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Teratogenicity may not be a yes or no question
Since thalidomide, the medical community has sought to ensure that we do not miss any safety signal that a drug could cause malformations or developmental delays after in utero exposure.
At the time of a drug’s debut, there are relatively small numbers of exposures in pregnancy, and it’s difficult to decipher teratogenicity. As the number of exposures increases, we are generally able to answer “yes” or “no” to the question of teratogenicity. But in the last decade or so, data on drug exposure in pregnancy has become robust enough – thanks in part to large registries – to provide potentially more useful answers on safety. Specifically, .
Animal studies show us that there is a dose dependent effect in pregnancy, and not every dose causes harm to the fetus. However, that information is not easily translated into clinical practice because of the vast differences between animal and human pharmacokinetics and sensitivity to toxicity.
The first drug that came into focus as having dose dependent teratogenicity in pregnancy is the epilepsy drug valproic acid. In the late 1980s, studies showed that the drug was associated with an increased risk for spina bifida. Later, more congenital malformations were linked to valproic acid, including oral cleft, cardiac and limb defects, developmental delays, lower IQ, and even autism. But in the last few years, an increasing number of studies point to a lower dose that may represent an acceptable risk for some pregnant women.
Looking at data from EURAP, an international registry of antiepileptic drugs and pregnancy, researchers showed that the dose of valproic acid with the greatest risk for harm was 1,500 mg per day or greater, with a 24% frequency of major congenital malformations. But at less than 700 mg per day, the frequency of major malformations dropped to 5.9% (Neurology. 2015 Sep 8;85[10]:866-72).
Another analysis of the EURAP data showed the same dose-dependent relationship with other drugs. The researchers calculated rates of major congenital malformations in 1,402 pregnancies exposed to carbamazepine, 1,280 on lamotrigine, 1,010 on valproic acid, and 217 on phenobarbital, and all showed that the frequency of birth defects increased along with the dose of the drug.
The study identified the dose for each drug with the lowest rates of malformation. For lamotrigine, it was a dose of less than 300 mg per day, with a 2% frequency of malformations. Similarly, the dose was less than 400 mg per day for carbamazepine (3.4% rate of malformations). Overall, risks of malformation were significantly higher in valproic acid and phenobarbital at all tested doses and carbamazepine at doses greater than 400 mg per day, compared with lamotrigine monotherapy at less than 300 mg per day (Lancet Neurol. 2011 Jul;10[7]:609-17).
The study is important because it gives us a benchmark for these drugs, allowing us to see the risks at lower doses.
But not all the data are in agreement. In 2016, a Cochrane review of different antiepileptic drugs in pregnancy found that only with valproic acid could the risk of a malformation be clearly linked to the size of the dose (Cochrane Database Syst Rev. 2016 Nov 7;11:CD010224).
Most recently, a large U.S. database of Medicaid patients, which included more than 1.3 million pregnancies, showed the dose-dependent risk of malformations associated with lithium, still widely used in treating bipolar disorder. The researchers examined the risk of cardiac malformations after first-trimester lithium exposure.
With the publication of each of these studies, we are moving toward an era where the question of teratogenicity is no longer just “yes” or “no,” but dose dependent. Soon, I hope we will be able to expand our knowledge by evaluating doses in milligrams per kilogram, rather than just a per day dose, thus addressing body size in evaluating the risk.
As more than half of pregnancies are unplanned, there are often times when women have been exposed to teratogens during early pregnancy and knowing the size of the risk is an invaluable decision-making tool. We don’t have the full risk picture yet, but it is growing clearer.
Dr. Koren is professor of pediatrics at Western University in Ontario and Tel Aviv University in Israel, and is the founder of the Motherisk Program. He reported having no relevant financial disclosures.
Since thalidomide, the medical community has sought to ensure that we do not miss any safety signal that a drug could cause malformations or developmental delays after in utero exposure.
At the time of a drug’s debut, there are relatively small numbers of exposures in pregnancy, and it’s difficult to decipher teratogenicity. As the number of exposures increases, we are generally able to answer “yes” or “no” to the question of teratogenicity. But in the last decade or so, data on drug exposure in pregnancy has become robust enough – thanks in part to large registries – to provide potentially more useful answers on safety. Specifically, .
Animal studies show us that there is a dose dependent effect in pregnancy, and not every dose causes harm to the fetus. However, that information is not easily translated into clinical practice because of the vast differences between animal and human pharmacokinetics and sensitivity to toxicity.
The first drug that came into focus as having dose dependent teratogenicity in pregnancy is the epilepsy drug valproic acid. In the late 1980s, studies showed that the drug was associated with an increased risk for spina bifida. Later, more congenital malformations were linked to valproic acid, including oral cleft, cardiac and limb defects, developmental delays, lower IQ, and even autism. But in the last few years, an increasing number of studies point to a lower dose that may represent an acceptable risk for some pregnant women.
Looking at data from EURAP, an international registry of antiepileptic drugs and pregnancy, researchers showed that the dose of valproic acid with the greatest risk for harm was 1,500 mg per day or greater, with a 24% frequency of major congenital malformations. But at less than 700 mg per day, the frequency of major malformations dropped to 5.9% (Neurology. 2015 Sep 8;85[10]:866-72).
Another analysis of the EURAP data showed the same dose-dependent relationship with other drugs. The researchers calculated rates of major congenital malformations in 1,402 pregnancies exposed to carbamazepine, 1,280 on lamotrigine, 1,010 on valproic acid, and 217 on phenobarbital, and all showed that the frequency of birth defects increased along with the dose of the drug.
The study identified the dose for each drug with the lowest rates of malformation. For lamotrigine, it was a dose of less than 300 mg per day, with a 2% frequency of malformations. Similarly, the dose was less than 400 mg per day for carbamazepine (3.4% rate of malformations). Overall, risks of malformation were significantly higher in valproic acid and phenobarbital at all tested doses and carbamazepine at doses greater than 400 mg per day, compared with lamotrigine monotherapy at less than 300 mg per day (Lancet Neurol. 2011 Jul;10[7]:609-17).
The study is important because it gives us a benchmark for these drugs, allowing us to see the risks at lower doses.
But not all the data are in agreement. In 2016, a Cochrane review of different antiepileptic drugs in pregnancy found that only with valproic acid could the risk of a malformation be clearly linked to the size of the dose (Cochrane Database Syst Rev. 2016 Nov 7;11:CD010224).
Most recently, a large U.S. database of Medicaid patients, which included more than 1.3 million pregnancies, showed the dose-dependent risk of malformations associated with lithium, still widely used in treating bipolar disorder. The researchers examined the risk of cardiac malformations after first-trimester lithium exposure.
With the publication of each of these studies, we are moving toward an era where the question of teratogenicity is no longer just “yes” or “no,” but dose dependent. Soon, I hope we will be able to expand our knowledge by evaluating doses in milligrams per kilogram, rather than just a per day dose, thus addressing body size in evaluating the risk.
As more than half of pregnancies are unplanned, there are often times when women have been exposed to teratogens during early pregnancy and knowing the size of the risk is an invaluable decision-making tool. We don’t have the full risk picture yet, but it is growing clearer.
Dr. Koren is professor of pediatrics at Western University in Ontario and Tel Aviv University in Israel, and is the founder of the Motherisk Program. He reported having no relevant financial disclosures.
Since thalidomide, the medical community has sought to ensure that we do not miss any safety signal that a drug could cause malformations or developmental delays after in utero exposure.
At the time of a drug’s debut, there are relatively small numbers of exposures in pregnancy, and it’s difficult to decipher teratogenicity. As the number of exposures increases, we are generally able to answer “yes” or “no” to the question of teratogenicity. But in the last decade or so, data on drug exposure in pregnancy has become robust enough – thanks in part to large registries – to provide potentially more useful answers on safety. Specifically, .
Animal studies show us that there is a dose dependent effect in pregnancy, and not every dose causes harm to the fetus. However, that information is not easily translated into clinical practice because of the vast differences between animal and human pharmacokinetics and sensitivity to toxicity.
The first drug that came into focus as having dose dependent teratogenicity in pregnancy is the epilepsy drug valproic acid. In the late 1980s, studies showed that the drug was associated with an increased risk for spina bifida. Later, more congenital malformations were linked to valproic acid, including oral cleft, cardiac and limb defects, developmental delays, lower IQ, and even autism. But in the last few years, an increasing number of studies point to a lower dose that may represent an acceptable risk for some pregnant women.
Looking at data from EURAP, an international registry of antiepileptic drugs and pregnancy, researchers showed that the dose of valproic acid with the greatest risk for harm was 1,500 mg per day or greater, with a 24% frequency of major congenital malformations. But at less than 700 mg per day, the frequency of major malformations dropped to 5.9% (Neurology. 2015 Sep 8;85[10]:866-72).
Another analysis of the EURAP data showed the same dose-dependent relationship with other drugs. The researchers calculated rates of major congenital malformations in 1,402 pregnancies exposed to carbamazepine, 1,280 on lamotrigine, 1,010 on valproic acid, and 217 on phenobarbital, and all showed that the frequency of birth defects increased along with the dose of the drug.
The study identified the dose for each drug with the lowest rates of malformation. For lamotrigine, it was a dose of less than 300 mg per day, with a 2% frequency of malformations. Similarly, the dose was less than 400 mg per day for carbamazepine (3.4% rate of malformations). Overall, risks of malformation were significantly higher in valproic acid and phenobarbital at all tested doses and carbamazepine at doses greater than 400 mg per day, compared with lamotrigine monotherapy at less than 300 mg per day (Lancet Neurol. 2011 Jul;10[7]:609-17).
The study is important because it gives us a benchmark for these drugs, allowing us to see the risks at lower doses.
But not all the data are in agreement. In 2016, a Cochrane review of different antiepileptic drugs in pregnancy found that only with valproic acid could the risk of a malformation be clearly linked to the size of the dose (Cochrane Database Syst Rev. 2016 Nov 7;11:CD010224).
Most recently, a large U.S. database of Medicaid patients, which included more than 1.3 million pregnancies, showed the dose-dependent risk of malformations associated with lithium, still widely used in treating bipolar disorder. The researchers examined the risk of cardiac malformations after first-trimester lithium exposure.
With the publication of each of these studies, we are moving toward an era where the question of teratogenicity is no longer just “yes” or “no,” but dose dependent. Soon, I hope we will be able to expand our knowledge by evaluating doses in milligrams per kilogram, rather than just a per day dose, thus addressing body size in evaluating the risk.
As more than half of pregnancies are unplanned, there are often times when women have been exposed to teratogens during early pregnancy and knowing the size of the risk is an invaluable decision-making tool. We don’t have the full risk picture yet, but it is growing clearer.
Dr. Koren is professor of pediatrics at Western University in Ontario and Tel Aviv University in Israel, and is the founder of the Motherisk Program. He reported having no relevant financial disclosures.
Consider neurodevelopmental impacts of hyperemesis gravidarum
Hyperemesis gravidarum (HG) affects just 1%-2% of pregnant women, but it’s clinical consequences are significant, with excess vomiting and dehydration, hospitalization, and the need for intravenous fluids being common in that group. In extreme cases, repeated vomiting has led to tears in the esophagus and severe dehydration has caused acute renal failure. All of that leaves aside the obvious suffering and distress it causes for women with the condition.
While studies continue to support the long-held theory that mild-to-moderate nausea and vomiting has a protective effect in pregnancy, that does not appear to be true for HG. Rather, the medical literature shows that HG is associated with small-for-gestational-age neonates, low birth weight, higher rates of preterm birth, and lower Apgar scores at 5 minutes.
I was one of the investigators on a study that prospectively followed more than 200 women with nausea and vomiting in pregnancy from 2006 to 2012. We found that children whose mothers were hospitalized for their symptoms – 22 in all – had significantly lower IQ scores at 3.5 years to 7 years, compared with children whose mothers were not hospitalized. Verbal IQ scores were 107.2 points vs. 112.7 (P = .04), performance IQ scores were 105.6 vs. 112.3 (P = .03), and full scale IQ was 108.7 vs. 114.2 (P = .05).
The study cohort included three groups: women treated with more than four tablets per day of doxylamine/pyridoxine (Diclegis); women treated with up to four tablets per day of the drug; and women who did not receive pharmacotherapy (Obstet Gynecol. 2015. doi: 10.1097/01.AOG.0000463229.81803.1a).
Hospitalized women in the study received antiemetics about a week later, experienced more severe symptoms, and were more likely to report depression. Overall, we found that duration of hospitalization, maternal depression, and maternal IQ all were significant predictors for these outcomes. However, daily antiemetic therapy was not associated with adverse outcomes.
Another study, published the same year, found that children exposed to HG had a more than three times increased risk for a neurodevelopmental diagnosis, including attention disorders, speech and language delays, and sensory disorders. The changes were more prevalent when women experienced symptoms early in pregnancy – prior to 5 weeks of gestation (Eur J Obstet Gynecol Reprod Biol. 2015 Jun;189:79-84).
The study compared neurodevelopmental outcomes for 312 children from 203 women with HG, with 169 children from 89 unaffected mothers. The findings are similar to those of our study, despite the differences in methodologies. Both studies found that the antiemetics were not associated with adverse outcomes, but the symptoms of HG appear to be the culprit.
While more research is needed to confirm these findings, it makes sense that the nutritional deficiencies created by excess vomiting and inability to eat are having an impact on the fetus.
It also raises an important question for the ob.gyn. about when to intervene in these women. Often, clinicians take a wait-and-see approach to nausea and vomiting in pregnancy, but the developing research suggests that earlier intervention would lead to better outcomes for mother and baby. One guide to determining that preventive antiemetics are necessary is to consider whether your patient has had HG in a previous pregnancy or if her mother or sister has experienced HG.
Another consideration is treating the nutritional deficiency that develops in women whose HG symptoms persist. These women are not simply in need of fluids and electrolytes but are missing essential vitamins and proteins. This is an area where much more research is needed, but clinicians can take a proactive approach by providing team care that includes consultation with a dietitians or nutritionist.
Finally, we cannot forget that maternal depression also appears to be significant predictor of poor fetal outcomes, so providing appropriate psychiatric treatment is essential.
Dr. Koren is professor of physiology/pharmacology and pediatrics at Western University in Ontario. He is the founder of the Motherisk Program. Dr. Koren was a principal investigator in the U.S. study that resulted in the approval of Diclegis, marketed by Duchesnay USA, and has served as a consultant to Duchesnay.
Hyperemesis gravidarum (HG) affects just 1%-2% of pregnant women, but it’s clinical consequences are significant, with excess vomiting and dehydration, hospitalization, and the need for intravenous fluids being common in that group. In extreme cases, repeated vomiting has led to tears in the esophagus and severe dehydration has caused acute renal failure. All of that leaves aside the obvious suffering and distress it causes for women with the condition.
While studies continue to support the long-held theory that mild-to-moderate nausea and vomiting has a protective effect in pregnancy, that does not appear to be true for HG. Rather, the medical literature shows that HG is associated with small-for-gestational-age neonates, low birth weight, higher rates of preterm birth, and lower Apgar scores at 5 minutes.
I was one of the investigators on a study that prospectively followed more than 200 women with nausea and vomiting in pregnancy from 2006 to 2012. We found that children whose mothers were hospitalized for their symptoms – 22 in all – had significantly lower IQ scores at 3.5 years to 7 years, compared with children whose mothers were not hospitalized. Verbal IQ scores were 107.2 points vs. 112.7 (P = .04), performance IQ scores were 105.6 vs. 112.3 (P = .03), and full scale IQ was 108.7 vs. 114.2 (P = .05).
The study cohort included three groups: women treated with more than four tablets per day of doxylamine/pyridoxine (Diclegis); women treated with up to four tablets per day of the drug; and women who did not receive pharmacotherapy (Obstet Gynecol. 2015. doi: 10.1097/01.AOG.0000463229.81803.1a).
Hospitalized women in the study received antiemetics about a week later, experienced more severe symptoms, and were more likely to report depression. Overall, we found that duration of hospitalization, maternal depression, and maternal IQ all were significant predictors for these outcomes. However, daily antiemetic therapy was not associated with adverse outcomes.
