User login
Treating influenza: A guide to antiviral safety in pregnancy
Oseltamivir and zanamivir are competitive inhibitors for the neuraminidase enzyme for the influenza virus. They block the surface receptor enzyme and prevent release of virus from the host cell, thus limiting propagation of the infection. These medications can be given as prophylaxis after exposure to influenza or can be given therapeutically for a suspected or confirmed infection. Oseltamivir is recommended for treatment of suspected or confirmed influenza infection in the special population of pregnant women, as the risk for complications of influenza is increased in this group.
Safety evidence
However, there are limited data on the safety and efficacy of the neuraminidase inhibitors in pregnancy. With respect to safety, there have been seven publications in the literature addressing the risk for major birth defects following treatment or prophylaxis with one or both of these products, with the majority of the published data relating to oseltamivir exposure.
In a review by Tanaka et al. in 2009, 90 pregnancies treated therapeutically with oseltamivir in the first trimester were reported to two teratogen information services in Japan; one major birth defect (1.1%) was reported (CMAJ. 2009 Jul 7;181[1-2]:55-8). A year later, Greer et al. published a retrospective chart review at a Texas hospital between 2003 and 2008. During that period, 137 pregnancies that involved a pharmacy record of dispensing of oseltamivir were identified. Of these, 18 were dispensed in the first trimester, and none were linked to a major birth defect outcome (Obstet Gynecol. 2010 Apr;115[4]:711-6).
A 2011 record linkage study in Sweden identified 86 pregnant women for whom oseltamivir (n=81) or zanamivir had been prescribed. Of these, four were linked to a major birth defect in the infant; however, only one of the four prescriptions had been filled in the first trimester (Pharmacoepidemiol Drug Saf. 2011 Oct;20[10]:1030-4). In 2013, Saito et al. reported on a case series gathered from 157 obstetric facilities in Japan. Among 156 infants born to women exposed to oseltamivir in the first trimester, 2 (1.3%) were reported to have a major congenital anomaly; there were no congenital malformations reported in the 15 first-trimester exposures to zanamivir (Am J Obstet Gynecol. 2013 Aug;209[2[:130.e1-9).
In 2014, a teratogen information service in the United Kingdom reported on eight first-trimester exposures to oseltamivir and 37 to zanamivir, with no major birth defects noted in either group (BJOG. 2014 Jun;121[7]:901-6). Additionally, a French prescription database study identified 49 pregnancies thought to be exposed to oseltamivir in the first trimester with one reported congenital anomaly (BJOG. 2014 Jun;121[7]:895-900).
Finally, the manufacturer of oseltamivir published a summary of pregnancies from global pharmacovigilance data accumulated through spontaneous reports and other studies between 2000 and 2012 (Pharmacoepidemiol Drug Saf. 2014 Oct;23[10]:1035-42). Outcomes were available for 1,875 infants. Among these, 81 (4.3%) had major birth defects. However, following case review, the authors indicated that only 11 of the defects (occurring in 9 infants) were biologically plausible based on the timing of the exposure to oseltamivir.
Efficacy examined
With respect to efficacy, two small studies have addressed the pharmacokinetics of oseltamivir in pregnancy to determine if the recommended dosages for nonpregnant individuals are appropriate for pregnancy.
In the earlier of the two studies, Greer et al. looked at the pharmacokinetics of oseltamivir in 30 pregnant women, 10 in each of the three trimesters, who were taking 75 mg of the drug either once or twice daily. Maternal samples were drawn before and after the first dose of oseltamivir. They found little evidence of differences across the three trimesters and concluded that the parent drug values were in the pharmacologic range for clinical efficacy (Am J Obstet Gynecol. 2011 Jun;204[6 Suppl 1]:S89-93).
In contrast, Pillai et al. enrolled a small sample of women being treated with oseltamivir; they evaluated pharmacokinetics for the active metabolite of oseltamivir following 48 or more hours of treatment in 29 pregnant and 35 nonpregnant women (Br J Clin Pharmacol. 2015 Nov;80[5]:1042-50). Significantly lower levels of the active metabolite were noted in the pregnant women, compared with nonpregnant women. The authors suggested that the physiologic changes of pregnancy, correlated with increased renal clearance, produced an approximate 30% lower exposure to the drug in the pregnant state. While they were not able to relate this to maternal or infant outcomes, this finding suggested that further work is needed to determine if dosing recommendations should be adjusted in pregnancy.
The current recommendation is that pregnant women or women within 2 weeks post partum be given oseltamivir for treatment of suspected or confirmed influenza regardless of trimester of pregnancy. The limited safety data that are currently available have not suggested an increased risk for major birth defects following treatment with this product. However, the data are sparse for oseltamivir and even more so for zanamivir. Larger studies focused on these treatments are needed.
Dr. Chambers is professor of pediatrics and director of clinical research at Rady Children’s Hospital, and associate director of the Clinical and Translational Research Institute at the University of California, San Diego. She is director of MotherToBaby California, past president of the Organization of Teratology Information Specialists, and past president of the Teratology Society. She reported having no financial disclosures relevant to this column, but has received research funding Roche-Genentech and GlaxoSmithKline unrelated to antiviral medications. Email her at [email protected].
