Maternal Circulating sFlt-1:PlGF Ratio and Stillbirth

Importance: Stillbirth remains a major global health challenge, particularly in low- and middle-income countries. Angiogenic imbalance, characterized by elevated soluble fms-like tyrosine kinase-1 (sFlt-1) and reduced placental growth factor (PlGF), is implicated in placental dysfunction, yet few studies have examined the association between the sFlt-1:PlGF ratio and stillbirth. Objective: To investigate the association between maternal circulating sFlt-1:PlGF ratio, using clinically relevant cutoffs, and risk of stillbirth. Design, Setting, and Participants: This case-control study included participants from 2 health clinics operated by the Dhaka Community Hospital Trust in rural Bangladesh. Pregnant women aged 18 years or older with ultrasonography-confirmed singleton pregnancies were enrolled before or at 16 weeks' gestation between March 1, 2008, and July 30, 2011. Those delivering stillborn infants (cases) were matched 1:2 with participants in the same cohort who delivered full-term live-born infants (controls). Data were analyzed between September 1, 2025, and January 1, 2026. Exposure: Maternal serum sFlt-1:PlGF ratio. Main Outcomes and Measures: The main outcome was stillbirth, defined as fetal death at 28 weeks' gestation or more. The association between sFlt-1:PlGF ratio cutoffs of greater than 38 and greater than 85 and stillbirth were estimated using Firth penalized logistic regression, with models adjusted using a propensity score incorporating maternal factors. Results: The analytic sample included 125 participants (mean [SD] age, 22.3 [3.8] years), of whom 39 were included in the stillbirth group and 86 in the live birth control group. After adjusting for propensity score, an sFlt-1:PlGF ratio greater than 38 was significantly associated with an increased odds of stillbirth (odds ratio [OR], 13.44; 95% CI, 2.03-88.89). Similar results were observed using the cutoff of 85 (OR, 12.95; 95% CI, 1.57-106.64). Elevated sFlt-1:PlGF ratios showed high positive predictive value for stillbirth at the cutoff of 38 (88.9%; 95% CI, 51.8%-99.7%) and 85 (85.7%; 95% CI, 42.1%-99.6%). Negative predictive values were moderate at 73.3% (95% CI, 64.3%-81.1%) and 72.0% (95% CI, 63.0%-79.9%), respectively, indicating that low ratios had a limited ability to rule out stillbirth. Conclusions and Relevance: This case-control study found that a high sFlt-1:PlGF ratio using clinically relevant thresholds was associated with stillbirth and corresponded to an estimated 13-fold increased risk. These findings suggest that angiogenic imbalance may contribute to stillbirth and highlight the potential utility of angiogenic markers as indicators of pregnancy complications in low-resource settings.