Association of fetal fraction with adverse pregnancy outcomes: a gestational-age-stratified retrospective study in southern Chinese women

Fetal fraction (FF), the proportion of fetal cell-free DNA in maternal plasma, reflects placental biology and is increasingly investigated as a potential marker of pregnancy health. Whether FF predicts adverse pregnancy outcomes (APOs) remains debated, in part because most studies apply fixed FF thresholds that ignore the physiological rise in FF across gestation. In this study, we examined the association between gestational-age-specific FF categories and APOs in a large southern Chinese cohort. In this retrospective cohort study, we evaluated 25,977 pregnant women who underwent non-invasive prenatal testing (NIPT) at 12 + 0 to 37 + 2 weeks of gestation. FF was grouped by gestational-age-specific percentiles into low (LFF, < 5th percentile, P5), normal (NFF), or high (HFF, > 95th percentile, P95). Primary associations with the composite and individual APOs were estimated by multivariable logistic regression and stabilized inverse-probability-of-treatment weighting (IPTW). Incremental predictive value was assessed by five-fold cross-validated area under the receiver operating characteristic curve (AUC) and decision-curve analysis. LFF was consistently associated with higher odds of the composite APO (odds ratio [OR] 1.51, 95% confidence interval [CI] 1.33–1.71; IPTW OR 1.60, 95% CI 1.38–1.86), as well as gestational diabetes mellitus (regression OR 1.51/ IPTW OR1.59), preeclampsia (OR 2.48/2.63), and gestational hypertension (OR 1.73/1.94), and these effects were robust to alternative LFF thresholds and IPTW balancing. Threshold sensitivity analyses using gestational-age-specific LFF, fixed FF < 5% and fixed FF < 4% yielded similar effect estimates. HFF showed inverse observational associations with these maternal outcomes. No significant associations emerged for preterm birth, intrauterine growth restriction, or low birth weight. Adding continuous FF to a clinical model improved discrimination only modestly (incremental AUC 0.0065) with limited net benefit. LFF was consistently associated with higher odds of major maternal pregnancy complications. This association persisted after IPTW-based covariate balancing. LFF may provide supplementary risk information when incorporated into a multivariable assessment. These findings support the further evaluation of LFF as a complementary marker within multivariable prenatal risk assessment frameworks.