Gideon Koren

www.motherisk.org

Last month, my associates and I published a case report of an apparently healthy full-term newborn who died at 13 days from morphine poisoning. The cause was determined to be a genetic polymorphism in the mother, which made her an ultrarapid metabolizer of codeine to morphine, via cytochrome P450 2D6 (CYP2D6).

The coroner investigating the death contacted us after detecting an extremely high blood morphine level in the baby, because the mother had been taking codeine for episiotomy pain and had been breast-feeding. We suspected the mother might have the polymorphism, identified in recent years in a population subgroup. In one case involving ultrarapid CYP2D6 metabolism, a healthy man almost died from morphine poisoning when he received codeine for dental pain (N. Engl. J. Med. 2004;351:2827–31).

Genetic testing of the mother, father, baby, and extended family members identified the mother (and maternal grandmother) as ultrarapid CYP2D6 metabolizers, but not the baby. Frozen breast milk had a morphine level far higher than described in the literature: 87 ng/mL, vs. the typical level of 1.9–20.5 ng/mL associated with maternal doses of 60 mg of codeine every 6 hours (Lancet 2006;368:704).

Overall, there has been the perception that codeine is safe for the baby during breast-feeding. The few studies that have evaluated breast milk in women taking codeine have not found high morphine levels, and the American Academy of Pediatrics and other authoritative bodies list codeine as compatible with breast-feeding.

In most cases, this remains true. But considering the common practice of prescribing codeine for pain after childbirth with episiotomy or by cesarean section, many babies may be at risk. The prevalence of ultrarapid metabolizer status ranges from 1% in Denmark and Finland to 10% in Greece and Portugal to 29% in Ethiopia.

A genetic test is commercially available, but it is expensive and is currently not routinely performed. Other options all have pros and cons. One could withhold codeine in the postpartum period, but codeine is sometimes clearly needed for pain.

Using a nonsteroidal anti-inflammatory drug and avoiding codeine when breast-feeding eliminates the risk of toxicity in the baby, but may not adequately control pain. Using a lower dose of codeine minimizes potential toxicity to the baby, but may not provide sufficient pain control for the mother, and the dose could still be too high if she is an ultrarapid metabolizer. Another option is to avoid breast-feeding while taking codeine, but the baby would lose the benefits of breast-feeding.

In our case the mother took codeine until the child died at 13 days, which is longer than usual. This suggests that use for no more than 2–3 days is advisable. In retrospect, there were clinical signs hinting that the mother was an ultrarapid metabolizer: Despite being on a low dose of codeine, in combination with paracetamol, she was somnolent and constipated, and the dose had to be reduced on the second day of treatment.

Be alert for signs and symptoms suggesting that a patient is an ultrarapid metabolizer, including somnolence, sleepiness, dizziness, and constipation. The metabolism to morphine by CYP2D6 is responsible for most of the analgesic and CNS depressant effects of codeine.

Why have cases like this one not been previously reported? I suspect such cases may not be as rare as we thought, but not all the cases are as tragic because the mothers do not take codeine for as long a time. For example, in a paper we published more than a decade ago on outcomes in babies exposed to drugs in breast milk, 25 women reported taking codeine while breast-feeding, and in five cases their babies were described as being sleepy. An abstract from a 1984 meeting described apnea in premature babies who were being breast-fed, which resolved as soon as their mothers stopped taking codeine. Interestingly, their symptoms began at about day 7, which was also the case in our report, suggesting it takes time for morphine to accumulate in the milk to dangerous levels.

Eventually, this is the type of pharmacogenetic information everyone will be aware of and will have available when presenting for medical care. For now, we are conducting a large case-control pharmacogenetic study funded by Genome Canada on babies who were breast-fed while the mother was using codeine to better define the scope of this issue.

www.motherisk.org

Last month, my associates and I published a case report of an apparently healthy full-term newborn who died at 13 days from morphine poisoning. The cause was determined to be a genetic polymorphism in the mother, which made her an ultrarapid metabolizer of codeine to morphine, via cytochrome P450 2D6 (CYP2D6).

The coroner investigating the death contacted us after detecting an extremely high blood morphine level in the baby, because the mother had been taking codeine for episiotomy pain and had been breast-feeding. We suspected the mother might have the polymorphism, identified in recent years in a population subgroup. In one case involving ultrarapid CYP2D6 metabolism, a healthy man almost died from morphine poisoning when he received codeine for dental pain (N. Engl. J. Med. 2004;351:2827–31).

Genetic testing of the mother, father, baby, and extended family members identified the mother (and maternal grandmother) as ultrarapid CYP2D6 metabolizers, but not the baby. Frozen breast milk had a morphine level far higher than described in the literature: 87 ng/mL, vs. the typical level of 1.9–20.5 ng/mL associated with maternal doses of 60 mg of codeine every 6 hours (Lancet 2006;368:704).

Overall, there has been the perception that codeine is safe for the baby during breast-feeding. The few studies that have evaluated breast milk in women taking codeine have not found high morphine levels, and the American Academy of Pediatrics and other authoritative bodies list codeine as compatible with breast-feeding.

In most cases, this remains true. But considering the common practice of prescribing codeine for pain after childbirth with episiotomy or by cesarean section, many babies may be at risk. The prevalence of ultrarapid metabolizer status ranges from 1% in Denmark and Finland to 10% in Greece and Portugal to 29% in Ethiopia.

A genetic test is commercially available, but it is expensive and is currently not routinely performed. Other options all have pros and cons. One could withhold codeine in the postpartum period, but codeine is sometimes clearly needed for pain.

Using a nonsteroidal anti-inflammatory drug and avoiding codeine when breast-feeding eliminates the risk of toxicity in the baby, but may not adequately control pain. Using a lower dose of codeine minimizes potential toxicity to the baby, but may not provide sufficient pain control for the mother, and the dose could still be too high if she is an ultrarapid metabolizer. Another option is to avoid breast-feeding while taking codeine, but the baby would lose the benefits of breast-feeding.

In our case the mother took codeine until the child died at 13 days, which is longer than usual. This suggests that use for no more than 2–3 days is advisable. In retrospect, there were clinical signs hinting that the mother was an ultrarapid metabolizer: Despite being on a low dose of codeine, in combination with paracetamol, she was somnolent and constipated, and the dose had to be reduced on the second day of treatment.

Be alert for signs and symptoms suggesting that a patient is an ultrarapid metabolizer, including somnolence, sleepiness, dizziness, and constipation. The metabolism to morphine by CYP2D6 is responsible for most of the analgesic and CNS depressant effects of codeine.

Why have cases like this one not been previously reported? I suspect such cases may not be as rare as we thought, but not all the cases are as tragic because the mothers do not take codeine for as long a time. For example, in a paper we published more than a decade ago on outcomes in babies exposed to drugs in breast milk, 25 women reported taking codeine while breast-feeding, and in five cases their babies were described as being sleepy. An abstract from a 1984 meeting described apnea in premature babies who were being breast-fed, which resolved as soon as their mothers stopped taking codeine. Interestingly, their symptoms began at about day 7, which was also the case in our report, suggesting it takes time for morphine to accumulate in the milk to dangerous levels.

Eventually, this is the type of pharmacogenetic information everyone will be aware of and will have available when presenting for medical care. For now, we are conducting a large case-control pharmacogenetic study funded by Genome Canada on babies who were breast-fed while the mother was using codeine to better define the scope of this issue.

www.motherisk.org

Last month, my associates and I published a case report of an apparently healthy full-term newborn who died at 13 days from morphine poisoning. The cause was determined to be a genetic polymorphism in the mother, which made her an ultrarapid metabolizer of codeine to morphine, via cytochrome P450 2D6 (CYP2D6).

The coroner investigating the death contacted us after detecting an extremely high blood morphine level in the baby, because the mother had been taking codeine for episiotomy pain and had been breast-feeding. We suspected the mother might have the polymorphism, identified in recent years in a population subgroup. In one case involving ultrarapid CYP2D6 metabolism, a healthy man almost died from morphine poisoning when he received codeine for dental pain (N. Engl. J. Med. 2004;351:2827–31).

Genetic testing of the mother, father, baby, and extended family members identified the mother (and maternal grandmother) as ultrarapid CYP2D6 metabolizers, but not the baby. Frozen breast milk had a morphine level far higher than described in the literature: 87 ng/mL, vs. the typical level of 1.9–20.5 ng/mL associated with maternal doses of 60 mg of codeine every 6 hours (Lancet 2006;368:704).

Overall, there has been the perception that codeine is safe for the baby during breast-feeding. The few studies that have evaluated breast milk in women taking codeine have not found high morphine levels, and the American Academy of Pediatrics and other authoritative bodies list codeine as compatible with breast-feeding.

In most cases, this remains true. But considering the common practice of prescribing codeine for pain after childbirth with episiotomy or by cesarean section, many babies may be at risk. The prevalence of ultrarapid metabolizer status ranges from 1% in Denmark and Finland to 10% in Greece and Portugal to 29% in Ethiopia.

A genetic test is commercially available, but it is expensive and is currently not routinely performed. Other options all have pros and cons. One could withhold codeine in the postpartum period, but codeine is sometimes clearly needed for pain.

Using a nonsteroidal anti-inflammatory drug and avoiding codeine when breast-feeding eliminates the risk of toxicity in the baby, but may not adequately control pain. Using a lower dose of codeine minimizes potential toxicity to the baby, but may not provide sufficient pain control for the mother, and the dose could still be too high if she is an ultrarapid metabolizer. Another option is to avoid breast-feeding while taking codeine, but the baby would lose the benefits of breast-feeding.

In our case the mother took codeine until the child died at 13 days, which is longer than usual. This suggests that use for no more than 2–3 days is advisable. In retrospect, there were clinical signs hinting that the mother was an ultrarapid metabolizer: Despite being on a low dose of codeine, in combination with paracetamol, she was somnolent and constipated, and the dose had to be reduced on the second day of treatment.

Be alert for signs and symptoms suggesting that a patient is an ultrarapid metabolizer, including somnolence, sleepiness, dizziness, and constipation. The metabolism to morphine by CYP2D6 is responsible for most of the analgesic and CNS depressant effects of codeine.

Why have cases like this one not been previously reported? I suspect such cases may not be as rare as we thought, but not all the cases are as tragic because the mothers do not take codeine for as long a time. For example, in a paper we published more than a decade ago on outcomes in babies exposed to drugs in breast milk, 25 women reported taking codeine while breast-feeding, and in five cases their babies were described as being sleepy. An abstract from a 1984 meeting described apnea in premature babies who were being breast-fed, which resolved as soon as their mothers stopped taking codeine. Interestingly, their symptoms began at about day 7, which was also the case in our report, suggesting it takes time for morphine to accumulate in the milk to dangerous levels.

Eventually, this is the type of pharmacogenetic information everyone will be aware of and will have available when presenting for medical care. For now, we are conducting a large case-control pharmacogenetic study funded by Genome Canada on babies who were breast-fed while the mother was using codeine to better define the scope of this issue.

www.motherisk.org

Last month, my associates and I published a case report of an apparently healthy full-term newborn who died at 13 days from morphine poisoning. The cause was determined to be a genetic polymorphism in the mother, which made her an ultrarapid metabolizer of codeine to morphine, via cytochrome P450 2D6 (CYP2D6).

The coroner investigating the death contacted us after detecting an extremely high blood morphine level in the baby, because the mother had been taking codeine for episiotomy pain and had been breast-feeding. We suspected the mother might have the polymorphism, identified in recent years in a population subgroup. In one case involving ultrarapid CYP2D6 metabolism, a healthy man almost died from morphine poisoning when he received codeine for dental pain (N. Engl. J. Med. 2004;351:2827–31).

Genetic testing of the mother, father, baby, and extended family members identified the mother (and maternal grandmother) as ultrarapid CYP2D6 metabolizers, but not the baby. Frozen breast milk had a morphine level far higher than described in the literature: 87 ng/mL, vs. the typical level of 1.9–20.5 ng/mL associated with maternal doses of 60 mg of codeine every 6 hours (Lancet 2006;368:704).

Overall, there has been the perception that codeine is safe for the baby during breast-feeding. The few studies that have evaluated breast milk in women taking codeine have not found high morphine levels, and the American Academy of Pediatrics and other authoritative bodies list codeine as compatible with breast-feeding.

In most cases, this remains true. But considering the common practice of prescribing codeine for pain after episiotomy or cesarean section, many babies may be at risk. The prevalence of ultrarapid metabolizer status ranges from 1% in Denmark and Finland to 10% in Greece and Portugal to 29% in Ethiopia.

