Maternal circulating sFlt-1/placental growth factor is a biomarker of fetal death associated with placental lesions of maternal vascular malperfusion

Fetal death is a major pregnancy complication, with rates of 5.5 per 1,000 births in the United States and substantially higher in India (24.7/1,000) and Pakistan (44.5/1,000). Maternal vascular malperfusion (MVM) is the most frequent placental lesion associated with fetal death, occurring in 58% of fetal deaths and 31% of preterm neonatal deaths in South Asia. Angiogenic imbalance, characterized by a low placental growth factor (PlGF) to soluble fms-like tyrosine kinase-1 (sFlt-1) ratio, has been associated with MVM and fetal death in high-income countries. We examined whether maternal serum concentrations of PlGF, sFlt-1, and their ratio differ between mothers with and without MVM among stillbirths and preterm neonatal deaths in India and Pakistan. This retrospective cohort analysis used data from the PURPOSe study (Project to Understand and Research Preterm Pregnancy Outcomes and Stillbirths in South Asia). Maternal blood was collected at delivery, and placental histopathology was classified according to the Amsterdam criteria. Serum PlGF and sFlt-1 were measured using Elecsys® immunoassays, with analyses stratified by gestational age. Placental MVM was present in 44-57% of stillbirths and 31-38% of preterm neonatal deaths. Between 28 and 36 weeks, women with MVM had significantly lower PlGF and higher sFlt-1 and sFlt-1/PlGF ratios (p<0.001). A tenfold decrease in PlGF or increase in the ratio was associated with MVM (OR 0.5 and 1.7, respectively). The maternal sFlt-1/PlGF ratio identifies pregnancies with fetal or neonatal death associated with placental MVM, particularly between 28 and 36 weeks' gestation.