Gideon Koren

Stopping a medication during pregnancy because of potential risks to the fetus is not an option for women who have had an organ transplant, because they risk losing the transplanted organ. Despite considerable concerns about the reproductive safety of cyclosporine, by far the most commonly used antirejection drug for several decades, the data have been reassuring.

Several years ago, a meta-analysis of 15 studies looking at pregnancy outcomes in women after cyclosporine therapy suggested that the prevalence rate of major malformations was not substantially different from the rate usually reported in studies in the general population. The analysis did suggest a trend toward an increased risk (Transplantation 2001;71:1051–5).

The neurotoxic side effects of cyclosporine in adult and pediatric patients have raised concerns about the potential effects on brain development in children exposed to the drug in utero. At Motherisk, we recently completed a prospective study evaluating IQ, language, and development in about 40 children of transplant recipients who took cyclosporine during pregnancy and in controls, correcting for the maternal socioeconomic education level and IQ. Follow-up of the children to ages 3–8 years found similar achievement in those exposed to cyclosporine and the controls. (This study has been presented at meetings, but not yet published.)

Cyclosporine use has decreased, largely because of its nephrotoxic side effects and the availability of newer, highly effective immunosuppressants. However, there are far fewer reproductive safety data available on the newer drugs. For one, mycophenolate mofetil (Cellcept), the available data are worrisome.

To date, the data do not suggest that tacrolimus (Prograf) is associated with an increased rate of major malformations, but there are still no data on the drug's effect on the neurobehavioral development of children exposed in utero.

Because cyclosporine, tacrolimus, and sirolimus are associated with some serious adverse effects, particularly chronic kidney damage, new drugs are being used—particularly mycophenolate mofetil (MMF)—which have similar effects on preventing rejection, but with far fewer nephrotoxic effects.

But evidence is beginning to emerge that MMF is associated with an increased rate of major malformations. The drug's label states that treatment should not be started until the patient has a negative pregnancy test, and women of childbearing age should use two forms of contraception.

In recent years, reports of malformations in babies exposed to MMF during the first trimester include microtia, cleft lip and palate, hypoplastic fingers and toenails, diaphragmatic hernia, congenital heart defects, and micrognathia. These reports come from small case series and case reports and do not prove causation, but they have raised concerns about the drug's reproductive safety because of the clustering of similar defects, instead of the distribution of malformations seen in the general population.

In a National Transplantation Pregnancy Registry (NTPR) study of outcomes of pregnancies exposed to MMF or sirolimus, there were 26 pregnancies, including 11 that ended in spontaneous abortions, in 18 kidney recipients treated with MMF. Of 15 live births, 4 (26.7%) had a structural malformation, including hypoplastic nails and shortened fifth fingers, microtia with and without cleft lip and palate, and a death in a neonate with microtia and other malformations.

Among the seven transplant recipients who received sirolimus (Rapamune) during pregnancy, there were three spontaneous abortions. Of the four live births, three had no malformations and one baby whose mother had been treated with MMF during pregnancy but had changed to sirolimus late in pregnancy had microtia and a cleft lip and palate (Transplantation 2006;82:1698–702).

Motherisk recently published a precautionary note about this drug in women in which we advised that a woman who has had a transplant and is on MMF and planning a pregnancy should consider switching to cyclosporine for a short period (Canadian Family Physician 2008;54:1112–3).

In addition, many women transplant recipients are also on corticosteroids, which are known to increase the risk for oral clefts. Many are also on azathioprine (Imuran). A trial comparing pregnancy outcomes in 189 women in Europe, Asia, and North America who took azathioprine during pregnancy with 230 women who took nonteratogenic drugs in pregnancy found no evidence of an increased rate of malformations, but the drug was associated with lower birth weight, gestational age, and prematurity (Birth Defects Res. A Clin. Mol. Teratol. 2007;696:701).

Stopping a medication during pregnancy because of potential risks to the fetus is not an option for women who have had an organ transplant, because they risk losing the transplanted organ. Despite considerable concerns about the reproductive safety of cyclosporine, by far the most commonly used antirejection drug for several decades, the data have been reassuring.

Several years ago, a meta-analysis of 15 studies looking at pregnancy outcomes in women after cyclosporine therapy suggested that the prevalence rate of major malformations was not substantially different from the rate usually reported in studies in the general population. The analysis did suggest a trend toward an increased risk (Transplantation 2001;71:1051–5).

The neurotoxic side effects of cyclosporine in adult and pediatric patients have raised concerns about the potential effects on brain development in children exposed to the drug in utero. At Motherisk, we recently completed a prospective study evaluating IQ, language, and development in about 40 children of transplant recipients who took cyclosporine during pregnancy and in controls, correcting for the maternal socioeconomic education level and IQ. Follow-up of the children to ages 3–8 years found similar achievement in those exposed to cyclosporine and the controls. (This study has been presented at meetings, but not yet published.)

Cyclosporine use has decreased, largely because of its nephrotoxic side effects and the availability of newer, highly effective immunosuppressants. However, there are far fewer reproductive safety data available on the newer drugs. For one, mycophenolate mofetil (Cellcept), the available data are worrisome.

To date, the data do not suggest that tacrolimus (Prograf) is associated with an increased rate of major malformations, but there are still no data on the drug's effect on the neurobehavioral development of children exposed in utero.

Because cyclosporine, tacrolimus, and sirolimus are associated with some serious adverse effects, particularly chronic kidney damage, new drugs are being used—particularly mycophenolate mofetil (MMF)—which have similar effects on preventing rejection, but with far fewer nephrotoxic effects.

But evidence is beginning to emerge that MMF is associated with an increased rate of major malformations. The drug's label states that treatment should not be started until the patient has a negative pregnancy test, and women of childbearing age should use two forms of contraception.

In recent years, reports of malformations in babies exposed to MMF during the first trimester include microtia, cleft lip and palate, hypoplastic fingers and toenails, diaphragmatic hernia, congenital heart defects, and micrognathia. These reports come from small case series and case reports and do not prove causation, but they have raised concerns about the drug's reproductive safety because of the clustering of similar defects, instead of the distribution of malformations seen in the general population.

In a National Transplantation Pregnancy Registry (NTPR) study of outcomes of pregnancies exposed to MMF or sirolimus, there were 26 pregnancies, including 11 that ended in spontaneous abortions, in 18 kidney recipients treated with MMF. Of 15 live births, 4 (26.7%) had a structural malformation, including hypoplastic nails and shortened fifth fingers, microtia with and without cleft lip and palate, and a death in a neonate with microtia and other malformations.

Among the seven transplant recipients who received sirolimus (Rapamune) during pregnancy, there were three spontaneous abortions. Of the four live births, three had no malformations and one baby whose mother had been treated with MMF during pregnancy but had changed to sirolimus late in pregnancy had microtia and a cleft lip and palate (Transplantation 2006;82:1698–702).

Motherisk recently published a precautionary note about this drug in women in which we advised that a woman who has had a transplant and is on MMF and planning a pregnancy should consider switching to cyclosporine for a short period (Canadian Family Physician 2008;54:1112–3).

In addition, many women transplant recipients are also on corticosteroids, which are known to increase the risk for oral clefts. Many are also on azathioprine (Imuran). A trial comparing pregnancy outcomes in 189 women in Europe, Asia, and North America who took azathioprine during pregnancy with 230 women who took nonteratogenic drugs in pregnancy found no evidence of an increased rate of malformations, but the drug was associated with lower birth weight, gestational age, and prematurity (Birth Defects Res. A Clin. Mol. Teratol. 2007;696:701).

Stopping a medication during pregnancy because of potential risks to the fetus is not an option for women who have had an organ transplant, because they risk losing the transplanted organ. Despite considerable concerns about the reproductive safety of cyclosporine, by far the most commonly used antirejection drug for several decades, the data have been reassuring.

Several years ago, a meta-analysis of 15 studies looking at pregnancy outcomes in women after cyclosporine therapy suggested that the prevalence rate of major malformations was not substantially different from the rate usually reported in studies in the general population. The analysis did suggest a trend toward an increased risk (Transplantation 2001;71:1051–5).

The neurotoxic side effects of cyclosporine in adult and pediatric patients have raised concerns about the potential effects on brain development in children exposed to the drug in utero. At Motherisk, we recently completed a prospective study evaluating IQ, language, and development in about 40 children of transplant recipients who took cyclosporine during pregnancy and in controls, correcting for the maternal socioeconomic education level and IQ. Follow-up of the children to ages 3–8 years found similar achievement in those exposed to cyclosporine and the controls. (This study has been presented at meetings, but not yet published.)

Cyclosporine use has decreased, largely because of its nephrotoxic side effects and the availability of newer, highly effective immunosuppressants. However, there are far fewer reproductive safety data available on the newer drugs. For one, mycophenolate mofetil (Cellcept), the available data are worrisome.

To date, the data do not suggest that tacrolimus (Prograf) is associated with an increased rate of major malformations, but there are still no data on the drug's effect on the neurobehavioral development of children exposed in utero.

Because cyclosporine, tacrolimus, and sirolimus are associated with some serious adverse effects, particularly chronic kidney damage, new drugs are being used—particularly mycophenolate mofetil (MMF)—which have similar effects on preventing rejection, but with far fewer nephrotoxic effects.

But evidence is beginning to emerge that MMF is associated with an increased rate of major malformations. The drug's label states that treatment should not be started until the patient has a negative pregnancy test, and women of childbearing age should use two forms of contraception.

In recent years, reports of malformations in babies exposed to MMF during the first trimester include microtia, cleft lip and palate, hypoplastic fingers and toenails, diaphragmatic hernia, congenital heart defects, and micrognathia. These reports come from small case series and case reports and do not prove causation, but they have raised concerns about the drug's reproductive safety because of the clustering of similar defects, instead of the distribution of malformations seen in the general population.

In a National Transplantation Pregnancy Registry (NTPR) study of outcomes of pregnancies exposed to MMF or sirolimus, there were 26 pregnancies, including 11 that ended in spontaneous abortions, in 18 kidney recipients treated with MMF. Of 15 live births, 4 (26.7%) had a structural malformation, including hypoplastic nails and shortened fifth fingers, microtia with and without cleft lip and palate, and a death in a neonate with microtia and other malformations.

Among the seven transplant recipients who received sirolimus (Rapamune) during pregnancy, there were three spontaneous abortions. Of the four live births, three had no malformations and one baby whose mother had been treated with MMF during pregnancy but had changed to sirolimus late in pregnancy had microtia and a cleft lip and palate (Transplantation 2006;82:1698–702).

Motherisk recently published a precautionary note about this drug in women in which we advised that a woman who has had a transplant and is on MMF and planning a pregnancy should consider switching to cyclosporine for a short period (Canadian Family Physician 2008;54:1112–3).

In addition, many women transplant recipients are also on corticosteroids, which are known to increase the risk for oral clefts. Many are also on azathioprine (Imuran). A trial comparing pregnancy outcomes in 189 women in Europe, Asia, and North America who took azathioprine during pregnancy with 230 women who took nonteratogenic drugs in pregnancy found no evidence of an increased rate of malformations, but the drug was associated with lower birth weight, gestational age, and prematurity (Birth Defects Res. A Clin. Mol. Teratol. 2007;696:701).

Poor adaptation syndrome in newborns exposed in late pregnancy to a selective serotonin reuptake inhibitor (SSRI) or selective norepinephrine reuptake inhibitor (SNRI)—with symptoms such as jitteriness, being inconsolable, and difficulty in feeding—were first described several years ago.

The most unusual feature of this syndrome that has not been described in babies experiencing opioid or benzodiazepine withdrawal is respiratory distress, which often needs respiratory support. These symptoms were present in about 20% of newborns exposed to an SSRI or SNRI late in pregnancy in a series of cases we studied. The good news is that those symptoms resolved, usually within several days; most of the babies were treated with sedation, after which they did well.

We reviewed all published reports of neonatal discontinuation syndrome after exposure to anti-depressants in late pregnancy and estimated that between 10% and 30% of babies exposed in utero to an SSRI or SNRI in that stage experienced some signs of withdrawal (Can. Med. Assoc. J. 2005;172:1457–9). Adults who stop these drugs abruptly can experience typical withdrawal symptoms, such as nervousness, unrest, tremors, insomnia, and even seizures, so it makes biologic sense that a newborn may develop withdrawal symptoms after exposure in utero.

It is often assumed that these symptoms are manifestations of withdrawal, but in some cases, they could be the signs of toxicity of these drugs—serotonergic syndrome—which in neonates are indistinguishable from those described in withdrawal.

Given what we know about the pharmacokinetics of the SSRIs and SNRIs and measured drug levels in newborns exposed in late pregnancy, it is highly likely that most observed cases represent genuine withdrawal.

Differentiating between toxicity and withdrawal may therefore be important. Based on the same pharmacologic rationale behind the treatment of newborns in opiate withdrawal with small doses of narcotics, it would make sense to treat the baby with antidepressant withdrawal symptoms with small amounts of the antidepressant. But if there is a chance that some cases are a result of toxic drug levels, one has to be careful with this approach.

The only way to determine if a baby is experiencing withdrawal or toxicity is with therapeutic drug monitoring, which currently is not practiced in newborns anywhere.

A European report of a baby exposed to the SNRI venlafaxine (Effexor) in late pregnancy, whose symptoms resolved after receiving a small dose of the drug, strengthened the concept that this might be a beneficial approach to treating neonatal withdrawal symptoms.

The Food and Drug Administration and Canadian authorities responded to reports of neonatal withdrawal syndrome with suggestions that physicians may consider tapering these antidepressants during the third trimester, which is included in the U.S. labels of these drugs.

