small amounts during the first postpartum week. The effects of this exposure on a nursing infant are unknown. Based on the potential for nursing infant harm, the drugs that probably should not be given during breastfeeding include the four antineoplastics, the atypical antipsychotic pimavanserin, and the diabetes injection lixisenatide.

Mr. Briggs is a clinical professor of pharmacy at the University of California, San Francisco, and an adjunct professor of pharmacy at the University of Southern California, Los Angeles, and at Washington State University, Spokane. He coauthored “Drugs in Pregnancy and Lactation,” and coedited “Diseases, Complications, and Drug Therapy in Obstetrics.” He reported having no relevant financial disclosures.

 

The Food and Drug Administration approved 22 new drug products in 12 pharmacologic classes in 2016. Additionally, daclizumab (Zenapax), which was approved several years ago for prophylaxis of acute organ rejection in patients receiving renal transplants, was approved for multiple sclerosis treatment (Zinbryta) last year, and sofosbuvir (Sovaldi), which was approved in 2013 for the treatment of hepatitis C virus, is now combined with velpatasvir (Epclusa) to treat all six major forms of hepatitis C.

There are 22 drugs that can be considered novel drugs. As defined by the FDA, novel drugs have never been approved for human use. There are no human pregnancy data for any of the newly approved drugs or drug combinations. As such, it is important to consider that high molecular weight drugs that probably do not cross the placenta in the first half of pregnancy may do so in late pregnancy.

Antineoplastics

Atezolizumab (Tecentriq) is a programmed death ligand–blocking antibody that is indicated for locally advanced or metastatic urothelial carcinoma and metastatic nonsmall cell lung cancer following platinum-containing chemotherapy. Animal reproduction studies have not been conducted, but, based on its mechanism of action, fetal exposure may increase the risk of developing immune-mediated disorders or altering the normal immune response. The molecular weight is high (145,000) and the terminal half-life is long (27 days).

Olaratumab (Lartruvo) is a platelet-derived growth factor receptor– alpha-blocking antibody. It is indicated, in combination with doxorubicin, for the treatment of soft tissue sarcoma. Although the estimated elimination half-life is long (about 11 days with a range of 6-24 days), the high molecular weight (about 154,000) should limit fetal exposure, at least in the first half of pregnancy. The drug should be avoided in pregnancy, however, based on the animal data, the mechanism of action, and its combination with doxorubicin.

Rucaparib (Rubraca) is a poly (adenosine diphosphate–ribose) polymerase inhibitor indicated for the treatment of ovarian cancer. The drug could cause human fetal harm based on the animal data, mechanism of action, relatively low molecular weight (about 556), and terminal half-life (17 hours).

Venetoclax (Venclexta) is a B-cell lymphoma 2 inhibitor indicated for the treatment of chronic lymphocytic leukemia. Although the animal data, molecular weight (about 868), and elimination half-life (about 26 hours) suggest embryo-fetal risk, the high plasma protein binding (99.9%) should limit the amount crossing the placenta.

Anti-infectives

There are two new monoclonal antibodies in this class. Bezlotoxumab (Zinplava) is used to reduce recurrence of Clostridium difficile. Animal reproduction studies have not been conducted. As the molecular weight is about 148,000, the drug will not cross the placenta, at least not in the first half of pregnancy. However, the drug has a long elimination half-life (about 19 days), so, depending on when it was given, it could cross in late pregnancy. Obiltoxaximab (Anthim), administered as a single IV dose, is indicated for the treatment of inhaled anthrax due to Bacillus anthracis. No fetal harm was observed in animal reproduction studies. The high molecular weight (about 148,000) suggests that the drug will not cross to the embryo and/or fetus, at least not in the first part of pregnancy.

Elbasvir/Grazoprevir (Zepatier) is indicated for the treatment of chronic hepatitis C virus genotype 1 or 4. Animal reproduction studies found no evidence of adverse developmental outcomes. The molecular weights of the two components are about 882 and 767, respectively. Both are extensively bound to plasma proteins, 99.9% and 98.8%, respectively, and the terminal half-lives are 24 and 31 hours. Thus, the product appears to be low risk if used in human pregnancy. However, it is contraindicated if given with ribavirin.

moodboard/Thinkstock

Velpatasvir/Sofosbuvir (Epclusa) is indicated for the treatment of chronic hepatitis C virus genotypes 1-6. No significant effects were found on embryo-fetal growth or pre- and postnatal development in animals with either drug. The molecular weights were about 883 and 529, respectively, whereas plasma protein binding was greater than 99.5% and 61%-65%, respectively. The median terminal half-lives were 15 and 0.5 hours, respectively. Taken in sum, the human embryo-fetal risk with this drug combination appears to be low.

Central nervous system agents

Brivaracetam (Briviact) is an anticonvulsant used to treat partial-onset seizures. Animal reproduction studies suggest moderate risk. The molecular weight (about 212), low plasma protein binding (less than or equal to 20%), and terminal plasma half-life of about 9 hours suggest that the drug will cross the placenta. The manufacturer recommends that the drug should be used in pregnancy only if the potential benefit justifies the potential risk to the embryo/fetus.

 

Pimavanserin (Nuplazid) is an atypical antipsychotic indicated for the treatment of hallucinations and delusions associated with Parkinson’s disease psychosis. Reproduction studies in animals suggest low risk. The molecular weight of the free base (about 428) and the long mean plasma half-lives of the parent drug and active metabolite (57 and 200 hours) suggest that the drug will cross the placenta. However, the high plasma protein binding (about 95%) may limit the exposure. Nevertheless, avoiding the period of organogenesis appears to be best.

Dermatologic agents

Crisaborole (Eucrisa) is indicated for topical treatment of mild to moderate atopic dermatitis. In 33 pediatric subjects (aged 2-17 years) who applied the ointment twice daily for 8 days, low amounts were absorbed systemically with plasma concentrations in the nanogram/milliliter range. Plasma protein binding was 97%. With oral formulations of the drug, animal reproduction studies suggest low risk. Taken in sum, the human pregnancy risk appears to be low.

Ixekizumab (Taltz) is a humanized interleukin-17A antagonist, administered subcutaneously, that is indicated for the treatment of adults with moderate to severe plaque psoriasis. The drug did not cause developmental toxicity in monkeys. The molecular weight for the drug’s protein backbone is 146,158, and the mean elimination half-life was 13 days. The human embryo-fetal risk in the first half of pregnancy appears to be low.

Diagnostic agents

Fluciclovine F 18 (Axumin) is a radioactive diagnostic agent indicated for positron emission tomography imaging in men with suspected prostate cancer. Since the agent is only used in men, there are no human or animal pregnancy data.

Gallium GA 68 dotatate injection, a diagnostic imaging agent to detect rare neuroendocrine tumors, is not yet on the market.

Endocrine/metabolic agents

Lixisenatide (Adlyxin) is a glucagon-like–peptide-1 receptor agonist that is administered subcutaneously. It is indicated as an adjunct to diet and exercise to improve glycemic control in type 2 diabetes. The drug was teratogenic in two animal species. The molecular weight is about 4,859, and the mean terminal half-life was about 3 hours. Since tight control of glucose levels in type 2 diabetes is required during pregnancy, insulin is the treatment of choice. Consequently, lixisenatide should not be used during pregnancy.

Gastrointestinal agents

Obeticholic acid (Ocaliva) is a farnesoid X receptor agonist that is given orally for the treatment of primary biliary cholangitis, in combination with ursodiol, or ursodeoxycholic acid. I have classified ursodiol as compatible in pregnancy in the 10th edition of “Drugs in Pregnancy and Lactation” (2011: Wolters Kluwer Health). The animal reproduction data for both drugs suggest low risk. Based on the molecular weight of obeticholic (about 421), the drug will probably cross to the embryo/fetus, but the high plasma protein binding (greater than 99%) may limit exposure. The elimination half-life is apparently unknown.

Hematologic agents

Defibrotide sodium (Defitelio), given as an intravenous infusion, is an oligonucleotide mixture. It is indicated for the treatment of hepatic veno-occlusive disease, also known as sinusoidal obstruction syndrome, with renal or pulmonary dysfunction following hematopoietic stem-cell transplantation. Animal reproduction studies in two species suggest risk. The mean molecular weight is 13,000-20,000. Plasma protein binding is an average 93%, and the elimination half-life is less than 2 hours. It is doubtful if the drug crosses the placenta, especially in the first half of pregnancy. If possible, avoid the drug in the second half of pregnancy.

Immunologics

Two indications have been approved for daclizumab. The first was in 2005 for the prophylaxis of acute organ rejection of renal transplants (Zenapax), and the second was in 2016 for the treatment of relapsing forms of multiple sclerosis (Zinbryta). Reproduction studies in monkeys with Zinbryta can be classified as low risk. The molecular weight (about 144,000) suggests that the drug will not cross the placenta, at least in the first half of pregnancy. However, depending on when the drug is given, the long elimination half-life of 21 days might allow the drug to cross in late pregnancy. Regardless, if the perceived maternal benefit exceeds the potential embryo-fetal risk, the drug should not be withheld because of pregnancy.

Muscular disorder agents

Eteplirsen (Exondys 51) is an antisense oligonucleotide that is given intravenously. It is indicated for the treatment of Duchenne muscular dystrophy in patients who have a confirmed mutation of the related gene, which is amenable to exon 51 skipping. There are no animal reproduction data. The molecular weight is about 10,306. This suggests that the drug will not cross the placenta, at least in the first half of pregnancy. The elimination half-life is 3-4 hours, and the plasma concentration 24 hours after a dose was 0.07% of the peak plasma concentration. The drug is given once weekly, and waiting for 24 hours or slightly longer after a dose should reduce the exposure, if any, of the embryo-fetus during the first half of pregnancy.

 

Nusinersen (Spinraza), a survival motor neuron 2 directed–antisense oligonucleotide, is given as an intrathecal dose. It is indicated for the treatment of spinal muscular atrophy. Subcutaneous doses in two animal species caused no developmental toxicity. The molecular weight of 7,501 suggests that the drug will not cross the human placenta, at least not in the first half of pregnancy. The mean terminal elimination half-life in cerebrospinal fluid was 135-177 days and 63-87 days in plasma.

Ophthalmic agents

Lifitegrast (Xiidra) is an ophthalmic solution of a lymphocyte function-associated–antigen-1 antagonist. It is indicated for the treatment of the signs and symptoms of dry eye disease. The animal reproduction data suggest low risk. The molecular weight is about 616, suggesting that the drug would cross the placenta. However, in a Phase III trial conducted before FDA approval, 47 patients with dry eye disease were given 1 drop twice daily for periods up to 360 days. Nine patients (19%) had plasma predose (trough) concentrations above 0.5 ng/mL, the lower limit of quantitation. Trough plasma concentrations in these patients ranged from 0.55 ng/mL to 3.74 ng/mL. These amounts do not appear to represent an embryo-fetal risk.

Respiratory agents

Reslizumab (Cinqair), an interleukin-5 antagonist monoclonal antibody, is given intravenously. It is indicated for add-on maintenance treatment of severe asthma in patients with an eosinophilic phenotype. Animal data in two species suggest low risk. The molecular weight is about 147,000, and the elimination half-life is about 24 days. This suggests that exposure of the embryo and fetus will be minimal, at least in the first half of pregnancy. The maternal benefit appears to outweigh the unknown embryo-fetal risk.

Lactation

None of the above drugs have been studied during breastfeeding. Many drugs, regardless of their molecular weight, will cross into milk in small amounts during the first postpartum week. The effects of this exposure on a nursing infant are unknown. Based on the potential for nursing infant harm, the drugs that probably should not be given during breastfeeding include the four antineoplastics, the atypical antipsychotic pimavanserin, and the diabetes injection lixisenatide.

Mr. Briggs is a clinical professor of pharmacy at the University of California, San Francisco, and an adjunct professor of pharmacy at the University of Southern California, Los Angeles, and at Washington State University, Spokane. He coauthored “Drugs in Pregnancy and Lactation,” and coedited “Diseases, Complications, and Drug Therapy in Obstetrics.” He reported having no relevant financial disclosures.

 

The Food and Drug Administration approved 22 new drug products in 12 pharmacologic classes in 2016. Additionally, daclizumab (Zenapax), which was approved several years ago for prophylaxis of acute organ rejection in patients receiving renal transplants, was approved for multiple sclerosis treatment (Zinbryta) last year, and sofosbuvir (Sovaldi), which was approved in 2013 for the treatment of hepatitis C virus, is now combined with velpatasvir (Epclusa) to treat all six major forms of hepatitis C.

There are 22 drugs that can be considered novel drugs. As defined by the FDA, novel drugs have never been approved for human use. There are no human pregnancy data for any of the newly approved drugs or drug combinations. As such, it is important to consider that high molecular weight drugs that probably do not cross the placenta in the first half of pregnancy may do so in late pregnancy.

Antineoplastics

Atezolizumab (Tecentriq) is a programmed death ligand–blocking antibody that is indicated for locally advanced or metastatic urothelial carcinoma and metastatic nonsmall cell lung cancer following platinum-containing chemotherapy. Animal reproduction studies have not been conducted, but, based on its mechanism of action, fetal exposure may increase the risk of developing immune-mediated disorders or altering the normal immune response. The molecular weight is high (145,000) and the terminal half-life is long (27 days).

Olaratumab (Lartruvo) is a platelet-derived growth factor receptor– alpha-blocking antibody. It is indicated, in combination with doxorubicin, for the treatment of soft tissue sarcoma. Although the estimated elimination half-life is long (about 11 days with a range of 6-24 days), the high molecular weight (about 154,000) should limit fetal exposure, at least in the first half of pregnancy. The drug should be avoided in pregnancy, however, based on the animal data, the mechanism of action, and its combination with doxorubicin.

Rucaparib (Rubraca) is a poly (adenosine diphosphate–ribose) polymerase inhibitor indicated for the treatment of ovarian cancer. The drug could cause human fetal harm based on the animal data, mechanism of action, relatively low molecular weight (about 556), and terminal half-life (17 hours).

Venetoclax (Venclexta) is a B-cell lymphoma 2 inhibitor indicated for the treatment of chronic lymphocytic leukemia. Although the animal data, molecular weight (about 868), and elimination half-life (about 26 hours) suggest embryo-fetal risk, the high plasma protein binding (99.9%) should limit the amount crossing the placenta.

Anti-infectives

There are two new monoclonal antibodies in this class. Bezlotoxumab (Zinplava) is used to reduce recurrence of Clostridium difficile. Animal reproduction studies have not been conducted. As the molecular weight is about 148,000, the drug will not cross the placenta, at least not in the first half of pregnancy. However, the drug has a long elimination half-life (about 19 days), so, depending on when it was given, it could cross in late pregnancy. Obiltoxaximab (Anthim), administered as a single IV dose, is indicated for the treatment of inhaled anthrax due to Bacillus anthracis. No fetal harm was observed in animal reproduction studies. The high molecular weight (about 148,000) suggests that the drug will not cross to the embryo and/or fetus, at least not in the first part of pregnancy.

Elbasvir/Grazoprevir (Zepatier) is indicated for the treatment of chronic hepatitis C virus genotype 1 or 4. Animal reproduction studies found no evidence of adverse developmental outcomes. The molecular weights of the two components are about 882 and 767, respectively. Both are extensively bound to plasma proteins, 99.9% and 98.8%, respectively, and the terminal half-lives are 24 and 31 hours. Thus, the product appears to be low risk if used in human pregnancy. However, it is contraindicated if given with ribavirin.

moodboard/Thinkstock

Velpatasvir/Sofosbuvir (Epclusa) is indicated for the treatment of chronic hepatitis C virus genotypes 1-6. No significant effects were found on embryo-fetal growth or pre- and postnatal development in animals with either drug. The molecular weights were about 883 and 529, respectively, whereas plasma protein binding was greater than 99.5% and 61%-65%, respectively. The median terminal half-lives were 15 and 0.5 hours, respectively. Taken in sum, the human embryo-fetal risk with this drug combination appears to be low.

Central nervous system agents

Brivaracetam (Briviact) is an anticonvulsant used to treat partial-onset seizures. Animal reproduction studies suggest moderate risk. The molecular weight (about 212), low plasma protein binding (less than or equal to 20%), and terminal plasma half-life of about 9 hours suggest that the drug will cross the placenta. The manufacturer recommends that the drug should be used in pregnancy only if the potential benefit justifies the potential risk to the embryo/fetus.

 

Pimavanserin (Nuplazid) is an atypical antipsychotic indicated for the treatment of hallucinations and delusions associated with Parkinson’s disease psychosis. Reproduction studies in animals suggest low risk. The molecular weight of the free base (about 428) and the long mean plasma half-lives of the parent drug and active metabolite (57 and 200 hours) suggest that the drug will cross the placenta. However, the high plasma protein binding (about 95%) may limit the exposure. Nevertheless, avoiding the period of organogenesis appears to be best.

Dermatologic agents

Crisaborole (Eucrisa) is indicated for topical treatment of mild to moderate atopic dermatitis. In 33 pediatric subjects (aged 2-17 years) who applied the ointment twice daily for 8 days, low amounts were absorbed systemically with plasma concentrations in the nanogram/milliliter range. Plasma protein binding was 97%. With oral formulations of the drug, animal reproduction studies suggest low risk. Taken in sum, the human pregnancy risk appears to be low.

Ixekizumab (Taltz) is a humanized interleukin-17A antagonist, administered subcutaneously, that is indicated for the treatment of adults with moderate to severe plaque psoriasis. The drug did not cause developmental toxicity in monkeys. The molecular weight for the drug’s protein backbone is 146,158, and the mean elimination half-life was 13 days. The human embryo-fetal risk in the first half of pregnancy appears to be low.

Diagnostic agents

Fluciclovine F 18 (Axumin) is a radioactive diagnostic agent indicated for positron emission tomography imaging in men with suspected prostate cancer. Since the agent is only used in men, there are no human or animal pregnancy data.

