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Background Hypertensive disorders of pregnancy (HDP) are associated with short-term cardiac structure and function abnormalities, but later life changes are not well studied. Objectives This study aimed to determine if HDP history is associated with echocardiographic differences 8 to 10 years after delivery, and if subgroups with placental maternal vascular malperfusion (MVM) lesions or current hypertension may be particularly affected. Methods Women with pregnancies delivered from 2008 to 2009 were selected from a clinical cohort with abstracted pregnancy and placental pathology data to undergo transthoracic echocardiography (2017 to 2020). Medical history, blood pressure, and weight were measured at the study visit. Results The authors enrolled 132 women (10 ± 1 years post-delivery, age 38 ± 6 years): 102 with normotensive pregnancies and 30 with HDP: pre-eclampsia (n = 21) or gestational hypertension (n = 9). Compared with women with normotensive pregnancies, those with HDP history were more likely to have current hypertension (63% vs. 26%; p Conclusions Women with both HDP history and current hypertension have pronounced differences in left ventricular structure and function a decade after pregnancy, warranting continued surveillance and targeted therapies for cardiovascular disease prevention.

BackgroundThere is growing evidence of sex differences in placental vascular development. The objective of this study was to investigate the effect of fetal sex on uterine artery pulsatility index (PI) throughout gestation in a cohort of normal and complicated pregnancies.MethodsA prospective longitudinal study was conducted in 240 pregnant women. Pulsed wave Doppler ultrasound of the proximal uterine arteries was performed at a 4-weekly interval between 14 and 40 weeks of gestation. The patients were classified retrospectively as normal or complicated (one or more of maternal preeclampsia, preterm birth, or small for gestational age). To assess if the change in uterine artery PI during gestation differed between normal and complicated pregnancies and between fetal sexes, the uterine artery PI was modeled using a linear function of gestational age and the rate of change was estimated from the slope.ResultsWhile the uterine artery PI did not differ over gestation between females and males for normal pregnancies, the trajectory of this index differed by fetal sex for pregnancies complicated by either preeclampsia, preterm birth, or fetal growth restriction (p< 0.0001). The male fetuses in the complicated pregnancy group had an elevated slope compared to the other groups (p< 0.0001), suggesting a more progressive deterioration in uteroplacental perfusion over gestation.ConclusionsThe uterine artery PI is widely used to assess uteroplacental function in clinical settings. The observation that this metric changes more rapidly in complicated pregnancies where the fetus was male highlights the importance of sex when interpreting hemodynamic markers of placental maturation.

POINTS CLES Une femme de 40 ans (gravida 2, para 1) a ete admise dans un hopital de soins tertiaires de Toronto, en Ontario. On a note chez elle : neutropenie familiale, diabete de grossesse et probleme d’infections bacteriennes a repetition, dont 3 episodes (sinusite, dermatite et

Introduction Wharton's jelly (WJ) is the mucoid connective tissue that surrounds the vessels in the human umbilical cord and provides protection from compression and torsion in response to fetal movement. WJ is known to be altered in the presence of pregnancy complications such as gestational diabetes mellitus and preeclampsia. The present study examined associations between the cross-sectional area of WJ measured by ultrasound and postpartum placental pathology and morphometry. Methods The area of WJ was measured by ultrasound in 156 eligible participants between 23 and 37 weeks’ gestation. Morphometric assessment of fixed cord cross sections was conducted, together with assessment of the cord and placenta for specific pathologies using standard criteria. Results From 156 participants, 123 ultrasound images met the data quality requirements and pathology reporting was completed for 99 placentas. 17 of the participants (14%) delivered a small for gestational age neonate and 32 of the 99 placentas examined (32%) had significant placental pathology findings. Area of WJ was associated with low birth weight (p = 0.002) and was associated with specific placental pathology (p = 0.01). WJ area was positively associated with placental dimensions such as width, length and surface area. Discussion Decreased WJ area is associated with clinically-significant placental pathology and WJ area scales proportionally with placental size. These findings suggest that WJ area correlates with functional capacity of the placenta and thus merits further evaluation alongside currently-available tests of placental function in clinical practice.

Background Evidence of placental maternal vascular malperfusion is associated with significant perinatal outcomes such as preeclampsia, intrauterine growth restriction and preterm birth. Elevations in pre-pregnancy blood pressure increase the risk for poor perinatal outcomes; however, the evidence linking pre-pregnancy blood pressure and placental malperfusion is sparse. Materials and methods We conducted a retrospective case-control study of women with singleton gestations with placental evaluations who delivered at Magee-Womens Hospital in 2012. Charts from 100 deliveries with placental malperfusion lesions (vasculopathy, advanced villous maturation, infarct, or fibrin deposition) and 102 deliveries without placental malperfusion were randomly selected for screening. Blood pressure, demographic, and clinical data were abstracted from pre-pregnancy electronic medical records and compared between women with and without subsequent placental malperfusion lesions. Results Overall, 48% of women had pre-pregnancy records, and these were similarly available for women with and without placental malperfusion. Women with placental malperfusion demonstrated a reduction in their pre- to early pregnancy decrease in diastolic blood pressure (DBP). Adjusted for race, pre-pregnancy BMI, age, pre-conception interval, and gestational age at the first prenatal visit, the difference in pre- to early pregnancy DBP was significantly less in women with placental malperfusion compared to those without this pathologic finding (− 1.35 mmHg drop vs − 5.6mmg, p Conclusion A blunted early gestation drop in DBP may be a risk factor for placental malperfusion, perhaps related to early pregnancy vascular maladaptation. The ability of the electronic medical record to provide pre-pregnancy data serves as an underutilized approach to study pre-pregnancy health.

OBJECTIVES—: To determine the relationship between blood flow in the fetal descending aorta and discordant umbilical arteries (UAs). METHODS—: Pulsed wave Doppler of both UAs and the descending aorta was performed at 4-weekly intervals between 14 and 40 weeks of gestation in 209 pregnant women. In datasets with discordant UAs, a linear mixed effects model was used to determine the categorical relationship between the UA pulsatility index (PI) (high, low and average) and the descending aorta PI. RESULTS—: Of the 209 cases, 81 had a discordance of greater than 25% in UA PI during one of their visits. There were no differences in birth outcomes between the groups with concordant and discordant UA PIs. In the cases with discordant UA PIs, the descending aorta PI was most strongly associated with both the average UA PI (P = .008), and with the UA with the lower PI (P = .008). CONCLUSIONS—: The relationship between blood flow in the descending aorta and UAs is consistent with the law for combining resistances in parallel. Measurements of the descending aorta PI, particularly in a scenario with discordant UAs, may inform the stability of the feto-placental circulation where discordant UA PIs are found.