Another study, published the same year, found that children exposed to HG had a more than three times increased risk for a neurodevelopmental diagnosis, including attention disorders, speech and language delays, and sensory disorders. The changes were more prevalent when women experienced symptoms early in pregnancy – prior to 5 weeks of gestation (Eur J Obstet Gynecol Reprod Biol. 2015 Jun;189:79-84).
The study compared neurodevelopmental outcomes for 312 children from 203 women with HG, with 169 children from 89 unaffected mothers. The findings are similar to those of our study, despite the differences in methodologies. Both studies found that the antiemetics were not associated with adverse outcomes, but the symptoms of HG appear to be the culprit.
While more research is needed to confirm these findings, it makes sense that the nutritional deficiencies created by excess vomiting and inability to eat are having an impact on the fetus.
It also raises an important question for the ob.gyn. about when to intervene in these women. Often, clinicians take a wait-and-see approach to nausea and vomiting in pregnancy, but the developing research suggests that earlier intervention would lead to better outcomes for mother and baby. One guide to determining that preventive antiemetics are necessary is to consider whether your patient has had HG in a previous pregnancy or if her mother or sister has experienced HG.
Another consideration is treating the nutritional deficiency that develops in women whose HG symptoms persist. These women are not simply in need of fluids and electrolytes but are missing essential vitamins and proteins. This is an area where much more research is needed, but clinicians can take a proactive approach by providing team care that includes consultation with a dietitians or nutritionist.
Finally, we cannot forget that maternal depression also appears to be significant predictor of poor fetal outcomes, so providing appropriate psychiatric treatment is essential.
Dr. Koren is professor of physiology/pharmacology and pediatrics at Western University in Ontario. He is the founder of the Motherisk Program. Dr. Koren was a principal investigator in the U.S. study that resulted in the approval of Diclegis, marketed by Duchesnay USA, and has served as a consultant to Duchesnay.
Hyperemesis gravidarum (HG) affects just 1%-2% of pregnant women, but it’s clinical consequences are significant, with excess vomiting and dehydration, hospitalization, and the need for intravenous fluids being common in that group. In extreme cases, repeated vomiting has led to tears in the esophagus and severe dehydration has caused acute renal failure. All of that leaves aside the obvious suffering and distress it causes for women with the condition.
While studies continue to support the long-held theory that mild-to-moderate nausea and vomiting has a protective effect in pregnancy, that does not appear to be true for HG. Rather, the medical literature shows that HG is associated with small-for-gestational-age neonates, low birth weight, higher rates of preterm birth, and lower Apgar scores at 5 minutes.
I was one of the investigators on a study that prospectively followed more than 200 women with nausea and vomiting in pregnancy from 2006 to 2012. We found that children whose mothers were hospitalized for their symptoms – 22 in all – had significantly lower IQ scores at 3.5 years to 7 years, compared with children whose mothers were not hospitalized. Verbal IQ scores were 107.2 points vs. 112.7 (P = .04), performance IQ scores were 105.6 vs. 112.3 (P = .03), and full scale IQ was 108.7 vs. 114.2 (P = .05).
The study cohort included three groups: women treated with more than four tablets per day of doxylamine/pyridoxine (Diclegis); women treated with up to four tablets per day of the drug; and women who did not receive pharmacotherapy (Obstet Gynecol. 2015. doi: 10.1097/01.AOG.0000463229.81803.1a).
Hospitalized women in the study received antiemetics about a week later, experienced more severe symptoms, and were more likely to report depression. Overall, we found that duration of hospitalization, maternal depression, and maternal IQ all were significant predictors for these outcomes. However, daily antiemetic therapy was not associated with adverse outcomes.
Another study, published the same year, found that children exposed to HG had a more than three times increased risk for a neurodevelopmental diagnosis, including attention disorders, speech and language delays, and sensory disorders. The changes were more prevalent when women experienced symptoms early in pregnancy – prior to 5 weeks of gestation (Eur J Obstet Gynecol Reprod Biol. 2015 Jun;189:79-84).
The study compared neurodevelopmental outcomes for 312 children from 203 women with HG, with 169 children from 89 unaffected mothers. The findings are similar to those of our study, despite the differences in methodologies. Both studies found that the antiemetics were not associated with adverse outcomes, but the symptoms of HG appear to be the culprit.
While more research is needed to confirm these findings, it makes sense that the nutritional deficiencies created by excess vomiting and inability to eat are having an impact on the fetus.
It also raises an important question for the ob.gyn. about when to intervene in these women. Often, clinicians take a wait-and-see approach to nausea and vomiting in pregnancy, but the developing research suggests that earlier intervention would lead to better outcomes for mother and baby. One guide to determining that preventive antiemetics are necessary is to consider whether your patient has had HG in a previous pregnancy or if her mother or sister has experienced HG.
Another consideration is treating the nutritional deficiency that develops in women whose HG symptoms persist. These women are not simply in need of fluids and electrolytes but are missing essential vitamins and proteins. This is an area where much more research is needed, but clinicians can take a proactive approach by providing team care that includes consultation with a dietitians or nutritionist.
Finally, we cannot forget that maternal depression also appears to be significant predictor of poor fetal outcomes, so providing appropriate psychiatric treatment is essential.
Dr. Koren is professor of physiology/pharmacology and pediatrics at Western University in Ontario. He is the founder of the Motherisk Program. Dr. Koren was a principal investigator in the U.S. study that resulted in the approval of Diclegis, marketed by Duchesnay USA, and has served as a consultant to Duchesnay.
How great is the risk from binge drinking in pregnancy?
Imagine this scenario: A couple goes on a Caribbean cruise with an all-you-can-eat buffet and an open bar. During the trip, they engage in 2 or 3 days of binge-style drinking, which is considered about four drinks in a single sitting. A few weeks after the trip, the woman finds out that she’s pregnant and calls your office wondering if there will be any harm to the fetus.
This is not a theoretical question. I have received many of these calls over the years, and in some cases the fear of adverse effects on the baby has led the couple to terminate the pregnancy.
Unfortunately, the literature has not been clear on the long-term impact of binge drinking in pregnancy. Animal studies suggest that it is the peak in the alcohol level created by binge drinking that causes damage to the fetus, rather than a sustained level of alcohol (although that obviously carries risk as well). The literature in humans has been controversial.
One of the most recent studies is a prospective cohort study of more than 1,600 women and their children sampled from the Danish National Birth Cohort. The investigators collected information on maternal alcohol use in early pregnancy and examined children at age 5 years using the Strengths and Difficulties Questionnaire (SDQ) completed by the mothers and a preschool teacher. It found no statistically significant association between binge drinking in early pregnancy and child behavior at age 5 years (BJOG. 2013 Aug;120[9]:1042-50).
In this study, the investigators corrected for parental education, maternal IQ, prenatal maternal smoking and postnatal parental smoking, the child’s age at testing, the child’s gender, maternal age, parity, marital status, family-home environment, prepregnancy maternal body mass index, and the child’s health status. After adjusting for confounders, they found no association between binge drinking and scores on the SDQ (odds ratio, 1.2; 95% confidence interval, 0.8-1.7 for behavioral scores and OR, 0.8; 95% CI, 0.6-1.2 for total difficulties scores). Additionally, the investigators analyzed low to moderate weekly alcohol consumption in early pregnancy and also could not find a significant effect (OR, 1.1; 95% CI, 0.5-2.3 for behavioral scores and OR, 1.1; 95% CI, 0.6-2.1 for the total difficulties scores).
This finding received a lot of press attention at the time, but it’s not the only study that has shown a lack of effect from binge drinking in contrast to the conventional wisdom on this subject.
A meta-analysis published in early 2014 further adds to the literature on this topic (Alcohol Clin Exp Res. 2014 Jan;38[1]:214-26).
The meta-analysis showed a small, but statistically significant effect on child’s cognition associated with binge drinking in pregnancy (Cohen’s d [a standardized mean difference score] −0.13; 95% CI, −0.21, −0.05). It did not include the 2013 Danish study.
The meta-analysis examined other levels of drinking in pregnancy, not just binging. Out of more than 1,500 papers that were examined, 34 studies met the criteria for inclusion, and just eight were included in the binge drinking analysis. The eight studies comprised more than 10,000 children who were tested from ages 6 months to 14 years. The researchers analyzed eight functional domains: academic performance, attention, behavior, cognition, memory, language and verbal development, executive function, and visual and motor development.
The researchers also separated the studies based on quality. When they analyzed the results for only high-quality studies, the cognition effect was not significant and no other associations were found with other child neuropsychological outcomes.
Several other studies have examined different endpoints, particularly hyperactivity and externalizing behaviors. While several studies show a trend toward those effects, mothers who binge drink also tend to be more externalizing in their own behavior.
An examination of the literature shows just how difficult it is to produce clear results that inform clinical practice. Adjusting for confounding factors from marital status to maternal IQ is just one hurdle. Another area that plagues researchers is that knowledge of drinking in early pregnancy is based on self-reports, and it is nearly impossible to know for sure if the reports of binging are accurate and also if there has been chronic alcohol use.
So what does all of this mean when it comes to advising women? There is no question that women should be advised not to drink when they are pregnant or planning a pregnancy. For a woman who engaged in binge drinking before she knew she was pregnant, it’s difficult to say that there is no effect. Instead, the collective evidence suggests there may be a small effect on cognition. In cases where binge drinking has occurred, children should be monitored as early as possible for any potential developmental effects.
Dr. Koren is professor of physiology/pharmacology and pediatrics at Western University in Ontario. He is the founder of the Motherisk Program. He reported having no relevant financial disclosures. Email him at obnews@frontlinemedcom.com.
Imagine this scenario: A couple goes on a Caribbean cruise with an all-you-can-eat buffet and an open bar. During the trip, they engage in 2 or 3 days of binge-style drinking, which is considered about four drinks in a single sitting. A few weeks after the trip, the woman finds out that she’s pregnant and calls your office wondering if there will be any harm to the fetus.
This is not a theoretical question. I have received many of these calls over the years, and in some cases the fear of adverse effects on the baby has led the couple to terminate the pregnancy.
Unfortunately, the literature has not been clear on the long-term impact of binge drinking in pregnancy. Animal studies suggest that it is the peak in the alcohol level created by binge drinking that causes damage to the fetus, rather than a sustained level of alcohol (although that obviously carries risk as well). The literature in humans has been controversial.
One of the most recent studies is a prospective cohort study of more than 1,600 women and their children sampled from the Danish National Birth Cohort. The investigators collected information on maternal alcohol use in early pregnancy and examined children at age 5 years using the Strengths and Difficulties Questionnaire (SDQ) completed by the mothers and a preschool teacher. It found no statistically significant association between binge drinking in early pregnancy and child behavior at age 5 years (BJOG. 2013 Aug;120[9]:1042-50).
In this study, the investigators corrected for parental education, maternal IQ, prenatal maternal smoking and postnatal parental smoking, the child’s age at testing, the child’s gender, maternal age, parity, marital status, family-home environment, prepregnancy maternal body mass index, and the child’s health status. After adjusting for confounders, they found no association between binge drinking and scores on the SDQ (odds ratio, 1.2; 95% confidence interval, 0.8-1.7 for behavioral scores and OR, 0.8; 95% CI, 0.6-1.2 for total difficulties scores). Additionally, the investigators analyzed low to moderate weekly alcohol consumption in early pregnancy and also could not find a significant effect (OR, 1.1; 95% CI, 0.5-2.3 for behavioral scores and OR, 1.1; 95% CI, 0.6-2.1 for the total difficulties scores).
This finding received a lot of press attention at the time, but it’s not the only study that has shown a lack of effect from binge drinking in contrast to the conventional wisdom on this subject.
A meta-analysis published in early 2014 further adds to the literature on this topic (Alcohol Clin Exp Res. 2014 Jan;38[1]:214-26).
The meta-analysis showed a small, but statistically significant effect on child’s cognition associated with binge drinking in pregnancy (Cohen’s d [a standardized mean difference score] −0.13; 95% CI, −0.21, −0.05). It did not include the 2013 Danish study.
The meta-analysis examined other levels of drinking in pregnancy, not just binging. Out of more than 1,500 papers that were examined, 34 studies met the criteria for inclusion, and just eight were included in the binge drinking analysis. The eight studies comprised more than 10,000 children who were tested from ages 6 months to 14 years. The researchers analyzed eight functional domains: academic performance, attention, behavior, cognition, memory, language and verbal development, executive function, and visual and motor development.
The researchers also separated the studies based on quality. When they analyzed the results for only high-quality studies, the cognition effect was not significant and no other associations were found with other child neuropsychological outcomes.
Several other studies have examined different endpoints, particularly hyperactivity and externalizing behaviors. While several studies show a trend toward those effects, mothers who binge drink also tend to be more externalizing in their own behavior.
An examination of the literature shows just how difficult it is to produce clear results that inform clinical practice. Adjusting for confounding factors from marital status to maternal IQ is just one hurdle. Another area that plagues researchers is that knowledge of drinking in early pregnancy is based on self-reports, and it is nearly impossible to know for sure if the reports of binging are accurate and also if there has been chronic alcohol use.
So what does all of this mean when it comes to advising women? There is no question that women should be advised not to drink when they are pregnant or planning a pregnancy. For a woman who engaged in binge drinking before she knew she was pregnant, it’s difficult to say that there is no effect. Instead, the collective evidence suggests there may be a small effect on cognition. In cases where binge drinking has occurred, children should be monitored as early as possible for any potential developmental effects.
Dr. Koren is professor of physiology/pharmacology and pediatrics at Western University in Ontario. He is the founder of the Motherisk Program. He reported having no relevant financial disclosures. Email him at obnews@frontlinemedcom.com.
Imagine this scenario: A couple goes on a Caribbean cruise with an all-you-can-eat buffet and an open bar. During the trip, they engage in 2 or 3 days of binge-style drinking, which is considered about four drinks in a single sitting. A few weeks after the trip, the woman finds out that she’s pregnant and calls your office wondering if there will be any harm to the fetus.
This is not a theoretical question. I have received many of these calls over the years, and in some cases the fear of adverse effects on the baby has led the couple to terminate the pregnancy.
Unfortunately, the literature has not been clear on the long-term impact of binge drinking in pregnancy. Animal studies suggest that it is the peak in the alcohol level created by binge drinking that causes damage to the fetus, rather than a sustained level of alcohol (although that obviously carries risk as well). The literature in humans has been controversial.
One of the most recent studies is a prospective cohort study of more than 1,600 women and their children sampled from the Danish National Birth Cohort. The investigators collected information on maternal alcohol use in early pregnancy and examined children at age 5 years using the Strengths and Difficulties Questionnaire (SDQ) completed by the mothers and a preschool teacher. It found no statistically significant association between binge drinking in early pregnancy and child behavior at age 5 years (BJOG. 2013 Aug;120[9]:1042-50).
In this study, the investigators corrected for parental education, maternal IQ, prenatal maternal smoking and postnatal parental smoking, the child’s age at testing, the child’s gender, maternal age, parity, marital status, family-home environment, prepregnancy maternal body mass index, and the child’s health status. After adjusting for confounders, they found no association between binge drinking and scores on the SDQ (odds ratio, 1.2; 95% confidence interval, 0.8-1.7 for behavioral scores and OR, 0.8; 95% CI, 0.6-1.2 for total difficulties scores). Additionally, the investigators analyzed low to moderate weekly alcohol consumption in early pregnancy and also could not find a significant effect (OR, 1.1; 95% CI, 0.5-2.3 for behavioral scores and OR, 1.1; 95% CI, 0.6-2.1 for the total difficulties scores).
This finding received a lot of press attention at the time, but it’s not the only study that has shown a lack of effect from binge drinking in contrast to the conventional wisdom on this subject.
A meta-analysis published in early 2014 further adds to the literature on this topic (Alcohol Clin Exp Res. 2014 Jan;38[1]:214-26).
The meta-analysis showed a small, but statistically significant effect on child’s cognition associated with binge drinking in pregnancy (Cohen’s d [a standardized mean difference score] −0.13; 95% CI, −0.21, −0.05). It did not include the 2013 Danish study.
