Nausea and vomiting of pregnancy (NVP) affects up to 80% of women during the first trimester. A smaller proportion of women (0.3%–3.0%) experience severe vomiting or hyperemesis gravidarum.  While milder cases of nausea and vomiting may resolve spontaneously or may respond to lifestyle and dietary changes, more severe forms of NVP may require treatment with medication.

Prior to the introduction of ondansetron (marketed as Zofran), there were few options for the management of NVP.  Women were most commonly treated with vitamin B6, doxylamine, and dopamine antagonists (e.g., metoclopramide, prochlorperazine), with variable results.  Ondansetron is a serotonin 5-HT3 receptor antagonist used for the prevention of nausea and vomiting.  This medication has been something of a miracle in helping manage the side effects of cancer chemotherapy, and ondansetron is now used to manage nausea and vomiting in many different clinical settings.  

Although not specifically approved by the FDA for the management of nausea and vomiting during pregnancy, ondansetron is now commonly used during pregnancy.  An insurance database study conducted in the United States indicates that the use of ondansetron during pregnancy has increased significantly, from < 1% of pregnancies in 2001 to 22.2% of pregnancies in 2014.  However, information regarding the reproductive safety of this medication has been confusing.  In a recent article published in the Journal of Clinical Psychiatry, Dr. Chittaranjan Andrade reviews the available data on the reproductive safety of ondansetron.  

The paper included data from a meta-analysis of 6 cohort and 2 case-control studies and the results of subsequently published cohort (n = 3) and case-control (n = 1) studies.  The meta-analysis from Kaplan and colleagues (2019) included 5,148 infants exposed to ondansetron.  In addition, a retrospective cohort study collected data from 88,446 pregnancies with first trimester exposure to ondansetron from the 2000–2013 Medicaid Analytic eXtract in the US. Although the findings lack consistency, it looks as if ondansetron exposure may be associated with an increased risk of heart defects and/or orofacial defects, and possibly may be associated with other major malformations.

Andrade notes, however, that we cannot rule out the possibility of unidentified confounding variables.  For example, women with severe NVP are more likely to have metabolic changes and nutritional deficiencies which may also affect risk for malformations.  

Andrade also questions the clinical significance of these findings, noting that the absolute increase in risk is very small.  For example, the increase in absolute (adjusted) risk was 0.03% for oral clefts.  For ventricular septal defects, the absolute increase in risk was only 0.3%.

Obstetricians are in a difficult position here.   While these data may raise some concerns, suggesting the possibility of a very small increase in absolute risk, many women experience severe nausea and vomiting which can interfere with functioning.  Furthermore, early treatment of nausea and vomiting of pregnancy is recommended to prevent progression to hyperemesis gravidarum.  From a mental health perspective, we also see that prolonged NVP, especially when severe, can lead to increased anxiety and depressive symptoms.  We have seen a number of cases where severe nausea and vomiting, with an overlay of anxiety and/ore depression, has led to the termination of the  pregnancy. 

Ruta Nonacs, MD PhD

Andrade C.  Major Congenital Malformation Risk After First Trimester Gestational Exposure to Oral or Intravenous Ondansetron.  J Clin Psychiatry. 2020 Jun 2;81(3):20f13472. Free Article

Erick M, et al. ACOG Practice Bulletin 189: Nausea and Vomiting of Pregnancy. Obstet Gynecol. 2018. 

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