A genetic test is commercially available, but it is expensive and is currently not routinely performed. Other options all have pros and cons. One could withhold codeine in the postpartum period, but codeine is sometimes clearly needed for pain. Using a nonsteroidal anti-inflammatory drug and avoiding codeine when breast-feeding eliminates the risk of toxicity in the baby, but may not adequately control pain. Using a lower dose of codeine minimizes potential toxicity to the baby, but may not provide sufficient pain control for the mother, and the dose could still be too high if she is an ultrarapid metabolizer. Another option is to avoid breast-feeding while taking codeine, but the baby would lose the benefits of breast-feeding.

In our case the mother took codeine until the child died at 13 days, which is longer than usual. This suggests that use for no more than 2–3 days is advisable. In retrospect, there were clinical signs hinting that the mother was an ultrarapid metabolizer: Despite being on a low dose of codeine, in combination with paracetamol, she was somnolent and constipated, and the dose had to be reduced on the second day of treatment.

Be alert for signs and symptoms suggesting that a patient is an ultrarapid metabolizer, including somnolence, sleepiness, dizziness, and constipation. The metabolism to morphine by CYP2D6 is responsible for most of the analgesic and CNS depressant effects of codeine.

Why have cases like this one not been previously reported? I suspect such cases may not be as rare as we thought, but not all the cases are as tragic because the mothers do not take codeine for as long a time. For example, in a paper we published more than a decade ago on outcomes in babies exposed to drugs in breast milk, 25 women reported taking codeine while breast-feeding, and in five cases their babies were described as being sleepy. An abstract from a 1984 meeting described apnea in premature babies who were being breast-fed, which resolved as soon as their mothers stopped taking codeine. Interestingly, their symptoms began at about day 7, which was also the case in our report, suggesting it takes time for morphine to accumulate in the milk to dangerous levels.

Eventually, this is the type of pharmacogenetic information everyone will be aware of and will have available when presenting for medical care. For now, we are conducting a large case-control pharmacogenetic study funded by Genome Canada on babies who were breast-fed while the mother was using codeine to better define the scope of this issue.

www.motherisk.org

Last month, my associates and I published a case report of an apparently healthy full-term newborn who died at 13 days from morphine poisoning. The cause was determined to be a genetic polymorphism in the mother, which made her an ultrarapid metabolizer of codeine to morphine, via cytochrome P450 2D6 (CYP2D6).

The coroner investigating the death contacted us after detecting an extremely high blood morphine level in the baby, because the mother had been taking codeine for episiotomy pain and had been breast-feeding. We suspected the mother might have the polymorphism, identified in recent years in a population subgroup. In one case involving ultrarapid CYP2D6 metabolism, a healthy man almost died from morphine poisoning when he received codeine for dental pain (N. Engl. J. Med. 2004;351:2827–31).

Genetic testing of the mother, father, baby, and extended family members identified the mother (and maternal grandmother) as ultrarapid CYP2D6 metabolizers, but not the baby. Frozen breast milk had a morphine level far higher than described in the literature: 87 ng/mL, vs. the typical level of 1.9–20.5 ng/mL associated with maternal doses of 60 mg of codeine every 6 hours (Lancet 2006;368:704).

Overall, there has been the perception that codeine is safe for the baby during breast-feeding. The few studies that have evaluated breast milk in women taking codeine have not found high morphine levels, and the American Academy of Pediatrics and other authoritative bodies list codeine as compatible with breast-feeding.

In most cases, this remains true. But considering the common practice of prescribing codeine for pain after episiotomy or cesarean section, many babies may be at risk. The prevalence of ultrarapid metabolizer status ranges from 1% in Denmark and Finland to 10% in Greece and Portugal to 29% in Ethiopia.

A genetic test is commercially available, but it is expensive and is currently not routinely performed. Other options all have pros and cons. One could withhold codeine in the postpartum period, but codeine is sometimes clearly needed for pain. Using a nonsteroidal anti-inflammatory drug and avoiding codeine when breast-feeding eliminates the risk of toxicity in the baby, but may not adequately control pain. Using a lower dose of codeine minimizes potential toxicity to the baby, but may not provide sufficient pain control for the mother, and the dose could still be too high if she is an ultrarapid metabolizer. Another option is to avoid breast-feeding while taking codeine, but the baby would lose the benefits of breast-feeding.

In our case the mother took codeine until the child died at 13 days, which is longer than usual. This suggests that use for no more than 2–3 days is advisable. In retrospect, there were clinical signs hinting that the mother was an ultrarapid metabolizer: Despite being on a low dose of codeine, in combination with paracetamol, she was somnolent and constipated, and the dose had to be reduced on the second day of treatment.

Be alert for signs and symptoms suggesting that a patient is an ultrarapid metabolizer, including somnolence, sleepiness, dizziness, and constipation. The metabolism to morphine by CYP2D6 is responsible for most of the analgesic and CNS depressant effects of codeine.

Why have cases like this one not been previously reported? I suspect such cases may not be as rare as we thought, but not all the cases are as tragic because the mothers do not take codeine for as long a time. For example, in a paper we published more than a decade ago on outcomes in babies exposed to drugs in breast milk, 25 women reported taking codeine while breast-feeding, and in five cases their babies were described as being sleepy. An abstract from a 1984 meeting described apnea in premature babies who were being breast-fed, which resolved as soon as their mothers stopped taking codeine. Interestingly, their symptoms began at about day 7, which was also the case in our report, suggesting it takes time for morphine to accumulate in the milk to dangerous levels.

Eventually, this is the type of pharmacogenetic information everyone will be aware of and will have available when presenting for medical care. For now, we are conducting a large case-control pharmacogenetic study funded by Genome Canada on babies who were breast-fed while the mother was using codeine to better define the scope of this issue.

www.motherisk.org

Last month, my associates and I published a case report of an apparently healthy full-term newborn who died at 13 days from morphine poisoning. The cause was determined to be a genetic polymorphism in the mother, which made her an ultrarapid metabolizer of codeine to morphine, via cytochrome P450 2D6 (CYP2D6).

The coroner investigating the death contacted us after detecting an extremely high blood morphine level in the baby, because the mother had been taking codeine for episiotomy pain and had been breast-feeding. We suspected the mother might have the polymorphism, identified in recent years in a population subgroup. In one case involving ultrarapid CYP2D6 metabolism, a healthy man almost died from morphine poisoning when he received codeine for dental pain (N. Engl. J. Med. 2004;351:2827–31).

Genetic testing of the mother, father, baby, and extended family members identified the mother (and maternal grandmother) as ultrarapid CYP2D6 metabolizers, but not the baby. Frozen breast milk had a morphine level far higher than described in the literature: 87 ng/mL, vs. the typical level of 1.9–20.5 ng/mL associated with maternal doses of 60 mg of codeine every 6 hours (Lancet 2006;368:704).

Overall, there has been the perception that codeine is safe for the baby during breast-feeding. The few studies that have evaluated breast milk in women taking codeine have not found high morphine levels, and the American Academy of Pediatrics and other authoritative bodies list codeine as compatible with breast-feeding.

In most cases, this remains true. But considering the common practice of prescribing codeine for pain after episiotomy or cesarean section, many babies may be at risk. The prevalence of ultrarapid metabolizer status ranges from 1% in Denmark and Finland to 10% in Greece and Portugal to 29% in Ethiopia.

A genetic test is commercially available, but it is expensive and is currently not routinely performed. Other options all have pros and cons. One could withhold codeine in the postpartum period, but codeine is sometimes clearly needed for pain. Using a nonsteroidal anti-inflammatory drug and avoiding codeine when breast-feeding eliminates the risk of toxicity in the baby, but may not adequately control pain. Using a lower dose of codeine minimizes potential toxicity to the baby, but may not provide sufficient pain control for the mother, and the dose could still be too high if she is an ultrarapid metabolizer. Another option is to avoid breast-feeding while taking codeine, but the baby would lose the benefits of breast-feeding.

In our case the mother took codeine until the child died at 13 days, which is longer than usual. This suggests that use for no more than 2–3 days is advisable. In retrospect, there were clinical signs hinting that the mother was an ultrarapid metabolizer: Despite being on a low dose of codeine, in combination with paracetamol, she was somnolent and constipated, and the dose had to be reduced on the second day of treatment.

Be alert for signs and symptoms suggesting that a patient is an ultrarapid metabolizer, including somnolence, sleepiness, dizziness, and constipation. The metabolism to morphine by CYP2D6 is responsible for most of the analgesic and CNS depressant effects of codeine.

Why have cases like this one not been previously reported? I suspect such cases may not be as rare as we thought, but not all the cases are as tragic because the mothers do not take codeine for as long a time. For example, in a paper we published more than a decade ago on outcomes in babies exposed to drugs in breast milk, 25 women reported taking codeine while breast-feeding, and in five cases their babies were described as being sleepy. An abstract from a 1984 meeting described apnea in premature babies who were being breast-fed, which resolved as soon as their mothers stopped taking codeine. Interestingly, their symptoms began at about day 7, which was also the case in our report, suggesting it takes time for morphine to accumulate in the milk to dangerous levels.

Eventually, this is the type of pharmacogenetic information everyone will be aware of and will have available when presenting for medical care. For now, we are conducting a large case-control pharmacogenetic study funded by Genome Canada on babies who were breast-fed while the mother was using codeine to better define the scope of this issue.

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.

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. 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 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.

Presently, we can't 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.

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. 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 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.

Presently, we can't 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.

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. 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 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.

Presently, we can't 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.

For more than 20 years, the risk of neural tube defects (NTDs) associated with first-trimester exposure to valproic acid has been well known: The estimated risk is 2%, about 10− to 20-fold higher than the baseline risk. With more widespread use of valproic acid, partly due to increasing use of the drug for psychiatric conditions, more data and larger controlled studies on its teratogenic effects have accumulated over the past 3–4 years, revealing an association with major malformations that previously had been reported anecdotally. The main anomalies that have been identified are cardiac and limb malformations.

The results of these studies reflect what we found in a metaanalysis of data from 13 cohort studies in the medical literature, published between 1982 and 2005. The studies in the metaanalysis, published in April in a Canadian journal, compared rates of major malformations among women who reported taking valproic acid during the first trimester with rates among pregnant women who were taking other antiepileptic drugs (AEDs) and among women who were not taking any such drugs.

Nearly 1,000 pregnant women were exposed to valproic acid in the 13 studies. The risk of major malformations, including NTDs, associated with exposure to valproic acid was twofold greater than the risk with exposure to other AEDs. The risk was 4.4-fold greater than in the healthy controls, representing a highly significant increase in risk among valproic acid-exposed pregnancies.

We could not include three studies comparing the neurobehavioral risks of in utero exposure to valproic acid and other AEDs in the metaanalysis, because of their different designs and the variety of cognitive tests used. Still, all three reported an association between valproic acid and developmental delays and cognitive deficits. The most prominent effect was on verbal IQ. More studies on the neurodevelopmental effects of in utero exposure that control for maternal education and other confounding factors need to be conducted to further examine these associations.

On the positive side, in 3 of the 13 studies that also looked at the dose-dependent effects of valproic acid, the threshold dose to cause malformations was about 1,000 mg/day, which has been reported over the past few years. This is true for all malformations associated with valproic acid, including NTDs. In one study, first-trimester valproic acid plasma levels in women were higher among those who had a child with a malformation; in another, a daily dose of 1,000 mg was associated with a significantly increased risk for major malformations, especially NTDs; and in the third, mothers who had a child with spina bifida were on a mean dose of 1,640 mg/day vs. a mean of 941 mg/day among those whose children had no malformations. The same studies indicated that at less than 600 mg/day, there was no increased risk.

These relatively new findings of major malformations other than NTDs and the potentially increased risk of cognitive effects of valproic acid are important for women and physicians to consider when women are planning a pregnancy. Sometimes, women who have been on a drug for epilepsy for many years may no longer need it. If a switch to another drug is not possible, patients need to be monitored closely for malformations, as has been the practice for NTDs, although there is no way to monitor for potential cognitive effects.

Another approach for women who are dependent on valproic acid is to make every effort to keep the daily dose at 600 mg or below or, if that is not feasible, under 1,000 mg/day. Patients should be monitored with ultrasound, fetal echocardiography, and maternal and amniotic α-fetoprotein testing.