Patients at high risk of severe preeclampsia and fetal growth restriction have low circulating levels of placental growth factor and features of maternal vascular malperfusion placental pathology at delivery. Multimodal screening and commencement of aspirin prophylaxis at 11 to 13 weeks' gestation markedly reduces the risk of preterm delivery with preeclampsia. However, the additional role of low-molecular-weight heparin and mechanisms of action remain uncertain. Because low-molecular-weight heparin augments the production and release of placental growth factor in vitro by both placental villi and vascular endothelium, it may be effective to suppress the risk of severe preeclampsia in a niche group of high-risk patients with low circulating placental growth factor in the early second trimester.This study aimed to define a gestational age-specific reference range for placental growth factor and to test the hypothesis that prophylactic low-molecular-weight heparin administered in the early second trimester may restore deficient circulating placental growth factor levels and thereby prolong pregnancy.Centile curves for circulating placental growth factor levels from 12 to 36 weeks' gestation were derived using quantile regression of combined data from a published cohort of 4207 unselected nulliparous patients in Cambridge, United Kingdom, at 4 sampling time points (12, 20, 28, and 36 weeks' gestation) and the White majority (n=531) of a healthy nulliparous cohort in Toronto, Canada, at 16 weeks' gestation using the same test platform. Within a specialty high-risk clinic in Toronto, a niche group of 7 patients with a circulating placental growth factor at the10th centile in the early second trimester received daily prophylactic low-molecular-weight heparin (enoxaparin; 40 mg subcutaneously) and were followed up until delivery (group 1). Their baseline characteristics, delivery details, and placental pathologies were compared with 5 similar patients who did not receive low-molecular-weight heparin during the observation period (group 2) and further with 21 patients who delivered with severe preeclampsia (group 3) in the same institution.A gestational age-specific reference range for placental growth factor levels at weekly intervals between 12 and 36 weeks was established for White women with singleton pregnancies. Within group 1, 5 of 7 patients demonstrated a sustained increase in circulating placental growth factor levels, whereas placental growth factor levels did not increase in group 2 or group 3 patients who did not receive low-molecular-weight heparin. Group 1 patients receiving low-molecular-weight heparin therapy exhibited a later gestation at delivery, relative to groups 2 and 3 (36 weeks [33-37] vs 23 weeks [22-26] and 28 weeks [27-31], respectively), and consequently had higher birthweights (1.93 kg [1.1-2.7] vs 0.32 kg [0.19-0.39] and 0.73 kg [0.52-1.03], respectively). The incidence of stillbirth was lowest in group 1 (14% [1 of 7]), relative to groups 2 and 3 (80% [4 of 5] and 29% [6 of 21], respectively). Maternal vascular malperfusion was the most common placental pathology found in association with abnormal uterine artery Doppler.In patients at high risk of a serious adverse pregnancy outcome owing to placental disease, the addition of low-molecular-weight heparin to aspirin prophylaxis in the early second trimester may restore deficient circulating placental growth factor to mediate an improved perinatal outcome. These data support the implementation of a multicenter pilot randomized control trial where patients are recruited primarily based on the assessment of placental function in the early second trimester.

Background: Preeclampsia is emerging as a sex-specific risk factor for cerebral small vessel disease (SVD) and dementia, but the reason is unknown. We assessed the relationship of maternal vascular malperfusion (MVM), a marker of placental SVD, with cognition and cerebral SVD in women with and without preeclampsia. We hypothesized women with both preeclampsia and MVM would perform worst on information processing speed and executive function.Methods: Women (n = 45; mean 10.5 years post-delivery; mean age: 41 years; 42.2% Black) were classified as preeclampsia-/MVM-, preeclampsia+/MVM-, or preeclampsia+/MVM+. Information processing speed, executive function, and memory were assessed. In a pilot sub-study of cerebrovascular reactivity (CVR; n = 22), cerebral blood flow during room-air breathing and breath-hold induced hypercapnia were obtained via arterial spin labeling MRI. Non-parametric tests and regression models were used to test associations.Results: Between-group cognitive differences were significant for information processing speed (p = 0.02); preeclampsia+/MVM+ had the lowest scores. Cerebral blood flow increased from room-air to breath-hold, globally and in all regions in the three groups, except the preeclampsia+/MVM+ parietal region (p = 0.12). Lower parietal CVR (less change from room-air breathing to breath-holding) was correlated with poorer information processing speed (partial ρ = 0.63, p = 0.005) and executive function (ρ = 0.50, p = 0.03) independent of preeclampsia/MVM status.Conclusion: Compared to women without preeclampsia and MVM, midlife women with both preeclampsia and MVM have worse information processing speed and may have blunted parietal CVR, an area important for information processing speed and executive function. MVM in women with preeclampsia is a promising sex-specific indicator of cerebrovascular integrity in midlife.

Background: The umbilical artery (UA) Doppler pulsatility index is used clinically to detect elevated feto-placental vascular resistance. However, this metric is confounded by variation in fetal cardiac function and is only moderately predictive of placental pathology. Our group developed a novel ultrasound methodology that measures wave reflections in the UA, thereby isolating a component of the Doppler signal that is specific to the placenta. The present study examined whether wave reflections in the UA are predictive of placental vascular pathology. Methods: Standard clinical Doppler ultrasound of the UAs was performed in 241 pregnant women. Of these, 40 women met narrowly defined preset criteria for the control group, 36 had maternal vascular malperfusion (MVM) and 16 had fetal vascular malperfusion (FVM). Using a computational procedure, the Doppler waveforms were decomposed into a pair of forward and backward propagating waves. Findings: Compared to controls, wave reflections were significantly elevated in women with either MVM (p

Objective To describe the evolution and evaluation of protocol-based multidisciplinary quality improvement (QI) in women undergoing cesarean hysterectomy for radiologically suspected and pathologically confirmed placenta accreta spectrum (PAS) disorders. Methods A single-center, retrospective cohort study was conducted of all patients undergoing cesarean hysterectomy for PAS disorders between March 2009 and June 2018. Two distinct periods were defined to compare outcomes: 2009-2011 (initial period) and 2017-2018 (current period). Primary outcomes included blood loss and administration of blood products. Secondary outcomes included perioperative levels of hemoglobin, adverse events and complications, time to mobilization, and length of hospitalization. Results Among the 105 consecutive patients identified, there were 26 in the initial period and 32 in the current period. With the implementation of all QI care bundles, median estimated surgical blood loss halved from 2000 mL in the initial period to 1000 mL in the current period, and fewer patients required allogenic blood transfusion (61.5% vs 25%). Patients in the current period demonstrated improved postoperative levels of hemoglobin compared to those in the initial period (101 g/L vs 89 g/L) and had a shorter median postoperative hospital stay (3 days vs 5 days). Conclusion These results support the implementation of a multifaceted QI and patient care initiative for women with PAS disorders.

