Plasma Short-Chain Fatty Acids and Hypertensive Disorders of Pregnancy: Results from a Nested Case-Control Study and Two-sample Mendelian Randomization Analysis

Background The temporal relationship between Short-chain fatty acids (SCFAs) and hypertensive disorders of pregnancy (HDP) is unclear. This study aimed to examine the temporal and probable causal relationship between them. Methods A nested case-control study including 387 pairs of cases with HDP and healthy controls was conducted. Seven SCFAs levels in plasma samples drawn at 16-20 gestational weeks before HDP were assayed by GC/MS. The individual and joint associations of SCFAs with HDP were examined by logistic regression and weighted quantile sum (WQS) regression, respectively, followed by two-sample bidirectional Mendelian randomization (MR) analysis to test the underlying causality. Results The univariate model found each interquartile increase in plasma valerate was associated with a 32.1% (OR=0.679, 95%CI=0.546-0.844) reduction in the risk of HDP, a 29.4%(OR=0.706, 95%CI=0.548-0.910) reduction in the risk of gestational hypertension (GH) and a 39.1% (OR=0.609, 95%CI=0.397-0.935) reduction in the risk of preeclampsia/chronic hypertension with superimposed preeclampsia (PE/CH-PE). However, after adjustment for covariates, valerate was only associated with the risk of HDP (OR=0.699, 95% CI=0.516-0.946). In addition, plasma isobutyrate and hexanoate were associated with lower risks of HDP and PE/CH-PE. Furthermore, SCFAs co-exposure could reduce the risks of HDP and GH. MR showed that plasma acetate (OR=0.784, 95%CI=0.64-0.962), valerate (OR=0.575, 95%CI=0.363-0.909) and isovalerate (OR=0.642, 95%CI=0.428-0.963) had protective causal effects on GH. Meanwhile, plasma acetate had protective causal effects on PE (OR=0.746, 95%CI=0.6-0.927). Conclusions The study suggested it is necessary to appropriately increase SCFAs levels during pregnancy to reduce the risk of HDP.