Evidence that reducing the dose can effectively reduce malformations came in a report last year from the Australian pregnancy registry for women on AEDs, which found the risk of fetal malformations was 13 times higher among women taking more than 1,100 mg of valproic acid per day as monotherapy, compared with women not taking an antiepileptic drug. Although the fetal malformation rate among those on lower doses was greater than the 2%–3% risk in the general population, the difference was not significant.

If possible, a different medication for controlling seizures should be considered. Carbamazepine (Tegretol) is considered by many neurologists and obstetricians to be the AED of choice in pregnancy, because the cumulative data to date do not reveal any risks of major malformations, except for spina bifida at about 1%, which is half the rate associated with valproic acid.

However, there are far fewer data on the reproductive risks of newer antiepileptics such as lamotrigine and gabapentin. Of the newer drugs, lamotrigine seems to be the most promising in terms of adverse fetal outcomes, but the number of pregnancies with data is much smaller than is available with valproic acid and carbamazepine.

For more than 20 years, the risk of neural tube defects (NTDs) associated with first-trimester exposure to valproic acid has been well known: The estimated risk is 2%, about 10− to 20-fold higher than the baseline risk. With more widespread use of valproic acid, partly due to increasing use of the drug for psychiatric conditions, more data and larger controlled studies on its teratogenic effects have accumulated over the past 3–4 years, revealing an association with major malformations that previously had been reported anecdotally. The main anomalies that have been identified are cardiac and limb malformations.

The results of these studies reflect what we found in a metaanalysis of data from 13 cohort studies in the medical literature, published between 1982 and 2005. The studies in the metaanalysis, published in April in a Canadian journal, compared rates of major malformations among women who reported taking valproic acid during the first trimester with rates among pregnant women who were taking other antiepileptic drugs (AEDs) and among women who were not taking any such drugs.

Nearly 1,000 pregnant women were exposed to valproic acid in the 13 studies. The risk of major malformations, including NTDs, associated with exposure to valproic acid was twofold greater than the risk with exposure to other AEDs. The risk was 4.4-fold greater than in the healthy controls, representing a highly significant increase in risk among valproic acid-exposed pregnancies.

We could not include three studies comparing the neurobehavioral risks of in utero exposure to valproic acid and other AEDs in the metaanalysis, because of their different designs and the variety of cognitive tests used. Still, all three reported an association between valproic acid and developmental delays and cognitive deficits. The most prominent effect was on verbal IQ. More studies on the neurodevelopmental effects of in utero exposure that control for maternal education and other confounding factors need to be conducted to further examine these associations.

On the positive side, in 3 of the 13 studies that also looked at the dose-dependent effects of valproic acid, the threshold dose to cause malformations was about 1,000 mg/day, which has been reported over the past few years. This is true for all malformations associated with valproic acid, including NTDs. In one study, first-trimester valproic acid plasma levels in women were higher among those who had a child with a malformation; in another, a daily dose of 1,000 mg was associated with a significantly increased risk for major malformations, especially NTDs; and in the third, mothers who had a child with spina bifida were on a mean dose of 1,640 mg/day vs. a mean of 941 mg/day among those whose children had no malformations. The same studies indicated that at less than 600 mg/day, there was no increased risk.

These relatively new findings of major malformations other than NTDs and the potentially increased risk of cognitive effects of valproic acid are important for women and physicians to consider when women are planning a pregnancy. Sometimes, women who have been on a drug for epilepsy for many years may no longer need it. If a switch to another drug is not possible, patients need to be monitored closely for malformations, as has been the practice for NTDs, although there is no way to monitor for potential cognitive effects.

Another approach for women who are dependent on valproic acid is to make every effort to keep the daily dose at 600 mg or below or, if that is not feasible, under 1,000 mg/day. Patients should be monitored with ultrasound, fetal echocardiography, and maternal and amniotic α-fetoprotein testing.

Evidence that reducing the dose can effectively reduce malformations came in a report last year from the Australian pregnancy registry for women on AEDs, which found the risk of fetal malformations was 13 times higher among women taking more than 1,100 mg of valproic acid per day as monotherapy, compared with women not taking an antiepileptic drug. Although the fetal malformation rate among those on lower doses was greater than the 2%–3% risk in the general population, the difference was not significant.

If possible, a different medication for controlling seizures should be considered. Carbamazepine (Tegretol) is considered by many neurologists and obstetricians to be the AED of choice in pregnancy, because the cumulative data to date do not reveal any risks of major malformations, except for spina bifida at about 1%, which is half the rate associated with valproic acid.

However, there are far fewer data on the reproductive risks of newer antiepileptics such as lamotrigine and gabapentin. Of the newer drugs, lamotrigine seems to be the most promising in terms of adverse fetal outcomes, but the number of pregnancies with data is much smaller than is available with valproic acid and carbamazepine.

For more than 20 years, the risk of neural tube defects (NTDs) associated with first-trimester exposure to valproic acid has been well known: The estimated risk is 2%, about 10− to 20-fold higher than the baseline risk. With more widespread use of valproic acid, partly due to increasing use of the drug for psychiatric conditions, more data and larger controlled studies on its teratogenic effects have accumulated over the past 3–4 years, revealing an association with major malformations that previously had been reported anecdotally. The main anomalies that have been identified are cardiac and limb malformations.

The results of these studies reflect what we found in a metaanalysis of data from 13 cohort studies in the medical literature, published between 1982 and 2005. The studies in the metaanalysis, published in April in a Canadian journal, compared rates of major malformations among women who reported taking valproic acid during the first trimester with rates among pregnant women who were taking other antiepileptic drugs (AEDs) and among women who were not taking any such drugs.

Nearly 1,000 pregnant women were exposed to valproic acid in the 13 studies. The risk of major malformations, including NTDs, associated with exposure to valproic acid was twofold greater than the risk with exposure to other AEDs. The risk was 4.4-fold greater than in the healthy controls, representing a highly significant increase in risk among valproic acid-exposed pregnancies.

We could not include three studies comparing the neurobehavioral risks of in utero exposure to valproic acid and other AEDs in the metaanalysis, because of their different designs and the variety of cognitive tests used. Still, all three reported an association between valproic acid and developmental delays and cognitive deficits. The most prominent effect was on verbal IQ. More studies on the neurodevelopmental effects of in utero exposure that control for maternal education and other confounding factors need to be conducted to further examine these associations.

On the positive side, in 3 of the 13 studies that also looked at the dose-dependent effects of valproic acid, the threshold dose to cause malformations was about 1,000 mg/day, which has been reported over the past few years. This is true for all malformations associated with valproic acid, including NTDs. In one study, first-trimester valproic acid plasma levels in women were higher among those who had a child with a malformation; in another, a daily dose of 1,000 mg was associated with a significantly increased risk for major malformations, especially NTDs; and in the third, mothers who had a child with spina bifida were on a mean dose of 1,640 mg/day vs. a mean of 941 mg/day among those whose children had no malformations. The same studies indicated that at less than 600 mg/day, there was no increased risk.

These relatively new findings of major malformations other than NTDs and the potentially increased risk of cognitive effects of valproic acid are important for women and physicians to consider when women are planning a pregnancy. Sometimes, women who have been on a drug for epilepsy for many years may no longer need it. If a switch to another drug is not possible, patients need to be monitored closely for malformations, as has been the practice for NTDs, although there is no way to monitor for potential cognitive effects.

Another approach for women who are dependent on valproic acid is to make every effort to keep the daily dose at 600 mg or below or, if that is not feasible, under 1,000 mg/day. Patients should be monitored with ultrasound, fetal echocardiography, and maternal and amniotic α-fetoprotein testing.

Evidence that reducing the dose can effectively reduce malformations came in a report last year from the Australian pregnancy registry for women on AEDs, which found the risk of fetal malformations was 13 times higher among women taking more than 1,100 mg of valproic acid per day as monotherapy, compared with women not taking an antiepileptic drug. Although the fetal malformation rate among those on lower doses was greater than the 2%–3% risk in the general population, the difference was not significant.

If possible, a different medication for controlling seizures should be considered. Carbamazepine (Tegretol) is considered by many neurologists and obstetricians to be the AED of choice in pregnancy, because the cumulative data to date do not reveal any risks of major malformations, except for spina bifida at about 1%, which is half the rate associated with valproic acid.

However, there are far fewer data on the reproductive risks of newer antiepileptics such as lamotrigine and gabapentin. Of the newer drugs, lamotrigine seems to be the most promising in terms of adverse fetal outcomes, but the number of pregnancies with data is much smaller than is available with valproic acid and carbamazepine.

For more than 20 years, the risk of neural tube defects (NTDs) associated with first-trimester exposure to valproic acid has been well known: The estimated risk is 2%, about 10− to 20-fold higher than the baseline risk. With more widespread use of valproic acid, partly due to increasing use of the drug for psychiatric conditions, more data and larger controlled studies on its teratogenic effects have accumulated over the past 3–4 years, revealing an association with major malformations that previously had been reported anecdotally. The main anomalies that have been identified are cardiac and limb malformations.

The results reflect what we found in a metaanalysis of data from 13 cohort studies in the medical literature. The studies in the metaanalysis, which will be published this month in a Canadian journal, compared rates of major malformations among women who reported taking valproic acid during the first trimester with rates among pregnant women who were taking other antiepileptic drugs (AEDs) and among women who were not taking any such drugs.

Nearly 1,000 pregnant women were exposed to valproic acid in the 13 studies. The risk of major malformations, including NTDs, associated with exposure to valproic acid was twofold greater than the risk with exposure to other AEDs. The risk was 4.4-fold greater than in the healthy controls, representing a highly significant increase in risk among valproic acid-exposed pregnancies.

We could not include three studies comparing the neurobehavioral risks of in-utero exposure to valproic acid and other AEDs in the metaanalysis, because of their different designs and the variety of cognitive tests used. Still, all three reported an association between valproic acid and developmental delays and cognitive deficits. The most prominent effect was on verbal IQ. More studies on the neurodevelopmental effects of in-utero exposure that control for maternal education and other confounding factors need to be conducted to further examine these associations.

On the positive side, in 3 of the 13 studies that also looked at the dose-dependent effects of valproic acid, the threshold dose needed to cause malformations was about 1,000 mg/day, which has been reported over the past few years. This is true for all malformations associated with valproic acid, including NTDs. In one study, first-trimester valproic acid plasma levels in women were higher among those who had a child with a malformation; in another, a daily dose of 1,000 mg was associated with a significantly increased risk for major malformations, especially NTDs; and in the third, mothers who had a child with spina bifida were on a mean dose of 1,640 mg/day vs. a mean of 941 mg/day among those whose children had no malformations. The same studies indicated that at a dose of less than 600 mg/day, there was no increased risk.

These relatively new findings of major malformations other than NTDs and the potentially increased risk of cognitive effects of valproic acid are important for women and physicians to consider when women are planning a pregnancy. Sometimes, women who have been on a drug for epilepsy for many years may no longer need it. If a switch to another drug is not possible, patients need to be monitored closely for malformations, as has been the practice for NTDs, although there is no way to monitor for potential cognitive effects.

Another approach for women who are dependent on valproic acid is to make every effort to keep the daily dose at 600 mg or below or, if that is not feasible, under 1,000 mg/day. Patients should be monitored with ultrasound, fetal echocardiography, and maternal and amniotic α-fetoprotein testing.

Evidence that reducing the dose can be effective in reducing malformations was provided by a report last year from the Australian pregnancy registry for women on AEDs, which found the risk of fetal malformations was 13 times higher among women taking more than 1,100 mg of valproic acid per day as monotherapy, compared with women not taking an antiepileptic drug. Although the malformation rate among those on lower doses was greater than the 2%–3% risk in the general population, the difference was not significant.

If possible, a different medication for controlling seizures should be considered. Carbamazepine (Tegretol) is considered by many neurologists and obstetricians to be the AED of choice in pregnancy, because the data to date do not reveal any risks of major malformations, except for spina bifida at about 1%, which is half the rate associated with valproic acid. There are fewer data on the reproductive risks of newer antiepileptics, such as lamotrigine and gabapentin. Of all the newer drugs, lamotrigine appears to be the most promising in terms of adverse fetal outcomes, but the number of pregnancies with data is much smaller than is available with valproic acid and carbamazepine.

For more than 20 years, the risk of neural tube defects (NTDs) associated with first-trimester exposure to valproic acid has been well known: The estimated risk is 2%, about 10− to 20-fold higher than the baseline risk. With more widespread use of valproic acid, partly due to increasing use of the drug for psychiatric conditions, more data and larger controlled studies on its teratogenic effects have accumulated over the past 3–4 years, revealing an association with major malformations that previously had been reported anecdotally. The main anomalies that have been identified are cardiac and limb malformations.