This is unfortunate, since the best predictor of postpartum depression is depression in late pregnancy. Up to 20% of women may be diagnosed with depression in pregnancy and may need treatment with an antidepressant. Many experts concur that stopping treatment late in pregnancy is not necessarily the ideal approach and that women with depression responsive to SSRIs or SNRIs should be properly treated, especially since the neonatal withdrawal syndrome is self-limited.

Exposure to an SSRI or SNRI late in pregnancy should be considered a possible cause in newborns with symptoms consistent with withdrawal. When symptoms of respiratory distress are present, hyaline membrane disease, aspiration, infections, cardiac malformations, and other possible causes of the symptoms need to be ruled out.

My colleagues and I believe that if a new mother is treated with an SSRI or SNRI for depression, discharging her and her newborn within the regular 24 hours is not ideal. Babies whose mothers were treated with antidepressants should be monitored closely for more than 24–48 hours after birth, and we are working to develop practice guidelines on discharge recommendations for women and for their babies who were exposed in utero to antidepressants.

There are no current official protocols on how to manage babies with these withdrawal symptoms, and neonates are most commonly managed with phenobarbital, which, after many years of use in this age group, has a strong safety record. In future studies, we hope to define the role of therapeutic drug monitoring in this situation, and whether treatment with low doses of the SSRI or SNRI would be safe and effective in severe cases.

Poor adaptation syndrome in newborns exposed in late pregnancy to a selective serotonin reuptake inhibitor (SSRI) or selective norepinephrine reuptake inhibitor (SNRI)—with symptoms such as jitteriness, being inconsolable, and difficulty in feeding—were first described several years ago.

The most unusual feature of this syndrome that has not been described in babies experiencing opioid or benzodiazepine withdrawal is respiratory distress, which often needs respiratory support. These symptoms were present in about 20% of newborns exposed to an SSRI or SNRI late in pregnancy in a series of cases we studied. The good news is that those symptoms resolved, usually within several days; most of the babies were treated with sedation, after which they did well.

We reviewed all published reports of neonatal discontinuation syndrome after exposure to anti-depressants in late pregnancy and estimated that between 10% and 30% of babies exposed in utero to an SSRI or SNRI in that stage experienced some signs of withdrawal (Can. Med. Assoc. J. 2005;172:1457–9). Adults who stop these drugs abruptly can experience typical withdrawal symptoms, such as nervousness, unrest, tremors, insomnia, and even seizures, so it makes biologic sense that a newborn may develop withdrawal symptoms after exposure in utero.

It is often assumed that these symptoms are manifestations of withdrawal, but in some cases, they could be the signs of toxicity of these drugs—serotonergic syndrome—which in neonates are indistinguishable from those described in withdrawal.

Given what we know about the pharmacokinetics of the SSRIs and SNRIs and measured drug levels in newborns exposed in late pregnancy, it is highly likely that most observed cases represent genuine withdrawal.

Differentiating between toxicity and withdrawal may therefore be important. Based on the same pharmacologic rationale behind the treatment of newborns in opiate withdrawal with small doses of narcotics, it would make sense to treat the baby with antidepressant withdrawal symptoms with small amounts of the antidepressant. But if there is a chance that some cases are a result of toxic drug levels, one has to be careful with this approach.

The only way to determine if a baby is experiencing withdrawal or toxicity is with therapeutic drug monitoring, which currently is not practiced in newborns anywhere.

A European report of a baby exposed to the SNRI venlafaxine (Effexor) in late pregnancy, whose symptoms resolved after receiving a small dose of the drug, strengthened the concept that this might be a beneficial approach to treating neonatal withdrawal symptoms.

The Food and Drug Administration and Canadian authorities responded to reports of neonatal withdrawal syndrome with suggestions that physicians may consider tapering these antidepressants during the third trimester, which is included in the U.S. labels of these drugs.

This is unfortunate, since the best predictor of postpartum depression is depression in late pregnancy. Up to 20% of women may be diagnosed with depression in pregnancy and may need treatment with an antidepressant. Many experts concur that stopping treatment late in pregnancy is not necessarily the ideal approach and that women with depression responsive to SSRIs or SNRIs should be properly treated, especially since the neonatal withdrawal syndrome is self-limited.

Exposure to an SSRI or SNRI late in pregnancy should be considered a possible cause in newborns with symptoms consistent with withdrawal. When symptoms of respiratory distress are present, hyaline membrane disease, aspiration, infections, cardiac malformations, and other possible causes of the symptoms need to be ruled out.

My colleagues and I believe that if a new mother is treated with an SSRI or SNRI for depression, discharging her and her newborn within the regular 24 hours is not ideal. Babies whose mothers were treated with antidepressants should be monitored closely for more than 24–48 hours after birth, and we are working to develop practice guidelines on discharge recommendations for women and for their babies who were exposed in utero to antidepressants.

There are no current official protocols on how to manage babies with these withdrawal symptoms, and neonates are most commonly managed with phenobarbital, which, after many years of use in this age group, has a strong safety record. In future studies, we hope to define the role of therapeutic drug monitoring in this situation, and whether treatment with low doses of the SSRI or SNRI would be safe and effective in severe cases.

Poor adaptation syndrome in newborns exposed in late pregnancy to a selective serotonin reuptake inhibitor (SSRI) or selective norepinephrine reuptake inhibitor (SNRI)—with symptoms such as jitteriness, being inconsolable, and difficulty in feeding—were first described several years ago.

The most unusual feature of this syndrome that has not been described in babies experiencing opioid or benzodiazepine withdrawal is respiratory distress, which often needs respiratory support. These symptoms were present in about 20% of newborns exposed to an SSRI or SNRI late in pregnancy in a series of cases we studied. The good news is that those symptoms resolved, usually within several days; most of the babies were treated with sedation, after which they did well.

We reviewed all published reports of neonatal discontinuation syndrome after exposure to anti-depressants in late pregnancy and estimated that between 10% and 30% of babies exposed in utero to an SSRI or SNRI in that stage experienced some signs of withdrawal (Can. Med. Assoc. J. 2005;172:1457–9). Adults who stop these drugs abruptly can experience typical withdrawal symptoms, such as nervousness, unrest, tremors, insomnia, and even seizures, so it makes biologic sense that a newborn may develop withdrawal symptoms after exposure in utero.

It is often assumed that these symptoms are manifestations of withdrawal, but in some cases, they could be the signs of toxicity of these drugs—serotonergic syndrome—which in neonates are indistinguishable from those described in withdrawal.

Given what we know about the pharmacokinetics of the SSRIs and SNRIs and measured drug levels in newborns exposed in late pregnancy, it is highly likely that most observed cases represent genuine withdrawal.

Differentiating between toxicity and withdrawal may therefore be important. Based on the same pharmacologic rationale behind the treatment of newborns in opiate withdrawal with small doses of narcotics, it would make sense to treat the baby with antidepressant withdrawal symptoms with small amounts of the antidepressant. But if there is a chance that some cases are a result of toxic drug levels, one has to be careful with this approach.

The only way to determine if a baby is experiencing withdrawal or toxicity is with therapeutic drug monitoring, which currently is not practiced in newborns anywhere.

A European report of a baby exposed to the SNRI venlafaxine (Effexor) in late pregnancy, whose symptoms resolved after receiving a small dose of the drug, strengthened the concept that this might be a beneficial approach to treating neonatal withdrawal symptoms.

The Food and Drug Administration and Canadian authorities responded to reports of neonatal withdrawal syndrome with suggestions that physicians may consider tapering these antidepressants during the third trimester, which is included in the U.S. labels of these drugs.

This is unfortunate, since the best predictor of postpartum depression is depression in late pregnancy. Up to 20% of women may be diagnosed with depression in pregnancy and may need treatment with an antidepressant. Many experts concur that stopping treatment late in pregnancy is not necessarily the ideal approach and that women with depression responsive to SSRIs or SNRIs should be properly treated, especially since the neonatal withdrawal syndrome is self-limited.

Exposure to an SSRI or SNRI late in pregnancy should be considered a possible cause in newborns with symptoms consistent with withdrawal. When symptoms of respiratory distress are present, hyaline membrane disease, aspiration, infections, cardiac malformations, and other possible causes of the symptoms need to be ruled out.

My colleagues and I believe that if a new mother is treated with an SSRI or SNRI for depression, discharging her and her newborn within the regular 24 hours is not ideal. Babies whose mothers were treated with antidepressants should be monitored closely for more than 24–48 hours after birth, and we are working to develop practice guidelines on discharge recommendations for women and for their babies who were exposed in utero to antidepressants.

There are no current official protocols on how to manage babies with these withdrawal symptoms, and neonates are most commonly managed with phenobarbital, which, after many years of use in this age group, has a strong safety record. In future studies, we hope to define the role of therapeutic drug monitoring in this situation, and whether treatment with low doses of the SSRI or SNRI would be safe and effective in severe cases.

Ever since the thalidomide disaster almost 50 years ago, people have been fearful of the possible teratogenic effects of medications, and many pregnant women believe almost any drug is teratogenic.

The way in which they and their families perceive the teratogenic risks of medications—even in medications with no such known risks—can result in unnecessary anxiety and sometimes even the unnecessary termination of a pregnancy.

But when women are provided with the available evidence and accurate information, those concerns can be put into the proper perspective, particularly these days, when more information about the reproductive safety of drugs is becoming available.

A striking example of the effects of an exaggerated perception of risk is provided by a 1987 report from Greece that estimated that in May 1986, the month after the Chernobyl nuclear accident in Ukraine, 23% of early pregnancies in Athens were terminated because of concerns about the radiation risk from the fallout of the accident (Br. Med. J. Clin. Res. Ed. 1987;295:1100).

When the Motherisk program, a teratogen information service, was started in 1985, the primary focus for me and my colleagues was to prevent malformations in cases in which women were exposed to genuine teratogens. But it soon became apparent to us that our work would also include preventing unnecessary terminations of pregnancies.

We received many calls from pregnant women who had been exposed to nonteratogenic drugs in early pregnancy and who were concerned nevertheless that there was a risk of having a baby with a malformation. They were considering terminating their pregnancies. Today, we continue to receive such calls, including some from women whose physicians have advised them to terminate pregnancy because of such an exposure.

Because of this experience, we have conducted studies for more than 20 years on how women perceive the teratogenic risk of medications and other exposures, such as dental x-rays, and we have shown how providing them with the available, accurate information has a significant impact on their misperceptions, swaying them away from choosing to terminate the pregnancy.

In our first study of 80 women who consulted Motherisk about drug, chemical, and radiation exposures, we used a visual analog scale measuring a woman's perception of risk during pregnancy, with a range of 0%–100%.

We were surprised to find that women exposed to nonteratogenic drugs such as acetaminophen, or to dental x-rays, which have no known fetal risk, considered themselves to be at about a 24% risk of having a major malformation, similar to the magnitude of risk associated with thalidomide. But after the women were provided with relevant information, this percentage dropped to about 14.5%, and there was a significant reduction in the tendency toward choosing to terminate the pregnancy (Am. J. Obstet. Gynecol. 1989;160:1190–4).

Since that time, we have conducted similar studies on the perceptions of risk associated with other exposures, including mild maternal drinking, x-rays, recreational cocaine use, and treatments for nausea and vomiting, with similar results. In a 1999 study, we found that evidence-based counseling of women with unfounded fears of the teratogenic risks of drug treatment for nausea and vomiting reduced the proportion of women in the study who mistakenly believed that antiemetic drug therapy increased the risk of major malformations (Reprod. Toxicol 1999;13:313–9).

Radiation exposure elicits huge anxieties, as does mild alcohol consumption and use of drugs that are teratogenic at high doses in animals, but have not been shown to be teratogenic in humans.

Because of the fear of fetal-alcohol syndrome, some women consider terminating pregnancy because of a few drinks they had before they knew they were pregnant—yet another example where misinformation and misperception unnecessarily lead to terminations of otherwise wanted pregnancies.

The lack of information in the product labeling of drugs contributes dramatically to these misperceptions of risk. The current pregnancy category letter labeling system in the United States remains unchanged, despite plans to revise the system.

Although more information about safety during pregnancy has been added to some drug labels, in most cases, labels suggest there are not enough data—even if relevant data exist. A physician who reads the fluoxetine label, for example, may not find adequate information to counsel a patient, despite evidence in the literature that the drug is safe in terms of morphology, as well as IQ and learning.

By providing evidence-based counseling, clinicians can address a patient's unrealistically high perception of risk and make a difference. Providers can obtain more information about the reproductive risks of drugs from the Organization of Teratology Information Specialists (866-626-6847 or www.otispregnancy.orgwww.motherisk.orgwww.womensmentalhealth.org

Ever since the thalidomide disaster almost 50 years ago, people have been fearful of the possible teratogenic effects of medications, and many pregnant women believe almost any drug is teratogenic.

The way in which they and their families perceive the teratogenic risks of medications—even in medications with no such known risks—can result in unnecessary anxiety and sometimes even the unnecessary termination of a pregnancy.

But when women are provided with the available evidence and accurate information, those concerns can be put into the proper perspective, particularly these days, when more information about the reproductive safety of drugs is becoming available.

A striking example of the effects of an exaggerated perception of risk is provided by a 1987 report from Greece that estimated that in May 1986, the month after the Chernobyl nuclear accident in Ukraine, 23% of early pregnancies in Athens were terminated because of concerns about the radiation risk from the fallout of the accident (Br. Med. J. Clin. Res. Ed. 1987;295:1100).

When the Motherisk program, a teratogen information service, was started in 1985, the primary focus for me and my colleagues was to prevent malformations in cases in which women were exposed to genuine teratogens. But it soon became apparent to us that our work would also include preventing unnecessary terminations of pregnancies.