Background Fetal sex is known to affect pregnancy outcomes. In current clinical practice, monitoring of fetal well-being is based on Doppler ultrasound measurements of major placental and fetal vessels. The objective of this study was to investigate the effect of fetal sex on Doppler parameters throughout gestation in healthy pregnancy. Methods A prospective study was conducted in 240 pregnant women with ultrasound examinations at a 4-weekly interval between 12 and 38 weeks of gestation. Pulsed Doppler spectra were collected for the umbilical arteries (UAs), middle cerebral artery (MCA), descending abdominal aorta (DAo), and ductus venosus (DV). Linear mixed effects models were used to determine if the pulsatility indices (PIs) of these vessels depended on gestational age and fetal sex. Results While there were no differences in the MCA PI and DV PIV over gestation between female and male fetuses, the trajectory of the UA and DAo PIs differed by fetal sex (p = 0.02 and p = 0.01, respectively). Conclusions Doppler ultrasound parameters were found to be dependent on fetal sex for some vessels and not for others in healthy pregnancies. Further investigations are needed to understand the physiological mechanisms for these sex differences and the relevance for disease processes in pregnancy.

Introduction Women with adverse pregnancy outcomes (APOs) have excess risk of later life cardiovascular disease (CVD) perhaps related to an underlying high-risk vascular phenotype. We sought to determine if placental evidence of maternal malperfusion in uncomplicated pregnancies is associated with an increased risk of APOs in subsequent pregnancies. Methods 536 women with more than one delivery and an initial uncomplicated pregnancy with placental pathology examination between 2008 and 2012 were included. APOs (small for gestational age, preterm delivery, or preeclampsia) were identified for each delivery. Multivariable log-binomial regression was used to estimate the risk of an APO in a subsequent pregnancy associated with MVM lesions in index pregnancy with adjustment for covariates. Results Placental pathology from the initial pregnancy was compared between women with no APO in any pregnancy (-APO/-APO; n = 403) and women with an initial uncomplicated pregnancy and a subsequent adverse outcome (-APO/+APO; n = 133). Women with MVM lesions had an increased risk of an APO in a subsequent pregnancy relative to women with no MVM lesions after adjusting for covariates (aOR = 1.61; 95%CI = 1.06–2.46). Decidual vasculopathy was found in 13/133 (9.8%) of -APO/+APO women compared with 16/403 (4.0%) of -APO/-APO women, with an adjusted odds ratio of 2.51 (95% CI = 1.31–4.80). Discussion MVM lesions found in placentas in uncomplicated pregnancies are associated with an increased risk of an adverse outcome in a subsequent pregnancy. Placental evidence of vascular malperfusion could offer a novel approach to risk stratification for subsequent pregnancy complications and perhaps future CVD.

Introduction The biological mechanisms that underlie racial disparities in placenta-mediated pregnancy complications remain unknown. Placental evidence of maternal vascular malperfusion (MVM), a common pathologic feature of these outcomes, represents hypoxic-ischemic damage to the placenta. We sought to separately estimate the risk of MVM and individual lesions associated with maternal race. Methods This was a retrospective cohort study of black and white women with singleton live births and placental pathology data at Magee-Womens Hospital during 2008–2012 (n = 15,581). MVM consisted of ≥1 individual lesions: low placental weight, decidual vasculopathy, accelerated villous maturation, infarcts, and fibrinoid deposition. We separately compared the incidence of MVM and individual lesions in black and white women using logistic regression with generalized estimating equations. Results After adjusting for covariates, black women had increased risks of MVM (aOR 1.14, 95% CI 1.05–1.23), low placental weight (aOR 1.41, 95% CI 1.28–1.55), and decidual vasculopathy (aOR 1.58, 95% CI 1.36–1.83), also observed in uncomplicated, preterm, and term births. Conversely, black women had decreased risk of infarcts (aOR 0.84, 95% CI 0.75–0.95) compared with white women, also observed in uncomplicated and full-term births. Race was not associated with accelerated villous maturation or fibrinoid deposition. Inverse probability weighting to account for potential selection bias generated similar results. Discussion Our findings suggest that excess risks of MVM, specifically low placental weight and decidual vasculopathy in black women may be due to a pathological susceptibility to an underlying high-risk vascular phenotype. The clinical significance of race differences in the occurrence of infarcts warrants further investigation.

The placenta is one of the most exciting organs. It is dynamic; its morphology and function continuously develop and adjust over its brief life span. It mediates the physiology of two distinct yet highly interconnected individuals. The pathology that develops in the placenta, and the adaptations the placenta undergoes to mitigate this pathology, may influence the later life health of the mother and baby (Circ Res, 116, 2015, 715; Hum Reprod Update, 17, 2011, 397; Nutr Rev 71, 2013, S88; Placenta, 36, 2015, S20). Pathological placenta examination may reveal macroscopic and microscopic patterns that provide valuable information to the obstetricians, neonatologists, and pediatricians caring for the family. The placenta often plays a key role in understanding adverse fetal outcomes such as hypoxic brain injury, cerebral palsy, fetal growth restriction, stillbirth, and neonatal death (Placenta, 35, 2014, 552; Placenta, 52, 2017, 58; Placenta, 30, 2009, 700; Obstet Gynecol, 114, 2009, 809; Clin Perinatol, 33, 2006, 503; Pediatr Dev Pathol, 11, 2008, 456; Arch Pathol Lab Med, 124, 2000, 1785). Moreover, it may help to understand the pathophysiology of pregnancy, improve management of subsequent pregnancies, and assist in medicolegal assessment. Placental pathologic examination may even provide evidence of susceptibility to adult-onset diseases such as diabetes (Pediatr Dev Pathol, 6, 2003, 54; Diabetes Metab, 36, 2010, 682; BJOG, 113, 2006, 1126; Int J Gynaecol Obstet, 104, 2009, S25; Zentralbl Gynakol, 97, 1975, 875). Pathologic examination of the placenta may thus be of tremendous value, particularly for those women experiencing an adverse pregnancy outcome. However, this potential utility may be entirely wasted, if the findings are not communicated in an effective manner to the appropriate clinicians. An optimized, readily understandable report of pathological findings is essential for clinical utility.

