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.