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Safety of ondansetron for nausea and vomiting of pregnancy
Nausea and vomiting of pregnancy (NVP) affects up to 80% of pregnant women, most commonly between 5 and 18 weeks of gestation. In addition, its extreme form, hyperemesis gravidarum, affects less than 3% of pregnancies.1 Certainly with hyperemesis gravidarum, and oftentimes with less severe NVP, pharmacologic treatment is desired or required. One of the choices for such treatment has been ondansetron, a 5-HT3 receptor antagonist, which has been used off label for NVP and is now available in generic form. However, there have been concerns raised regarding the fetal safety of this medication, last reviewed in Ob.Gyn. News by Gideon Koren, MD, in a commentary published in 2013.
Since then, the escalating use of ondansetron in the United States has been described using a large dataset covering 2.3 million, predominantly commercially insured, pregnancies that resulted in live births from 2001 to 2015.1 Over that period of time, any outpatient pharmacy dispensing of an antiemetic in pregnancy increased from 17.0% in 2001 to 27.2% in 2014. That increase was entirely accounted for by a dramatic rise in oral ondansetron use beginning in 2006. By 2014, 22.4% of pregnancies in the database had received a prescription for ondansetron.
There have been two studies that have suggested an increased risk in specific major birth defects with first-trimester ondansetron use. The first, published in 2012, used data from the National Birth Defects Prevention case control study from 1997 to 2004 to examine risks with NVP and its treatments for the most common noncardiac defects in the dataset. These included cleft lip with or without cleft palate, cleft palate alone, neural tube defects, and hypospadias. NVP itself was not associated with any increased risks for the selected defects. In contrast, ondansetron was associated with an increased risk for cleft palate alone based on seven exposed cases (adjusted odds ratio, 2.37; 95% confidence interval, 1.18-4.76).2
A second study published in 2014 used data from the Swedish Medical Birth Register from 1998 to 2012 to identify 1,349 infants whose mothers reported taking ondansetron in early pregnancy. While no overall increased risk of major birth defects was found with early pregnancy ondansetron use, compared with no such use, there was a significant increased risk noted for cardiovascular defects, particularly cardiac septum defects (any cardiac defect OR, 1.62; 95% CI, 1.04-2.14; cardiac septum defects risk ratio, 2.05; 95% CI, 1.19-3.28).3 No cases of cleft palate were reported among exposed cases in that study.
In contrast, in another study, Danish National Birth Cohort data on 608,385 pregnancies from 2004 to 2011 were used to compare major birth defect outcomes among 1,233 women exposed to ondansetron in the first trimester with those of 4,392 unexposed women.4 The birth prevalence of any major birth defect was identical (2.9%) in both exposed and unexposed groups (adjusted prevalence OR, 1.12; 95% CI, 0.69-1.82). No cases of cleft palate were reported among exposed cases and the crude OR for any cardiac defect approximated the null (1.04; 95% CI, 0.52-1.95). Two other smaller or less well-designed studies did not support an increased risk for major birth defects overall (Fejzo et al. 2016 Jul;62:87-91; Einarson et al. 2004Aug 23. doi: 10.1111/j.1471-0528.2004.00236.x).
To date, although the data are conflicting, they are consistent with either a small increased risk for selected cardiac defects and perhaps cleft palate, or no increased risk at all. However, with recent data indicating that nearly one-quarter of insured pregnant women in the United States have been prescribed ondansetron in early pregnancy, there is an urgency to conduct additional rigorous studies of sufficient sample size to determine on balance if there is a small individual increased risk associated with this treatment that translates to a larger public health problem.
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 also director of MotherToBaby California, a past president of the Organization of Teratology Information Specialists, and past president of the Teratology Society. She has no conflicts of interest to disclose related to this column.
References:
1. Taylor LG et al. Antiemetic use among pregnant women in the United States: the escalating use of ondansetron. Pharmacoepidemiol Drug Saf. 2017 May;26(5):592-6.
2. Anderka M et al. Medications used to treat nausea and vomiting of pregnancy and the risk of selected birth defects. Birth Defects Res A Clin Mol Teratol. 2012 Jan;94(1):22-30.
3. Danielsson B et al. Use of ondansetron during pregnancy and congenital malformations in the infant. Reprod Toxicol. 2014 Dec;50:134-7.
4. Pasternak B et al. Ondansetron in pregnancy and risk of adverse fetal outcomes. N Engl J Med. 2013 Feb 28;368(9):814-23.
Nausea and vomiting of pregnancy (NVP) affects up to 80% of pregnant women, most commonly between 5 and 18 weeks of gestation. In addition, its extreme form, hyperemesis gravidarum, affects less than 3% of pregnancies.1 Certainly with hyperemesis gravidarum, and oftentimes with less severe NVP, pharmacologic treatment is desired or required. One of the choices for such treatment has been ondansetron, a 5-HT3 receptor antagonist, which has been used off label for NVP and is now available in generic form. However, there have been concerns raised regarding the fetal safety of this medication, last reviewed in Ob.Gyn. News by Gideon Koren, MD, in a commentary published in 2013.
Since then, the escalating use of ondansetron in the United States has been described using a large dataset covering 2.3 million, predominantly commercially insured, pregnancies that resulted in live births from 2001 to 2015.1 Over that period of time, any outpatient pharmacy dispensing of an antiemetic in pregnancy increased from 17.0% in 2001 to 27.2% in 2014. That increase was entirely accounted for by a dramatic rise in oral ondansetron use beginning in 2006. By 2014, 22.4% of pregnancies in the database had received a prescription for ondansetron.
There have been two studies that have suggested an increased risk in specific major birth defects with first-trimester ondansetron use. The first, published in 2012, used data from the National Birth Defects Prevention case control study from 1997 to 2004 to examine risks with NVP and its treatments for the most common noncardiac defects in the dataset. These included cleft lip with or without cleft palate, cleft palate alone, neural tube defects, and hypospadias. NVP itself was not associated with any increased risks for the selected defects. In contrast, ondansetron was associated with an increased risk for cleft palate alone based on seven exposed cases (adjusted odds ratio, 2.37; 95% confidence interval, 1.18-4.76).2
A second study published in 2014 used data from the Swedish Medical Birth Register from 1998 to 2012 to identify 1,349 infants whose mothers reported taking ondansetron in early pregnancy. While no overall increased risk of major birth defects was found with early pregnancy ondansetron use, compared with no such use, there was a significant increased risk noted for cardiovascular defects, particularly cardiac septum defects (any cardiac defect OR, 1.62; 95% CI, 1.04-2.14; cardiac septum defects risk ratio, 2.05; 95% CI, 1.19-3.28).3 No cases of cleft palate were reported among exposed cases in that study.
In contrast, in another study, Danish National Birth Cohort data on 608,385 pregnancies from 2004 to 2011 were used to compare major birth defect outcomes among 1,233 women exposed to ondansetron in the first trimester with those of 4,392 unexposed women.4 The birth prevalence of any major birth defect was identical (2.9%) in both exposed and unexposed groups (adjusted prevalence OR, 1.12; 95% CI, 0.69-1.82). No cases of cleft palate were reported among exposed cases and the crude OR for any cardiac defect approximated the null (1.04; 95% CI, 0.52-1.95). Two other smaller or less well-designed studies did not support an increased risk for major birth defects overall (Fejzo et al. 2016 Jul;62:87-91; Einarson et al. 2004Aug 23. doi: 10.1111/j.1471-0528.2004.00236.x).
To date, although the data are conflicting, they are consistent with either a small increased risk for selected cardiac defects and perhaps cleft palate, or no increased risk at all. However, with recent data indicating that nearly one-quarter of insured pregnant women in the United States have been prescribed ondansetron in early pregnancy, there is an urgency to conduct additional rigorous studies of sufficient sample size to determine on balance if there is a small individual increased risk associated with this treatment that translates to a larger public health problem.
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 also director of MotherToBaby California, a past president of the Organization of Teratology Information Specialists, and past president of the Teratology Society. She has no conflicts of interest to disclose related to this column.
References:
1. Taylor LG et al. Antiemetic use among pregnant women in the United States: the escalating use of ondansetron. Pharmacoepidemiol Drug Saf. 2017 May;26(5):592-6.
2. Anderka M et al. Medications used to treat nausea and vomiting of pregnancy and the risk of selected birth defects. Birth Defects Res A Clin Mol Teratol. 2012 Jan;94(1):22-30.
3. Danielsson B et al. Use of ondansetron during pregnancy and congenital malformations in the infant. Reprod Toxicol. 2014 Dec;50:134-7.
4. Pasternak B et al. Ondansetron in pregnancy and risk of adverse fetal outcomes. N Engl J Med. 2013 Feb 28;368(9):814-23.
Nausea and vomiting of pregnancy (NVP) affects up to 80% of pregnant women, most commonly between 5 and 18 weeks of gestation. In addition, its extreme form, hyperemesis gravidarum, affects less than 3% of pregnancies.1 Certainly with hyperemesis gravidarum, and oftentimes with less severe NVP, pharmacologic treatment is desired or required. One of the choices for such treatment has been ondansetron, a 5-HT3 receptor antagonist, which has been used off label for NVP and is now available in generic form. However, there have been concerns raised regarding the fetal safety of this medication, last reviewed in Ob.Gyn. News by Gideon Koren, MD, in a commentary published in 2013.
Since then, the escalating use of ondansetron in the United States has been described using a large dataset covering 2.3 million, predominantly commercially insured, pregnancies that resulted in live births from 2001 to 2015.1 Over that period of time, any outpatient pharmacy dispensing of an antiemetic in pregnancy increased from 17.0% in 2001 to 27.2% in 2014. That increase was entirely accounted for by a dramatic rise in oral ondansetron use beginning in 2006. By 2014, 22.4% of pregnancies in the database had received a prescription for ondansetron.