The placental pathologies that develop in the context of hypoxic insults to the fetus and placenta are termed maternal vascular malperfusion (MVM). On molecular analysis, these lesions primarily show evidence of oxidative damage, suggesting that they arise in the context of hypoxia-reperfusion injury. The earliest abnormalities are likely incomplete or absent remodeling of maternal spiral arteries (decidual arteriopathy). These vascular remodeling defects then lead to subsequent damage patterns, including accelerated villous maturation, distal villous hypoplasia, increased syncytial knots, villous infarction, retroplacental hemorrhage, and placental hypoplasia. MVM may occur in a surprisingly wide array of clinical disorders, but the relation between these clinical disorders and placental MVM is complex. It seems likely that these clinical disorders represent final common pathways for multiple etiologies, only some of which result in MVM. Birth Defects Research 109:1345-1357, 2017.© 2017 Wiley Periodicals, Inc.

Introduction Preterm birth is a heterogeneous phenotype, with placental abnormalities underlying many cases. The etiology of preterm births that occur in the absence of placental abnormalities, however, remain enigmatic and we considered that early pregnancy biomarkers may provide clues. Methods Women from a hospital-based cohort (2008–2012, n = 397) were randomly selected within 6 strata of term and preterm birth with and without placental decidual vasculopathy (arteriopathy), intrauterine inflammation/infection (acute chorioamnionitis), or no lesions. Lipids and inflammatory markers were analyzed in first trimester samples (12.5 ± 0.6 weeks) and related to outcome groups (referent, term births with no lesions). Factor analysis then clustered analytes and related these to preterm birth groups, adjusted for covariates and stratified by pre-pregnancy obesity. Results Three biomarker patterns were identified. Immune activation cytokines (33% of the variance) were associated with preterm birth with no lesions (aOR 1.5, 95%CI 1.1–2.1), particularly among obese women. In contrast, inflammatory chemokines (9% of variance) were associated with term and preterm vasculopathy among non-obese women (aOR 2.6 [1.3, 4.7] and 2.0 [1.1, 3.0], respectively). Discussion The early pregnancy maternal immune profile is related to preterm births classified according to placental lesions, and these associations vary according to obesity status.

Introduction: Women with placentally mediated pregnancy complications such as preeclampsia have excess hypertension and cardiovascular disease later in life, but the underlying pathophysiology linking these conditions is unknown. Hypothesis: We considered that histological examination of the placenta may reveal maternal vascular impairments that identify a group susceptible to blood pressure (BP) elevations a decade after delivery, including elevations that may only be detectable using out of office BP measurement. Method: Women with a singleton live birth at Magee-Womens Hospital (Pittsburgh, PA) during 2008-2009 were enrolled 8-10 years after delivery (n=248). Pregnancy features and placental pathology were abstracted from medical records. Women with placental vasculopathy (several related lesions arising from impaired remodeling of maternal myometrial and decidual arteries, n=24) or infarcts (n=32) were compared to women with neither lesion (n=192). Clinic BP was measured three times by trained research staff using a standard protocol and a validated home BP device. Women were trained to measure their BP twice daily for 7 days using the same device mentioned above. Subsequently, time and date stamped BP measures were downloaded (mean 12.2 measures ± 4.5). BP status (elevated, stage 1, stage 2) was identified using the 2018 ACC/AHA guidelines for clinic and home BP measures. Sustained normotensive, white coat, masked, and sustained hypertension status were classified. Results: Women were, on average, 37 years of age at measurement. In analysis controlled for age and race (p-value < 0.05) those with placental vasculopathy had higher mean diastolic BP in clinic and at home (80.5 ± 13.3 mmHg, 79.9 ± 10.4, respectively) than women without vascular lesions in the placenta (75.4 ± 9.8 mmHg and 74.3 ±8.6, respectively). In addition, women with placental vasculopathy had a higher prevalence of masked hypertension (higher elevated BP status measured at home vs. in clinic; 37.5% vs. 14.1%) that persisted after accounting for maternal age and race (adjusted OR 4.7, 95% confidence interval 1.6, 13.8). Vasculopathy associations were similar after excluding women with preeclampsia (n=42), the pregnancy complication most strongly associated with placental vascular pathology. There were modest, non-significant associations between placental infarcts and all measures of maternal blood pressure. Conclusions: Irrespective of prior preecclampsia, women with placental evidence of vasculopathy have excess hypertension and particularly masked hypertension in the decade after pregnancy. Our results emphasize the value of out of office blood pressure measurement, and indicate that placental vasculopathy may be pathophysiologically related to development of hypertension before age 50.

Maternal vascular malperfusion (MVM) lesions represent hypoxic-ischemic damage to the placenta, and they are associated with adverse pregnancy outcomes. Women with gestational diabetes (GDM) are at increased risk for pregnancy complications, so we set out to characterize the prevalence and clinical correlates of MVM lesions in this cohort.This was a retrospective cohort study of 1187/1374 (86.4%) women with GDM delivered between 2009 and 2012 who had placental pathology available. Placental lesions of all types were tabulated and grouped into constructs of related entities. MVM lesions specifically included villous infarcts, decidual vasculopathy, increased syncytial knots, perivillous fibrin, and fibrin deposition. We compared maternal characteristics between women with and without MVM lesions, and we also assessed the impact of these lesions on birth weight, preterm birth, and pre-eclampsia using multivariable logistic regression analysis.MVM lesions were the most common placental lesion type in women with GDM (n = 362, 30.5%). Excess gestational weight gain was independently associated with MVM lesions (aOR 1.42, 95% CI 1.06-1.91, p = 0.02) after adjusting for maternal characteristics. MVM lesions were associated with lower birth weight (-90.3 g, 95% CI -148.0 to -32.7, p = 0.002), as well as a 2-fold increased risk for delivery of a small for gestational age infant (10.8 vs 5.9%, p = 0.01) in overweight and obese women. MVM lesions were also associated with increased risk for preterm birth34 weeks (adjusted OR 2.36, 95% CI 1.31-4.23, p = 0.004) and hypertensive disorders of pregnancy (HDP; adjusted OR 1.58, 95% CI 1.13-2.22, p = 0.02).Placental maternal vascular malperfusion lesions may be one pathway linking excess gestational weight gain to adverse pregnancy outcomes in women with GDM, and future studies are needed to identify metabolic factors that may explain this association.