We received many calls from pregnant women who had been exposed to nonteratogenic drugs in early pregnancy and who were concerned nevertheless that there was a risk of having a baby with a malformation. They were considering terminating their pregnancies. Today, we continue to receive such calls, including some from women whose physicians have advised them to terminate pregnancy because of such an exposure.

Because of this experience, we have conducted studies for more than 20 years on how women perceive the teratogenic risk of medications and other exposures, such as dental x-rays, and we have shown how providing them with the available, accurate information has a significant impact on their misperceptions, swaying them away from choosing to terminate the pregnancy.

In our first study of 80 women who consulted Motherisk about drug, chemical, and radiation exposures, we used a visual analog scale measuring a woman's perception of risk during pregnancy, with a range of 0%–100%.

We were surprised to find that women exposed to nonteratogenic drugs such as acetaminophen, or to dental x-rays, which have no known fetal risk, considered themselves to be at about a 24% risk of having a major malformation, similar to the magnitude of risk associated with thalidomide. But after the women were provided with relevant information, this percentage dropped to about 14.5%, and there was a significant reduction in the tendency toward choosing to terminate the pregnancy (Am. J. Obstet. Gynecol. 1989;160:1190–4).

Since that time, we have conducted similar studies on the perceptions of risk associated with other exposures, including mild maternal drinking, x-rays, recreational cocaine use, and treatments for nausea and vomiting, with similar results. In a 1999 study, we found that evidence-based counseling of women with unfounded fears of the teratogenic risks of drug treatment for nausea and vomiting reduced the proportion of women in the study who mistakenly believed that antiemetic drug therapy increased the risk of major malformations (Reprod. Toxicol 1999;13:313–9).

Radiation exposure elicits huge anxieties, as does mild alcohol consumption and use of drugs that are teratogenic at high doses in animals, but have not been shown to be teratogenic in humans.

Because of the fear of fetal-alcohol syndrome, some women consider terminating pregnancy because of a few drinks they had before they knew they were pregnant—yet another example where misinformation and misperception unnecessarily lead to terminations of otherwise wanted pregnancies.

The lack of information in the product labeling of drugs contributes dramatically to these misperceptions of risk. The current pregnancy category letter labeling system in the United States remains unchanged, despite plans to revise the system.

Although more information about safety during pregnancy has been added to some drug labels, in most cases, labels suggest there are not enough data—even if relevant data exist. A physician who reads the fluoxetine label, for example, may not find adequate information to counsel a patient, despite evidence in the literature that the drug is safe in terms of morphology, as well as IQ and learning.

By providing evidence-based counseling, clinicians can address a patient's unrealistically high perception of risk and make a difference. Providers can obtain more information about the reproductive risks of drugs from the Organization of Teratology Information Specialists (866-626-6847 or www.otispregnancy.orgwww.motherisk.orgwww.womensmentalhealth.org

Ever since the thalidomide disaster almost 50 years ago, people have been fearful of the possible teratogenic effects of medications, and many pregnant women believe almost any drug is teratogenic.

The way in which they and their families perceive the teratogenic risks of medications—even in medications with no such known risks—can result in unnecessary anxiety and sometimes even the unnecessary termination of a pregnancy.

But when women are provided with the available evidence and accurate information, those concerns can be put into the proper perspective, particularly these days, when more information about the reproductive safety of drugs is becoming available.

A striking example of the effects of an exaggerated perception of risk is provided by a 1987 report from Greece that estimated that in May 1986, the month after the Chernobyl nuclear accident in Ukraine, 23% of early pregnancies in Athens were terminated because of concerns about the radiation risk from the fallout of the accident (Br. Med. J. Clin. Res. Ed. 1987;295:1100).

When the Motherisk program, a teratogen information service, was started in 1985, the primary focus for me and my colleagues was to prevent malformations in cases in which women were exposed to genuine teratogens. But it soon became apparent to us that our work would also include preventing unnecessary terminations of pregnancies.

We received many calls from pregnant women who had been exposed to nonteratogenic drugs in early pregnancy and who were concerned nevertheless that there was a risk of having a baby with a malformation. They were considering terminating their pregnancies. Today, we continue to receive such calls, including some from women whose physicians have advised them to terminate pregnancy because of such an exposure.

Because of this experience, we have conducted studies for more than 20 years on how women perceive the teratogenic risk of medications and other exposures, such as dental x-rays, and we have shown how providing them with the available, accurate information has a significant impact on their misperceptions, swaying them away from choosing to terminate the pregnancy.

In our first study of 80 women who consulted Motherisk about drug, chemical, and radiation exposures, we used a visual analog scale measuring a woman's perception of risk during pregnancy, with a range of 0%–100%.

We were surprised to find that women exposed to nonteratogenic drugs such as acetaminophen, or to dental x-rays, which have no known fetal risk, considered themselves to be at about a 24% risk of having a major malformation, similar to the magnitude of risk associated with thalidomide. But after the women were provided with relevant information, this percentage dropped to about 14.5%, and there was a significant reduction in the tendency toward choosing to terminate the pregnancy (Am. J. Obstet. Gynecol. 1989;160:1190–4).

Since that time, we have conducted similar studies on the perceptions of risk associated with other exposures, including mild maternal drinking, x-rays, recreational cocaine use, and treatments for nausea and vomiting, with similar results. In a 1999 study, we found that evidence-based counseling of women with unfounded fears of the teratogenic risks of drug treatment for nausea and vomiting reduced the proportion of women in the study who mistakenly believed that antiemetic drug therapy increased the risk of major malformations (Reprod. Toxicol 1999;13:313–9).

Radiation exposure elicits huge anxieties, as does mild alcohol consumption and use of drugs that are teratogenic at high doses in animals, but have not been shown to be teratogenic in humans.

Because of the fear of fetal-alcohol syndrome, some women consider terminating pregnancy because of a few drinks they had before they knew they were pregnant—yet another example where misinformation and misperception unnecessarily lead to terminations of otherwise wanted pregnancies.

The lack of information in the product labeling of drugs contributes dramatically to these misperceptions of risk. The current pregnancy category letter labeling system in the United States remains unchanged, despite plans to revise the system.

Although more information about safety during pregnancy has been added to some drug labels, in most cases, labels suggest there are not enough data—even if relevant data exist. A physician who reads the fluoxetine label, for example, may not find adequate information to counsel a patient, despite evidence in the literature that the drug is safe in terms of morphology, as well as IQ and learning.

By providing evidence-based counseling, clinicians can address a patient's unrealistically high perception of risk and make a difference. Providers can obtain more information about the reproductive risks of drugs from the Organization of Teratology Information Specialists (866-626-6847 or www.otispregnancy.orgwww.motherisk.orgwww.womensmentalhealth.org

www.motherisk.org

This month, the Society of Obstetricians and Gynecologists of Canada is releasing new guidelines on folic acid supplementation in pregnant women, recommending prenatal vitamins that include 5 mg of folate in certain patients. Unless providers can ensure excellent daily compliance with the typical prenatal vitamin containing 0.8–1.1 mg of folate, the society is recommending this higher folate dose during pregnancy.

The basis of the new recommendation is evidence indicating that compliance with prenatal vitamins is not ideal, and as a result, prevention of neural tube defects with folate supplementation is suboptimal, as shown by several studies.

The current recommendation in the United States and Canada is that women of reproductive age consume at least 400 mcg of folic acid/day through a prenatal multivitamin, foods fortified with folic acid, or both to reduce their risk of having a baby with a neural tube defect (NTD) such as spina bifida, anencephaly, and other malformations. The amount of folic acid currently recommended for women who have already had a child with an NTD is 4 mg/day.

The recommendation for folic acid supplementation prenatally and during pregnancy was formed in the early 1990s. Subsequent fortification of enriched cereal grain products in 1998 in North America has had a marked impact on the rate of babies born with NTDs over the last decade.

Over the last several years, however, there have been questions raised about whether the folic acid dose included in prenatal vitamins is adequate to prevent NTDs.

For example, in a report published in 2001, using data from studies correlating the folic acid supplementation and the associated serum folate concentrations, and a large cohort study of the NTD risk based on serum folate, the authors determined that 5 mg of folic acid per day would prevent almost 90% of women from having a baby with an NTD. Nicholas Wald and his colleagues concluded that the currently recommended dose would protect only part of the population from NTDs, and recommended that women planning to become pregnant should take a 5-mg dose of folic acid per day (Lancet 2001;358:2069–73).

Corroborating this calculation were findings from a study of a large group of reproductive-aged Ontario women aged 15–45 years in 2005 and 2006, whose folic acid intake was unknown. We measured erythrocyte folate levels and determined that 40% of these women did not achieve the 900-nmol level needed to protect against NTDs, despite the fortification of flour and the recommendation that all women of reproductive age consume 400 mcg of folic acid daily. These findings, published in an abstract last year, strengthened our belief that the 5-mg recommendation is probably correct.

One of the two main arguments against an increase in folic acid is that an excess of folic acid in the diet can mask pernicious anemia, caused by vitamin B₁₂ deficiency in older people. However, since flour was fortified, there has been no evidence of an increasing problem with pernicious anemia.

The second major concern is the potential effect of folate in increasing the risk of some cancers, which includes evidence that folic acid supplementation may increase the growth or number of colorectal polyps. However, the bulk of currently available data indicate that an adequate folic acid level decreases the risk of about 10 cancers, including colon cancer. Clearly, if a risk of cancer exists, it would be associated with long-term exposure to folic acid and would be a potential concern for people who consume a large amount of folic acid in flour-based products, not pregnant women who take an increased amount for a limited period of time.

In a recently completed clinical study of pregnant women at the Motherisk Program, we found that despite the women being under supervision, the compliance rate with prenatal multivitamins was surprisingly low—an average of 53%–58%, ranging from 0% to 100%. The likelihood that a substantial proportion of women prescribed a prenatal vitamin containing 1 mg of folic acid per tablet will miss a few days every week strengthens the recommendation that the inclusion of a higher dose of folic acid in prenatal vitamins would be beneficial for women who may not be entirely compliant with their daily vitamin intake, and that many more women, with less than ideal compliance, would have protective folate levels if the supplement contained 5 mg/day.

In October, the Centers for Disease Control and Prevention reported on a California Department of Public Health survey of women in the state who were aged 18–44 years, which found that the overall prevalence of women taking folic acid-containing supplements was stable from 2002 (40%) to 2006 (41%). But the rate decreased among Hispanic women, who are at a greater risk of having a baby with an NTD, from about 33% in 2002 to about 30% in 2006, a significant difference (MMWR 2007; 56:1106–9).

One prenatal vitamin tablet typically contains 1 mg of folic acid. A Canadian manufacturer recently introduced a prenatal vitamin containing 5 mg of folic acid, which was approved by the Canadian authorities in response to our conviction that such a product is necessary, and other companies may follow.

Now is the time, we believe, to move forward with this new guideline, and we hope that the American College of Obstetricians and Gynecologists will follow.

www.motherisk.org

This month, the Society of Obstetricians and Gynecologists of Canada is releasing new guidelines on folic acid supplementation in pregnant women, recommending prenatal vitamins that include 5 mg of folate in certain patients. Unless providers can ensure excellent daily compliance with the typical prenatal vitamin containing 0.8–1.1 mg of folate, the society is recommending this higher folate dose during pregnancy.

The basis of the new recommendation is evidence indicating that compliance with prenatal vitamins is not ideal, and as a result, prevention of neural tube defects with folate supplementation is suboptimal, as shown by several studies.

The current recommendation in the United States and Canada is that women of reproductive age consume at least 400 mcg of folic acid/day through a prenatal multivitamin, foods fortified with folic acid, or both to reduce their risk of having a baby with a neural tube defect (NTD) such as spina bifida, anencephaly, and other malformations. The amount of folic acid currently recommended for women who have already had a child with an NTD is 4 mg/day.

The recommendation for folic acid supplementation prenatally and during pregnancy was formed in the early 1990s. Subsequent fortification of enriched cereal grain products in 1998 in North America has had a marked impact on the rate of babies born with NTDs over the last decade.

Over the last several years, however, there have been questions raised about whether the folic acid dose included in prenatal vitamins is adequate to prevent NTDs.

For example, in a report published in 2001, using data from studies correlating the folic acid supplementation and the associated serum folate concentrations, and a large cohort study of the NTD risk based on serum folate, the authors determined that 5 mg of folic acid per day would prevent almost 90% of women from having a baby with an NTD. Nicholas Wald and his colleagues concluded that the currently recommended dose would protect only part of the population from NTDs, and recommended that women planning to become pregnant should take a 5-mg dose of folic acid per day (Lancet 2001;358:2069–73).

Corroborating this calculation were findings from a study of a large group of reproductive-aged Ontario women aged 15–45 years in 2005 and 2006, whose folic acid intake was unknown. We measured erythrocyte folate levels and determined that 40% of these women did not achieve the 900-nmol level needed to protect against NTDs, despite the fortification of flour and the recommendation that all women of reproductive age consume 400 mcg of folic acid daily. These findings, published in an abstract last year, strengthened our belief that the 5-mg recommendation is probably correct.

One of the two main arguments against an increase in folic acid is that an excess of folic acid in the diet can mask pernicious anemia, caused by vitamin B₁₂ deficiency in older people. However, since flour was fortified, there has been no evidence of an increasing problem with pernicious anemia.

The second major concern is the potential effect of folate in increasing the risk of some cancers, which includes evidence that folic acid supplementation may increase the growth or number of colorectal polyps. However, the bulk of currently available data indicate that an adequate folic acid level decreases the risk of about 10 cancers, including colon cancer. Clearly, if a risk of cancer exists, it would be associated with long-term exposure to folic acid and would be a potential concern for people who consume a large amount of folic acid in flour-based products, not pregnant women who take an increased amount for a limited period of time.