The results reflect what we found in a metaanalysis of data from 13 cohort studies in the medical literature. The studies in the metaanalysis, which will be published this month in a Canadian journal, compared rates of major malformations among women who reported taking valproic acid during the first trimester with rates among pregnant women who were taking other antiepileptic drugs (AEDs) and among women who were not taking any such drugs.

Nearly 1,000 pregnant women were exposed to valproic acid in the 13 studies. The risk of major malformations, including NTDs, associated with exposure to valproic acid was twofold greater than the risk with exposure to other AEDs. The risk was 4.4-fold greater than in the healthy controls, representing a highly significant increase in risk among valproic acid-exposed pregnancies.

We could not include three studies comparing the neurobehavioral risks of in-utero exposure to valproic acid and other AEDs in the metaanalysis, because of their different designs and the variety of cognitive tests used. Still, all three reported an association between valproic acid and developmental delays and cognitive deficits. The most prominent effect was on verbal IQ. More studies on the neurodevelopmental effects of in-utero exposure that control for maternal education and other confounding factors need to be conducted to further examine these associations.

On the positive side, in 3 of the 13 studies that also looked at the dose-dependent effects of valproic acid, the threshold dose needed to cause malformations was about 1,000 mg/day, which has been reported over the past few years. This is true for all malformations associated with valproic acid, including NTDs. In one study, first-trimester valproic acid plasma levels in women were higher among those who had a child with a malformation; in another, a daily dose of 1,000 mg was associated with a significantly increased risk for major malformations, especially NTDs; and in the third, mothers who had a child with spina bifida were on a mean dose of 1,640 mg/day vs. a mean of 941 mg/day among those whose children had no malformations. The same studies indicated that at a dose of less than 600 mg/day, there was no increased risk.

These relatively new findings of major malformations other than NTDs and the potentially increased risk of cognitive effects of valproic acid are important for women and physicians to consider when women are planning a pregnancy. Sometimes, women who have been on a drug for epilepsy for many years may no longer need it. If a switch to another drug is not possible, patients need to be monitored closely for malformations, as has been the practice for NTDs, although there is no way to monitor for potential cognitive effects.

Another approach for women who are dependent on valproic acid is to make every effort to keep the daily dose at 600 mg or below or, if that is not feasible, under 1,000 mg/day. Patients should be monitored with ultrasound, fetal echocardiography, and maternal and amniotic α-fetoprotein testing.

Evidence that reducing the dose can be effective in reducing malformations was provided by a report last year from the Australian pregnancy registry for women on AEDs, which found the risk of fetal malformations was 13 times higher among women taking more than 1,100 mg of valproic acid per day as monotherapy, compared with women not taking an antiepileptic drug. Although the malformation rate among those on lower doses was greater than the 2%–3% risk in the general population, the difference was not significant.

If possible, a different medication for controlling seizures should be considered. Carbamazepine (Tegretol) is considered by many neurologists and obstetricians to be the AED of choice in pregnancy, because the data to date do not reveal any risks of major malformations, except for spina bifida at about 1%, which is half the rate associated with valproic acid. There are fewer data on the reproductive risks of newer antiepileptics, such as lamotrigine and gabapentin. Of all the newer drugs, lamotrigine appears to be the most promising in terms of adverse fetal outcomes, but the number of pregnancies with data is much smaller than is available with valproic acid and carbamazepine.

For more than 20 years, the risk of neural tube defects (NTDs) associated with first-trimester exposure to valproic acid has been well known: The estimated risk is 2%, about 10− to 20-fold higher than the baseline risk. With more widespread use of valproic acid, partly due to increasing use of the drug for psychiatric conditions, more data and larger controlled studies on its teratogenic effects have accumulated over the past 3–4 years, revealing an association with major malformations that previously had been reported anecdotally. The main anomalies that have been identified are cardiac and limb malformations.

The results reflect what we found in a metaanalysis of data from 13 cohort studies in the medical literature. The studies in the metaanalysis, which will be published this month in a Canadian journal, compared rates of major malformations among women who reported taking valproic acid during the first trimester with rates among pregnant women who were taking other antiepileptic drugs (AEDs) and among women who were not taking any such drugs.

Nearly 1,000 pregnant women were exposed to valproic acid in the 13 studies. The risk of major malformations, including NTDs, associated with exposure to valproic acid was twofold greater than the risk with exposure to other AEDs. The risk was 4.4-fold greater than in the healthy controls, representing a highly significant increase in risk among valproic acid-exposed pregnancies.

We could not include three studies comparing the neurobehavioral risks of in-utero exposure to valproic acid and other AEDs in the metaanalysis, because of their different designs and the variety of cognitive tests used. Still, all three reported an association between valproic acid and developmental delays and cognitive deficits. The most prominent effect was on verbal IQ. More studies on the neurodevelopmental effects of in-utero exposure that control for maternal education and other confounding factors need to be conducted to further examine these associations.

On the positive side, in 3 of the 13 studies that also looked at the dose-dependent effects of valproic acid, the threshold dose needed to cause malformations was about 1,000 mg/day, which has been reported over the past few years. This is true for all malformations associated with valproic acid, including NTDs. In one study, first-trimester valproic acid plasma levels in women were higher among those who had a child with a malformation; in another, a daily dose of 1,000 mg was associated with a significantly increased risk for major malformations, especially NTDs; and in the third, mothers who had a child with spina bifida were on a mean dose of 1,640 mg/day vs. a mean of 941 mg/day among those whose children had no malformations. The same studies indicated that at a dose of less than 600 mg/day, there was no increased risk.

These relatively new findings of major malformations other than NTDs and the potentially increased risk of cognitive effects of valproic acid are important for women and physicians to consider when women are planning a pregnancy. Sometimes, women who have been on a drug for epilepsy for many years may no longer need it. If a switch to another drug is not possible, patients need to be monitored closely for malformations, as has been the practice for NTDs, although there is no way to monitor for potential cognitive effects.

Another approach for women who are dependent on valproic acid is to make every effort to keep the daily dose at 600 mg or below or, if that is not feasible, under 1,000 mg/day. Patients should be monitored with ultrasound, fetal echocardiography, and maternal and amniotic α-fetoprotein testing.

Evidence that reducing the dose can be effective in reducing malformations was provided by a report last year from the Australian pregnancy registry for women on AEDs, which found the risk of fetal malformations was 13 times higher among women taking more than 1,100 mg of valproic acid per day as monotherapy, compared with women not taking an antiepileptic drug. Although the malformation rate among those on lower doses was greater than the 2%–3% risk in the general population, the difference was not significant.

If possible, a different medication for controlling seizures should be considered. Carbamazepine (Tegretol) is considered by many neurologists and obstetricians to be the AED of choice in pregnancy, because the data to date do not reveal any risks of major malformations, except for spina bifida at about 1%, which is half the rate associated with valproic acid. There are fewer data on the reproductive risks of newer antiepileptics, such as lamotrigine and gabapentin. Of all the newer drugs, lamotrigine appears to be the most promising in terms of adverse fetal outcomes, but the number of pregnancies with data is much smaller than is available with valproic acid and carbamazepine.

www.motherisk.org

The widespread prescribing of corticosteroids in medicine includes many clinical situations during pregnancy, which naturally raises concerns about the safety of these drugs in pregnant women. Over the past several years, information on this topic has begun to accumulate, providing stronger evidence about the safety of inhaled corticosteroids in this population.

Most recently, in October, the largest study to date, conducted by the Organization of Teratology Information Services (OTIS), on the use of medications for asthma during pregnancy and their effects on fetal growth was published. The main finding was that treatment of pregnant women with β₂-agonists and inhaled steroids did not have adverse effects on fetal growth and that systemic corticosteroids had a minimal effect on birth weight and length.

The prospective study compared birth size and the incidence of babies born small for gestational age (SGA) in 654 infants whose mothers had taken inhaled or systemic corticosteroids and β₂-agonists for asthma during pregnancy with birth size and incidence of SGA in 303 infants whose mothers did not have asthma. Women from North America were enrolled between 1998 and 2003. There were no significant differences in the incidence of SGA for weight between the groups. There was a small reduction in birth weight among those exposed to systemic steroids: In this group, the mean birth weight, adjusted for other risk factors, was 3,373 g, compared with a mean of 3,540 g among controls, 3,552 g among those exposed to β₂-agonists only, and 3,524 g among those exposed to inhaled steroids.

Mean birth weight and mean birth length, adjusted for risk factors, among infants whose mothers had been treated with inhaled steroids were not significantly different from those of controls or of infants whose mothers had used β₂-agonists only. The adjusted mean birth lengths were 51.3 cm in the inhaled steroid group and 51.5 cm in the β₂-agonist group.

The authors, from the University of California, San Diego and the OTIS Research Group, concluded that these results were “reassuring and support the recommendations of adequate control of severe asthma during pregnancy,” and that “the modest effect of systemic steroids on fetal growth should be weighed against the necessity to achieve adequate control of severe persistent asthma and to prevent hypoxia during pregnancy” (J. Allergy Clin. Immunol. 2005;116:503–9).

While these conclusions are not novel, this study is a major breakthrough because it combines information from teratology information centers in North America to provide much larger numbers than were available previously.

Women and physicians should be informed there are some risks: In 2000, my colleagues and I published a metaanalysis of all available studies of women who were given high-dose steroids during pregnancy for various reasons. The results clearly indicated that the use of systemic steroids during the first trimester was associated with a two- to threefold greater risk of oral clefts. This finding was consistent with extensive animal data that have shown the same association.

However, inhaled corticosteroids, commonly used as first-line therapy for asthma, result in an extremely low systemic dose, and none of the available reviews on the use of inhaled steroids during pregnancy have found any association with a greater risk of oral clefts. The β₂-agonist albuterol is not teratogenic.

There is emerging evidence that repeated weekly corticosteroid injections for fetal lung maturation in cases of premature rupture of the membranes may result in brain damage in some babies. But this is not relevant to the use of inhaled corticosteroids in pregnant women with asthma.

Therefore, based on this recent study and previous data, pregnant women should be encouraged not to neglect their asthma therapy because of concerns about potential effects on the fetus. The risks include higher rates of perinatal complications, mostly prematurity, when asthma is poorly controlled. We are aware of fatal cases of women who stopped much-needed asthma treatment during pregnancy.

The authors of an editorial accompanying the OTIS study state that inhaled steroids “do not seem to significantly impair fetal growth,” but add that “before ruling out with confidence any potential adverse effect” of inhaled steroids on fetal growth, “there is a need for larger studies adequately powered to answer this question” (J. Allergy Clin. Immunol. 2005;116:501–2). While I agree that we always need more studies, the risk-benefit ratios should dictate optimal treatment of maternal asthma.

www.motherisk.org

The widespread prescribing of corticosteroids in medicine includes many clinical situations during pregnancy, which naturally raises concerns about the safety of these drugs in pregnant women. Over the past several years, information on this topic has begun to accumulate, providing stronger evidence about the safety of inhaled corticosteroids in this population.

Most recently, in October, the largest study to date, conducted by the Organization of Teratology Information Services (OTIS), on the use of medications for asthma during pregnancy and their effects on fetal growth was published. The main finding was that treatment of pregnant women with β₂-agonists and inhaled steroids did not have adverse effects on fetal growth and that systemic corticosteroids had a minimal effect on birth weight and length.

The prospective study compared birth size and the incidence of babies born small for gestational age (SGA) in 654 infants whose mothers had taken inhaled or systemic corticosteroids and β₂-agonists for asthma during pregnancy with birth size and incidence of SGA in 303 infants whose mothers did not have asthma. Women from North America were enrolled between 1998 and 2003. There were no significant differences in the incidence of SGA for weight between the groups. There was a small reduction in birth weight among those exposed to systemic steroids: In this group, the mean birth weight, adjusted for other risk factors, was 3,373 g, compared with a mean of 3,540 g among controls, 3,552 g among those exposed to β₂-agonists only, and 3,524 g among those exposed to inhaled steroids.

Mean birth weight and mean birth length, adjusted for risk factors, among infants whose mothers had been treated with inhaled steroids were not significantly different from those of controls or of infants whose mothers had used β₂-agonists only. The adjusted mean birth lengths were 51.3 cm in the inhaled steroid group and 51.5 cm in the β₂-agonist group.