Prominent syncytial knots (SK) in placentas signal advanced gestation or placental malperfusion, reflecting exposures that adversely affect placental development and pregnancy outcomes. Molecular-level interrogations of syncytiotrophoblast have altered perceptions of and raised questions about the function and disposition of SK. Quantifying SK and achieving acceptable levels of interrater reliability have been challenging. Our objective was to develop a simple, reproducible protocol for counting SK and demonstrate interrater reliability overall and within 3 parameters, ie, preterm vs term delivery, presence vs absence of diffuse prominent SK (DPSK), and SK relationship with a lesion, all of which could influence measurement reproducibility and interpretation. Criteria for defining SK and a grid system drawn on glass slides were developed for counting percentage of villi with SK. One disc section each from 151 placentas, sampled from 8 groups defined by the 3 parameters, was assessed by 2 pretrained pathologists. The resulting weighted kappa statistic for overall interrater agreement was 0.60 (very good) and Spearman correlation coefficient for ranking quartiles was >0.70. Agreement was best for preterm placentas, kappa = 0.61, and those only showing DPSK associated with a lesion, kappa = 0.67. Agreement was low in the absence of DPSK, kappa = 0.22, or when DPSK was present in a placenta not associated with a lesion, kappa = 0.32. The proposed method offers a potentially reliable approach for categorizing SK counts as normal vs abnormal or providing continuous measure counts. More extensive pretraining, focused on placentas with few SK and those without an associated lesion, is recommended to improve agreement.

Context.-The value of placental examination in investigations of adverse pregnancy outcomes may be compromised by sampling and definition differences between laboratories.Objective.-To establish an agreed-upon protocol for sampling the placenta, and for diagnostic criteria for placental lesions. Recommendations would cover reporting placentas in tertiary centers as well as in community hospitals and district general hospitals, and are also relevant to the scientific research community.Data Sources.-Areas of controversy or uncertainty were explored prior to a 1-day meeting where placental and perinatal pathologists, and maternal-fetal medicine specialists discussed available evidence and subsequently reached consensus where possible.Conclusions.-The group agreed on sets of uniform sampling criteria, placental gross descriptors, pathologic terminologies, and diagnostic criteria. The terminology and microscopic descriptions for maternal vascular malperfusion, fetal vascular malperfusion, delayed villous maturation, patterns of ascending intrauterine infection, and villitis of unknown etiology were agreed upon. Topics requiring further discussion were highlighted. Ongoing developments in our understanding of the pathology of the placenta, scientific bases of the maternofetoplacental triad, and evolution of the clinical significance of defined lesions may necessitate further refinements of these consensus guidelines. The proposed structure will assist in international comparability of clinicopathologic and scientific studies and assist in refining the significance of lesions associated with adverse pregnancy and later health outcomes.

Background Placental laser equatorialization or “solomonization” during treatment for twin–twin transfusion syndrome (TTTS) is associated with improved pregnancy outcomes. Concern exists, however, about the extent of placental injury caused by the technique, and of its ability to create “dichorionization,” or complete separation of the fetal vascular circuits. Case Study A “solomonized” placenta was histologically examined for depth of cell damage. Solomonization produces complete devascularization of the chorionic plate, but has minimal effect on the underlying villi. The median depth of the effect was 2,823 µm, or

Maternal vasculopathy encompasses several related lesions, including incomplete physiologic remodelling, fibrinoid necrosis, and atherosis, that occur within the maternal blood vessels feeding the placenta. These lesions are thought to develop early in gestation, but their effects do not generally arise until the latter half of pregnancy. The alterations in the maternal vasculature change both the volume and flow characteristics of the blood entering the placenta, resulting in hypoxic/oxidative damage. Maternal vasculopathy is associated most closely with the hypertensive disorders of pregnancy but can also be found in several other adverse pregnancy outcomes.

Syncytial knots are a common histologic feature of the placenta. This overarching term includes four specific subtypes of syncytial knots, including syncytial sprouts, true knots, false knots and syncytial bridges. Wave-like syncytial knots represent a specific architectural arrangement of syncytial knots generally found at earlier gestational ages. Increased syncytial knots have long been associated with adverse pregnancy outcomes, including preeclampsia and fetal growth restriction, and are a defining feature of maternal vascular malperfusion. More specifically, increased syncytial knots appear to arise in response to hypoxic or hypoxia-reperfusion injury to the placenta.

The placental pathology report is an essential but often overlooked element in the communication of pathologic findings to clinicians. This chapter will first discuss the utility of the placental pathology report and the different uses clinicians may have for it. Next, the basic format of a placental pathology report will be described. The significance of each section will be assessed. Finally, formatting techniques that can make a placental pathology report less confusing and more easily understandable to the clinicians will be presented.