Oseltamivir and zanamivir are competitive inhibitors for the neuraminidase enzyme for the influenza virus. They block the surface receptor enzyme and prevent release of virus from the host cell, thus limiting propagation of the infection. These medications can be given as prophylaxis after exposure to influenza or can be given therapeutically for a suspected or confirmed infection. Oseltamivir is recommended for treatment of suspected or confirmed influenza infection in the special population of pregnant women, as the risk for complications of influenza is increased in this group.
Safety evidence
However, there are limited data on the safety and efficacy of the neuraminidase inhibitors in pregnancy. With respect to safety, there have been seven publications in the literature addressing the risk for major birth defects following treatment or prophylaxis with one or both of these products, with the majority of the published data relating to oseltamivir exposure.
In a review by Tanaka et al. in 2009, 90 pregnancies treated therapeutically with oseltamivir in the first trimester were reported to two teratogen information services in Japan; one major birth defect (1.1%) was reported (CMAJ. 2009 Jul 7;181[1-2]:55-8). A year later, Greer et al. published a retrospective chart review at a Texas hospital between 2003 and 2008. During that period, 137 pregnancies that involved a pharmacy record of dispensing of oseltamivir were identified. Of these, 18 were dispensed in the first trimester, and none were linked to a major birth defect outcome (Obstet Gynecol. 2010 Apr;115[4]:711-6).
A 2011 record linkage study in Sweden identified 86 pregnant women for whom oseltamivir (n=81) or zanamivir had been prescribed. Of these, four were linked to a major birth defect in the infant; however, only one of the four prescriptions had been filled in the first trimester (Pharmacoepidemiol Drug Saf. 2011 Oct;20[10]:1030-4). In 2013, Saito et al. reported on a case series gathered from 157 obstetric facilities in Japan. Among 156 infants born to women exposed to oseltamivir in the first trimester, 2 (1.3%) were reported to have a major congenital anomaly; there were no congenital malformations reported in the 15 first-trimester exposures to zanamivir (Am J Obstet Gynecol. 2013 Aug;209[2[:130.e1-9).
In 2014, a teratogen information service in the United Kingdom reported on eight first-trimester exposures to oseltamivir and 37 to zanamivir, with no major birth defects noted in either group (BJOG. 2014 Jun;121[7]:901-6). Additionally, a French prescription database study identified 49 pregnancies thought to be exposed to oseltamivir in the first trimester with one reported congenital anomaly (BJOG. 2014 Jun;121[7]:895-900).
Finally, the manufacturer of oseltamivir published a summary of pregnancies from global pharmacovigilance data accumulated through spontaneous reports and other studies between 2000 and 2012 (Pharmacoepidemiol Drug Saf. 2014 Oct;23[10]:1035-42). Outcomes were available for 1,875 infants. Among these, 81 (4.3%) had major birth defects. However, following case review, the authors indicated that only 11 of the defects (occurring in 9 infants) were biologically plausible based on the timing of the exposure to oseltamivir.
Efficacy examined
With respect to efficacy, two small studies have addressed the pharmacokinetics of oseltamivir in pregnancy to determine if the recommended dosages for nonpregnant individuals are appropriate for pregnancy.
In the earlier of the two studies, Greer et al. looked at the pharmacokinetics of oseltamivir in 30 pregnant women, 10 in each of the three trimesters, who were taking 75 mg of the drug either once or twice daily. Maternal samples were drawn before and after the first dose of oseltamivir. They found little evidence of differences across the three trimesters and concluded that the parent drug values were in the pharmacologic range for clinical efficacy (Am J Obstet Gynecol. 2011 Jun;204[6 Suppl 1]:S89-93).
In contrast, Pillai et al. enrolled a small sample of women being treated with oseltamivir; they evaluated pharmacokinetics for the active metabolite of oseltamivir following 48 or more hours of treatment in 29 pregnant and 35 nonpregnant women (Br J Clin Pharmacol. 2015 Nov;80[5]:1042-50). Significantly lower levels of the active metabolite were noted in the pregnant women, compared with nonpregnant women. The authors suggested that the physiologic changes of pregnancy, correlated with increased renal clearance, produced an approximate 30% lower exposure to the drug in the pregnant state. While they were not able to relate this to maternal or infant outcomes, this finding suggested that further work is needed to determine if dosing recommendations should be adjusted in pregnancy.
The current recommendation is that pregnant women or women within 2 weeks post partum be given oseltamivir for treatment of suspected or confirmed influenza regardless of trimester of pregnancy. The limited safety data that are currently available have not suggested an increased risk for major birth defects following treatment with this product. However, the data are sparse for oseltamivir and even more so for zanamivir. Larger studies focused on these treatments are needed.
Dr. Chambers is professor of pediatrics and director of clinical research at Rady Children’s Hospital, and associate director of the Clinical and Translational Research Institute at the University of California, San Diego. She is director of MotherToBaby California, past president of the Organization of Teratology Information Specialists, and past president of the Teratology Society. She reported having no financial disclosures relevant to this column, but has received research funding Roche-Genentech and GlaxoSmithKline unrelated to antiviral medications. Email her at [email protected].
Oseltamivir and zanamivir are competitive inhibitors for the neuraminidase enzyme for the influenza virus. They block the surface receptor enzyme and prevent release of virus from the host cell, thus limiting propagation of the infection. These medications can be given as prophylaxis after exposure to influenza or can be given therapeutically for a suspected or confirmed infection. Oseltamivir is recommended for treatment of suspected or confirmed influenza infection in the special population of pregnant women, as the risk for complications of influenza is increased in this group.
