Background Hyperemesis gravidarum (HG) is a severe complication of pregnancy affecting around 1% of pregnancies globally. Objective To investigate whether ondansetron use during pregnancy is associated with increased rates of abnormal pregnancy outcomes. Search strategy PubMed, Embase, the Cochrane Library, CINAHL, CNKI, CBM, WANFANG, and ClinicalTrials.gov were searched for citations published in any language from inception to 15 December 2021. Selection criteria Eligible studies included any observational study. Data collection and analysis We used odds ratios (ORs) and 95% confidence intervals (CIs) as a measure of the association between ondansetron and abnormal pregnancy outcomes. Main results Of 1,558 citations screened, 19 articles were included. No significant increased risk for overall congenital malformations (OR=1.10,95% CI:0.94–1.29, Low certainty), cleft palate (OR=0.78,95% CI:0.37–1.64, Very Low certainty), stillbirth (OR=0.60,95% CI:0.40–0.91, Low certainty) or preterm birth (OR=0.78,95% CI:0.37–1.64, Low certainty) were identified in our primary analysis. However, the results of our primary analysis indicated that ondansetron use during pregnancy was associated with significantly increased rates of heart defects (OR=1.06,95% CI:1.02–1.11, Moderate certainty) and other organ malformations (OR=1.09,95% CI:1.03–1.16, Moderate certainty) when exposed infants were compared with healthy or disease-matched controls. Conclusion Ondansetron use during pregnancy was associated with a significant increase in rate of some abnormal pregnancy outcomes in our primary analysis. In conclusion, 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.