Zika virus (ZIKV) infection during pregnancy in humans is associated with an increased incidence of congenital anomalies including microcephaly as well as fetal death and miscarriage and collectively has been referred to as Congenital Zika Syndrome (CZS). Animal models for ZIKV infection in pregnancy have been developed including mice and non-human primates (NHPs). In macaques, fetal CZS outcomes from maternal ZIKV infection range from none to significant. In the present study we develop the olive baboon (Papio anubis), as a model for vertical transfer of ZIKV during pregnancy. Four mid-gestation, timed-pregnant baboons were inoculated with the French Polynesian ZIKV isolate (104 ffu). This study specifically focused on the acute phase of vertical transfer. Dams were terminated at 7 days post infection (dpi; n = 1), 14 dpi (n = 2) and 21 dpi (n = 1). All dams exhibited mild to moderate rash and conjunctivitis. Viremia peaked at 5–7 dpi with only one of three dams remaining mildly viremic at 14 dpi. An anti-ZIKV IgM response was observed by 14 dpi in all three dams studied to this stage, and two dams developed a neutralizing IgG response by either 14 dpi or 21 dpi, the latter included transfer of the IgG to the fetus (cord blood). A systemic inflammatory response (increased IL2, IL6, IL7, IL15, IL16) was observed in three of four dams. Vertical transfer of ZIKV to the placenta was observed in three pregnancies (n = 2 at 14 dpi and n = 1 at 21 dpi) and ZIKV was detected in fetal tissues in two pregnancies: one associated with fetal death at ~14 dpi, and the other in a viable fetus at 21 dpi. ZIKV RNA was detected in the fetal cerebral cortex and other tissues of both of these fetuses. In the fetus studied at 21 dpi with vertical transfer of virus to the CNS, the frontal cerebral cortex exhibited notable defects in radial glia, radial glial fibers, disorganized migration of immature neurons to the cortical layers, and signs of pathology in immature oligodendrocytes. In addition, indices of pronounced neuroinflammation were observed including astrogliosis, increased microglia and IL6 expression. Of interest, in one fetus examined at 14 dpi without detection of ZIKV RNA in brain and other fetal tissues, increased neuroinflammation (IL6 and microglia) was observed in the cortex. Although the placenta of the 14 dpi dam with fetal death showed considerable pathology, only minor pathology was noted in the other three placentas. ZIKV was detected immunohistochemically in two placentas (14 dpi) and one placenta at 21 dpi but not at 7 dpi. This is the first study to examine the early events of vertical transfer of ZIKV in a NHP infected at mid-gestation. The baboon thus represents an additional NHP as a model for ZIKV induced brain pathologies to contrast and compare to humans as well as other NHPs., Author summary Zika virus is endemic in the Americas, primarily spread through mosquitos and sexual contact. Zika virus infection during pregnancy in women is associated with a variety of fetal pathologies now referred to as Congenital Zika Syndrome (CZS), with the most severe pathology being fetal microcephaly. Developing model organisms that faithfully recreate Zika infection in humans is critical for future development of treatments and preventions. In our present study, we infected Olive baboons at mid-gestation with Zika virus and studied the acute period of viremia and transfer of Zika virus to the fetus during the first three weeks after infection to better understand the timing and mechanisms of transfer of ZIKV across the placenta, leading to CZS. We observed Zika virus transfer to fetuses resulting in fetal death in one pregnancy and in a second pregnancy, significant damage to the frontal cortex of the fetal brain at a critical period of neurodevelopment in primates. Thus, the baboon provides a promising new non-human primate model to further compare and contrast the consequences of Zika virus infection in pregnancy to humans and other non-human primates.

Background: In high-income countries, maternal obesity is one of the most important modifiable causes of stillbirth, yet the pathways underpinning this association remain unclear. Objective: We estimated the association between maternal prepregnancy body mass index (BMI) and the risk of stillbirth defined by pathophysiologic contributors or causes. Design: Using a case-cohort design, we randomly sampled 1829 singleton deliveries from a cohort of 68,437 eligible deliveries at Magee-Womens Hospital in Pittsburgh, Pennsylvania (2003–2010), and augmented it with all remaining cases of stillbirth for a total of 658 cases. Stillbirths were classified based on probable cause(s) of death (maternal medical conditions, obstetric complications, fetal abnormalities, placental diseases, and infection). A panel of clinical experts reviewed medical records, placental tissue slides and pathology reports, and fetal postmortem reports of all stillbirths. Causes of fetal death were assigned by using the Stillbirth Collaborative Research Network Initial Causes of Fetal Death protocol from the Eunice Kennedy Shriver National Institute of Child Health and Human Development. Proportional hazards models were used to estimate the BMI-stillbirth association after adjustment for confounders. Results: The rate of stillbirth among lean, overweight, obese, and severely obese women was 7.7, 10.6, 13.9, and 17.3 per 1000 live-born and stillborn infants, respectively. Adjusted stillbirth HRs (95% CIs) were 1.4 (1.1, 1.8) for overweight, 1.8 (1.3, 2.4) for obese, and 2.0 (1.5, 2.8) for severely obese women, respectively, compared with lean women; associations strengthened when limited to antepartum stillbirths. Obesity and severe obesity were associated with stillbirth resulting from placental diseases, hypertension, fetal anomalies, and umbilical cord abnormalities. BMI was not related to stillbirth caused by placental abruption, obstetric conditions, or infection. Conclusions: Multiple mechanisms appear to link obesity to stillbirth. Interventions to reduce stillbirth among obese mothers should consider targeting stillbirth due to hypertension and placental diseases—the most common causes of fetal death in this at-risk group.

The placental lesions classically ascribed to placental hypoxia, here denoted maternal malperfusion (MMP), are among the more significant that a placental pathologist may encounter. Yet the appearance of these lesions may be subtle, and the clinical implication of their diagnosis is frequently unclear. The aim of this review is to provide a more nuanced perspective on the clinical utility of placental pathology for the detection of MMP. The review will first detail MMP lesions in the placenta and discuss their associations with pregnancy complications. The review will then delve into the diagnostic and interpretive difficulties of these lesions. Finally, recent research findings that may aid in the development of better diagnostic tools will be briefly discussed.

Autoinflammatory diseases are caused by pathologic activation of the innate immune system. Primary hemophagocytic lymphohistiocytosis (HLH) is an aggressive syndrome of excessive immune activation caused by monogenic mutations resulting in cytotoxic cell defects and subsequent failure to eliminate activated macrophages. Secondary HLH is often diagnosed in cases without a known Mendelian inheritance. However, some cases of “secondary” HLH have been shown to harbor mutations with partial dysfunction of the cytotoxic system. Recently, macrophage intrinsic abnormalities caused by NLRC4 inflammasome mutations have been linked to autoinflammation and recurrent macrophage activation syndromes resembling a primary HLH. We report a case of a former 28-week preterm infant with congenital anemia, ascites, and a heavy edematous placenta with fetal thrombotic vasculopathy, who developed hepatosplenomegaly and unexplained systemic inflammation with laboratory features of HLH in the early postnatal course and died at 2 months of age. Postmortem examination confirmed the hepatosplenomegaly with marked sinusoidal hemophagocytosis, along with striking hemophagocytosis in the bone marrow and lymph nodes. There was extensive acute and chronic ischemic bowel disease with matted bowel loops, fibrous adhesions, and patchy necrotizing enterocolitis features. Whole exome sequencing analysis demonstrated a novel mosaic heterozygous NLRC4 512 C> T (p.Ser171Phe) de novo mutation predicated to cause a dominant, gain-of-function mutation resulting in a constitutively active protein. The assembly of NLRC4-containing inflammasomes via an induced self-propagation mechanism likely enables a perpetuating process of systemic macrophage activation, presumed to be initiated in utero in this patient.

Key Clinical Message We present the prenatal case of a 12.5-Mb duplication involving 6q25-qter and a 12.2-Mb deletion encompassing 10q26-qter diagnosed by aCGH, while conventional karyotype showed normal results. The genotype–phenotype correlation between individual microarray and clinical findings adds to the emerging atlas of chromosomal abnormalities associated with specific prenatal ultrasound abnormalities.