Safety evidence
However, there are limited data on the safety and efficacy of the neuraminidase inhibitors in pregnancy. With respect to safety, there have been seven publications in the literature addressing the risk for major birth defects following treatment or prophylaxis with one or both of these products, with the majority of the published data relating to oseltamivir exposure.
In a review by Tanaka et al. in 2009, 90 pregnancies treated therapeutically with oseltamivir in the first trimester were reported to two teratogen information services in Japan; one major birth defect (1.1%) was reported (CMAJ. 2009 Jul 7;181[1-2]:55-8). A year later, Greer et al. published a retrospective chart review at a Texas hospital between 2003 and 2008. During that period, 137 pregnancies that involved a pharmacy record of dispensing of oseltamivir were identified. Of these, 18 were dispensed in the first trimester, and none were linked to a major birth defect outcome (Obstet Gynecol. 2010 Apr;115[4]:711-6).
A 2011 record linkage study in Sweden identified 86 pregnant women for whom oseltamivir (n=81) or zanamivir had been prescribed. Of these, four were linked to a major birth defect in the infant; however, only one of the four prescriptions had been filled in the first trimester (Pharmacoepidemiol Drug Saf. 2011 Oct;20[10]:1030-4). In 2013, Saito et al. reported on a case series gathered from 157 obstetric facilities in Japan. Among 156 infants born to women exposed to oseltamivir in the first trimester, 2 (1.3%) were reported to have a major congenital anomaly; there were no congenital malformations reported in the 15 first-trimester exposures to zanamivir (Am J Obstet Gynecol. 2013 Aug;209[2[:130.e1-9).
In 2014, a teratogen information service in the United Kingdom reported on eight first-trimester exposures to oseltamivir and 37 to zanamivir, with no major birth defects noted in either group (BJOG. 2014 Jun;121[7]:901-6). Additionally, a French prescription database study identified 49 pregnancies thought to be exposed to oseltamivir in the first trimester with one reported congenital anomaly (BJOG. 2014 Jun;121[7]:895-900).
Finally, the manufacturer of oseltamivir published a summary of pregnancies from global pharmacovigilance data accumulated through spontaneous reports and other studies between 2000 and 2012 (Pharmacoepidemiol Drug Saf. 2014 Oct;23[10]:1035-42). Outcomes were available for 1,875 infants. Among these, 81 (4.3%) had major birth defects. However, following case review, the authors indicated that only 11 of the defects (occurring in 9 infants) were biologically plausible based on the timing of the exposure to oseltamivir.
Efficacy examined
With respect to efficacy, two small studies have addressed the pharmacokinetics of oseltamivir in pregnancy to determine if the recommended dosages for nonpregnant individuals are appropriate for pregnancy.
In the earlier of the two studies, Greer et al. looked at the pharmacokinetics of oseltamivir in 30 pregnant women, 10 in each of the three trimesters, who were taking 75 mg of the drug either once or twice daily. Maternal samples were drawn before and after the first dose of oseltamivir. They found little evidence of differences across the three trimesters and concluded that the parent drug values were in the pharmacologic range for clinical efficacy (Am J Obstet Gynecol. 2011 Jun;204[6 Suppl 1]:S89-93).
In contrast, Pillai et al. enrolled a small sample of women being treated with oseltamivir; they evaluated pharmacokinetics for the active metabolite of oseltamivir following 48 or more hours of treatment in 29 pregnant and 35 nonpregnant women (Br J Clin Pharmacol. 2015 Nov;80[5]:1042-50). Significantly lower levels of the active metabolite were noted in the pregnant women, compared with nonpregnant women. The authors suggested that the physiologic changes of pregnancy, correlated with increased renal clearance, produced an approximate 30% lower exposure to the drug in the pregnant state. While they were not able to relate this to maternal or infant outcomes, this finding suggested that further work is needed to determine if dosing recommendations should be adjusted in pregnancy.
The current recommendation is that pregnant women or women within 2 weeks post partum be given oseltamivir for treatment of suspected or confirmed influenza regardless of trimester of pregnancy. The limited safety data that are currently available have not suggested an increased risk for major birth defects following treatment with this product. However, the data are sparse for oseltamivir and even more so for zanamivir. Larger studies focused on these treatments are needed.
Dr. Chambers is professor of pediatrics and director of clinical research at Rady Children’s Hospital, and associate director of the Clinical and Translational Research Institute at the University of California, San Diego. She is director of MotherToBaby California, past president of the Organization of Teratology Information Specialists, and past president of the Teratology Society. She reported having no financial disclosures relevant to this column, but has received research funding Roche-Genentech and GlaxoSmithKline unrelated to antiviral medications. Email her at [email protected].
To drink or not to drink – What do you tell your patients?
It has been more than 40 years since fetal alcohol syndrome was first recognized as a brain disorder leading to a wide range of learning and behavior problems – fetal alcohol spectrum disorders – in children prenatally exposed to alcohol.
Over that time, obstetric providers have played a key role in counseling patients, both preconception and during pregnancy, about the risks associated with various amounts and patterns of alcohol consumption. This advice is critical as about half of women of reproductive age in the United States consume some alcohol, and about half of pregnancies are not planned, leading to a high prevalence of exposure to alcohol prior to pregnancy recognition.
But how much alcohol at what specific time in early pregnancy leads to a known risk of learning and behavior problems as children reach school age?