The authors, from the University of California, San Diego and the OTIS Research Group, concluded that these results were “reassuring and support the recommendations of adequate control of severe asthma during pregnancy,” and that “the modest effect of systemic steroids on fetal growth should be weighed against the necessity to achieve adequate control of severe persistent asthma and to prevent hypoxia during pregnancy” (J. Allergy Clin. Immunol. 2005;116:503–9).

While these conclusions are not novel, this study is a major breakthrough because it combines information from teratology information centers in North America to provide much larger numbers than were available previously.

Women and physicians should be informed there are some risks: In 2000, my colleagues and I published a metaanalysis of all available studies of women who were given high-dose steroids during pregnancy for various reasons. The results clearly indicated that the use of systemic steroids during the first trimester was associated with a two- to threefold greater risk of oral clefts. This finding was consistent with extensive animal data that have shown the same association.

However, inhaled corticosteroids, commonly used as first-line therapy for asthma, result in an extremely low systemic dose, and none of the available reviews on the use of inhaled steroids during pregnancy have found any association with a greater risk of oral clefts. The β₂-agonist albuterol is not teratogenic.

There is emerging evidence that repeated weekly corticosteroid injections for fetal lung maturation in cases of premature rupture of the membranes may result in brain damage in some babies. But this is not relevant to the use of inhaled corticosteroids in pregnant women with asthma.

Therefore, based on this recent study and previous data, pregnant women should be encouraged not to neglect their asthma therapy because of concerns about potential effects on the fetus. The risks include higher rates of perinatal complications, mostly prematurity, when asthma is poorly controlled. We are aware of fatal cases of women who stopped much-needed asthma treatment during pregnancy.

The authors of an editorial accompanying the OTIS study state that inhaled steroids “do not seem to significantly impair fetal growth,” but add that “before ruling out with confidence any potential adverse effect” of inhaled steroids on fetal growth, “there is a need for larger studies adequately powered to answer this question” (J. Allergy Clin. Immunol. 2005;116:501–2). While I agree that we always need more studies, the risk-benefit ratios should dictate optimal treatment of maternal asthma.

www.motherisk.org

The widespread prescribing of corticosteroids in medicine includes many clinical situations during pregnancy, which naturally raises concerns about the safety of these drugs in pregnant women. Over the past several years, information on this topic has begun to accumulate, providing stronger evidence about the safety of inhaled corticosteroids in this population.

Most recently, in October, the largest study to date, conducted by the Organization of Teratology Information Services (OTIS), on the use of medications for asthma during pregnancy and their effects on fetal growth was published. The main finding was that treatment of pregnant women with β₂-agonists and inhaled steroids did not have adverse effects on fetal growth and that systemic corticosteroids had a minimal effect on birth weight and length.

The prospective study compared birth size and the incidence of babies born small for gestational age (SGA) in 654 infants whose mothers had taken inhaled or systemic corticosteroids and β₂-agonists for asthma during pregnancy with birth size and incidence of SGA in 303 infants whose mothers did not have asthma. Women from North America were enrolled between 1998 and 2003. There were no significant differences in the incidence of SGA for weight between the groups. There was a small reduction in birth weight among those exposed to systemic steroids: In this group, the mean birth weight, adjusted for other risk factors, was 3,373 g, compared with a mean of 3,540 g among controls, 3,552 g among those exposed to β₂-agonists only, and 3,524 g among those exposed to inhaled steroids.

Mean birth weight and mean birth length, adjusted for risk factors, among infants whose mothers had been treated with inhaled steroids were not significantly different from those of controls or of infants whose mothers had used β₂-agonists only. The adjusted mean birth lengths were 51.3 cm in the inhaled steroid group and 51.5 cm in the β₂-agonist group.

The authors, from the University of California, San Diego and the OTIS Research Group, concluded that these results were “reassuring and support the recommendations of adequate control of severe asthma during pregnancy,” and that “the modest effect of systemic steroids on fetal growth should be weighed against the necessity to achieve adequate control of severe persistent asthma and to prevent hypoxia during pregnancy” (J. Allergy Clin. Immunol. 2005;116:503–9).

While these conclusions are not novel, this study is a major breakthrough because it combines information from teratology information centers in North America to provide much larger numbers than were available previously.

Women and physicians should be informed there are some risks: In 2000, my colleagues and I published a metaanalysis of all available studies of women who were given high-dose steroids during pregnancy for various reasons. The results clearly indicated that the use of systemic steroids during the first trimester was associated with a two- to threefold greater risk of oral clefts. This finding was consistent with extensive animal data that have shown the same association.

However, inhaled corticosteroids, commonly used as first-line therapy for asthma, result in an extremely low systemic dose, and none of the available reviews on the use of inhaled steroids during pregnancy have found any association with a greater risk of oral clefts. The β₂-agonist albuterol is not teratogenic.

There is emerging evidence that repeated weekly corticosteroid injections for fetal lung maturation in cases of premature rupture of the membranes may result in brain damage in some babies. But this is not relevant to the use of inhaled corticosteroids in pregnant women with asthma.

Therefore, based on this recent study and previous data, pregnant women should be encouraged not to neglect their asthma therapy because of concerns about potential effects on the fetus. The risks include higher rates of perinatal complications, mostly prematurity, when asthma is poorly controlled. We are aware of fatal cases of women who stopped much-needed asthma treatment during pregnancy.

The authors of an editorial accompanying the OTIS study state that inhaled steroids “do not seem to significantly impair fetal growth,” but add that “before ruling out with confidence any potential adverse effect” of inhaled steroids on fetal growth, “there is a need for larger studies adequately powered to answer this question” (J. Allergy Clin. Immunol. 2005;116:501–2). While I agree that we always need more studies, the risk-benefit ratios should dictate optimal treatment of maternal asthma.

www.motherisk.org

A recently published study on recreational drug use during pregnancy and the possible link to fetal gastroschisis highlights an increasingly important area of research: hair testing as a biomarker for pregnancy exposure to recreational drugs or drugs of abuse. Our laboratory is one of several sites in North America with expertise in measuring these substances in hair, an area many obstetricians may not be aware of.

Clearly, it can be difficult to determine the types of chemicals or drugs a fetus may have been exposed to by relying on what a woman says she took during her pregnancy. Forensic science has provided us with a great deal of help in this area.

Forensic scientists have known for some time that drugs taken by an individual are grown into the hair, and do not go away. The first use of this technology was to detect long-term exposure to heavy metals. Over the last 15–20 years, more drugs of abuse have been determined to grow into adult hair, including cocaine, heroin, marijuana, LSD, amphetamine, and methamphetamine. In 1988, we determined that the same is true for the baby. Because the hair present at birth grows during the last 3 months of gestation, an analysis of a baby's hair can provide information on possible drug exposure during that time. We have now shown this is true for almost every drug of abuse, as well as nicotine.

With babies, the same substances can also be measured in meconium, and exposure can be traced to as early as 14 weeks' gestation, when meconium begins to form. Hair and meconium testing have become quite routine in certain settings in North America, with the predominant use among child protection agencies or children's aid societies. This testing is also used for research and clinical purposes and by neonatologists, pediatricians, and other health care professionals who have a medical reason to test, often in the context of diagnosing issues in the child, and when maternal consent is provided. For such studies to be conducted, the guardian's consent is needed; sensitive attitudes and high ethical standards need to be practiced.

It's possible to use meconium analysis to test for excessive maternal alcohol intake by measuring fatty acid ethyl esters, conjugates of alcohol with fatty acids, which stay in the meconium of the baby. Recent work from investigators in Berlin determined that fatty acid ethyl esters can also be measured in the hair of the parents. Animal studies indicate they can be measured in a baby's hair, which is being investigated in human studies that are underway.

Analyzing hair samples provides an opportunity to look, not just at one sample of urine or blood that represents the last day or so of exposure but, rather, long-term exposure. At our laboratory, we use hair testing to determine when exposure occurred, which eliminates the uncertainties when this information is obtained from the individual.

Last year we published a review (Clin. Biochemistry 2004;37:429–38) that discussed hair and meconium testing to confirm the prenatal use of alcohol and tobacco. It is important for clinicians to recognize that positive neonatal or meconium tests for drugs of abuse are strong evidence for maternal addiction, as these drugs have been used long after the mother knew that she had conceived.

In a study conducted at the Motherisk laboratory published in 2003 (Arch. Dis. Child. Fetal Neonatal Ed. 2003; 88:F98-F100), we found that meconium was somewhat more sensitive than hair samples of newborns for detecting cocaine and cannabis, and found a significant correlation between hair and meconium levels of cocaine, cannabis, and opiates. We concluded that both methods were useful biologic markers of illicit drug exposure in utero and also useful in suspicious cases where the neonatal urine test is negative.

In the recent gastroschisis study, investigators used maternal hair analysis from samples taken between 14 and 33 weeks' gestation in 22 pregnant women with a fetus diagnosed with the disorder and in 25 pregnant women with a normal fetus (BJOG 2005;112:1022–5).

Although the study is small and therefore cannot establish an association, it marks the first time that “objective measurements of maternal intake of recreational drug compounds at these critical periods of development for the fetus have been carried out,” as the researchers noted.

This effort should be welcomed. Clearly, hair testing can be a very powerful tool in these studies and in individual cases to help determine whether a woman is using drugs.

www.motherisk.org

A recently published study on recreational drug use during pregnancy and the possible link to fetal gastroschisis highlights an increasingly important area of research: hair testing as a biomarker for pregnancy exposure to recreational drugs or drugs of abuse. Our laboratory is one of several sites in North America with expertise in measuring these substances in hair, an area many obstetricians may not be aware of.

Clearly, it can be difficult to determine the types of chemicals or drugs a fetus may have been exposed to by relying on what a woman says she took during her pregnancy. Forensic science has provided us with a great deal of help in this area.

Forensic scientists have known for some time that drugs taken by an individual are grown into the hair, and do not go away. The first use of this technology was to detect long-term exposure to heavy metals. Over the last 15–20 years, more drugs of abuse have been determined to grow into adult hair, including cocaine, heroin, marijuana, LSD, amphetamine, and methamphetamine. In 1988, we determined that the same is true for the baby. Because the hair present at birth grows during the last 3 months of gestation, an analysis of a baby's hair can provide information on possible drug exposure during that time. We have now shown this is true for almost every drug of abuse, as well as nicotine.

With babies, the same substances can also be measured in meconium, and exposure can be traced to as early as 14 weeks' gestation, when meconium begins to form. Hair and meconium testing have become quite routine in certain settings in North America, with the predominant use among child protection agencies or children's aid societies. This testing is also used for research and clinical purposes and by neonatologists, pediatricians, and other health care professionals who have a medical reason to test, often in the context of diagnosing issues in the child, and when maternal consent is provided. For such studies to be conducted, the guardian's consent is needed; sensitive attitudes and high ethical standards need to be practiced.

It's possible to use meconium analysis to test for excessive maternal alcohol intake by measuring fatty acid ethyl esters, conjugates of alcohol with fatty acids, which stay in the meconium of the baby. Recent work from investigators in Berlin determined that fatty acid ethyl esters can also be measured in the hair of the parents. Animal studies indicate they can be measured in a baby's hair, which is being investigated in human studies that are underway.

Analyzing hair samples provides an opportunity to look, not just at one sample of urine or blood that represents the last day or so of exposure but, rather, long-term exposure. At our laboratory, we use hair testing to determine when exposure occurred, which eliminates the uncertainties when this information is obtained from the individual.

Last year we published a review (Clin. Biochemistry 2004;37:429–38) that discussed hair and meconium testing to confirm the prenatal use of alcohol and tobacco. It is important for clinicians to recognize that positive neonatal or meconium tests for drugs of abuse are strong evidence for maternal addiction, as these drugs have been used long after the mother knew that she had conceived.

In a study conducted at the Motherisk laboratory published in 2003 (Arch. Dis. Child. Fetal Neonatal Ed. 2003; 88:F98-F100), we found that meconium was somewhat more sensitive than hair samples of newborns for detecting cocaine and cannabis, and found a significant correlation between hair and meconium levels of cocaine, cannabis, and opiates. We concluded that both methods were useful biologic markers of illicit drug exposure in utero and also useful in suspicious cases where the neonatal urine test is negative.

In the recent gastroschisis study, investigators used maternal hair analysis from samples taken between 14 and 33 weeks' gestation in 22 pregnant women with a fetus diagnosed with the disorder and in 25 pregnant women with a normal fetus (BJOG 2005;112:1022–5).