Gallium GA 68 dotatate injection, a diagnostic imaging agent to detect rare neuroendocrine tumors, is not yet on the market.

Endocrine/metabolic agents

Lixisenatide (Adlyxin) is a glucagon-like–peptide-1 receptor agonist that is administered subcutaneously. It is indicated as an adjunct to diet and exercise to improve glycemic control in type 2 diabetes. The drug was teratogenic in two animal species. The molecular weight is about 4,859, and the mean terminal half-life was about 3 hours. Since tight control of glucose levels in type 2 diabetes is required during pregnancy, insulin is the treatment of choice. Consequently, lixisenatide should not be used during pregnancy.

Gastrointestinal agents

Obeticholic acid (Ocaliva) is a farnesoid X receptor agonist that is given orally for the treatment of primary biliary cholangitis, in combination with ursodiol, or ursodeoxycholic acid. I have classified ursodiol as compatible in pregnancy in the 10th edition of “Drugs in Pregnancy and Lactation” (2011: Wolters Kluwer Health). The animal reproduction data for both drugs suggest low risk. Based on the molecular weight of obeticholic (about 421), the drug will probably cross to the embryo/fetus, but the high plasma protein binding (greater than 99%) may limit exposure. The elimination half-life is apparently unknown.

Hematologic agents

Defibrotide sodium (Defitelio), given as an intravenous infusion, is an oligonucleotide mixture. It is indicated for the treatment of hepatic veno-occlusive disease, also known as sinusoidal obstruction syndrome, with renal or pulmonary dysfunction following hematopoietic stem-cell transplantation. Animal reproduction studies in two species suggest risk. The mean molecular weight is 13,000-20,000. Plasma protein binding is an average 93%, and the elimination half-life is less than 2 hours. It is doubtful if the drug crosses the placenta, especially in the first half of pregnancy. If possible, avoid the drug in the second half of pregnancy.

Immunologics

Two indications have been approved for daclizumab. The first was in 2005 for the prophylaxis of acute organ rejection of renal transplants (Zenapax), and the second was in 2016 for the treatment of relapsing forms of multiple sclerosis (Zinbryta). Reproduction studies in monkeys with Zinbryta can be classified as low risk. The molecular weight (about 144,000) suggests that the drug will not cross the placenta, at least in the first half of pregnancy. However, depending on when the drug is given, the long elimination half-life of 21 days might allow the drug to cross in late pregnancy. Regardless, if the perceived maternal benefit exceeds the potential embryo-fetal risk, the drug should not be withheld because of pregnancy.

Muscular disorder agents

Eteplirsen (Exondys 51) is an antisense oligonucleotide that is given intravenously. It is indicated for the treatment of Duchenne muscular dystrophy in patients who have a confirmed mutation of the related gene, which is amenable to exon 51 skipping. There are no animal reproduction data. The molecular weight is about 10,306. This suggests that the drug will not cross the placenta, at least in the first half of pregnancy. The elimination half-life is 3-4 hours, and the plasma concentration 24 hours after a dose was 0.07% of the peak plasma concentration. The drug is given once weekly, and waiting for 24 hours or slightly longer after a dose should reduce the exposure, if any, of the embryo-fetus during the first half of pregnancy.

 

Nusinersen (Spinraza), a survival motor neuron 2 directed–antisense oligonucleotide, is given as an intrathecal dose. It is indicated for the treatment of spinal muscular atrophy. Subcutaneous doses in two animal species caused no developmental toxicity. The molecular weight of 7,501 suggests that the drug will not cross the human placenta, at least not in the first half of pregnancy. The mean terminal elimination half-life in cerebrospinal fluid was 135-177 days and 63-87 days in plasma.

Ophthalmic agents

Lifitegrast (Xiidra) is an ophthalmic solution of a lymphocyte function-associated–antigen-1 antagonist. It is indicated for the treatment of the signs and symptoms of dry eye disease. The animal reproduction data suggest low risk. The molecular weight is about 616, suggesting that the drug would cross the placenta. However, in a Phase III trial conducted before FDA approval, 47 patients with dry eye disease were given 1 drop twice daily for periods up to 360 days. Nine patients (19%) had plasma predose (trough) concentrations above 0.5 ng/mL, the lower limit of quantitation. Trough plasma concentrations in these patients ranged from 0.55 ng/mL to 3.74 ng/mL. These amounts do not appear to represent an embryo-fetal risk.

Respiratory agents

Reslizumab (Cinqair), an interleukin-5 antagonist monoclonal antibody, is given intravenously. It is indicated for add-on maintenance treatment of severe asthma in patients with an eosinophilic phenotype. Animal data in two species suggest low risk. The molecular weight is about 147,000, and the elimination half-life is about 24 days. This suggests that exposure of the embryo and fetus will be minimal, at least in the first half of pregnancy. The maternal benefit appears to outweigh the unknown embryo-fetal risk.

Lactation

None of the above drugs have been studied during breastfeeding. Many drugs, regardless of their molecular weight, will cross into milk in small amounts during the first postpartum week. The effects of this exposure on a nursing infant are unknown. Based on the potential for nursing infant harm, the drugs that probably should not be given during breastfeeding include the four antineoplastics, the atypical antipsychotic pimavanserin, and the diabetes injection lixisenatide.

Mr. Briggs is a clinical professor of pharmacy at the University of California, San Francisco, and an adjunct professor of pharmacy at the University of Southern California, Los Angeles, and at Washington State University, Spokane. He coauthored “Drugs in Pregnancy and Lactation,” and coedited “Diseases, Complications, and Drug Therapy in Obstetrics.” He reported having no relevant financial disclosures.

 

Over the last decade, appreciation of the prevalence of perinatal depression – depression during pregnancy and/or the postpartum period – along with interest and willingness to diagnose and to treat these disorders across primary care, obstetric, and psychiatric clinical settings – has grown.

The passage of the Affordable Care Act in 2010 included the Melanie Blocker Stokes MOTHERS Act, which provides federal funding for programs to enhance awareness of postpartum depression and conduct research into its causes and treatment. At the same time, there has been increasing destigmatization associated with perinatal mood and anxiety disorders across many communities, and enhanced knowledge among clinicians and the public regarding evidence-based treatments, which mitigate suffering from untreated perinatal psychiatric illness.

There also has been a wave of interest around the country in establishing consistent screening for postpartum depression across a range of clinical settings. Approximately 40 states have instituted guidelines and recommendations regarding screening for postpartum depression. These positive developments, in part, follow recommendations from both the U.S. Preventive Services Task Force and the American College of Obstetricians and Gynecologists to move toward routine screening for depression, particularly among vulnerable populations such as pregnant and postpartum women. Both groups coupled their screening recommendations with a call for adequate systems to ensure treatment and follow-up but neither suggested how to implement it (Obstet Gynecol. 2015;125:1268-71, JAMA. 2016 Jan. 26;315[4]:380-7).

The importance of identification of perinatal depression cannot be overestimated given the impact of untreated perinatal mood and anxiety disorders on women and families. Unfortunately, data describing the outcomes of these screening initiatives have been profoundly lacking.

There are many unanswered questions. What proportion of women get screened from state to state? What are the obstacles to screening across different sociodemographic populations? If screened, what proportion of women are referred for treatment and receive appropriate treatment? Of those who receive treatment, how many recover emotional well-being? These are all critically relevant questions and one has to wonder if they would be the same from other nonpsychiatric disease states. For example, would one screen for HIV or cervical cancer and not know the number of women who screened positive but failed to go on to receive referral or frank treatment?

This knowledge gap with respect to outcome of screening for perinatal depression was highlighted in one of the few studies that addresses this specific question. Published in 2016, the systematic review describes the so-called “perinatal depression treatment cascade” – the cumulative shortfalls in clinical recognition, initiation of treatment, adequacy of treatment, and treatment response among women with either depression during pregnancy or postpartum depression (J Clin Psychiatry. 2016 Sep;77[9]:1189-1200).

The investigators included 32 studies where they were able to look specifically at this question of what happens to women who are identified as having either antenatal depression or postpartum depression. In total, six studies examined the rate of treatment of women who had been diagnosed with antenatal depression, resulting in a weighted mean treatment rate of 13.6%. For women identified as having postpartum depression, four studies examined showed a weighted mean treatment rate of 15.8%. What that means is that even if we have a sensitive and specific screening tool and we look only at women who have screened positive, we still have just 14% and 16% of women receiving treatment of any kind.

Drilling down to the issue of treatment adequacy – defined in the review as at least 6 weeks of daily use of antidepressants or at least 6 weeks of psychotherapy – the picture is unfortunately worse. Among the entire population of women with diagnosed antenatal depression, 8.6% received an adequate trial of treatment. Similarly, 6.3% of women with diagnosed postpartum depression received an adequate trial of treatment.

Continuing down the treatment cascade, remission rates also were extremely low. The overall weighted mean remission rate – reflecting the percentage of women who actually ended up getting well – was just 4.8% for women with antenatal depression and 3.2% for women with postpartum depression. These are striking, although perhaps not surprising, data. It suggests, at least in part, the fundamental absence of adequate referral networks and systems for follow-up for those women who suffer from perinatal depression.

It is well established that postpartum depression is the most common complication in modern obstetrics. The data presented in this paper suggest that most women identified with perinatal depressive illness are not getting well. Assuming a prevalence of 10% for antenatal depression and 13% for postpartum depression, there are about 657,000 women with antenatal depression and about 550,000 women with postpartum depression in the United States. If this review is correct, more than 31,000 women with antenatal depression and almost 18,000 women with postpartum depression achieved remission. That leaves more than 600,000 women with undermanaged depression in pregnancy and more than 500,000 women with incompletely treated postpartum depression.

This is a wake-up call to consider a refocusing of effort. The importance of identification of women suffering from postpartum depression is clear and intuitive. We should certainly not abandon screening, but perhaps there has been an overemphasis on identification and incomplete attention to ensuring that referral networks and opportunities for clinical follow-up are in place following positive screening. There also has been inadequate focus on the obstacles to getting women in to see clinicians and getting those clinicians up to speed on the evidence base that supports treatment, both pharmacologic or nonpharmacologic.

Right now, we don’t even know for sure what obstacles exist to referral and treatment. Surveys of community clinicians suggest that collaborative care in managing reproductive-age women or pregnant and postpartum women has not evolved to the point where we have a clear, user-friendly system for getting patients referred and treated. In Massachusetts, where I practice, we have a state-funded effort (MCPAP [Massachusetts Child Psychiatry Access Program] for Moms) to train colleagues in obstetrics about how to identify and treat perinatal depression; perinatal psychiatrists also are available to consult with community-based clinicians. However, we do not have data to tell us if these efforts and the resources used to support them have yielded improvement in the overall symptom burden associated with perinatal mood disorders.

The bottom line is that even after identification of perinatal depression through screening programs, we still have women suffering in silence. It is so easy to get on the bandwagon regarding screening, but it seems even more challenging to design the systems that will accommodate the volume of women who are being identified. The fact that we do not have parallel efforts focusing on getting these women referred and treated, and a system to monitor improvement, conjures the image of setting off to sail without checking whether the boat is equipped with life preservers.
 

 

Dr. Cohen is the director of the Center for Women’s Mental Health at Massachusetts General Hospital in Boston, which provides information resources and conducts clinical care and research in reproductive mental health. He has been a consultant to manufacturers of psychiatric medications.

 

Over the last decade, appreciation of the prevalence of perinatal depression – depression during pregnancy and/or the postpartum period – along with interest and willingness to diagnose and to treat these disorders across primary care, obstetric, and psychiatric clinical settings – has grown.

The passage of the Affordable Care Act in 2010 included the Melanie Blocker Stokes MOTHERS Act, which provides federal funding for programs to enhance awareness of postpartum depression and conduct research into its causes and treatment. At the same time, there has been increasing destigmatization associated with perinatal mood and anxiety disorders across many communities, and enhanced knowledge among clinicians and the public regarding evidence-based treatments, which mitigate suffering from untreated perinatal psychiatric illness.

There also has been a wave of interest around the country in establishing consistent screening for postpartum depression across a range of clinical settings. Approximately 40 states have instituted guidelines and recommendations regarding screening for postpartum depression. These positive developments, in part, follow recommendations from both the U.S. Preventive Services Task Force and the American College of Obstetricians and Gynecologists to move toward routine screening for depression, particularly among vulnerable populations such as pregnant and postpartum women. Both groups coupled their screening recommendations with a call for adequate systems to ensure treatment and follow-up but neither suggested how to implement it (Obstet Gynecol. 2015;125:1268-71, JAMA. 2016 Jan. 26;315[4]:380-7).

The importance of identification of perinatal depression cannot be overestimated given the impact of untreated perinatal mood and anxiety disorders on women and families. Unfortunately, data describing the outcomes of these screening initiatives have been profoundly lacking.

There are many unanswered questions. What proportion of women get screened from state to state? What are the obstacles to screening across different sociodemographic populations? If screened, what proportion of women are referred for treatment and receive appropriate treatment? Of those who receive treatment, how many recover emotional well-being? These are all critically relevant questions and one has to wonder if they would be the same from other nonpsychiatric disease states. For example, would one screen for HIV or cervical cancer and not know the number of women who screened positive but failed to go on to receive referral or frank treatment?

This knowledge gap with respect to outcome of screening for perinatal depression was highlighted in one of the few studies that addresses this specific question. Published in 2016, the systematic review describes the so-called “perinatal depression treatment cascade” – the cumulative shortfalls in clinical recognition, initiation of treatment, adequacy of treatment, and treatment response among women with either depression during pregnancy or postpartum depression (J Clin Psychiatry. 2016 Sep;77[9]:1189-1200).

The investigators included 32 studies where they were able to look specifically at this question of what happens to women who are identified as having either antenatal depression or postpartum depression. In total, six studies examined the rate of treatment of women who had been diagnosed with antenatal depression, resulting in a weighted mean treatment rate of 13.6%. For women identified as having postpartum depression, four studies examined showed a weighted mean treatment rate of 15.8%. What that means is that even if we have a sensitive and specific screening tool and we look only at women who have screened positive, we still have just 14% and 16% of women receiving treatment of any kind.

Drilling down to the issue of treatment adequacy – defined in the review as at least 6 weeks of daily use of antidepressants or at least 6 weeks of psychotherapy – the picture is unfortunately worse. Among the entire population of women with diagnosed antenatal depression, 8.6% received an adequate trial of treatment. Similarly, 6.3% of women with diagnosed postpartum depression received an adequate trial of treatment.

Continuing down the treatment cascade, remission rates also were extremely low. The overall weighted mean remission rate – reflecting the percentage of women who actually ended up getting well – was just 4.8% for women with antenatal depression and 3.2% for women with postpartum depression. These are striking, although perhaps not surprising, data. It suggests, at least in part, the fundamental absence of adequate referral networks and systems for follow-up for those women who suffer from perinatal depression.

It is well established that postpartum depression is the most common complication in modern obstetrics. The data presented in this paper suggest that most women identified with perinatal depressive illness are not getting well. Assuming a prevalence of 10% for antenatal depression and 13% for postpartum depression, there are about 657,000 women with antenatal depression and about 550,000 women with postpartum depression in the United States. If this review is correct, more than 31,000 women with antenatal depression and almost 18,000 women with postpartum depression achieved remission. That leaves more than 600,000 women with undermanaged depression in pregnancy and more than 500,000 women with incompletely treated postpartum depression.

This is a wake-up call to consider a refocusing of effort. The importance of identification of women suffering from postpartum depression is clear and intuitive. We should certainly not abandon screening, but perhaps there has been an overemphasis on identification and incomplete attention to ensuring that referral networks and opportunities for clinical follow-up are in place following positive screening. There also has been inadequate focus on the obstacles to getting women in to see clinicians and getting those clinicians up to speed on the evidence base that supports treatment, both pharmacologic or nonpharmacologic.

Right now, we don’t even know for sure what obstacles exist to referral and treatment. Surveys of community clinicians suggest that collaborative care in managing reproductive-age women or pregnant and postpartum women has not evolved to the point where we have a clear, user-friendly system for getting patients referred and treated. In Massachusetts, where I practice, we have a state-funded effort (MCPAP [Massachusetts Child Psychiatry Access Program] for Moms) to train colleagues in obstetrics about how to identify and treat perinatal depression; perinatal psychiatrists also are available to consult with community-based clinicians. However, we do not have data to tell us if these efforts and the resources used to support them have yielded improvement in the overall symptom burden associated with perinatal mood disorders.

The bottom line is that even after identification of perinatal depression through screening programs, we still have women suffering in silence. It is so easy to get on the bandwagon regarding screening, but it seems even more challenging to design the systems that will accommodate the volume of women who are being identified. The fact that we do not have parallel efforts focusing on getting these women referred and treated, and a system to monitor improvement, conjures the image of setting off to sail without checking whether the boat is equipped with life preservers.
 

 

Dr. Cohen is the director of the Center for Women’s Mental Health at Massachusetts General Hospital in Boston, which provides information resources and conducts clinical care and research in reproductive mental health. He has been a consultant to manufacturers of psychiatric medications.

 

Over the last decade, appreciation of the prevalence of perinatal depression – depression during pregnancy and/or the postpartum period – along with interest and willingness to diagnose and to treat these disorders across primary care, obstetric, and psychiatric clinical settings – has grown.

The passage of the Affordable Care Act in 2010 included the Melanie Blocker Stokes MOTHERS Act, which provides federal funding for programs to enhance awareness of postpartum depression and conduct research into its causes and treatment. At the same time, there has been increasing destigmatization associated with perinatal mood and anxiety disorders across many communities, and enhanced knowledge among clinicians and the public regarding evidence-based treatments, which mitigate suffering from untreated perinatal psychiatric illness.