The U.S. Surgeon General’s Office and the Centers for Disease Control and Prevention recommend that alcohol be avoided entirely during all weeks of pregnancy, as there is no known safe amount, type of beverage, or timing in gestation that a woman can consume alcohol. However, in recent years, a number of publications have suggested that “low to moderate” alcohol consumption in pregnancy is not demonstrably harmful to the developing fetus, at least in terms of learning ability.
Three recently published studies exemplify the dilemma. Colleen M. O’Leary et. al. examined educational achievement in 8- to 9-year olds in Western Australia (Pediatrics 2013;132:e468-75). The sample was a population-based cohort of 4,056 infants randomly ascertained with births between 1995 and 1997 whose mothers had responded to a postnatal survey about health behaviors including alcohol consumption. Researchers linked these infants to a midwives database to obtain birth details and to an educational testing database to obtain measures of school achievement.
Children were not evaluated for the physical features or a diagnosis of FAS or something on the FASD spectrum. Low alcohol consumption was defined as 1-2 standard drinks (10 g alcohol per standard drink in Australia) per occasion and fewer than 7 drinks per week. Moderate alcohol consumption was defined as 3-4 standard drinks per occasion and no more than 7 drinks per week. Binge drinking was defined as 5 or more drinks per occasion less frequently than weekly, and heavy drinking was defined as more than 7 standard drinks per week including binge drinking weekly or more often.
Underachievement in reading and writing was significantly associated with either heavy first trimester or binge drinking in late pregnancy. However, achievement in numeracy, reading, spelling and writing was not significantly impaired with low to moderate prenatal alcohol exposure.
In a study of a sample derived from the Danish National Birth Cohort, 1,628 women and their children were sampled from the original cohort based on maternal alcohol drinking patterns reported in pregnancy (BJOG 2012;119:1191-1200). The child’s IQ was assessed at 5 years of age.
Children were not specifically evaluated for the physical features of FAS or a diagnosis of something on the FASD spectrum. Levels of alcohol consumption were categorized as none, average intake of 1-4 standard drinks per week (12 g alcohol per standard drink in Denmark), 5-8 standard drinks per week, and more than 8 standard drinks per week. There were no differences in the performance of children whose mothers consumed up to 8 standard drinks per week at some point in pregnancy compared to children whose mothers abstained.
In a subsequently published study in which researchers used the same sample, the parent and teacher versions of the Strengths and Difficulties Questionnaire, a standard behavioral screening tool, were completed by the mothers and the preschool teachers (BJOG 2013;120:1042-50). After adjustment for confounders, overall there were no significant associations found for any drinking category compared to abstainers.
Many experts asked to comment on these findings emphasized that these studies were limited to a few measures of learning and behavior in young children that may not be reflective of the range of alcohol-related developmental effects. They also pointed out the great difficulty in obtaining an accurate report of alcohol exposure in the absence of a sensitive and specific biomarker.
For example, recall of specific quantities, frequencies, and timing of alcohol consumption either after delivery (the Australian study) or in a single prenatal interview that was conducted sometime between 7 and 39 weeks’ gestation (the Danish study) may be inaccurate. This could be because of difficulty in remembering these details, as well as the influence of the social unacceptability of drinking during pregnancy.
However, as emphasized in the conclusions drawn by both research teams, negative findings for low to moderate alcohol exposure should not be overinterpreted to represent a finding of no risk for this type of exposure. The data are clear that heavy prenatal alcohol exposure, and in particular binge drinking, pose substantial risks for alcohol-related problems, including cognitive and behavioral deficits.
Decades of research have also demonstrated that there is large variability in individual susceptibility to the effects of prenatal alcohol. In addition to the alcohol itself, alcohol metabolizing genotype, maternal age, socioeconomic status, nutrition, and other factors likely play a role in modifying or mediating the effects for the individual mother and her child.
Since obstetric providers and their patients cannot know who is most susceptible, the current CDC and Surgeon General’s recommendations are the most prudent.
Dr. Chambers is professor of pediatrics and director of clinical research at Rady Children’s Hospital, and associate director of the Clinical and Translational Research Institute at the University of California, San Diego. She is director of MotherToBaby California, past president of the Organization of Teratology Information Specialists, and past president of the Teratology Society. She has no relevant financial disclosures. To comment, e-mail her at [email protected].
It has been more than 40 years since fetal alcohol syndrome was first recognized as a brain disorder leading to a wide range of learning and behavior problems – fetal alcohol spectrum disorders – in children prenatally exposed to alcohol.
Over that time, obstetric providers have played a key role in counseling patients, both preconception and during pregnancy, about the risks associated with various amounts and patterns of alcohol consumption. This advice is critical as about half of women of reproductive age in the United States consume some alcohol, and about half of pregnancies are not planned, leading to a high prevalence of exposure to alcohol prior to pregnancy recognition.
But how much alcohol at what specific time in early pregnancy leads to a known risk of learning and behavior problems as children reach school age?
The U.S. Surgeon General’s Office and the Centers for Disease Control and Prevention recommend that alcohol be avoided entirely during all weeks of pregnancy, as there is no known safe amount, type of beverage, or timing in gestation that a woman can consume alcohol. However, in recent years, a number of publications have suggested that “low to moderate” alcohol consumption in pregnancy is not demonstrably harmful to the developing fetus, at least in terms of learning ability.