The meta-analysis examined other levels of drinking in pregnancy, not just binging. Out of more than 1,500 papers that were examined, 34 studies met the criteria for inclusion, and just eight were included in the binge drinking analysis. The eight studies comprised more than 10,000 children who were tested from ages 6 months to 14 years. The researchers analyzed eight functional domains: academic performance, attention, behavior, cognition, memory, language and verbal development, executive function, and visual and motor development.
The researchers also separated the studies based on quality. When they analyzed the results for only high-quality studies, the cognition effect was not significant and no other associations were found with other child neuropsychological outcomes.
Several other studies have examined different endpoints, particularly hyperactivity and externalizing behaviors. While several studies show a trend toward those effects, mothers who binge drink also tend to be more externalizing in their own behavior.
An examination of the literature shows just how difficult it is to produce clear results that inform clinical practice. Adjusting for confounding factors from marital status to maternal IQ is just one hurdle. Another area that plagues researchers is that knowledge of drinking in early pregnancy is based on self-reports, and it is nearly impossible to know for sure if the reports of binging are accurate and also if there has been chronic alcohol use.
So what does all of this mean when it comes to advising women? There is no question that women should be advised not to drink when they are pregnant or planning a pregnancy. For a woman who engaged in binge drinking before she knew she was pregnant, it’s difficult to say that there is no effect. Instead, the collective evidence suggests there may be a small effect on cognition. In cases where binge drinking has occurred, children should be monitored as early as possible for any potential developmental effects.
Dr. Koren is professor of physiology/pharmacology and pediatrics at Western University in Ontario. He is the founder of the Motherisk Program. He reported having no relevant financial disclosures. Email him at obnews@frontlinemedcom.com.
New FASD diagnosis guidelines: Comprehensive or overly broad?
One of the most challenging elements in making a diagnosis of fetal alcohol spectrum disorders is obtaining a thorough history of the mother’s drinking during pregnancy. This is something that ob.gyns. have struggled with for many years, and while there are ways to improve the collection of this information, it’s often an uncomfortable conversation that yields unreliable answers.
In August, a group of experts on fetal alcohol spectrum disorders (FASD), organized by the National Institute on Alcohol Abuse and Alcoholism, proposed new clinical guidelines for diagnosing these disorders, the first update since 2005 (Pediatrics. 2016;138[2]:e20154256). The update creates a more inclusive definition of FASD and puts a greater emphasis on the sometimes subtle physical and behavioral changes that occur in children.
Growth restriction
The updated diagnosis begins with the acknowledgment of maternal drinking during pregnancy and growth restriction in the infant, which the new guidelines set at the 10th percentile. That’s an important change because it significantly increases sensitivity, expanding the number of infants who could be diagnosed by raising the growth restriction threshold from the third percentile. Clinicians must take into account other factors, such as the size of the natural parents and whether growth restriction could be caused by other conditions.
Facial changes
A key component on the FASD diagnosis is the assessment of facial changes. The three typical facial changes that have been used to make this diagnosis since the 1970s include short palpebral fissures, a shallow or lack of philtrum, and a thin vermilion border of the upper lip. Previously, if all three of these facial features were present, a history of maternal drinking was not needed in the diagnosis of fetal alcohol syndrome. If two of the three features were present, it was considered partial fetal alcohol syndrome. Now, if maternal drinking has been determined, it’s not necessary to have all three facial features to make a diagnosis of fetal alcohol syndrome.
For the first time, the guidelines describe other facial changes common in FASD that can be used to diagnose partial fetal alcohol syndrome, including a flat nasal bridge, epicanthal folds, and other signs. Again, the guidelines increase sensitivity and make it likely that more cases will be picked up through these criteria.
Neurobehavioral changes
The most devastating part of FASD are the complex neurobehavioral changes, resulting from damage to the fetal brain. Under the updated guidelines, the authors relaxed the criteria so that children can be diagnosed if they have domains of either intellectual impairment or behavioral changes that are 1.5 standard deviations below the age-adjusted mean, rather than the previous 2 standard deviations.
The challenge with making this change is that unlike with the facial changes, there’s a lack of specificity in assessing intellectual impairment and behavioral changes. In addition, these issues often emerge with other conditions unrelated to fetal exposure to alcohol.
Sensitivity vs. specificity
Statistically, the authors of the updated guidelines have moved to increase sensitivity, reaching more children who need interventions for the devastating manifestations of FASD. But the price of this expansion of the diagnostic criteria is a decrease in specificity. The authors seek to combat this potential lack of specificity by emphasizing that an FASD diagnosis should be made not by a single clinician but by a multidisciplinary team that includes physicians, a psychologist, social worker, and speech and language specialists.
While a specialized team will certainly help to make a better diagnosis, the literature shows very large variability in obtaining FASD diagnosis by using different guidelines. A May 2016 paper in Alcoholism: Clinical & Experimental Research found wide diagnostic variation of between roughly 5% (using guidelines from the Centers for Disease Control and Prevention) and 60% (using 2006 guidelines from Hoyme et al.) in the same group of alcohol- and drug-exposed children, when five different guidelines were used (doi: 10.1111/acer.13032). This type of variation would not be acceptable in other conditions, such as autism or attention-deficit/hyperactivity disorder, and it highlights a serious unresolved gap in advancing FASD.
Ob.gyn. role
The role for the ob.gyn. is a complicated one, both in terms of diagnosis and prevention of FASD. Quite often the mother is abusing both alcohol and drugs and the infant may be at risk for neonatal abstinence syndrome in addition to FASD. And because alcohol abuse is often chronic, this is an issue that could affect future children.
While there are still many unanswered questions on the genetics of FASD, we do know that it’s not an equal opportunity condition. Mothers who have had a child with the syndrome have a higher likelihood of its occurring with a second child, compared with mothers who drink heavily but did not have a previous child with FASD.
For now, it’s imperative that ob.gyns. continue to ask about drinking in a nonjudgmental way and that they ask this question of all their patients, not just ones they consider to be in high risk populations.
Dr. Koren is professor of physiology/pharmacology at Western University in Ontario. He is the founder of the Motherisk Program. He reported having no relevant financial disclosures. Email him at obnews@frontlinemedcom.com.
One of the most challenging elements in making a diagnosis of fetal alcohol spectrum disorders is obtaining a thorough history of the mother’s drinking during pregnancy. This is something that ob.gyns. have struggled with for many years, and while there are ways to improve the collection of this information, it’s often an uncomfortable conversation that yields unreliable answers.
In August, a group of experts on fetal alcohol spectrum disorders (FASD), organized by the National Institute on Alcohol Abuse and Alcoholism, proposed new clinical guidelines for diagnosing these disorders, the first update since 2005 (Pediatrics. 2016;138[2]:e20154256). The update creates a more inclusive definition of FASD and puts a greater emphasis on the sometimes subtle physical and behavioral changes that occur in children.
Growth restriction
The updated diagnosis begins with the acknowledgment of maternal drinking during pregnancy and growth restriction in the infant, which the new guidelines set at the 10th percentile. That’s an important change because it significantly increases sensitivity, expanding the number of infants who could be diagnosed by raising the growth restriction threshold from the third percentile. Clinicians must take into account other factors, such as the size of the natural parents and whether growth restriction could be caused by other conditions.
Facial changes
A key component on the FASD diagnosis is the assessment of facial changes. The three typical facial changes that have been used to make this diagnosis since the 1970s include short palpebral fissures, a shallow or lack of philtrum, and a thin vermilion border of the upper lip. Previously, if all three of these facial features were present, a history of maternal drinking was not needed in the diagnosis of fetal alcohol syndrome. If two of the three features were present, it was considered partial fetal alcohol syndrome. Now, if maternal drinking has been determined, it’s not necessary to have all three facial features to make a diagnosis of fetal alcohol syndrome.
For the first time, the guidelines describe other facial changes common in FASD that can be used to diagnose partial fetal alcohol syndrome, including a flat nasal bridge, epicanthal folds, and other signs. Again, the guidelines increase sensitivity and make it likely that more cases will be picked up through these criteria.
Neurobehavioral changes
The most devastating part of FASD are the complex neurobehavioral changes, resulting from damage to the fetal brain. Under the updated guidelines, the authors relaxed the criteria so that children can be diagnosed if they have domains of either intellectual impairment or behavioral changes that are 1.5 standard deviations below the age-adjusted mean, rather than the previous 2 standard deviations.
The challenge with making this change is that unlike with the facial changes, there’s a lack of specificity in assessing intellectual impairment and behavioral changes. In addition, these issues often emerge with other conditions unrelated to fetal exposure to alcohol.
Sensitivity vs. specificity
Statistically, the authors of the updated guidelines have moved to increase sensitivity, reaching more children who need interventions for the devastating manifestations of FASD. But the price of this expansion of the diagnostic criteria is a decrease in specificity. The authors seek to combat this potential lack of specificity by emphasizing that an FASD diagnosis should be made not by a single clinician but by a multidisciplinary team that includes physicians, a psychologist, social worker, and speech and language specialists.
While a specialized team will certainly help to make a better diagnosis, the literature shows very large variability in obtaining FASD diagnosis by using different guidelines. A May 2016 paper in Alcoholism: Clinical & Experimental Research found wide diagnostic variation of between roughly 5% (using guidelines from the Centers for Disease Control and Prevention) and 60% (using 2006 guidelines from Hoyme et al.) in the same group of alcohol- and drug-exposed children, when five different guidelines were used (doi: 10.1111/acer.13032). This type of variation would not be acceptable in other conditions, such as autism or attention-deficit/hyperactivity disorder, and it highlights a serious unresolved gap in advancing FASD.
Ob.gyn. role
The role for the ob.gyn. is a complicated one, both in terms of diagnosis and prevention of FASD. Quite often the mother is abusing both alcohol and drugs and the infant may be at risk for neonatal abstinence syndrome in addition to FASD. And because alcohol abuse is often chronic, this is an issue that could affect future children.
While there are still many unanswered questions on the genetics of FASD, we do know that it’s not an equal opportunity condition. Mothers who have had a child with the syndrome have a higher likelihood of its occurring with a second child, compared with mothers who drink heavily but did not have a previous child with FASD.
For now, it’s imperative that ob.gyns. continue to ask about drinking in a nonjudgmental way and that they ask this question of all their patients, not just ones they consider to be in high risk populations.
Dr. Koren is professor of physiology/pharmacology at Western University in Ontario. He is the founder of the Motherisk Program. He reported having no relevant financial disclosures. Email him at obnews@frontlinemedcom.com.
One of the most challenging elements in making a diagnosis of fetal alcohol spectrum disorders is obtaining a thorough history of the mother’s drinking during pregnancy. This is something that ob.gyns. have struggled with for many years, and while there are ways to improve the collection of this information, it’s often an uncomfortable conversation that yields unreliable answers.
In August, a group of experts on fetal alcohol spectrum disorders (FASD), organized by the National Institute on Alcohol Abuse and Alcoholism, proposed new clinical guidelines for diagnosing these disorders, the first update since 2005 (Pediatrics. 2016;138[2]:e20154256). The update creates a more inclusive definition of FASD and puts a greater emphasis on the sometimes subtle physical and behavioral changes that occur in children.
Growth restriction
The updated diagnosis begins with the acknowledgment of maternal drinking during pregnancy and growth restriction in the infant, which the new guidelines set at the 10th percentile. That’s an important change because it significantly increases sensitivity, expanding the number of infants who could be diagnosed by raising the growth restriction threshold from the third percentile. Clinicians must take into account other factors, such as the size of the natural parents and whether growth restriction could be caused by other conditions.
Facial changes
A key component on the FASD diagnosis is the assessment of facial changes. The three typical facial changes that have been used to make this diagnosis since the 1970s include short palpebral fissures, a shallow or lack of philtrum, and a thin vermilion border of the upper lip. Previously, if all three of these facial features were present, a history of maternal drinking was not needed in the diagnosis of fetal alcohol syndrome. If two of the three features were present, it was considered partial fetal alcohol syndrome. Now, if maternal drinking has been determined, it’s not necessary to have all three facial features to make a diagnosis of fetal alcohol syndrome.
For the first time, the guidelines describe other facial changes common in FASD that can be used to diagnose partial fetal alcohol syndrome, including a flat nasal bridge, epicanthal folds, and other signs. Again, the guidelines increase sensitivity and make it likely that more cases will be picked up through these criteria.
Neurobehavioral changes
The most devastating part of FASD are the complex neurobehavioral changes, resulting from damage to the fetal brain. Under the updated guidelines, the authors relaxed the criteria so that children can be diagnosed if they have domains of either intellectual impairment or behavioral changes that are 1.5 standard deviations below the age-adjusted mean, rather than the previous 2 standard deviations.
The challenge with making this change is that unlike with the facial changes, there’s a lack of specificity in assessing intellectual impairment and behavioral changes. In addition, these issues often emerge with other conditions unrelated to fetal exposure to alcohol.
Sensitivity vs. specificity
Statistically, the authors of the updated guidelines have moved to increase sensitivity, reaching more children who need interventions for the devastating manifestations of FASD. But the price of this expansion of the diagnostic criteria is a decrease in specificity. The authors seek to combat this potential lack of specificity by emphasizing that an FASD diagnosis should be made not by a single clinician but by a multidisciplinary team that includes physicians, a psychologist, social worker, and speech and language specialists.
While a specialized team will certainly help to make a better diagnosis, the literature shows very large variability in obtaining FASD diagnosis by using different guidelines. A May 2016 paper in Alcoholism: Clinical & Experimental Research found wide diagnostic variation of between roughly 5% (using guidelines from the Centers for Disease Control and Prevention) and 60% (using 2006 guidelines from Hoyme et al.) in the same group of alcohol- and drug-exposed children, when five different guidelines were used (doi: 10.1111/acer.13032). This type of variation would not be acceptable in other conditions, such as autism or attention-deficit/hyperactivity disorder, and it highlights a serious unresolved gap in advancing FASD.
Ob.gyn. role
The role for the ob.gyn. is a complicated one, both in terms of diagnosis and prevention of FASD. Quite often the mother is abusing both alcohol and drugs and the infant may be at risk for neonatal abstinence syndrome in addition to FASD. And because alcohol abuse is often chronic, this is an issue that could affect future children.
While there are still many unanswered questions on the genetics of FASD, we do know that it’s not an equal opportunity condition. Mothers who have had a child with the syndrome have a higher likelihood of its occurring with a second child, compared with mothers who drink heavily but did not have a previous child with FASD.
For now, it’s imperative that ob.gyns. continue to ask about drinking in a nonjudgmental way and that they ask this question of all their patients, not just ones they consider to be in high risk populations.
Dr. Koren is professor of physiology/pharmacology at Western University in Ontario. He is the founder of the Motherisk Program. He reported having no relevant financial disclosures. Email him at obnews@frontlinemedcom.com.
Combatting misperceptions in prenatal exposures
It’s clear that for pregnant women and the physicians who care for them, the risk of using medications in pregnancy is a significant issue. Unfortunately, sometimes the perception of that risk is much greater than the reality and drives behavior that can harm women and their babies.
Before the tragedy of thalidomide, the medical community held the general belief that drugs and chemicals do not cross the placenta, so there was no need to fear fetal malformations from medication use in pregnancy. In 1961, thalidomide became a formative event that changed everyone’s perception, with many people adopting the belief that every drug could be dangerous. In reality, though, very few medications prescribed today are known teratogens that cause malformations.
In recent years, an increasing number of drugs have been shown to be “safe.” The issue with the term safe is that there can always be more cases and more studies showing some very small risk that was previously unknown. But, in general, there are more reassuring studies in the literature than ones showing drugs to be dangerous in pregnancy.
The Bendectin example
In the highly charged medicolegal atmosphere in which we practice, physicians are afraid to be sued. If you remember that about 3% of babies are born with malformations just by chance, and that mothers will likely be taking some type of medication, there is always the possibility of a bad outcome that could cast blame on a drug.
In the 1970s, a lot of that litigation centered around the morning sickness drug Bendectin – originally formulated with doxylamine succinate, pyridoxine HCl, and dicyclomine HCl, and later reformulated without the dicyclomine. The drug was taken off the U.S. market by the manufacturer in 1983 because the company couldn’t afford the high cost of litigation and insurance, despite the fact that a panel convened by the Food and Drug Administration said there was no association between Bendectin and human birth defects.
