Environmental exposure to bisphenol analogues and unexplained recurrent miscarriage: A case-control study

The use of bisphenol A (BPA) has been substantially limited since 2010 due to its toxicity to human health. A group of bisphenol analogues that are structurally similar to BPA have been developed as the alternatives and used widely. The reproductive toxicity of these emerging chemicals has caused substantial concerns in recent years. Whether bisphenol analogues affect miscarriage, especially unexplained recurrent miscarriage (URM), remains to be explored. We conducted a hospital-based, case-control study with 1180 URM cases and 571 controls in China from 2014 to 2016. Concentrations of six bisphenol analogues (BPA, BPAF, BPAP, BPB, BPP and BPS) were measured in the urine samples collected at median intervals of 7.6 months after last miscarriage (interquartile ranges: 4.8, 14.7 months). Multiple logistic regression, Bayesian kernel machine regression (BKMR) and quantile g-computation (q-gcomp) were used to assess the relationship of bisphenol analogues with URM risk. We observed significantly higher levels of all urinary bisphenols in the cases than the controls. After controlling for potential confounders, bisphenol analogues were significantly associated with increased odds of URM in varying degrees. A dose-response pattern was observed for the associations of BPAF, BPAP and BPB quartiles with URM. The mixed exposure of six bisphenol analogues was positively associated with the risk of URM (adjusted odds ratio (aOR) = 1.25; 1.11-1.42), which was mainly driven by BPAP (60.1%), BPAF (25.1%) and BPA (14.8%). After age stratification, the risks tended to be higher in women aged 30 years or older, compared to women <30 years. Our large case-control study indicates that environmental exposure to bisphenol analogues is associated with an increased risk of URM. Older women may be more vulnerable to the insult.