There also has been a wave of interest around the country in establishing consistent screening for postpartum depression across a range of clinical settings. Approximately 40 states have instituted guidelines and recommendations regarding screening for postpartum depression. These positive developments, in part, follow recommendations from both the U.S. Preventive Services Task Force and the American College of Obstetricians and Gynecologists to move toward routine screening for depression, particularly among vulnerable populations such as pregnant and postpartum women. Both groups coupled their screening recommendations with a call for adequate systems to ensure treatment and follow-up but neither suggested how to implement it (Obstet Gynecol. 2015;125:1268-71, JAMA. 2016 Jan. 26;315[4]:380-7).

The importance of identification of perinatal depression cannot be overestimated given the impact of untreated perinatal mood and anxiety disorders on women and families. Unfortunately, data describing the outcomes of these screening initiatives have been profoundly lacking.

There are many unanswered questions. What proportion of women get screened from state to state? What are the obstacles to screening across different sociodemographic populations? If screened, what proportion of women are referred for treatment and receive appropriate treatment? Of those who receive treatment, how many recover emotional well-being? These are all critically relevant questions and one has to wonder if they would be the same from other nonpsychiatric disease states. For example, would one screen for HIV or cervical cancer and not know the number of women who screened positive but failed to go on to receive referral or frank treatment?

This knowledge gap with respect to outcome of screening for perinatal depression was highlighted in one of the few studies that addresses this specific question. Published in 2016, the systematic review describes the so-called “perinatal depression treatment cascade” – the cumulative shortfalls in clinical recognition, initiation of treatment, adequacy of treatment, and treatment response among women with either depression during pregnancy or postpartum depression (J Clin Psychiatry. 2016 Sep;77[9]:1189-1200).

The investigators included 32 studies where they were able to look specifically at this question of what happens to women who are identified as having either antenatal depression or postpartum depression. In total, six studies examined the rate of treatment of women who had been diagnosed with antenatal depression, resulting in a weighted mean treatment rate of 13.6%. For women identified as having postpartum depression, four studies examined showed a weighted mean treatment rate of 15.8%. What that means is that even if we have a sensitive and specific screening tool and we look only at women who have screened positive, we still have just 14% and 16% of women receiving treatment of any kind.

Drilling down to the issue of treatment adequacy – defined in the review as at least 6 weeks of daily use of antidepressants or at least 6 weeks of psychotherapy – the picture is unfortunately worse. Among the entire population of women with diagnosed antenatal depression, 8.6% received an adequate trial of treatment. Similarly, 6.3% of women with diagnosed postpartum depression received an adequate trial of treatment.

Continuing down the treatment cascade, remission rates also were extremely low. The overall weighted mean remission rate – reflecting the percentage of women who actually ended up getting well – was just 4.8% for women with antenatal depression and 3.2% for women with postpartum depression. These are striking, although perhaps not surprising, data. It suggests, at least in part, the fundamental absence of adequate referral networks and systems for follow-up for those women who suffer from perinatal depression.

It is well established that postpartum depression is the most common complication in modern obstetrics. The data presented in this paper suggest that most women identified with perinatal depressive illness are not getting well. Assuming a prevalence of 10% for antenatal depression and 13% for postpartum depression, there are about 657,000 women with antenatal depression and about 550,000 women with postpartum depression in the United States. If this review is correct, more than 31,000 women with antenatal depression and almost 18,000 women with postpartum depression achieved remission. That leaves more than 600,000 women with undermanaged depression in pregnancy and more than 500,000 women with incompletely treated postpartum depression.

This is a wake-up call to consider a refocusing of effort. The importance of identification of women suffering from postpartum depression is clear and intuitive. We should certainly not abandon screening, but perhaps there has been an overemphasis on identification and incomplete attention to ensuring that referral networks and opportunities for clinical follow-up are in place following positive screening. There also has been inadequate focus on the obstacles to getting women in to see clinicians and getting those clinicians up to speed on the evidence base that supports treatment, both pharmacologic or nonpharmacologic.

Right now, we don’t even know for sure what obstacles exist to referral and treatment. Surveys of community clinicians suggest that collaborative care in managing reproductive-age women or pregnant and postpartum women has not evolved to the point where we have a clear, user-friendly system for getting patients referred and treated. In Massachusetts, where I practice, we have a state-funded effort (MCPAP [Massachusetts Child Psychiatry Access Program] for Moms) to train colleagues in obstetrics about how to identify and treat perinatal depression; perinatal psychiatrists also are available to consult with community-based clinicians. However, we do not have data to tell us if these efforts and the resources used to support them have yielded improvement in the overall symptom burden associated with perinatal mood disorders.

The bottom line is that even after identification of perinatal depression through screening programs, we still have women suffering in silence. It is so easy to get on the bandwagon regarding screening, but it seems even more challenging to design the systems that will accommodate the volume of women who are being identified. The fact that we do not have parallel efforts focusing on getting these women referred and treated, and a system to monitor improvement, conjures the image of setting off to sail without checking whether the boat is equipped with life preservers.
 

 

Dr. Cohen is the director of the Center for Women’s Mental Health at Massachusetts General Hospital in Boston, which provides information resources and conducts clinical care and research in reproductive mental health. He has been a consultant to manufacturers of psychiatric medications.

 

Imagine this scenario: A couple goes on a Caribbean cruise with an all-you-can-eat buffet and an open bar. During the trip, they engage in 2 or 3 days of binge-style drinking, which is considered about four drinks in a single sitting. A few weeks after the trip, the woman finds out that she’s pregnant and calls your office wondering if there will be any harm to the fetus.

This is not a theoretical question. I have received many of these calls over the years, and in some cases the fear of adverse effects on the baby has led the couple to terminate the pregnancy. When we consider the general rise in binge drinking in North America and the fact that about half of all pregnancies are unplanned, this is a very real concern.

The first step is to find out whether the binging occurred during the “none or all period” before implantation, or whether it happened after implantation, reaching the embryo, where the teratogenic risk becomes more tangible.

Unfortunately, the literature has not been clear on the long-term impact of binge drinking in pregnancy. Animal studies suggest that it is the peak in the alcohol level created by binge drinking that causes damage to the fetus, rather than a sustained level of alcohol (although that obviously carries risk as well). The literature in humans has been controversial.

One of the most recent studies is a prospective cohort study of more than 1,600 women and their children sampled from the Danish National Birth Cohort. The investigators collected information on maternal alcohol use in early pregnancy and examined children at age 5 years using the Strengths and Difficulties Questionnaire (SDQ) completed by the mothers and a preschool teacher. It found no statistically significant association between binge drinking in early pregnancy and child behavior at age 5 years (BJOG. 2013 Aug;120[9]:1042-50).

In this study, the investigators corrected for parental education, maternal IQ, prenatal maternal smoking and postnatal parental smoking, the child’s age at testing, the child’s gender, maternal age, parity, marital status, family-home environment, prepregnancy maternal body mass index, and the child’s health status. After adjusting for confounders, they found no association between binge drinking and scores on the SDQ (odds ratio, 1.2; 95% confidence interval, 0.8-1.7 for behavioral scores and OR, 0.8; 95% CI, 0.6-1.2 for total difficulties scores). Additionally, the investigators analyzed low to moderate weekly alcohol consumption in early pregnancy and also could not find a significant effect (OR, 1.1; 95% CI, 0.5-2.3 for behavioral scores and OR, 1.1; 95% CI, 0.6-2.1 for the total difficulties scores).

This finding received a lot of press attention at the time, but it’s not the only study that has shown a lack of effect from binge drinking in contrast to the conventional wisdom on this subject.

A meta-analysis published in early 2014 further adds to the literature on this topic (Alcohol Clin Exp Res. 2014 Jan;38[1]:214-26).

The meta-analysis showed a small, but statistically significant effect on child’s cognition associated with binge drinking in pregnancy (Cohen’s d [a standardized mean difference score] −0.13; 95% CI, −0.21, −0.05). It did not include the 2013 Danish study.

The meta-analysis examined other levels of drinking in pregnancy, not just binging. Out of more than 1,500 papers that were examined, 34 studies met the criteria for inclusion, and just eight were included in the binge drinking analysis. The eight studies comprised more than 10,000 children who were tested from ages 6 months to 14 years. The researchers analyzed eight functional domains: academic performance, attention, behavior, cognition, memory, language and verbal development, executive function, and visual and motor development.

The researchers also separated the studies based on quality. When they analyzed the results for only high-quality studies, the cognition effect was not significant and no other associations were found with other child neuropsychological outcomes.

Several other studies have examined different endpoints, particularly hyperactivity and externalizing behaviors. While several studies show a trend toward those effects, mothers who binge drink also tend to be more externalizing in their own behavior.

An examination of the literature shows just how difficult it is to produce clear results that inform clinical practice. Adjusting for confounding factors from marital status to maternal IQ is just one hurdle. Another area that plagues researchers is that knowledge of drinking in early pregnancy is based on self-reports, and it is nearly impossible to know for sure if the reports of binging are accurate and also if there has been chronic alcohol use.

So what does all of this mean when it comes to advising women? There is no question that women should be advised not to drink when they are pregnant or planning a pregnancy. For a woman who engaged in binge drinking before she knew she was pregnant, it’s difficult to say that there is no effect. Instead, the collective evidence suggests there may be a small effect on cognition. In cases where binge drinking has occurred, children should be monitored as early as possible for any potential developmental effects.
 

 

Dr. Koren is professor of physiology/pharmacology and pediatrics at Western University in Ontario. He is the founder of the Motherisk Program. He reported having no relevant financial disclosures. Email him at obnews@frontlinemedcom.com.

 

Imagine this scenario: A couple goes on a Caribbean cruise with an all-you-can-eat buffet and an open bar. During the trip, they engage in 2 or 3 days of binge-style drinking, which is considered about four drinks in a single sitting. A few weeks after the trip, the woman finds out that she’s pregnant and calls your office wondering if there will be any harm to the fetus.

This is not a theoretical question. I have received many of these calls over the years, and in some cases the fear of adverse effects on the baby has led the couple to terminate the pregnancy. When we consider the general rise in binge drinking in North America and the fact that about half of all pregnancies are unplanned, this is a very real concern.

The first step is to find out whether the binging occurred during the “none or all period” before implantation, or whether it happened after implantation, reaching the embryo, where the teratogenic risk becomes more tangible.

Unfortunately, the literature has not been clear on the long-term impact of binge drinking in pregnancy. Animal studies suggest that it is the peak in the alcohol level created by binge drinking that causes damage to the fetus, rather than a sustained level of alcohol (although that obviously carries risk as well). The literature in humans has been controversial.

One of the most recent studies is a prospective cohort study of more than 1,600 women and their children sampled from the Danish National Birth Cohort. The investigators collected information on maternal alcohol use in early pregnancy and examined children at age 5 years using the Strengths and Difficulties Questionnaire (SDQ) completed by the mothers and a preschool teacher. It found no statistically significant association between binge drinking in early pregnancy and child behavior at age 5 years (BJOG. 2013 Aug;120[9]:1042-50).

In this study, the investigators corrected for parental education, maternal IQ, prenatal maternal smoking and postnatal parental smoking, the child’s age at testing, the child’s gender, maternal age, parity, marital status, family-home environment, prepregnancy maternal body mass index, and the child’s health status. After adjusting for confounders, they found no association between binge drinking and scores on the SDQ (odds ratio, 1.2; 95% confidence interval, 0.8-1.7 for behavioral scores and OR, 0.8; 95% CI, 0.6-1.2 for total difficulties scores). Additionally, the investigators analyzed low to moderate weekly alcohol consumption in early pregnancy and also could not find a significant effect (OR, 1.1; 95% CI, 0.5-2.3 for behavioral scores and OR, 1.1; 95% CI, 0.6-2.1 for the total difficulties scores).

This finding received a lot of press attention at the time, but it’s not the only study that has shown a lack of effect from binge drinking in contrast to the conventional wisdom on this subject.

A meta-analysis published in early 2014 further adds to the literature on this topic (Alcohol Clin Exp Res. 2014 Jan;38[1]:214-26).

The meta-analysis showed a small, but statistically significant effect on child’s cognition associated with binge drinking in pregnancy (Cohen’s d [a standardized mean difference score] −0.13; 95% CI, −0.21, −0.05). It did not include the 2013 Danish study.

The meta-analysis examined other levels of drinking in pregnancy, not just binging. Out of more than 1,500 papers that were examined, 34 studies met the criteria for inclusion, and just eight were included in the binge drinking analysis. The eight studies comprised more than 10,000 children who were tested from ages 6 months to 14 years. The researchers analyzed eight functional domains: academic performance, attention, behavior, cognition, memory, language and verbal development, executive function, and visual and motor development.

The researchers also separated the studies based on quality. When they analyzed the results for only high-quality studies, the cognition effect was not significant and no other associations were found with other child neuropsychological outcomes.

Several other studies have examined different endpoints, particularly hyperactivity and externalizing behaviors. While several studies show a trend toward those effects, mothers who binge drink also tend to be more externalizing in their own behavior.

An examination of the literature shows just how difficult it is to produce clear results that inform clinical practice. Adjusting for confounding factors from marital status to maternal IQ is just one hurdle. Another area that plagues researchers is that knowledge of drinking in early pregnancy is based on self-reports, and it is nearly impossible to know for sure if the reports of binging are accurate and also if there has been chronic alcohol use.

So what does all of this mean when it comes to advising women? There is no question that women should be advised not to drink when they are pregnant or planning a pregnancy. For a woman who engaged in binge drinking before she knew she was pregnant, it’s difficult to say that there is no effect. Instead, the collective evidence suggests there may be a small effect on cognition. In cases where binge drinking has occurred, children should be monitored as early as possible for any potential developmental effects.
 

 

Dr. Koren is professor of physiology/pharmacology and pediatrics at Western University in Ontario. He is the founder of the Motherisk Program. He reported having no relevant financial disclosures. Email him at obnews@frontlinemedcom.com.

 

Imagine this scenario: A couple goes on a Caribbean cruise with an all-you-can-eat buffet and an open bar. During the trip, they engage in 2 or 3 days of binge-style drinking, which is considered about four drinks in a single sitting. A few weeks after the trip, the woman finds out that she’s pregnant and calls your office wondering if there will be any harm to the fetus.

This is not a theoretical question. I have received many of these calls over the years, and in some cases the fear of adverse effects on the baby has led the couple to terminate the pregnancy. When we consider the general rise in binge drinking in North America and the fact that about half of all pregnancies are unplanned, this is a very real concern.

The first step is to find out whether the binging occurred during the “none or all period” before implantation, or whether it happened after implantation, reaching the embryo, where the teratogenic risk becomes more tangible.

Unfortunately, the literature has not been clear on the long-term impact of binge drinking in pregnancy. Animal studies suggest that it is the peak in the alcohol level created by binge drinking that causes damage to the fetus, rather than a sustained level of alcohol (although that obviously carries risk as well). The literature in humans has been controversial.

One of the most recent studies is a prospective cohort study of more than 1,600 women and their children sampled from the Danish National Birth Cohort. The investigators collected information on maternal alcohol use in early pregnancy and examined children at age 5 years using the Strengths and Difficulties Questionnaire (SDQ) completed by the mothers and a preschool teacher. It found no statistically significant association between binge drinking in early pregnancy and child behavior at age 5 years (BJOG. 2013 Aug;120[9]:1042-50).

In this study, the investigators corrected for parental education, maternal IQ, prenatal maternal smoking and postnatal parental smoking, the child’s age at testing, the child’s gender, maternal age, parity, marital status, family-home environment, prepregnancy maternal body mass index, and the child’s health status. After adjusting for confounders, they found no association between binge drinking and scores on the SDQ (odds ratio, 1.2; 95% confidence interval, 0.8-1.7 for behavioral scores and OR, 0.8; 95% CI, 0.6-1.2 for total difficulties scores). Additionally, the investigators analyzed low to moderate weekly alcohol consumption in early pregnancy and also could not find a significant effect (OR, 1.1; 95% CI, 0.5-2.3 for behavioral scores and OR, 1.1; 95% CI, 0.6-2.1 for the total difficulties scores).

This finding received a lot of press attention at the time, but it’s not the only study that has shown a lack of effect from binge drinking in contrast to the conventional wisdom on this subject.

A meta-analysis published in early 2014 further adds to the literature on this topic (Alcohol Clin Exp Res. 2014 Jan;38[1]:214-26).

The meta-analysis showed a small, but statistically significant effect on child’s cognition associated with binge drinking in pregnancy (Cohen’s d [a standardized mean difference score] −0.13; 95% CI, −0.21, −0.05). It did not include the 2013 Danish study.

The meta-analysis examined other levels of drinking in pregnancy, not just binging. Out of more than 1,500 papers that were examined, 34 studies met the criteria for inclusion, and just eight were included in the binge drinking analysis. The eight studies comprised more than 10,000 children who were tested from ages 6 months to 14 years. The researchers analyzed eight functional domains: academic performance, attention, behavior, cognition, memory, language and verbal development, executive function, and visual and motor development.

The researchers also separated the studies based on quality. When they analyzed the results for only high-quality studies, the cognition effect was not significant and no other associations were found with other child neuropsychological outcomes.

Several other studies have examined different endpoints, particularly hyperactivity and externalizing behaviors. While several studies show a trend toward those effects, mothers who binge drink also tend to be more externalizing in their own behavior.

An examination of the literature shows just how difficult it is to produce clear results that inform clinical practice. Adjusting for confounding factors from marital status to maternal IQ is just one hurdle. Another area that plagues researchers is that knowledge of drinking in early pregnancy is based on self-reports, and it is nearly impossible to know for sure if the reports of binging are accurate and also if there has been chronic alcohol use.

So what does all of this mean when it comes to advising women? There is no question that women should be advised not to drink when they are pregnant or planning a pregnancy. For a woman who engaged in binge drinking before she knew she was pregnant, it’s difficult to say that there is no effect. Instead, the collective evidence suggests there may be a small effect on cognition. In cases where binge drinking has occurred, children should be monitored as early as possible for any potential developmental effects.
 

 

Dr. Koren is professor of physiology/pharmacology and pediatrics at Western University in Ontario. He is the founder of the Motherisk Program. He reported having no relevant financial disclosures. Email him at obnews@frontlinemedcom.com.