There have been two studies that have suggested an increased risk in specific major birth defects with first-trimester ondansetron use. The first, published in 2012, used data from the National Birth Defects Prevention case control study from 1997 to 2004 to examine risks with NVP and its treatments for the most common noncardiac defects in the dataset. These included cleft lip with or without cleft palate, cleft palate alone, neural tube defects, and hypospadias. NVP itself was not associated with any increased risks for the selected defects. In contrast, ondansetron was associated with an increased risk for cleft palate alone based on seven exposed cases (adjusted odds ratio, 2.37; 95% confidence interval, 1.18-4.76).2
A second study published in 2014 used data from the Swedish Medical Birth Register from 1998 to 2012 to identify 1,349 infants whose mothers reported taking ondansetron in early pregnancy. While no overall increased risk of major birth defects was found with early pregnancy ondansetron use, compared with no such use, there was a significant increased risk noted for cardiovascular defects, particularly cardiac septum defects (any cardiac defect OR, 1.62; 95% CI, 1.04-2.14; cardiac septum defects risk ratio, 2.05; 95% CI, 1.19-3.28).3 No cases of cleft palate were reported among exposed cases in that study.
In contrast, in another study, Danish National Birth Cohort data on 608,385 pregnancies from 2004 to 2011 were used to compare major birth defect outcomes among 1,233 women exposed to ondansetron in the first trimester with those of 4,392 unexposed women.4 The birth prevalence of any major birth defect was identical (2.9%) in both exposed and unexposed groups (adjusted prevalence OR, 1.12; 95% CI, 0.69-1.82). No cases of cleft palate were reported among exposed cases and the crude OR for any cardiac defect approximated the null (1.04; 95% CI, 0.52-1.95). Two other smaller or less well-designed studies did not support an increased risk for major birth defects overall (Fejzo et al. 2016 Jul;62:87-91; Einarson et al. 2004Aug 23. doi: 10.1111/j.1471-0528.2004.00236.x).
To date, although the data are conflicting, they are consistent with either a small increased risk for selected cardiac defects and perhaps cleft palate, or no increased risk at all. However, with recent data indicating that nearly one-quarter of insured pregnant women in the United States have been prescribed ondansetron in early pregnancy, there is an urgency to conduct additional rigorous studies of sufficient sample size to determine on balance if there is a small individual increased risk associated with this treatment that translates to a larger public health problem.
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 also director of MotherToBaby California, a past president of the Organization of Teratology Information Specialists, and past president of the Teratology Society. She has no conflicts of interest to disclose related to this column.
References:
1. Taylor LG et al. Antiemetic use among pregnant women in the United States: the escalating use of ondansetron. Pharmacoepidemiol Drug Saf. 2017 May;26(5):592-6.
2. Anderka M et al. Medications used to treat nausea and vomiting of pregnancy and the risk of selected birth defects. Birth Defects Res A Clin Mol Teratol. 2012 Jan;94(1):22-30.
3. Danielsson B et al. Use of ondansetron during pregnancy and congenital malformations in the infant. Reprod Toxicol. 2014 Dec;50:134-7.
4. Pasternak B et al. Ondansetron in pregnancy and risk of adverse fetal outcomes. N Engl J Med. 2013 Feb 28;368(9):814-23.
Influenza vaccination of pregnant women needs surveillance
Seasonal influenza vaccine is specifically recommended for women who are or who might become pregnant in the flu season. This special population is targeted for vaccination because pregnant women are at increased risks of serious complications if infected with influenza virus. Despite this recommendation, recent evidence indicates that still fewer than 50% of women in the United States are vaccinated during pregnancy (MMWR Morb Mortal Wkly Rep. 2016 Dec 9;65[48]:1370-3).
Potential reasons for this lack of uptake are concerns about safety of the vaccine for mothers and fetuses (Vaccine. 2012 Dec 17;31[1]:213-8). This has highlighted the need for systematic safety surveillance for influenza vaccination with each subsequent seasonal formulation. To that end, season-specific studies of birth and infant outcomes since the 2009 season have been conducted; findings have been generally reassuring (Vaccine. 2016 Aug 17;34[37]:4443-9; Vaccine. 2016 Aug 17;34[37]:4450-9).
The authors found a doubling of risk for spontaneous abortion within that 28-day exposure window, but no association if the vaccination took place outside that period. This was in contrast to null findings for a similar analysis that the same group had conducted for vaccination in the 2005-2006 and 2006-2007 seasons. Of further interest, the authors noted even higher risks among women who had also been vaccinated for influenza in the previous season (adjusted odds ratio, 7.7; 95% confidence interval, 2.2-27.3). The highest odds ratios were among women who had been vaccinated in the 2010-2011 season and had also been vaccinated with monovalent pandemic H1N1 vaccine in the 2009-2010 season (aOR, 32.5; 95% CI, 2.9-359.0).
The VSD findings raise interesting questions about the biologic plausibility of strain-specific risks for spontaneous abortion, and risks of receiving a second vaccine containing the same strain in a subsequent season. However, this study should be interpreted with caution. With respect to the overall finding of a doubling of risk for spontaneous abortion, this is inconsistent with previous studies. A systematic review of 19 observational studies, 14 of which included exposure to the 2009 monovalent pandemic H1N1 strain, noted hazard ratios or odds ratios for spontaneous abortion ranging from 0.45 to 1.23 and 95% confidence intervals that crossed or were below the null (Vaccine. 2015 Apr 27;33[18]:2108-17). More recently, the Vaccines and Medications in Pregnancy Surveillance System investigators evaluated spontaneous abortion in pregnancies exposed to influenza vaccine over four seasons from 2010 to 2014 and found an overall hazard ratio of 1.09 (95% CI, 0.49-2.40).
However, there are a number of limitations that must be considered. Many previous studies, including the VSD analysis, could have had misclassification of exposure, especially in recent years when vaccines are often received in nontraditional settings. The VSD study findings could have been influenced by unmeasured confounding. For example, there could be differential vaccine uptake in women with comorbidities that are also associated with spontaneous abortion, such as subfertility and psychiatric disorders.
In summary, at present the data viewed as a whole do not support a change to the current recommendation that pregnant women be vaccinated for influenza regardless of trimester. However, these data do call for continued surveillance for the safety of each seasonal formulation of influenza vaccine, and for further exploration of the association between repeat vaccination and spontaneous abortion in other datasets.
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 also director of MotherToBaby California, a past president of the Organization of Teratology Information Specialists, and past president of the Teratology Society. She has no direct conflicts of interest to disclose, but has received grant funding to study influenza vaccine from the Biomedical Advanced Research and Development Authority (BARDA) in the Department of Health and Human Services, and from Seqirus Corporation.
Seasonal influenza vaccine is specifically recommended for women who are or who might become pregnant in the flu season. This special population is targeted for vaccination because pregnant women are at increased risks of serious complications if infected with influenza virus. Despite this recommendation, recent evidence indicates that still fewer than 50% of women in the United States are vaccinated during pregnancy (MMWR Morb Mortal Wkly Rep. 2016 Dec 9;65[48]:1370-3).
Potential reasons for this lack of uptake are concerns about safety of the vaccine for mothers and fetuses (Vaccine. 2012 Dec 17;31[1]:213-8). This has highlighted the need for systematic safety surveillance for influenza vaccination with each subsequent seasonal formulation. To that end, season-specific studies of birth and infant outcomes since the 2009 season have been conducted; findings have been generally reassuring (Vaccine. 2016 Aug 17;34[37]:4443-9; Vaccine. 2016 Aug 17;34[37]:4450-9).
The authors found a doubling of risk for spontaneous abortion within that 28-day exposure window, but no association if the vaccination took place outside that period. This was in contrast to null findings for a similar analysis that the same group had conducted for vaccination in the 2005-2006 and 2006-2007 seasons. Of further interest, the authors noted even higher risks among women who had also been vaccinated for influenza in the previous season (adjusted odds ratio, 7.7; 95% confidence interval, 2.2-27.3). The highest odds ratios were among women who had been vaccinated in the 2010-2011 season and had also been vaccinated with monovalent pandemic H1N1 vaccine in the 2009-2010 season (aOR, 32.5; 95% CI, 2.9-359.0).
The VSD findings raise interesting questions about the biologic plausibility of strain-specific risks for spontaneous abortion, and risks of receiving a second vaccine containing the same strain in a subsequent season. However, this study should be interpreted with caution. With respect to the overall finding of a doubling of risk for spontaneous abortion, this is inconsistent with previous studies. A systematic review of 19 observational studies, 14 of which included exposure to the 2009 monovalent pandemic H1N1 strain, noted hazard ratios or odds ratios for spontaneous abortion ranging from 0.45 to 1.23 and 95% confidence intervals that crossed or were below the null (Vaccine. 2015 Apr 27;33[18]:2108-17). More recently, the Vaccines and Medications in Pregnancy Surveillance System investigators evaluated spontaneous abortion in pregnancies exposed to influenza vaccine over four seasons from 2010 to 2014 and found an overall hazard ratio of 1.09 (95% CI, 0.49-2.40).
However, there are a number of limitations that must be considered. Many previous studies, including the VSD analysis, could have had misclassification of exposure, especially in recent years when vaccines are often received in nontraditional settings. The VSD study findings could have been influenced by unmeasured confounding. For example, there could be differential vaccine uptake in women with comorbidities that are also associated with spontaneous abortion, such as subfertility and psychiatric disorders.
In summary, at present the data viewed as a whole do not support a change to the current recommendation that pregnant women be vaccinated for influenza regardless of trimester. However, these data do call for continued surveillance for the safety of each seasonal formulation of influenza vaccine, and for further exploration of the association between repeat vaccination and spontaneous abortion in other datasets.
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 also director of MotherToBaby California, a past president of the Organization of Teratology Information Specialists, and past president of the Teratology Society. She has no direct conflicts of interest to disclose, but has received grant funding to study influenza vaccine from the Biomedical Advanced Research and Development Authority (BARDA) in the Department of Health and Human Services, and from Seqirus Corporation.
