Placental differences between severe fetal growth restriction and hypertensive disorders of pregnancy requiring early preterm delivery: Morphometric analysis of the villous tree supported by artificial intelligence.

BACKGROUND: The "great obstetrical syndromes" of fetal growth restriction and hypertensive disorders of pregnancy can occur individually or be interrelated. Placental pathologic findings often overlap between these conditions, regardless of whether one or both diagnoses are present. Quantification of placental villous structures in each of these settings may identify distinct differences in developmental pathways.

OBJECTIVE: To determine how quantity and surface area of placental villi and vessels differ between severe, early-onset fetal growth restriction with absent/reversed umbilical artery Doppler indices, hypertensive disorders of pregnancy, and the two conditions combined among subjects with disease severity warranting early preterm delivery. We hypothesize that trajectories of placental morphogenesis diverge after a common initiating insult of deep defective placentation. Specifically, we postulate that only villi are affected in pregnancy-related hypertension, whereas both villous and vascular structures are proportionally diminished in severe fetal growth restriction, with no additional effect when hypertension is concomitantly present.

STUDY DESIGN: In this retrospective cohort study, paraffin-embedded placental tissue was obtained from four groups: [1] Severe fetal growth restriction with absent/reversed umbilical artery end-diastolic velocities and hypertensive disorders of pregnancy, [2] Severe fetal growth restriction with absent/reversed umbilical artery Doppler indices and no hypertension,[3] Gestational age-matched, appropriately grown pregnancies with hypertensive disease, and [4] Gestational age-matched, appropriately grown pregnancies without hypertension. Dual immunohistochemistry for cytokeratin-7 (trophoblast) and CD34 (endothelial cells) was performed followed by artificial intelligence-driven morphometric analyses. Number of villi, total villous area, number of fetoplacental vessels, and total vascular area across villi within a uniform region of interest were quantified. Quantitative analyses of placental structures were modeled with linear regression.

RESULTS: Placentas from pregnancies complicated by hypertensive disorders of pregnancy exhibited significantly fewer stem villi (-282 stem villi, 95% CI: [-467, -98], p<0.01), smaller stem villous area (-4.3 mm2 , 95% CI: [-7.3, -1.2], p<0.01), and fewer stem villous vessels (-4967 stem villous vessels, 95% CI [-8501, -1433], p<0.01), with no difference in total vascular area. In contrast, placental abnormalities in severe growth restriction were limited to terminal villi, with global decreases in number of villi (-873 terminal villi, 95% CI: [-1501, -246], p<0.01), villous area (-1.5 mm2 , 95% CI: [-2.7, -0.4], p<0.01), number of blood vessels (-5165 terminal villous vessels, 95% CI: [-8201, -2128], p<0.01), and vascular area (-0.6 mm2 , 95% CI: [-1.1, -0.1], p=0.02). The combination of hypertension and growth restriction had no additional effect beyond the individual impact of each state.

CONCLUSION: Pregnancies complicated by hypertensive disorders of pregnancy exhibited defects in the stem villi only, whereas placental abnormalities in severely growth restricted pregnancies with absent/reversed umbilical artery end-diastolic velocities were limited to the terminal villi. There were no significant statistical interactions with the combination of growth restriction and hypertension, suggesting that distinct pathophysiologic pathways downstream of the initial insult of defective placentation are involved in each entity and do not synergize to result in more severe pathologic consequences. Delineating mechanisms underlying the divergence in placental development after a common inciting event of defective deep placentation may shed light on new targets for prevention or treatment.