Although the study is small and therefore cannot establish an association, it marks the first time that “objective measurements of maternal intake of recreational drug compounds at these critical periods of development for the fetus have been carried out,” as the researchers noted.

This effort should be welcomed. Clearly, hair testing can be a very powerful tool in these studies and in individual cases to help determine whether a woman is using drugs.

www.motherisk.org

A recently published study on recreational drug use during pregnancy and the possible link to fetal gastroschisis highlights an increasingly important area of research: hair testing as a biomarker for pregnancy exposure to recreational drugs or drugs of abuse. Our laboratory is one of several sites in North America with expertise in measuring these substances in hair, an area many obstetricians may not be aware of.

Clearly, it can be difficult to determine the types of chemicals or drugs a fetus may have been exposed to by relying on what a woman says she took during her pregnancy. Forensic science has provided us with a great deal of help in this area.

Forensic scientists have known for some time that drugs taken by an individual are grown into the hair, and do not go away. The first use of this technology was to detect long-term exposure to heavy metals. Over the last 15–20 years, more drugs of abuse have been determined to grow into adult hair, including cocaine, heroin, marijuana, LSD, amphetamine, and methamphetamine. In 1988, we determined that the same is true for the baby. Because the hair present at birth grows during the last 3 months of gestation, an analysis of a baby's hair can provide information on possible drug exposure during that time. We have now shown this is true for almost every drug of abuse, as well as nicotine.

With babies, the same substances can also be measured in meconium, and exposure can be traced to as early as 14 weeks' gestation, when meconium begins to form. Hair and meconium testing have become quite routine in certain settings in North America, with the predominant use among child protection agencies or children's aid societies. This testing is also used for research and clinical purposes and by neonatologists, pediatricians, and other health care professionals who have a medical reason to test, often in the context of diagnosing issues in the child, and when maternal consent is provided. For such studies to be conducted, the guardian's consent is needed; sensitive attitudes and high ethical standards need to be practiced.

It's possible to use meconium analysis to test for excessive maternal alcohol intake by measuring fatty acid ethyl esters, conjugates of alcohol with fatty acids, which stay in the meconium of the baby. Recent work from investigators in Berlin determined that fatty acid ethyl esters can also be measured in the hair of the parents. Animal studies indicate they can be measured in a baby's hair, which is being investigated in human studies that are underway.

Analyzing hair samples provides an opportunity to look, not just at one sample of urine or blood that represents the last day or so of exposure but, rather, long-term exposure. At our laboratory, we use hair testing to determine when exposure occurred, which eliminates the uncertainties when this information is obtained from the individual.

Last year we published a review (Clin. Biochemistry 2004;37:429–38) that discussed hair and meconium testing to confirm the prenatal use of alcohol and tobacco. It is important for clinicians to recognize that positive neonatal or meconium tests for drugs of abuse are strong evidence for maternal addiction, as these drugs have been used long after the mother knew that she had conceived.

In a study conducted at the Motherisk laboratory published in 2003 (Arch. Dis. Child. Fetal Neonatal Ed. 2003; 88:F98-F100), we found that meconium was somewhat more sensitive than hair samples of newborns for detecting cocaine and cannabis, and found a significant correlation between hair and meconium levels of cocaine, cannabis, and opiates. We concluded that both methods were useful biologic markers of illicit drug exposure in utero and also useful in suspicious cases where the neonatal urine test is negative.

In the recent gastroschisis study, investigators used maternal hair analysis from samples taken between 14 and 33 weeks' gestation in 22 pregnant women with a fetus diagnosed with the disorder and in 25 pregnant women with a normal fetus (BJOG 2005;112:1022–5).

Although the study is small and therefore cannot establish an association, it marks the first time that “objective measurements of maternal intake of recreational drug compounds at these critical periods of development for the fetus have been carried out,” as the researchers noted.

This effort should be welcomed. Clearly, hair testing can be a very powerful tool in these studies and in individual cases to help determine whether a woman is using drugs.

www.motherisk.org

The widespread prescribing of corticosteroids in medicine includes many clinical situations during pregnancy, which naturally raises concerns about the safety of these drugs in pregnant women. Over the past several years, information on this topic has begun to accumulate, providing stronger evidence about the safety of inhaled corticosteroids in this population.

Most recently, in October, the largest study to date, conducted by the Organization of Teratology Information Services (OTIS), on the use of medications for asthma during pregnancy and their effects on fetal growth was published. The main finding was that treatment of pregnant women with ?2-agonists and inhaled steroids did not have adverse effects on fetal growth and that systemic corticosteroids had a minimal effect on birth weight and length.

The prospective study compared birth size and the incidence of babies born small for gestational age (SGA) in 654 infants whose mothers had taken inhaled or systemic corticosteroids and ?2-agonists for asthma during pregnancy with birth size and incidence of SGA in 303 infants whose mothers did not have asthma. Women from North America were enrolled between 1998 and 2003. There were no significant differences in the incidence of SGA for weight between the groups. There was a small reduction in birth weight among those exposed to systemic steroids: In this group, the mean birth weight, adjusted for other risk factors, was 3,373 g, compared with a mean of 3,540 g among controls, 3,552 g among those exposed to ?2-agonists only, and 3,524 g among those exposed to inhaled steroids.

Mean birth weight and mean birth length, adjusted for risk factors, among infants whose mothers had been treated with inhaled steroids were not significantly different from those of controls or of infants whose mothers had used ?2-agonists only. The adjusted mean birth lengths were 51.3 cm in the inhaled steroid group and 51.5 cm in the ?2-agonist group.

The authors, from the University of California, San Diego and the OTIS Research Group, concluded that these results were “reassuring and support the recommendations of adequate control of severe asthma during pregnancy,” and that “the modest effect of systemic steroids on fetal growth should be weighed against the necessity to achieve adequate control of severe persistent asthma and to prevent hypoxia during pregnancy” (J. Allergy Clin. Immunol. 2005;116:503-9).

While these conclusions are not novel, this study is a major breakthrough because it combines information from teratology information centers in North America to provide much larger numbers than were available previously.

Women and physicians should be informed there are some risks: In 2000, my colleagues and I published a metaanalysis of all available studies of women who were given high-dose steroids during pregnancy for various reasons. The results clearly indicated that the use of systemic steroids during the first trimester was associated with a two- to threefold greater risk of oral clefts. This finding was consistent with extensive animal data that have shown the same association.

However, inhaled corticosteroids, commonly used as first-line therapy for asthma, result in an extremely low systemic dose, and none of the available reviews on the use of inhaled steroids during pregnancy have found any association with a greater risk of oral clefts. The ?2-agonist albuterol is not teratogenic.

There is emerging evidence that repeated weekly corticosteroid injections for fetal lung maturation in cases of premature rupture of the membranes may result in brain damage in some babies. But this is not relevant to the use of inhaled corticosteroids in pregnant women with asthma.

Therefore, based on this recent study and previous data, pregnant women should be encouraged not to neglect their asthma therapy because of concerns about potential effects on the fetus. The risks include higher rates of perinatal complications, mostly prematurity, when asthma is poorly controlled. We are aware of fatal cases of women who stopped much-needed asthma treatment during pregnancy.

The authors of an editorial accompanying the OTIS study state that inhaled steroids “do not seem to significantly impair fetal growth,” but add that “before ruling out with confidence any potential adverse effect” of inhaled steroids on fetal growth, “there is a need for larger studies adequately powered to answer this question” (J. Allergy Clin. Immunol. 2005;116:501-2). While I agree we always need more studies, the risk-benefit ratios should dictate optimal treatment of maternal asthma.

www.motherisk.org

The widespread prescribing of corticosteroids in medicine includes many clinical situations during pregnancy, which naturally raises concerns about the safety of these drugs in pregnant women. Over the past several years, information on this topic has begun to accumulate, providing stronger evidence about the safety of inhaled corticosteroids in this population.

Most recently, in October, the largest study to date, conducted by the Organization of Teratology Information Services (OTIS), on the use of medications for asthma during pregnancy and their effects on fetal growth was published. The main finding was that treatment of pregnant women with ?2-agonists and inhaled steroids did not have adverse effects on fetal growth and that systemic corticosteroids had a minimal effect on birth weight and length.

The prospective study compared birth size and the incidence of babies born small for gestational age (SGA) in 654 infants whose mothers had taken inhaled or systemic corticosteroids and ?2-agonists for asthma during pregnancy with birth size and incidence of SGA in 303 infants whose mothers did not have asthma. Women from North America were enrolled between 1998 and 2003. There were no significant differences in the incidence of SGA for weight between the groups. There was a small reduction in birth weight among those exposed to systemic steroids: In this group, the mean birth weight, adjusted for other risk factors, was 3,373 g, compared with a mean of 3,540 g among controls, 3,552 g among those exposed to ?2-agonists only, and 3,524 g among those exposed to inhaled steroids.

Mean birth weight and mean birth length, adjusted for risk factors, among infants whose mothers had been treated with inhaled steroids were not significantly different from those of controls or of infants whose mothers had used ?2-agonists only. The adjusted mean birth lengths were 51.3 cm in the inhaled steroid group and 51.5 cm in the ?2-agonist group.

The authors, from the University of California, San Diego and the OTIS Research Group, concluded that these results were “reassuring and support the recommendations of adequate control of severe asthma during pregnancy,” and that “the modest effect of systemic steroids on fetal growth should be weighed against the necessity to achieve adequate control of severe persistent asthma and to prevent hypoxia during pregnancy” (J. Allergy Clin. Immunol. 2005;116:503-9).

While these conclusions are not novel, this study is a major breakthrough because it combines information from teratology information centers in North America to provide much larger numbers than were available previously.

Women and physicians should be informed there are some risks: In 2000, my colleagues and I published a metaanalysis of all available studies of women who were given high-dose steroids during pregnancy for various reasons. The results clearly indicated that the use of systemic steroids during the first trimester was associated with a two- to threefold greater risk of oral clefts. This finding was consistent with extensive animal data that have shown the same association.

However, inhaled corticosteroids, commonly used as first-line therapy for asthma, result in an extremely low systemic dose, and none of the available reviews on the use of inhaled steroids during pregnancy have found any association with a greater risk of oral clefts. The ?2-agonist albuterol is not teratogenic.

There is emerging evidence that repeated weekly corticosteroid injections for fetal lung maturation in cases of premature rupture of the membranes may result in brain damage in some babies. But this is not relevant to the use of inhaled corticosteroids in pregnant women with asthma.

Therefore, based on this recent study and previous data, pregnant women should be encouraged not to neglect their asthma therapy because of concerns about potential effects on the fetus. The risks include higher rates of perinatal complications, mostly prematurity, when asthma is poorly controlled. We are aware of fatal cases of women who stopped much-needed asthma treatment during pregnancy.

The authors of an editorial accompanying the OTIS study state that inhaled steroids “do not seem to significantly impair fetal growth,” but add that “before ruling out with confidence any potential adverse effect” of inhaled steroids on fetal growth, “there is a need for larger studies adequately powered to answer this question” (J. Allergy Clin. Immunol. 2005;116:501-2). While I agree we always need more studies, the risk-benefit ratios should dictate optimal treatment of maternal asthma.

www.motherisk.org

The widespread prescribing of corticosteroids in medicine includes many clinical situations during pregnancy, which naturally raises concerns about the safety of these drugs in pregnant women. Over the past several years, information on this topic has begun to accumulate, providing stronger evidence about the safety of inhaled corticosteroids in this population.

Most recently, in October, the largest study to date, conducted by the Organization of Teratology Information Services (OTIS), on the use of medications for asthma during pregnancy and their effects on fetal growth was published. The main finding was that treatment of pregnant women with ?2-agonists and inhaled steroids did not have adverse effects on fetal growth and that systemic corticosteroids had a minimal effect on birth weight and length.

The prospective study compared birth size and the incidence of babies born small for gestational age (SGA) in 654 infants whose mothers had taken inhaled or systemic corticosteroids and ?2-agonists for asthma during pregnancy with birth size and incidence of SGA in 303 infants whose mothers did not have asthma. Women from North America were enrolled between 1998 and 2003. There were no significant differences in the incidence of SGA for weight between the groups. There was a small reduction in birth weight among those exposed to systemic steroids: In this group, the mean birth weight, adjusted for other risk factors, was 3,373 g, compared with a mean of 3,540 g among controls, 3,552 g among those exposed to ?2-agonists only, and 3,524 g among those exposed to inhaled steroids.