In a recently completed clinical study of pregnant women at the Motherisk Program, we found that despite the women being under supervision, the compliance rate with prenatal multivitamins was surprisingly low—an average of 53%–58%, ranging from 0% to 100%. The likelihood that a substantial proportion of women prescribed a prenatal vitamin containing 1 mg of folic acid per tablet will miss a few days every week strengthens the recommendation that the inclusion of a higher dose of folic acid in prenatal vitamins would be beneficial for women who may not be entirely compliant with their daily vitamin intake, and that many more women, with less than ideal compliance, would have protective folate levels if the supplement contained 5 mg/day.

In October, the Centers for Disease Control and Prevention reported on a California Department of Public Health survey of women in the state who were aged 18–44 years, which found that the overall prevalence of women taking folic acid-containing supplements was stable from 2002 (40%) to 2006 (41%). But the rate decreased among Hispanic women, who are at a greater risk of having a baby with an NTD, from about 33% in 2002 to about 30% in 2006, a significant difference (MMWR 2007; 56:1106–9).

One prenatal vitamin tablet typically contains 1 mg of folic acid. A Canadian manufacturer recently introduced a prenatal vitamin containing 5 mg of folic acid, which was approved by the Canadian authorities in response to our conviction that such a product is necessary, and other companies may follow.

Now is the time, we believe, to move forward with this new guideline, and we hope that the American College of Obstetricians and Gynecologists will follow.

www.motherisk.org

This month, the Society of Obstetricians and Gynecologists of Canada is releasing new guidelines on folic acid supplementation in pregnant women, recommending prenatal vitamins that include 5 mg of folate in certain patients. Unless providers can ensure excellent daily compliance with the typical prenatal vitamin containing 0.8–1.1 mg of folate, the society is recommending this higher folate dose during pregnancy.

The basis of the new recommendation is evidence indicating that compliance with prenatal vitamins is not ideal, and as a result, prevention of neural tube defects with folate supplementation is suboptimal, as shown by several studies.

The current recommendation in the United States and Canada is that women of reproductive age consume at least 400 mcg of folic acid/day through a prenatal multivitamin, foods fortified with folic acid, or both to reduce their risk of having a baby with a neural tube defect (NTD) such as spina bifida, anencephaly, and other malformations. The amount of folic acid currently recommended for women who have already had a child with an NTD is 4 mg/day.

The recommendation for folic acid supplementation prenatally and during pregnancy was formed in the early 1990s. Subsequent fortification of enriched cereal grain products in 1998 in North America has had a marked impact on the rate of babies born with NTDs over the last decade.

Over the last several years, however, there have been questions raised about whether the folic acid dose included in prenatal vitamins is adequate to prevent NTDs.

For example, in a report published in 2001, using data from studies correlating the folic acid supplementation and the associated serum folate concentrations, and a large cohort study of the NTD risk based on serum folate, the authors determined that 5 mg of folic acid per day would prevent almost 90% of women from having a baby with an NTD. Nicholas Wald and his colleagues concluded that the currently recommended dose would protect only part of the population from NTDs, and recommended that women planning to become pregnant should take a 5-mg dose of folic acid per day (Lancet 2001;358:2069–73).

Corroborating this calculation were findings from a study of a large group of reproductive-aged Ontario women aged 15–45 years in 2005 and 2006, whose folic acid intake was unknown. We measured erythrocyte folate levels and determined that 40% of these women did not achieve the 900-nmol level needed to protect against NTDs, despite the fortification of flour and the recommendation that all women of reproductive age consume 400 mcg of folic acid daily. These findings, published in an abstract last year, strengthened our belief that the 5-mg recommendation is probably correct.

One of the two main arguments against an increase in folic acid is that an excess of folic acid in the diet can mask pernicious anemia, caused by vitamin B₁₂ deficiency in older people. However, since flour was fortified, there has been no evidence of an increasing problem with pernicious anemia.

The second major concern is the potential effect of folate in increasing the risk of some cancers, which includes evidence that folic acid supplementation may increase the growth or number of colorectal polyps. However, the bulk of currently available data indicate that an adequate folic acid level decreases the risk of about 10 cancers, including colon cancer. Clearly, if a risk of cancer exists, it would be associated with long-term exposure to folic acid and would be a potential concern for people who consume a large amount of folic acid in flour-based products, not pregnant women who take an increased amount for a limited period of time.

In a recently completed clinical study of pregnant women at the Motherisk Program, we found that despite the women being under supervision, the compliance rate with prenatal multivitamins was surprisingly low—an average of 53%–58%, ranging from 0% to 100%. The likelihood that a substantial proportion of women prescribed a prenatal vitamin containing 1 mg of folic acid per tablet will miss a few days every week strengthens the recommendation that the inclusion of a higher dose of folic acid in prenatal vitamins would be beneficial for women who may not be entirely compliant with their daily vitamin intake, and that many more women, with less than ideal compliance, would have protective folate levels if the supplement contained 5 mg/day.

In October, the Centers for Disease Control and Prevention reported on a California Department of Public Health survey of women in the state who were aged 18–44 years, which found that the overall prevalence of women taking folic acid-containing supplements was stable from 2002 (40%) to 2006 (41%). But the rate decreased among Hispanic women, who are at a greater risk of having a baby with an NTD, from about 33% in 2002 to about 30% in 2006, a significant difference (MMWR 2007; 56:1106–9).

One prenatal vitamin tablet typically contains 1 mg of folic acid. A Canadian manufacturer recently introduced a prenatal vitamin containing 5 mg of folic acid, which was approved by the Canadian authorities in response to our conviction that such a product is necessary, and other companies may follow.

Now is the time, we believe, to move forward with this new guideline, and we hope that the American College of Obstetricians and Gynecologists will follow.

www.motherisk.org

The etiology of autism is not yet clear and the debate continues about whether the increase in prevalence noted in the past few decades is actual or is because of better diagnosis. However, the evidence for a genetic link is accumulating, as is evidence that mercury in vaccines is not behind the increased prevalence.

Because the disease appears in the second or third year of life, the potential association with early childhood vaccines has been the subject of many studies over the past 15–20 years. Children receive many vaccines during the first few years of their lives; until 2002, thimerosal, a preservative that contains ethylmercury, was used as a preservative in routine early childhood vaccines. To a lesser degree, prenatal exposure to Rh immune globulin—which, until 2001 in the United States, contained thimerosal—has also elicited concern. Because organic mercury is a proven developmental neurotoxin, exposure to it in utero or in early childhood has raised concerns.

In utero exposure to mercury in environmental accidents, especially organic mercury, has been associated with brain damage and pediatric diagnoses such as cerebral palsy—but not autism. Some of the most compelling evidence indicating that vaccines containing thimerosal are not a cause of autism was provided in studies that looked at population-based databases of children in Denmark, Sweden, and California.

Although the prevalence of autism increased in all three places from 1985 through the 1990s, the average exposure to vaccines containing mercury increased only in the United States. In Sweden and Denmark, where the use of mercury-containing vaccines began to decrease in the late 1980s and was eliminated by the early 1990s, there was still an increase in the diagnosis of autism.

An important study published last month provides compelling evidence that prenatal exposure to thimerosal in Rh immune globulin is not a likely cause of the increase in autism, either. These results should help allay lingering concerns about exposure to ethylmercury via thimerosal in vaccines and Rh immune globulin.

The new study analyzed records of families that have children with an autism spectrum disorder (ASD), who had been seen at the Thompson Center for Autism and Neurodevelopmental Disorders at the University of Missouri-Columbia, between 2004 and 2006. Of 214 mothers with 230 children diagnosed with ASD between 1995 and 2005, 33 (15.4%) were Rh negative, which was similar to the rates among mothers in control groups. Of these 33 women, 29 (88%) had received Rh immune globulin that contained thimerosal while pregnant.

Based on comparisons with families of children with Down syndrome and other de novo chromosome disorders who came to the university for care, and two other populations—patients blood typed at the hospital in 2005 and 2006, and a population who had donated blood during 2005—the investigators determined that Rh-negative status was not higher among the mothers of children with autism. In addition, the mothers of children with autism were not more likely to have been exposed to antepartum Rh immune globulin containing thimerosal, and were not more likely to have an Rh-negative incompatible pregnancy. These findings were also true for autism subtypes.

The authors concluded that the results “support the consensus that exposure to ethylmercury in thimerosal is not the cause of the increased prevalence of autism” (Am. J. Med. Genet. Part A 2007;143A:1397–407).

Therefore, based on the information currently available, it is fair to say there is no compelling evidence indicating that exposure of the developing brain to mercury, either in the fetus or the developing child, is a cause of autism. And as the authors point out, these findings also have implications for other countries, where multidose vials that contain thimerosal continue to be used.

As for other potential prenatal causes of autism, there have been more case reports of autism in children exposed in utero to valproic acid, isotretinoin, or alcohol than one would expect. But I emphasize that these are case reports and merely associations at this point, not proven causes.

Efforts are underway to further investigate the possible association between prenatal exposure to valproic acid and autism. At the Motherisk Program, a teratogen information service at the Hospital for Sick Children in Toronto, we are following the long-term development of children exposed in utero to valproic acid, which we hope will pick up an association with autism, if such a link exists.

www.motherisk.org

The etiology of autism is not yet clear and the debate continues about whether the increase in prevalence noted in the past few decades is actual or is because of better diagnosis. However, the evidence for a genetic link is accumulating, as is evidence that mercury in vaccines is not behind the increased prevalence.

Because the disease appears in the second or third year of life, the potential association with early childhood vaccines has been the subject of many studies over the past 15–20 years. Children receive many vaccines during the first few years of their lives; until 2002, thimerosal, a preservative that contains ethylmercury, was used as a preservative in routine early childhood vaccines. To a lesser degree, prenatal exposure to Rh immune globulin—which, until 2001 in the United States, contained thimerosal—has also elicited concern. Because organic mercury is a proven developmental neurotoxin, exposure to it in utero or in early childhood has raised concerns.

In utero exposure to mercury in environmental accidents, especially organic mercury, has been associated with brain damage and pediatric diagnoses such as cerebral palsy—but not autism. Some of the most compelling evidence indicating that vaccines containing thimerosal are not a cause of autism was provided in studies that looked at population-based databases of children in Denmark, Sweden, and California.

Although the prevalence of autism increased in all three places from 1985 through the 1990s, the average exposure to vaccines containing mercury increased only in the United States. In Sweden and Denmark, where the use of mercury-containing vaccines began to decrease in the late 1980s and was eliminated by the early 1990s, there was still an increase in the diagnosis of autism.

An important study published last month provides compelling evidence that prenatal exposure to thimerosal in Rh immune globulin is not a likely cause of the increase in autism, either. These results should help allay lingering concerns about exposure to ethylmercury via thimerosal in vaccines and Rh immune globulin.

The new study analyzed records of families that have children with an autism spectrum disorder (ASD), who had been seen at the Thompson Center for Autism and Neurodevelopmental Disorders at the University of Missouri-Columbia, between 2004 and 2006. Of 214 mothers with 230 children diagnosed with ASD between 1995 and 2005, 33 (15.4%) were Rh negative, which was similar to the rates among mothers in control groups. Of these 33 women, 29 (88%) had received Rh immune globulin that contained thimerosal while pregnant.

Based on comparisons with families of children with Down syndrome and other de novo chromosome disorders who came to the university for care, and two other populations—patients blood typed at the hospital in 2005 and 2006, and a population who had donated blood during 2005—the investigators determined that Rh-negative status was not higher among the mothers of children with autism. In addition, the mothers of children with autism were not more likely to have been exposed to antepartum Rh immune globulin containing thimerosal, and were not more likely to have an Rh-negative incompatible pregnancy. These findings were also true for autism subtypes.

The authors concluded that the results “support the consensus that exposure to ethylmercury in thimerosal is not the cause of the increased prevalence of autism” (Am. J. Med. Genet. Part A 2007;143A:1397–407).

Therefore, based on the information currently available, it is fair to say there is no compelling evidence indicating that exposure of the developing brain to mercury, either in the fetus or the developing child, is a cause of autism. And as the authors point out, these findings also have implications for other countries, where multidose vials that contain thimerosal continue to be used.

As for other potential prenatal causes of autism, there have been more case reports of autism in children exposed in utero to valproic acid, isotretinoin, or alcohol than one would expect. But I emphasize that these are case reports and merely associations at this point, not proven causes.

Efforts are underway to further investigate the possible association between prenatal exposure to valproic acid and autism. At the Motherisk Program, a teratogen information service at the Hospital for Sick Children in Toronto, we are following the long-term development of children exposed in utero to valproic acid, which we hope will pick up an association with autism, if such a link exists.

www.motherisk.org

The etiology of autism is not yet clear and the debate continues about whether the increase in prevalence noted in the past few decades is actual or is because of better diagnosis. However, the evidence for a genetic link is accumulating, as is evidence that mercury in vaccines is not behind the increased prevalence.

Because the disease appears in the second or third year of life, the potential association with early childhood vaccines has been the subject of many studies over the past 15–20 years. Children receive many vaccines during the first few years of their lives; until 2002, thimerosal, a preservative that contains ethylmercury, was used as a preservative in routine early childhood vaccines. To a lesser degree, prenatal exposure to Rh immune globulin—which, until 2001 in the United States, contained thimerosal—has also elicited concern. Because organic mercury is a proven developmental neurotoxin, exposure to it in utero or in early childhood has raised concerns.

In utero exposure to mercury in environmental accidents, especially organic mercury, has been associated with brain damage and pediatric diagnoses such as cerebral palsy—but not autism. Some of the most compelling evidence indicating that vaccines containing thimerosal are not a cause of autism was provided in studies that looked at population-based databases of children in Denmark, Sweden, and California.