 

Among pregnant women, acetaminophen is the most commonly used pain reliever, and likely the most commonly used of any medication. Estimates suggest that anywhere from 40% to greater than 65% of pregnant women use an acetaminophen-containing product at some time in pregnancy. Recently, concerns have been raised in several studies about potential increased risks for a variety of neurobehavioral outcomes including attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorders (ASD), cognitive deficits, and other behavior problems.

A 2013 study conducted in the Norwegian Mother and Child Cohort Study (pregnant women enrolled 1999-2008) evaluated 2,919 same-sex siblings at 3 years of age whose mothers were enrolled in the cohort during pregnancy. Prenatal exposure to acetaminophen was collected from maternal interview data during and shortly after pregnancy. Behavioral performance in the children was measured using validated maternal questionnaires. After adjustment for maternal febrile illness, infection, and comorbidities, use of acetaminophen for 28 days or more in pregnancy was associated with poorer gross motor and communication performance, more externalizing and internalizing behaviors, and higher activity levels in the offspring. Exposure for less than 28 days was associated with poor gross motor skills only. There were no associations found between ibuprofen use in pregnancy and any of the neurobehavioral outcomes.¹

A 2014 study from the Danish National Birth Cohort (pregnant women enrolled 1996-2002) examined data on 64,322 live-born children linked to hyperkinetic disorder diagnoses from the Danish National Hospital, Copenhagen, and linked to ADHD medication treatment from the Danish Prescription Registry. Additionally, mothers of a subset of 40,916 children completed a Strengths and Difficulties Questionnaire at 7 years of age. Adjusted risks were significantly increased for hyperkinetic disorders (hazard ratio 1.37; 95% confidence interval, 1.19-1.59), ADHD medication use (HR,1.29; 95% CI, 1.15-1.44) and for ADHD (relative risk 1.13; 95% CI, 1.01-1.27). The associations were stronger if acetaminophen was used in more than one trimester, and with increasing frequency of use.²

Four additional studies on this topic were published in 2016. One study from the Avon Longitudinal Study of Parents and Children followed 7,796 pregnant women enrolled in Bristol, England, in 1991-1992. This study’s findings were similar to the Danish cohort, with increased risks for conduct problems and hyperactivity symptoms as assessed in the Strengths and Difficulties Questionnaire at 7 years of age. In contrast, there was no association found with postnatal maternal acetaminophen use or paternal use.³

©Ingram Publishing/Thinkstock

A second study from the Spanish Birth Cohort (2004-2007) involved 2,644 children evaluated using the Bayley Scales of Infant and Toddler Development at approximately 1 year of age and McCarthy Scales of Children’s Abilities. These standardized tests were administered by trained psychologists. Additional assessments such as the Childhood Autism Spectrum Test and several parent and teacher checklists were also completed. Those children with any prenatal acetaminophen exposure exhibited more hyperactivity and impulsivity, but there were no differences in mental or psychomotor development at 1 year of age, and no differences on cognitive or motor development or social competence at 5 years of age.⁴

Two additional studies published in 2016 were from the Danish cohort described above. The first assessed long term follow-up for an average of 12.7 years linked to incidence of ASD or infantile autism in the Danish Psychiatric and Hospital Registries. An increased risk for ASD was found only when the diagnosis was accompanied by hyperkinetic symptoms (RR,1.51; 95% CI, 1.19-1.92), and this risk was most pronounced when acetaminophen was used in the last half of pregnancy.⁵

The second study examined a smaller subset of 1,491 children who were tested at 5 years of age by trained psychologists using the Wechsler Preschool and Primary Scale of Intelligence – a measure of IQ. Maternal fever and acetaminophen use in pregnancy were associated with small but significant deficits. For example, children of mothers who used acetaminophen but reported no fever had on average a 3.4 point deficit in performance IQ, compared with children of mothers who reported neither. However, mothers who reported both acetaminophen use and fever showed no differences.⁶

The authors of the studies described above, as well as other experts in the field, have discussed the biological plausibility of such associations being causal. The endocrine disruptive effects of acetaminophen and/or an impact on oxidative stress have been suggested as possible mechanisms, although no convincing data have supported these theories to date. Several of the studies have been criticized for reliance on maternal report of the outcomes, and all studies relied on maternal report of the exposure, which raises possibilities for bias and misclassification. However, some studies included assessments by trained psychologists or linkage to diagnoses recorded in national health registries. Control for confounding is always problematic in observational studies, especially with long-term outcomes. The sibling-pair study conducted in Norway attempted to control for genetic and environmental confounding using this design. Confounding by indication is also a concern. Adjustment for maternal fever, infections, or other comorbidities may have addressed some of this concern; however, as with acetaminophen, vague and perhaps inaccurate maternal report of these events may be problematic. Findings for another pain reliever, ibuprofen, showed no association in one study, which provides some reassurance.

At the present time, the impacts on behavior including hyperactivity and perhaps ASD are most prominent in the published reports stemming from four countries with large cohort studies. There is conflicting evidence of any impact on cognitive performance. All associations reported are quite modest with relative risks in the 1.5 or lower range. Nevertheless, acetaminophen is a medication taken by most women in pregnancy, so the broad impact, if these associations are causal, is not trivial. Clinically, an urgent concern would be that women or clinicians might ignore the current advice to take acetaminophen to reduce maternal fever. In that regard, it is reassuring that the Danish Cohort study found no impact on IQ when acetaminophen was used to treat a fever, while fever itself was associated with increased risks.

In studies which examined frequency of use, longer duration was often associated with higher risks. However, no study reported on dose. Future studies should capture dose, as well as better information on the underlying conditions being treated. The findings from these epidemiologic studies also call for additional experimental work to better understand possible mechanisms. In the meantime, as with any over-the-counter medication, judicious and appropriate use of acetaminophen should be advised.

 

References

1. Int J Epidemiol. 2013 Dec;42(6):1702-13.

2. JAMA Pediatr. 2014 Apr;168(4):313-20.

3. JAMA Pediatr. 2016 Oct 1;170(10):964-970.

4. Int. J. Epidemiol. 2016 June 28. doi: 10.1093/ije/dyw115.

5. Autism Res. 2016 Sep;9(9):951-8.

6. Epidemiology. 2016 Nov;27(6):912-8.
 

Dr. Chambers is a professor of pediatrics and director of clinical research at Rady Children’s Hospital, and associate director of the Clinical and Translational Research Institute at the University of California, San Diego. She is director of MotherToBaby California, a past president of the Organization of Teratology Information Specialists, and past president of the Teratology Society. She has no relevant financial disclosures. To comment, e-mail her at obnews@frontlinemedcom.com.

 

Among pregnant women, acetaminophen is the most commonly used pain reliever, and likely the most commonly used of any medication. Estimates suggest that anywhere from 40% to greater than 65% of pregnant women use an acetaminophen-containing product at some time in pregnancy. Recently, concerns have been raised in several studies about potential increased risks for a variety of neurobehavioral outcomes including attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorders (ASD), cognitive deficits, and other behavior problems.

A 2013 study conducted in the Norwegian Mother and Child Cohort Study (pregnant women enrolled 1999-2008) evaluated 2,919 same-sex siblings at 3 years of age whose mothers were enrolled in the cohort during pregnancy. Prenatal exposure to acetaminophen was collected from maternal interview data during and shortly after pregnancy. Behavioral performance in the children was measured using validated maternal questionnaires. After adjustment for maternal febrile illness, infection, and comorbidities, use of acetaminophen for 28 days or more in pregnancy was associated with poorer gross motor and communication performance, more externalizing and internalizing behaviors, and higher activity levels in the offspring. Exposure for less than 28 days was associated with poor gross motor skills only. There were no associations found between ibuprofen use in pregnancy and any of the neurobehavioral outcomes.¹

A 2014 study from the Danish National Birth Cohort (pregnant women enrolled 1996-2002) examined data on 64,322 live-born children linked to hyperkinetic disorder diagnoses from the Danish National Hospital, Copenhagen, and linked to ADHD medication treatment from the Danish Prescription Registry. Additionally, mothers of a subset of 40,916 children completed a Strengths and Difficulties Questionnaire at 7 years of age. Adjusted risks were significantly increased for hyperkinetic disorders (hazard ratio 1.37; 95% confidence interval, 1.19-1.59), ADHD medication use (HR,1.29; 95% CI, 1.15-1.44) and for ADHD (relative risk 1.13; 95% CI, 1.01-1.27). The associations were stronger if acetaminophen was used in more than one trimester, and with increasing frequency of use.²

Four additional studies on this topic were published in 2016. One study from the Avon Longitudinal Study of Parents and Children followed 7,796 pregnant women enrolled in Bristol, England, in 1991-1992. This study’s findings were similar to the Danish cohort, with increased risks for conduct problems and hyperactivity symptoms as assessed in the Strengths and Difficulties Questionnaire at 7 years of age. In contrast, there was no association found with postnatal maternal acetaminophen use or paternal use.³

©Ingram Publishing/Thinkstock

A second study from the Spanish Birth Cohort (2004-2007) involved 2,644 children evaluated using the Bayley Scales of Infant and Toddler Development at approximately 1 year of age and McCarthy Scales of Children’s Abilities. These standardized tests were administered by trained psychologists. Additional assessments such as the Childhood Autism Spectrum Test and several parent and teacher checklists were also completed. Those children with any prenatal acetaminophen exposure exhibited more hyperactivity and impulsivity, but there were no differences in mental or psychomotor development at 1 year of age, and no differences on cognitive or motor development or social competence at 5 years of age.⁴

Two additional studies published in 2016 were from the Danish cohort described above. The first assessed long term follow-up for an average of 12.7 years linked to incidence of ASD or infantile autism in the Danish Psychiatric and Hospital Registries. An increased risk for ASD was found only when the diagnosis was accompanied by hyperkinetic symptoms (RR,1.51; 95% CI, 1.19-1.92), and this risk was most pronounced when acetaminophen was used in the last half of pregnancy.⁵

The second study examined a smaller subset of 1,491 children who were tested at 5 years of age by trained psychologists using the Wechsler Preschool and Primary Scale of Intelligence – a measure of IQ. Maternal fever and acetaminophen use in pregnancy were associated with small but significant deficits. For example, children of mothers who used acetaminophen but reported no fever had on average a 3.4 point deficit in performance IQ, compared with children of mothers who reported neither. However, mothers who reported both acetaminophen use and fever showed no differences.⁶

The authors of the studies described above, as well as other experts in the field, have discussed the biological plausibility of such associations being causal. The endocrine disruptive effects of acetaminophen and/or an impact on oxidative stress have been suggested as possible mechanisms, although no convincing data have supported these theories to date. Several of the studies have been criticized for reliance on maternal report of the outcomes, and all studies relied on maternal report of the exposure, which raises possibilities for bias and misclassification. However, some studies included assessments by trained psychologists or linkage to diagnoses recorded in national health registries. Control for confounding is always problematic in observational studies, especially with long-term outcomes. The sibling-pair study conducted in Norway attempted to control for genetic and environmental confounding using this design. Confounding by indication is also a concern. Adjustment for maternal fever, infections, or other comorbidities may have addressed some of this concern; however, as with acetaminophen, vague and perhaps inaccurate maternal report of these events may be problematic. Findings for another pain reliever, ibuprofen, showed no association in one study, which provides some reassurance.

At the present time, the impacts on behavior including hyperactivity and perhaps ASD are most prominent in the published reports stemming from four countries with large cohort studies. There is conflicting evidence of any impact on cognitive performance. All associations reported are quite modest with relative risks in the 1.5 or lower range. Nevertheless, acetaminophen is a medication taken by most women in pregnancy, so the broad impact, if these associations are causal, is not trivial. Clinically, an urgent concern would be that women or clinicians might ignore the current advice to take acetaminophen to reduce maternal fever. In that regard, it is reassuring that the Danish Cohort study found no impact on IQ when acetaminophen was used to treat a fever, while fever itself was associated with increased risks.

In studies which examined frequency of use, longer duration was often associated with higher risks. However, no study reported on dose. Future studies should capture dose, as well as better information on the underlying conditions being treated. The findings from these epidemiologic studies also call for additional experimental work to better understand possible mechanisms. In the meantime, as with any over-the-counter medication, judicious and appropriate use of acetaminophen should be advised.

 

References

1. Int J Epidemiol. 2013 Dec;42(6):1702-13.

2. JAMA Pediatr. 2014 Apr;168(4):313-20.

3. JAMA Pediatr. 2016 Oct 1;170(10):964-970.

4. Int. J. Epidemiol. 2016 June 28. doi: 10.1093/ije/dyw115.

5. Autism Res. 2016 Sep;9(9):951-8.

6. Epidemiology. 2016 Nov;27(6):912-8.
 

Dr. Chambers is a professor of pediatrics and director of clinical research at Rady Children’s Hospital, and associate director of the Clinical and Translational Research Institute at the University of California, San Diego. She is director of MotherToBaby California, a past president of the Organization of Teratology Information Specialists, and past president of the Teratology Society. She has no relevant financial disclosures. To comment, e-mail her at obnews@frontlinemedcom.com.

 

Among pregnant women, acetaminophen is the most commonly used pain reliever, and likely the most commonly used of any medication. Estimates suggest that anywhere from 40% to greater than 65% of pregnant women use an acetaminophen-containing product at some time in pregnancy. Recently, concerns have been raised in several studies about potential increased risks for a variety of neurobehavioral outcomes including attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorders (ASD), cognitive deficits, and other behavior problems.

A 2013 study conducted in the Norwegian Mother and Child Cohort Study (pregnant women enrolled 1999-2008) evaluated 2,919 same-sex siblings at 3 years of age whose mothers were enrolled in the cohort during pregnancy. Prenatal exposure to acetaminophen was collected from maternal interview data during and shortly after pregnancy. Behavioral performance in the children was measured using validated maternal questionnaires. After adjustment for maternal febrile illness, infection, and comorbidities, use of acetaminophen for 28 days or more in pregnancy was associated with poorer gross motor and communication performance, more externalizing and internalizing behaviors, and higher activity levels in the offspring. Exposure for less than 28 days was associated with poor gross motor skills only. There were no associations found between ibuprofen use in pregnancy and any of the neurobehavioral outcomes.¹

A 2014 study from the Danish National Birth Cohort (pregnant women enrolled 1996-2002) examined data on 64,322 live-born children linked to hyperkinetic disorder diagnoses from the Danish National Hospital, Copenhagen, and linked to ADHD medication treatment from the Danish Prescription Registry. Additionally, mothers of a subset of 40,916 children completed a Strengths and Difficulties Questionnaire at 7 years of age. Adjusted risks were significantly increased for hyperkinetic disorders (hazard ratio 1.37; 95% confidence interval, 1.19-1.59), ADHD medication use (HR,1.29; 95% CI, 1.15-1.44) and for ADHD (relative risk 1.13; 95% CI, 1.01-1.27). The associations were stronger if acetaminophen was used in more than one trimester, and with increasing frequency of use.²

Four additional studies on this topic were published in 2016. One study from the Avon Longitudinal Study of Parents and Children followed 7,796 pregnant women enrolled in Bristol, England, in 1991-1992. This study’s findings were similar to the Danish cohort, with increased risks for conduct problems and hyperactivity symptoms as assessed in the Strengths and Difficulties Questionnaire at 7 years of age. In contrast, there was no association found with postnatal maternal acetaminophen use or paternal use.³

©Ingram Publishing/Thinkstock

A second study from the Spanish Birth Cohort (2004-2007) involved 2,644 children evaluated using the Bayley Scales of Infant and Toddler Development at approximately 1 year of age and McCarthy Scales of Children’s Abilities. These standardized tests were administered by trained psychologists. Additional assessments such as the Childhood Autism Spectrum Test and several parent and teacher checklists were also completed. Those children with any prenatal acetaminophen exposure exhibited more hyperactivity and impulsivity, but there were no differences in mental or psychomotor development at 1 year of age, and no differences on cognitive or motor development or social competence at 5 years of age.⁴

Two additional studies published in 2016 were from the Danish cohort described above. The first assessed long term follow-up for an average of 12.7 years linked to incidence of ASD or infantile autism in the Danish Psychiatric and Hospital Registries. An increased risk for ASD was found only when the diagnosis was accompanied by hyperkinetic symptoms (RR,1.51; 95% CI, 1.19-1.92), and this risk was most pronounced when acetaminophen was used in the last half of pregnancy.⁵

The second study examined a smaller subset of 1,491 children who were tested at 5 years of age by trained psychologists using the Wechsler Preschool and Primary Scale of Intelligence – a measure of IQ. Maternal fever and acetaminophen use in pregnancy were associated with small but significant deficits. For example, children of mothers who used acetaminophen but reported no fever had on average a 3.4 point deficit in performance IQ, compared with children of mothers who reported neither. However, mothers who reported both acetaminophen use and fever showed no differences.⁶

The authors of the studies described above, as well as other experts in the field, have discussed the biological plausibility of such associations being causal. The endocrine disruptive effects of acetaminophen and/or an impact on oxidative stress have been suggested as possible mechanisms, although no convincing data have supported these theories to date. Several of the studies have been criticized for reliance on maternal report of the outcomes, and all studies relied on maternal report of the exposure, which raises possibilities for bias and misclassification. However, some studies included assessments by trained psychologists or linkage to diagnoses recorded in national health registries. Control for confounding is always problematic in observational studies, especially with long-term outcomes. The sibling-pair study conducted in Norway attempted to control for genetic and environmental confounding using this design. Confounding by indication is also a concern. Adjustment for maternal fever, infections, or other comorbidities may have addressed some of this concern; however, as with acetaminophen, vague and perhaps inaccurate maternal report of these events may be problematic. Findings for another pain reliever, ibuprofen, showed no association in one study, which provides some reassurance.