Preterm birth has staggering health implications, and yet the causes of most cases are still unknown. Placental features have been understudied as an etiology for preterm birth, and the association between placental pathologic lesions and neonatal outcomes are incompletely understood.We sought to characterize births according to placental pathology and relate these to adverse neonatal outcomes.We studied 20,091 births (15,710 term and 4381 preterm) with placental evaluations. Births were classified according to the presence or absence of placental lesions consistent with malperfusion (vasculopathy, infarct, advanced villous maturation, perivillous fibrin, fibrin deposition) and intrauterine inflammation/infection (chorioamnionitis, funisitis, vasculitis). Outcomes were gestational week of delivery, birthweight z-score, neonatal respiratory distress syndrome, and intraventricular hemorrhage.Among all preterm births, evidence of placental malperfusion was identified more often than inflammation/infection (50.6% vs 27.3%, P .0001). Placental malperfusion was associated with reduced fetal growth (adjusted birthweight z-score, -0.83, P.0001) and lesions of inflammation/infection were associated with earlier delivery (adjusted difference -2.08 weeks, P.0001) than those with no lesions. When both placental lesions were present, earlier delivery (adjusted difference -2.28 weeks, P.0001) and reduced fetal growth (adjusted birthweight z-score difference, -0.24, P = .001) were observed more often than when neither lesion was present. Findings were similar when restricted to cases of spontaneous preterm birth. Intraventricular hemorrhage was higher in preterm births with malperfusion lesions than cases with no lesions (7.6% vs 3.4%; odds ratio, 1.98; confidence interval, 1.18-3.32), accounting for gestational age and other covariates.Placental pathology provides important insight into subtypes of preterm birth with adverse neonatal outcomes. Co-occurrence of malperfusion and inflammation/infection, especially among spontaneous preterm births, may be a novel pattern of placental injury linked to severe adverse outcomes.

Background Scant data on placental lymphatic vessels have pointed to the absence of lymphatic circulation. A recent study on mesenchymal dysplasia (MD), however, has identified pathologic lymphangiogenesis using the D2-40 lymphatic marker. These conflicting data have prompted us to investigate whether lymphatic vessels are present in normal developing placentas and in placental disorders characterized by cistern formation. Design Seventeen human placentas without significant pathological abnormality ranging from 12 to 39 weeks of gestational age were studied. Cisternal placental disorders were represented by mesenchymal dysplasia ( n = 1), partial hydatitiform mole ( n = 2), spontaneous abortion ( n = 3) and complete hydatiform mole ( n = 2). To identify lymphatic vessels, we used lymphatic endothelial markers Prox-1 and D2-40. The pan-endothelial marker CD31 was used to highlight overall placental vasculature and to determine if the lining cells of cisterns were of endothelial origin. Lymphatic marker positivity was assessed in maternal (decidual) as well as in fetal (chorionic villous) vasculature. Results No staining with Prox-1 or D2-40 was identified in fetal vessels in developing or term placentas, or in selected cisternal placental disorders, although both markers highlighted a number of thin-walled decidual vessels. Cistern lining cells were negative for Prox-1, D2-40 and CD31. D2-40 consistently marked stromal cells in chorionic villi and highlighted perivascular/pericellular extracellular matrix. Conclusion We established that no lymphatic vasculature is present in the chorionic villi during development, at term or in selected edematous placental disorders. The cisternal lining cells are not endothelial cells; most likely they are of stromal cell origin. Lymphangiogenesis is a part of decidual vascular remodeling during gestation.

Oval cells are hepatocytic precursors that proliferate in late-stage cirrhosis and that give rise to a subset of human hepatocellular carcinomas. Although liver regeneration typically occurs through replication of existing hepatocytes, oval cells proliferate only when hepatocyte proliferation is inhibited. Transforming growth factor-β (TGF-β) is a key inhibitory cytokine for hepatocytes, both in vitro and in vivo. Because TGF-β levels are elevated in chronic liver injury when oval cells arise, we hypothesized that oval cells may be less responsive to the growth inhibitory effects of this cytokine. To examine TGF-β signaling in vivo in oval cells, we analyzed livers of rats fed a choline-deficient, ethionine-supplemented (CDE) diet for phospho-Smad2. Phospho-Smad2 was detected in more than 80% of hepatocytes, but staining was substantially reduced in oval cells. Ki67 staining, in contrast, was significantly more common in oval cells than hepatocytes. To understand the inverse relationship between TGF-β signaling and proliferation in oval cells and hepatocytes, we examined TGF-β signaling in vitro. TGF-β caused marked growth inhibition in primary hepatocytes and the AML12 hepatocyte cell line. Two oval cell lines, LE/2 and LE/6, were less responsive. The greater sensitivity of the hepatocytes to TGF-β–induced growth inhibition may result from the absence of Smad6 in these cells. Conclusion: Our results indicate that oval cells, both in vivo and in vitro, are less sensitive to TGF-β–induced growth inhibition than hepatocytes. These findings further suggest an underlying mechanism for the proliferation of oval cells in an environment inhibitory to hepatocytic proliferation. (HEPATOLOGY 2007;45:31–41.)

The transforming growth factor beta (TGF-beta) signaling pathway, which is activated by the TGF-beta receptor complex consisting of type I and type II TGF-beta receptors (TGFBR1 and TGFBR2), regulates cell growth and death. TGF-beta and components of its signaling pathway, particularly TGFBR2, have been implicated as tumor suppressor genes and important antimitogenic factors in the gastrointestinal tract and liver. An in vivo approach to study these effects has been hindered by the embryonic lethality of Tgfbr2(-/-) mice and poor viability of the Tgfb1(-/-) mice. Consequently, we have developed a hepatocyte-specific Tgfbr2 knockout mouse, the Alb-cre Tgfbr2(flx/flx) mouse, to study the physiologically relevant effects of TGF-beta signaling on epithelial cell proliferation in vivo. After 70% hepatectomy, we observed increased proliferation and an increased liver mass : body weight ratio in the Alb-cre Tgfbr2(flx/flx) mice compared to Tgfbr2(flx/flx) mice. We also observed decreased expression and increased phosphorylation of p130 in the livers from the Alb-cre Tgfbr2(flx/flx) mice as well as increased expression of cyclin E, which is transcriptionally regulated, in part, by p130:E2F4. Consistent with these results, in a hepatocyte cell line derived from the Tgfbr2(flx/flx) mice, we found that TGF-beta increases the nuclear localization of E2F4, and presumably the transcriptional repression of the p130:E2F4 complex. Thus, we have demonstrated that TGF-beta signaling in vivo regulates the mitogenic response in the regenerating liver, affecting the liver mass : body weight ratio after partial hepatectomy, and that these mitogenic responses are accompanied by alterations in p130 expression and phosphorylation, implicating p130 as one of the proteins regulated in vivo by TGF-beta during liver regeneration.

