Ondansetron (Zofran®)

Ondansetron use increased from less than 1% of pregnancies in 2001 to 22.2% in 2014, with the highest use in the first trimester. Further, in 2008, ondansetron prescriptions for NVP increased from 50,000 each month in 2008, to 110,000 each month by the end of 2013.

Overall, and in comparison to other antiemetics, ondansetron has been shown to be very effective at reducing NVP symptoms in women with varying degrees of NVP severity, including women with HG. Further, ondansetron does not produce the adverse sedative effects of other medications.

However, it is still unclear exactly what type of effect ondansetron has in decreasing symptoms, or why it is so effective in some women. At least one study found no difference in serotonin levels among pregnant women with HG and pregnant women without HG, as well as non-pregnant women. Further, ondansetron is not completely effective across the board in women with NVP.

In a large, multicenter cohort study published in April 2021, there was no association between ondansetron exposure (anti-nausea medication) during pregnancy and increased risk of fetal death, pregnancy loss, stillbirth, or major birth defects compared with exposure to other anti-nausea drugs.

Interestingly, an additional study using the same large data set as one of the studies above, and published the same year (2013), did not reach this conclusion, and determined ondansetron was not teratogenic.

According to a 2014 literature review associated with the Motherisk Program, the author noted, “the fact that the same large registry in Denmark (897,018 vs. 608,385) can be investigated to yield such opposing results is concerning” and more research and clarity was needed.

Additional studies published in 2016 and 2018 did not find an increased risk of cardiac malformations with ondansetron use.

A separate May 2016 review noted that despite a possible increased risk for cardiac defects, a finding not replicated in other studies, the overall risk of birth defects associated with ondansetron exposure appears to be low.

Regarding how ondansetron could cause cardiac malformations, it is theorized that ondansetron can block HERG (gene) potassium channels to the heart, theoretically causing heart rhythm disturbances in the embryo, depending on the dose. This was confirmed in animal studies using doses higher than human doses. This effect can be exacerbated with low potassium, which can occur with severe electrolyte imbalance (and therefore, severe NVP/HG). However, further studies are necessary to understand this mechanism.

The nasal and maxillary processes of the face fuse to form the upper lip. The two palatine shelves fuse to complete the soft palate (mouth/nose).  If fusion does not occur correctly, a cleft lip or cleft palate occurs at the boundary (sources differ dramatically on timing; fusion may occur anywhere between 10 and 14 weeks of pregnancy; average appears to be 10 weeks).

A separate study published in April 2016 did not find an association between ondansetron and birth defects, including cleft lip and/or palate or cardiac malformations.  Conversely, the study found evidence suggesting that women who took ondansetron were less likely to have a miscarriage or a stillbirth. The authors also indicated that extreme NVP itself could be a cause of adverse findings.

The mechanism for how ondansetron could cause cleft lip and/or palate is not clear.

However, it is also possible that women's symptoms may be too severe at their first appointment, at which point HCPs may skip these steps and prescribe ondansetron or metoclopramide (Reglan®), which are on the same "line" on ACOG's treatment algorithm (see Resources).

ACOG recommends women also be counseled regarding the available data as well as the risks and benefits of ondansetron use prior to 10 weeks of gestation.

Of note, EMA also noted that cardiac septal defects and oral cleft are not rare occurrences during pregnancy. Congenital heart defects are the most common cause of major congenital anomalies and isolated orofacial clefts are one of the most common types of birth defects in the United States, adding to the nuance of evaluating all existing data.

Further, in December 2020, researchers from The European Network of Teratology Information Services wrote that implementation of the regulatory step by the EMA is not well-evidenced and does not serve the interest of pregnant women with severe nausea and vomiting. (Note: Teratology is the study of teratogens, "outside" factors that can be harmful during pregnancy). 

UKTIS further noted the background risk for orofacial cleft is 11 per 10,000 pregnancies; the risk of orofacial cleft is 14 per 10,000 pregnancies following ondansetron use in the first trimester.

In January 2020, the U.K. Medicines & Healthcare products Regulatory Agency noted there is a growing body of evidence on the use of ondansetron in pregnancy that does not suggest an increase in the risk of overall congenital malformations combined; however, ondansetron may be associated with a small fetal increased risk of cleft lip and/or cleft palate.

According to the FDA, additional common adverse side effects of ondansetron include anxiety, irritability, weakness, dry mouth, chills, drowsiness, insomnia, and diarrhea.

Because ondansetron helps prevent nausea and vomiting by blocking serotonin, serotonin can accumulate and lead to serotonin syndrome, which is essentially a type of poisoning that is life threatening. However, this is more likely to occur in women taking more than one serotonin blocker/SSRI.

There are many contraindications to using ondansetron, and HCPs may want women off all other antiemetics, antihistamines, and/or SSRIs while taking it. Women need to discuss all risks and benefits, side effects, and contradictions of taking the medication with their HCP.