At the present time, the impacts on behavior including hyperactivity and perhaps ASD are most prominent in the published reports stemming from four countries with large cohort studies. There is conflicting evidence of any impact on cognitive performance. All associations reported are quite modest with relative risks in the 1.5 or lower range. Nevertheless, acetaminophen is a medication taken by most women in pregnancy, so the broad impact, if these associations are causal, is not trivial. Clinically, an urgent concern would be that women or clinicians might ignore the current advice to take acetaminophen to reduce maternal fever. In that regard, it is reassuring that the Danish Cohort study found no impact on IQ when acetaminophen was used to treat a fever, while fever itself was associated with increased risks.

In studies which examined frequency of use, longer duration was often associated with higher risks. However, no study reported on dose. Future studies should capture dose, as well as better information on the underlying conditions being treated. The findings from these epidemiologic studies also call for additional experimental work to better understand possible mechanisms. In the meantime, as with any over-the-counter medication, judicious and appropriate use of acetaminophen should be advised.

 

References

1. Int J Epidemiol. 2013 Dec;42(6):1702-13.

2. JAMA Pediatr. 2014 Apr;168(4):313-20.

3. JAMA Pediatr. 2016 Oct 1;170(10):964-970.

4. Int. J. Epidemiol. 2016 June 28. doi: 10.1093/ije/dyw115.

5. Autism Res. 2016 Sep;9(9):951-8.

6. Epidemiology. 2016 Nov;27(6):912-8.
 

Dr. Chambers is a professor of pediatrics and director of clinical research at Rady Children’s Hospital, and associate director of the Clinical and Translational Research Institute at the University of California, San Diego. She is director of MotherToBaby California, a past president of the Organization of Teratology Information Specialists, and past president of the Teratology Society. She has no relevant financial disclosures. To comment, e-mail her at obnews@frontlinemedcom.com.

 

Lipid-lowering medications are some of the most commonly prescribed drugs in the United States. But while much is known about their general safety, the data are limited when it comes to pregnancy and breastfeeding.

Antilipemic agents are a pharmacologic class that contains 18 drugs. The class is divided into eight subclasses: bile acid sequestrants; fibric acid derivatives, HMG-CoA inhibitors; immunoglobulins; monoclonal antibodies; oligonucleotide inhibitors; vitamins; as well as two miscellaneous drugs, ezetimibe (Zetia) and lomitapide (Juxtapid). Another antilipemic – dextrothyroxine – has been removed from the market by the manufacturer.

Bile acid sequestrants

Bile acid sequestrants include cholestyramine (Prevalite, Questran), colesevelam (Welchol), and colestipol (Colestid). These drugs have the potential to cause fetal toxicity. This assessment is based on their mechanism of action. These agents are not absorbed systemically, or absorption is very poor and they bind bile acids into a nonabsorbable complex. This action can reduce intestinal absorption of fat-soluble vitamins A, D, E, and K.

In one case, the mother was taking cholestyramine beginning at 19 weeks’ gestation for intrahepatic cholestasis. Ten weeks later, reduced fetal movements were noted, and fetal ultrasound scans revealed expanding bilateral subdural hematomas with hydrocephalus, an enlarged liver, and bilateral pleural effusions. The mother’s prothrombin ratio was markedly elevated but responded to intravenous vitamin K. Labor was induced to deliver a 1,660-g infant who died 15 minutes after birth.¹

Reports of fetal harm have not been located for the other two agents in this class, but there is only one case report involving five women for colesevelam and no reports for colestipol. Nevertheless, both of these drugs have the potential to cause fetal hemorrhage if they are taken for prolonged periods in pregnancy.

Fibric acid derivatives

The fibric acid derivatives subclass includes fenofibrate (Tricor, Lofibra) and gemfibrozil (Lopid).

©Jupiterimages/Thinkstock.com

Fenofibrate is indicated as adjunctive therapy to diet for the treatment of primary hypercholesterolemia or mixed dyslipidemia, and for hypertriglyceridemia. The drug was embryotoxic in rats and rabbits at doses less than 10 times the maximum human dose. There are three reports describing the use of the drug in human pregnancy. In one case a woman was treated in the third trimester and, in the second case, during the first 8 weeks’ gestation. Both pregnancies ended in healthy male infants. In a third case, a woman was treated with fenofibrate for acute pancreatitis due to hyperlipidemia and with carbimazole for Graves’ disease. She stopped the drug when her pregnancy was diagnosed (unspecified gestational age). At 18 weeks’ gestation, intrauterine death was confirmed.²

Six reports, involving 13 pregnancies, have described the use of gemfibrozil during all phases of pregnancy. No teratogenic effects were observed in these cases. In one woman, similar concentrations of gemfibrozil and its active metabolite were found in the umbilical vein and artery at levels within the normal reference for adults.

Statins

There are seven HMG-CoA inhibitors, known as statins: atorvastatin (Lipitor), fluvastatin (Lescol), lovastatin (Mevacor), pitavastatin (Livalo), pravastatin (Pravachol), rosuvastatin (Crestor), and simvastatin (Zocor).

The interruption of cholesterol-lowering therapy during pregnancy should have no effect on the long-term treatment of hyperlipidemia. Moreover, cholesterol and products synthesized by cholesterol are important during fetal development as shown by the rise in maternal cholesterol levels during pregnancy. Although the potential for embryo-fetal harm has not been clearly documented, and that potential may eventually be confirmed as low, the use of these agents in the first trimester are best classified as contraindicated.

One consideration in estimating the embryo-fetal risk of statins is their classification as either lipophilic or hydrophilic. Three of the seven statins are hydrophilic (fluvastatin, pravastatin, and rosuvastatin); the remaining four agents are lipophilic. In a 2004 review of 70 reports, all adverse birth outcomes were reported following exposure to lipophilic statins (atorvastatin, lovastatin, or simvastatin) and none with the hydrophilic pravastatin. The authors stated that the findings were due to the fact that lipophilic agents equilibrate between maternal and embryonic compartments, whereas pravastatin is minimally present in the embryo.³ If this is indeed the case, and a statin must be used during pregnancy, fluvastatin, pravastatin, or rosuvastatin appears to be best.

RogerAshford/Thinkstock

Two other indications for statins in pregnancy have been studied. A 2016 study involved 21 patients with obstetric antiphospholipid syndrome that was refractory to low-dose aspirin plus low-molecular-weight heparin. In 11 patients, pravastatin was added to the therapy while in a control group of 10 patients, the standard therapy (aspirin plus heparin) was continued. All the patients had developed preeclampsia and/or intrauterine growth restriction during the standard therapy. The outcomes (live births and gestational age at birth) in the pravastatin group were superior to those in the control group.⁴

Pravastatin also has been used for the prevention and treatment of preeclampsia.^5,6 Although the teratogenic potential of these agents has not been fully determined, the risk for birth defects, if any, appears to be low even when exposure occurs during organogenesis.^7,8,9 Nevertheless, avoiding these products during the first trimester appears to be best.
 

 

Immunoglobulins

The only immunoglobulin in the antilipemic class is evolocumab (Repatha), which has no human pregnancy data. It is an immunoglobulin G2 that is indicated as an adjunct to diet and maximally tolerated statin therapy. It is also indicated as an adjunct to diet and other low-density lipoprotein–lowering therapies in patients with homozygous familial hypercholesterolemia who require additional lowering. No adverse embryo-fetal effects were observed in monkeys. Because statins are contraindicated in the first trimester, the drug, if combined with a statin, can also be classified as contraindicated. However, if the drug is used alone, the embryo-fetal risk appears to be low based on the animal data.

Monoclonal antibodies

The protein alirocumab (Praluent) is a human monoclonal antibody. It is indicated as an adjunct to diet and maximally tolerated statin therapy for the treatment of adults with heterozygous familial hypercholesterolemia or clinical atherosclerotic cardiovascular disease. There are no human pregnancy data. The animal data in rats and monkeys suggest low embryo-fetal risk. However, suppression of the humoral immune response to keyhole hemocyanin antigen was observed in infant monkeys at 4-6 months of age. The significance of this in human infants is apparently unknown. Because statins are contraindicated in the first trimester, the drug should not be used with these agents during that period.

Oligonucleotide inhibitors

No reports describing the use of mipomersen (Kynamro), an oligonucleotide inhibitor of apolipoprotein B-100 synthesis, in human pregnancy have been located. The drug is indicated as an adjunct to lipid-lowering medications and diet to reduce low-density lipoprotein cholesterol, apolipoprotein B, total cholesterol, and non–high-density lipoprotein cholesterol in patients with homozygous familial hypercholesterolemia. It has a very long (1-2 months) elimination half-life. The drug caused fetal toxicity in rats, but not in mice or rabbits.

Vitamins

Niacin is a water-soluble B complex vitamin that is converted in vivo to niacinamide. Niacin has no known embryo-fetal risk.

Miscellaneous agents

The two agents in the miscellaneous category are ezetimibe and lomitapide. Ezetimibe is indicated, either alone or in combination with a statin, as adjunctive therapy to diet for the reduction of cholesterol and triglycerides. Statins are contraindicated in the first trimester, but ezetimibe alone could be used during that period if treatment of the mother was mandated. The drug caused no problems in rabbits, but in rats, a dose 10 times the human exposure increased the incidence of skeletal abnormalities. In one report, a woman with homozygous familial hypercholesterolemia was treated with direct adsorption of lipoprotein apheresis, ezetimibe, and rosuvastatin. When pregnancy was discovered (gestational age not specified), the two drugs were stopped but biweekly apheresis was continued. At 37 weeks’ gestation, the patient gave birth to a healthy 2,400-g male infant.¹⁰

There are no human pregnancy data with lomitapide. It is indicated as an adjunct to a low-fat diet and other lipid-lowering treatments, including low-density lipoprotein apheresis where available, to reduce LDL cholesterol, total cholesterol, apolipoprotein B, and non–high-density lipoprotein cholesterol in patients with homozygous familial hypercholesterolemia. At doses less than 10 times the human dose, the drug caused congenital malformations and embryo-fetal death in rats, rabbits, and ferrets. The manufacturer classifies the drug as contraindicated in pregnancy because of the animal data.

Breastfeeding

Only niacin, pravastatin, and rosuvastatin have data regarding human milk concentrations. Niacin and its active form – niacinamide – are excreted into breast milk.

The average peak milk level in 11 lactating women given pravastatin 20 mg twice daily for 2.5 days was 3.9 mcg/L, whereas the level for the active metabolite was 2.1 mcg/L. Based on these data, a fully breastfed infant would receive daily about 1.4% of the mother’s weight-adjusted dose.¹¹

A 31-year-old woman was treated with rosuvastatin for familial hypercholesterolemia while breastfeeding her infant. The drug was stopped during breastfeeding but was restarted at 33 days post partum. Breast milk concentrations of the drug were 1.2 times serum levels (about 22 ng/mL vs. 18 ng/mL). Unfortunately, no information was provided on the status of the nursing infant.¹²

Three of the above agents have high molecular weights - alirocumab, evolocumab, and mipomersen - and are probably not excreted into mature breast milk. Moreover, colesevelam is not absorbed, and very small amounts of colestipol are absorbed by mothers. Several antilipemic agents have characteristics (for example, low molecular weight or long elimination half-life) that suggest they will be excreted into breast milk: ezetimibe, fenofibric acid (active metabolite of fenofibrate), gemfibrozil, lomitapide, and all the statins.

Taken in sum, all of the antilipemics, with the exception of niacin, have the potential to cause a deficiency of fat-soluble vitamins (A, D, E, K) in mother’s milk and in the nursing infant. Deficiency is a concern for all of these vitamins, but especially for vitamin K, because it could cause bruising, petechiae, hematomas, and bleeding in the nursing infant. In addition, antilipemics could cause low levels in milk of cholesterol and lipids, which are required by a nursing infant. Consequently, they should not be used by mothers who are breastfeeding an infant.
 

 

References

1. Br J Obstet Gynaecol. 1995 Feb;102(2):169-70.

2. J Matern Fetal Neonatal Med. 2015 May;28(8):954-8.

3. Am J Med Genet A. 2004 Dec 15;131(3):287-98.

4. J Clin Invest. 2016 Aug 1;126(8):2933-40.

5. Hypertension. 2015 Sep;66(3):687-97.

6. Am J Obstet Gynecol. 2016 Jun;214(6):720.e1-720.e17.

7. Birth Defects Res A Clin Mol Teratol. 2005 Nov;73(11):888-96.

8. Reprod Toxicol. 2008 Oct;26(2):175-7.

9. Ann Pharmacother. 2012 Oct;46(10):1419-24.

10. Open Cardiovasc Med J. 2015 Dec 29;9:114-7.

11. J Clin Pharmacol. 1988;28:942.

12. Am J Med. 2013 Sep;126(9):e7-e8.
 

Mr. Briggs is clinical professor of pharmacy at the University of California, San Francisco, and adjunct professor of pharmacy at the University of Southern California, Los Angeles, and Washington State University, Spokane. He is coauthor of “Drugs in Pregnancy and Lactation,” and coeditor of “Diseases, Complications, and Drug Therapy in Obstetrics.” He has no relevant financial disclosures.

 

Lipid-lowering medications are some of the most commonly prescribed drugs in the United States. But while much is known about their general safety, the data are limited when it comes to pregnancy and breastfeeding.

Antilipemic agents are a pharmacologic class that contains 18 drugs. The class is divided into eight subclasses: bile acid sequestrants; fibric acid derivatives, HMG-CoA inhibitors; immunoglobulins; monoclonal antibodies; oligonucleotide inhibitors; vitamins; as well as two miscellaneous drugs, ezetimibe (Zetia) and lomitapide (Juxtapid). Another antilipemic – dextrothyroxine – has been removed from the market by the manufacturer.

Bile acid sequestrants

Bile acid sequestrants include cholestyramine (Prevalite, Questran), colesevelam (Welchol), and colestipol (Colestid). These drugs have the potential to cause fetal toxicity. This assessment is based on their mechanism of action. These agents are not absorbed systemically, or absorption is very poor and they bind bile acids into a nonabsorbable complex. This action can reduce intestinal absorption of fat-soluble vitamins A, D, E, and K.

In one case, the mother was taking cholestyramine beginning at 19 weeks’ gestation for intrahepatic cholestasis. Ten weeks later, reduced fetal movements were noted, and fetal ultrasound scans revealed expanding bilateral subdural hematomas with hydrocephalus, an enlarged liver, and bilateral pleural effusions. The mother’s prothrombin ratio was markedly elevated but responded to intravenous vitamin K. Labor was induced to deliver a 1,660-g infant who died 15 minutes after birth.¹

Reports of fetal harm have not been located for the other two agents in this class, but there is only one case report involving five women for colesevelam and no reports for colestipol. Nevertheless, both of these drugs have the potential to cause fetal hemorrhage if they are taken for prolonged periods in pregnancy.

Fibric acid derivatives

The fibric acid derivatives subclass includes fenofibrate (Tricor, Lofibra) and gemfibrozil (Lopid).

©Jupiterimages/Thinkstock.com

Fenofibrate is indicated as adjunctive therapy to diet for the treatment of primary hypercholesterolemia or mixed dyslipidemia, and for hypertriglyceridemia. The drug was embryotoxic in rats and rabbits at doses less than 10 times the maximum human dose. There are three reports describing the use of the drug in human pregnancy. In one case a woman was treated in the third trimester and, in the second case, during the first 8 weeks’ gestation. Both pregnancies ended in healthy male infants. In a third case, a woman was treated with fenofibrate for acute pancreatitis due to hyperlipidemia and with carbimazole for Graves’ disease. She stopped the drug when her pregnancy was diagnosed (unspecified gestational age). At 18 weeks’ gestation, intrauterine death was confirmed.²

Six reports, involving 13 pregnancies, have described the use of gemfibrozil during all phases of pregnancy. No teratogenic effects were observed in these cases. In one woman, similar concentrations of gemfibrozil and its active metabolite were found in the umbilical vein and artery at levels within the normal reference for adults.

Statins

There are seven HMG-CoA inhibitors, known as statins: atorvastatin (Lipitor), fluvastatin (Lescol), lovastatin (Mevacor), pitavastatin (Livalo), pravastatin (Pravachol), rosuvastatin (Crestor), and simvastatin (Zocor).

The interruption of cholesterol-lowering therapy during pregnancy should have no effect on the long-term treatment of hyperlipidemia. Moreover, cholesterol and products synthesized by cholesterol are important during fetal development as shown by the rise in maternal cholesterol levels during pregnancy. Although the potential for embryo-fetal harm has not been clearly documented, and that potential may eventually be confirmed as low, the use of these agents in the first trimester are best classified as contraindicated.

One consideration in estimating the embryo-fetal risk of statins is their classification as either lipophilic or hydrophilic. Three of the seven statins are hydrophilic (fluvastatin, pravastatin, and rosuvastatin); the remaining four agents are lipophilic. In a 2004 review of 70 reports, all adverse birth outcomes were reported following exposure to lipophilic statins (atorvastatin, lovastatin, or simvastatin) and none with the hydrophilic pravastatin. The authors stated that the findings were due to the fact that lipophilic agents equilibrate between maternal and embryonic compartments, whereas pravastatin is minimally present in the embryo.³ If this is indeed the case, and a statin must be used during pregnancy, fluvastatin, pravastatin, or rosuvastatin appears to be best.

RogerAshford/Thinkstock

Two other indications for statins in pregnancy have been studied. A 2016 study involved 21 patients with obstetric antiphospholipid syndrome that was refractory to low-dose aspirin plus low-molecular-weight heparin. In 11 patients, pravastatin was added to the therapy while in a control group of 10 patients, the standard therapy (aspirin plus heparin) was continued. All the patients had developed preeclampsia and/or intrauterine growth restriction during the standard therapy. The outcomes (live births and gestational age at birth) in the pravastatin group were superior to those in the control group.⁴

Pravastatin also has been used for the prevention and treatment of preeclampsia.^5,6 Although the teratogenic potential of these agents has not been fully determined, the risk for birth defects, if any, appears to be low even when exposure occurs during organogenesis.^7,8,9 Nevertheless, avoiding these products during the first trimester appears to be best.
 