Mean birth weight and mean birth length, adjusted for risk factors, among infants whose mothers had been treated with inhaled steroids were not significantly different from those of controls or of infants whose mothers had used ?2-agonists only. The adjusted mean birth lengths were 51.3 cm in the inhaled steroid group and 51.5 cm in the ?2-agonist group.

The authors, from the University of California, San Diego and the OTIS Research Group, concluded that these results were “reassuring and support the recommendations of adequate control of severe asthma during pregnancy,” and that “the modest effect of systemic steroids on fetal growth should be weighed against the necessity to achieve adequate control of severe persistent asthma and to prevent hypoxia during pregnancy” (J. Allergy Clin. Immunol. 2005;116:503-9).

While these conclusions are not novel, this study is a major breakthrough because it combines information from teratology information centers in North America to provide much larger numbers than were available previously.

Women and physicians should be informed there are some risks: In 2000, my colleagues and I published a metaanalysis of all available studies of women who were given high-dose steroids during pregnancy for various reasons. The results clearly indicated that the use of systemic steroids during the first trimester was associated with a two- to threefold greater risk of oral clefts. This finding was consistent with extensive animal data that have shown the same association.

However, inhaled corticosteroids, commonly used as first-line therapy for asthma, result in an extremely low systemic dose, and none of the available reviews on the use of inhaled steroids during pregnancy have found any association with a greater risk of oral clefts. The ?2-agonist albuterol is not teratogenic.

There is emerging evidence that repeated weekly corticosteroid injections for fetal lung maturation in cases of premature rupture of the membranes may result in brain damage in some babies. But this is not relevant to the use of inhaled corticosteroids in pregnant women with asthma.

Therefore, based on this recent study and previous data, pregnant women should be encouraged not to neglect their asthma therapy because of concerns about potential effects on the fetus. The risks include higher rates of perinatal complications, mostly prematurity, when asthma is poorly controlled. We are aware of fatal cases of women who stopped much-needed asthma treatment during pregnancy.

The authors of an editorial accompanying the OTIS study state that inhaled steroids “do not seem to significantly impair fetal growth,” but add that “before ruling out with confidence any potential adverse effect” of inhaled steroids on fetal growth, “there is a need for larger studies adequately powered to answer this question” (J. Allergy Clin. Immunol. 2005;116:501-2). While I agree we always need more studies, the risk-benefit ratios should dictate optimal treatment of maternal asthma.

www.motherisk.org

A recently published study on recreational drug use during pregnancy and the possible link to fetal gastroschisis highlights an increasingly important area of research: hair testing as a biomarker for pregnancy exposure to recreational drugs or drugs of abuse. Our laboratory is one of several sites in North America with expertise in measuring these substances in hair, an area many physicians may not be aware of.

Clearly, it can be difficult to determine the types of chemicals or drugs a fetus may have been exposed to by relying on what a woman says she took during pregnancy. The area of forensic science has provided us with a great deal of help in this area.

Forensic scientists have known for some time that drugs taken by an individual are grown into the hair, and do not go away. The first use of this technology was to detect long-term exposure to heavy metals. Over the last 15–20 years, more drugs of abuse have been determined to grow into adult hair, including cocaine, heroin, marijuana, LSD, amphetamine, and methamphetamine. In 1988, we determined that the same is true for the baby. Because the hair present at birth grows during the last 3 months of gestation, an analysis of a baby's hair can provide information on possible drug exposure during that time. We have now shown this is true for almost every drug of abuse, as well as nicotine.

With babies, the same substances can also be measured in meconium, and exposure can be traced to as early as 14 weeks' gestation, when meconium begins to form. Hair and meconium testing have become quite routine in certain settings in North America, with the predominant use among child protection agencies or children's aid societies. This testing is also used for research and clinical purposes and by neonatologists and other health care professionals who have a medical reason to test, often in the context of diagnosing issues in the child, and when maternal consent is provided. For such studies to be conducted, the guardian's consent is needed; sensitive attitudes and high ethical standards need to be practiced.

It's possible to use meconium analysis to test for excessive maternal alcohol intake by measuring fatty acid ethyl esters, conjugates of alcohol with fatty acids, which stay in the meconium of the baby. Recent work from investigators in Berlin determined that fatty acid ethyl esters can also be measured in the hair of the parents. Animal studies indicate they can be measured in a baby's hair, which is being investigated in human studies that are underway.

Analyzing hair samples provides an opportunity to look, not just at one sample of urine or blood that represents the last day or so of exposure but, rather, long-term exposure. At our laboratory, we use hair testing to determine when exposure occurred, which eliminates the uncertainties when this information is obtained from the individual.

Last year we published a review (Clin. Biochemistry 2004;37:429–38) that discussed hair and meconium testing to confirm the prenatal use of alcohol and tobacco. It is important for clinicians to recognize that positive neonatal or meconium tests for drugs of abuse are strong evidence for maternal addiction, as these drugs have been used long after the mother knew she had conceived.

In a study conducted at the Motherisk laboratory published in 2003 (Arch. Dis. Child. Fetal Neonatal Ed. 2003;88:F98-F100), we found that meconium was somewhat more sensitive than hair samples of newborns for detecting cocaine and cannabis, and found a significant correlation between hair and meconium levels of cocaine, cannabis, and opiates. We concluded that both methods were useful biologic markers of illicit drug exposure in utero and also useful in suspicious cases where the neonatal urine test is negative.

In the recent gastroschisis study, investigators used maternal hair analysis from samples taken between 14 and 33 weeks' gestation in 22 pregnant women with a fetus diagnosed with the disorder and in 25 pregnant women with a normal fetus (BJOG 2005;112:1022–5).

In 10 of the 22 cases of babies with gastroschisis, there was evidence on enzyme-linked immunosorbent assay (ELISA) that the mother had taken a recreational drug during the periconceptional period and in the first trimester. But when they checked these results against those obtained from gas chromatography with mass spectrometry (GCMS), which is most specific, four cases (three of cocaine use and one of methamphetamine use) were confirmed.

While the study is small and therefore cannot establish an association, it marks the first time that “objective measurements of maternal intake of recreational drug compounds at these critical periods of development for the fetus have been carried out,” as the researchers noted. This effort should be welcomed. Clearly, hair testing can be a very powerful tool in these studies and in individual cases to help determine whether a woman is using drugs.

www.motherisk.org

A recently published study on recreational drug use during pregnancy and the possible link to fetal gastroschisis highlights an increasingly important area of research: hair testing as a biomarker for pregnancy exposure to recreational drugs or drugs of abuse. Our laboratory is one of several sites in North America with expertise in measuring these substances in hair, an area many physicians may not be aware of.

Clearly, it can be difficult to determine the types of chemicals or drugs a fetus may have been exposed to by relying on what a woman says she took during pregnancy. The area of forensic science has provided us with a great deal of help in this area.

Forensic scientists have known for some time that drugs taken by an individual are grown into the hair, and do not go away. The first use of this technology was to detect long-term exposure to heavy metals. Over the last 15–20 years, more drugs of abuse have been determined to grow into adult hair, including cocaine, heroin, marijuana, LSD, amphetamine, and methamphetamine. In 1988, we determined that the same is true for the baby. Because the hair present at birth grows during the last 3 months of gestation, an analysis of a baby's hair can provide information on possible drug exposure during that time. We have now shown this is true for almost every drug of abuse, as well as nicotine.

With babies, the same substances can also be measured in meconium, and exposure can be traced to as early as 14 weeks' gestation, when meconium begins to form. Hair and meconium testing have become quite routine in certain settings in North America, with the predominant use among child protection agencies or children's aid societies. This testing is also used for research and clinical purposes and by neonatologists and other health care professionals who have a medical reason to test, often in the context of diagnosing issues in the child, and when maternal consent is provided. For such studies to be conducted, the guardian's consent is needed; sensitive attitudes and high ethical standards need to be practiced.

It's possible to use meconium analysis to test for excessive maternal alcohol intake by measuring fatty acid ethyl esters, conjugates of alcohol with fatty acids, which stay in the meconium of the baby. Recent work from investigators in Berlin determined that fatty acid ethyl esters can also be measured in the hair of the parents. Animal studies indicate they can be measured in a baby's hair, which is being investigated in human studies that are underway.

Analyzing hair samples provides an opportunity to look, not just at one sample of urine or blood that represents the last day or so of exposure but, rather, long-term exposure. At our laboratory, we use hair testing to determine when exposure occurred, which eliminates the uncertainties when this information is obtained from the individual.

Last year we published a review (Clin. Biochemistry 2004;37:429–38) that discussed hair and meconium testing to confirm the prenatal use of alcohol and tobacco. It is important for clinicians to recognize that positive neonatal or meconium tests for drugs of abuse are strong evidence for maternal addiction, as these drugs have been used long after the mother knew she had conceived.

In a study conducted at the Motherisk laboratory published in 2003 (Arch. Dis. Child. Fetal Neonatal Ed. 2003;88:F98-F100), we found that meconium was somewhat more sensitive than hair samples of newborns for detecting cocaine and cannabis, and found a significant correlation between hair and meconium levels of cocaine, cannabis, and opiates. We concluded that both methods were useful biologic markers of illicit drug exposure in utero and also useful in suspicious cases where the neonatal urine test is negative.

In the recent gastroschisis study, investigators used maternal hair analysis from samples taken between 14 and 33 weeks' gestation in 22 pregnant women with a fetus diagnosed with the disorder and in 25 pregnant women with a normal fetus (BJOG 2005;112:1022–5).

In 10 of the 22 cases of babies with gastroschisis, there was evidence on enzyme-linked immunosorbent assay (ELISA) that the mother had taken a recreational drug during the periconceptional period and in the first trimester. But when they checked these results against those obtained from gas chromatography with mass spectrometry (GCMS), which is most specific, four cases (three of cocaine use and one of methamphetamine use) were confirmed.

While the study is small and therefore cannot establish an association, it marks the first time that “objective measurements of maternal intake of recreational drug compounds at these critical periods of development for the fetus have been carried out,” as the researchers noted. This effort should be welcomed. Clearly, hair testing can be a very powerful tool in these studies and in individual cases to help determine whether a woman is using drugs.

www.motherisk.org

A recently published study on recreational drug use during pregnancy and the possible link to fetal gastroschisis highlights an increasingly important area of research: hair testing as a biomarker for pregnancy exposure to recreational drugs or drugs of abuse. Our laboratory is one of several sites in North America with expertise in measuring these substances in hair, an area many physicians may not be aware of.

Clearly, it can be difficult to determine the types of chemicals or drugs a fetus may have been exposed to by relying on what a woman says she took during pregnancy. The area of forensic science has provided us with a great deal of help in this area.

Forensic scientists have known for some time that drugs taken by an individual are grown into the hair, and do not go away. The first use of this technology was to detect long-term exposure to heavy metals. Over the last 15–20 years, more drugs of abuse have been determined to grow into adult hair, including cocaine, heroin, marijuana, LSD, amphetamine, and methamphetamine. In 1988, we determined that the same is true for the baby. Because the hair present at birth grows during the last 3 months of gestation, an analysis of a baby's hair can provide information on possible drug exposure during that time. We have now shown this is true for almost every drug of abuse, as well as nicotine.

With babies, the same substances can also be measured in meconium, and exposure can be traced to as early as 14 weeks' gestation, when meconium begins to form. Hair and meconium testing have become quite routine in certain settings in North America, with the predominant use among child protection agencies or children's aid societies. This testing is also used for research and clinical purposes and by neonatologists and other health care professionals who have a medical reason to test, often in the context of diagnosing issues in the child, and when maternal consent is provided. For such studies to be conducted, the guardian's consent is needed; sensitive attitudes and high ethical standards need to be practiced.

It's possible to use meconium analysis to test for excessive maternal alcohol intake by measuring fatty acid ethyl esters, conjugates of alcohol with fatty acids, which stay in the meconium of the baby. Recent work from investigators in Berlin determined that fatty acid ethyl esters can also be measured in the hair of the parents. Animal studies indicate they can be measured in a baby's hair, which is being investigated in human studies that are underway.

Analyzing hair samples provides an opportunity to look, not just at one sample of urine or blood that represents the last day or so of exposure but, rather, long-term exposure. At our laboratory, we use hair testing to determine when exposure occurred, which eliminates the uncertainties when this information is obtained from the individual.