Seasonal influenza vaccine is specifically recommended for women who are or who might become pregnant in the flu season. This special population is targeted for vaccination because pregnant women are at increased risks of serious complications if infected with influenza virus. Despite this recommendation, recent evidence indicates that still fewer than 50% of women in the United States are vaccinated during pregnancy (MMWR Morb Mortal Wkly Rep. 2016 Dec 9;65[48]:1370-3).
Potential reasons for this lack of uptake are concerns about safety of the vaccine for mothers and fetuses (Vaccine. 2012 Dec 17;31[1]:213-8). This has highlighted the need for systematic safety surveillance for influenza vaccination with each subsequent seasonal formulation. To that end, season-specific studies of birth and infant outcomes since the 2009 season have been conducted; findings have been generally reassuring (Vaccine. 2016 Aug 17;34[37]:4443-9; Vaccine. 2016 Aug 17;34[37]:4450-9).
The authors found a doubling of risk for spontaneous abortion within that 28-day exposure window, but no association if the vaccination took place outside that period. This was in contrast to null findings for a similar analysis that the same group had conducted for vaccination in the 2005-2006 and 2006-2007 seasons. Of further interest, the authors noted even higher risks among women who had also been vaccinated for influenza in the previous season (adjusted odds ratio, 7.7; 95% confidence interval, 2.2-27.3). The highest odds ratios were among women who had been vaccinated in the 2010-2011 season and had also been vaccinated with monovalent pandemic H1N1 vaccine in the 2009-2010 season (aOR, 32.5; 95% CI, 2.9-359.0).
The VSD findings raise interesting questions about the biologic plausibility of strain-specific risks for spontaneous abortion, and risks of receiving a second vaccine containing the same strain in a subsequent season. However, this study should be interpreted with caution. With respect to the overall finding of a doubling of risk for spontaneous abortion, this is inconsistent with previous studies. A systematic review of 19 observational studies, 14 of which included exposure to the 2009 monovalent pandemic H1N1 strain, noted hazard ratios or odds ratios for spontaneous abortion ranging from 0.45 to 1.23 and 95% confidence intervals that crossed or were below the null (Vaccine. 2015 Apr 27;33[18]:2108-17). More recently, the Vaccines and Medications in Pregnancy Surveillance System investigators evaluated spontaneous abortion in pregnancies exposed to influenza vaccine over four seasons from 2010 to 2014 and found an overall hazard ratio of 1.09 (95% CI, 0.49-2.40).
However, there are a number of limitations that must be considered. Many previous studies, including the VSD analysis, could have had misclassification of exposure, especially in recent years when vaccines are often received in nontraditional settings. The VSD study findings could have been influenced by unmeasured confounding. For example, there could be differential vaccine uptake in women with comorbidities that are also associated with spontaneous abortion, such as subfertility and psychiatric disorders.
In summary, at present the data viewed as a whole do not support a change to the current recommendation that pregnant women be vaccinated for influenza regardless of trimester. However, these data do call for continued surveillance for the safety of each seasonal formulation of influenza vaccine, and for further exploration of the association between repeat vaccination and spontaneous abortion in other datasets.
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 also director of MotherToBaby California, a past president of the Organization of Teratology Information Specialists, and past president of the Teratology Society. She has no direct conflicts of interest to disclose, but has received grant funding to study influenza vaccine from the Biomedical Advanced Research and Development Authority (BARDA) in the Department of Health and Human Services, and from Seqirus Corporation.
Opioid antagonists in pregnancy: Naltrexone or not?
With the increasing concern about rising rates of opioid abuse in the general population, including women of reproductive age and pregnant and breastfeeding women, clear guidelines regarding treatment in pregnancy and lactation are needed.
The Committee on Obstetric Practice of the American College of Obstetricians and Gynecologists and the American Society of Addiction Medicine addressed this issue comprehensively in the ACOG Committee Opinion issued in August 2017.1 In this document, universal screening and medication-assisted treatment for opioid use disorder were recommended. Opioid agonists including methadone and buprenorphine were considered the treatments with the most evidence of benefit, and limited concern about adverse fetal effects, other than predictable and treatable neonatal abstinence syndrome.
Two types of scenarios make this topic relevant. In the first, a woman who has been successful in avoiding relapse by naltrexone treatment, although advised not to become pregnant, could inadvertently conceive. She would then be at risk of relapse if treatment were discontinued. In the second, a woman who overdoses with an opioid in pregnancy might require rapid detoxification with naltrexone in order to survive. In either case, there are quite limited data on potential fetal consequences.
In a 2001 report, Hulse et al. described a series of fetal outcomes following prenatal naltrexone exposure. In one set of cases accumulated from three countries, rapid opiate detoxification with naltrexone was performed for 18 pregnant women. One woman received two detoxification treatments. Two treatments occurred in the first trimester, 11 in the second, and 6 in the third. Maternal and fetal outcomes were said to be unremarkable, except for two cases of low birth weight infants (less than 2,500 g). In another set of cases, seven opioid-dependent women in Australia who had been maintained on 50 mg naltrexone per day became pregnant. In six of the seven cases, naltrexone was discontinued at 7 weeks’ gestation because of the unknown risks of teratogenicity. Of these, three restarted naltrexone maintenance therapy in the second trimester. One mother continued naltrexone throughout pregnancy. One of the seven women delivered at 36 weeks by induction for high blood pressure, and the infant was less than 2,500 g. One other term infant was small at 2,625 g. Otherwise, outcomes were considered normal.3
In two subsequent reports by some of the same authors, pregnancy outcomes in 9 and 17 heroin users with naltrexone implants were unremarkable and comparable to those of women on methadone maintenance therapy.4,5
While the very limited data on naltrexone safety in pregnancy have not suggested substantial increased risks, the numbers are too small to provide strong reassurance, and the animal data remain concerning. Long-term behavioral outcome studies are also lacking. More research in this area is needed to weigh the safety of naltrexone for the fetus against the risk of relapse with discontinuation of this drug.
Dr. Chambers is a professor of pediatrics and director of clinical research at Rady Children’s Hospital and associate director of the Clinical and Translational Research Institute at the University of California, San Diego. She is also director of MotherToBaby California, a past president of the Organization of Teratology Information Specialists, and past president of the Teratology Society. She has no relevant financial disclosures.
References
1. Obstet Gynecol. 2017 Aug;130(2):e81-e94.
2. Curr Neuropharmacol. 2008 Jun;6(2):125–50.
3. Aust N Z J Obstet Gynaecol. 2001 Nov;41(4):424-8.
4. Aust N Z J Obstet Gynaecol. 2002 Feb;42(1):104-5.
5. Int J Gynaecol Obstet. 2004 May;85(2):170-1.
6. Drugs. 2017 Jul;77(11):1211-9.
With the increasing concern about rising rates of opioid abuse in the general population, including women of reproductive age and pregnant and breastfeeding women, clear guidelines regarding treatment in pregnancy and lactation are needed.
The Committee on Obstetric Practice of the American College of Obstetricians and Gynecologists and the American Society of Addiction Medicine addressed this issue comprehensively in the ACOG Committee Opinion issued in August 2017.1 In this document, universal screening and medication-assisted treatment for opioid use disorder were recommended. Opioid agonists including methadone and buprenorphine were considered the treatments with the most evidence of benefit, and limited concern about adverse fetal effects, other than predictable and treatable neonatal abstinence syndrome.
Two types of scenarios make this topic relevant. In the first, a woman who has been successful in avoiding relapse by naltrexone treatment, although advised not to become pregnant, could inadvertently conceive. She would then be at risk of relapse if treatment were discontinued. In the second, a woman who overdoses with an opioid in pregnancy might require rapid detoxification with naltrexone in order to survive. In either case, there are quite limited data on potential fetal consequences.
In a 2001 report, Hulse et al. described a series of fetal outcomes following prenatal naltrexone exposure. In one set of cases accumulated from three countries, rapid opiate detoxification with naltrexone was performed for 18 pregnant women. One woman received two detoxification treatments. Two treatments occurred in the first trimester, 11 in the second, and 6 in the third. Maternal and fetal outcomes were said to be unremarkable, except for two cases of low birth weight infants (less than 2,500 g). In another set of cases, seven opioid-dependent women in Australia who had been maintained on 50 mg naltrexone per day became pregnant. In six of the seven cases, naltrexone was discontinued at 7 weeks’ gestation because of the unknown risks of teratogenicity. Of these, three restarted naltrexone maintenance therapy in the second trimester. One mother continued naltrexone throughout pregnancy. One of the seven women delivered at 36 weeks by induction for high blood pressure, and the infant was less than 2,500 g. One other term infant was small at 2,625 g. Otherwise, outcomes were considered normal.3
In two subsequent reports by some of the same authors, pregnancy outcomes in 9 and 17 heroin users with naltrexone implants were unremarkable and comparable to those of women on methadone maintenance therapy.4,5
While the very limited data on naltrexone safety in pregnancy have not suggested substantial increased risks, the numbers are too small to provide strong reassurance, and the animal data remain concerning. Long-term behavioral outcome studies are also lacking. More research in this area is needed to weigh the safety of naltrexone for the fetus against the risk of relapse with discontinuation of this drug.
Dr. Chambers is a professor of pediatrics and director of clinical research at Rady Children’s Hospital and associate director of the Clinical and Translational Research Institute at the University of California, San Diego. She is also director of MotherToBaby California, a past president of the Organization of Teratology Information Specialists, and past president of the Teratology Society. She has no relevant financial disclosures.
References
1. Obstet Gynecol. 2017 Aug;130(2):e81-e94.
2. Curr Neuropharmacol. 2008 Jun;6(2):125–50.
3. Aust N Z J Obstet Gynaecol. 2001 Nov;41(4):424-8.
4. Aust N Z J Obstet Gynaecol. 2002 Feb;42(1):104-5.
5. Int J Gynaecol Obstet. 2004 May;85(2):170-1.
6. Drugs. 2017 Jul;77(11):1211-9.
With the increasing concern about rising rates of opioid abuse in the general population, including women of reproductive age and pregnant and breastfeeding women, clear guidelines regarding treatment in pregnancy and lactation are needed.