Three recently published studies exemplify the dilemma. Colleen M. O’Leary et. al. examined educational achievement in 8- to 9-year olds in Western Australia (Pediatrics 2013;132:e468-75). The sample was a population-based cohort of 4,056 infants randomly ascertained with births between 1995 and 1997 whose mothers had responded to a postnatal survey about health behaviors including alcohol consumption. Researchers linked these infants to a midwives database to obtain birth details and to an educational testing database to obtain measures of school achievement.
Children were not evaluated for the physical features or a diagnosis of FAS or something on the FASD spectrum. Low alcohol consumption was defined as 1-2 standard drinks (10 g alcohol per standard drink in Australia) per occasion and fewer than 7 drinks per week. Moderate alcohol consumption was defined as 3-4 standard drinks per occasion and no more than 7 drinks per week. Binge drinking was defined as 5 or more drinks per occasion less frequently than weekly, and heavy drinking was defined as more than 7 standard drinks per week including binge drinking weekly or more often.
Underachievement in reading and writing was significantly associated with either heavy first trimester or binge drinking in late pregnancy. However, achievement in numeracy, reading, spelling and writing was not significantly impaired with low to moderate prenatal alcohol exposure.
In a study of a sample derived from the Danish National Birth Cohort, 1,628 women and their children were sampled from the original cohort based on maternal alcohol drinking patterns reported in pregnancy (BJOG 2012;119:1191-1200). The child’s IQ was assessed at 5 years of age.
Children were not specifically evaluated for the physical features of FAS or a diagnosis of something on the FASD spectrum. Levels of alcohol consumption were categorized as none, average intake of 1-4 standard drinks per week (12 g alcohol per standard drink in Denmark), 5-8 standard drinks per week, and more than 8 standard drinks per week. There were no differences in the performance of children whose mothers consumed up to 8 standard drinks per week at some point in pregnancy compared to children whose mothers abstained.
In a subsequently published study in which researchers used the same sample, the parent and teacher versions of the Strengths and Difficulties Questionnaire, a standard behavioral screening tool, were completed by the mothers and the preschool teachers (BJOG 2013;120:1042-50). After adjustment for confounders, overall there were no significant associations found for any drinking category compared to abstainers.
Many experts asked to comment on these findings emphasized that these studies were limited to a few measures of learning and behavior in young children that may not be reflective of the range of alcohol-related developmental effects. They also pointed out the great difficulty in obtaining an accurate report of alcohol exposure in the absence of a sensitive and specific biomarker.
For example, recall of specific quantities, frequencies, and timing of alcohol consumption either after delivery (the Australian study) or in a single prenatal interview that was conducted sometime between 7 and 39 weeks’ gestation (the Danish study) may be inaccurate. This could be because of difficulty in remembering these details, as well as the influence of the social unacceptability of drinking during pregnancy.
However, as emphasized in the conclusions drawn by both research teams, negative findings for low to moderate alcohol exposure should not be overinterpreted to represent a finding of no risk for this type of exposure. The data are clear that heavy prenatal alcohol exposure, and in particular binge drinking, pose substantial risks for alcohol-related problems, including cognitive and behavioral deficits.
Decades of research have also demonstrated that there is large variability in individual susceptibility to the effects of prenatal alcohol. In addition to the alcohol itself, alcohol metabolizing genotype, maternal age, socioeconomic status, nutrition, and other factors likely play a role in modifying or mediating the effects for the individual mother and her child.
Since obstetric providers and their patients cannot know who is most susceptible, the current CDC and Surgeon General’s recommendations are the most prudent.
Dr. Chambers is professor of pediatrics and director of clinical research at Rady Children’s Hospital, and associate director of the Clinical and Translational Research Institute at the University of California, San Diego. She is director of MotherToBaby California, past president of the Organization of Teratology Information Specialists, and past president of the Teratology Society. She has no relevant financial disclosures. To comment, e-mail her at [email protected].
It has been more than 40 years since fetal alcohol syndrome was first recognized as a brain disorder leading to a wide range of learning and behavior problems – fetal alcohol spectrum disorders – in children prenatally exposed to alcohol.
Over that time, obstetric providers have played a key role in counseling patients, both preconception and during pregnancy, about the risks associated with various amounts and patterns of alcohol consumption. This advice is critical as about half of women of reproductive age in the United States consume some alcohol, and about half of pregnancies are not planned, leading to a high prevalence of exposure to alcohol prior to pregnancy recognition.
But how much alcohol at what specific time in early pregnancy leads to a known risk of learning and behavior problems as children reach school age?
The U.S. Surgeon General’s Office and the Centers for Disease Control and Prevention recommend that alcohol be avoided entirely during all weeks of pregnancy, as there is no known safe amount, type of beverage, or timing in gestation that a woman can consume alcohol. However, in recent years, a number of publications have suggested that “low to moderate” alcohol consumption in pregnancy is not demonstrably harmful to the developing fetus, at least in terms of learning ability.
Three recently published studies exemplify the dilemma. Colleen M. O’Leary et. al. examined educational achievement in 8- to 9-year olds in Western Australia (Pediatrics 2013;132:e468-75). The sample was a population-based cohort of 4,056 infants randomly ascertained with births between 1995 and 1997 whose mothers had responded to a postnatal survey about health behaviors including alcohol consumption. Researchers linked these infants to a midwives database to obtain birth details and to an educational testing database to obtain measures of school achievement.
