sFlt-1/PlGF at 36 weeks' gestation: association with spontaneous onset of labor and intrapartum fetal compromise in low-risk pregnancies.

Background: Prior evidence showed that placental dysfunction triggers spontaneous preterm or term births, and intrapartum fetal compromise, often requiring urgent delivery and exposing both fetus and mother to significant risks. Predicting spontaneous labor onset and intrapartum fetal compromise could improve obstetric management and outcomes, but this is currently difficult, particularly in low-risk population.

Objective: The objective of this study is to examine whether placental dysfunction assessed at 36 weeks by the soluble fms-like tyrosine kinase-1 (sFlt-1) to placental growth factor (PlGF) ratio, associates with interval to spontaneous onset of labor and intrapartum fetal compromise requiring cesarean delivery, in a routinely examined population.

Study design: Retrospective analysis of prospectively collected data of women with singleton pregnancies undergoing routine assessment at 35⁺⁰-36⁺⁶ weeks' gestation at King's College Hospital (London, England). Using a General Linear Model the study examined outcomes related to the sFlt-1/PlGF ratio including the time interval from testing to spontaneous onset of labor, and the subsequent rate of fetal compromise requiring cesarean delivery. Patients undergoing induction of labor, and prelabour cesarean deliveries were excluded from the study.. Competing risks regression and Cox regression models were used to estimate the cumulative incidence and risk of the outcomes of interest RESULTS: In the screened population of 45,375 patients, 23,831 (52.5%) had spontaneous onset of labor and were included in the analysis. Cases with sFlt-1/PlGF ratio ˃50 vs. ≤50 delivered about one week earlier (39.2 vs. 40.0 weeks; p˂0.001). General linear model showed that greater sFlt-1/PlGF ratio associated with earlier spontaneous onset of labor (p<0.001), particularly in multiparous women A significant effects on sFlt-1/PlGF ratio values was, as expected, observed for those cases who developed preeclampsia and in women of advanced age.Cumulative incidence for spontaneous onset of labor was significantly higher in cases with sFlt-1/PlGF ˃50 vs. ≤50. Cox regression showed that the risk of spontaneous onset of labor increased with sFlt-1/PlGF ˃50 (hazard ratio [HR] 1.424; 95% CI 1.253-1.618; p˂0.001) and, as expected, the risk was mitigated over time from s-Flt-1/PlGF measurement to spontaneous labour onset (p˂0.001). Cases with vs. without intrapartum fetal compromise had higher mean sFlt-1/PlGF ratio (21.79 vs. 17.67; p˂0.001). Qualitative addition of fetal compromise to the general linear model showed higher sFlt-1/PlGF ratio in cases with, compared to those without, fetal compromise (p=0.014). Competing risks regression showed a positive dose-response effect for fetal compromise with increasing sFlt-1/PlGF ratios (p˂0.001). Above and below the optimal cut-off of 50 the quoted cumulative incidences were 6.7% vs. 4.7%, respectively (p<0.001). The effect of the sFlt-1/PlGF ratio remained significant even after adjusting for preeclampsia, which is a well-known major risk factor for fetal compromise. Finally, the proportion of cases with intrapartum fetal compromise having sFlt-1/PlGF ratio >50 decreased from 35% to 0% with advancing gestation.

Conclusions: This study shows that increased sFlt1/PLGF ratio at 36 weeks associates with earlier gestational age at spontaneous onset of labor and higher rates of intrapartum fetal compromise. There are two major implications: sFlt1-/PLGF ratio ˃50 indicates imminent labor onset with about 40% mean risk increase and immediate clinical translation for term pregnancies monitoring. Additionally raising sFlt1-/PLGF ratios increase the risk of intrapartum fetal compromise, though outcome variability indicates reassessment within multi-marker models.