It took nearly 20 years before the FDA declared that the drug had been withdrawn from the market for reasons unrelated to safety and effectiveness. In the meantime, American women remained without an FDA-approved medication to treat morning sickness, and there was a more than twofold increase in hospitalization rates for pregnant women with hyperemesis gravidarum (Can J Public Health. 1995 Jan-Feb;86[1]:66-70). The lesson here is that perceptions in the absence of evidence can lead to grave outcomes.
Exaggeration of risk
Over the years, my colleagues and I have studied how pregnant women perceive drug risk by simply asking them to estimate the risk to their baby from the medication they are currently taking. What we discovered was that women exposed to nonteratogenic drugs consider themselves at a risk of about 25% for having a child with a major malformation. In reality, the risk is between 1% and 3% and has nothing to do with the drug itself. It became clear that there is a huge perception of risk when women are exposed to drugs that should not increase that risk (Am J Obstet Gynecol. 1989 May;160[5 Pt 1]:1190-4).
The same study also showed that many of the women who gave exaggerated risk assessments said they would consider termination of the pregnancy. Even after hearing the drug is safe, some women were still considering termination.
Sadly, women terminating a pregnancy because of a perceived risk for malformation is not unique to this study. In the 1980s, following the explosion at Chernobyl in the Ukraine, women in Athens were told that they had a high risk for malformation in their children because of radiation exposure. Statistics show that during that month, nearly a quarter of early pregnancies in Athens were terminated (Br Med J [Clin Res Ed] 1987;295:1100).
We have further found that women exposed to radiation for diagnostic purposes estimate a high risk of malformation. This type of estimate is likely influenced by the effects of radiation at Hiroshima and Nagasaki, but there is no comparison between the extremely high amounts of radiation in those incidents, compared with the very low amounts in diagnostic tests. Still, we found that women again considered termination because of their perceived risk from radiation.
Social economics are also part of this. Women who are single mothers are more likely to terminate a pregnancy, or consider termination, after exposure to a drug in pregnancy. Women with psychiatric conditions have a similar tendency. On the other hand, women with chronic diseases – who may be used to the effects of a certain medications – are less likely to suggest termination because of perceived risk.
Communicating risk
These are important concepts to consider in the context of the emerging threat of Zika virus and the news from the Centers for Disease Control and Prevention that it is a definitive cause of microcephaly and other severe fetal malformations. While there is a real risk for pregnant women, both through mosquitoes and sexual contact, women are likely to perceive the highest level of risk. In South America, where therapeutic abortion is often not an option, accurate risk communication is critical.
When medications are prescribed during pregnancy, the first step is determining that a drug is truly needed, often in consultation with a specialist. Once that determination is made, it’s key to ensure that women and their families are familiar with the known risk or the lack of risk based on the best available data. There are resources for physicians to help understand and communicate about drug risks in pregnancy, including information from the Organization of Teratology Information Specialists. It’s also important to note that in every pregnancy, there is a 1%-3% risk of major malformations, even if the drug itself is safe. And it can’t hurt to think defensively and document that conversation and that the patient appears to have understood the concept of risk.
Dr. Koren is professor of pharmacology and pharmacy at the University of Toronto. He is the founding director of the Motherisk Program. He reported having been a paid consultant for Novartis and for Duchesnay, which makes Diclegis to treat nausea and vomiting in pregnancy.
It’s clear that for pregnant women and the physicians who care for them, the risk of using medications in pregnancy is a significant issue. Unfortunately, sometimes the perception of that risk is much greater than the reality and drives behavior that can harm women and their babies.
Before the tragedy of thalidomide, the medical community held the general belief that drugs and chemicals do not cross the placenta, so there was no need to fear fetal malformations from medication use in pregnancy. In 1961, thalidomide became a formative event that changed everyone’s perception, with many people adopting the belief that every drug could be dangerous. In reality, though, very few medications prescribed today are known teratogens that cause malformations.
In recent years, an increasing number of drugs have been shown to be “safe.” The issue with the term safe is that there can always be more cases and more studies showing some very small risk that was previously unknown. But, in general, there are more reassuring studies in the literature than ones showing drugs to be dangerous in pregnancy.
The Bendectin example
In the highly charged medicolegal atmosphere in which we practice, physicians are afraid to be sued. If you remember that about 3% of babies are born with malformations just by chance, and that mothers will likely be taking some type of medication, there is always the possibility of a bad outcome that could cast blame on a drug.
In the 1970s, a lot of that litigation centered around the morning sickness drug Bendectin – originally formulated with doxylamine succinate, pyridoxine HCl, and dicyclomine HCl, and later reformulated without the dicyclomine. The drug was taken off the U.S. market by the manufacturer in 1983 because the company couldn’t afford the high cost of litigation and insurance, despite the fact that a panel convened by the Food and Drug Administration said there was no association between Bendectin and human birth defects.
It took nearly 20 years before the FDA declared that the drug had been withdrawn from the market for reasons unrelated to safety and effectiveness. In the meantime, American women remained without an FDA-approved medication to treat morning sickness, and there was a more than twofold increase in hospitalization rates for pregnant women with hyperemesis gravidarum (Can J Public Health. 1995 Jan-Feb;86[1]:66-70). The lesson here is that perceptions in the absence of evidence can lead to grave outcomes.
Exaggeration of risk
Over the years, my colleagues and I have studied how pregnant women perceive drug risk by simply asking them to estimate the risk to their baby from the medication they are currently taking. What we discovered was that women exposed to nonteratogenic drugs consider themselves at a risk of about 25% for having a child with a major malformation. In reality, the risk is between 1% and 3% and has nothing to do with the drug itself. It became clear that there is a huge perception of risk when women are exposed to drugs that should not increase that risk (Am J Obstet Gynecol. 1989 May;160[5 Pt 1]:1190-4).
The same study also showed that many of the women who gave exaggerated risk assessments said they would consider termination of the pregnancy. Even after hearing the drug is safe, some women were still considering termination.
Sadly, women terminating a pregnancy because of a perceived risk for malformation is not unique to this study. In the 1980s, following the explosion at Chernobyl in the Ukraine, women in Athens were told that they had a high risk for malformation in their children because of radiation exposure. Statistics show that during that month, nearly a quarter of early pregnancies in Athens were terminated (Br Med J [Clin Res Ed] 1987;295:1100).
We have further found that women exposed to radiation for diagnostic purposes estimate a high risk of malformation. This type of estimate is likely influenced by the effects of radiation at Hiroshima and Nagasaki, but there is no comparison between the extremely high amounts of radiation in those incidents, compared with the very low amounts in diagnostic tests. Still, we found that women again considered termination because of their perceived risk from radiation.
Social economics are also part of this. Women who are single mothers are more likely to terminate a pregnancy, or consider termination, after exposure to a drug in pregnancy. Women with psychiatric conditions have a similar tendency. On the other hand, women with chronic diseases – who may be used to the effects of a certain medications – are less likely to suggest termination because of perceived risk.
Communicating risk
These are important concepts to consider in the context of the emerging threat of Zika virus and the news from the Centers for Disease Control and Prevention that it is a definitive cause of microcephaly and other severe fetal malformations. While there is a real risk for pregnant women, both through mosquitoes and sexual contact, women are likely to perceive the highest level of risk. In South America, where therapeutic abortion is often not an option, accurate risk communication is critical.
When medications are prescribed during pregnancy, the first step is determining that a drug is truly needed, often in consultation with a specialist. Once that determination is made, it’s key to ensure that women and their families are familiar with the known risk or the lack of risk based on the best available data. There are resources for physicians to help understand and communicate about drug risks in pregnancy, including information from the Organization of Teratology Information Specialists. It’s also important to note that in every pregnancy, there is a 1%-3% risk of major malformations, even if the drug itself is safe. And it can’t hurt to think defensively and document that conversation and that the patient appears to have understood the concept of risk.
Dr. Koren is professor of pharmacology and pharmacy at the University of Toronto. He is the founding director of the Motherisk Program. He reported having been a paid consultant for Novartis and for Duchesnay, which makes Diclegis to treat nausea and vomiting in pregnancy.
It’s clear that for pregnant women and the physicians who care for them, the risk of using medications in pregnancy is a significant issue. Unfortunately, sometimes the perception of that risk is much greater than the reality and drives behavior that can harm women and their babies.
Before the tragedy of thalidomide, the medical community held the general belief that drugs and chemicals do not cross the placenta, so there was no need to fear fetal malformations from medication use in pregnancy. In 1961, thalidomide became a formative event that changed everyone’s perception, with many people adopting the belief that every drug could be dangerous. In reality, though, very few medications prescribed today are known teratogens that cause malformations.
In recent years, an increasing number of drugs have been shown to be “safe.” The issue with the term safe is that there can always be more cases and more studies showing some very small risk that was previously unknown. But, in general, there are more reassuring studies in the literature than ones showing drugs to be dangerous in pregnancy.
The Bendectin example
In the highly charged medicolegal atmosphere in which we practice, physicians are afraid to be sued. If you remember that about 3% of babies are born with malformations just by chance, and that mothers will likely be taking some type of medication, there is always the possibility of a bad outcome that could cast blame on a drug.
In the 1970s, a lot of that litigation centered around the morning sickness drug Bendectin – originally formulated with doxylamine succinate, pyridoxine HCl, and dicyclomine HCl, and later reformulated without the dicyclomine. The drug was taken off the U.S. market by the manufacturer in 1983 because the company couldn’t afford the high cost of litigation and insurance, despite the fact that a panel convened by the Food and Drug Administration said there was no association between Bendectin and human birth defects.
It took nearly 20 years before the FDA declared that the drug had been withdrawn from the market for reasons unrelated to safety and effectiveness. In the meantime, American women remained without an FDA-approved medication to treat morning sickness, and there was a more than twofold increase in hospitalization rates for pregnant women with hyperemesis gravidarum (Can J Public Health. 1995 Jan-Feb;86[1]:66-70). The lesson here is that perceptions in the absence of evidence can lead to grave outcomes.
Exaggeration of risk
Over the years, my colleagues and I have studied how pregnant women perceive drug risk by simply asking them to estimate the risk to their baby from the medication they are currently taking. What we discovered was that women exposed to nonteratogenic drugs consider themselves at a risk of about 25% for having a child with a major malformation. In reality, the risk is between 1% and 3% and has nothing to do with the drug itself. It became clear that there is a huge perception of risk when women are exposed to drugs that should not increase that risk (Am J Obstet Gynecol. 1989 May;160[5 Pt 1]:1190-4).
The same study also showed that many of the women who gave exaggerated risk assessments said they would consider termination of the pregnancy. Even after hearing the drug is safe, some women were still considering termination.
Sadly, women terminating a pregnancy because of a perceived risk for malformation is not unique to this study. In the 1980s, following the explosion at Chernobyl in the Ukraine, women in Athens were told that they had a high risk for malformation in their children because of radiation exposure. Statistics show that during that month, nearly a quarter of early pregnancies in Athens were terminated (Br Med J [Clin Res Ed] 1987;295:1100).
We have further found that women exposed to radiation for diagnostic purposes estimate a high risk of malformation. This type of estimate is likely influenced by the effects of radiation at Hiroshima and Nagasaki, but there is no comparison between the extremely high amounts of radiation in those incidents, compared with the very low amounts in diagnostic tests. Still, we found that women again considered termination because of their perceived risk from radiation.
Social economics are also part of this. Women who are single mothers are more likely to terminate a pregnancy, or consider termination, after exposure to a drug in pregnancy. Women with psychiatric conditions have a similar tendency. On the other hand, women with chronic diseases – who may be used to the effects of a certain medications – are less likely to suggest termination because of perceived risk.
Communicating risk
These are important concepts to consider in the context of the emerging threat of Zika virus and the news from the Centers for Disease Control and Prevention that it is a definitive cause of microcephaly and other severe fetal malformations. While there is a real risk for pregnant women, both through mosquitoes and sexual contact, women are likely to perceive the highest level of risk. In South America, where therapeutic abortion is often not an option, accurate risk communication is critical.
When medications are prescribed during pregnancy, the first step is determining that a drug is truly needed, often in consultation with a specialist. Once that determination is made, it’s key to ensure that women and their families are familiar with the known risk or the lack of risk based on the best available data. There are resources for physicians to help understand and communicate about drug risks in pregnancy, including information from the Organization of Teratology Information Specialists. It’s also important to note that in every pregnancy, there is a 1%-3% risk of major malformations, even if the drug itself is safe. And it can’t hurt to think defensively and document that conversation and that the patient appears to have understood the concept of risk.
Dr. Koren is professor of pharmacology and pharmacy at the University of Toronto. He is the founding director of the Motherisk Program. He reported having been a paid consultant for Novartis and for Duchesnay, which makes Diclegis to treat nausea and vomiting in pregnancy.
Biologic treatment in pregnancy requires balancing risks
The effectiveness of immunoglobulin biologic treatments in controlling chronic and potentially debilitating autoimmune diseases such as rheumatoid arthritis and ulcerative colitis means that more physicians are faced with the question of how to handle the use of these drugs in pregnancy.
While immunoglobulin G (IgG) biologicals are large molecules, there is no doubt that they cross the placenta through specific transport systems with a long half life in infants, creating potential risks for immunocompromise in early life. At the same time, these biologicals are essential, in many cases, for controlling the pregnant woman’s disease and allowing her to carry a pregnancy successfully by avoiding disease flare.
For ob.gyns., successful management of a pregnancy in which the woman is taking an immunoglobulin biological, such as an anti–tumor necrosis factor (TNF)-alpha agent, requires an understanding of not only which drugs cross the placenta, but when they do so and at what levels.
Crossing the placenta
Along with my student Juejing Ling, I recently reviewed the question of how the use of immunoglobulin biologicals in pregnancy affects the vaccination of infants in an article published in Expert Review of Vaccines (2015 Dec 7:1-18 doi: 10.1586/14760584.2016.1115351). Our analysis relates only to biologicals with partial or full IgG structure, as they are capable of crossing the placenta.
Data are still limited about the use of immunoglobulin biologicals in pregnancy, but measurement of umbilical cord blood has shown high levels of anti-TNF IgG in newborn serum, raising concerns about how these neonates will respond to vaccinations.
Neonates rely on maternal IgG transport to prevent infection in the first few months of life and that transport process begins around 12 weeks gestation. Fetal IgG levels begin to rise at 13-18 weeks and reach 120%-130% of maternal levels when the fetus reaches full term. In contrast, fusion proteins that contain the Fc portion and Fab fragment appear to have limited ability to cross the placenta. As a result, chimeric and full human IgG antibodies such as infliximab, adalimumab, and rituximab have demonstrated high levels of placental transport, while other agents, such as etanercept, appear to cross the placenta at lower levels.
Hence, due to the ineffective clearance, certain immunoglobulin biologicals actually have a higher concentration and a longer half life in neonates than in mothers. For instance, with infliximab, studies show that levels in the umbilical cord were up to fourfold higher than maternal levels, even when the drug was discontinued at 30 weeks of pregnancy or earlier. Due to long neonatal half life, infliximab levels became undetectable in infant serum only between 2-7 months, compared with 1-2 weeks in adults. Adalimumab is similar, where concentrations of the drug in neonates can be 150% of the maternal serum level and detectable for about 3 months after birth.
Transport of anti-TNFs is also possible through breastfeeding, although studies indicate that the levels are very low.
Infection risk
Due to the immunosuppressive effect of anti-TNF immunoglobulin biologicals, newborn infection is a real concern. Review of the literature showed that severe and moderate neutropenia and skin infection were reported in four neonates born to two women with ulcerative colitis who had taken infliximab throughout pregnancy.
Some other studies have followed infants who had detectable biological levels at birth after in utero exposure. In general, there is normal development in the first year without overt infection. However, there have been case reports of infections with varicella or upper respiratory infections in infants exposed to infliximab before 30 weeks’ gestation.
There is very little data on the long-term immune system impacts for infants exposed to immunoglobulin biologicals in utero. However, these agents are generally not at detectable levels after 1 year.
