Jacobs Anna, Al-Juboori Saif I, Dobrinskikh Evgenia, Bolt Matthew A, Sammel Mary D, Lijewski Virginia, Post Miriam D, Small James M, Su Emily J
Rocky Vista University College of Osteopathic Medicine, Parker, CO.
Section of Neonatology, Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO.
Am J Obstet Gynecol. 2024 Nov;231(5):552.e1-552.e13. doi: 10.1016/j.ajog.2024.02.291. Epub 2024 Feb 27.
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 1 or both diagnoses are present. Quantification of placental villous structures in each of these settings may identify distinct differences in developmental pathways.
This study aimed to determine how the quantity and surface area of placental villi and vessels differ between severe, early-onset fetal growth restriction with absent or reversed umbilical artery Doppler indices and hypertensive disorders of pregnancy or the 2 conditions combined among subjects with disease severity that warrant early preterm delivery. We hypothesized that the trajectories of placental morphogenesis diverge after a common initiating insult of deep defective placentation. Specifically, we postulated 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.
In this retrospective cohort study, paraffin-embedded placental tissue was obtained from 4 groups, namely (1) patients with severe fetal growth restriction with absent or reversed umbilical artery end-diastolic velocities and hypertensive disorders of pregnancy, (2) patients with severe fetal growth restriction with absent or 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. The 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 using linear regression.
Placentas from pregnancies complicated by hypertensive disorders of pregnancy exhibited significantly fewer stem villi (-282 stem villi; 95% confidence interval, -467 to -98; P<.01), a smaller stem villous area (-4.3 mm; 95% confidence interval, -7.3 to -1.2; P<.01), and fewer stem villous vessels (-4967 stem villous vessels; 95% confidence interval, -8501 to -1433; P<.01) with no difference in the total vascular area. In contrast, placental abnormalities in cases with severe growth restriction were limited to terminal villi with global decreases in the number of villi (-873 terminal villi; 95% confidence interval, -1501 to -246; P<.01), the villous area (-1.5 mm; 95% confidence interval, -2.7 to -0.4; P<.01), the number of blood vessels (-5165 terminal villous vessels; 95% confidence interval, -8201 to -2128; P<.01), and the vascular area (-0.6 mm; 95% confidence interval, -1.1 to -0.1; P=.02). The combination of hypertension and growth restriction had no additional effect beyond the individual impact of each state.
Pregnancies complicated by hypertensive disorders of pregnancy exhibited defects in the stem villi only, whereas placental abnormalities in severely growth restricted pregnancies with absent or reversed umbilical artery end-diastolic velocities were limited to the terminal villi. There were no significant statistical interactions in the combination of growth restriction and hypertension, suggesting that distinct pathophysiological pathways downstream of the initial insult of defective placentation are involved in each entity and do not synergize to lead to more severe pathologic consequences. Delineating mechanisms that underly the divergence in placental development after a common inciting event of defective deep placentation may shed light on new targets for prevention or treatment.
胎儿生长受限和妊娠期高血压疾病这两大产科综合征可单独出现或相互关联。无论是否存在一种或两种诊断，这些情况之间的胎盘病理表现通常存在重叠。对每种情况下胎盘绒毛结构进行量化，可能会发现发育途径中的明显差异。
本研究旨在确定，在因疾病严重程度而需要早期早产的受试者中，伴有脐动脉多普勒指数缺失或倒置的严重早发型胎儿生长受限与妊娠期高血压疾病或这两种情况合并存在时，胎盘绒毛和血管的数量及表面积有何不同。我们假设，在胎盘深层发育缺陷这一共同起始损伤后，胎盘形态发生的轨迹会出现分歧。具体而言，我们推测在妊娠相关高血压中仅绒毛受到影响，而在严重胎儿生长受限中绒毛和血管结构均成比例减少，同时存在高血压时无额外影响。
在这项回顾性队列研究中，从4组中获取石蜡包埋的胎盘组织，即（1）伴有脐动脉舒张末期血流速度缺失或倒置及妊娠期高血压疾病的严重胎儿生长受限患者；（2）伴有脐动脉多普勒指数缺失或倒置且无高血压的严重胎儿生长受限患者；（3）孕周匹配、生长正常且患有高血压疾病的孕妇；（4）孕周匹配、生长正常且无高血压的孕妇。进行细胞角蛋白-7（滋养细胞）和CD34（内皮细胞）的双重免疫组化，随后进行人工智能驱动的形态计量分析。对一个统一感兴趣区域内的绒毛数量、总绒毛面积、胎儿胎盘血管数量以及绒毛内的总血管面积进行量化。使用线性回归对胎盘结构进行定量分析。
并发妊娠期高血压疾病的妊娠胎盘显示，干绒毛显著减少（减少282条干绒毛；95%置信区间为-467至-98；P<0.01），干绒毛面积减小（减小4.3平方毫米；95%置信区间为-7.3至-1.2；P<0.01），干绒毛血管减少（减少4967条干绒毛血管；95%置信区间为-8501至-1433；P<0.01），而总血管面积无差异。相比之下，严重生长受限病例中的胎盘异常仅限于终末绒毛，绒毛数量总体减少（减少873条终末绒毛；95%置信区间为-1501至-246；P<0.01），绒毛面积减小（减小1.5平方毫米；95%置信区间为-2.7至-0.4；P<0.01），血管数量减少（减少终末绒毛血管5165条；95%置信区间为-8201至-2128；P<0.01），血管面积减小（减小0.6平方毫米；95%置信区间为-1.1至-0.1；P=0.02）。高血压和生长受限合并存在时，除了每种状态的个体影响外，没有额外影响。
并发妊娠期高血压疾病的妊娠仅在干绒毛出现缺陷，而伴有脐动脉舒张末期血流速度缺失或倒置的严重生长受限妊娠中的胎盘异常仅限于终末绒毛。生长受限和高血压合并存在时无显著统计学交互作用，这表明胎盘深层发育缺陷这一初始损伤下游的不同病理生理途径参与了每种情况，且不会协同导致更严重的病理后果。阐明胎盘深层发育缺陷这一共同激发事件后胎盘发育分歧的潜在机制，可能会为预防或治疗的新靶点提供线索。