The Committee on Obstetric Practice of the American College of Obstetricians and Gynecologists and the American Society of Addiction Medicine addressed this issue comprehensively in the ACOG Committee Opinion issued in August 2017.1 In this document, universal screening and medication-assisted treatment for opioid use disorder were recommended. Opioid agonists including methadone and buprenorphine were considered the treatments with the most evidence of benefit, and limited concern about adverse fetal effects, other than predictable and treatable neonatal abstinence syndrome.
Two types of scenarios make this topic relevant. In the first, a woman who has been successful in avoiding relapse by naltrexone treatment, although advised not to become pregnant, could inadvertently conceive. She would then be at risk of relapse if treatment were discontinued. In the second, a woman who overdoses with an opioid in pregnancy might require rapid detoxification with naltrexone in order to survive. In either case, there are quite limited data on potential fetal consequences.
In a 2001 report, Hulse et al. described a series of fetal outcomes following prenatal naltrexone exposure. In one set of cases accumulated from three countries, rapid opiate detoxification with naltrexone was performed for 18 pregnant women. One woman received two detoxification treatments. Two treatments occurred in the first trimester, 11 in the second, and 6 in the third. Maternal and fetal outcomes were said to be unremarkable, except for two cases of low birth weight infants (less than 2,500 g). In another set of cases, seven opioid-dependent women in Australia who had been maintained on 50 mg naltrexone per day became pregnant. In six of the seven cases, naltrexone was discontinued at 7 weeks’ gestation because of the unknown risks of teratogenicity. Of these, three restarted naltrexone maintenance therapy in the second trimester. One mother continued naltrexone throughout pregnancy. One of the seven women delivered at 36 weeks by induction for high blood pressure, and the infant was less than 2,500 g. One other term infant was small at 2,625 g. Otherwise, outcomes were considered normal.3
In two subsequent reports by some of the same authors, pregnancy outcomes in 9 and 17 heroin users with naltrexone implants were unremarkable and comparable to those of women on methadone maintenance therapy.4,5
While the very limited data on naltrexone safety in pregnancy have not suggested substantial increased risks, the numbers are too small to provide strong reassurance, and the animal data remain concerning. Long-term behavioral outcome studies are also lacking. More research in this area is needed to weigh the safety of naltrexone for the fetus against the risk of relapse with discontinuation of this drug.
Dr. Chambers is a professor of pediatrics and director of clinical research at Rady Children’s Hospital and associate director of the Clinical and Translational Research Institute at the University of California, San Diego. She is also director of MotherToBaby California, a past president of the Organization of Teratology Information Specialists, and past president of the Teratology Society. She has no relevant financial disclosures.
References
1. Obstet Gynecol. 2017 Aug;130(2):e81-e94.
2. Curr Neuropharmacol. 2008 Jun;6(2):125–50.
3. Aust N Z J Obstet Gynaecol. 2001 Nov;41(4):424-8.
4. Aust N Z J Obstet Gynaecol. 2002 Feb;42(1):104-5.
5. Int J Gynaecol Obstet. 2004 May;85(2):170-1.
6. Drugs. 2017 Jul;77(11):1211-9.
Safety of corticosteroids in pregnancy: Is it the drug or the disease?
Corticosteroids such as prednisone are relatively frequently administered in pregnancy for their immunosuppressive and anti-inflammatory effects. Treatment may be initiated on a short-term basis for acute conditions. Alternatively, treatment may be more or less ongoing for severe chronic diseases such as asthma or a variety of other autoimmune conditions when disease symptoms do not remit in pregnancy. However, the safety of corticosteroid use with respect to risk of specific birth defects, preterm delivery, and low birth weight has been the subject of debate over some time.
Concerns about the teratogenicity of corticosteroids were raised as early as the 1950s, based on animal studies suggesting an increased risk for oral clefts. The association between corticosteroids and oral clefts has also been observed in some human epidemiologic studies. However, results of these studies have been inconsistent.
Similar to the NBDPS findings, in a large Danish cohort study covering 832,636 live births from 1996 to 2008, exposure to any corticosteroids during the first trimester was not associated with an increased risk for cleft lip or cleft palate. Only those exposed to topical corticosteroids had a higher risk of cleft lip with or without cleft palate (odds ratio, 1.45; 95% CI, 1.03-2.05).3 Another, smaller Danish study covered primiparous births from 1999 to 2009 (n = 83,043). The unadjusted odds of oral clefts following exposure to any corticosteroids (inhaled or oral) in the first trimester was null (OR, 0.4; 95% CI, 0.1-2.8).4
Inconsistencies across these studies, as speculated by authors of the NBDPS analysis, may result from a lack of information on the dose of drug used by the mother, the indication for its use, or any measure of the severity of the underlying maternal disease for which the corticosteroids were prescribed. It is possible that maternal disease or disease activity in and of itself is a direct cause of oral clefts or that corticosteroids are linked to increased risk for clefts through co-occurring other exposures such as smoking, alcohol, or obesity. However, these questions have yet to be answered.
With respect to other birth outcomes, a few disease-specific studies have examined birth weight or intrauterine growth restriction following corticosteroid use. In general, study findings have been reassuring. Among Danish women with Crohn’s disease, corticosteroids were not associated with reduced birth weight after adjusting for gestational age and disease activity (adjusted risk ratio, 1.1; 95% CI, 0.2-5.7).5 In another study of pregnant women with rheumatoid arthritis, birth weight was not associated with prednisone use after adjustment for gestational age at delivery and sex of the newborn.6 In a third cohort study of pregnant women with systemic lupus erythematosus, there was no a significant elevation in odds of intrauterine growth restriction following prednisone use.7
Several disease-specific studies have also examined corticosteroid use and risk of preterm birth. From the Danish cohort of pregnant women with Crohn’s disease, the researchers reported no association between prednisolone and preterm birth after adjustment for covariates. In contrast, in a separate Danish cohort of pregnant women with irritable bowel disease, there was an increased risk of preterm delivery following systemic corticosteroid use, compared with women without disease (adjusted hazard ratio, 6.3; 95% CI, 3.1-12.7).8 However, data were not available to address underlying disease severity as a possible contributing factor. Of note, among women with irritable bowel disease who did not use medication in pregnancy, there was a 50% increase in the risk of preterm birth, compared with women without disease (aHR, 1.5; 95% CI, 1.0-2.4). This suggests that the disease itself contributed to the increased risk of preterm birth.
Currently available data regarding corticosteroid use and adverse birth outcomes are generally reassuring. Recent estimates for oral clefts suggest a low elevation in risk, if any at all. This translates to a very low absolute risk for clefts, which occur in the general population in approximately 1 in 1,000 births. The clinical benefit of adequate treatment in the first trimester for inflammatory or immune-mediated diseases may far outweigh any small and tenuous risks for oral clefts.
With respect to reduced birth weight and preterm delivery, available evidence suggests either no association or that maternal disease and disease severity are driving any increased risks noted for these outcomes. Future studies of pregnancy safety for medications used to treat maternal diseases that themselves are potentially linked to adverse outcomes must incorporate appropriate measures of disease type and disease severity in the study designs.
Dr. Chambers is a professor of pediatrics and director of clinical research at Rady Children’s Hospital and associate director of the Clinical and Translational Research Institute at the University of California, San Diego. She is also director of MotherToBaby California, a past president of the Organization of Teratology Information Specialists, and past president of the Teratology Society. She has no relevant financial disclosures. To comment, e-mail her at obnews@frontlinemedcom.com.
References
1. Teratology. 2000 Dec;62(6):385-92.
2. Birth Defects Res A Clin Mol Teratol. 2014 Jun;100(6):499-506.
3. CMAJ. 2011 Apr 19;183(7):796-804.
4. Am J Ther. 2014 Mar-Apr;21(2):73-80.
5. Am J Gastroenterol. 2007 Jul;102(7):1406-13.
6. Arthritis Rheum. 2009 Nov;60(11):3196-206.
7. Lupus. 2010 Dec;19(14):1665-73.
8. PLoS One. 2015 Jun 17;10(6):e0129567.
Corticosteroids such as prednisone are relatively frequently administered in pregnancy for their immunosuppressive and anti-inflammatory effects. Treatment may be initiated on a short-term basis for acute conditions. Alternatively, treatment may be more or less ongoing for severe chronic diseases such as asthma or a variety of other autoimmune conditions when disease symptoms do not remit in pregnancy. However, the safety of corticosteroid use with respect to risk of specific birth defects, preterm delivery, and low birth weight has been the subject of debate over some time.
Concerns about the teratogenicity of corticosteroids were raised as early as the 1950s, based on animal studies suggesting an increased risk for oral clefts. The association between corticosteroids and oral clefts has also been observed in some human epidemiologic studies. However, results of these studies have been inconsistent.
Similar to the NBDPS findings, in a large Danish cohort study covering 832,636 live births from 1996 to 2008, exposure to any corticosteroids during the first trimester was not associated with an increased risk for cleft lip or cleft palate. Only those exposed to topical corticosteroids had a higher risk of cleft lip with or without cleft palate (odds ratio, 1.45; 95% CI, 1.03-2.05).3 Another, smaller Danish study covered primiparous births from 1999 to 2009 (n = 83,043). The unadjusted odds of oral clefts following exposure to any corticosteroids (inhaled or oral) in the first trimester was null (OR, 0.4; 95% CI, 0.1-2.8).4
Inconsistencies across these studies, as speculated by authors of the NBDPS analysis, may result from a lack of information on the dose of drug used by the mother, the indication for its use, or any measure of the severity of the underlying maternal disease for which the corticosteroids were prescribed. It is possible that maternal disease or disease activity in and of itself is a direct cause of oral clefts or that corticosteroids are linked to increased risk for clefts through co-occurring other exposures such as smoking, alcohol, or obesity. However, these questions have yet to be answered.