 

Immunoglobulins

The only immunoglobulin in the antilipemic class is evolocumab (Repatha), which has no human pregnancy data. It is an immunoglobulin G2 that is indicated as an adjunct to diet and maximally tolerated statin therapy. It is also indicated as an adjunct to diet and other low-density lipoprotein–lowering therapies in patients with homozygous familial hypercholesterolemia who require additional lowering. No adverse embryo-fetal effects were observed in monkeys. Because statins are contraindicated in the first trimester, the drug, if combined with a statin, can also be classified as contraindicated. However, if the drug is used alone, the embryo-fetal risk appears to be low based on the animal data.

Monoclonal antibodies

The protein alirocumab (Praluent) is a human monoclonal antibody. It is indicated as an adjunct to diet and maximally tolerated statin therapy for the treatment of adults with heterozygous familial hypercholesterolemia or clinical atherosclerotic cardiovascular disease. There are no human pregnancy data. The animal data in rats and monkeys suggest low embryo-fetal risk. However, suppression of the humoral immune response to keyhole hemocyanin antigen was observed in infant monkeys at 4-6 months of age. The significance of this in human infants is apparently unknown. Because statins are contraindicated in the first trimester, the drug should not be used with these agents during that period.

Oligonucleotide inhibitors

No reports describing the use of mipomersen (Kynamro), an oligonucleotide inhibitor of apolipoprotein B-100 synthesis, in human pregnancy have been located. The drug is indicated as an adjunct to lipid-lowering medications and diet to reduce low-density lipoprotein cholesterol, apolipoprotein B, total cholesterol, and non–high-density lipoprotein cholesterol in patients with homozygous familial hypercholesterolemia. It has a very long (1-2 months) elimination half-life. The drug caused fetal toxicity in rats, but not in mice or rabbits.

Vitamins

Niacin is a water-soluble B complex vitamin that is converted in vivo to niacinamide. Niacin has no known embryo-fetal risk.

Miscellaneous agents

The two agents in the miscellaneous category are ezetimibe and lomitapide. Ezetimibe is indicated, either alone or in combination with a statin, as adjunctive therapy to diet for the reduction of cholesterol and triglycerides. Statins are contraindicated in the first trimester, but ezetimibe alone could be used during that period if treatment of the mother was mandated. The drug caused no problems in rabbits, but in rats, a dose 10 times the human exposure increased the incidence of skeletal abnormalities. In one report, a woman with homozygous familial hypercholesterolemia was treated with direct adsorption of lipoprotein apheresis, ezetimibe, and rosuvastatin. When pregnancy was discovered (gestational age not specified), the two drugs were stopped but biweekly apheresis was continued. At 37 weeks’ gestation, the patient gave birth to a healthy 2,400-g male infant.¹⁰

There are no human pregnancy data with lomitapide. It is indicated as an adjunct to a low-fat diet and other lipid-lowering treatments, including low-density lipoprotein apheresis where available, to reduce LDL cholesterol, total cholesterol, apolipoprotein B, and non–high-density lipoprotein cholesterol in patients with homozygous familial hypercholesterolemia. At doses less than 10 times the human dose, the drug caused congenital malformations and embryo-fetal death in rats, rabbits, and ferrets. The manufacturer classifies the drug as contraindicated in pregnancy because of the animal data.

Breastfeeding

Only niacin, pravastatin, and rosuvastatin have data regarding human milk concentrations. Niacin and its active form – niacinamide – are excreted into breast milk.

The average peak milk level in 11 lactating women given pravastatin 20 mg twice daily for 2.5 days was 3.9 mcg/L, whereas the level for the active metabolite was 2.1 mcg/L. Based on these data, a fully breastfed infant would receive daily about 1.4% of the mother’s weight-adjusted dose.¹¹

A 31-year-old woman was treated with rosuvastatin for familial hypercholesterolemia while breastfeeding her infant. The drug was stopped during breastfeeding but was restarted at 33 days post partum. Breast milk concentrations of the drug were 1.2 times serum levels (about 22 ng/mL vs. 18 ng/mL). Unfortunately, no information was provided on the status of the nursing infant.¹²

Three of the above agents have high molecular weights - alirocumab, evolocumab, and mipomersen - and are probably not excreted into mature breast milk. Moreover, colesevelam is not absorbed, and very small amounts of colestipol are absorbed by mothers. Several antilipemic agents have characteristics (for example, low molecular weight or long elimination half-life) that suggest they will be excreted into breast milk: ezetimibe, fenofibric acid (active metabolite of fenofibrate), gemfibrozil, lomitapide, and all the statins.

Taken in sum, all of the antilipemics, with the exception of niacin, have the potential to cause a deficiency of fat-soluble vitamins (A, D, E, K) in mother’s milk and in the nursing infant. Deficiency is a concern for all of these vitamins, but especially for vitamin K, because it could cause bruising, petechiae, hematomas, and bleeding in the nursing infant. In addition, antilipemics could cause low levels in milk of cholesterol and lipids, which are required by a nursing infant. Consequently, they should not be used by mothers who are breastfeeding an infant.
 

 

References

1. Br J Obstet Gynaecol. 1995 Feb;102(2):169-70.

2. J Matern Fetal Neonatal Med. 2015 May;28(8):954-8.

3. Am J Med Genet A. 2004 Dec 15;131(3):287-98.

4. J Clin Invest. 2016 Aug 1;126(8):2933-40.

5. Hypertension. 2015 Sep;66(3):687-97.

6. Am J Obstet Gynecol. 2016 Jun;214(6):720.e1-720.e17.

7. Birth Defects Res A Clin Mol Teratol. 2005 Nov;73(11):888-96.

8. Reprod Toxicol. 2008 Oct;26(2):175-7.

9. Ann Pharmacother. 2012 Oct;46(10):1419-24.

10. Open Cardiovasc Med J. 2015 Dec 29;9:114-7.

11. J Clin Pharmacol. 1988;28:942.

12. Am J Med. 2013 Sep;126(9):e7-e8.
 

Mr. Briggs is clinical professor of pharmacy at the University of California, San Francisco, and adjunct professor of pharmacy at the University of Southern California, Los Angeles, and Washington State University, Spokane. He is coauthor of “Drugs in Pregnancy and Lactation,” and coeditor of “Diseases, Complications, and Drug Therapy in Obstetrics.” He has no relevant financial disclosures.

 

Lipid-lowering medications are some of the most commonly prescribed drugs in the United States. But while much is known about their general safety, the data are limited when it comes to pregnancy and breastfeeding.

Antilipemic agents are a pharmacologic class that contains 18 drugs. The class is divided into eight subclasses: bile acid sequestrants; fibric acid derivatives, HMG-CoA inhibitors; immunoglobulins; monoclonal antibodies; oligonucleotide inhibitors; vitamins; as well as two miscellaneous drugs, ezetimibe (Zetia) and lomitapide (Juxtapid). Another antilipemic – dextrothyroxine – has been removed from the market by the manufacturer.

Bile acid sequestrants

Bile acid sequestrants include cholestyramine (Prevalite, Questran), colesevelam (Welchol), and colestipol (Colestid). These drugs have the potential to cause fetal toxicity. This assessment is based on their mechanism of action. These agents are not absorbed systemically, or absorption is very poor and they bind bile acids into a nonabsorbable complex. This action can reduce intestinal absorption of fat-soluble vitamins A, D, E, and K.

In one case, the mother was taking cholestyramine beginning at 19 weeks’ gestation for intrahepatic cholestasis. Ten weeks later, reduced fetal movements were noted, and fetal ultrasound scans revealed expanding bilateral subdural hematomas with hydrocephalus, an enlarged liver, and bilateral pleural effusions. The mother’s prothrombin ratio was markedly elevated but responded to intravenous vitamin K. Labor was induced to deliver a 1,660-g infant who died 15 minutes after birth.¹

Reports of fetal harm have not been located for the other two agents in this class, but there is only one case report involving five women for colesevelam and no reports for colestipol. Nevertheless, both of these drugs have the potential to cause fetal hemorrhage if they are taken for prolonged periods in pregnancy.

Fibric acid derivatives

The fibric acid derivatives subclass includes fenofibrate (Tricor, Lofibra) and gemfibrozil (Lopid).

©Jupiterimages/Thinkstock.com

Fenofibrate is indicated as adjunctive therapy to diet for the treatment of primary hypercholesterolemia or mixed dyslipidemia, and for hypertriglyceridemia. The drug was embryotoxic in rats and rabbits at doses less than 10 times the maximum human dose. There are three reports describing the use of the drug in human pregnancy. In one case a woman was treated in the third trimester and, in the second case, during the first 8 weeks’ gestation. Both pregnancies ended in healthy male infants. In a third case, a woman was treated with fenofibrate for acute pancreatitis due to hyperlipidemia and with carbimazole for Graves’ disease. She stopped the drug when her pregnancy was diagnosed (unspecified gestational age). At 18 weeks’ gestation, intrauterine death was confirmed.²

Six reports, involving 13 pregnancies, have described the use of gemfibrozil during all phases of pregnancy. No teratogenic effects were observed in these cases. In one woman, similar concentrations of gemfibrozil and its active metabolite were found in the umbilical vein and artery at levels within the normal reference for adults.

Statins

There are seven HMG-CoA inhibitors, known as statins: atorvastatin (Lipitor), fluvastatin (Lescol), lovastatin (Mevacor), pitavastatin (Livalo), pravastatin (Pravachol), rosuvastatin (Crestor), and simvastatin (Zocor).

The interruption of cholesterol-lowering therapy during pregnancy should have no effect on the long-term treatment of hyperlipidemia. Moreover, cholesterol and products synthesized by cholesterol are important during fetal development as shown by the rise in maternal cholesterol levels during pregnancy. Although the potential for embryo-fetal harm has not been clearly documented, and that potential may eventually be confirmed as low, the use of these agents in the first trimester are best classified as contraindicated.

One consideration in estimating the embryo-fetal risk of statins is their classification as either lipophilic or hydrophilic. Three of the seven statins are hydrophilic (fluvastatin, pravastatin, and rosuvastatin); the remaining four agents are lipophilic. In a 2004 review of 70 reports, all adverse birth outcomes were reported following exposure to lipophilic statins (atorvastatin, lovastatin, or simvastatin) and none with the hydrophilic pravastatin. The authors stated that the findings were due to the fact that lipophilic agents equilibrate between maternal and embryonic compartments, whereas pravastatin is minimally present in the embryo.³ If this is indeed the case, and a statin must be used during pregnancy, fluvastatin, pravastatin, or rosuvastatin appears to be best.

RogerAshford/Thinkstock

Two other indications for statins in pregnancy have been studied. A 2016 study involved 21 patients with obstetric antiphospholipid syndrome that was refractory to low-dose aspirin plus low-molecular-weight heparin. In 11 patients, pravastatin was added to the therapy while in a control group of 10 patients, the standard therapy (aspirin plus heparin) was continued. All the patients had developed preeclampsia and/or intrauterine growth restriction during the standard therapy. The outcomes (live births and gestational age at birth) in the pravastatin group were superior to those in the control group.⁴

Pravastatin also has been used for the prevention and treatment of preeclampsia.^5,6 Although the teratogenic potential of these agents has not been fully determined, the risk for birth defects, if any, appears to be low even when exposure occurs during organogenesis.^7,8,9 Nevertheless, avoiding these products during the first trimester appears to be best.
 

 

Immunoglobulins

The only immunoglobulin in the antilipemic class is evolocumab (Repatha), which has no human pregnancy data. It is an immunoglobulin G2 that is indicated as an adjunct to diet and maximally tolerated statin therapy. It is also indicated as an adjunct to diet and other low-density lipoprotein–lowering therapies in patients with homozygous familial hypercholesterolemia who require additional lowering. No adverse embryo-fetal effects were observed in monkeys. Because statins are contraindicated in the first trimester, the drug, if combined with a statin, can also be classified as contraindicated. However, if the drug is used alone, the embryo-fetal risk appears to be low based on the animal data.

Monoclonal antibodies

The protein alirocumab (Praluent) is a human monoclonal antibody. It is indicated as an adjunct to diet and maximally tolerated statin therapy for the treatment of adults with heterozygous familial hypercholesterolemia or clinical atherosclerotic cardiovascular disease. There are no human pregnancy data. The animal data in rats and monkeys suggest low embryo-fetal risk. However, suppression of the humoral immune response to keyhole hemocyanin antigen was observed in infant monkeys at 4-6 months of age. The significance of this in human infants is apparently unknown. Because statins are contraindicated in the first trimester, the drug should not be used with these agents during that period.

Oligonucleotide inhibitors

No reports describing the use of mipomersen (Kynamro), an oligonucleotide inhibitor of apolipoprotein B-100 synthesis, in human pregnancy have been located. The drug is indicated as an adjunct to lipid-lowering medications and diet to reduce low-density lipoprotein cholesterol, apolipoprotein B, total cholesterol, and non–high-density lipoprotein cholesterol in patients with homozygous familial hypercholesterolemia. It has a very long (1-2 months) elimination half-life. The drug caused fetal toxicity in rats, but not in mice or rabbits.

Vitamins

Niacin is a water-soluble B complex vitamin that is converted in vivo to niacinamide. Niacin has no known embryo-fetal risk.

Miscellaneous agents

The two agents in the miscellaneous category are ezetimibe and lomitapide. Ezetimibe is indicated, either alone or in combination with a statin, as adjunctive therapy to diet for the reduction of cholesterol and triglycerides. Statins are contraindicated in the first trimester, but ezetimibe alone could be used during that period if treatment of the mother was mandated. The drug caused no problems in rabbits, but in rats, a dose 10 times the human exposure increased the incidence of skeletal abnormalities. In one report, a woman with homozygous familial hypercholesterolemia was treated with direct adsorption of lipoprotein apheresis, ezetimibe, and rosuvastatin. When pregnancy was discovered (gestational age not specified), the two drugs were stopped but biweekly apheresis was continued. At 37 weeks’ gestation, the patient gave birth to a healthy 2,400-g male infant.¹⁰

There are no human pregnancy data with lomitapide. It is indicated as an adjunct to a low-fat diet and other lipid-lowering treatments, including low-density lipoprotein apheresis where available, to reduce LDL cholesterol, total cholesterol, apolipoprotein B, and non–high-density lipoprotein cholesterol in patients with homozygous familial hypercholesterolemia. At doses less than 10 times the human dose, the drug caused congenital malformations and embryo-fetal death in rats, rabbits, and ferrets. The manufacturer classifies the drug as contraindicated in pregnancy because of the animal data.

Breastfeeding

Only niacin, pravastatin, and rosuvastatin have data regarding human milk concentrations. Niacin and its active form – niacinamide – are excreted into breast milk.

The average peak milk level in 11 lactating women given pravastatin 20 mg twice daily for 2.5 days was 3.9 mcg/L, whereas the level for the active metabolite was 2.1 mcg/L. Based on these data, a fully breastfed infant would receive daily about 1.4% of the mother’s weight-adjusted dose.¹¹

A 31-year-old woman was treated with rosuvastatin for familial hypercholesterolemia while breastfeeding her infant. The drug was stopped during breastfeeding but was restarted at 33 days post partum. Breast milk concentrations of the drug were 1.2 times serum levels (about 22 ng/mL vs. 18 ng/mL). Unfortunately, no information was provided on the status of the nursing infant.¹²

Three of the above agents have high molecular weights - alirocumab, evolocumab, and mipomersen - and are probably not excreted into mature breast milk. Moreover, colesevelam is not absorbed, and very small amounts of colestipol are absorbed by mothers. Several antilipemic agents have characteristics (for example, low molecular weight or long elimination half-life) that suggest they will be excreted into breast milk: ezetimibe, fenofibric acid (active metabolite of fenofibrate), gemfibrozil, lomitapide, and all the statins.

Taken in sum, all of the antilipemics, with the exception of niacin, have the potential to cause a deficiency of fat-soluble vitamins (A, D, E, K) in mother’s milk and in the nursing infant. Deficiency is a concern for all of these vitamins, but especially for vitamin K, because it could cause bruising, petechiae, hematomas, and bleeding in the nursing infant. In addition, antilipemics could cause low levels in milk of cholesterol and lipids, which are required by a nursing infant. Consequently, they should not be used by mothers who are breastfeeding an infant.
 

 

References

1. Br J Obstet Gynaecol. 1995 Feb;102(2):169-70.

2. J Matern Fetal Neonatal Med. 2015 May;28(8):954-8.

3. Am J Med Genet A. 2004 Dec 15;131(3):287-98.

4. J Clin Invest. 2016 Aug 1;126(8):2933-40.

5. Hypertension. 2015 Sep;66(3):687-97.

6. Am J Obstet Gynecol. 2016 Jun;214(6):720.e1-720.e17.

7. Birth Defects Res A Clin Mol Teratol. 2005 Nov;73(11):888-96.

8. Reprod Toxicol. 2008 Oct;26(2):175-7.

9. Ann Pharmacother. 2012 Oct;46(10):1419-24.

10. Open Cardiovasc Med J. 2015 Dec 29;9:114-7.

11. J Clin Pharmacol. 1988;28:942.

12. Am J Med. 2013 Sep;126(9):e7-e8.
 

Mr. Briggs is clinical professor of pharmacy at the University of California, San Francisco, and adjunct professor of pharmacy at the University of Southern California, Los Angeles, and Washington State University, Spokane. He is coauthor of “Drugs in Pregnancy and Lactation,” and coeditor of “Diseases, Complications, and Drug Therapy in Obstetrics.” He has no relevant financial disclosures.

Editor’s note: As Ob.Gyn. News celebrates its 50th anniversary, we wanted to know how far the medical community has come in identifying and mitigating drug risks during pregnancy and in the postpartum period. In this article, our four expert columnists share their experiences trying to find and interpret critical pregnancy data, as well as how they weigh the potential risks and benefits for their patients.