Impact on vaccination
Although these IgG biologicals will clear the infants’ systems after several months of life (generally by 8 months), another concern is for how their presence in the early months impacts neonatal vaccination, specifically live attenuated vaccines such as MMR (measles, mumps and rubella), BCG for tuberculosis, oral polio, rotavirus vaccine, and the intranasal influenza vaccine.
Generally, outcomes among infants exposed to anti-TNFs have been good. For instance, reports looking at 24 children with exposure to anti-TNFs found no complications with the MMR vaccine. But a famous case report identified one infant who died at 4.5 months after receiving the BCG vaccine at 3 months. The mother, who had Crohn’s disease, had been taking infliximab 10 mg/kg every 8 weeks throughout her pregnancy.
Another study of 15 infants in the Czech Republic who were exposed to infliximab in utero and received BCG vaccination within 1 week of birth found that three of the infants developed large local skin reactions. One of the three children also developed axillary lymphadenopathy. All of the children recovered without the need for anti-tuberculosis therapy.
So what do these complications mean for vaccination strategies? Both the European Crohn’s and Colitis Organisation and the World Congress of Gastroenterology recommend that in terms of non-live vaccines, it’s safe to follow the same vaccine schedule as infants not exposed to biologicals in utero. When it comes to live attenuated vaccines such as rotavirus, oral polio, and BCG, these infants should be treated as immunocompromised and not receive these vaccines until after 6 months of age, when the biologicals should be at undetectable levels.
Future directions
Given that most infections and other adverse events happen after late exposure in pregnancy, some have recommended discontinuing anti-TNF treatment before the third trimester. In fact, this has become a common management practice. However, this should be an individualized decision made after discussion between a woman and her physician or physicians. Any benefits from early discontinuation of an immunoglobulin biological therapy should be weighed against the risk of disease flare, which also has real potential to complicate pregnancy.
The evidence presented here not only shines a light on the possible risk to infants, but also on the need for more high-quality evidence on which physicians can base decisions. Most of the available evidence is drawn from case reports and registry databases. Both of these suffer from a lack of control groups. To answer these questions definitively, we need more well-controlled studies of large populations. I strongly urge readers to follow the amazing work led by Dr. Uma Mahadevan and her colleagues at the University of California, San Francisco on biological use in pregnancy and long-term outcomes. As we wait for more evidence, we all look forward to the development of newer biologic agents that can help women control autoimmune disease without crossing the placenta.
Dr. Koren is professor of pharmacology and pharmacy at the University of Toronto. He is the founding director of the Motherisk Program. He reported having no financial disclosures related to this article. Email him at obnews@frontlinemedcom.com.
The effectiveness of immunoglobulin biologic treatments in controlling chronic and potentially debilitating autoimmune diseases such as rheumatoid arthritis and ulcerative colitis means that more physicians are faced with the question of how to handle the use of these drugs in pregnancy.
While immunoglobulin G (IgG) biologicals are large molecules, there is no doubt that they cross the placenta through specific transport systems with a long half life in infants, creating potential risks for immunocompromise in early life. At the same time, these biologicals are essential, in many cases, for controlling the pregnant woman’s disease and allowing her to carry a pregnancy successfully by avoiding disease flare.
For ob.gyns., successful management of a pregnancy in which the woman is taking an immunoglobulin biological, such as an anti–tumor necrosis factor (TNF)-alpha agent, requires an understanding of not only which drugs cross the placenta, but when they do so and at what levels.
Crossing the placenta
Along with my student Juejing Ling, I recently reviewed the question of how the use of immunoglobulin biologicals in pregnancy affects the vaccination of infants in an article published in Expert Review of Vaccines (2015 Dec 7:1-18 doi: 10.1586/14760584.2016.1115351). Our analysis relates only to biologicals with partial or full IgG structure, as they are capable of crossing the placenta.
Data are still limited about the use of immunoglobulin biologicals in pregnancy, but measurement of umbilical cord blood has shown high levels of anti-TNF IgG in newborn serum, raising concerns about how these neonates will respond to vaccinations.
Neonates rely on maternal IgG transport to prevent infection in the first few months of life and that transport process begins around 12 weeks gestation. Fetal IgG levels begin to rise at 13-18 weeks and reach 120%-130% of maternal levels when the fetus reaches full term. In contrast, fusion proteins that contain the Fc portion and Fab fragment appear to have limited ability to cross the placenta. As a result, chimeric and full human IgG antibodies such as infliximab, adalimumab, and rituximab have demonstrated high levels of placental transport, while other agents, such as etanercept, appear to cross the placenta at lower levels.
Hence, due to the ineffective clearance, certain immunoglobulin biologicals actually have a higher concentration and a longer half life in neonates than in mothers. For instance, with infliximab, studies show that levels in the umbilical cord were up to fourfold higher than maternal levels, even when the drug was discontinued at 30 weeks of pregnancy or earlier. Due to long neonatal half life, infliximab levels became undetectable in infant serum only between 2-7 months, compared with 1-2 weeks in adults. Adalimumab is similar, where concentrations of the drug in neonates can be 150% of the maternal serum level and detectable for about 3 months after birth.
Transport of anti-TNFs is also possible through breastfeeding, although studies indicate that the levels are very low.
Infection risk
Due to the immunosuppressive effect of anti-TNF immunoglobulin biologicals, newborn infection is a real concern. Review of the literature showed that severe and moderate neutropenia and skin infection were reported in four neonates born to two women with ulcerative colitis who had taken infliximab throughout pregnancy.
Some other studies have followed infants who had detectable biological levels at birth after in utero exposure. In general, there is normal development in the first year without overt infection. However, there have been case reports of infections with varicella or upper respiratory infections in infants exposed to infliximab before 30 weeks’ gestation.
There is very little data on the long-term immune system impacts for infants exposed to immunoglobulin biologicals in utero. However, these agents are generally not at detectable levels after 1 year.
Impact on vaccination
Although these IgG biologicals will clear the infants’ systems after several months of life (generally by 8 months), another concern is for how their presence in the early months impacts neonatal vaccination, specifically live attenuated vaccines such as MMR (measles, mumps and rubella), BCG for tuberculosis, oral polio, rotavirus vaccine, and the intranasal influenza vaccine.
Generally, outcomes among infants exposed to anti-TNFs have been good. For instance, reports looking at 24 children with exposure to anti-TNFs found no complications with the MMR vaccine. But a famous case report identified one infant who died at 4.5 months after receiving the BCG vaccine at 3 months. The mother, who had Crohn’s disease, had been taking infliximab 10 mg/kg every 8 weeks throughout her pregnancy.
Another study of 15 infants in the Czech Republic who were exposed to infliximab in utero and received BCG vaccination within 1 week of birth found that three of the infants developed large local skin reactions. One of the three children also developed axillary lymphadenopathy. All of the children recovered without the need for anti-tuberculosis therapy.
So what do these complications mean for vaccination strategies? Both the European Crohn’s and Colitis Organisation and the World Congress of Gastroenterology recommend that in terms of non-live vaccines, it’s safe to follow the same vaccine schedule as infants not exposed to biologicals in utero. When it comes to live attenuated vaccines such as rotavirus, oral polio, and BCG, these infants should be treated as immunocompromised and not receive these vaccines until after 6 months of age, when the biologicals should be at undetectable levels.
Future directions
Given that most infections and other adverse events happen after late exposure in pregnancy, some have recommended discontinuing anti-TNF treatment before the third trimester. In fact, this has become a common management practice. However, this should be an individualized decision made after discussion between a woman and her physician or physicians. Any benefits from early discontinuation of an immunoglobulin biological therapy should be weighed against the risk of disease flare, which also has real potential to complicate pregnancy.
The evidence presented here not only shines a light on the possible risk to infants, but also on the need for more high-quality evidence on which physicians can base decisions. Most of the available evidence is drawn from case reports and registry databases. Both of these suffer from a lack of control groups. To answer these questions definitively, we need more well-controlled studies of large populations. I strongly urge readers to follow the amazing work led by Dr. Uma Mahadevan and her colleagues at the University of California, San Francisco on biological use in pregnancy and long-term outcomes. As we wait for more evidence, we all look forward to the development of newer biologic agents that can help women control autoimmune disease without crossing the placenta.
Dr. Koren is professor of pharmacology and pharmacy at the University of Toronto. He is the founding director of the Motherisk Program. He reported having no financial disclosures related to this article. Email him at obnews@frontlinemedcom.com.
The effectiveness of immunoglobulin biologic treatments in controlling chronic and potentially debilitating autoimmune diseases such as rheumatoid arthritis and ulcerative colitis means that more physicians are faced with the question of how to handle the use of these drugs in pregnancy.
While immunoglobulin G (IgG) biologicals are large molecules, there is no doubt that they cross the placenta through specific transport systems with a long half life in infants, creating potential risks for immunocompromise in early life. At the same time, these biologicals are essential, in many cases, for controlling the pregnant woman’s disease and allowing her to carry a pregnancy successfully by avoiding disease flare.
For ob.gyns., successful management of a pregnancy in which the woman is taking an immunoglobulin biological, such as an anti–tumor necrosis factor (TNF)-alpha agent, requires an understanding of not only which drugs cross the placenta, but when they do so and at what levels.
Crossing the placenta
Along with my student Juejing Ling, I recently reviewed the question of how the use of immunoglobulin biologicals in pregnancy affects the vaccination of infants in an article published in Expert Review of Vaccines (2015 Dec 7:1-18 doi: 10.1586/14760584.2016.1115351). Our analysis relates only to biologicals with partial or full IgG structure, as they are capable of crossing the placenta.
Data are still limited about the use of immunoglobulin biologicals in pregnancy, but measurement of umbilical cord blood has shown high levels of anti-TNF IgG in newborn serum, raising concerns about how these neonates will respond to vaccinations.
Neonates rely on maternal IgG transport to prevent infection in the first few months of life and that transport process begins around 12 weeks gestation. Fetal IgG levels begin to rise at 13-18 weeks and reach 120%-130% of maternal levels when the fetus reaches full term. In contrast, fusion proteins that contain the Fc portion and Fab fragment appear to have limited ability to cross the placenta. As a result, chimeric and full human IgG antibodies such as infliximab, adalimumab, and rituximab have demonstrated high levels of placental transport, while other agents, such as etanercept, appear to cross the placenta at lower levels.
Hence, due to the ineffective clearance, certain immunoglobulin biologicals actually have a higher concentration and a longer half life in neonates than in mothers. For instance, with infliximab, studies show that levels in the umbilical cord were up to fourfold higher than maternal levels, even when the drug was discontinued at 30 weeks of pregnancy or earlier. Due to long neonatal half life, infliximab levels became undetectable in infant serum only between 2-7 months, compared with 1-2 weeks in adults. Adalimumab is similar, where concentrations of the drug in neonates can be 150% of the maternal serum level and detectable for about 3 months after birth.
Transport of anti-TNFs is also possible through breastfeeding, although studies indicate that the levels are very low.
Infection risk
Due to the immunosuppressive effect of anti-TNF immunoglobulin biologicals, newborn infection is a real concern. Review of the literature showed that severe and moderate neutropenia and skin infection were reported in four neonates born to two women with ulcerative colitis who had taken infliximab throughout pregnancy.
Some other studies have followed infants who had detectable biological levels at birth after in utero exposure. In general, there is normal development in the first year without overt infection. However, there have been case reports of infections with varicella or upper respiratory infections in infants exposed to infliximab before 30 weeks’ gestation.
There is very little data on the long-term immune system impacts for infants exposed to immunoglobulin biologicals in utero. However, these agents are generally not at detectable levels after 1 year.
Impact on vaccination
Although these IgG biologicals will clear the infants’ systems after several months of life (generally by 8 months), another concern is for how their presence in the early months impacts neonatal vaccination, specifically live attenuated vaccines such as MMR (measles, mumps and rubella), BCG for tuberculosis, oral polio, rotavirus vaccine, and the intranasal influenza vaccine.
Generally, outcomes among infants exposed to anti-TNFs have been good. For instance, reports looking at 24 children with exposure to anti-TNFs found no complications with the MMR vaccine. But a famous case report identified one infant who died at 4.5 months after receiving the BCG vaccine at 3 months. The mother, who had Crohn’s disease, had been taking infliximab 10 mg/kg every 8 weeks throughout her pregnancy.
Another study of 15 infants in the Czech Republic who were exposed to infliximab in utero and received BCG vaccination within 1 week of birth found that three of the infants developed large local skin reactions. One of the three children also developed axillary lymphadenopathy. All of the children recovered without the need for anti-tuberculosis therapy.
So what do these complications mean for vaccination strategies? Both the European Crohn’s and Colitis Organisation and the World Congress of Gastroenterology recommend that in terms of non-live vaccines, it’s safe to follow the same vaccine schedule as infants not exposed to biologicals in utero. When it comes to live attenuated vaccines such as rotavirus, oral polio, and BCG, these infants should be treated as immunocompromised and not receive these vaccines until after 6 months of age, when the biologicals should be at undetectable levels.
Future directions
Given that most infections and other adverse events happen after late exposure in pregnancy, some have recommended discontinuing anti-TNF treatment before the third trimester. In fact, this has become a common management practice. However, this should be an individualized decision made after discussion between a woman and her physician or physicians. Any benefits from early discontinuation of an immunoglobulin biological therapy should be weighed against the risk of disease flare, which also has real potential to complicate pregnancy.
The evidence presented here not only shines a light on the possible risk to infants, but also on the need for more high-quality evidence on which physicians can base decisions. Most of the available evidence is drawn from case reports and registry databases. Both of these suffer from a lack of control groups. To answer these questions definitively, we need more well-controlled studies of large populations. I strongly urge readers to follow the amazing work led by Dr. Uma Mahadevan and her colleagues at the University of California, San Francisco on biological use in pregnancy and long-term outcomes. As we wait for more evidence, we all look forward to the development of newer biologic agents that can help women control autoimmune disease without crossing the placenta.
Dr. Koren is professor of pharmacology and pharmacy at the University of Toronto. He is the founding director of the Motherisk Program. He reported having no financial disclosures related to this article. Email him at obnews@frontlinemedcom.com.
High dose folic acid promising in preventing cardiac malformations
When most physicians and patients hear about folic acid, they automatically think about its role in preventing spina bifida and other neural tube defects. But there are now more than 20 years of data that point toward a larger role for folic acid in preventing common, and in some cases devastating, congenital heart defects.
The various published studies leave little doubt that folic acid can significantly reduce the risk for many common cardiac malformations, but other questions remain. For instance, what is the minimum dose for protection? And should health authorities around the world consider recommending a much higher dose of folic acid for short-term use in pregnant women and those trying to conceive?
Early research on cardiac malformations
One of the early studies showing the promise of folic acid beyond neural tube defects was published in 1996. The randomized, double-blind controlled trial in Hungary compared the effect of periconceptional multivitamin supplements containing 0.8 mg of folic acid versus trace element supplements on neural tube defects and other congenital abnormalities. The multivitamin supplement group had a significant reduction in urinary tract abnormalities, and in the rate of sporadic cardiovascular malformations, specifically ventricular septal defects (Am J Med Genet. 1996 Mar 15;62 [2]:179-83.).
In 2004, the same researchers confirmed their results using a controlled, cohort trial that matched pregnant women from regional antenatal care clinics who did not take vitamin supplements to pregnant women who did take supplements containing 0.8 mg folic acid. The results were similar. From a total of 3,056 offspring evaluated, 31 congenital cardiovascular malformations occurred in the group with folic acid supplementation, compared with 50 in the group without, for a 40% lower risk overall, although the main impact was seen among ventricular septal defects (Birth Defects Res A Clin Mol Teratol. 2004 Nov;70[11]:853-61.).
Our own group examined the evidence in a meta-analysis published in 2006 and found significant support for an expanded role for folic acid (J Obstet Gynaecol Can. 2006 Aug;28[8]:680-9.).
The major issue with the available studies is the lack of highest-quality evidence. While some of the studies were randomized trials, you can no longer conduct a true randomized design and withhold folic acid from women; it’s simply not ethical knowing what we know about the preventive benefits of folic acid for neural tube defects. But the literature – which includes quality cohort and case-controlled studies – is convincing.
