Ondansetron Should Not Be First Choice for Nausea in Pregnancy

Troy Brown, RN

April 08, 2016

Ondansetron given to relieve nausea and vomiting in pregnant women during the first trimester is associated with a low risk for birth defects, and possibly a small increase in the incidence of cardiac malformations in newborns, according to a systematic review published online April 4 in Obstetrics & Gynecology.

On balance, however, Shaun D. Carstairs, MD, from the Division of Medical Toxicology, Department of Emergency Medicine, University of California, San Diego, conclude that ondansetron should be considered a good option when other treatments are insufficient.

"If first-line agents for the treatment of nausea and vomiting in pregnancy are not felt to control a patient's symptoms adequately, particularly after the first 10 weeks, health care providers and patients should be reassured that ondansetron use during pregnancy is generally safe and is a highly effective measure for control of nausea and vomiting in pregnancy, and its use should be considered in patients in whom other methods have failed," he writes.

Writing in an accompanying commentary, Lara L. Siminerio, PharmD, from the Department of Epidemiology, Graduate School of Public Health, Department of Obstetrics, Gynecology and Reproductive Sciences, School of Medicine, Magee Womens Hospital of the University of Pittsburgh Medical Center, Pennsylvania, and colleagues endorse that view.

"In the face of recent questioning of the safety of ondansetron use in pregnancy, it is [our] opinion that current data do not support a reluctance to treat women with ondansetron in clinical practice. The maternal benefit of treatment for nausea and vomiting of pregnancy and hyperemesis gravidarum with ondansetron outweighs the risks," Dr Siminerio and colleagues write.

"Teratogen exposure is relevant during the period of organogenesis, yet, in previous studies, the majority of the women began ondansetron after the heart is fully formed at approximately 8 weeks of gestation," they explain. "Only [one study] tested the effect of limiting the exposure window to 2–8 weeks or 4–10 weeks of gestation and confirmed their null findings."

Eight Studies Available

Dr Carstairs identified eight studies for their review. To be included, studies needed to be written in English, report the results of original research, report on ondansetron exposure during the first trimester, include structural birth defects as an outcome, and include a comparison population of patients who were not exposed to ondansetron.

A large cohort study that analyzed data on 608,385 pregnancies found no significant association between ondansetron exposure and the incidence of major birth defects (odds ratio [OR], 1.12; 95% confidence interval [CI], 0.69 - 1.82), small for gestational age (OR, 1.13; 95% CI, 0.89 - 1.44), low birth weight (OR, 0.76; 95% CI, 0.51 - 1.13), or preterm delivery (OR, 0.90; 95% CI, 0.66 - 1.25).

"This was the only study to account for maternal medical history, including diabetes mellitus of any type, which is known to increase risk of congenital heart defects," Dr Siminerio and colleagues write in their commentary. "We conclude that the strongest evidence comes from [this study]."

In addition, one study analyzed data from 4524 cases and 5859 controls and saw no evidence of increased risk for three of the four birth defects examined: cleft lip, neural tube defects, or hypospadias. However, the risk for the fourth defect examined, cleft palate, was approximately twofold higher in neonates exposed to ondansetron in utero during the first trimester (OR, 2.37; 95% CI, 1.18 - 4.76), with 11 cleft palate cases among the 55 exposed neonates and 514 cases among the 4479 unexposed neonates.

"The relatively small sample size in this study limits the interpretability of these results, and no other studies thus far have demonstrated the increased risk for cleft palate reported in this study," Dr Carstairs cautions.

One report that was published in abstract form only analyzed data from two case-control studies with a total of 10,354 women, 354 of whom were exposed to ondansetron during their pregnancies. The risk for cleft palate was not significantly increased in one study (OR, 1.5; 95% CI, 0.9 - 2.5), and it was significantly decreased in the other study (OR, 0.4; 95% CI, 0.2 - 0.8). The risk for renal agenesis or dysplasia was modestly increased in one study (OR, 2.3; 95% CI, 1.3 - 4.0).

Two other studies found a small increase in the risk for cardiac defects. One was a cohort study of 1.5 million births with 1349 newborns who were exposed to ondansetron in utero. The risks for total malformations (OR, 0.95; 95% CI, 0.72 - 1.26) or "relatively severe" malformations (OR, 1.11; 95% CI, 0.81 - 1.53) were not significantly increased. The risk for cardiac malformations was slightly increased compared with that for newborns exposed to meclizine in utero (OR, 1.62; 95% CI, 1.04 - 2.14). Most of the cardiac defects in this study were septal defects (17 of 19 total; OR, 2.05; 95% CI, 1.19 - 3.28).

Another study included a total of 897,018 births, 1248 of which occurred in women given a prescription for ondansetron during pregnancy. There were 58 congenital malformations (4.7%) in the ondansetron-exposed group and 31,357 congenital malformations (3.5%) in the nonexposed group. Ondansetron exposure was associated with a small increase in the risk for major malformations (OR, 1.3; 95% CI, 1.0 - 1.7). The prevalence of heart defects, which accounted for most of the increased malformations, was apparently doubled (OR, 2.0; 95% CI, 1.3 - 3.1).

"It is critical to note that although this study is frequently cited, it was published only as an abstract and never as a peer-reviewed article. The abstract lacks critical information such as the total number of heart defects in the study," Dr Siminerio and colleagues write. "[This study] found a significantly increased risk of cardiac malformations, but because of this lack of peer review and incomplete information, it is inappropriate to use these findings in any critical assessment of ondansetron."

A small study that compared the risk for birth defects in 176 women exposed to ondansetron during the first trimester with two groups of unexposed women showed no significant differences between the groups in the number of stillbirths or miscarriages, incidence of major malformations, gestational age at birth, and mean birth weights. However, the study was underpowered and would have detected only "a fivefold increase in the incidence of major malformations," the authors write.

Similarly, there were no malformations in an observational cohort study of 65 women who were exposed to ondansetron during the first trimester.

Finally, a study looked at 263 newborns born to 251 women who were exposed to ondansetron during pregnancy (81% during the first trimester). There was a small but insignificant increase in the risk for any major birth defect in babies who were born to women exposed during the first trimester (OR, 1.2; 95% CI, 0.6 - 2.2). The risk for obstructive renal defects was significantly increased (OR, 6.2; 95% CI, 2.0 - 19.5), but the number of cases was less than five, and the confidence interval was wide.

Benefit Outweighs Risks

"First-line agents such as ginger or pyridoxine and doxylamine are not always effective for treating nausea and vomiting in pregnancy, and the known risks associated with suboptimally treated nausea and vomiting in pregnancy or hyperemesis gravidarum need to be weighed against the very small potential risks associated with ondansetron use," Dr Carstairs concludes.

Dr Carstairs and the commentators have disclosed no relevant financial relationships.

Obstet Gynecol. Published online April 4, 2016. Article abstract, Commentary extract

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