The search for information

The biggest advance in the past 50 years is the availability of information, even though limited, relating to the effects of drugs in pregnancy and lactation. In the first few years of this period, it was a daunting task to obtain this information. I can recall spending hours in the hospital’s medical library going through huge volumes of Index Medicus to obtain references that the library could order for me. The appearance of Thomas H. Shepard’s first edition (Catalog of Teratogenic Agents) in 1973 was a step forward and in 1977, O.P. Heinonen and colleagues’ book (Birth Defects and Drugs in Pregnancy) was helpful.

Purestock/Thinkstock

My first edition (Briggs et al., Drugs in Pregnancy and Lactation) came out in 1983 and was followed in 1993 by James L. Schardein’s book (Chemically Induced Birth Defects). In 2001, the first edition of the European book by Christof Schaefer et al. (Drugs During Pregnancy and Lactation) was released.

Although all of the above sources were helpful, any book in an evolving field will not have the newest information. Two important services, TERIS and Reprotox, were started to allow clinicians to contact them for up-to-date data. Nevertheless, the biggest change was the availability of current information from the U.S. National Library of Medicine via Toxnet, PubMed, and LactMed, relating to the effects of drugs in pregnancy and lactation.

The biggest unanswered question is why so many drugs have minimal, if any, human pregnancy and breastfeeding data? In my 11th edition (in press), about 1,443 drugs are reviewed. The majority have little or no human pregnancy data. The situation is even worse for breastfeeding data. In either situation, it places the clinician in a difficult position. How do we inform the patient regarding the potential embryo, fetal, or nursing infant risk? If the maternal benefit from the drug clearly outweighs the unknown risk, then the clinician can explain this to the patient. However, such situations appear to be infrequent and, in breastfeeding, the infant can be bottle fed. In contrast, in most pregnancy cases the comparison of the maternal benefit to the potential embryo/fetal risk is unknown. So what does the clinician do?

My method is to ask three questions. First, are there other drugs with a similar mechanism of action that have some human data? In most cases, the answer to this question is no, but even when there are data, it is typically very limited. Second, does the drug cross the human placenta? The answer is typically based on the molecular weight. Any drug with a molecular weight less than 1,000 daltons probably crosses. In the second half of pregnancy, especially in the third trimester, almost every drug crosses. Third, do the animal pregnancy data predict embryo/fetal risk? It was thought that it could if the dose causing harm was less than or equal to 10 times the human dose based on BSA or AUC and there were no signs of maternal toxicity. However, using data from my 10th edition, I and eight coauthors, all of whom are knowledgeable on the effects of drugs in pregnancy, found that the animal data for 311 drugs raised the possibility of human embryo-fetal harm that current data confirmed in only 75 (24%) of the drugs (Am J Obstet Gynecol. 2015 Dec;213[6]:810-5).

The system needs to be fixed. One method is to give the Food and Drug Administration the authority to require manufacturers of drugs likely to be used in pregnancy to gather and publish data on their use in pregnancy. That sounds reasonable, but will it ever occur?
 

Mr. Briggs is clinical professor of pharmacy at the University of California, San Francisco, and adjunct professor of pharmacy at the University of Southern California, Los Angeles, and Washington State University, Spokane. He is coauthor of “Drugs in Pregnancy and Lactation,” and coeditor of “Diseases, Complications, and Drug Therapy in Obstetrics.” He has no relevant financial disclosures.

Learning the lessons of the past

During the last 50 years, two of the most potent known human teratogens, thalidomide and isotretinoin, became available for prescription in the United States. Thanks to the efforts of Frances Kelsey, MD, PhD, at the FDA, the initial application for approval of thalidomide in the United States was denied in the early 1960s. Subsequently, based on evidence from other countries where thalidomide was marketed that the drug can cause a pattern of serious birth defects, a very strict pregnancy prevention program was implemented when the drug was finally approved in the United States in 2006.

 

This has produced excellent results in terms of limiting the number of exposed pregnancies. In contrast, when isotretinoin was first approved in the United States in 1982, no pregnancy prevention program was in place. By the late 1980s, it was clear that the drug was linked with a pattern of serious birth defects in numerous infants. Successively more stringent pregnancy prevention/restricted distribution programs were implemented over the years, culminating with the current iPledge program. Despite these unprecedented measures, exposed pregnancies continue to occur and remain a challenge in terms of prevention.

Over the last 50 years, we have also seen an important evolution in our ability to conduct pregnancy exposure safety studies. Though we still have limited ability to conduct clinical trials in pregnant women, the need for good quality observational studies has become more widely accepted. The Centers for Disease Control and Prevention’s National Birth Defects Prevention Study (now in its most recent iteration known as BD STEPS) has been one very important source of data on the safety of a wide variety of medications. Using a case-control study design, women who have delivered infants with specific birth defects and comparison women who have delivered non-malformed infants are interviewed about their exposures in pregnancy. These data have been extremely helpful in generating new hypotheses, confirming or refuting findings from other studies, and in testing hypotheses regarding the safety of medications widely used in women of reproductive age. These analyses, for example, have contributed to the large body of literature now available on the safety of antidepressant medications in pregnancy.

At the same time, in the last 30 years, we have seen a tremendous increase in the number of pregnancy registries required or recommended upon approval of a new drug in the United States. These registry studies, while challenging to complete in a timely manner, have steadily improved in terms of rigor, and several disease-based pregnancy exposure studies have been implemented, which have allowed us to better understand the comparative risks or safety of anticonvulsants and antiretroviral drugs, to name a few.

It is important to note that with all these advances in the last 50 years, we still have a huge gap in knowledge about medication safety in pregnancy and lactation. Recent reviews suggest that more than 80% of drugs currently marketed have insufficient or no data available. If we include over-the-counter medications, the knowledge gap grows larger. With the 2014 approval of the long-awaited Pregnancy and Lactation Labeling Rule, clinicians are now beginning to experience the elimination of the old A-B-C-D-X category system for pregnancy safety. In its place, data-driven product labels are required. These are expected to provide the clinician with a clear summary of the relevant studies for a given medication, and to place these in the context of the background risks for the underlying maternal disease being treated, as well as the population risks. However, it is painfully clear that we have a long way to go to generate the needed, high-quality data, to populate those labels.
 

Dr. Chambers is a professor of pediatrics and director of clinical research at Rady Children’s Hospital, San Diego, and associate director of the Clinical and Translational Research Institute at the University of California, San Diego. She is director of MotherToBaby California, a past president of the Organization of Teratology Information Specialists, and past president of the Teratology Society. She has no relevant financial disclosures.

Moving toward personalized medicine

Nowhere is a lack of actionable data more pronounced than in the impact of mental health drugs in pregnancy.

As Dr. Briggs and Dr. Chambers have outlined, the quality of data regarding the reproductive safety of medications across the therapeutic spectrum has historically been fair at best. The methodology and the rigor has been sparse and to a large extent, in psychiatry, we were only able to look for signals of concern. Prior to the late 1980s and early 1990s, there was little to guide clinicians on the safety of even very commonly used psychiatric medications during pregnancy. The health implications for women of reproductive age are extraordinary and yet that urgency was not matched by the level of investigation until more recently.

The last 25 years, however, has brought a commitment to the systematic study of reproductive safety. From cohort studies, to large analyses of administrative databases and global registries, we’re now able to look at what medications women took during pregnancy and study the specific outcomes. These studies don’t provide complete information, but the dedication to and the identification of reproductive safety as a major public health issue for women is a huge advance.

In psychiatry, we have rapidly improving data informing women about the risk for major congenital malformations. The clinical dilemma of weighing the necessity to stay on a medication to prevent relapse of a psychiatric disorder with the potential risk of malformation in the fetus is a wrenching one for the mother-to-be. Only good information can help patients, together with their physician, make collaborative decisions that make sense for them. Given the same information and the same severity of illness, women will make different decisions, and that’s a good thing. The calculus couples use to make these private decisions is unique to those involved. But they are able to move through the process because they have a platform of high-quality information.

So where do we go in the future? We need to get beyond the question of risk of major malformations and move toward understanding the long-term neurodevelopmental implications of prenatal exposures – whether such exposures confer risk or are even potentially salutary. One needs only look at the vast body of literature regarding fetal exposure to selective serotonin reuptake inhibitors (SSRIs) to observe the realization of this trend. When it comes to SSRIs, a fairly clear picture has emerged that they pose little absolute risk in terms of congenital malformations. What is missing is how SSRIs impact a child’s learning and development at age 3, 5, and 10. There have been a few studies in this area, but not a single, large prospective study that accurately quantifies both exposure to SSRIs and maternal psychiatric illness during pregnancy.

I expect that the future will also bring a greater understanding of the impact of untreated mental illness on the risk for obstetrical, neonatal, and longer-term neurodevelopmental outcomes. Most of the safety concerns have centered around the effect of fetal exposure to medications, but we also need to better understand how untreated psychiatric disorders impact the spectrum of relevant outcomes.

Getting back to the dilemma faced by pregnant women who really need medication to sustain emotional well-being, there simply is no perfect answer. No decision is perfect or risk free. What we can hope is that we’ll have personalized approaches that take into account the best available data and the patient’s individual situation and wishes. We’ve already come a long way toward meeting that goal, and I’m optimistic about where we’re going.
 

 

Dr. Cohen is the director of the Center for Women’s Mental Health at Massachusetts General Hospital in Boston, which provides information resources and conducts clinical care and research in reproductive mental health. He has been a consultant to manufacturers of psychiatric medications.

Perception of risk

Every year, numerous new medicines are approved by the FDA without data in pregnancy. Animal studies may show a problem that doesn’t appear in humans, or as was the case with thalidomide, the problem may not be apparent in animals and show up later in humans. There are many drugs that are safe in pregnancy, but women are understandably afraid of the potential impact on fetal development.

While my colleagues have presented the advances we’ve made in understanding the actual risks of medications during the prenatal period, it’s also important to focus on the perception of risk and to recognize that the reality and the perception can be vastly different.

I started to look at this area in 1989, just a few years after starting the Motherisk Program. We discovered that women exposed to nonteratogenic drugs were assigning a 25% likelihood of having a malformed child, when the actual risk for those drugs was between 1% and 3% and is unrelated to the drug being taken.

At the same time, we began to ask women, using a visual analog scale, what would be their trend toward continuing or terminating pregnancy? Over several studies, we found that the likelihood of termination was high, and certainly much higher than was supported by the evidence of actual harm to the fetus. Specifically, if a woman received information about the safety of the drug and she still gave more than a 50% probability of terminating the pregnancy when surveyed, there was a good chance that she would terminate the pregnancy.

When you consider that most of the drugs that women are commonly prescribed in pregnancy – from most painkillers to antidepressants – are not known to cause malformations in pregnancy, you begin to see how problematic an inflated perception of risk can become.

But we see different trends in women with serious and chronic health problems, such as lupus or epilepsy. These women are typically under the care of a subspecialist, who in many cases has developed a significant knowledge base and comfort level around prescribing the drugs in this area and is able to communicate more clearly to patients both the risks to the fetus and the consequences of failure to treat their condition.

So clearly, the role of the physician and the ob.gyn. in particular is critical. It’s no secret that physicians face a negative legal climate that encourages defensive medicine and that they are often hesitant to tell women, without reservation, that it is okay to take a drug. But we must all remember that it is very easy to cause a woman not to take a medication in pregnancy and often that’s not what’s best for her health. Many women now postpone the age of starting a family and more have chronic conditions that require treatment. The idea of not treating certain conditions for the length of a pregnancy is not always a viable option. Yet there are quite a few women who would consider termination “just to be on the safe side.” That must be taken very seriously by the medical profession.
 

Dr. Koren is a professor of physiology/pharmacology at Western University, London, Ont., and a professor of medicine at Tel Aviv University. He is the founder of the Motherisk Program. He reported being a paid consultant for Duchesnay and Novartis.

Editor’s note: As Ob.Gyn. News celebrates its 50th anniversary, we wanted to know how far the medical community has come in identifying and mitigating drug risks during pregnancy and in the postpartum period. In this article, our four expert columnists share their experiences trying to find and interpret critical pregnancy data, as well as how they weigh the potential risks and benefits for their patients.

The search for information

The biggest advance in the past 50 years is the availability of information, even though limited, relating to the effects of drugs in pregnancy and lactation. In the first few years of this period, it was a daunting task to obtain this information. I can recall spending hours in the hospital’s medical library going through huge volumes of Index Medicus to obtain references that the library could order for me. The appearance of Thomas H. Shepard’s first edition (Catalog of Teratogenic Agents) in 1973 was a step forward and in 1977, O.P. Heinonen and colleagues’ book (Birth Defects and Drugs in Pregnancy) was helpful.

Purestock/Thinkstock

My first edition (Briggs et al., Drugs in Pregnancy and Lactation) came out in 1983 and was followed in 1993 by James L. Schardein’s book (Chemically Induced Birth Defects). In 2001, the first edition of the European book by Christof Schaefer et al. (Drugs During Pregnancy and Lactation) was released.

Although all of the above sources were helpful, any book in an evolving field will not have the newest information. Two important services, TERIS and Reprotox, were started to allow clinicians to contact them for up-to-date data. Nevertheless, the biggest change was the availability of current information from the U.S. National Library of Medicine via Toxnet, PubMed, and LactMed, relating to the effects of drugs in pregnancy and lactation.

The biggest unanswered question is why so many drugs have minimal, if any, human pregnancy and breastfeeding data? In my 11th edition (in press), about 1,443 drugs are reviewed. The majority have little or no human pregnancy data. The situation is even worse for breastfeeding data. In either situation, it places the clinician in a difficult position. How do we inform the patient regarding the potential embryo, fetal, or nursing infant risk? If the maternal benefit from the drug clearly outweighs the unknown risk, then the clinician can explain this to the patient. However, such situations appear to be infrequent and, in breastfeeding, the infant can be bottle fed. In contrast, in most pregnancy cases the comparison of the maternal benefit to the potential embryo/fetal risk is unknown. So what does the clinician do?

My method is to ask three questions. First, are there other drugs with a similar mechanism of action that have some human data? In most cases, the answer to this question is no, but even when there are data, it is typically very limited. Second, does the drug cross the human placenta? The answer is typically based on the molecular weight. Any drug with a molecular weight less than 1,000 daltons probably crosses. In the second half of pregnancy, especially in the third trimester, almost every drug crosses. Third, do the animal pregnancy data predict embryo/fetal risk? It was thought that it could if the dose causing harm was less than or equal to 10 times the human dose based on BSA or AUC and there were no signs of maternal toxicity. However, using data from my 10th edition, I and eight coauthors, all of whom are knowledgeable on the effects of drugs in pregnancy, found that the animal data for 311 drugs raised the possibility of human embryo-fetal harm that current data confirmed in only 75 (24%) of the drugs (Am J Obstet Gynecol. 2015 Dec;213[6]:810-5).

The system needs to be fixed. One method is to give the Food and Drug Administration the authority to require manufacturers of drugs likely to be used in pregnancy to gather and publish data on their use in pregnancy. That sounds reasonable, but will it ever occur?
 

Mr. Briggs is clinical professor of pharmacy at the University of California, San Francisco, and adjunct professor of pharmacy at the University of Southern California, Los Angeles, and Washington State University, Spokane. He is coauthor of “Drugs in Pregnancy and Lactation,” and coeditor of “Diseases, Complications, and Drug Therapy in Obstetrics.” He has no relevant financial disclosures.

Learning the lessons of the past

During the last 50 years, two of the most potent known human teratogens, thalidomide and isotretinoin, became available for prescription in the United States. Thanks to the efforts of Frances Kelsey, MD, PhD, at the FDA, the initial application for approval of thalidomide in the United States was denied in the early 1960s. Subsequently, based on evidence from other countries where thalidomide was marketed that the drug can cause a pattern of serious birth defects, a very strict pregnancy prevention program was implemented when the drug was finally approved in the United States in 2006.

 

This has produced excellent results in terms of limiting the number of exposed pregnancies. In contrast, when isotretinoin was first approved in the United States in 1982, no pregnancy prevention program was in place. By the late 1980s, it was clear that the drug was linked with a pattern of serious birth defects in numerous infants. Successively more stringent pregnancy prevention/restricted distribution programs were implemented over the years, culminating with the current iPledge program. Despite these unprecedented measures, exposed pregnancies continue to occur and remain a challenge in terms of prevention.

Over the last 50 years, we have also seen an important evolution in our ability to conduct pregnancy exposure safety studies. Though we still have limited ability to conduct clinical trials in pregnant women, the need for good quality observational studies has become more widely accepted. The Centers for Disease Control and Prevention’s National Birth Defects Prevention Study (now in its most recent iteration known as BD STEPS) has been one very important source of data on the safety of a wide variety of medications. Using a case-control study design, women who have delivered infants with specific birth defects and comparison women who have delivered non-malformed infants are interviewed about their exposures in pregnancy. These data have been extremely helpful in generating new hypotheses, confirming or refuting findings from other studies, and in testing hypotheses regarding the safety of medications widely used in women of reproductive age. These analyses, for example, have contributed to the large body of literature now available on the safety of antidepressant medications in pregnancy.

At the same time, in the last 30 years, we have seen a tremendous increase in the number of pregnancy registries required or recommended upon approval of a new drug in the United States. These registry studies, while challenging to complete in a timely manner, have steadily improved in terms of rigor, and several disease-based pregnancy exposure studies have been implemented, which have allowed us to better understand the comparative risks or safety of anticonvulsants and antiretroviral drugs, to name a few.

It is important to note that with all these advances in the last 50 years, we still have a huge gap in knowledge about medication safety in pregnancy and lactation. Recent reviews suggest that more than 80% of drugs currently marketed have insufficient or no data available. If we include over-the-counter medications, the knowledge gap grows larger. With the 2014 approval of the long-awaited Pregnancy and Lactation Labeling Rule, clinicians are now beginning to experience the elimination of the old A-B-C-D-X category system for pregnancy safety. In its place, data-driven product labels are required. These are expected to provide the clinician with a clear summary of the relevant studies for a given medication, and to place these in the context of the background risks for the underlying maternal disease being treated, as well as the population risks. However, it is painfully clear that we have a long way to go to generate the needed, high-quality data, to populate those labels.
 

