Chronic histiocytic intervillositis of the placenta: clinical outcomes and relationships with circulating placental growth factor and uterine artery Doppler waveforms.

Abstract

Chronic histiocytic intervillositis is a rare placental disorder characterized by maternal macrophage accumulation within the intervillous space of the placenta. Local cytokine release by these immune cells mediates injury to the developing placental villi, resulting in a spectrum of early pregnancy loss, severe fetal growth restriction, or stillbirth. Despite good evidence that chronic histiocytic intervillositis begins in early pregnancy, no effective risk assessment tools exist to predict pregnancy outcomes and, thus, appropriate fetal surveillance. This study aimed to explore the role of serial circulating placental growth factor and uterine artery Doppler waveform assessments beginning in the early second trimester in pregnancies that were found to be complicated by chronic histiocytic intervillositis of the placenta. Single-center historical cohort study of pregnancy outcomes in pregnancies with a confirmed pathologic diagnosis of placental chronic histiocytic intervillositis between March 2010 and August 2025. Maternal demographics, uterine artery Doppler waveform indices, circulating placental growth factor levels, and maternal and perinatal outcomes were abstracted from electronic medical record systems. Placental growth factor testing was available from 2017 onward. Abnormal uterine artery Doppler was defined as a mean pulsatility index of >95th percentile or bilateral early diastolic notching. Placental growth factor levels of <10th percentile for gestational age were considered abnormal. Diagnostic test characteristics (with 95% confidence intervals), including sensitivity, specificity, and likelihood ratios, were estimated to assess the performance of low circulating placental growth factor and uterine artery Doppler waveforms for subsequent stillbirth. Overall, 66 patients met the inclusion criteria, with a mean maternal age of 33.2 ± 5.1 years. Only 13 pregnancies (20%) were delivered at term (>37 weeks of gestation). Stillbirth occurred in 17 pregnancies (26%), and 44 infants (67%) were discharged alive. Among live births, 50% had birthweights below the 10th percentile (birth weight: mean ± standard deviation, 1341 ± 1009 g). Placental growth factor was below the 10th percentile in nearly all cases, including all 17 pregnancies resulting in a stillbirth. Between 16 and 23 weeks of gestation, low placental growth factor showed high sensitivity for stillbirth (0.95 [95% confidence interval, 0.77-0.99]) but limited specificity (0.50 [95% confidence interval, 0.18-0.82]), with a modest positive likelihood ratio (1.9 [95% confidence interval, 0.82-4.40]) and a low negative likelihood ratio (0.10 [95% confidence interval, 0.02-0.65]), indicating strong rule-out performance. Of note, 27 of 45 tested patients (60%) had normal uterine artery mean pulsatility index values. Of the 18 patients with abnormal uterine artery Dopplers, 7 (39%) had coexistent maternal vascular malperfusion. Abnormal uterine artery Doppler at 16 to 23 weeks of gestation was not associated with the subsequent risk of stillbirth (likelihood ratio, 1.22 [95% confidence interval, 0.19-7.61]); sensitivity, 0.22 [95% confidence interval, 0.05-0.50]; and specificity, 0.81 [95% confidence interval, 0.05-0.25]). Pregnancies complicated by chronic histiocytic intervillositis have a high rate of adverse pregnancy outcomes, including extreme preterm delivery and associated stillbirth due to severe fetal growth restriction. Low circulating maternal placental growth factor level in the early second trimester of pregnancy may serve as a useful early biomarker for evolving chronic histiocytic intervillositis. In contrast, uterine artery Doppler waveforms were less informative when chronic histiocytic intervillositis was the only placental pathology diagnosis. Serial placental growth factor tests in the early second trimester of pregnancy may be a useful prognostic marker in subsequent pregnancies after a placental diagnosis of chronic histiocytic intervillositis, including the potential to provide in vivo evidence of the effects of various proposed drug regimens to prevent chronic histiocytic intervillositis recurrence.