Children were not evaluated for the physical features or a diagnosis of FAS or something on the FASD spectrum. Low alcohol consumption was defined as 1-2 standard drinks (10 g alcohol per standard drink in Australia) per occasion and fewer than 7 drinks per week. Moderate alcohol consumption was defined as 3-4 standard drinks per occasion and no more than 7 drinks per week. Binge drinking was defined as 5 or more drinks per occasion less frequently than weekly, and heavy drinking was defined as more than 7 standard drinks per week including binge drinking weekly or more often.
Underachievement in reading and writing was significantly associated with either heavy first trimester or binge drinking in late pregnancy. However, achievement in numeracy, reading, spelling and writing was not significantly impaired with low to moderate prenatal alcohol exposure.
In a study of a sample derived from the Danish National Birth Cohort, 1,628 women and their children were sampled from the original cohort based on maternal alcohol drinking patterns reported in pregnancy (BJOG 2012;119:1191-1200). The child’s IQ was assessed at 5 years of age.
Children were not specifically evaluated for the physical features of FAS or a diagnosis of something on the FASD spectrum. Levels of alcohol consumption were categorized as none, average intake of 1-4 standard drinks per week (12 g alcohol per standard drink in Denmark), 5-8 standard drinks per week, and more than 8 standard drinks per week. There were no differences in the performance of children whose mothers consumed up to 8 standard drinks per week at some point in pregnancy compared to children whose mothers abstained.
In a subsequently published study in which researchers used the same sample, the parent and teacher versions of the Strengths and Difficulties Questionnaire, a standard behavioral screening tool, were completed by the mothers and the preschool teachers (BJOG 2013;120:1042-50). After adjustment for confounders, overall there were no significant associations found for any drinking category compared to abstainers.
Many experts asked to comment on these findings emphasized that these studies were limited to a few measures of learning and behavior in young children that may not be reflective of the range of alcohol-related developmental effects. They also pointed out the great difficulty in obtaining an accurate report of alcohol exposure in the absence of a sensitive and specific biomarker.
For example, recall of specific quantities, frequencies, and timing of alcohol consumption either after delivery (the Australian study) or in a single prenatal interview that was conducted sometime between 7 and 39 weeks’ gestation (the Danish study) may be inaccurate. This could be because of difficulty in remembering these details, as well as the influence of the social unacceptability of drinking during pregnancy.
However, as emphasized in the conclusions drawn by both research teams, negative findings for low to moderate alcohol exposure should not be overinterpreted to represent a finding of no risk for this type of exposure. The data are clear that heavy prenatal alcohol exposure, and in particular binge drinking, pose substantial risks for alcohol-related problems, including cognitive and behavioral deficits.
Decades of research have also demonstrated that there is large variability in individual susceptibility to the effects of prenatal alcohol. In addition to the alcohol itself, alcohol metabolizing genotype, maternal age, socioeconomic status, nutrition, and other factors likely play a role in modifying or mediating the effects for the individual mother and her child.
Since obstetric providers and their patients cannot know who is most susceptible, the current CDC and Surgeon General’s recommendations are the most prudent.
Dr. Chambers is professor of pediatrics and director of clinical research at Rady Children’s Hospital, and associate director of the Clinical and Translational Research Institute at the University of California, San Diego. She is director of MotherToBaby California, past president of the Organization of Teratology Information Specialists, and past president of the Teratology Society. She has no relevant financial disclosures. To comment, e-mail her at [email protected].
Evaluating the impact of FDA’s pregnancy and lactation labeling rule
Since 1979, obstetric and other health care providers who treat pregnant or potentially pregnant and breastfeeding women have relied heavily on the Food and Drug Administration’s pregnancy labeling categories for pharmaceuticals – the familiar A, B, C, D, X. However, as early as 1997, a public hearing was held that challenged the value of these labels as typically used in clinical practice by both providers and patients.
Now, 17 years later, in December 2014, the FDA has released the “Pregnancy and Lactation Labeling Rule” (also known as PLLR or final rule). In brief, the revised label will require that:
• Contact information be prominently listed for a pregnancy exposure registry for the drug, when one is available.
• Narrative sections be presented that include a risk summary, clinical considerations, and the supporting data.
• A lactation subsection be included that provides information about using the drug while breastfeeding, such as the amount of drug in breast milk and potential effects on the breastfed infant.
• A subsection on females and males of reproductive potential be included, when necessary, with information about the need for pregnancy testing, contraception recommendations, and information about infertility as it relates to the drug.
The labeling changes go into effect on June 30, 2015. Prescription drugs and biologic products submitted for FDA review after that date will use the new format immediately, while labeling for prescription drugs approved on or after June 30, 2001, will be phased in gradually.
Why are these changes needed, and what impact will they likely have for clinical practice?
First a bit of history – the pregnancy label A, B, C, D, X categories were initially introduced in the 1970s, following the recognition that thalidomide was a human teratogen. The intention was to help the clinician deal in a more standardized way with the increasing amount of experimental animal data and human reports generated for drugs that might be used by women of reproductive potential.
However, the letter categories, and their accompanying standard text statements, were frequently misinterpreted in oversimplistic and inaccurate ways (Birth Defects Res. Part A 2007,79:627-30). Clinicians and patients often believe that risk increases as you move across the letter categories; for example, that a category C drug is worse than a category B drug for a given patient.