With respect to other birth outcomes, a few disease-specific studies have examined birth weight or intrauterine growth restriction following corticosteroid use. In general, study findings have been reassuring. Among Danish women with Crohn’s disease, corticosteroids were not associated with reduced birth weight after adjusting for gestational age and disease activity (adjusted risk ratio, 1.1; 95% CI, 0.2-5.7).5 In another study of pregnant women with rheumatoid arthritis, birth weight was not associated with prednisone use after adjustment for gestational age at delivery and sex of the newborn.6 In a third cohort study of pregnant women with systemic lupus erythematosus, there was no a significant elevation in odds of intrauterine growth restriction following prednisone use.7
Several disease-specific studies have also examined corticosteroid use and risk of preterm birth. From the Danish cohort of pregnant women with Crohn’s disease, the researchers reported no association between prednisolone and preterm birth after adjustment for covariates. In contrast, in a separate Danish cohort of pregnant women with irritable bowel disease, there was an increased risk of preterm delivery following systemic corticosteroid use, compared with women without disease (adjusted hazard ratio, 6.3; 95% CI, 3.1-12.7).8 However, data were not available to address underlying disease severity as a possible contributing factor. Of note, among women with irritable bowel disease who did not use medication in pregnancy, there was a 50% increase in the risk of preterm birth, compared with women without disease (aHR, 1.5; 95% CI, 1.0-2.4). This suggests that the disease itself contributed to the increased risk of preterm birth.
Currently available data regarding corticosteroid use and adverse birth outcomes are generally reassuring. Recent estimates for oral clefts suggest a low elevation in risk, if any at all. This translates to a very low absolute risk for clefts, which occur in the general population in approximately 1 in 1,000 births. The clinical benefit of adequate treatment in the first trimester for inflammatory or immune-mediated diseases may far outweigh any small and tenuous risks for oral clefts.
With respect to reduced birth weight and preterm delivery, available evidence suggests either no association or that maternal disease and disease severity are driving any increased risks noted for these outcomes. Future studies of pregnancy safety for medications used to treat maternal diseases that themselves are potentially linked to adverse outcomes must incorporate appropriate measures of disease type and disease severity in the study designs.
Dr. Chambers is a professor of pediatrics and director of clinical research at Rady Children’s Hospital and associate director of the Clinical and Translational Research Institute at the University of California, San Diego. She is also director of MotherToBaby California, a past president of the Organization of Teratology Information Specialists, and past president of the Teratology Society. She has no relevant financial disclosures. To comment, e-mail her at obnews@frontlinemedcom.com.
References
1. Teratology. 2000 Dec;62(6):385-92.
2. Birth Defects Res A Clin Mol Teratol. 2014 Jun;100(6):499-506.
3. CMAJ. 2011 Apr 19;183(7):796-804.
4. Am J Ther. 2014 Mar-Apr;21(2):73-80.
5. Am J Gastroenterol. 2007 Jul;102(7):1406-13.
6. Arthritis Rheum. 2009 Nov;60(11):3196-206.
7. Lupus. 2010 Dec;19(14):1665-73.
8. PLoS One. 2015 Jun 17;10(6):e0129567.
Corticosteroids such as prednisone are relatively frequently administered in pregnancy for their immunosuppressive and anti-inflammatory effects. Treatment may be initiated on a short-term basis for acute conditions. Alternatively, treatment may be more or less ongoing for severe chronic diseases such as asthma or a variety of other autoimmune conditions when disease symptoms do not remit in pregnancy. However, the safety of corticosteroid use with respect to risk of specific birth defects, preterm delivery, and low birth weight has been the subject of debate over some time.
Concerns about the teratogenicity of corticosteroids were raised as early as the 1950s, based on animal studies suggesting an increased risk for oral clefts. The association between corticosteroids and oral clefts has also been observed in some human epidemiologic studies. However, results of these studies have been inconsistent.
Similar to the NBDPS findings, in a large Danish cohort study covering 832,636 live births from 1996 to 2008, exposure to any corticosteroids during the first trimester was not associated with an increased risk for cleft lip or cleft palate. Only those exposed to topical corticosteroids had a higher risk of cleft lip with or without cleft palate (odds ratio, 1.45; 95% CI, 1.03-2.05).3 Another, smaller Danish study covered primiparous births from 1999 to 2009 (n = 83,043). The unadjusted odds of oral clefts following exposure to any corticosteroids (inhaled or oral) in the first trimester was null (OR, 0.4; 95% CI, 0.1-2.8).4
Inconsistencies across these studies, as speculated by authors of the NBDPS analysis, may result from a lack of information on the dose of drug used by the mother, the indication for its use, or any measure of the severity of the underlying maternal disease for which the corticosteroids were prescribed. It is possible that maternal disease or disease activity in and of itself is a direct cause of oral clefts or that corticosteroids are linked to increased risk for clefts through co-occurring other exposures such as smoking, alcohol, or obesity. However, these questions have yet to be answered.
With respect to other birth outcomes, a few disease-specific studies have examined birth weight or intrauterine growth restriction following corticosteroid use. In general, study findings have been reassuring. Among Danish women with Crohn’s disease, corticosteroids were not associated with reduced birth weight after adjusting for gestational age and disease activity (adjusted risk ratio, 1.1; 95% CI, 0.2-5.7).5 In another study of pregnant women with rheumatoid arthritis, birth weight was not associated with prednisone use after adjustment for gestational age at delivery and sex of the newborn.6 In a third cohort study of pregnant women with systemic lupus erythematosus, there was no a significant elevation in odds of intrauterine growth restriction following prednisone use.7
Several disease-specific studies have also examined corticosteroid use and risk of preterm birth. From the Danish cohort of pregnant women with Crohn’s disease, the researchers reported no association between prednisolone and preterm birth after adjustment for covariates. In contrast, in a separate Danish cohort of pregnant women with irritable bowel disease, there was an increased risk of preterm delivery following systemic corticosteroid use, compared with women without disease (adjusted hazard ratio, 6.3; 95% CI, 3.1-12.7).8 However, data were not available to address underlying disease severity as a possible contributing factor. Of note, among women with irritable bowel disease who did not use medication in pregnancy, there was a 50% increase in the risk of preterm birth, compared with women without disease (aHR, 1.5; 95% CI, 1.0-2.4). This suggests that the disease itself contributed to the increased risk of preterm birth.
Currently available data regarding corticosteroid use and adverse birth outcomes are generally reassuring. Recent estimates for oral clefts suggest a low elevation in risk, if any at all. This translates to a very low absolute risk for clefts, which occur in the general population in approximately 1 in 1,000 births. The clinical benefit of adequate treatment in the first trimester for inflammatory or immune-mediated diseases may far outweigh any small and tenuous risks for oral clefts.
With respect to reduced birth weight and preterm delivery, available evidence suggests either no association or that maternal disease and disease severity are driving any increased risks noted for these outcomes. Future studies of pregnancy safety for medications used to treat maternal diseases that themselves are potentially linked to adverse outcomes must incorporate appropriate measures of disease type and disease severity in the study designs.
Dr. Chambers is a professor of pediatrics and director of clinical research at Rady Children’s Hospital and associate director of the Clinical and Translational Research Institute at the University of California, San Diego. She is also director of MotherToBaby California, a past president of the Organization of Teratology Information Specialists, and past president of the Teratology Society. She has no relevant financial disclosures. To comment, e-mail her at obnews@frontlinemedcom.com.
References
1. Teratology. 2000 Dec;62(6):385-92.
2. Birth Defects Res A Clin Mol Teratol. 2014 Jun;100(6):499-506.
3. CMAJ. 2011 Apr 19;183(7):796-804.
4. Am J Ther. 2014 Mar-Apr;21(2):73-80.
5. Am J Gastroenterol. 2007 Jul;102(7):1406-13.
6. Arthritis Rheum. 2009 Nov;60(11):3196-206.
7. Lupus. 2010 Dec;19(14):1665-73.
8. PLoS One. 2015 Jun 17;10(6):e0129567.
Acetaminophen use in pregnancy: What is the evidence?
Among pregnant women, acetaminophen is the most commonly used pain reliever, and likely the most commonly used of any medication. Estimates suggest that anywhere from 40% to greater than 65% of pregnant women use an acetaminophen-containing product at some time in pregnancy. Recently, concerns have been raised in several studies about potential increased risks for a variety of neurobehavioral outcomes including attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorders (ASD), cognitive deficits, and other behavior problems.
A 2013 study conducted in the Norwegian Mother and Child Cohort Study (pregnant women enrolled 1999-2008) evaluated 2,919 same-sex siblings at 3 years of age whose mothers were enrolled in the cohort during pregnancy. Prenatal exposure to acetaminophen was collected from maternal interview data during and shortly after pregnancy. Behavioral performance in the children was measured using validated maternal questionnaires. After adjustment for maternal febrile illness, infection, and comorbidities, use of acetaminophen for 28 days or more in pregnancy was associated with poorer gross motor and communication performance, more externalizing and internalizing behaviors, and higher activity levels in the offspring. Exposure for less than 28 days was associated with poor gross motor skills only. There were no associations found between ibuprofen use in pregnancy and any of the neurobehavioral outcomes.1
Four additional studies on this topic were published in 2016. One study from the Avon Longitudinal Study of Parents and Children followed 7,796 pregnant women enrolled in Bristol, England, in 1991-1992. This study’s findings were similar to the Danish cohort, with increased risks for conduct problems and hyperactivity symptoms as assessed in the Strengths and Difficulties Questionnaire at 7 years of age. In contrast, there was no association found with postnatal maternal acetaminophen use or paternal use.3
Two additional studies published in 2016 were from the Danish cohort described above. The first assessed long term follow-up for an average of 12.7 years linked to incidence of ASD or infantile autism in the Danish Psychiatric and Hospital Registries. An increased risk for ASD was found only when the diagnosis was accompanied by hyperkinetic symptoms (RR,1.51; 95% CI, 1.19-1.92), and this risk was most pronounced when acetaminophen was used in the last half of pregnancy.5
The second study examined a smaller subset of 1,491 children who were tested at 5 years of age by trained psychologists using the Wechsler Preschool and Primary Scale of Intelligence – a measure of IQ. Maternal fever and acetaminophen use in pregnancy were associated with small but significant deficits. For example, children of mothers who used acetaminophen but reported no fever had on average a 3.4 point deficit in performance IQ, compared with children of mothers who reported neither. However, mothers who reported both acetaminophen use and fever showed no differences.6
The authors of the studies described above, as well as other experts in the field, have discussed the biological plausibility of such associations being causal. The endocrine disruptive effects of acetaminophen and/or an impact on oxidative stress have been suggested as possible mechanisms, although no convincing data have supported these theories to date. Several of the studies have been criticized for reliance on maternal report of the outcomes, and all studies relied on maternal report of the exposure, which raises possibilities for bias and misclassification. However, some studies included assessments by trained psychologists or linkage to diagnoses recorded in national health registries. Control for confounding is always problematic in observational studies, especially with long-term outcomes. The sibling-pair study conducted in Norway attempted to control for genetic and environmental confounding using this design. Confounding by indication is also a concern. Adjustment for maternal fever, infections, or other comorbidities may have addressed some of this concern; however, as with acetaminophen, vague and perhaps inaccurate maternal report of these events may be problematic. Findings for another pain reliever, ibuprofen, showed no association in one study, which provides some reassurance.