High dose best?
While some studies have shown a protective effect of folic acid in congenital heart defects at low levels, such as the 0.8 mg used in the early Hungarian studies, other studies indicate that more is better.
A review of 13 studies published in the Lancet shows that for every 0.1 mg/day increase in folic acid intake in women aged 20-35 years, there is a corresponding 0.94 ng/mL increase in serum folate concentrations and that translates into reduced risk of defects, at least in terms of neural tube defects (Lancet. 2001 Dec 15;358[9298]:2069-73.).
Most recently, some of the same researchers that published the early reports out of Hungary on protection against congenital heart defects showed evidence that a variety of congenital heart defects could be reduced with folic acid supplementation of between 3 mg and 6 mg daily (Eur J Obstet Gynecol Reprod Biol. 2015 Jul 9;193:34-9.).
The study evaluated 3,567 infants with various congenital heart defects and 5,395 matched controls. The researchers excluded women taking multivitamins that contained folic acid and stratified the women taking folic acid alone into three subgroups: those who took folic acid anytime during pregnancy, those who took it during the “critical period” for development of malformations based on medical records and self-reported information, and those who took it during the “critical period” based on medical records alone.
During the study period, there was only one type of folic acid tablet available in Hungary – a 3-mg tablet. On average, the daily dose was 5.6 mg.
Most women began folic acid supplementation around 6-11 weeks’ gestation, coinciding with their first prenatal visit. There was a significant drop in the prevalence of cases with ventricular septal defect (odds ratio, 0.57), tetralogy of Fallot (OR, 0.53), d-transposition of great arteries (OR, 0.47), and atrial septal defect secundum (OR, 0.63) when pregnant women took high doses of folic acid during the critical period for congenital heart defect development.
Overall, the researchers concluded that about 40% of severe congenital heart defects could be prevented using high doses of folic acid during the critical period.
This is a significant reduction for a common and serious problem among pregnant women. While it’s true that there are more surgical solutions available today, cardiac malformations are still a major source of morbidity and mortality among children, and it can be the motivation for parents to terminate a pregnancy in cases where there are serious, complicated malformations.
Prevention is always the best option and this research suggests, once again, that folic acid may offer even more benefits.
The study also shows that there was no clear difference in reduction of congenital heart defects based on either a 3-mg or 6-mg dose, except with atrial septal defect secundum. In that case, the 3-mg dose reduced risk by only 10%, compared with more than 40% at 6 mg. But the researchers were quick to point out that more research is needed to look at the dose-response relationship.
The 5.6-mg average daily dose is significant because it is far above the 0.4-mg level recommended by the Centers for Disease Control and Prevention and the level frequently prescribed for pregnant women – 0.8 mg to 1 mg.
We know that some women may benefit from more folic acid, such as women who have previously given birth to a child with neural tube defects. But there are more subgroups that could benefit from higher doses of folic acid, including women taking antifolate medications such as antiepileptic drugs, methotrexate, and sulfonamides. Women who don’t consume enough vegetables and don’t take a multivitamin could benefit from high doses, as well would obese women, smokers, and women with diabetes.
For years the concern has been that folic acid at higher levels could increase the risk for certain cancers, but the evidence there is uncertain. Additionally, that risk would be triggered only after years of exposure, while the benefits of high-dose folic acid could be achieved in a matter of months. I don’t think the evidence of harm is convincing enough to stop us from considering that high-dose folic acid could be used in the general population.
One of the encouraging aspects of using folic acid to prevent congenital heart defects is that the critical window for influencing malformations is larger than with neural tube defects. While folic acid must be given in the first 28 days of pregnancy to have a benefit, the window of opportunity is 1-2 months longer for cardiac malformations.
The bottom line is that high-dose folic acid to prevent congenital heart defects is a target ripe for further research. While randomized controlled trials aren’t possible, there are plenty of high-quality studies that could be conducted to provide clinicians with the information they need to prevent these devastating malformations.
Dr. Koren is professor of pharmacology and pharmacy at the University of Toronto. He is the founding director of the Motherisk Program. He received grant support to conduct studies on folic acid from Duchesnay. He has been a consultant to several companies that produce vitamins in the context of pregnancy, including Bayer. Email him at obnews@frontlinemedcom.com.
When most physicians and patients hear about folic acid, they automatically think about its role in preventing spina bifida and other neural tube defects. But there are now more than 20 years of data that point toward a larger role for folic acid in preventing common, and in some cases devastating, congenital heart defects.
The various published studies leave little doubt that folic acid can significantly reduce the risk for many common cardiac malformations, but other questions remain. For instance, what is the minimum dose for protection? And should health authorities around the world consider recommending a much higher dose of folic acid for short-term use in pregnant women and those trying to conceive?
Early research on cardiac malformations
One of the early studies showing the promise of folic acid beyond neural tube defects was published in 1996. The randomized, double-blind controlled trial in Hungary compared the effect of periconceptional multivitamin supplements containing 0.8 mg of folic acid versus trace element supplements on neural tube defects and other congenital abnormalities. The multivitamin supplement group had a significant reduction in urinary tract abnormalities, and in the rate of sporadic cardiovascular malformations, specifically ventricular septal defects (Am J Med Genet. 1996 Mar 15;62 [2]:179-83.).
In 2004, the same researchers confirmed their results using a controlled, cohort trial that matched pregnant women from regional antenatal care clinics who did not take vitamin supplements to pregnant women who did take supplements containing 0.8 mg folic acid. The results were similar. From a total of 3,056 offspring evaluated, 31 congenital cardiovascular malformations occurred in the group with folic acid supplementation, compared with 50 in the group without, for a 40% lower risk overall, although the main impact was seen among ventricular septal defects (Birth Defects Res A Clin Mol Teratol. 2004 Nov;70[11]:853-61.).
Our own group examined the evidence in a meta-analysis published in 2006 and found significant support for an expanded role for folic acid (J Obstet Gynaecol Can. 2006 Aug;28[8]:680-9.).
The major issue with the available studies is the lack of highest-quality evidence. While some of the studies were randomized trials, you can no longer conduct a true randomized design and withhold folic acid from women; it’s simply not ethical knowing what we know about the preventive benefits of folic acid for neural tube defects. But the literature – which includes quality cohort and case-controlled studies – is convincing.
High dose best?
While some studies have shown a protective effect of folic acid in congenital heart defects at low levels, such as the 0.8 mg used in the early Hungarian studies, other studies indicate that more is better.
A review of 13 studies published in the Lancet shows that for every 0.1 mg/day increase in folic acid intake in women aged 20-35 years, there is a corresponding 0.94 ng/mL increase in serum folate concentrations and that translates into reduced risk of defects, at least in terms of neural tube defects (Lancet. 2001 Dec 15;358[9298]:2069-73.).
Most recently, some of the same researchers that published the early reports out of Hungary on protection against congenital heart defects showed evidence that a variety of congenital heart defects could be reduced with folic acid supplementation of between 3 mg and 6 mg daily (Eur J Obstet Gynecol Reprod Biol. 2015 Jul 9;193:34-9.).
The study evaluated 3,567 infants with various congenital heart defects and 5,395 matched controls. The researchers excluded women taking multivitamins that contained folic acid and stratified the women taking folic acid alone into three subgroups: those who took folic acid anytime during pregnancy, those who took it during the “critical period” for development of malformations based on medical records and self-reported information, and those who took it during the “critical period” based on medical records alone.
During the study period, there was only one type of folic acid tablet available in Hungary – a 3-mg tablet. On average, the daily dose was 5.6 mg.
Most women began folic acid supplementation around 6-11 weeks’ gestation, coinciding with their first prenatal visit. There was a significant drop in the prevalence of cases with ventricular septal defect (odds ratio, 0.57), tetralogy of Fallot (OR, 0.53), d-transposition of great arteries (OR, 0.47), and atrial septal defect secundum (OR, 0.63) when pregnant women took high doses of folic acid during the critical period for congenital heart defect development.
Overall, the researchers concluded that about 40% of severe congenital heart defects could be prevented using high doses of folic acid during the critical period.
This is a significant reduction for a common and serious problem among pregnant women. While it’s true that there are more surgical solutions available today, cardiac malformations are still a major source of morbidity and mortality among children, and it can be the motivation for parents to terminate a pregnancy in cases where there are serious, complicated malformations.
Prevention is always the best option and this research suggests, once again, that folic acid may offer even more benefits.
The study also shows that there was no clear difference in reduction of congenital heart defects based on either a 3-mg or 6-mg dose, except with atrial septal defect secundum. In that case, the 3-mg dose reduced risk by only 10%, compared with more than 40% at 6 mg. But the researchers were quick to point out that more research is needed to look at the dose-response relationship.
The 5.6-mg average daily dose is significant because it is far above the 0.4-mg level recommended by the Centers for Disease Control and Prevention and the level frequently prescribed for pregnant women – 0.8 mg to 1 mg.
We know that some women may benefit from more folic acid, such as women who have previously given birth to a child with neural tube defects. But there are more subgroups that could benefit from higher doses of folic acid, including women taking antifolate medications such as antiepileptic drugs, methotrexate, and sulfonamides. Women who don’t consume enough vegetables and don’t take a multivitamin could benefit from high doses, as well would obese women, smokers, and women with diabetes.
For years the concern has been that folic acid at higher levels could increase the risk for certain cancers, but the evidence there is uncertain. Additionally, that risk would be triggered only after years of exposure, while the benefits of high-dose folic acid could be achieved in a matter of months. I don’t think the evidence of harm is convincing enough to stop us from considering that high-dose folic acid could be used in the general population.
One of the encouraging aspects of using folic acid to prevent congenital heart defects is that the critical window for influencing malformations is larger than with neural tube defects. While folic acid must be given in the first 28 days of pregnancy to have a benefit, the window of opportunity is 1-2 months longer for cardiac malformations.
The bottom line is that high-dose folic acid to prevent congenital heart defects is a target ripe for further research. While randomized controlled trials aren’t possible, there are plenty of high-quality studies that could be conducted to provide clinicians with the information they need to prevent these devastating malformations.
Dr. Koren is professor of pharmacology and pharmacy at the University of Toronto. He is the founding director of the Motherisk Program. He received grant support to conduct studies on folic acid from Duchesnay. He has been a consultant to several companies that produce vitamins in the context of pregnancy, including Bayer. Email him at obnews@frontlinemedcom.com.
When most physicians and patients hear about folic acid, they automatically think about its role in preventing spina bifida and other neural tube defects. But there are now more than 20 years of data that point toward a larger role for folic acid in preventing common, and in some cases devastating, congenital heart defects.
The various published studies leave little doubt that folic acid can significantly reduce the risk for many common cardiac malformations, but other questions remain. For instance, what is the minimum dose for protection? And should health authorities around the world consider recommending a much higher dose of folic acid for short-term use in pregnant women and those trying to conceive?
Early research on cardiac malformations
One of the early studies showing the promise of folic acid beyond neural tube defects was published in 1996. The randomized, double-blind controlled trial in Hungary compared the effect of periconceptional multivitamin supplements containing 0.8 mg of folic acid versus trace element supplements on neural tube defects and other congenital abnormalities. The multivitamin supplement group had a significant reduction in urinary tract abnormalities, and in the rate of sporadic cardiovascular malformations, specifically ventricular septal defects (Am J Med Genet. 1996 Mar 15;62 [2]:179-83.).
In 2004, the same researchers confirmed their results using a controlled, cohort trial that matched pregnant women from regional antenatal care clinics who did not take vitamin supplements to pregnant women who did take supplements containing 0.8 mg folic acid. The results were similar. From a total of 3,056 offspring evaluated, 31 congenital cardiovascular malformations occurred in the group with folic acid supplementation, compared with 50 in the group without, for a 40% lower risk overall, although the main impact was seen among ventricular septal defects (Birth Defects Res A Clin Mol Teratol. 2004 Nov;70[11]:853-61.).
Our own group examined the evidence in a meta-analysis published in 2006 and found significant support for an expanded role for folic acid (J Obstet Gynaecol Can. 2006 Aug;28[8]:680-9.).
The major issue with the available studies is the lack of highest-quality evidence. While some of the studies were randomized trials, you can no longer conduct a true randomized design and withhold folic acid from women; it’s simply not ethical knowing what we know about the preventive benefits of folic acid for neural tube defects. But the literature – which includes quality cohort and case-controlled studies – is convincing.
High dose best?
While some studies have shown a protective effect of folic acid in congenital heart defects at low levels, such as the 0.8 mg used in the early Hungarian studies, other studies indicate that more is better.
A review of 13 studies published in the Lancet shows that for every 0.1 mg/day increase in folic acid intake in women aged 20-35 years, there is a corresponding 0.94 ng/mL increase in serum folate concentrations and that translates into reduced risk of defects, at least in terms of neural tube defects (Lancet. 2001 Dec 15;358[9298]:2069-73.).
Most recently, some of the same researchers that published the early reports out of Hungary on protection against congenital heart defects showed evidence that a variety of congenital heart defects could be reduced with folic acid supplementation of between 3 mg and 6 mg daily (Eur J Obstet Gynecol Reprod Biol. 2015 Jul 9;193:34-9.).
The study evaluated 3,567 infants with various congenital heart defects and 5,395 matched controls. The researchers excluded women taking multivitamins that contained folic acid and stratified the women taking folic acid alone into three subgroups: those who took folic acid anytime during pregnancy, those who took it during the “critical period” for development of malformations based on medical records and self-reported information, and those who took it during the “critical period” based on medical records alone.
During the study period, there was only one type of folic acid tablet available in Hungary – a 3-mg tablet. On average, the daily dose was 5.6 mg.
Most women began folic acid supplementation around 6-11 weeks’ gestation, coinciding with their first prenatal visit. There was a significant drop in the prevalence of cases with ventricular septal defect (odds ratio, 0.57), tetralogy of Fallot (OR, 0.53), d-transposition of great arteries (OR, 0.47), and atrial septal defect secundum (OR, 0.63) when pregnant women took high doses of folic acid during the critical period for congenital heart defect development.
Overall, the researchers concluded that about 40% of severe congenital heart defects could be prevented using high doses of folic acid during the critical period.
This is a significant reduction for a common and serious problem among pregnant women. While it’s true that there are more surgical solutions available today, cardiac malformations are still a major source of morbidity and mortality among children, and it can be the motivation for parents to terminate a pregnancy in cases where there are serious, complicated malformations.
Prevention is always the best option and this research suggests, once again, that folic acid may offer even more benefits.
The study also shows that there was no clear difference in reduction of congenital heart defects based on either a 3-mg or 6-mg dose, except with atrial septal defect secundum. In that case, the 3-mg dose reduced risk by only 10%, compared with more than 40% at 6 mg. But the researchers were quick to point out that more research is needed to look at the dose-response relationship.
The 5.6-mg average daily dose is significant because it is far above the 0.4-mg level recommended by the Centers for Disease Control and Prevention and the level frequently prescribed for pregnant women – 0.8 mg to 1 mg.
We know that some women may benefit from more folic acid, such as women who have previously given birth to a child with neural tube defects. But there are more subgroups that could benefit from higher doses of folic acid, including women taking antifolate medications such as antiepileptic drugs, methotrexate, and sulfonamides. Women who don’t consume enough vegetables and don’t take a multivitamin could benefit from high doses, as well would obese women, smokers, and women with diabetes.
For years the concern has been that folic acid at higher levels could increase the risk for certain cancers, but the evidence there is uncertain. Additionally, that risk would be triggered only after years of exposure, while the benefits of high-dose folic acid could be achieved in a matter of months. I don’t think the evidence of harm is convincing enough to stop us from considering that high-dose folic acid could be used in the general population.
One of the encouraging aspects of using folic acid to prevent congenital heart defects is that the critical window for influencing malformations is larger than with neural tube defects. While folic acid must be given in the first 28 days of pregnancy to have a benefit, the window of opportunity is 1-2 months longer for cardiac malformations.
The bottom line is that high-dose folic acid to prevent congenital heart defects is a target ripe for further research. While randomized controlled trials aren’t possible, there are plenty of high-quality studies that could be conducted to provide clinicians with the information they need to prevent these devastating malformations.