Although the prevalence of autism increased in all three places from 1985 through the 1990s, the average exposure to vaccines containing mercury increased only in the United States. In Sweden and Denmark, where the use of mercury-containing vaccines began to decrease in the late 1980s and was eliminated by the early 1990s, there was still an increase in the diagnosis of autism.

An important study published last month provides compelling evidence that prenatal exposure to thimerosal in Rh immune globulin is not a likely cause of the increase in autism, either. These results should help allay lingering concerns about exposure to ethylmercury via thimerosal in vaccines and Rh immune globulin.

The new study analyzed records of families that have children with an autism spectrum disorder (ASD), who had been seen at the Thompson Center for Autism and Neurodevelopmental Disorders at the University of Missouri-Columbia, between 2004 and 2006. Of 214 mothers with 230 children diagnosed with ASD between 1995 and 2005, 33 (15.4%) were Rh negative, which was similar to the rates among mothers in control groups. Of these 33 women, 29 (88%) had received Rh immune globulin that contained thimerosal while pregnant.

Based on comparisons with families of children with Down syndrome and other de novo chromosome disorders who came to the university for care, and two other populations—patients blood typed at the hospital in 2005 and 2006, and a population who had donated blood during 2005—the investigators determined that Rh-negative status was not higher among the mothers of children with autism. In addition, the mothers of children with autism were not more likely to have been exposed to antepartum Rh immune globulin containing thimerosal, and were not more likely to have an Rh-negative incompatible pregnancy. These findings were also true for autism subtypes.

The authors concluded that the results “support the consensus that exposure to ethylmercury in thimerosal is not the cause of the increased prevalence of autism” (Am. J. Med. Genet. Part A 2007;143A:1397–407).

Therefore, based on the information currently available, it is fair to say there is no compelling evidence indicating that exposure of the developing brain to mercury, either in the fetus or the developing child, is a cause of autism. And as the authors point out, these findings also have implications for other countries, where multidose vials that contain thimerosal continue to be used.

As for other potential prenatal causes of autism, there have been more case reports of autism in children exposed in utero to valproic acid, isotretinoin, or alcohol than one would expect. But I emphasize that these are case reports and merely associations at this point, not proven causes.

Efforts are underway to further investigate the possible association between prenatal exposure to valproic acid and autism. At the Motherisk Program, a teratogen information service at the Hospital for Sick Children in Toronto, we are following the long-term development of children exposed in utero to valproic acid, which we hope will pick up an association with autism, if such a link exists.

www.motherisk.org

The etiology of autism is not yet clear and the debate continues about whether the increase in prevalence noted in the past few decades is actual or is because of better diagnosis. However, the evidence for a genetic link is accumulating, as is evidence that mercury in vaccines is not behind the increased prevalence.

Because the disease appears in the second or third year of life, the potential association with early childhood vaccines has been the subject of many studies over the past 15-20 years. Children receive many vaccines during the first few years of their lives; until 2002, thimerosal, a preservative that contains ethylmercury, was used as a preservative in routine early childhood vaccines. To a lesser degree, prenatal exposure to Rh immune globulin–which, until 2001 in the United States, contained thimerosal–has also elicited concern. Because organic mercury is a proven developmental neurotoxin, exposure to it in utero or in early childhood has raised concerns.

In utero exposure to mercury in environmental accidents, especially organic mercury, has been associated with brain damage and pediatric diagnoses such as cerebral palsy–but not autism. Some of the most compelling evidence indicating that vaccines containing thimerosal are not a cause of autism was provided in studies that looked at population-based databases of children in Denmark, Sweden, and California.

Although the prevalence of autism increased in all three places from 1985 through the 1990s, the average exposure to vaccines containing mercury increased only in the United States. In Sweden and Denmark, where the use of mercury-containing vaccines began to decrease in the late 1980s and was eliminated by the early 1990s, there was still an increase in the diagnosis of autism.

An important study published this month provides compelling evidence that prenatal exposure to thimerosal in Rh immune globulin (RhIg) is not a likely cause of the increase in autism, either. These results should help allay lingering concerns about exposure to ethylmercury via thimerosal in vaccines and Rh immune globulin.

The new study analyzed records of families that have children with an autism spectrum disorder (ASD), who had been seen at the Thompson Center for Autism and Neurodevelopmental Disorders at the University of Missouri-Columbia, between 2004 and 2006. Of 214 mothers with 230 children diagnosed with ASD between 1995 and 2005, 33 (15.4%) were Rh negative, which was similar to the rates among mothers in control groups. Of these 33 women, 29 (88%) had received Rh immune globulin that contained thimerosal while pregnant. Based on comparisons with families of children with Down syndrome and other de novo chromosome disorders who came to the university for care, and two other populations–patients blood typed at the hospital in 2005 and 2006, and a population who had donated blood during 2005–the investigators determined that Rh-negative status was not higher among the mothers of children with autism. In addition, the mothers of children with autism were not more likely to have been exposed to antepartum Rh immune globulin containing thimerosal, and were not more likely to have an Rh-negative incompatible pregnancy. These findings were also true for autism subtypes. The authors concluded that the results “support the consensus that exposure to ethylmercury in thimerosal is not the cause of the increased prevalence of autism” (Am. J. Med. Genet. Part A 2007;143A:1397-407).

Therefore, based on the information currently available, it is fair to say there is no compelling evidence indicating that exposure of the developing brain to mercury, either in the fetus or the developing child, is a cause of autism. And as the authors point out, these findings also have implications for other countries, where multidose vials that contain thimerosal continue to be used.

As for other potential prenatal causes of autism, there have been more case reports of autism in children exposed in utero to valproic acid, isotretinoin, or alcohol than one would expect. But I emphasize that these are case reports and merely associations at this point, not proven causes.

Efforts are underway to further investigate the possible association between prenatal exposure to valproic acid and autism. At the Motherisk Program, a teratogen information service at the Hospital for Sick Children in Toronto, we are following the long-term development of children exposed in utero to valproic acid, which we hope will pick up an association with autism, if such a link exists.

www.motherisk.org

The etiology of autism is not yet clear and the debate continues about whether the increase in prevalence noted in the past few decades is actual or is because of better diagnosis. However, the evidence for a genetic link is accumulating, as is evidence that mercury in vaccines is not behind the increased prevalence.

Because the disease appears in the second or third year of life, the potential association with early childhood vaccines has been the subject of many studies over the past 15-20 years. Children receive many vaccines during the first few years of their lives; until 2002, thimerosal, a preservative that contains ethylmercury, was used as a preservative in routine early childhood vaccines. To a lesser degree, prenatal exposure to Rh immune globulin–which, until 2001 in the United States, contained thimerosal–has also elicited concern. Because organic mercury is a proven developmental neurotoxin, exposure to it in utero or in early childhood has raised concerns.

In utero exposure to mercury in environmental accidents, especially organic mercury, has been associated with brain damage and pediatric diagnoses such as cerebral palsy–but not autism. Some of the most compelling evidence indicating that vaccines containing thimerosal are not a cause of autism was provided in studies that looked at population-based databases of children in Denmark, Sweden, and California.

Although the prevalence of autism increased in all three places from 1985 through the 1990s, the average exposure to vaccines containing mercury increased only in the United States. In Sweden and Denmark, where the use of mercury-containing vaccines began to decrease in the late 1980s and was eliminated by the early 1990s, there was still an increase in the diagnosis of autism.

An important study published this month provides compelling evidence that prenatal exposure to thimerosal in Rh immune globulin (RhIg) is not a likely cause of the increase in autism, either. These results should help allay lingering concerns about exposure to ethylmercury via thimerosal in vaccines and Rh immune globulin.

The new study analyzed records of families that have children with an autism spectrum disorder (ASD), who had been seen at the Thompson Center for Autism and Neurodevelopmental Disorders at the University of Missouri-Columbia, between 2004 and 2006. Of 214 mothers with 230 children diagnosed with ASD between 1995 and 2005, 33 (15.4%) were Rh negative, which was similar to the rates among mothers in control groups. Of these 33 women, 29 (88%) had received Rh immune globulin that contained thimerosal while pregnant. Based on comparisons with families of children with Down syndrome and other de novo chromosome disorders who came to the university for care, and two other populations–patients blood typed at the hospital in 2005 and 2006, and a population who had donated blood during 2005–the investigators determined that Rh-negative status was not higher among the mothers of children with autism. In addition, the mothers of children with autism were not more likely to have been exposed to antepartum Rh immune globulin containing thimerosal, and were not more likely to have an Rh-negative incompatible pregnancy. These findings were also true for autism subtypes. The authors concluded that the results “support the consensus that exposure to ethylmercury in thimerosal is not the cause of the increased prevalence of autism” (Am. J. Med. Genet. Part A 2007;143A:1397-407).

Therefore, based on the information currently available, it is fair to say there is no compelling evidence indicating that exposure of the developing brain to mercury, either in the fetus or the developing child, is a cause of autism. And as the authors point out, these findings also have implications for other countries, where multidose vials that contain thimerosal continue to be used.

As for other potential prenatal causes of autism, there have been more case reports of autism in children exposed in utero to valproic acid, isotretinoin, or alcohol than one would expect. But I emphasize that these are case reports and merely associations at this point, not proven causes.

Efforts are underway to further investigate the possible association between prenatal exposure to valproic acid and autism. At the Motherisk Program, a teratogen information service at the Hospital for Sick Children in Toronto, we are following the long-term development of children exposed in utero to valproic acid, which we hope will pick up an association with autism, if such a link exists.

www.motherisk.org

The etiology of autism is not yet clear and the debate continues about whether the increase in prevalence noted in the past few decades is actual or is because of better diagnosis. However, the evidence for a genetic link is accumulating, as is evidence that mercury in vaccines is not behind the increased prevalence.

Because the disease appears in the second or third year of life, the potential association with early childhood vaccines has been the subject of many studies over the past 15-20 years. Children receive many vaccines during the first few years of their lives; until 2002, thimerosal, a preservative that contains ethylmercury, was used as a preservative in routine early childhood vaccines. To a lesser degree, prenatal exposure to Rh immune globulin–which, until 2001 in the United States, contained thimerosal–has also elicited concern. Because organic mercury is a proven developmental neurotoxin, exposure to it in utero or in early childhood has raised concerns.

In utero exposure to mercury in environmental accidents, especially organic mercury, has been associated with brain damage and pediatric diagnoses such as cerebral palsy–but not autism. Some of the most compelling evidence indicating that vaccines containing thimerosal are not a cause of autism was provided in studies that looked at population-based databases of children in Denmark, Sweden, and California.

Although the prevalence of autism increased in all three places from 1985 through the 1990s, the average exposure to vaccines containing mercury increased only in the United States. In Sweden and Denmark, where the use of mercury-containing vaccines began to decrease in the late 1980s and was eliminated by the early 1990s, there was still an increase in the diagnosis of autism.

An important study published this month provides compelling evidence that prenatal exposure to thimerosal in Rh immune globulin (RhIg) is not a likely cause of the increase in autism, either. These results should help allay lingering concerns about exposure to ethylmercury via thimerosal in vaccines and Rh immune globulin.

The new study analyzed records of families that have children with an autism spectrum disorder (ASD), who had been seen at the Thompson Center for Autism and Neurodevelopmental Disorders at the University of Missouri-Columbia, between 2004 and 2006. Of 214 mothers with 230 children diagnosed with ASD between 1995 and 2005, 33 (15.4%) were Rh negative, which was similar to the rates among mothers in control groups. Of these 33 women, 29 (88%) had received Rh immune globulin that contained thimerosal while pregnant. Based on comparisons with families of children with Down syndrome and other de novo chromosome disorders who came to the university for care, and two other populations–patients blood typed at the hospital in 2005 and 2006, and a population who had donated blood during 2005–the investigators determined that Rh-negative status was not higher among the mothers of children with autism. In addition, the mothers of children with autism were not more likely to have been exposed to antepartum Rh immune globulin containing thimerosal, and were not more likely to have an Rh-negative incompatible pregnancy. These findings were also true for autism subtypes. The authors concluded that the results “support the consensus that exposure to ethylmercury in thimerosal is not the cause of the increased prevalence of autism” (Am. J. Med. Genet. Part A 2007;143A:1397-407).

Therefore, based on the information currently available, it is fair to say there is no compelling evidence indicating that exposure of the developing brain to mercury, either in the fetus or the developing child, is a cause of autism. And as the authors point out, these findings also have implications for other countries, where multidose vials that contain thimerosal continue to be used.

As for other potential prenatal causes of autism, there have been more case reports of autism in children exposed in utero to valproic acid, isotretinoin, or alcohol than one would expect. But I emphasize that these are case reports and merely associations at this point, not proven causes.

Efforts are underway to further investigate the possible association between prenatal exposure to valproic acid and autism. At the Motherisk Program, a teratogen information service at the Hospital for Sick Children in Toronto, we are following the long-term development of children exposed in utero to valproic acid, which we hope will pick up an association with autism, if such a link exists.

www.motherisk.org

Concerns about the adverse effects of maternal cocaine use during pregnancy on children exposed in utero have been the focus of many studies since the 1980s, when cocaine use began to increase, first among more affluent socioeconomic groups, then shifting to lower-income groups with the advent of cheap crack cocaine.

During the mid to late 1980s, reports suggested that cocaine use during pregnancy caused congenital malformations, which were followed by other reports suggesting that cocaine had adverse effects on long-term neurodevelopment in children exposed in utero. However, more recent systematic reviews of a large number of cases have not found an association between in utero exposure to cocaine and an increase in malformations of any kind, and these original concerns have not been borne out.