At the present time, the impacts on behavior including hyperactivity and perhaps ASD are most prominent in the published reports stemming from four countries with large cohort studies. There is conflicting evidence of any impact on cognitive performance. All associations reported are quite modest with relative risks in the 1.5 or lower range. Nevertheless, acetaminophen is a medication taken by most women in pregnancy, so the broad impact, if these associations are causal, is not trivial. Clinically, an urgent concern would be that women or clinicians might ignore the current advice to take acetaminophen to reduce maternal fever. In that regard, it is reassuring that the Danish Cohort study found no impact on IQ when acetaminophen was used to treat a fever, while fever itself was associated with increased risks.
In studies which examined frequency of use, longer duration was often associated with higher risks. However, no study reported on dose. Future studies should capture dose, as well as better information on the underlying conditions being treated. The findings from these epidemiologic studies also call for additional experimental work to better understand possible mechanisms. In the meantime, as with any over-the-counter medication, judicious and appropriate use of acetaminophen should be advised.
References
1. Int J Epidemiol. 2013 Dec;42(6):1702-13.
2. JAMA Pediatr. 2014 Apr;168(4):313-20.
3. JAMA Pediatr. 2016 Oct 1;170(10):964-970.
4. Int. J. Epidemiol. 2016 June 28. doi: 10.1093/ije/dyw115.
5. Autism Res. 2016 Sep;9(9):951-8.
6. Epidemiology. 2016 Nov;27(6):912-8.
Dr. Chambers is a professor of pediatrics and director of clinical research at Rady Children’s Hospital, and associate director of the Clinical and Translational Research Institute at the University of California, San Diego. She is director of MotherToBaby California, a past president of the Organization of Teratology Information Specialists, and past president of the Teratology Society. She has no relevant financial disclosures. To comment, e-mail her at obnews@frontlinemedcom.com.
Among pregnant women, acetaminophen is the most commonly used pain reliever, and likely the most commonly used of any medication. Estimates suggest that anywhere from 40% to greater than 65% of pregnant women use an acetaminophen-containing product at some time in pregnancy. Recently, concerns have been raised in several studies about potential increased risks for a variety of neurobehavioral outcomes including attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorders (ASD), cognitive deficits, and other behavior problems.
A 2013 study conducted in the Norwegian Mother and Child Cohort Study (pregnant women enrolled 1999-2008) evaluated 2,919 same-sex siblings at 3 years of age whose mothers were enrolled in the cohort during pregnancy. Prenatal exposure to acetaminophen was collected from maternal interview data during and shortly after pregnancy. Behavioral performance in the children was measured using validated maternal questionnaires. After adjustment for maternal febrile illness, infection, and comorbidities, use of acetaminophen for 28 days or more in pregnancy was associated with poorer gross motor and communication performance, more externalizing and internalizing behaviors, and higher activity levels in the offspring. Exposure for less than 28 days was associated with poor gross motor skills only. There were no associations found between ibuprofen use in pregnancy and any of the neurobehavioral outcomes.1
Four additional studies on this topic were published in 2016. One study from the Avon Longitudinal Study of Parents and Children followed 7,796 pregnant women enrolled in Bristol, England, in 1991-1992. This study’s findings were similar to the Danish cohort, with increased risks for conduct problems and hyperactivity symptoms as assessed in the Strengths and Difficulties Questionnaire at 7 years of age. In contrast, there was no association found with postnatal maternal acetaminophen use or paternal use.3
Two additional studies published in 2016 were from the Danish cohort described above. The first assessed long term follow-up for an average of 12.7 years linked to incidence of ASD or infantile autism in the Danish Psychiatric and Hospital Registries. An increased risk for ASD was found only when the diagnosis was accompanied by hyperkinetic symptoms (RR,1.51; 95% CI, 1.19-1.92), and this risk was most pronounced when acetaminophen was used in the last half of pregnancy.5
The second study examined a smaller subset of 1,491 children who were tested at 5 years of age by trained psychologists using the Wechsler Preschool and Primary Scale of Intelligence – a measure of IQ. Maternal fever and acetaminophen use in pregnancy were associated with small but significant deficits. For example, children of mothers who used acetaminophen but reported no fever had on average a 3.4 point deficit in performance IQ, compared with children of mothers who reported neither. However, mothers who reported both acetaminophen use and fever showed no differences.6
The authors of the studies described above, as well as other experts in the field, have discussed the biological plausibility of such associations being causal. The endocrine disruptive effects of acetaminophen and/or an impact on oxidative stress have been suggested as possible mechanisms, although no convincing data have supported these theories to date. Several of the studies have been criticized for reliance on maternal report of the outcomes, and all studies relied on maternal report of the exposure, which raises possibilities for bias and misclassification. However, some studies included assessments by trained psychologists or linkage to diagnoses recorded in national health registries. Control for confounding is always problematic in observational studies, especially with long-term outcomes. The sibling-pair study conducted in Norway attempted to control for genetic and environmental confounding using this design. Confounding by indication is also a concern. Adjustment for maternal fever, infections, or other comorbidities may have addressed some of this concern; however, as with acetaminophen, vague and perhaps inaccurate maternal report of these events may be problematic. Findings for another pain reliever, ibuprofen, showed no association in one study, which provides some reassurance.
At the present time, the impacts on behavior including hyperactivity and perhaps ASD are most prominent in the published reports stemming from four countries with large cohort studies. There is conflicting evidence of any impact on cognitive performance. All associations reported are quite modest with relative risks in the 1.5 or lower range. Nevertheless, acetaminophen is a medication taken by most women in pregnancy, so the broad impact, if these associations are causal, is not trivial. Clinically, an urgent concern would be that women or clinicians might ignore the current advice to take acetaminophen to reduce maternal fever. In that regard, it is reassuring that the Danish Cohort study found no impact on IQ when acetaminophen was used to treat a fever, while fever itself was associated with increased risks.
In studies which examined frequency of use, longer duration was often associated with higher risks. However, no study reported on dose. Future studies should capture dose, as well as better information on the underlying conditions being treated. The findings from these epidemiologic studies also call for additional experimental work to better understand possible mechanisms. In the meantime, as with any over-the-counter medication, judicious and appropriate use of acetaminophen should be advised.
References
1. Int J Epidemiol. 2013 Dec;42(6):1702-13.
2. JAMA Pediatr. 2014 Apr;168(4):313-20.
3. JAMA Pediatr. 2016 Oct 1;170(10):964-970.
4. Int. J. Epidemiol. 2016 June 28. doi: 10.1093/ije/dyw115.
5. Autism Res. 2016 Sep;9(9):951-8.
6. Epidemiology. 2016 Nov;27(6):912-8.
Dr. Chambers is a professor of pediatrics and director of clinical research at Rady Children’s Hospital, and associate director of the Clinical and Translational Research Institute at the University of California, San Diego. She is director of MotherToBaby California, a past president of the Organization of Teratology Information Specialists, and past president of the Teratology Society. She has no relevant financial disclosures. To comment, e-mail her at obnews@frontlinemedcom.com.
Among pregnant women, acetaminophen is the most commonly used pain reliever, and likely the most commonly used of any medication. Estimates suggest that anywhere from 40% to greater than 65% of pregnant women use an acetaminophen-containing product at some time in pregnancy. Recently, concerns have been raised in several studies about potential increased risks for a variety of neurobehavioral outcomes including attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorders (ASD), cognitive deficits, and other behavior problems.
