Gestational age-specific reference intervals for placental growth factor and its application in singleton and twin pregnancies: a population-based cohort study

Placental growth factor (PLGF) dynamics exhibit significant variations between singleton and twin pregnancies, necessitating distinct clinical reference intervals. This large study established and validated trimester-specific reference intervals (RIs) for maternal PLGF levels in 16,877 singleton and 940 twin pregnancies, with subsequent evaluation of their predictive accuracy for pregnancy complications. Key findings revealed that twin pregnancies demonstrated elevated median PLGF concentrations compared to singletons from 1st (≤13 weeks) through 2nd-late (22-27 weeks), followed by a reversal of this trend in the 3rd-early (28-32 weeks) with significantly lower PLGF levels persisting until delivery. Chorionicity did not influence PLGF levels in twins (<i>p</i> > 0.05). Using the 2.5th-97.5th percentile ranges, gestational age-specific RIs were defined for both cohorts. In validation cohorts comprising pregnancies complicated by preeclampsia (PE), fetal growth restriction (FGR), placental abruption (PA), or postpartum hemorrhage (PPH), PLGF thresholds were stratified relative to lower reference limits (LRLs). PLGF concentrations below 80%, 100%, and 120% of LRLs were strongly associated with elevated risks for all studied complications. Adjusted logistic regression models demonstrated a dose-dependent relationship, with adjusted odds ratios (aOR) escalating inversely to PLGF thresholds: aOR = 3.2 (95% CI: 2.5-4.1) at 120% LRL, increasing to aOR = 8.7 (95% CI: 6.3-12.0) at 80% LRL. These findings confirm that trimester-specific PLGF RIs effectively stratify pregnancy risks, with sub-LRL values serving as independent predictors of adverse outcomes. This established RIs enhance obstetric risk assessment frameworks, supporting PLGF integration as a complementary biomarker for targeted monitoring and early intervention in both singleton and twin pregnancies.