Clinicians and patients also commonly think that drugs in the same category have the same level of risk, or that there is a similar quantity and quality of information to support that risk category. Frequently cited examples of misinterpretation include those drugs assigned a category X, for example, label text indicating that the drug is “contraindicated in women who are or may become pregnant.” In reality, in some cases, the X category has been applied to drugs with known human teratogenic potential (such as isotretinoin or thalidomide). However, in other cases, the X has been assigned to drugs for which there were no or very limited human data indicating risk (such as ribavirin or leflunomide) or for which the treatment for the underlying condition would not be necessary or advisable in pregnancy (such as statins or some weight loss drugs).
There is no differentiation made in the category X label for varying risks specifically related to dose and timing of exposure in gestation. In each of these situations where there are no clear-cut human data, inadvertent exposure to the drug in an unplanned pregnancy can easily lead to the misunderstanding that the drug is known to cause birth defects in humans.
The immediate impact of the PLLR label revision will be to require narrative sections that describe the actual data, provide a summary of risks, and also present clinical considerations that may include the risk of undertreatment or no treatment with the drug. The new format is intended to provide the clinician (and the patient) with more comprehensive information on which to base decisions.
The downside of the label revision is that clinicians will have to learn to interpret more comprehensive information and deal with the unknowns, which are many.
The other major impact of the label revision will be to highlight the clear lack of sufficient human data for most drugs currently marketed in the United States. A recent review of drugs (both prescription and over the counter) approved by the FDA between 2000 and 2010 found that 73.3% had no human data available that was relevant to pregnancy safety (Am. J. Med. Genet. C. Semin. Med. Genet. 157C:175-82).
In the short term, the learning curve for label writers and the end users of such labels will be steep. However, clinicians and patients can contribute to the compilation of data for most drugs by more proactively engaging in pregnancy and lactation safety studies. Information about the existence of any pregnancy registries in drug labeling has been recommended in the past, but will now be required. Acting on that information by enrolling patients in these studies can ensure that labels can more quickly be populated with evidence-based data that can better inform patient care.
Dr. Chambers is a professor of pediatrics and director of clinical research at Rady Children’s Hospital, and associate director of the Clinical and Translational Research Institute at the University of California, San Diego. She is director of MotherToBaby California, a past president of the Organization of Teratology Information Specialists, and past president of the Teratology Society. She has no relevant financial disclosures. To comment, e-mail her at [email protected].
Since 1979, obstetric and other health care providers who treat pregnant or potentially pregnant and breastfeeding women have relied heavily on the Food and Drug Administration’s pregnancy labeling categories for pharmaceuticals – the familiar A, B, C, D, X. However, as early as 1997, a public hearing was held that challenged the value of these labels as typically used in clinical practice by both providers and patients.
Now, 17 years later, in December 2014, the FDA has released the “Pregnancy and Lactation Labeling Rule” (also known as PLLR or final rule). In brief, the revised label will require that:
• Contact information be prominently listed for a pregnancy exposure registry for the drug, when one is available.
• Narrative sections be presented that include a risk summary, clinical considerations, and the supporting data.
• A lactation subsection be included that provides information about using the drug while breastfeeding, such as the amount of drug in breast milk and potential effects on the breastfed infant.
• A subsection on females and males of reproductive potential be included, when necessary, with information about the need for pregnancy testing, contraception recommendations, and information about infertility as it relates to the drug.
The labeling changes go into effect on June 30, 2015. Prescription drugs and biologic products submitted for FDA review after that date will use the new format immediately, while labeling for prescription drugs approved on or after June 30, 2001, will be phased in gradually.
Why are these changes needed, and what impact will they likely have for clinical practice?
First a bit of history – the pregnancy label A, B, C, D, X categories were initially introduced in the 1970s, following the recognition that thalidomide was a human teratogen. The intention was to help the clinician deal in a more standardized way with the increasing amount of experimental animal data and human reports generated for drugs that might be used by women of reproductive potential.
However, the letter categories, and their accompanying standard text statements, were frequently misinterpreted in oversimplistic and inaccurate ways (Birth Defects Res. Part A 2007,79:627-30). Clinicians and patients often believe that risk increases as you move across the letter categories; for example, that a category C drug is worse than a category B drug for a given patient.
Clinicians and patients also commonly think that drugs in the same category have the same level of risk, or that there is a similar quantity and quality of information to support that risk category. Frequently cited examples of misinterpretation include those drugs assigned a category X, for example, label text indicating that the drug is “contraindicated in women who are or may become pregnant.” In reality, in some cases, the X category has been applied to drugs with known human teratogenic potential (such as isotretinoin or thalidomide). However, in other cases, the X has been assigned to drugs for which there were no or very limited human data indicating risk (such as ribavirin or leflunomide) or for which the treatment for the underlying condition would not be necessary or advisable in pregnancy (such as statins or some weight loss drugs).
There is no differentiation made in the category X label for varying risks specifically related to dose and timing of exposure in gestation. In each of these situations where there are no clear-cut human data, inadvertent exposure to the drug in an unplanned pregnancy can easily lead to the misunderstanding that the drug is known to cause birth defects in humans.
The immediate impact of the PLLR label revision will be to require narrative sections that describe the actual data, provide a summary of risks, and also present clinical considerations that may include the risk of undertreatment or no treatment with the drug. The new format is intended to provide the clinician (and the patient) with more comprehensive information on which to base decisions.
The downside of the label revision is that clinicians will have to learn to interpret more comprehensive information and deal with the unknowns, which are many.