The role of transforming growth factor β (TGF-β) in carcinogenesis is complex, with tumor suppressor and pro-oncogenic activities depending on the particular tumor cell and its stage in malignant progression. We previously have demonstrated in breast cancer cell lines that Smad2/3 signaling played a dominant role in mediating tumor suppressor effects on well-differentiated breast cancer cell lines grown as xenografts and prometastatic effects on a more invasive, metastatic cell line. Our present data based on selective interference with activation of endogenous Smad2 and Smad3 by stable expression of a mutant form of the TGF-β type I receptor (RImL45) unable to bind Smad2/3 but with a functional kinase again show that reduction in Smad2/3 signaling by expression of RImL45 enhanced the malignancy of xenografted tumors of the well-differentiated MCF10A-derived tumor cell line MCF10CA1h, resulting in formation of larger tumors with a higher proliferative index and more malignant histologic features. In contrast, expression of RImL45 in the more aggressive MCF10CA1a cell line strongly suppressed formation of lung metastases following tail vein injection. These results suggest a causal, dominant role for the endogenous Smad2/3 signaling pathway in the tumor suppressor and prometastatic activities of TGF-β in these cells. Using an in vitro assay, we further show that non-Smad signaling pathways, including p38 and c-Jun NH2-terminal kinase, cooperate with TGF-β/Smads in enhancing migration of metastatic MCF10CA1a cells, but that, although necessary for migration, these other pathways are not sufficient for metastasis.

Background Opioid use disorder among pregnant women is associated with adverse perinatal outcomes and is increasing in the United States. The standard of care for pregnant women with opioid use disorder is opioid maintenance therapy including either methadone or buprenorphine, which can be initiated at any time during pregnancy. These medications are known to cross the placenta but their placental and fetal effects have not been well characterized. Delayed villous maturation, a placental finding associated with stillbirth, was observed in placentas exposed to opioid maintenance therapy. Given the association of delayed villous maturation with stillbirth, and the possible relationship between opioid maintenance therapy and delayed villous maturation, this study was undertaken to explore the association between opioid maintenance therapy and this placental finding. Delayed villous maturation was not previously reported in placentas exposed to opioids or opioid maintenance therapy. Objective This study sought to compare risk of delayed villous maturation in term placentas exposed and unexposed to opioid maintenance therapy with buprenorphine or methadone. Study Design This was a retrospective cohort study conducted between 2010 through 2012 at Magee-Womens Hospital comparing delayed villous maturation in placentas of women with opioid use disorder exposed to either buprenorphine (n = 86) or methadone (n = 268) versus women without opioid use disorder (n = 978). Potential covariates were assessed in univariate analyses with none significantly associated with delayed villous maturation. The final model used conditional logistic regression adjusting for smoking status alone. Results Among women without opioid use disorder (and therefore not exposed to opioid maintenance therapy), delayed villous maturation was identified in 5.7% of placentas while the prevalence among women treated with buprenorphine or methadone was 8.1% and 10.8%. Overall, the crude odds of being diagnosed with delayed villous maturation were significantly greater in those exposed to opioid maintenance therapy compared to those not exposed (odds ratio, 1.86; 95% confidence interval, 1.20–2.89). When considered separately, women treated with methadone had significantly greater odds of having a placenta with delayed villous maturation than women without exposure to opioid maintenance therapy (odds ratio, 2.00; 95% confidence interval, 1.52–3.20). Women treated with buprenorphine did not have significantly greater odds of this placental diagnosis when compared to the women unexposed to opioid maintenance therapy (odds ratio, 1.46; 95% confidence interval, 0.64–3.31). Results were similar after accounting for smoking. Conclusion Delayed villous maturation was more common in the placentas of women exposed to opioid maintenance therapy. Further studies are required to characterize rates and extent of delayed villous maturation in the general population as well as to differentiate between possible effects of opioid exposure (eg, heroin, illicit use of prescription opioids) vs those of opioid maintenance therapy (buprenorphine and methadone).

Early in pregnancy, trophoblast invasion into the decidua and inner myometrium is essential for establishment of proper implantation, maternal-fetal exchange, and immunological tolerance of the feto-placental allograft. Unlike villous trophoblasts (VTs), extravillous trophoblasts (EVTs) are unique in their capacity to invade the maternal decidua and myometrium. The largest human microRNA (miRNA) gene cluster, the chromosome 19 miRNA cluster (C19MC), is expressed almost exclusively in the placenta and, rarely, in certain tumors and undifferentiated cells. In the work reported here, we found that the expression of C19MC miRNAs is higher in VTs than in EVTs. Using a bacterial artificial chromosome (BAC)-mediated overexpression of C19MC miRNAs in an EVT-derived cell line, which does not naturally express these miRNAs, we found that C19MC miRNAs selectively attenuate cell migration without affecting cell proliferation or apoptosis. A microarray analysis revealed that C19MC miRNAs regulate target transcripts related to cellular movement. Our data also implicated a specific C19MC member, miR-519d, indirectly regulating the EVT invasive phenotype by targeting CXCL6, NR4A2 and FOXL2 transcripts through a 3′UTR miRNA-responsive element. Together, our data suggest a role for C19MC miRNAs in modulating the migration of EVTs.

Background: Maternal vitamin D deficiency has been linked to fetal growth restriction, but the underlying mechanisms are unclear. Objective: We tested the hypothesis that poor maternal 25-hydroxyvitamin D [25(OH)D] is associated with increased risk of placental vascular pathology. Design: Maternal serum 25(OH)D was measured at ≤26 wk of gestation in a random subcohort of term, singleton infants in the Collaborative Perinatal Project (1959–1966; n = 2048). A dichotomous vascular construct was created from the presence of any of 12 pathologies identified on placental examinations, including evidence of placental abruption, infarction, hypoxia, decidual vasculopathy, or thrombosis of fetal vessels (n = 240 cases). Results: The relation between 25(OH)D and vascular pathology was modified by infant sex (P = 0.003). A maternal 25(OH)D concentration ≥80 compared with