Women who use cocaine have many other risk factors for poor neonatal outcome and adverse long-term effects on the child than women who don't use cocaine, which may include low socioeconomic class, smoking, poor nutrition, and abuse of other drugs.

Over the years, studies have more carefully controlled for these other factors, comparing women who used cocaine during pregnancy to women in similar environments who had the same risk factors but did not use cocaine, and these studies have not found any association between maternal cocaine use and congenital defects or long-term effects in children.

In 2001, investigators performing a review of 36 prospective studies of prenatal cocaine exposure in children aged 6 years and younger found no convincing consistent evidence that in utero cocaine exposure was associated with negative effects on physical growth, developmental test scores, or receptive or expressive language.

They concluded that “many findings once thought to be specific effects of in utero cocaine exposure can be explained in whole or in part by other factors, including prenatal exposure to tobacco, marijuana, or alcohol and the quality of the child's environment” (JAMA 2001;285:1613–25).

While these and later studies constitute the overall picture, some well-designed studies have suggested that prenatal cocaine exposure does have some serious adverse effects, most notably, a greater risk of prematurity and higher rates of placenta previa.

There are also reports that some addicted women take high doses of cocaine near the end of pregnancy because they believe it may induce labor, which can result in placental bleeding and shock, potentially resulting in adverse, long-term effects on brain development in the baby.

An important consideration for obstetricians and other health care professionals who follow women who may use cocaine during pregnancy and those who follow their children is that continuing use of cocaine after a woman knows she is pregnant is recognized as essentially a sine qua non for addiction.

Many women may not disclose they use cocaine during a history, but our laboratory and others have developed methods of ascertaining whether a baby has been exposed to cocaine in utero, such as analysis of neonatal hair and meconium, biomarkers for maternal cocaine use that are validated and widely used by social services and clinicians in the United States and Canada.

Cocaine and its metabolite benzoylecgonine accumulate in fetal hair during the last trimester, so a positive test is a strong indicator that the mother used cocaine during the sixth or seventh month.

Cocaine and benzoylecgonine also accumulate in meconium, which is produced in midpregnancy, so a positive meconium test is an indication of use earlier in pregnancy. The meconium analysis can be used during the first few days post partum, while the hair analysis can be used for up to 3 months after the baby's birth.

Studies have documented damage to the brain in monkeys exposed in utero to cocaine at doses equivalent to doses that are typically used in humans.

Why similar findings have not been found in human studies speaks volumes to the plasticity of the newborn's or young child's brain and the ability to recover, if early environmental factors, with optimal stimulation, are favorable. This is an important area of research that is not yet fully resolved.

We conducted a study comparing children exposed in utero to cocaine who had been adopted by stable families, where presumably, environmental factors were normal, with biologic children of mothers from the same socioeconomic class.

The IQs of the adopted children were significantly lower than those of the comparator group, although the families were not aware of any neurodevelopmental problems with the children. This suggests that even in an optimal situation, however, not all damage can be reversed by brain plasticity.

Some studies have suggested that there may be an effect of fetal cocaine exposure on some specialized executive functions, such as the ability to perform complex tasks, or more refined functions, but the verdict on this issue is still out.

We and others continue to follow children who have been exposed in utero to cocaine, and are trying to understand sources of variability and why some children are affected and others are not.

www.motherisk.org

Concerns about the adverse effects of maternal cocaine use during pregnancy on children exposed in utero have been the focus of many studies since the 1980s, when cocaine use began to increase, first among more affluent socioeconomic groups, then shifting to lower-income groups with the advent of cheap crack cocaine.

During the mid to late 1980s, reports suggested that cocaine use during pregnancy caused congenital malformations, which were followed by other reports suggesting that cocaine had adverse effects on long-term neurodevelopment in children exposed in utero. However, more recent systematic reviews of a large number of cases have not found an association between in utero exposure to cocaine and an increase in malformations of any kind, and these original concerns have not been borne out.

Women who use cocaine have many other risk factors for poor neonatal outcome and adverse long-term effects on the child than women who don't use cocaine, which may include low socioeconomic class, smoking, poor nutrition, and abuse of other drugs.

Over the years, studies have more carefully controlled for these other factors, comparing women who used cocaine during pregnancy to women in similar environments who had the same risk factors but did not use cocaine, and these studies have not found any association between maternal cocaine use and congenital defects or long-term effects in children.

In 2001, investigators performing a review of 36 prospective studies of prenatal cocaine exposure in children aged 6 years and younger found no convincing consistent evidence that in utero cocaine exposure was associated with negative effects on physical growth, developmental test scores, or receptive or expressive language.

They concluded that “many findings once thought to be specific effects of in utero cocaine exposure can be explained in whole or in part by other factors, including prenatal exposure to tobacco, marijuana, or alcohol and the quality of the child's environment” (JAMA 2001;285:1613–25).

While these and later studies constitute the overall picture, some well-designed studies have suggested that prenatal cocaine exposure does have some serious adverse effects, most notably, a greater risk of prematurity and higher rates of placenta previa.

There are also reports that some addicted women take high doses of cocaine near the end of pregnancy because they believe it may induce labor, which can result in placental bleeding and shock, potentially resulting in adverse, long-term effects on brain development in the baby.

An important consideration for obstetricians and other health care professionals who follow women who may use cocaine during pregnancy and those who follow their children is that continuing use of cocaine after a woman knows she is pregnant is recognized as essentially a sine qua non for addiction.

Many women may not disclose they use cocaine during a history, but our laboratory and others have developed methods of ascertaining whether a baby has been exposed to cocaine in utero, such as analysis of neonatal hair and meconium, biomarkers for maternal cocaine use that are validated and widely used by social services and clinicians in the United States and Canada.

Cocaine and its metabolite benzoylecgonine accumulate in fetal hair during the last trimester, so a positive test is a strong indicator that the mother used cocaine during the sixth or seventh month.

Cocaine and benzoylecgonine also accumulate in meconium, which is produced in midpregnancy, so a positive meconium test is an indication of use earlier in pregnancy. The meconium analysis can be used during the first few days post partum, while the hair analysis can be used for up to 3 months after the baby's birth.

Studies have documented damage to the brain in monkeys exposed in utero to cocaine at doses equivalent to doses that are typically used in humans.

Why similar findings have not been found in human studies speaks volumes to the plasticity of the newborn's or young child's brain and the ability to recover, if early environmental factors, with optimal stimulation, are favorable. This is an important area of research that is not yet fully resolved.

We conducted a study comparing children exposed in utero to cocaine who had been adopted by stable families, where presumably, environmental factors were normal, with biologic children of mothers from the same socioeconomic class.

The IQs of the adopted children were significantly lower than those of the comparator group, although the families were not aware of any neurodevelopmental problems with the children. This suggests that even in an optimal situation, however, not all damage can be reversed by brain plasticity.

Some studies have suggested that there may be an effect of fetal cocaine exposure on some specialized executive functions, such as the ability to perform complex tasks, or more refined functions, but the verdict on this issue is still out.

We and others continue to follow children who have been exposed in utero to cocaine, and are trying to understand sources of variability and why some children are affected and others are not.

www.motherisk.org

Concerns about the adverse effects of maternal cocaine use during pregnancy on children exposed in utero have been the focus of many studies since the 1980s, when cocaine use began to increase, first among more affluent socioeconomic groups, then shifting to lower-income groups with the advent of cheap crack cocaine.

During the mid to late 1980s, reports suggested that cocaine use during pregnancy caused congenital malformations, which were followed by other reports suggesting that cocaine had adverse effects on long-term neurodevelopment in children exposed in utero. However, more recent systematic reviews of a large number of cases have not found an association between in utero exposure to cocaine and an increase in malformations of any kind, and these original concerns have not been borne out.

Women who use cocaine have many other risk factors for poor neonatal outcome and adverse long-term effects on the child than women who don't use cocaine, which may include low socioeconomic class, smoking, poor nutrition, and abuse of other drugs.

Over the years, studies have more carefully controlled for these other factors, comparing women who used cocaine during pregnancy to women in similar environments who had the same risk factors but did not use cocaine, and these studies have not found any association between maternal cocaine use and congenital defects or long-term effects in children.

In 2001, investigators performing a review of 36 prospective studies of prenatal cocaine exposure in children aged 6 years and younger found no convincing consistent evidence that in utero cocaine exposure was associated with negative effects on physical growth, developmental test scores, or receptive or expressive language.

They concluded that “many findings once thought to be specific effects of in utero cocaine exposure can be explained in whole or in part by other factors, including prenatal exposure to tobacco, marijuana, or alcohol and the quality of the child's environment” (JAMA 2001;285:1613–25).

While these and later studies constitute the overall picture, some well-designed studies have suggested that prenatal cocaine exposure does have some serious adverse effects, most notably, a greater risk of prematurity and higher rates of placenta previa.

There are also reports that some addicted women take high doses of cocaine near the end of pregnancy because they believe it may induce labor, which can result in placental bleeding and shock, potentially resulting in adverse, long-term effects on brain development in the baby.

An important consideration for obstetricians and other health care professionals who follow women who may use cocaine during pregnancy and those who follow their children is that continuing use of cocaine after a woman knows she is pregnant is recognized as essentially a sine qua non for addiction.

Many women may not disclose they use cocaine during a history, but our laboratory and others have developed methods of ascertaining whether a baby has been exposed to cocaine in utero, such as analysis of neonatal hair and meconium, biomarkers for maternal cocaine use that are validated and widely used by social services and clinicians in the United States and Canada.

Cocaine and its metabolite benzoylecgonine accumulate in fetal hair during the last trimester, so a positive test is a strong indicator that the mother used cocaine during the sixth or seventh month.

Cocaine and benzoylecgonine also accumulate in meconium, which is produced in midpregnancy, so a positive meconium test is an indication of use earlier in pregnancy. The meconium analysis can be used during the first few days post partum, while the hair analysis can be used for up to 3 months after the baby's birth.

Studies have documented damage to the brain in monkeys exposed in utero to cocaine at doses equivalent to doses that are typically used in humans.

Why similar findings have not been found in human studies speaks volumes to the plasticity of the newborn's or young child's brain and the ability to recover, if early environmental factors, with optimal stimulation, are favorable. This is an important area of research that is not yet fully resolved.

We conducted a study comparing children exposed in utero to cocaine who had been adopted by stable families, where presumably, environmental factors were normal, with biologic children of mothers from the same socioeconomic class.

The IQs of the adopted children were significantly lower than those of the comparator group, although the families were not aware of any neurodevelopmental problems with the children. This suggests that even in an optimal situation, however, not all damage can be reversed by brain plasticity.

Some studies have suggested that there may be an effect of fetal cocaine exposure on some specialized executive functions, such as the ability to perform complex tasks, or more refined functions, but the verdict on this issue is still out.

We and others continue to follow children who have been exposed in utero to cocaine, and are trying to understand sources of variability and why some children are affected and others are not.

www.motherisk.org

When treatment for gestational diabetes is indicated, the drug of choice, insulin, can be problematic for some women because of the need for daily injections, which can affect compliance. The cost of therapy may also be an issue for women in lower socioeconomic groups.

The use of oral hypoglycemic agents for treating women with gestational diabetes has not been recommended in the past because many of these drugs cross the placenta, increasing the risk of neonatal hypoglycemia. But there are now several studies that provide encouraging data suggesting that the second-generation sulfonylurea glyburide is a safe option for both the woman and baby.

The first study indicating that glyburide might be a safe option for treating gestational diabetes was conducted in 1994, using the human placental perfusion model, which entails taking the term placenta after birth and reconstructing the blood vessels of the mother and newborn to determine whether a drug crosses the placenta. The investigators showed that while most of the oral hypoglycemic drugs tested crossed the placenta, a minimal amount of glyburide passed the placenta (Am. J. Obstet. Gynecol. 1994;171:653–60).

One of the investigators, Dr. Oded Langer, and associates conducted a randomized, controlled trial comparing insulin with glyburide in 404 women with singleton pregnancies and gestational diabetes who started treatment between 11 and 33 weeks' gestation. The study was published in 2000. Both treatments were equally effective in achieving the target level of glycemic control in the women, with 4% of women on glyburide requiring treatment with insulin.

Importantly, there were no significant differences in neonatal complications between the two groups: The percentages of babies who were large for gestational age, had macrosomia, had lung complications, were hypoglycemic, were admitted to neonatal intensive care units, or had fetal anomalies were similar in both groups. Serum insulin levels in the cord were similar in both groups, and no glyburide was detected in the cord serum of babies in the glyburide group, confirming the 1993 study (N. Engl. J. Med. 2000;343:1134–8).

A recent meta-analysis completed by Motherisk of all studies on this topic also found no evidence of an increased risk to the newborn associated with glyburide treatment, corroborating the 2000 study.

Why glyburide does not cross the placenta is an interesting question, one that several research groups are investigating. The placenta is not just a passive barrier, and it has different carrier systems that can selectively efflux different drugs from the baby back to the mother. We also know that the opposite occurs. For example, the placenta carries iron from the mother to the baby; even when the mother is anemic, the placenta ensures that the baby receives iron.

We published a paper earlier this year using the same placental perfusion model used in the 1993 study, but put glyburide on both sides of the placenta and found that it is actively pumped from the baby to the mother (Am. J. Obstet. Gynecol. 2006;195:270–4). The central thinking now is that the most likely placental transporter for glyburide is the breast cancer-resistant protein abundantly available in the placenta.

Glyburide provides an example of a drug that has not been given to women with gestational diabetes because of the false impression that it does cross the placenta, but the available data indicate that despite being a small molecule, it does not.

