Why only one-quarter of placental fetal growth restriction triggers preeclampsia? Clinical risk factors in 2060 cases in a 24-year cohort of 90,000 births

OBJECTIVES: To compare risk factors between preeclampsia-associated fetal growth restriction (PFGR) and non-preeclamptic vascular FGR (VFGR) in a cohort of 96,094 consecutive singleton non-malformed pregnancies (≥22 weeks gestation) to identify susceptibility and protective factors differentiating maternal tolerance from overt hypertensive disease. DESIGN: Observational population-based cohort study over 24.5 years at a university maternity center. RESULTS: Among 94,435 non-malformed births, 9,356 (10.0%) were SGA, with 2,060 (22%) classified as FGR based on abnormal Doppler indices: 529 PFGR (25.7%) and 1,531 VFGR (74.3%). VFGR predominated in late-onset cases (≥34 weeks; 78% vs. 46% early-onset <34 weeks). Compared to VFGR, PFGR mothers were older (mean 28 vs. 27 years), had higher pre-pregnancy BMI (25.9-26.8 vs. 24.0-24.4 kg/m2), and greater gestational weight gain (by 1-3 kg). Obesity (BMI ≥ 30 kg/m2) increased PFGR risk (OR 1.4-2.1), while underweight (BMI < 18.5 kg/m2) (OR 0.36-0.50) and smoking (OR 0.36-0.51) was protective for PFGR. Chronic hypertension (OR 2.8-3.0), previous preeclampsia (OR 3.3-9.9 in multiparas), primipaternity (OR 2.1-6.8), and renal disease (OR 5.0-7.8) were key risks for PFGR, with stronger effects in early-onset. Neonatal outcomes were similarly poor in early-onset PFGR/VFGR but worse in late-onset PFGR (e.g., higher prematurity, fetal death). Multivariable models confirmed independent associations of PFGR with age, BMI, chronic hypertension, primipaternity, previous abortion, and smoking (protective). CONCLUSIONS: This study reveals VFGR as the majority of placental-mediated FGR, with PFGR distinguished by metabolic, vascular, and immunological risks. These insights prioritize research into maternal protective mechanisms, potentially enabling targeted predictions and interventions to mitigate FGR's impacts on mothers and offspring.