A 2013 study conducted in the Norwegian Mother and Child Cohort Study (pregnant women enrolled 1999-2008) evaluated 2,919 same-sex siblings at 3 years of age whose mothers were enrolled in the cohort during pregnancy. Prenatal exposure to acetaminophen was collected from maternal interview data during and shortly after pregnancy. Behavioral performance in the children was measured using validated maternal questionnaires. After adjustment for maternal febrile illness, infection, and comorbidities, use of acetaminophen for 28 days or more in pregnancy was associated with poorer gross motor and communication performance, more externalizing and internalizing behaviors, and higher activity levels in the offspring. Exposure for less than 28 days was associated with poor gross motor skills only. There were no associations found between ibuprofen use in pregnancy and any of the neurobehavioral outcomes.1
Four additional studies on this topic were published in 2016. One study from the Avon Longitudinal Study of Parents and Children followed 7,796 pregnant women enrolled in Bristol, England, in 1991-1992. This study’s findings were similar to the Danish cohort, with increased risks for conduct problems and hyperactivity symptoms as assessed in the Strengths and Difficulties Questionnaire at 7 years of age. In contrast, there was no association found with postnatal maternal acetaminophen use or paternal use.3
Two additional studies published in 2016 were from the Danish cohort described above. The first assessed long term follow-up for an average of 12.7 years linked to incidence of ASD or infantile autism in the Danish Psychiatric and Hospital Registries. An increased risk for ASD was found only when the diagnosis was accompanied by hyperkinetic symptoms (RR,1.51; 95% CI, 1.19-1.92), and this risk was most pronounced when acetaminophen was used in the last half of pregnancy.5
The second study examined a smaller subset of 1,491 children who were tested at 5 years of age by trained psychologists using the Wechsler Preschool and Primary Scale of Intelligence – a measure of IQ. Maternal fever and acetaminophen use in pregnancy were associated with small but significant deficits. For example, children of mothers who used acetaminophen but reported no fever had on average a 3.4 point deficit in performance IQ, compared with children of mothers who reported neither. However, mothers who reported both acetaminophen use and fever showed no differences.6
The authors of the studies described above, as well as other experts in the field, have discussed the biological plausibility of such associations being causal. The endocrine disruptive effects of acetaminophen and/or an impact on oxidative stress have been suggested as possible mechanisms, although no convincing data have supported these theories to date. Several of the studies have been criticized for reliance on maternal report of the outcomes, and all studies relied on maternal report of the exposure, which raises possibilities for bias and misclassification. However, some studies included assessments by trained psychologists or linkage to diagnoses recorded in national health registries. Control for confounding is always problematic in observational studies, especially with long-term outcomes. The sibling-pair study conducted in Norway attempted to control for genetic and environmental confounding using this design. Confounding by indication is also a concern. Adjustment for maternal fever, infections, or other comorbidities may have addressed some of this concern; however, as with acetaminophen, vague and perhaps inaccurate maternal report of these events may be problematic. Findings for another pain reliever, ibuprofen, showed no association in one study, which provides some reassurance.
At the present time, the impacts on behavior including hyperactivity and perhaps ASD are most prominent in the published reports stemming from four countries with large cohort studies. There is conflicting evidence of any impact on cognitive performance. All associations reported are quite modest with relative risks in the 1.5 or lower range. Nevertheless, acetaminophen is a medication taken by most women in pregnancy, so the broad impact, if these associations are causal, is not trivial. Clinically, an urgent concern would be that women or clinicians might ignore the current advice to take acetaminophen to reduce maternal fever. In that regard, it is reassuring that the Danish Cohort study found no impact on IQ when acetaminophen was used to treat a fever, while fever itself was associated with increased risks.
In studies which examined frequency of use, longer duration was often associated with higher risks. However, no study reported on dose. Future studies should capture dose, as well as better information on the underlying conditions being treated. The findings from these epidemiologic studies also call for additional experimental work to better understand possible mechanisms. In the meantime, as with any over-the-counter medication, judicious and appropriate use of acetaminophen should be advised.
References
1. Int J Epidemiol. 2013 Dec;42(6):1702-13.
2. JAMA Pediatr. 2014 Apr;168(4):313-20.
3. JAMA Pediatr. 2016 Oct 1;170(10):964-970.
4. Int. J. Epidemiol. 2016 June 28. doi: 10.1093/ije/dyw115.
5. Autism Res. 2016 Sep;9(9):951-8.
6. Epidemiology. 2016 Nov;27(6):912-8.
Dr. Chambers is a professor of pediatrics and director of clinical research at Rady Children’s Hospital, and associate director of the Clinical and Translational Research Institute at the University of California, San Diego. She is director of MotherToBaby California, a past president of the Organization of Teratology Information Specialists, and past president of the Teratology Society. She has no relevant financial disclosures. To comment, e-mail her at obnews@frontlinemedcom.com.
Approaches to smoking cessation before and during pregnancy
Data consistently support the negative impact of tobacco use in pregnancy with respect to pregnancy outcome, and the benefits of discontinuation or reduction as early as possible.
Recent analyses by investigators at the National Center on Birth Defects and Developmental Disabilities at the Centers for Disease Control and Prevention suggest that more than 6% of oral clefts, or 430 affected infants per year in the United States, could be prevented annually if women can discontinue tobacco use prior to conception (Birth Defects Res A Clin Mol Teratol. 2014 Nov;100[11]:822-5). Similarly, preconception smoking cessation could prevent the 1.4% of nonsyndromic congenital heart defects that are attributable to maternal smoking in the first trimester (J Pediatr. 2015 Apr;166[4]:978-984.e2).
With respect to the risk for adverse outcomes beyond the first trimester, recent data also show clearly that the trimester of discontinuation is related to intrauterine growth restriction in a dose-response fashion (Obstet Gynecol. 2015 Jun;125[6]:1452-9).
In a recent population-based retrospective cohort study of 927,424 singleton births 2006-2012 in Ohio, the adjusted relative risk of infant birth weight less than the 5th percentile for those women who discontinued smoking after the first trimester compared with nonsmokers was 1.25 (95% confidence interval, 1.17-1.33); for those who discontinued after the second trimester the relative risk was 1.83 (95% CI, 1.68-1.99); and for those who smoked throughout pregnancy the relative risk was 2.44 (95% CI, 2.37-2.51).
Given the compelling reasons to encourage women to stop smoking or at least to reduce harm during pregnancy, options for assistance with smoking cessation are of high interest. Beyond simple screening and advice to quit, cognitive behavioral therapy has been shown to provide some benefit. The addition of pharmacologic treatment with nicotine replacement therapy (NRT) has been studied in six randomized clinical trials (RCTs) conducted in pregnant women, four of which compared NRT plus advice/behavioral support to placebo plus advice/behavioral support, and two of which compared NRT plus advice/behavioral support to advice/behavioral support alone.
In a recent Cochrane systematic review of these studies, no statistically significant evidence of effectiveness was demonstrated for NRT versus placebo/control in a pooled sample of 1,745 pregnant patients (risk ratio, 1.33, 95% CI, 0.93-1.91). However, there was high heterogeneity in the dose of NRT and the delivery method (e.g., gum, patch) across studies, and poor adherence to the NRT treatment in all trials (Cochrane Database Syst Rev. 2012 Sep 12;9:CD010078).
With respect to safety, in the same Cochrane review there were no statistically significant differences in rates of miscarriage, stillbirth, premature birth, birth weight, low birth weight, admissions to neonatal intensive care, or neonatal death between NRT and control groups. However, small sample sizes and adherence issues across these trials hampered the interpretability of these data.
One relatively large claims database study from the United Kingdom, which was published recently, examined major congenital anomalies following prescription of NRT. The investigators found no increased risks for most major defects following NRT prescription; the only significant association was with respiratory defects (Pediatrics. 2015 May;135[5]:859-67).
The general thinking has been that for a woman who is unable to quit smoking without pharmacological assistance, NRT that delivers nicotine alone to the developing fetus may be a better option than exposure to the multiple toxins that are contained in tobacco smoke. However, there is considerable controversy over the potential adverse neurotoxic effects of nicotine itself and long-term neurodevelopmental studies on children prenatally exposed to NRT are lacking.
Other options include bupropion and varenicline, neither of which have been studied in RCTs in pregnancy. Bupropion has been evaluated in a small controlled cohort study, a claims database study (n = 1,236 first-trimester exposed), and two case-control studies. None of these studies was focused on use of bupropion exclusively for smoking cessation, but rather for the more common indication of maternal depression. The first two studies suggested no increased risks for adverse pregnancy outcomes compared to women the same underlying conditions; the case control studies suggested small increased risks for heart defects but not the same ones in both studies (Expert Opin Drug Saf. 2014 Dec;13[12]:1721-31). The limited data on varenicline are too sparse to make any inferences.
Another possible alternative that has been gaining in popularity are e-cigarettes or related vapor products, which are touted to have advantages with respect to harm reduction, primarily because of possible improved adherence due to their similarity to conventional smoking. However, there is large variability in the amount of nicotine in the vapor of various e-cigarette brands, and some have suggested that e-cigarette users engage in longer puff duration than do those who smoke conventional cigarettes. To my knowledge, there are no controlled studies of e-cigarette use in pregnancy, but the concerns previously raised regarding nicotine exposure in any form likely apply to this delivery method (Birth Defects Res A Clin Mol Teratol. 2015 Mar;103[3]:186-95).
What is the role of the obstetrician in identifying nicotine and tobacco exposure in their patients and encouraging cessation or reduction prior to and during pregnancy?
The first responsibility is to screen pregnant women. A recent survey study suggests that 40% of the responding ob.gyns. never screened pregnant patients for use of noncombustible tobacco products such as e-cigarettes (Am J Obstet Gynecol. 2014 Dec;211[6]:695.e1-7). In the United States, an analysis of the Pregnancy Risk Assessment Monitoring System data collected across several states from 2009 to 2010 suggests that about a quarter of 3,559 pregnant women who reported smoking in the 3 months before pregnancy did not receive any interventions to stop smoking (Prev Med. 2015 Sep;78:92-100). In addition, four out of five ob.gyns. surveyed in 2012 were unaware of the Affordable Care Act provision that requires states to provide tobacco cessation coverage for pregnant Medicaid beneficiaries (Prev Med Rep. 2015;2:686-88).
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 from GlaxoSmithKline and Pfizer for unrelated products.
Data consistently support the negative impact of tobacco use in pregnancy with respect to pregnancy outcome, and the benefits of discontinuation or reduction as early as possible.
Recent analyses by investigators at the National Center on Birth Defects and Developmental Disabilities at the Centers for Disease Control and Prevention suggest that more than 6% of oral clefts, or 430 affected infants per year in the United States, could be prevented annually if women can discontinue tobacco use prior to conception (Birth Defects Res A Clin Mol Teratol. 2014 Nov;100[11]:822-5). Similarly, preconception smoking cessation could prevent the 1.4% of nonsyndromic congenital heart defects that are attributable to maternal smoking in the first trimester (J Pediatr. 2015 Apr;166[4]:978-984.e2).
With respect to the risk for adverse outcomes beyond the first trimester, recent data also show clearly that the trimester of discontinuation is related to intrauterine growth restriction in a dose-response fashion (Obstet Gynecol. 2015 Jun;125[6]:1452-9).