These novel findings may have major implications for women with gestational diabetes who require treatment because many would be happy not to have to use insulin daily. In many parts of the world, glyburide is already widely used for treating gestational diabetes. And although some women will require insulin, or a combination of glyburide with insulin, there are many women with gestational diabetes who will do well with glyburide. Glyburide is available as a generic, which is a significant cost advantage.

Finally, this may be one of the first examples of a medication that is considered safe to use in pregnancy because it has been found not to cross the placenta. In the future, drug therapy in pregnancy may involve the development of drugs that are pumped by the placenta back to the mother, using placental transporters to control fetal exposure (Placenta 2006;27:861–8).

www.motherisk.org

When treatment for gestational diabetes is indicated, the drug of choice, insulin, can be problematic for some women because of the need for daily injections, which can affect compliance. The cost of therapy may also be an issue for women in lower socioeconomic groups.

The use of oral hypoglycemic agents for treating women with gestational diabetes has not been recommended in the past because many of these drugs cross the placenta, increasing the risk of neonatal hypoglycemia. But there are now several studies that provide encouraging data suggesting that the second-generation sulfonylurea glyburide is a safe option for both the woman and baby.

The first study indicating that glyburide might be a safe option for treating gestational diabetes was conducted in 1994, using the human placental perfusion model, which entails taking the term placenta after birth and reconstructing the blood vessels of the mother and newborn to determine whether a drug crosses the placenta. The investigators showed that while most of the oral hypoglycemic drugs tested crossed the placenta, a minimal amount of glyburide passed the placenta (Am. J. Obstet. Gynecol. 1994;171:653–60).

One of the investigators, Dr. Oded Langer, and associates conducted a randomized, controlled trial comparing insulin with glyburide in 404 women with singleton pregnancies and gestational diabetes who started treatment between 11 and 33 weeks' gestation. The study was published in 2000. Both treatments were equally effective in achieving the target level of glycemic control in the women, with 4% of women on glyburide requiring treatment with insulin.

Importantly, there were no significant differences in neonatal complications between the two groups: The percentages of babies who were large for gestational age, had macrosomia, had lung complications, were hypoglycemic, were admitted to neonatal intensive care units, or had fetal anomalies were similar in both groups. Serum insulin levels in the cord were similar in both groups, and no glyburide was detected in the cord serum of babies in the glyburide group, confirming the 1993 study (N. Engl. J. Med. 2000;343:1134–8).

A recent meta-analysis completed by Motherisk of all studies on this topic also found no evidence of an increased risk to the newborn associated with glyburide treatment, corroborating the 2000 study.

Why glyburide does not cross the placenta is an interesting question, one that several research groups are investigating. The placenta is not just a passive barrier, and it has different carrier systems that can selectively efflux different drugs from the baby back to the mother. We also know that the opposite occurs. For example, the placenta carries iron from the mother to the baby; even when the mother is anemic, the placenta ensures that the baby receives iron.

We published a paper earlier this year using the same placental perfusion model used in the 1993 study, but put glyburide on both sides of the placenta and found that it is actively pumped from the baby to the mother (Am. J. Obstet. Gynecol. 2006;195:270–4). The central thinking now is that the most likely placental transporter for glyburide is the breast cancer-resistant protein abundantly available in the placenta.

Glyburide provides an example of a drug that has not been given to women with gestational diabetes because of the false impression that it does cross the placenta, but the available data indicate that despite being a small molecule, it does not.

These novel findings may have major implications for women with gestational diabetes who require treatment because many would be happy not to have to use insulin daily. In many parts of the world, glyburide is already widely used for treating gestational diabetes. And although some women will require insulin, or a combination of glyburide with insulin, there are many women with gestational diabetes who will do well with glyburide. Glyburide is available as a generic, which is a significant cost advantage.

Finally, this may be one of the first examples of a medication that is considered safe to use in pregnancy because it has been found not to cross the placenta. In the future, drug therapy in pregnancy may involve the development of drugs that are pumped by the placenta back to the mother, using placental transporters to control fetal exposure (Placenta 2006;27:861–8).

www.motherisk.org

When treatment for gestational diabetes is indicated, the drug of choice, insulin, can be problematic for some women because of the need for daily injections, which can affect compliance. The cost of therapy may also be an issue for women in lower socioeconomic groups.

The use of oral hypoglycemic agents for treating women with gestational diabetes has not been recommended in the past because many of these drugs cross the placenta, increasing the risk of neonatal hypoglycemia. But there are now several studies that provide encouraging data suggesting that the second-generation sulfonylurea glyburide is a safe option for both the woman and baby.

The first study indicating that glyburide might be a safe option for treating gestational diabetes was conducted in 1994, using the human placental perfusion model, which entails taking the term placenta after birth and reconstructing the blood vessels of the mother and newborn to determine whether a drug crosses the placenta. The investigators showed that while most of the oral hypoglycemic drugs tested crossed the placenta, a minimal amount of glyburide passed the placenta (Am. J. Obstet. Gynecol. 1994;171:653–60).

One of the investigators, Dr. Oded Langer, and associates conducted a randomized, controlled trial comparing insulin with glyburide in 404 women with singleton pregnancies and gestational diabetes who started treatment between 11 and 33 weeks' gestation. The study was published in 2000. Both treatments were equally effective in achieving the target level of glycemic control in the women, with 4% of women on glyburide requiring treatment with insulin.

Importantly, there were no significant differences in neonatal complications between the two groups: The percentages of babies who were large for gestational age, had macrosomia, had lung complications, were hypoglycemic, were admitted to neonatal intensive care units, or had fetal anomalies were similar in both groups. Serum insulin levels in the cord were similar in both groups, and no glyburide was detected in the cord serum of babies in the glyburide group, confirming the 1993 study (N. Engl. J. Med. 2000;343:1134–8).

A recent meta-analysis completed by Motherisk of all studies on this topic also found no evidence of an increased risk to the newborn associated with glyburide treatment, corroborating the 2000 study.

Why glyburide does not cross the placenta is an interesting question, one that several research groups are investigating. The placenta is not just a passive barrier, and it has different carrier systems that can selectively efflux different drugs from the baby back to the mother. We also know that the opposite occurs. For example, the placenta carries iron from the mother to the baby; even when the mother is anemic, the placenta ensures that the baby receives iron.

We published a paper earlier this year using the same placental perfusion model used in the 1993 study, but put glyburide on both sides of the placenta and found that it is actively pumped from the baby to the mother (Am. J. Obstet. Gynecol. 2006;195:270–4). The central thinking now is that the most likely placental transporter for glyburide is the breast cancer-resistant protein abundantly available in the placenta.

Glyburide provides an example of a drug that has not been given to women with gestational diabetes because of the false impression that it does cross the placenta, but the available data indicate that despite being a small molecule, it does not.

These novel findings may have major implications for women with gestational diabetes who require treatment because many would be happy not to have to use insulin daily. In many parts of the world, glyburide is already widely used for treating gestational diabetes. And although some women will require insulin, or a combination of glyburide with insulin, there are many women with gestational diabetes who will do well with glyburide. Glyburide is available as a generic, which is a significant cost advantage.

Finally, this may be one of the first examples of a medication that is considered safe to use in pregnancy because it has been found not to cross the placenta. In the future, drug therapy in pregnancy may involve the development of drugs that are pumped by the placenta back to the mother, using placental transporters to control fetal exposure (Placenta 2006;27:861–8).

www.motherisk.org

When treatment for gestational diabetes is indicated, the drug of choice, insulin, can be problematic for some women because of the need for daily injections, which can affect compliance. The cost of therapy may also be an issue for women in lower socioeconomic groups.

The use of oral hypoglycemic agents for treating women with gestational diabetes has not been recommended in the past because many of these drugs cross the placenta, increasing the risk of neonatal hypoglycemia. But there are now several studies that provide encouraging data suggesting that the second-generation sulfonylurea glyburide is a safe option for both the woman and baby.

The first study indicating that glyburide might be a safe option for treating gestational diabetes was conducted in 1994, using the human placental perfusion model, which entails taking the term placenta after birth and reconstructing the blood vessels of the mother and newborn to determine whether a drug crosses the placenta. The investigators showed that while most of the oral hypoglycemic drugs tested crossed the placenta, a minimal amount of glyburide passed the placenta (Am. J. Obstet. Gynecol. 1994;171:653–60).

One of the investigators, Dr. Oded Langer, and associates conducted a randomized, controlled trial comparing insulin with glyburide in 404 women with singleton pregnancies and gestational diabetes who started treatment between 11 and 33 weeks' gestation.

The study was published in 2000. Both treatments were equally effective in achieving the target level of glycemic control in the women, with 4% of women on glyburide requiring treatment with insulin. Importantly, there were no significant differences in neonatal complications between the two groups: The percentages of babies who were large for gestational age, had macrosomia, had lung complications, were hypoglycemic, were admitted to neonatal intensive care units, or had fetal anomalies were similar in both groups. Serum insulin levels in the cord were similar in both groups, and no glyburide was detected in the cord serum of babies in the glyburide group, confirming the 1993 study (N. Engl. J. Med. 2000;343:1134–8).

A recently completed meta-analysis by Motherisk of all studies on this topic also found no evidence of an increased risk to the newborn associated with glyburide treatment, corroborating the 2000 study.

Why glyburide does not cross the placenta is an interesting question, one that several research groups are investigating. The placenta is not just a passive barrier, and it has different carrier systems that can selectively efflux different drugs from the baby back to the mother. We also know that the opposite occurs. For example, the placenta carries iron from the mother to the baby; even when the mother is anemic, the placenta ensures that the baby receives iron.

We published a paper earlier this year using the same placental perfusion model used in the 1993 study, but put glyburide on both sides of the placenta and found that it is actively pumped from the baby to the mother (Am. J. Obstet. Gynecol. 2006;195:270–4). The central thinking now is that the most likely placental transporter for glyburide is the breast cancer-resistant protein abundantly available in the placenta.

Glyburide provides an example of a drug that has not been given to women with gestational diabetes because of the false impression that it does cross the placenta, but the available data indicate that despite being a small molecule, it does not.

These novel findings may have major implications for women with gestational diabetes who require treatment because many would be happy not to have to use insulin daily. In many parts of the world, glyburide is already widely used for treating gestational diabetes. And although some women will require insulin, or a combination of glyburide with insulin, there are many women with gestational diabetes who will do well with glyburide. Glyburide is available as a generic, which is a significant cost advantage.

Finally, this may be one of the first examples of a medication that is considered safe to use in pregnancy because it has been found not to cross the placenta. In the future, drug therapy in pregnancy may involve the development of drugs that are pumped by the placenta back to the mother, using placental transporters to control fetal exposure (Placenta 2006;27:861–8).

www.motherisk.org

When treatment for gestational diabetes is indicated, the drug of choice, insulin, can be problematic for some women because of the need for daily injections, which can affect compliance. The cost of therapy may also be an issue for women in lower socioeconomic groups.

The use of oral hypoglycemic agents for treating women with gestational diabetes has not been recommended in the past because many of these drugs cross the placenta, increasing the risk of neonatal hypoglycemia. But there are now several studies that provide encouraging data suggesting that the second-generation sulfonylurea glyburide is a safe option for both the woman and baby.

The first study indicating that glyburide might be a safe option for treating gestational diabetes was conducted in 1994, using the human placental perfusion model, which entails taking the term placenta after birth and reconstructing the blood vessels of the mother and newborn to determine whether a drug crosses the placenta. The investigators showed that while most of the oral hypoglycemic drugs tested crossed the placenta, a minimal amount of glyburide passed the placenta (Am. J. Obstet. Gynecol. 1994;171:653–60).

One of the investigators, Dr. Oded Langer, and associates conducted a randomized, controlled trial comparing insulin with glyburide in 404 women with singleton pregnancies and gestational diabetes who started treatment between 11 and 33 weeks' gestation.

The study was published in 2000. Both treatments were equally effective in achieving the target level of glycemic control in the women, with 4% of women on glyburide requiring treatment with insulin. Importantly, there were no significant differences in neonatal complications between the two groups: The percentages of babies who were large for gestational age, had macrosomia, had lung complications, were hypoglycemic, were admitted to neonatal intensive care units, or had fetal anomalies were similar in both groups. Serum insulin levels in the cord were similar in both groups, and no glyburide was detected in the cord serum of babies in the glyburide group, confirming the 1993 study (N. Engl. J. Med. 2000;343:1134–8).

A recently completed meta-analysis by Motherisk of all studies on this topic also found no evidence of an increased risk to the newborn associated with glyburide treatment, corroborating the 2000 study.

Why glyburide does not cross the placenta is an interesting question, one that several research groups are investigating. The placenta is not just a passive barrier, and it has different carrier systems that can selectively efflux different drugs from the baby back to the mother. We also know that the opposite occurs. For example, the placenta carries iron from the mother to the baby; even when the mother is anemic, the placenta ensures that the baby receives iron.

We published a paper earlier this year using the same placental perfusion model used in the 1993 study, but put glyburide on both sides of the placenta and found that it is actively pumped from the baby to the mother (Am. J. Obstet. Gynecol. 2006;195:270–4). The central thinking now is that the most likely placental transporter for glyburide is the breast cancer-resistant protein abundantly available in the placenta.

Glyburide provides an example of a drug that has not been given to women with gestational diabetes because of the false impression that it does cross the placenta, but the available data indicate that despite being a small molecule, it does not.

These novel findings may have major implications for women with gestational diabetes who require treatment because many would be happy not to have to use insulin daily. In many parts of the world, glyburide is already widely used for treating gestational diabetes. And although some women will require insulin, or a combination of glyburide with insulin, there are many women with gestational diabetes who will do well with glyburide. Glyburide is available as a generic, which is a significant cost advantage.

