Risk of orofacial malformations associated with the use of ondansetron in early pregnancy

HSA would like to update healthcare professionals on recent published epidemiological studies examining the risk of congenital malformations associated with the use of ondansetron in early pregnancy. A small increased risk of orofacial malformations was observed in infants of women administered ondansetron during the first trimester of pregnancy. However, conflicting results were obtained regarding cardiac malformations.

Ondansetron is an antiemetic agent and acts as a selective serotonin 5-HT3 receptor antagonist. It has been registered in Singapore since 1990 and is indicated for the management of nausea and vomiting induced by cytotoxic chemotherapy and radiotherapy, as well as for the prevention and treatment of post-operative nausea and vomiting.

Ondansetron has been used off-label as second-line therapy for the management of nausea and vomiting of pregnancy and hyperemesis gravidarum.1 Studies in the US observed a marked increase in ondansetron off-label use, from less than 1% before 2000 to nearly one-quarter in 2014, and its use was most common in the first trimester of pregnancy.2,3

 

Findings from recently published large epidemiological studies

A number of studies, which have attempted to evaluate the risk of congenital malformations associated with the use of ondansetron during pregnancy, have yielded conflicting results. Two recent large epidemiological studies have added to the body of evidence, suggesting that exposure to ondansetron during the first trimester of pregnancy is associated with a small increased risk of orofacial malformations in infants.

The first study was a retrospective cohort study of US health insurance claims data that reviewed more than 1.8 million pregnancies with more than 88,000 exposed to ondansetron in the first trimester.4 The study concluded that first trimester exposure to ondansetron was associated with a small but statistically significant increased risk of oral clefts in infants (adjusted relative risk 1.24, 95% CI 1.03-1.48), corresponding to a risk difference of 2.7 (95% CI 0.2-5.2) per 10,000 births. No apparent increase in the risk of cardiac malformations or overall congenital malformations was observed after accounting for measured confounders.

The second study was a nested case-control study using another US administrative claims database that included more than 860,000 mother-infant pairs.5 Since antiemetics were prescribed prophylactically to be used on an “as-needed” basis, the authors sought to minimise the risk of exposure misclassification in prescription data by examining a subset of 5,557 pregnancies with confirmed medical administration of ondansetron in their primary analysis. Based on this subset, first trimester exposure to ondansetron was found to be associated with an increased risk of cardiac defects (adjusted odds ratio [OR] 1.43, 95% CI 1.28–1.61) in infants, compared to those with no exposure to antiemetic during pregnancy. A trend towards an increased risk of orofacial cleft defects was also observed, although it did not reach statistical significance (adjusted OR 1.30, 95% CI 0.75–2.25).

These two studies were among the 12 studies included in a recent meta-analysis which confirmed an increased risk of orofacial clefts associated with first trimester exposure to ondansetron (pooled OR 1.22, 95% CI 1.00-1.49; p=0.0496), without heterogeneity between the included studies.6 The main analysis of overall cardiac malformations, however, did not reach statistical significance and the heterogeneity between studies was found to be substantial.

 

Regulatory actions taken by EMA and MHRA

In January 2020, the UK Medicines & Healthcare Products Regulatory Agency (MHRA) issued a safety communication regarding the risk of orofacial malformations with ondansetron, and cautioned on the use of ondansetron outside of its authorised indications.7 This followed an earlier review of the above-mentioned epidemiological studies by the European Medicines Agency (EMA), which concluded that these studies were considered sufficiently robust to indicate that the use of ondansetron during the first trimester was associated with a small increased risk in orofacial malformations, despite some limitations inherent to the data sources.8 As a result, the European product information for ondansetron-containing products were updated to highlight this risk, and that the available epidemiological studies on cardiac malformations showed conflicting results.

 

Local situation and HSA’s advisory

To date, HSA has not received any local reports of congenital malformations associated with ondansetron use. The local package inserts for all ondansetron-containing products are being  updated to highlight the findings of the studies mentioned above.

Healthcare professionals are reminded on the approved indications for ondansetron, and to take into consideration the above safety information when prescribing ondansetron. Healthcare professionals are also encouraged to report to HSA any suspected cases of congenital malformations related to the use of ondansetron.

 

References

  1. Nat Rev Dis Primers 2019; 5: 62
  2. Obstet Gynecol 2018; 132: 385-394
  3. Pharmacoepidemiol Drug Saf 2017; 26: 592-596
  4. JAMA 2018; 320: 2429-2437
  5. Reprod Toxicol 2019; 83: 14-20
  6. Birth Defects Res 2020; first published: 18 May
  7. https://www.gov.uk/drug-safety-update/ondansetron-small-increased-risk-of-oral-clefts-following-use-in-the-first-12-weeks-of-pregnancy
  8. https://www.ema.europa.eu/en/documents/prac-recommendation/prac-recommendations-signals-adopted-8-11-july-2019-prac-meeting_en.pdf
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