Last year we published a review (Clin. Biochemistry 2004;37:429–38) that discussed hair and meconium testing to confirm the prenatal use of alcohol and tobacco. It is important for clinicians to recognize that positive neonatal or meconium tests for drugs of abuse are strong evidence for maternal addiction, as these drugs have been used long after the mother knew she had conceived.

In a study conducted at the Motherisk laboratory published in 2003 (Arch. Dis. Child. Fetal Neonatal Ed. 2003;88:F98-F100), we found that meconium was somewhat more sensitive than hair samples of newborns for detecting cocaine and cannabis, and found a significant correlation between hair and meconium levels of cocaine, cannabis, and opiates. We concluded that both methods were useful biologic markers of illicit drug exposure in utero and also useful in suspicious cases where the neonatal urine test is negative.

In the recent gastroschisis study, investigators used maternal hair analysis from samples taken between 14 and 33 weeks' gestation in 22 pregnant women with a fetus diagnosed with the disorder and in 25 pregnant women with a normal fetus (BJOG 2005;112:1022–5).

In 10 of the 22 cases of babies with gastroschisis, there was evidence on enzyme-linked immunosorbent assay (ELISA) that the mother had taken a recreational drug during the periconceptional period and in the first trimester. But when they checked these results against those obtained from gas chromatography with mass spectrometry (GCMS), which is most specific, four cases (three of cocaine use and one of methamphetamine use) were confirmed.

While the study is small and therefore cannot establish an association, it marks the first time that “objective measurements of maternal intake of recreational drug compounds at these critical periods of development for the fetus have been carried out,” as the researchers noted. This effort should be welcomed. Clearly, hair testing can be a very powerful tool in these studies and in individual cases to help determine whether a woman is using drugs.

www.motherisk.org

Ginger in many forms is taken by pregnant women, with the hopes of alleviating the nausea and vomiting of pregnancy. These forms range from ginger tea, cookies, crystals, and sugars to inhaled powder and capsules containing ginger, as well as fresh ginger.

In a recently published metaanalysis of studies on ginger's use as an antiemetic during pregnancy, the authors concluded that the herbal supplement may be safe and effective for managing the nausea and vomiting of pregnancy (NVP). They noted, however, that more observational studies and larger randomized trials were needed before a definitive statement on safety could be made (Obstet. Gynecol. 2005;105:849–56).

The metaanalysis included six double-blind, randomized controlled trials of almost 700 women and an observational study that my colleagues and I conducted on 187 women taking ginger. This is the first metaanalysis of studies on the use of ginger as an antiemetic during pregnancy. In the six randomized controlled trials, 500–1,500 mg daily of ginger were used for 3 days to 3 weeks in women who were at less than 20 weeks' gestation (Am. J. Obstet. Gynecol. 2003;189:1374–7).

In four trials, ginger was more effective than placebo in controlling symptoms of NVP, and in the two remaining trials, ginger was as effective as vitamin B₆ although I would add that vitamin B₆—when used alone—is effective mostly for mild cases of NVP.

No serious adverse effects or pregnancy-related problems were detected in the five studies that looked at safety. The outcomes evaluated in the randomized trials included prepartum hemorrhage, preeclampsia, preterm birth, congential abnormalities, major malformations, perinatal and neonatal death, birth weights, and gestational age.

In the prospective observational study, we looked primarily at fetal safety, comparing outcomes in 187 pregnant women who took ginger in the first trimester with another 187 women who during the first trimester took drugs known to be nonteratogenic. With one exception, we found no significant differences in adverse pregnancy outcomes between the two groups.

The exception was that there were significantly more infants with birth weights of less than 2,500 g in the comparison group (6.4%, vs 1.6% in the ginger group), even though there were eight pairs of twins in the ginger group. There were two major malformations in the comparison group, and three in the ginger group (a ventricular septal defect, right lung abnormality, and kidney abnormality). At age 2, the daughter of a mother who took 1,000 mg of ginger per day from weeks 11–20 of gestation, as well as doxylamine/vitamin B₆ in the first trimester, was diagnosed with idiopathic central precocious puberty. This may be a random finding.

In a subgroup of 66 women, we evaluated the effectiveness of ginger by asking them to rank from 0 to 10 how well ginger controlled NVP, with 0 as no effect and 10 as a maximal effect. The mean score was 3.3, not a very strong effect. Moreover, when we considered the form of ginger used, only capsules containing ginger were associated with an effect significantly greater than zero.

Thus, our observational study put effectiveness against placebo into context: While it is helpful to show in randomized controlled trials that ginger has a better antiemetic effect than placebo, the effect is very mild. Needless to say, many pregnant women are much more comfortable taking a natural product than a medication because of the perception that natural products are safer. But they should be aware that these products are not necessarily as effective as medicinal products, which in the United States and Canada, include ondansetron and metoclopramide.

At Motherisk, we advise women who call about ginger that it is probably safe and may help ease mild NVP, but it is unlikely to help with moderate to severe NVP.

A precautionary note: Women should also be aware that since there are many formulations of ginger, the amount of ginger in a given form is almost never certain. This is because natural products are not regulated with the same scrutiny as drugs. At this point, more studies comparing ginger with placebo probably are not needed. What would make sense now is to compare the safety and effectiveness of ginger and drugs, such as ondansetron and doxylamine and vitamin B₆, medicinal products that have been proved to be safe and effective for nausea and vomiting in pregnant women.

www.motherisk.org

Ginger in many forms is taken by pregnant women, with the hopes of alleviating the nausea and vomiting of pregnancy. These forms range from ginger tea, cookies, crystals, and sugars to inhaled powder and capsules containing ginger, as well as fresh ginger.

In a recently published metaanalysis of studies on ginger's use as an antiemetic during pregnancy, the authors concluded that the herbal supplement may be safe and effective for managing the nausea and vomiting of pregnancy (NVP). They noted, however, that more observational studies and larger randomized trials were needed before a definitive statement on safety could be made (Obstet. Gynecol. 2005;105:849–56).

The metaanalysis included six double-blind, randomized controlled trials of almost 700 women and an observational study that my colleagues and I conducted on 187 women taking ginger. This is the first metaanalysis of studies on the use of ginger as an antiemetic during pregnancy. In the six randomized controlled trials, 500–1,500 mg daily of ginger were used for 3 days to 3 weeks in women who were at less than 20 weeks' gestation (Am. J. Obstet. Gynecol. 2003;189:1374–7).

In four trials, ginger was more effective than placebo in controlling symptoms of NVP, and in the two remaining trials, ginger was as effective as vitamin B₆ although I would add that vitamin B₆—when used alone—is effective mostly for mild cases of NVP.

No serious adverse effects or pregnancy-related problems were detected in the five studies that looked at safety. The outcomes evaluated in the randomized trials included prepartum hemorrhage, preeclampsia, preterm birth, congential abnormalities, major malformations, perinatal and neonatal death, birth weights, and gestational age.

In the prospective observational study, we looked primarily at fetal safety, comparing outcomes in 187 pregnant women who took ginger in the first trimester with another 187 women who during the first trimester took drugs known to be nonteratogenic. With one exception, we found no significant differences in adverse pregnancy outcomes between the two groups.

The exception was that there were significantly more infants with birth weights of less than 2,500 g in the comparison group (6.4%, vs 1.6% in the ginger group), even though there were eight pairs of twins in the ginger group. There were two major malformations in the comparison group, and three in the ginger group (a ventricular septal defect, right lung abnormality, and kidney abnormality). At age 2, the daughter of a mother who took 1,000 mg of ginger per day from weeks 11–20 of gestation, as well as doxylamine/vitamin B₆ in the first trimester, was diagnosed with idiopathic central precocious puberty. This may be a random finding.

In a subgroup of 66 women, we evaluated the effectiveness of ginger by asking them to rank from 0 to 10 how well ginger controlled NVP, with 0 as no effect and 10 as a maximal effect. The mean score was 3.3, not a very strong effect. Moreover, when we considered the form of ginger used, only capsules containing ginger were associated with an effect significantly greater than zero.

Thus, our observational study put effectiveness against placebo into context: While it is helpful to show in randomized controlled trials that ginger has a better antiemetic effect than placebo, the effect is very mild. Needless to say, many pregnant women are much more comfortable taking a natural product than a medication because of the perception that natural products are safer. But they should be aware that these products are not necessarily as effective as medicinal products, which in the United States and Canada, include ondansetron and metoclopramide.

At Motherisk, we advise women who call about ginger that it is probably safe and may help ease mild NVP, but it is unlikely to help with moderate to severe NVP.

A precautionary note: Women should also be aware that since there are many formulations of ginger, the amount of ginger in a given form is almost never certain. This is because natural products are not regulated with the same scrutiny as drugs. At this point, more studies comparing ginger with placebo probably are not needed. What would make sense now is to compare the safety and effectiveness of ginger and drugs, such as ondansetron and doxylamine and vitamin B₆, medicinal products that have been proved to be safe and effective for nausea and vomiting in pregnant women.

www.motherisk.org

Ginger in many forms is taken by pregnant women, with the hopes of alleviating the nausea and vomiting of pregnancy. These forms range from ginger tea, cookies, crystals, and sugars to inhaled powder and capsules containing ginger, as well as fresh ginger.

In a recently published metaanalysis of studies on ginger's use as an antiemetic during pregnancy, the authors concluded that the herbal supplement may be safe and effective for managing the nausea and vomiting of pregnancy (NVP). They noted, however, that more observational studies and larger randomized trials were needed before a definitive statement on safety could be made (Obstet. Gynecol. 2005;105:849–56).

The metaanalysis included six double-blind, randomized controlled trials of almost 700 women and an observational study that my colleagues and I conducted on 187 women taking ginger. This is the first metaanalysis of studies on the use of ginger as an antiemetic during pregnancy. In the six randomized controlled trials, 500–1,500 mg daily of ginger were used for 3 days to 3 weeks in women who were at less than 20 weeks' gestation (Am. J. Obstet. Gynecol. 2003;189:1374–7).

In four trials, ginger was more effective than placebo in controlling symptoms of NVP, and in the two remaining trials, ginger was as effective as vitamin B₆ although I would add that vitamin B₆—when used alone—is effective mostly for mild cases of NVP.

No serious adverse effects or pregnancy-related problems were detected in the five studies that looked at safety. The outcomes evaluated in the randomized trials included prepartum hemorrhage, preeclampsia, preterm birth, congential abnormalities, major malformations, perinatal and neonatal death, birth weights, and gestational age.

In the prospective observational study, we looked primarily at fetal safety, comparing outcomes in 187 pregnant women who took ginger in the first trimester with another 187 women who during the first trimester took drugs known to be nonteratogenic. With one exception, we found no significant differences in adverse pregnancy outcomes between the two groups.

The exception was that there were significantly more infants with birth weights of less than 2,500 g in the comparison group (6.4%, vs 1.6% in the ginger group), even though there were eight pairs of twins in the ginger group. There were two major malformations in the comparison group, and three in the ginger group (a ventricular septal defect, right lung abnormality, and kidney abnormality). At age 2, the daughter of a mother who took 1,000 mg of ginger per day from weeks 11–20 of gestation, as well as doxylamine/vitamin B₆ in the first trimester, was diagnosed with idiopathic central precocious puberty. This may be a random finding.

In a subgroup of 66 women, we evaluated the effectiveness of ginger by asking them to rank from 0 to 10 how well ginger controlled NVP, with 0 as no effect and 10 as a maximal effect. The mean score was 3.3, not a very strong effect. Moreover, when we considered the form of ginger used, only capsules containing ginger were associated with an effect significantly greater than zero.

Thus, our observational study put effectiveness against placebo into context: While it is helpful to show in randomized controlled trials that ginger has a better antiemetic effect than placebo, the effect is very mild. Needless to say, many pregnant women are much more comfortable taking a natural product than a medication because of the perception that natural products are safer. But they should be aware that these products are not necessarily as effective as medicinal products, which in the United States and Canada, include ondansetron and metoclopramide.

At Motherisk, we advise women who call about ginger that it is probably safe and may help ease mild NVP, but it is unlikely to help with moderate to severe NVP.

A precautionary note: Women should also be aware that since there are many formulations of ginger, the amount of ginger in a given form is almost never certain. This is because natural products are not regulated with the same scrutiny as drugs. At this point, more studies comparing ginger with placebo probably are not needed. What would make sense now is to compare the safety and effectiveness of ginger and drugs, such as ondansetron and doxylamine and vitamin B₆, medicinal products that have been proved to be safe and effective for nausea and vomiting in pregnant women.