In a recent population-based retrospective cohort study of 927,424 singleton births 2006-2012 in Ohio, the adjusted relative risk of infant birth weight less than the 5th percentile for those women who discontinued smoking after the first trimester compared with nonsmokers was 1.25 (95% confidence interval, 1.17-1.33); for those who discontinued after the second trimester the relative risk was 1.83 (95% CI, 1.68-1.99); and for those who smoked throughout pregnancy the relative risk was 2.44 (95% CI, 2.37-2.51).
Given the compelling reasons to encourage women to stop smoking or at least to reduce harm during pregnancy, options for assistance with smoking cessation are of high interest. Beyond simple screening and advice to quit, cognitive behavioral therapy has been shown to provide some benefit. The addition of pharmacologic treatment with nicotine replacement therapy (NRT) has been studied in six randomized clinical trials (RCTs) conducted in pregnant women, four of which compared NRT plus advice/behavioral support to placebo plus advice/behavioral support, and two of which compared NRT plus advice/behavioral support to advice/behavioral support alone.
In a recent Cochrane systematic review of these studies, no statistically significant evidence of effectiveness was demonstrated for NRT versus placebo/control in a pooled sample of 1,745 pregnant patients (risk ratio, 1.33, 95% CI, 0.93-1.91). However, there was high heterogeneity in the dose of NRT and the delivery method (e.g., gum, patch) across studies, and poor adherence to the NRT treatment in all trials (Cochrane Database Syst Rev. 2012 Sep 12;9:CD010078).
With respect to safety, in the same Cochrane review there were no statistically significant differences in rates of miscarriage, stillbirth, premature birth, birth weight, low birth weight, admissions to neonatal intensive care, or neonatal death between NRT and control groups. However, small sample sizes and adherence issues across these trials hampered the interpretability of these data.
One relatively large claims database study from the United Kingdom, which was published recently, examined major congenital anomalies following prescription of NRT. The investigators found no increased risks for most major defects following NRT prescription; the only significant association was with respiratory defects (Pediatrics. 2015 May;135[5]:859-67).
The general thinking has been that for a woman who is unable to quit smoking without pharmacological assistance, NRT that delivers nicotine alone to the developing fetus may be a better option than exposure to the multiple toxins that are contained in tobacco smoke. However, there is considerable controversy over the potential adverse neurotoxic effects of nicotine itself and long-term neurodevelopmental studies on children prenatally exposed to NRT are lacking.
Other options include bupropion and varenicline, neither of which have been studied in RCTs in pregnancy. Bupropion has been evaluated in a small controlled cohort study, a claims database study (n = 1,236 first-trimester exposed), and two case-control studies. None of these studies was focused on use of bupropion exclusively for smoking cessation, but rather for the more common indication of maternal depression. The first two studies suggested no increased risks for adverse pregnancy outcomes compared to women the same underlying conditions; the case control studies suggested small increased risks for heart defects but not the same ones in both studies (Expert Opin Drug Saf. 2014 Dec;13[12]:1721-31). The limited data on varenicline are too sparse to make any inferences.
Another possible alternative that has been gaining in popularity are e-cigarettes or related vapor products, which are touted to have advantages with respect to harm reduction, primarily because of possible improved adherence due to their similarity to conventional smoking. However, there is large variability in the amount of nicotine in the vapor of various e-cigarette brands, and some have suggested that e-cigarette users engage in longer puff duration than do those who smoke conventional cigarettes. To my knowledge, there are no controlled studies of e-cigarette use in pregnancy, but the concerns previously raised regarding nicotine exposure in any form likely apply to this delivery method (Birth Defects Res A Clin Mol Teratol. 2015 Mar;103[3]:186-95).
What is the role of the obstetrician in identifying nicotine and tobacco exposure in their patients and encouraging cessation or reduction prior to and during pregnancy?
The first responsibility is to screen pregnant women. A recent survey study suggests that 40% of the responding ob.gyns. never screened pregnant patients for use of noncombustible tobacco products such as e-cigarettes (Am J Obstet Gynecol. 2014 Dec;211[6]:695.e1-7). In the United States, an analysis of the Pregnancy Risk Assessment Monitoring System data collected across several states from 2009 to 2010 suggests that about a quarter of 3,559 pregnant women who reported smoking in the 3 months before pregnancy did not receive any interventions to stop smoking (Prev Med. 2015 Sep;78:92-100). In addition, four out of five ob.gyns. surveyed in 2012 were unaware of the Affordable Care Act provision that requires states to provide tobacco cessation coverage for pregnant Medicaid beneficiaries (Prev Med Rep. 2015;2:686-88).
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 from GlaxoSmithKline and Pfizer for unrelated products.
Data consistently support the negative impact of tobacco use in pregnancy with respect to pregnancy outcome, and the benefits of discontinuation or reduction as early as possible.
Recent analyses by investigators at the National Center on Birth Defects and Developmental Disabilities at the Centers for Disease Control and Prevention suggest that more than 6% of oral clefts, or 430 affected infants per year in the United States, could be prevented annually if women can discontinue tobacco use prior to conception (Birth Defects Res A Clin Mol Teratol. 2014 Nov;100[11]:822-5). Similarly, preconception smoking cessation could prevent the 1.4% of nonsyndromic congenital heart defects that are attributable to maternal smoking in the first trimester (J Pediatr. 2015 Apr;166[4]:978-984.e2).
With respect to the risk for adverse outcomes beyond the first trimester, recent data also show clearly that the trimester of discontinuation is related to intrauterine growth restriction in a dose-response fashion (Obstet Gynecol. 2015 Jun;125[6]:1452-9).
In a recent population-based retrospective cohort study of 927,424 singleton births 2006-2012 in Ohio, the adjusted relative risk of infant birth weight less than the 5th percentile for those women who discontinued smoking after the first trimester compared with nonsmokers was 1.25 (95% confidence interval, 1.17-1.33); for those who discontinued after the second trimester the relative risk was 1.83 (95% CI, 1.68-1.99); and for those who smoked throughout pregnancy the relative risk was 2.44 (95% CI, 2.37-2.51).
Given the compelling reasons to encourage women to stop smoking or at least to reduce harm during pregnancy, options for assistance with smoking cessation are of high interest. Beyond simple screening and advice to quit, cognitive behavioral therapy has been shown to provide some benefit. The addition of pharmacologic treatment with nicotine replacement therapy (NRT) has been studied in six randomized clinical trials (RCTs) conducted in pregnant women, four of which compared NRT plus advice/behavioral support to placebo plus advice/behavioral support, and two of which compared NRT plus advice/behavioral support to advice/behavioral support alone.
In a recent Cochrane systematic review of these studies, no statistically significant evidence of effectiveness was demonstrated for NRT versus placebo/control in a pooled sample of 1,745 pregnant patients (risk ratio, 1.33, 95% CI, 0.93-1.91). However, there was high heterogeneity in the dose of NRT and the delivery method (e.g., gum, patch) across studies, and poor adherence to the NRT treatment in all trials (Cochrane Database Syst Rev. 2012 Sep 12;9:CD010078).
With respect to safety, in the same Cochrane review there were no statistically significant differences in rates of miscarriage, stillbirth, premature birth, birth weight, low birth weight, admissions to neonatal intensive care, or neonatal death between NRT and control groups. However, small sample sizes and adherence issues across these trials hampered the interpretability of these data.
One relatively large claims database study from the United Kingdom, which was published recently, examined major congenital anomalies following prescription of NRT. The investigators found no increased risks for most major defects following NRT prescription; the only significant association was with respiratory defects (Pediatrics. 2015 May;135[5]:859-67).
The general thinking has been that for a woman who is unable to quit smoking without pharmacological assistance, NRT that delivers nicotine alone to the developing fetus may be a better option than exposure to the multiple toxins that are contained in tobacco smoke. However, there is considerable controversy over the potential adverse neurotoxic effects of nicotine itself and long-term neurodevelopmental studies on children prenatally exposed to NRT are lacking.
Other options include bupropion and varenicline, neither of which have been studied in RCTs in pregnancy. Bupropion has been evaluated in a small controlled cohort study, a claims database study (n = 1,236 first-trimester exposed), and two case-control studies. None of these studies was focused on use of bupropion exclusively for smoking cessation, but rather for the more common indication of maternal depression. The first two studies suggested no increased risks for adverse pregnancy outcomes compared to women the same underlying conditions; the case control studies suggested small increased risks for heart defects but not the same ones in both studies (Expert Opin Drug Saf. 2014 Dec;13[12]:1721-31). The limited data on varenicline are too sparse to make any inferences.
Another possible alternative that has been gaining in popularity are e-cigarettes or related vapor products, which are touted to have advantages with respect to harm reduction, primarily because of possible improved adherence due to their similarity to conventional smoking. However, there is large variability in the amount of nicotine in the vapor of various e-cigarette brands, and some have suggested that e-cigarette users engage in longer puff duration than do those who smoke conventional cigarettes. To my knowledge, there are no controlled studies of e-cigarette use in pregnancy, but the concerns previously raised regarding nicotine exposure in any form likely apply to this delivery method (Birth Defects Res A Clin Mol Teratol. 2015 Mar;103[3]:186-95).
What is the role of the obstetrician in identifying nicotine and tobacco exposure in their patients and encouraging cessation or reduction prior to and during pregnancy?
The first responsibility is to screen pregnant women. A recent survey study suggests that 40% of the responding ob.gyns. never screened pregnant patients for use of noncombustible tobacco products such as e-cigarettes (Am J Obstet Gynecol. 2014 Dec;211[6]:695.e1-7). In the United States, an analysis of the Pregnancy Risk Assessment Monitoring System data collected across several states from 2009 to 2010 suggests that about a quarter of 3,559 pregnant women who reported smoking in the 3 months before pregnancy did not receive any interventions to stop smoking (Prev Med. 2015 Sep;78:92-100). In addition, four out of five ob.gyns. surveyed in 2012 were unaware of the Affordable Care Act provision that requires states to provide tobacco cessation coverage for pregnant Medicaid beneficiaries (Prev Med Rep. 2015;2:686-88).
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 from GlaxoSmithKline and Pfizer for unrelated products.