Dr. Chambers is a professor of pediatrics and director of clinical research at Rady Children’s Hospital, San Diego, and associate director of the Clinical and Translational Research Institute at the University of California, San Diego. She is director of MotherToBaby California, a past president of the Organization of Teratology Information Specialists, and past president of the Teratology Society. She has no relevant financial disclosures.

Moving toward personalized medicine

Nowhere is a lack of actionable data more pronounced than in the impact of mental health drugs in pregnancy.

As Dr. Briggs and Dr. Chambers have outlined, the quality of data regarding the reproductive safety of medications across the therapeutic spectrum has historically been fair at best. The methodology and the rigor has been sparse and to a large extent, in psychiatry, we were only able to look for signals of concern. Prior to the late 1980s and early 1990s, there was little to guide clinicians on the safety of even very commonly used psychiatric medications during pregnancy. The health implications for women of reproductive age are extraordinary and yet that urgency was not matched by the level of investigation until more recently.

The last 25 years, however, has brought a commitment to the systematic study of reproductive safety. From cohort studies, to large analyses of administrative databases and global registries, we’re now able to look at what medications women took during pregnancy and study the specific outcomes. These studies don’t provide complete information, but the dedication to and the identification of reproductive safety as a major public health issue for women is a huge advance.

In psychiatry, we have rapidly improving data informing women about the risk for major congenital malformations. The clinical dilemma of weighing the necessity to stay on a medication to prevent relapse of a psychiatric disorder with the potential risk of malformation in the fetus is a wrenching one for the mother-to-be. Only good information can help patients, together with their physician, make collaborative decisions that make sense for them. Given the same information and the same severity of illness, women will make different decisions, and that’s a good thing. The calculus couples use to make these private decisions is unique to those involved. But they are able to move through the process because they have a platform of high-quality information.

So where do we go in the future? We need to get beyond the question of risk of major malformations and move toward understanding the long-term neurodevelopmental implications of prenatal exposures – whether such exposures confer risk or are even potentially salutary. One needs only look at the vast body of literature regarding fetal exposure to selective serotonin reuptake inhibitors (SSRIs) to observe the realization of this trend. When it comes to SSRIs, a fairly clear picture has emerged that they pose little absolute risk in terms of congenital malformations. What is missing is how SSRIs impact a child’s learning and development at age 3, 5, and 10. There have been a few studies in this area, but not a single, large prospective study that accurately quantifies both exposure to SSRIs and maternal psychiatric illness during pregnancy.

I expect that the future will also bring a greater understanding of the impact of untreated mental illness on the risk for obstetrical, neonatal, and longer-term neurodevelopmental outcomes. Most of the safety concerns have centered around the effect of fetal exposure to medications, but we also need to better understand how untreated psychiatric disorders impact the spectrum of relevant outcomes.

Getting back to the dilemma faced by pregnant women who really need medication to sustain emotional well-being, there simply is no perfect answer. No decision is perfect or risk free. What we can hope is that we’ll have personalized approaches that take into account the best available data and the patient’s individual situation and wishes. We’ve already come a long way toward meeting that goal, and I’m optimistic about where we’re going.
 

 

Dr. Cohen is the director of the Center for Women’s Mental Health at Massachusetts General Hospital in Boston, which provides information resources and conducts clinical care and research in reproductive mental health. He has been a consultant to manufacturers of psychiatric medications.

Perception of risk

Every year, numerous new medicines are approved by the FDA without data in pregnancy. Animal studies may show a problem that doesn’t appear in humans, or as was the case with thalidomide, the problem may not be apparent in animals and show up later in humans. There are many drugs that are safe in pregnancy, but women are understandably afraid of the potential impact on fetal development.

While my colleagues have presented the advances we’ve made in understanding the actual risks of medications during the prenatal period, it’s also important to focus on the perception of risk and to recognize that the reality and the perception can be vastly different.

I started to look at this area in 1989, just a few years after starting the Motherisk Program. We discovered that women exposed to nonteratogenic drugs were assigning a 25% likelihood of having a malformed child, when the actual risk for those drugs was between 1% and 3% and is unrelated to the drug being taken.

At the same time, we began to ask women, using a visual analog scale, what would be their trend toward continuing or terminating pregnancy? Over several studies, we found that the likelihood of termination was high, and certainly much higher than was supported by the evidence of actual harm to the fetus. Specifically, if a woman received information about the safety of the drug and she still gave more than a 50% probability of terminating the pregnancy when surveyed, there was a good chance that she would terminate the pregnancy.

When you consider that most of the drugs that women are commonly prescribed in pregnancy – from most painkillers to antidepressants – are not known to cause malformations in pregnancy, you begin to see how problematic an inflated perception of risk can become.

But we see different trends in women with serious and chronic health problems, such as lupus or epilepsy. These women are typically under the care of a subspecialist, who in many cases has developed a significant knowledge base and comfort level around prescribing the drugs in this area and is able to communicate more clearly to patients both the risks to the fetus and the consequences of failure to treat their condition.

So clearly, the role of the physician and the ob.gyn. in particular is critical. It’s no secret that physicians face a negative legal climate that encourages defensive medicine and that they are often hesitant to tell women, without reservation, that it is okay to take a drug. But we must all remember that it is very easy to cause a woman not to take a medication in pregnancy and often that’s not what’s best for her health. Many women now postpone the age of starting a family and more have chronic conditions that require treatment. The idea of not treating certain conditions for the length of a pregnancy is not always a viable option. Yet there are quite a few women who would consider termination “just to be on the safe side.” That must be taken very seriously by the medical profession.
 

Dr. Koren is a professor of physiology/pharmacology at Western University, London, Ont., and a professor of medicine at Tel Aviv University. He is the founder of the Motherisk Program. He reported being a paid consultant for Duchesnay and Novartis.

Editor’s note: As Ob.Gyn. News celebrates its 50th anniversary, we wanted to know how far the medical community has come in identifying and mitigating drug risks during pregnancy and in the postpartum period. In this article, our four expert columnists share their experiences trying to find and interpret critical pregnancy data, as well as how they weigh the potential risks and benefits for their patients.

The search for information

The biggest advance in the past 50 years is the availability of information, even though limited, relating to the effects of drugs in pregnancy and lactation. In the first few years of this period, it was a daunting task to obtain this information. I can recall spending hours in the hospital’s medical library going through huge volumes of Index Medicus to obtain references that the library could order for me. The appearance of Thomas H. Shepard’s first edition (Catalog of Teratogenic Agents) in 1973 was a step forward and in 1977, O.P. Heinonen and colleagues’ book (Birth Defects and Drugs in Pregnancy) was helpful.

Purestock/Thinkstock

My first edition (Briggs et al., Drugs in Pregnancy and Lactation) came out in 1983 and was followed in 1993 by James L. Schardein’s book (Chemically Induced Birth Defects). In 2001, the first edition of the European book by Christof Schaefer et al. (Drugs During Pregnancy and Lactation) was released.

Although all of the above sources were helpful, any book in an evolving field will not have the newest information. Two important services, TERIS and Reprotox, were started to allow clinicians to contact them for up-to-date data. Nevertheless, the biggest change was the availability of current information from the U.S. National Library of Medicine via Toxnet, PubMed, and LactMed, relating to the effects of drugs in pregnancy and lactation.

The biggest unanswered question is why so many drugs have minimal, if any, human pregnancy and breastfeeding data? In my 11th edition (in press), about 1,443 drugs are reviewed. The majority have little or no human pregnancy data. The situation is even worse for breastfeeding data. In either situation, it places the clinician in a difficult position. How do we inform the patient regarding the potential embryo, fetal, or nursing infant risk? If the maternal benefit from the drug clearly outweighs the unknown risk, then the clinician can explain this to the patient. However, such situations appear to be infrequent and, in breastfeeding, the infant can be bottle fed. In contrast, in most pregnancy cases the comparison of the maternal benefit to the potential embryo/fetal risk is unknown. So what does the clinician do?

My method is to ask three questions. First, are there other drugs with a similar mechanism of action that have some human data? In most cases, the answer to this question is no, but even when there are data, it is typically very limited. Second, does the drug cross the human placenta? The answer is typically based on the molecular weight. Any drug with a molecular weight less than 1,000 daltons probably crosses. In the second half of pregnancy, especially in the third trimester, almost every drug crosses. Third, do the animal pregnancy data predict embryo/fetal risk? It was thought that it could if the dose causing harm was less than or equal to 10 times the human dose based on BSA or AUC and there were no signs of maternal toxicity. However, using data from my 10th edition, I and eight coauthors, all of whom are knowledgeable on the effects of drugs in pregnancy, found that the animal data for 311 drugs raised the possibility of human embryo-fetal harm that current data confirmed in only 75 (24%) of the drugs (Am J Obstet Gynecol. 2015 Dec;213[6]:810-5).

The system needs to be fixed. One method is to give the Food and Drug Administration the authority to require manufacturers of drugs likely to be used in pregnancy to gather and publish data on their use in pregnancy. That sounds reasonable, but will it ever occur?
 

Mr. Briggs is clinical professor of pharmacy at the University of California, San Francisco, and adjunct professor of pharmacy at the University of Southern California, Los Angeles, and Washington State University, Spokane. He is coauthor of “Drugs in Pregnancy and Lactation,” and coeditor of “Diseases, Complications, and Drug Therapy in Obstetrics.” He has no relevant financial disclosures.

Learning the lessons of the past

During the last 50 years, two of the most potent known human teratogens, thalidomide and isotretinoin, became available for prescription in the United States. Thanks to the efforts of Frances Kelsey, MD, PhD, at the FDA, the initial application for approval of thalidomide in the United States was denied in the early 1960s. Subsequently, based on evidence from other countries where thalidomide was marketed that the drug can cause a pattern of serious birth defects, a very strict pregnancy prevention program was implemented when the drug was finally approved in the United States in 2006.

 

This has produced excellent results in terms of limiting the number of exposed pregnancies. In contrast, when isotretinoin was first approved in the United States in 1982, no pregnancy prevention program was in place. By the late 1980s, it was clear that the drug was linked with a pattern of serious birth defects in numerous infants. Successively more stringent pregnancy prevention/restricted distribution programs were implemented over the years, culminating with the current iPledge program. Despite these unprecedented measures, exposed pregnancies continue to occur and remain a challenge in terms of prevention.

Over the last 50 years, we have also seen an important evolution in our ability to conduct pregnancy exposure safety studies. Though we still have limited ability to conduct clinical trials in pregnant women, the need for good quality observational studies has become more widely accepted. The Centers for Disease Control and Prevention’s National Birth Defects Prevention Study (now in its most recent iteration known as BD STEPS) has been one very important source of data on the safety of a wide variety of medications. Using a case-control study design, women who have delivered infants with specific birth defects and comparison women who have delivered non-malformed infants are interviewed about their exposures in pregnancy. These data have been extremely helpful in generating new hypotheses, confirming or refuting findings from other studies, and in testing hypotheses regarding the safety of medications widely used in women of reproductive age. These analyses, for example, have contributed to the large body of literature now available on the safety of antidepressant medications in pregnancy.

At the same time, in the last 30 years, we have seen a tremendous increase in the number of pregnancy registries required or recommended upon approval of a new drug in the United States. These registry studies, while challenging to complete in a timely manner, have steadily improved in terms of rigor, and several disease-based pregnancy exposure studies have been implemented, which have allowed us to better understand the comparative risks or safety of anticonvulsants and antiretroviral drugs, to name a few.

It is important to note that with all these advances in the last 50 years, we still have a huge gap in knowledge about medication safety in pregnancy and lactation. Recent reviews suggest that more than 80% of drugs currently marketed have insufficient or no data available. If we include over-the-counter medications, the knowledge gap grows larger. With the 2014 approval of the long-awaited Pregnancy and Lactation Labeling Rule, clinicians are now beginning to experience the elimination of the old A-B-C-D-X category system for pregnancy safety. In its place, data-driven product labels are required. These are expected to provide the clinician with a clear summary of the relevant studies for a given medication, and to place these in the context of the background risks for the underlying maternal disease being treated, as well as the population risks. However, it is painfully clear that we have a long way to go to generate the needed, high-quality data, to populate those labels.
 

Dr. Chambers is a professor of pediatrics and director of clinical research at Rady Children’s Hospital, San Diego, and associate director of the Clinical and Translational Research Institute at the University of California, San Diego. She is director of MotherToBaby California, a past president of the Organization of Teratology Information Specialists, and past president of the Teratology Society. She has no relevant financial disclosures.

Moving toward personalized medicine

Nowhere is a lack of actionable data more pronounced than in the impact of mental health drugs in pregnancy.

As Dr. Briggs and Dr. Chambers have outlined, the quality of data regarding the reproductive safety of medications across the therapeutic spectrum has historically been fair at best. The methodology and the rigor has been sparse and to a large extent, in psychiatry, we were only able to look for signals of concern. Prior to the late 1980s and early 1990s, there was little to guide clinicians on the safety of even very commonly used psychiatric medications during pregnancy. The health implications for women of reproductive age are extraordinary and yet that urgency was not matched by the level of investigation until more recently.

The last 25 years, however, has brought a commitment to the systematic study of reproductive safety. From cohort studies, to large analyses of administrative databases and global registries, we’re now able to look at what medications women took during pregnancy and study the specific outcomes. These studies don’t provide complete information, but the dedication to and the identification of reproductive safety as a major public health issue for women is a huge advance.

In psychiatry, we have rapidly improving data informing women about the risk for major congenital malformations. The clinical dilemma of weighing the necessity to stay on a medication to prevent relapse of a psychiatric disorder with the potential risk of malformation in the fetus is a wrenching one for the mother-to-be. Only good information can help patients, together with their physician, make collaborative decisions that make sense for them. Given the same information and the same severity of illness, women will make different decisions, and that’s a good thing. The calculus couples use to make these private decisions is unique to those involved. But they are able to move through the process because they have a platform of high-quality information.

So where do we go in the future? We need to get beyond the question of risk of major malformations and move toward understanding the long-term neurodevelopmental implications of prenatal exposures – whether such exposures confer risk or are even potentially salutary. One needs only look at the vast body of literature regarding fetal exposure to selective serotonin reuptake inhibitors (SSRIs) to observe the realization of this trend. When it comes to SSRIs, a fairly clear picture has emerged that they pose little absolute risk in terms of congenital malformations. What is missing is how SSRIs impact a child’s learning and development at age 3, 5, and 10. There have been a few studies in this area, but not a single, large prospective study that accurately quantifies both exposure to SSRIs and maternal psychiatric illness during pregnancy.

I expect that the future will also bring a greater understanding of the impact of untreated mental illness on the risk for obstetrical, neonatal, and longer-term neurodevelopmental outcomes. Most of the safety concerns have centered around the effect of fetal exposure to medications, but we also need to better understand how untreated psychiatric disorders impact the spectrum of relevant outcomes.

Getting back to the dilemma faced by pregnant women who really need medication to sustain emotional well-being, there simply is no perfect answer. No decision is perfect or risk free. What we can hope is that we’ll have personalized approaches that take into account the best available data and the patient’s individual situation and wishes. We’ve already come a long way toward meeting that goal, and I’m optimistic about where we’re going.
 

 

Dr. Cohen is the director of the Center for Women’s Mental Health at Massachusetts General Hospital in Boston, which provides information resources and conducts clinical care and research in reproductive mental health. He has been a consultant to manufacturers of psychiatric medications.

Perception of risk

Every year, numerous new medicines are approved by the FDA without data in pregnancy. Animal studies may show a problem that doesn’t appear in humans, or as was the case with thalidomide, the problem may not be apparent in animals and show up later in humans. There are many drugs that are safe in pregnancy, but women are understandably afraid of the potential impact on fetal development.

While my colleagues have presented the advances we’ve made in understanding the actual risks of medications during the prenatal period, it’s also important to focus on the perception of risk and to recognize that the reality and the perception can be vastly different.

I started to look at this area in 1989, just a few years after starting the Motherisk Program. We discovered that women exposed to nonteratogenic drugs were assigning a 25% likelihood of having a malformed child, when the actual risk for those drugs was between 1% and 3% and is unrelated to the drug being taken.

At the same time, we began to ask women, using a visual analog scale, what would be their trend toward continuing or terminating pregnancy? Over several studies, we found that the likelihood of termination was high, and certainly much higher than was supported by the evidence of actual harm to the fetus. Specifically, if a woman received information about the safety of the drug and she still gave more than a 50% probability of terminating the pregnancy when surveyed, there was a good chance that she would terminate the pregnancy.

When you consider that most of the drugs that women are commonly prescribed in pregnancy – from most painkillers to antidepressants – are not known to cause malformations in pregnancy, you begin to see how problematic an inflated perception of risk can become.

But we see different trends in women with serious and chronic health problems, such as lupus or epilepsy. These women are typically under the care of a subspecialist, who in many cases has developed a significant knowledge base and comfort level around prescribing the drugs in this area and is able to communicate more clearly to patients both the risks to the fetus and the consequences of failure to treat their condition.

So clearly, the role of the physician and the ob.gyn. in particular is critical. It’s no secret that physicians face a negative legal climate that encourages defensive medicine and that they are often hesitant to tell women, without reservation, that it is okay to take a drug. But we must all remember that it is very easy to cause a woman not to take a medication in pregnancy and often that’s not what’s best for her health. Many women now postpone the age of starting a family and more have chronic conditions that require treatment. The idea of not treating certain conditions for the length of a pregnancy is not always a viable option. Yet there are quite a few women who would consider termination “just to be on the safe side.” That must be taken very seriously by the medical profession.
 

Dr. Koren is a professor of physiology/pharmacology at Western University, London, Ont., and a professor of medicine at Tel Aviv University. He is the founder of the Motherisk Program. He reported being a paid consultant for Duchesnay and Novartis.