The other major impact of the label revision will be to highlight the clear lack of sufficient human data for most drugs currently marketed in the United States. A recent review of drugs (both prescription and over the counter) approved by the FDA between 2000 and 2010 found that 73.3% had no human data available that was relevant to pregnancy safety (Am. J. Med. Genet. C. Semin. Med. Genet. 157C:175-82).
In the short term, the learning curve for label writers and the end users of such labels will be steep. However, clinicians and patients can contribute to the compilation of data for most drugs by more proactively engaging in pregnancy and lactation safety studies. Information about the existence of any pregnancy registries in drug labeling has been recommended in the past, but will now be required. Acting on that information by enrolling patients in these studies can ensure that labels can more quickly be populated with evidence-based data that can better inform patient care.
Dr. Chambers is a professor of pediatrics and director of clinical research at Rady Children’s Hospital, and associate director of the Clinical and Translational Research Institute at the University of California, San Diego. She is director of MotherToBaby California, a past president of the Organization of Teratology Information Specialists, and past president of the Teratology Society. She has no relevant financial disclosures. To comment, e-mail her at [email protected].
Since 1979, obstetric and other health care providers who treat pregnant or potentially pregnant and breastfeeding women have relied heavily on the Food and Drug Administration’s pregnancy labeling categories for pharmaceuticals – the familiar A, B, C, D, X. However, as early as 1997, a public hearing was held that challenged the value of these labels as typically used in clinical practice by both providers and patients.
Now, 17 years later, in December 2014, the FDA has released the “Pregnancy and Lactation Labeling Rule” (also known as PLLR or final rule). In brief, the revised label will require that:
• Contact information be prominently listed for a pregnancy exposure registry for the drug, when one is available.
• Narrative sections be presented that include a risk summary, clinical considerations, and the supporting data.
• A lactation subsection be included that provides information about using the drug while breastfeeding, such as the amount of drug in breast milk and potential effects on the breastfed infant.
• A subsection on females and males of reproductive potential be included, when necessary, with information about the need for pregnancy testing, contraception recommendations, and information about infertility as it relates to the drug.
The labeling changes go into effect on June 30, 2015. Prescription drugs and biologic products submitted for FDA review after that date will use the new format immediately, while labeling for prescription drugs approved on or after June 30, 2001, will be phased in gradually.
Why are these changes needed, and what impact will they likely have for clinical practice?
First a bit of history – the pregnancy label A, B, C, D, X categories were initially introduced in the 1970s, following the recognition that thalidomide was a human teratogen. The intention was to help the clinician deal in a more standardized way with the increasing amount of experimental animal data and human reports generated for drugs that might be used by women of reproductive potential.
However, the letter categories, and their accompanying standard text statements, were frequently misinterpreted in oversimplistic and inaccurate ways (Birth Defects Res. Part A 2007,79:627-30). Clinicians and patients often believe that risk increases as you move across the letter categories; for example, that a category C drug is worse than a category B drug for a given patient.
Clinicians and patients also commonly think that drugs in the same category have the same level of risk, or that there is a similar quantity and quality of information to support that risk category. Frequently cited examples of misinterpretation include those drugs assigned a category X, for example, label text indicating that the drug is “contraindicated in women who are or may become pregnant.” In reality, in some cases, the X category has been applied to drugs with known human teratogenic potential (such as isotretinoin or thalidomide). However, in other cases, the X has been assigned to drugs for which there were no or very limited human data indicating risk (such as ribavirin or leflunomide) or for which the treatment for the underlying condition would not be necessary or advisable in pregnancy (such as statins or some weight loss drugs).
There is no differentiation made in the category X label for varying risks specifically related to dose and timing of exposure in gestation. In each of these situations where there are no clear-cut human data, inadvertent exposure to the drug in an unplanned pregnancy can easily lead to the misunderstanding that the drug is known to cause birth defects in humans.
The immediate impact of the PLLR label revision will be to require narrative sections that describe the actual data, provide a summary of risks, and also present clinical considerations that may include the risk of undertreatment or no treatment with the drug. The new format is intended to provide the clinician (and the patient) with more comprehensive information on which to base decisions.
The downside of the label revision is that clinicians will have to learn to interpret more comprehensive information and deal with the unknowns, which are many.
The other major impact of the label revision will be to highlight the clear lack of sufficient human data for most drugs currently marketed in the United States. A recent review of drugs (both prescription and over the counter) approved by the FDA between 2000 and 2010 found that 73.3% had no human data available that was relevant to pregnancy safety (Am. J. Med. Genet. C. Semin. Med. Genet. 157C:175-82).
In the short term, the learning curve for label writers and the end users of such labels will be steep. However, clinicians and patients can contribute to the compilation of data for most drugs by more proactively engaging in pregnancy and lactation safety studies. Information about the existence of any pregnancy registries in drug labeling has been recommended in the past, but will now be required. Acting on that information by enrolling patients in these studies can ensure that labels can more quickly be populated with evidence-based data that can better inform patient care.
Dr. Chambers is a professor of pediatrics and director of clinical research at Rady Children’s Hospital, and associate director of the Clinical and Translational Research Institute at the University of California, San Diego. She is director of MotherToBaby California, a past president of the Organization of Teratology Information Specialists, and past president of the Teratology Society. She has no relevant financial disclosures. To comment, e-mail her at [email protected].