Dr. Koren is professor of pharmacology and pharmacy at the University of Toronto. He is the founding director of the Motherisk Program. He received grant support to conduct studies on folic acid from Duchesnay. He has been a consultant to several companies that produce vitamins in the context of pregnancy, including Bayer. Email him at obnews@frontlinemedcom.com.
Examining the success of folic acid supplementation
The Centers for Disease Control and Prevention’s recent report updating the estimated number of neural tube defects prevented by folic acid fortification of enriched cereal grain products clearly shows the huge impact of fortification: From 1999 through 2011, fortification prevented neural tube defects in about 1,300 births a year in the United States (MMWR 2015;64:1-5).
This is a dramatic example of how a relatively simple public health intervention – in this case, the mandatory addition of an inexpensive B vitamin to a portion of the food supply – is having a dramatic impact on a major birth defect.
Unfortunately, though, people may develop similar expectations that other micronutrients during pregnancy may prevent other birth defects or improve developmental outcomes, without adequate supportive evidence. For example, experimental animal studies have suggested that supplements of polyunsaturated fatty acids (PUFAs) during pregnancy improve brain development in the offspring (J. Perinat. Med. 2008;36;5-14). While there is no evidence that this is true in humans, there are prenatal vitamins that include PUFAs on the market.
Based on a review of nine randomized controlled studies that compared long chain PUFA supplementation to a placebo or no supplement in pregnant women, my colleagues and I concluded that the available research “regarding the maternal supplementation of PUFAs in retinal and neurocognitive development of the infant is not consistent in showing a benefit to supplementation” (Obstet.Gynecol. Int. 2012 [doi:10.1155/2012/591531]).
In a somewhat similar manner, an increasing number of women are taking megavitamins as part of their lifestyle, with the belief that “more is better.”
Megavitamins may not necessarily be harmless. There is evidence from randomized trials that evaluated vitamin E or vitamin C for preeclampsia that vitamin E supplementation during pregnancy may cause intrauterine growth restriction (IUGR). This was confirmed by a study of 82 women who had been exposed to high doses of vitamin E supplements ranging from 400 IU to 1,200 IU a day during the first trimester. At Motherisk, we found that the mean birth weight among the babies of the women who had been exposed to high doses of vitamin E was significantly lower than the mean birth weight of the babies of the controls. But we did not find a significant difference in the rates of live births, preterm delivery, miscarriages, or stillbirths (Reprod. Toxicol. 2005;20:85-8). These women were on vitamin E as part of their lifestyle and not for any particular medical reason.
The medical community needs to keep in mind that while the folic acid fortification of flour and other products has shown dramatic effects in the overall population, as the CDC report shows, it may not meet the needs of specific populations of women who are at a greater risk of having a baby with a neural tube defect. As pointed out in the Morbidity and Mortality Weekly Report, these groups include Hispanic women, who may not consume as much folic acid or are at a greater risk of having a genetic polymorphism that makes them more susceptible to a folate insufficiency.
Flour fortification provides relatively small amounts of folic acid, possibly 200 mcg more a day, at best. But it has been shown that a woman who has had a previous child with a neural tube defect, a high-risk group, needs 5 mg per day to have an impact on prevention (Lancet 1991;338:131-7).
It is therefore important to keep in mind that there are high-risk groups who may need more than the amount provided by flour fortification. These groups include women on antiepileptic drugs or drugs that have antifolate activity, such as sulfonamide and methotrexate; as well as those with some genetic polymorphisms in the folate cycle.
Women who smoke also tend to have lower folate levels, as do women with diabetes or who are obese. Women with celiac disease may have lower folate levels because they do not eat bread or flour-based products. Low-income women who may not eat sufficient green leafy vegetables, which are expensive and contain high levels of folic acid, may also be at greater risk.
A question that is still not resolved is whether folic acid can prevent other malformations, not just neural tube defects. There is some evidence that folic acid supplementation may also reduce the risk of cardiovascular defects and oral clefts. A randomized trial comparing folic acid to no folic acid to address these questions would be unethical. Instead, observational studies could evaluate the rate of these malformations after the fortification program began. Despite this major public health advance, we should always try to do even better and prevent more cases of neural tube defects and other malformations.
Dr. Koren is professor of pediatrics, pharmacology, pharmacy, and medical genetics at the University of Toronto. He is director of the Motherisk Program. He received grant support to conduct studies on folic acid from Duchesnay Inc., Canada. E-mail him at obnews@frontlinemedcom.com.
The Centers for Disease Control and Prevention’s recent report updating the estimated number of neural tube defects prevented by folic acid fortification of enriched cereal grain products clearly shows the huge impact of fortification: From 1999 through 2011, fortification prevented neural tube defects in about 1,300 births a year in the United States (MMWR 2015;64:1-5).
This is a dramatic example of how a relatively simple public health intervention – in this case, the mandatory addition of an inexpensive B vitamin to a portion of the food supply – is having a dramatic impact on a major birth defect.
Unfortunately, though, people may develop similar expectations that other micronutrients during pregnancy may prevent other birth defects or improve developmental outcomes, without adequate supportive evidence. For example, experimental animal studies have suggested that supplements of polyunsaturated fatty acids (PUFAs) during pregnancy improve brain development in the offspring (J. Perinat. Med. 2008;36;5-14). While there is no evidence that this is true in humans, there are prenatal vitamins that include PUFAs on the market.
Based on a review of nine randomized controlled studies that compared long chain PUFA supplementation to a placebo or no supplement in pregnant women, my colleagues and I concluded that the available research “regarding the maternal supplementation of PUFAs in retinal and neurocognitive development of the infant is not consistent in showing a benefit to supplementation” (Obstet.Gynecol. Int. 2012 [doi:10.1155/2012/591531]).
In a somewhat similar manner, an increasing number of women are taking megavitamins as part of their lifestyle, with the belief that “more is better.”
Megavitamins may not necessarily be harmless. There is evidence from randomized trials that evaluated vitamin E or vitamin C for preeclampsia that vitamin E supplementation during pregnancy may cause intrauterine growth restriction (IUGR). This was confirmed by a study of 82 women who had been exposed to high doses of vitamin E supplements ranging from 400 IU to 1,200 IU a day during the first trimester. At Motherisk, we found that the mean birth weight among the babies of the women who had been exposed to high doses of vitamin E was significantly lower than the mean birth weight of the babies of the controls. But we did not find a significant difference in the rates of live births, preterm delivery, miscarriages, or stillbirths (Reprod. Toxicol. 2005;20:85-8). These women were on vitamin E as part of their lifestyle and not for any particular medical reason.
The medical community needs to keep in mind that while the folic acid fortification of flour and other products has shown dramatic effects in the overall population, as the CDC report shows, it may not meet the needs of specific populations of women who are at a greater risk of having a baby with a neural tube defect. As pointed out in the Morbidity and Mortality Weekly Report, these groups include Hispanic women, who may not consume as much folic acid or are at a greater risk of having a genetic polymorphism that makes them more susceptible to a folate insufficiency.
Flour fortification provides relatively small amounts of folic acid, possibly 200 mcg more a day, at best. But it has been shown that a woman who has had a previous child with a neural tube defect, a high-risk group, needs 5 mg per day to have an impact on prevention (Lancet 1991;338:131-7).
It is therefore important to keep in mind that there are high-risk groups who may need more than the amount provided by flour fortification. These groups include women on antiepileptic drugs or drugs that have antifolate activity, such as sulfonamide and methotrexate; as well as those with some genetic polymorphisms in the folate cycle.
Women who smoke also tend to have lower folate levels, as do women with diabetes or who are obese. Women with celiac disease may have lower folate levels because they do not eat bread or flour-based products. Low-income women who may not eat sufficient green leafy vegetables, which are expensive and contain high levels of folic acid, may also be at greater risk.
A question that is still not resolved is whether folic acid can prevent other malformations, not just neural tube defects. There is some evidence that folic acid supplementation may also reduce the risk of cardiovascular defects and oral clefts. A randomized trial comparing folic acid to no folic acid to address these questions would be unethical. Instead, observational studies could evaluate the rate of these malformations after the fortification program began. Despite this major public health advance, we should always try to do even better and prevent more cases of neural tube defects and other malformations.
Dr. Koren is professor of pediatrics, pharmacology, pharmacy, and medical genetics at the University of Toronto. He is director of the Motherisk Program. He received grant support to conduct studies on folic acid from Duchesnay Inc., Canada. E-mail him at obnews@frontlinemedcom.com.
The Centers for Disease Control and Prevention’s recent report updating the estimated number of neural tube defects prevented by folic acid fortification of enriched cereal grain products clearly shows the huge impact of fortification: From 1999 through 2011, fortification prevented neural tube defects in about 1,300 births a year in the United States (MMWR 2015;64:1-5).
This is a dramatic example of how a relatively simple public health intervention – in this case, the mandatory addition of an inexpensive B vitamin to a portion of the food supply – is having a dramatic impact on a major birth defect.
Unfortunately, though, people may develop similar expectations that other micronutrients during pregnancy may prevent other birth defects or improve developmental outcomes, without adequate supportive evidence. For example, experimental animal studies have suggested that supplements of polyunsaturated fatty acids (PUFAs) during pregnancy improve brain development in the offspring (J. Perinat. Med. 2008;36;5-14). While there is no evidence that this is true in humans, there are prenatal vitamins that include PUFAs on the market.
Based on a review of nine randomized controlled studies that compared long chain PUFA supplementation to a placebo or no supplement in pregnant women, my colleagues and I concluded that the available research “regarding the maternal supplementation of PUFAs in retinal and neurocognitive development of the infant is not consistent in showing a benefit to supplementation” (Obstet.Gynecol. Int. 2012 [doi:10.1155/2012/591531]).
In a somewhat similar manner, an increasing number of women are taking megavitamins as part of their lifestyle, with the belief that “more is better.”
Megavitamins may not necessarily be harmless. There is evidence from randomized trials that evaluated vitamin E or vitamin C for preeclampsia that vitamin E supplementation during pregnancy may cause intrauterine growth restriction (IUGR). This was confirmed by a study of 82 women who had been exposed to high doses of vitamin E supplements ranging from 400 IU to 1,200 IU a day during the first trimester. At Motherisk, we found that the mean birth weight among the babies of the women who had been exposed to high doses of vitamin E was significantly lower than the mean birth weight of the babies of the controls. But we did not find a significant difference in the rates of live births, preterm delivery, miscarriages, or stillbirths (Reprod. Toxicol. 2005;20:85-8). These women were on vitamin E as part of their lifestyle and not for any particular medical reason.
The medical community needs to keep in mind that while the folic acid fortification of flour and other products has shown dramatic effects in the overall population, as the CDC report shows, it may not meet the needs of specific populations of women who are at a greater risk of having a baby with a neural tube defect. As pointed out in the Morbidity and Mortality Weekly Report, these groups include Hispanic women, who may not consume as much folic acid or are at a greater risk of having a genetic polymorphism that makes them more susceptible to a folate insufficiency.
Flour fortification provides relatively small amounts of folic acid, possibly 200 mcg more a day, at best. But it has been shown that a woman who has had a previous child with a neural tube defect, a high-risk group, needs 5 mg per day to have an impact on prevention (Lancet 1991;338:131-7).
It is therefore important to keep in mind that there are high-risk groups who may need more than the amount provided by flour fortification. These groups include women on antiepileptic drugs or drugs that have antifolate activity, such as sulfonamide and methotrexate; as well as those with some genetic polymorphisms in the folate cycle.
Women who smoke also tend to have lower folate levels, as do women with diabetes or who are obese. Women with celiac disease may have lower folate levels because they do not eat bread or flour-based products. Low-income women who may not eat sufficient green leafy vegetables, which are expensive and contain high levels of folic acid, may also be at greater risk.
A question that is still not resolved is whether folic acid can prevent other malformations, not just neural tube defects. There is some evidence that folic acid supplementation may also reduce the risk of cardiovascular defects and oral clefts. A randomized trial comparing folic acid to no folic acid to address these questions would be unethical. Instead, observational studies could evaluate the rate of these malformations after the fortification program began. Despite this major public health advance, we should always try to do even better and prevent more cases of neural tube defects and other malformations.
Dr. Koren is professor of pediatrics, pharmacology, pharmacy, and medical genetics at the University of Toronto. He is director of the Motherisk Program. He received grant support to conduct studies on folic acid from Duchesnay Inc., Canada. E-mail him at obnews@frontlinemedcom.com.
Topiramate
At Motherisk, we receive increasing numbers of queries from women and clinicians about the use of topiramate during pregnancy, mostly related to its use for migraine or seizures.Topiramate is approved for treatment of seizures and for migraine prevention, and in 2012, the Food and Drug Administration approved the combination of extended-release topiramate with the stimulant phentermine (Qsymia) as a chronic treatment for weight management.
When topiramate was initially approved in 1996, human reproductive data were scarce, but animal data suggested that a high dose of topiramate in rats and rabbits may induce some congenital malformations. Since that time, quite a few studies – but not all – have suggested that topiramate may be associated with an increased risk of oral clefts (cleft lip and cleft palate). Studies that have found an increased risk associated with first trimester exposure to topiramate include the North American AED Pregnancy Registry, which found a rate of 14 cases per 1,000 – more than tenfold greater than the rate in the general population.
For seizures and migraines, the FDA has labeled topiramate a pregnancy category D drug (there is evidence of human fetal risk, but “the potential benefits from the use of the drug in pregnant women may be acceptable despite its potential risks.” ) For Qsymia, however, topiramate is contraindicated in pregnancy and is a pregnancy category X, because its use “can cause fetal harm and weight loss offers no potential benefit to a pregnant woman,” the labeling states.
Based on arecent analysis of six controlled studies in the literature of more than 3,000 pregnancies exposed during the first trimester, we determinedthat the risk of oral clefts associated with first trimester exposure was increased by sixfold over controls. To put this into context, in the general population, oral clefts occur in less than 1% (0.07%), whereas in the studies, the rate was 0.36%, about a fivefold increase.
Until the approval of the weight loss indication, women of reproductive age with epilepsy or migraines prescribed topiramate were a relatively small group. But because obesity is so common, we are now in a situation where a drug that is likely a human teratogen, based on strong evidence, will be used by far more women of childbearing age, and an increase in unintended pregnancies exposed to the drug probably will occur. In phase III clinical trials of Qsymia, quite a few women got pregnant, which is not surprising since women who are obese may have more difficulty knowing they are pregnant, for hormonal and other reasons.
Clinicians and women who take the drug for weight loss need to be aware of this risk. It is important to counsel women of childbearing age who are on this medication about the need for contraception during treatment, and to have a pregnancy test before treatment, and every month during treatment. An important factor to keep in mind is that the maximum topiramate dose for weight loss is 92 mg a day, while the typical epilepsy dose is 200-400 mg a day, and for migraines, is 100 mg a day. It may turn out that the same risk may not be evident with the lower dose.
As the labeling states, women who become pregnant while on this drug should stop taking it immediately, and clinicians should counsel them about the possible risks to the fetus. Health care providers and patients should report pregnancies exposed to Qsymia to the Qsymia Pregnancy Surveillance Program, which is monitoring maternal-fetal outcomes of exposed pregnancies, at 888-998-4887, or the FDA’s MedWatch program at 800-332-1088.
Dr. Koren is professor of pediatrics, pharmacology, pharmacy, medicine, and medical genetics at the University of Toronto. He heads the Research Leadership for Better Pharmacotherapy During Pregnancy and Lactation at the Hospital for Sick Children, Toronto, where he is director of the Motherisk Program. He was a consultant to Vivus, the manufacturer of Qsymia. E-mail him at obnews@frontlinemedcom.com.
At Motherisk, we receive increasing numbers of queries from women and clinicians about the use of topiramate during pregnancy, mostly related to its use for migraine or seizures.Topiramate is approved for treatment of seizures and for migraine prevention, and in 2012, the Food and Drug Administration approved the combination of extended-release topiramate with the stimulant phentermine (Qsymia) as a chronic treatment for weight management.
