OBJECTIVES: To investigate the association between fertilization in vitro (IVF) and severe maternal morbidities (SMM), and further examine the potential mediation effect of multiple gestations on SMM.

METHODS: A retrospective cohort study was conducted at six hospitals in China. Pregnant women after 20 gestational weeks were included and were categorized into two groups based on mode of conception: IVF versus spontaneous conception. Multivariable logistic regression was used to examine the association between IVF and SMM; standard methods were used to test the mediation effect of multiple gestations.

RESULTS: In total, 22,368 eligible pregnant women were included, among which 497 (2.22%) received IVF, and 776 developed SMM (incidence 34.69/1000 live births, 95%CI 32.29/1000-37.09/1000). Model 1 showed that IVF was associated with higher risk of SMM (adjusted odds ratio, aOR 1.54, 95%CI 1.03-2.29). Model 2 showed that IVF was strongly associated with multiple gestations (aOR 14.75, 95%CI 11.38-19.10). Model 3 - adding multiple gestations to model 1 – showed that IVF was not statistically associated with SMM (aOR 0.89, 95%CI 0.58-1.36), but multiple gestations was associated with higher risk of SMM (aOR 5.92, 95%CI 4.88-7.83). Using the established rule for judging effect modification, the three models confirmed that multiple gestations was a mediator between IVF and SMM. Model 4 – only among singleton pregnancies – further showed that IVF was not associated with SMM (aOR 0.70, 95%CI 0.37-1.32).

CONCLUSIONS: The impact of IVF on SMM was medicated by multiple gestations, which highlights careful consideration about multiple embryo implantation, given its potential consequence to multiple gestations.