背景:胎儿生长受限和妊娠期高血压疾病的“大产科综合征”可以单独发生或相互关联。胎盘病理结果通常在这些情况之间重叠,无论一个或两个诊断是否存在。在这些设置中的每一个中胎盘绒毛结构的定量可以识别发育途径的不同差异。
目的:为了确定胎盘绒毛和血管的数量和表面积在严重,早发性胎儿生长受限伴脐动脉多普勒指数缺失/逆转,妊娠高血压疾病,在疾病严重程度需要早期早产的受试者中,两种情况相结合。我们假设胎盘形态发生的轨迹在深缺陷胎盘形成的共同起始损伤后会发散。具体来说,我们假设只有绒毛在妊娠相关的高血压中受到影响,而绒毛和血管结构在严重的胎儿生长受限中都成比例地减少,当同时存在高血压时没有额外的作用。
方法:在这项回顾性队列研究中,从四组获得石蜡包埋的胎盘组织:[1]严重的胎儿生长受限,脐动脉舒张末期速度缺失/逆转和妊娠高血压疾病,[2]严重胎儿生长受限,脐动脉多普勒指数缺失/逆转,无高血压,[3]妊娠年龄匹配,适当增长的妊娠高血压疾病,和[4]妊娠年龄匹配,适当生长的怀孕没有高血压。对细胞角蛋白7(滋养层)和CD34(内皮细胞)进行双重免疫组织化学,然后进行人工智能驱动的形态计量学分析。绒毛的数量,绒毛总面积,胎儿胎盘血管的数量,和跨绒毛的总血管面积在一个统一的感兴趣的区域被量化。胎盘结构的定量分析用线性回归建模。
结果:妊娠合并高血压疾病的胎盘表现出明显更少的茎绒毛(-282茎绒毛,95%CI:[-467,-98],p<0.01),较小的茎绒毛面积(-4.3mm2,95%CI:[-7.3,-1.2],p<0.01),和更少的茎绒毛血管(-4967茎绒毛血管,95%CI[-8501,-1433],p<0.01),血管总面积没有差异。相比之下,严重生长受限的胎盘异常仅限于晚期绒毛,随着全球绒毛数量的减少(-873终端绒毛,95%CI:[-1501,-246],p<0.01),绒毛面积(-1.5mm2,95%CI:[-2.7,-0.4],p<0.01),血管数量(-5165个末端绒毛血管,95%CI:[-8201,-2128],p<0.01),和血管面积(-0.6mm2,95%CI:[-1.1,-0.1],p=0.02)。除了每种状态的个体影响外,高血压和生长受限的组合没有其他作用。
结论:妊娠合并高血压疾病的妊娠仅在茎绒毛中表现出缺陷,而严重生长受限妊娠的胎盘异常,脐动脉舒张末期速度缺失/逆转,仅限于终末绒毛。生长受限和高血压的组合没有显著的统计学交互作用,这表明胎盘缺陷初始损伤下游的不同病理生理途径涉及每个实体,并且不会协同作用导致更严重的病理后果。在深胎盘缺陷的常见诱因事件后,描绘胎盘发育差异的潜在机制可能会揭示预防或治疗的新目标。
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 1 or both diagnoses are present. Quantification of placental villous structures in each of these settings may identify distinct differences in developmental pathways.
OBJECTIVE: 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.
METHODS: 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.
RESULTS: 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 mm2; 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 mm2; 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 mm2; 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.
CONCLUSIONS: 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.