When topiramate was initially approved in 1996, human reproductive data were scarce, but animal data suggested that a high dose of topiramate in rats and rabbits may induce some congenital malformations. Since that time, quite a few studies – but not all – have suggested that topiramate may be associated with an increased risk of oral clefts (cleft lip and cleft palate). Studies that have found an increased risk associated with first trimester exposure to topiramate include the North American AED Pregnancy Registry, which found a rate of 14 cases per 1,000 – more than tenfold greater than the rate in the general population.
For seizures and migraines, the FDA has labeled topiramate a pregnancy category D drug (there is evidence of human fetal risk, but “the potential benefits from the use of the drug in pregnant women may be acceptable despite its potential risks.” ) For Qsymia, however, topiramate is contraindicated in pregnancy and is a pregnancy category X, because its use “can cause fetal harm and weight loss offers no potential benefit to a pregnant woman,” the labeling states.
Based on arecent analysis of six controlled studies in the literature of more than 3,000 pregnancies exposed during the first trimester, we determinedthat the risk of oral clefts associated with first trimester exposure was increased by sixfold over controls. To put this into context, in the general population, oral clefts occur in less than 1% (0.07%), whereas in the studies, the rate was 0.36%, about a fivefold increase.
Until the approval of the weight loss indication, women of reproductive age with epilepsy or migraines prescribed topiramate were a relatively small group. But because obesity is so common, we are now in a situation where a drug that is likely a human teratogen, based on strong evidence, will be used by far more women of childbearing age, and an increase in unintended pregnancies exposed to the drug probably will occur. In phase III clinical trials of Qsymia, quite a few women got pregnant, which is not surprising since women who are obese may have more difficulty knowing they are pregnant, for hormonal and other reasons.
Clinicians and women who take the drug for weight loss need to be aware of this risk. It is important to counsel women of childbearing age who are on this medication about the need for contraception during treatment, and to have a pregnancy test before treatment, and every month during treatment. An important factor to keep in mind is that the maximum topiramate dose for weight loss is 92 mg a day, while the typical epilepsy dose is 200-400 mg a day, and for migraines, is 100 mg a day. It may turn out that the same risk may not be evident with the lower dose.
As the labeling states, women who become pregnant while on this drug should stop taking it immediately, and clinicians should counsel them about the possible risks to the fetus. Health care providers and patients should report pregnancies exposed to Qsymia to the Qsymia Pregnancy Surveillance Program, which is monitoring maternal-fetal outcomes of exposed pregnancies, at 888-998-4887, or the FDA’s MedWatch program at 800-332-1088.
Dr. Koren is professor of pediatrics, pharmacology, pharmacy, medicine, and medical genetics at the University of Toronto. He heads the Research Leadership for Better Pharmacotherapy During Pregnancy and Lactation at the Hospital for Sick Children, Toronto, where he is director of the Motherisk Program. He was a consultant to Vivus, the manufacturer of Qsymia. E-mail him at obnews@frontlinemedcom.com.
At Motherisk, we receive increasing numbers of queries from women and clinicians about the use of topiramate during pregnancy, mostly related to its use for migraine or seizures.Topiramate is approved for treatment of seizures and for migraine prevention, and in 2012, the Food and Drug Administration approved the combination of extended-release topiramate with the stimulant phentermine (Qsymia) as a chronic treatment for weight management.
When topiramate was initially approved in 1996, human reproductive data were scarce, but animal data suggested that a high dose of topiramate in rats and rabbits may induce some congenital malformations. Since that time, quite a few studies – but not all – have suggested that topiramate may be associated with an increased risk of oral clefts (cleft lip and cleft palate). Studies that have found an increased risk associated with first trimester exposure to topiramate include the North American AED Pregnancy Registry, which found a rate of 14 cases per 1,000 – more than tenfold greater than the rate in the general population.
For seizures and migraines, the FDA has labeled topiramate a pregnancy category D drug (there is evidence of human fetal risk, but “the potential benefits from the use of the drug in pregnant women may be acceptable despite its potential risks.” ) For Qsymia, however, topiramate is contraindicated in pregnancy and is a pregnancy category X, because its use “can cause fetal harm and weight loss offers no potential benefit to a pregnant woman,” the labeling states.
Based on arecent analysis of six controlled studies in the literature of more than 3,000 pregnancies exposed during the first trimester, we determinedthat the risk of oral clefts associated with first trimester exposure was increased by sixfold over controls. To put this into context, in the general population, oral clefts occur in less than 1% (0.07%), whereas in the studies, the rate was 0.36%, about a fivefold increase.
Until the approval of the weight loss indication, women of reproductive age with epilepsy or migraines prescribed topiramate were a relatively small group. But because obesity is so common, we are now in a situation where a drug that is likely a human teratogen, based on strong evidence, will be used by far more women of childbearing age, and an increase in unintended pregnancies exposed to the drug probably will occur. In phase III clinical trials of Qsymia, quite a few women got pregnant, which is not surprising since women who are obese may have more difficulty knowing they are pregnant, for hormonal and other reasons.
Clinicians and women who take the drug for weight loss need to be aware of this risk. It is important to counsel women of childbearing age who are on this medication about the need for contraception during treatment, and to have a pregnancy test before treatment, and every month during treatment. An important factor to keep in mind is that the maximum topiramate dose for weight loss is 92 mg a day, while the typical epilepsy dose is 200-400 mg a day, and for migraines, is 100 mg a day. It may turn out that the same risk may not be evident with the lower dose.
As the labeling states, women who become pregnant while on this drug should stop taking it immediately, and clinicians should counsel them about the possible risks to the fetus. Health care providers and patients should report pregnancies exposed to Qsymia to the Qsymia Pregnancy Surveillance Program, which is monitoring maternal-fetal outcomes of exposed pregnancies, at 888-998-4887, or the FDA’s MedWatch program at 800-332-1088.
Dr. Koren is professor of pediatrics, pharmacology, pharmacy, medicine, and medical genetics at the University of Toronto. He heads the Research Leadership for Better Pharmacotherapy During Pregnancy and Lactation at the Hospital for Sick Children, Toronto, where he is director of the Motherisk Program. He was a consultant to Vivus, the manufacturer of Qsymia. E-mail him at obnews@frontlinemedcom.com.
Polyunsaturated fatty acid supplementation
Supplementation with polyunsaturated fatty acids – or omega-3 fatty acids – during pregnancy is an important topic because of unproven claims that polyunsaturated fatty acids (PUFAs) improve fetal brain and eye development if taken during pregnancy, resulting in unnecessary expense for many women who buy these products. In Canada, there are prenatal vitamins available that contain omega-3 fatty acids with a statement that the product "helps support cognitive health and/or brain function" or that omega-3 fatty acids "support "healthy fetal brain and eye development." These are misleading, inappropriate statements, considering that there is no compelling evidence to support these claims.
Claims about the benefits of PUFA supplementation during pregnancy, which have circulated for about a decade, originate from studies that show that when PUFAs are restricted during pregnancy, fetal brain development can be adversely affected, particularly in animals. Other data include several human studies that have linked high cognitive scores to a high seafood content of the maternal diet. The highest levels of PUFAs are measured in the retina, which is part of the visual acuity claim.
My colleagues and I addressed the uncertainties about the benefits of PUFA supplementation in a systematic review of nine randomized controlled trials comparing visual and neurobehavioral outcomes in infants whose mothers received PUFA supplements during gestation with control women who received placebos. Three studies evaluated retinal development and six evaluated neurodevelopment; most ended the supplement at delivery, and evaluations were conducted during the first year, or up to age 2.5, 4, and 7 years in different studies.
Overall, there was no evidence of a beneficial effect of PUFA supplementation during pregnancy on neurodevelopment (IQ, language behaviors) or on visual acuity. As we concluded, there were "very limited, if any" benefits identified, and in the studies with statistically significant differences between the two groups, "the differences were small and of little potential clinical importance" (Obstet. Gynecol. Int. 2012 [doi:10.1155/2012/591531]).
A study published in May 2014 also found no beneficial effect of prenatal supplementation with 800 mg/day of omega-3 fatty acid docosahexaenoic acid (DHA) on neurodevelopmental outcomes in children followed to age 4 years, and the authors concluded that the data "do not support prenatal DHA supplementation to enhance early childhood development." The randomized placebo-controlled study evaluated about 650 children at age 4 years, whose mothers had received the supplement or 333 who received placebo. The mean cognitive scores were not different between the two groups, and the proportion of children with delayed or advanced scores also did not differ between the two groups, nor did other objective assessments of cognition, language, and executive functioning (JAMA 2014;311:1802-4).
Based on the lack of evidence to date, there is no reason to add PUFAs to prenatal vitamins or recommend that women take a PUFA supplement during pregnancy.
The bottom line for clinicians/health care providers is that although the available evidence today has found no detrimental effects of even high doses of omega-3 fatty acid supplementation (up to 3.7 g/day), with the present state of knowledge, there is no evidence that prenatal supplementation with PUFAs improves brain development or acuity of vision in children. Instead of supplementation with PUFA during pregnancy, women should consume a diet with adequate PUFAs, with food that includes eggs and fish, with caution about the mercury content of fish.
Dr. Koren is professor of pediatrics, pharmacology, pharmacy, medicine, and medical genetics at the University of Toronto. He heads the Research Leadership for Better Pharmacotherapy During Pregnancy and Lactation at the Hospital for Sick Children, Toronto, where he is director of the Motherisk Program. He also holds the Ivey Chair in Molecular Toxicology at the department of medicine, University of Western Ontario, London. He had no disclosures relevant to this topic. E-mail him at obnews@frontlinemedcom.com.
Supplementation with polyunsaturated fatty acids – or omega-3 fatty acids – during pregnancy is an important topic because of unproven claims that polyunsaturated fatty acids (PUFAs) improve fetal brain and eye development if taken during pregnancy, resulting in unnecessary expense for many women who buy these products. In Canada, there are prenatal vitamins available that contain omega-3 fatty acids with a statement that the product "helps support cognitive health and/or brain function" or that omega-3 fatty acids "support "healthy fetal brain and eye development." These are misleading, inappropriate statements, considering that there is no compelling evidence to support these claims.
Claims about the benefits of PUFA supplementation during pregnancy, which have circulated for about a decade, originate from studies that show that when PUFAs are restricted during pregnancy, fetal brain development can be adversely affected, particularly in animals. Other data include several human studies that have linked high cognitive scores to a high seafood content of the maternal diet. The highest levels of PUFAs are measured in the retina, which is part of the visual acuity claim.
My colleagues and I addressed the uncertainties about the benefits of PUFA supplementation in a systematic review of nine randomized controlled trials comparing visual and neurobehavioral outcomes in infants whose mothers received PUFA supplements during gestation with control women who received placebos. Three studies evaluated retinal development and six evaluated neurodevelopment; most ended the supplement at delivery, and evaluations were conducted during the first year, or up to age 2.5, 4, and 7 years in different studies.
Overall, there was no evidence of a beneficial effect of PUFA supplementation during pregnancy on neurodevelopment (IQ, language behaviors) or on visual acuity. As we concluded, there were "very limited, if any" benefits identified, and in the studies with statistically significant differences between the two groups, "the differences were small and of little potential clinical importance" (Obstet. Gynecol. Int. 2012 [doi:10.1155/2012/591531]).
A study published in May 2014 also found no beneficial effect of prenatal supplementation with 800 mg/day of omega-3 fatty acid docosahexaenoic acid (DHA) on neurodevelopmental outcomes in children followed to age 4 years, and the authors concluded that the data "do not support prenatal DHA supplementation to enhance early childhood development." The randomized placebo-controlled study evaluated about 650 children at age 4 years, whose mothers had received the supplement or 333 who received placebo. The mean cognitive scores were not different between the two groups, and the proportion of children with delayed or advanced scores also did not differ between the two groups, nor did other objective assessments of cognition, language, and executive functioning (JAMA 2014;311:1802-4).
Based on the lack of evidence to date, there is no reason to add PUFAs to prenatal vitamins or recommend that women take a PUFA supplement during pregnancy.
The bottom line for clinicians/health care providers is that although the available evidence today has found no detrimental effects of even high doses of omega-3 fatty acid supplementation (up to 3.7 g/day), with the present state of knowledge, there is no evidence that prenatal supplementation with PUFAs improves brain development or acuity of vision in children. Instead of supplementation with PUFA during pregnancy, women should consume a diet with adequate PUFAs, with food that includes eggs and fish, with caution about the mercury content of fish.
Dr. Koren is professor of pediatrics, pharmacology, pharmacy, medicine, and medical genetics at the University of Toronto. He heads the Research Leadership for Better Pharmacotherapy During Pregnancy and Lactation at the Hospital for Sick Children, Toronto, where he is director of the Motherisk Program. He also holds the Ivey Chair in Molecular Toxicology at the department of medicine, University of Western Ontario, London. He had no disclosures relevant to this topic. E-mail him at obnews@frontlinemedcom.com.
Supplementation with polyunsaturated fatty acids – or omega-3 fatty acids – during pregnancy is an important topic because of unproven claims that polyunsaturated fatty acids (PUFAs) improve fetal brain and eye development if taken during pregnancy, resulting in unnecessary expense for many women who buy these products. In Canada, there are prenatal vitamins available that contain omega-3 fatty acids with a statement that the product "helps support cognitive health and/or brain function" or that omega-3 fatty acids "support "healthy fetal brain and eye development." These are misleading, inappropriate statements, considering that there is no compelling evidence to support these claims.
Claims about the benefits of PUFA supplementation during pregnancy, which have circulated for about a decade, originate from studies that show that when PUFAs are restricted during pregnancy, fetal brain development can be adversely affected, particularly in animals. Other data include several human studies that have linked high cognitive scores to a high seafood content of the maternal diet. The highest levels of PUFAs are measured in the retina, which is part of the visual acuity claim.
My colleagues and I addressed the uncertainties about the benefits of PUFA supplementation in a systematic review of nine randomized controlled trials comparing visual and neurobehavioral outcomes in infants whose mothers received PUFA supplements during gestation with control women who received placebos. Three studies evaluated retinal development and six evaluated neurodevelopment; most ended the supplement at delivery, and evaluations were conducted during the first year, or up to age 2.5, 4, and 7 years in different studies.
Overall, there was no evidence of a beneficial effect of PUFA supplementation during pregnancy on neurodevelopment (IQ, language behaviors) or on visual acuity. As we concluded, there were "very limited, if any" benefits identified, and in the studies with statistically significant differences between the two groups, "the differences were small and of little potential clinical importance" (Obstet. Gynecol. Int. 2012 [doi:10.1155/2012/591531]).
A study published in May 2014 also found no beneficial effect of prenatal supplementation with 800 mg/day of omega-3 fatty acid docosahexaenoic acid (DHA) on neurodevelopmental outcomes in children followed to age 4 years, and the authors concluded that the data "do not support prenatal DHA supplementation to enhance early childhood development." The randomized placebo-controlled study evaluated about 650 children at age 4 years, whose mothers had received the supplement or 333 who received placebo. The mean cognitive scores were not different between the two groups, and the proportion of children with delayed or advanced scores also did not differ between the two groups, nor did other objective assessments of cognition, language, and executive functioning (JAMA 2014;311:1802-4).
Based on the lack of evidence to date, there is no reason to add PUFAs to prenatal vitamins or recommend that women take a PUFA supplement during pregnancy.
The bottom line for clinicians/health care providers is that although the available evidence today has found no detrimental effects of even high doses of omega-3 fatty acid supplementation (up to 3.7 g/day), with the present state of knowledge, there is no evidence that prenatal supplementation with PUFAs improves brain development or acuity of vision in children. Instead of supplementation with PUFA during pregnancy, women should consume a diet with adequate PUFAs, with food that includes eggs and fish, with caution about the mercury content of fish.
Dr. Koren is professor of pediatrics, pharmacology, pharmacy, medicine, and medical genetics at the University of Toronto. He heads the Research Leadership for Better Pharmacotherapy During Pregnancy and Lactation at the Hospital for Sick Children, Toronto, where he is director of the Motherisk Program. He also holds the Ivey Chair in Molecular Toxicology at the department of medicine, University of Western Ontario, London. He had no disclosures relevant to this topic. E-mail him at obnews@frontlinemedcom.com.
