Discussion

Principal findings

Our exhaustive literature search revealed inconsistent and conflicting results regarding the risk of abnormal pregnancy outcomes with ondansetron use during pregnancy. The majority of the published safety studies on ondansetron exposure in early pregnancy indicates that the risk of birth defects resulting from use of ondansetron is small. Our results regarding overall congenital malformations in exposed vs. healthy or disease-matched controls were in line with the results of the previous cohort studies.52–54 Our analysis found a significant decrease in the rate of stillbirth or miscarriage following ondansetron use during pregnancy. However, the results of our primary analysis which used the studies with the highest quality assessment score indicated that ondansetron use during pregnancy was associated with significantly increased rates of heart defects and other organ malformations (including craniosynostosis, diaphragmatic hernia, laryngeal cleft, relatively severe malformation and other defects) when exposed infants were compared with healthy or disease-matched controls.
There were differences in the analysis of previously published systematic reviews on the effects of ondansetron on abnormal pregnancy outcomes. Kaplan et al. ’s analysis showed that no significant increased risk for major malformations, heart defects, orofacial clefts, genitourinary malformations or hypospadias were identified. Picot et al.’s found that first trimester exposure to ondansetron was found to be associated with an increased risk of ventricular septal defects (VSD) (OR 1.11, 95% CI 1.00–1.23) and oral clefts (OR 1.22, 95% CI 1.00–1.49).53 Lavecchia et al.’s study’s secondary analysis found an increased risk of specific defects, such as cardiovascular defects and cleft palate were conflicted.54 Carstairs’s analysis found that the overall risk of birth defects associated with ondansetron exposure appears to be low and there may be a small increase in the incidence of cardiac abnormalities in ondansetron-exposed neonates.55 As a result, no system review to date has indicated an increase in the rate of
major malformations following ondansetron use during pregnancy. A very important point of debate among the previous studies regarding ondansetron use during pregnancy is the consequent risk of heart defects, cleft palate and other malformations. Our meta-analysis of observational studies regarding the heart defects and other organ malformations detected significant increase in risk with ondansetron used during pregnancy when exposed infants were compared with healthy and disease matched controls, respectively.
In order to determine the specific type of malformation, we further classified it, and the results showed that among the cardiac malformation results, only other circulatory system malformations had a significant increase in the incidence of abnormalities; In other organ malformations, significant increase in the rate of craniosynostosis, diaphragmatic hernia, laryngeal cleft, relatively severe malformation and other defects were detected. Data regarding this domain was limited to from Zambelli-Weiner et al. and Parker et al. two case-control studies.45,48 The first of which compare the first trimester exposure to ondansetron was associated with increased risk of cardiac (OR: 1.52 95% CI:1.35–1.70) and orofacial cleft defects (OR: 1.32 95% CI: 0.76–2.28) in offspring compared to women with no antiemetic exposure during pregnancy.45 The second study found that modest increases in risk were observed for cleft palate (adjusted OR 1.6, 95% CI 1.1–2.3) in the National Birth Defects Prevention Study and renal agenesis–dysgenesis (adjusted OR 1.8, 95% CI 1.1–3.0) in the Birth Defects Study.46 Given the limited number of studies included in the respective analysis, this area undoubtedly requires further exploration.
Off-label ondansetron use among pregnant women is on a steep rise.56-57 Hyperemesis gravidarum that does not respond to other treatments may be considered with ondansetron, but because of the simultaneous strengthening of maternal and fetal testing. Although these adverse findings may be the result of chance, ondansetron should not be considered as a first-choice treatment for NVP in the first trimester.

Strengths and limitations

Strengths of our review include the relatively large number of studies (19) and the very large number of participants (9,440,626)
from 9 countries. This study included not only cohort studies, but also case-control studies, taking into account case reports. At the same time, we used the adjusted effect value, and the result was closer to the real effect. Moreover, our review rated the certainty of evidence for each exposure using the GRADE approach.
Our work does have limitations, the most important of these relates to the classify of abnormal pregnancy outcomes. In our review, we only classify the type of heart defects and other organ malformations. Different differentiation methods may get different results, however, due to the limited number of outcomes of the same type reported in the studies, further classification could not be supported. For some outcomes, the number of participants included in the study was small and the findings may not be reliable. At the same time, our systematic review did not process ORs/RRs/HRs conversion, so the aggregate values may be biased.

Conclusions and implications for future research

In conclusion, the use of ondansetron during pregnancy was not associated with a significantly increased rate of overall major congenital malformations, orofacial clefts, stillbirth and preterm birth in our primary analysis. Our review raised concerns about ondansetron exposure during pregnancy, in particular due to the risk of heart defects (other circulatory defects in particular) and other organ malformations (craniosynostosis, diaphragmatic hernia, laryngeal cleft, relatively severe malformation and other defects) after prenatal exposure to ondansetron. However, our review found that ondansetron should not use as first-line treatment for NVP. But for sever and incurable NVP, clinician can consider use moderate amount ondansetron to treat NVP with close monitoring.
Based on the results of this review, ondansetron use during pregnancy was associated with some abnormal pregnancy outcomes. However, the published studies have not divided the basic maternal characteristics (age, ethnicity, etc.) in detail, and the dosage of ondansetron has not been further analyzed. There are few research data on defects in the urinary system, nervous system and so on, and the credibility of the results needs to be improved. Therefore, in future studies, the corresponding parts should be supplemented and improved.
Disclosure of interests No author had any financial conflict of interest.
Contribution to authorship XC, LG and CLL conceived the study. all authors contributed to revisions and
approved the final version.
Details of ethics approval Not applicable.
Funding This research was not funded by any institution or individual.