Finally, this may be one of the first examples of a medication that is considered safe to use in pregnancy because it has been found not to cross the placenta. In the future, drug therapy in pregnancy may involve the development of drugs that are pumped by the placenta back to the mother, using placental transporters to control fetal exposure (Placenta 2006;27:861–8).

www.motherisk.org

When treatment for gestational diabetes is indicated, the drug of choice, insulin, can be problematic for some women because of the need for daily injections, which can affect compliance. The cost of therapy may also be an issue for women in lower socioeconomic groups.

The use of oral hypoglycemic agents for treating women with gestational diabetes has not been recommended in the past because many of these drugs cross the placenta, increasing the risk of neonatal hypoglycemia. But there are now several studies that provide encouraging data suggesting that the second-generation sulfonylurea glyburide is a safe option for both the woman and baby.

The first study indicating that glyburide might be a safe option for treating gestational diabetes was conducted in 1994, using the human placental perfusion model, which entails taking the term placenta after birth and reconstructing the blood vessels of the mother and newborn to determine whether a drug crosses the placenta. The investigators showed that while most of the oral hypoglycemic drugs tested crossed the placenta, a minimal amount of glyburide passed the placenta (Am. J. Obstet. Gynecol. 1994;171:653–60).

One of the investigators, Dr. Oded Langer, and associates conducted a randomized, controlled trial comparing insulin with glyburide in 404 women with singleton pregnancies and gestational diabetes who started treatment between 11 and 33 weeks' gestation.

The study was published in 2000. Both treatments were equally effective in achieving the target level of glycemic control in the women, with 4% of women on glyburide requiring treatment with insulin. Importantly, there were no significant differences in neonatal complications between the two groups: The percentages of babies who were large for gestational age, had macrosomia, had lung complications, were hypoglycemic, were admitted to neonatal intensive care units, or had fetal anomalies were similar in both groups. Serum insulin levels in the cord were similar in both groups, and no glyburide was detected in the cord serum of babies in the glyburide group, confirming the 1993 study (N. Engl. J. Med. 2000;343:1134–8).

A recently completed meta-analysis by Motherisk of all studies on this topic also found no evidence of an increased risk to the newborn associated with glyburide treatment, corroborating the 2000 study.

Why glyburide does not cross the placenta is an interesting question, one that several research groups are investigating. The placenta is not just a passive barrier, and it has different carrier systems that can selectively efflux different drugs from the baby back to the mother. We also know that the opposite occurs. For example, the placenta carries iron from the mother to the baby; even when the mother is anemic, the placenta ensures that the baby receives iron.

We published a paper earlier this year using the same placental perfusion model used in the 1993 study, but put glyburide on both sides of the placenta and found that it is actively pumped from the baby to the mother (Am. J. Obstet. Gynecol. 2006;195:270–4). The central thinking now is that the most likely placental transporter for glyburide is the breast cancer-resistant protein abundantly available in the placenta.

Glyburide provides an example of a drug that has not been given to women with gestational diabetes because of the false impression that it does cross the placenta, but the available data indicate that despite being a small molecule, it does not.

These novel findings may have major implications for women with gestational diabetes who require treatment because many would be happy not to have to use insulin daily. In many parts of the world, glyburide is already widely used for treating gestational diabetes. And although some women will require insulin, or a combination of glyburide with insulin, there are many women with gestational diabetes who will do well with glyburide. Glyburide is available as a generic, which is a significant cost advantage.

Finally, this may be one of the first examples of a medication that is considered safe to use in pregnancy because it has been found not to cross the placenta. In the future, drug therapy in pregnancy may involve the development of drugs that are pumped by the placenta back to the mother, using placental transporters to control fetal exposure (Placenta 2006;27:861–8).

www.motherisk.org

There is some evidence that the use of vitamins in general and folic acid in particular may inhibit the development of some types of cancer in adults, although the data are not from randomized trials and are debated.

There are also several studies suggesting folic acid may protect against certain pediatric cancers, and a recently reported metaanalysis conducted by Motherisk found that prenatal vitamin use during pregnancy was associated with a reduced risk of some pediatric cancers.

Several years ago, we reported the results of a study in Ontario that found an association between folic acid fortification of flour and a 50% decrease in the prevalence of pediatric neuroblastoma, an apparent protective effect.

We conducted this study after the Pediatric Oncology Group in Ontario asked us if we could identify an environmental explanation for the fewer cases of neuroblastoma in children in Ontario, a trend they first noticed in the late 1990s. This group keeps records of all the pediatric cancers in the province.

The only factor we could identify was that in 1997 and 1998, folic acid fortification of flour became compulsory in Canada, as in the United States, so virtually every citizen, unless they did not eat flour-based products, was exposed to greater levels of folic acid.

We were able to show that indeed, year by year, with the introduction of folic acid fortification of flour, there was a parallel decrease in the number of neuroblastomas diagnosed in young children in Ontario (Clin. Pharmacol. Ther. 2003;74:288–94).

Intrigued by these results, we looked into whether other investigators had arrived at similar observations about multivitamin supplementation and pediatric cancers.

We conducted a metaanalysis of all eight case-control studies published between 1994 and 2005 of prenatal multivitamin supplementation and pediatric cancer rates, comparing the rates of cancer in their children with matched controls whose mothers did not use supplements.

The studies were conducted between 1976 and 2002; all were either conducted in the United States, or included U.S. sites.

These results were presented by Ingrid Goh, a graduate student in Motherisk, at the American Society of Clinical Pharmacology and Therapeutics meeting in March 2006.

We found that for several prominent pediatric cancers—brain tumors, early-age leukemias (in the first year of life), and neuroblastomas, tumors that are believed to start in utero—the rates were substantially lower among the children of women who took prenatal vitamins containing folic acid during pregnancy.

The risk of leukemia was reduced by 36%, the risk of pediatric brain tumors reduced by 35%, and the risk of neuroblastoma by 57%—all statistically significant reductions.

The metaanalysis has limitations, including the retrospective design of the studies, and likely variations in the composition of multivitamins; it is possible that another characteristic of women who are motivated enough to take multivitamins could contribute to the lower cancer rates.

Therefore, at present, these studies show a trend and an association, but are not necessarily proof of causation.

Still, as far as we know, this is the first systematic review that has investigated such a protective effect for the use of multivitamins by pregnant women, and provides the first evidence suggesting that prenatal vitamins may have a protective effect in reducing the risk of pediatric cancer and that it may be possible to reduce the risk of certain childhood cancers in utero.

This finding is important because for the most part, not much is known about how to prevent pediatric cancers. These findings may also contribute to the understanding of the etiology of cancer.

Folic acid, for example, is involved in many intracellular processes, and it has been hypothesized that folate deficiencies and cancers in children may be related to partially altered DNA methylation and impaired DNA synthesis and repair.

Currently, we can not separate what constituents in the multivitamin are responsible for the protective effect; this will be much more difficult to sort out.

Despite the limitations of the studies in the metaanalysis, they represent another level of evidence for physicians and women that highlight the importance of prenatal supplementation with a multivitamin containing folic acid.

www.motherisk.org

There is some evidence that the use of vitamins in general and folic acid in particular may inhibit the development of some types of cancer in adults, although the data are not from randomized trials and are debated.

There are also several studies suggesting folic acid may protect against certain pediatric cancers, and a recently reported metaanalysis conducted by Motherisk found that prenatal vitamin use during pregnancy was associated with a reduced risk of some pediatric cancers.

Several years ago, we reported the results of a study in Ontario that found an association between folic acid fortification of flour and a 50% decrease in the prevalence of pediatric neuroblastoma, an apparent protective effect.

We conducted this study after the Pediatric Oncology Group in Ontario asked us if we could identify an environmental explanation for the fewer cases of neuroblastoma in children in Ontario, a trend they first noticed in the late 1990s. This group keeps records of all the pediatric cancers in the province.

The only factor we could identify was that in 1997 and 1998, folic acid fortification of flour became compulsory in Canada, as in the United States, so virtually every citizen, unless they did not eat flour-based products, was exposed to greater levels of folic acid.

We were able to show that indeed, year by year, with the introduction of folic acid fortification of flour, there was a parallel decrease in the number of neuroblastomas diagnosed in young children in Ontario (Clin. Pharmacol. Ther. 2003;74:288–94).

Intrigued by these results, we looked into whether other investigators had arrived at similar observations about multivitamin supplementation and pediatric cancers.

We conducted a metaanalysis of all eight case-control studies published between 1994 and 2005 of prenatal multivitamin supplementation and pediatric cancer rates, comparing the rates of cancer in their children with matched controls whose mothers did not use supplements.

The studies were conducted between 1976 and 2002; all were either conducted in the United States, or included U.S. sites.

These results were presented by Ingrid Goh, a graduate student in Motherisk, at the American Society of Clinical Pharmacology and Therapeutics meeting in March 2006.

We found that for several prominent pediatric cancers—brain tumors, early-age leukemias (in the first year of life), and neuroblastomas, tumors that are believed to start in utero—the rates were substantially lower among the children of women who took prenatal vitamins containing folic acid during pregnancy.

The risk of leukemia was reduced by 36%, the risk of pediatric brain tumors reduced by 35%, and the risk of neuroblastoma by 57%—all statistically significant reductions.

The metaanalysis has limitations, including the retrospective design of the studies, and likely variations in the composition of multivitamins; it is possible that another characteristic of women who are motivated enough to take multivitamins could contribute to the lower cancer rates.

Therefore, at present, these studies show a trend and an association, but are not necessarily proof of causation.

Still, as far as we know, this is the first systematic review that has investigated such a protective effect for the use of multivitamins by pregnant women, and provides the first evidence suggesting that prenatal vitamins may have a protective effect in reducing the risk of pediatric cancer and that it may be possible to reduce the risk of certain childhood cancers in utero.

This finding is important because for the most part, not much is known about how to prevent pediatric cancers. These findings may also contribute to the understanding of the etiology of cancer.

Folic acid, for example, is involved in many intracellular processes, and it has been hypothesized that folate deficiencies and cancers in children may be related to partially altered DNA methylation and impaired DNA synthesis and repair.

Currently, we can not separate what constituents in the multivitamin are responsible for the protective effect; this will be much more difficult to sort out.

Despite the limitations of the studies in the metaanalysis, they represent another level of evidence for physicians and women that highlight the importance of prenatal supplementation with a multivitamin containing folic acid.

www.motherisk.org

There is some evidence that the use of vitamins in general and folic acid in particular may inhibit the development of some types of cancer in adults, although the data are not from randomized trials and are debated.

There are also several studies suggesting folic acid may protect against certain pediatric cancers, and a recently reported metaanalysis conducted by Motherisk found that prenatal vitamin use during pregnancy was associated with a reduced risk of some pediatric cancers.

Several years ago, we reported the results of a study in Ontario that found an association between folic acid fortification of flour and a 50% decrease in the prevalence of pediatric neuroblastoma, an apparent protective effect.

We conducted this study after the Pediatric Oncology Group in Ontario asked us if we could identify an environmental explanation for the fewer cases of neuroblastoma in children in Ontario, a trend they first noticed in the late 1990s. This group keeps records of all the pediatric cancers in the province.

The only factor we could identify was that in 1997 and 1998, folic acid fortification of flour became compulsory in Canada, as in the United States, so virtually every citizen, unless they did not eat flour-based products, was exposed to greater levels of folic acid.

We were able to show that indeed, year by year, with the introduction of folic acid fortification of flour, there was a parallel decrease in the number of neuroblastomas diagnosed in young children in Ontario (Clin. Pharmacol. Ther. 2003;74:288–94).

Intrigued by these results, we looked into whether other investigators had arrived at similar observations about multivitamin supplementation and pediatric cancers.

We conducted a metaanalysis of all eight case-control studies published between 1994 and 2005 of prenatal multivitamin supplementation and pediatric cancer rates, comparing the rates of cancer in their children with matched controls whose mothers did not use supplements.

The studies were conducted between 1976 and 2002; all were either conducted in the United States, or included U.S. sites.

These results were presented by Ingrid Goh, a graduate student in Motherisk, at the American Society of Clinical Pharmacology and Therapeutics meeting in March 2006.

We found that for several prominent pediatric cancers—brain tumors, early-age leukemias (in the first year of life), and neuroblastomas, tumors that are believed to start in utero—the rates were substantially lower among the children of women who took prenatal vitamins containing folic acid during pregnancy.

The risk of leukemia was reduced by 36%, the risk of pediatric brain tumors reduced by 35%, and the risk of neuroblastoma by 57%—all statistically significant reductions.

The metaanalysis has limitations, including the retrospective design of the studies, and likely variations in the composition of multivitamins; it is possible that another characteristic of women who are motivated enough to take multivitamins could contribute to the lower cancer rates.

Therefore, at present, these studies show a trend and an association, but are not necessarily proof of causation.

Still, as far as we know, this is the first systematic review that has investigated such a protective effect for the use of multivitamins by pregnant women, and provides the first evidence suggesting that prenatal vitamins may have a protective effect in reducing the risk of pediatric cancer and that it may be possible to reduce the risk of certain childhood cancers in utero.

This finding is important because for the most part, not much is known about how to prevent pediatric cancers. These findings may also contribute to the understanding of the etiology of cancer.

Folic acid, for example, is involved in many intracellular processes, and it has been hypothesized that folate deficiencies and cancers in children may be related to partially altered DNA methylation and impaired DNA synthesis and repair.

Currently, we can not separate what constituents in the multivitamin are responsible for the protective effect; this will be much more difficult to sort out.

Despite the limitations of the studies in the metaanalysis, they represent another level of evidence for physicians and women that highlight the importance of prenatal supplementation with a multivitamin containing folic acid.