Maternal Vascular Malperfusion Research Articles

Circulating maternal placental growth factor responses to low-molecular-weight heparin in pregnant patients at risk of placental dysfunction

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 invitro 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 the <10th 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.

Application of Machine Learning to Identify Placental Lesions of Maternal Vascular Malperfusion in Cases of Preeclampsia and Fetal Growth Restriction

Application of Machine Learning to Identify Placental Lesions of Maternal Vascular Malperfusion in Cases of Preeclampsia and Fetal Growth Restriction

Association of Placental Pathology With Childhood Blood Pressure Among Children Born Preterm.

The in utero pathologies underlying the link between preterm birth and offspring high blood pressure (BP) are still unknown. We investigated the prospective associations of placental histopathological findings with childhood BP among children born preterm. Our study sample included 546 mother-child pairs with preterm birth (before 37 weeks gestation) enrolled from 1999 to 2013 at the Boston Medical Center. Early preterm birth was defined as gestational age between 23 and 34 weeks. We histologically classified maternal placental pathology using the latest recommended categories: no placental complications, histologic chorioamnionitis, maternal vascular malperfusion, and other placental complications. We calculated age-, sex-, and height-specific systolic BP (SBP) percentiles for children using the 2017 American Academy of Pediatrics Clinical Practice Guideline. We used linear regression models with generalized estimating equations to examine the associations. The mean (standard deviation (SD)) postnatal follow-up of the study children was 9.29 (4.1) years. After adjusting for potential confounders, histologic chorioamnionitis was associated with a 5.42 percentile higher childhood SBP (95% confidence interval: 0.32, 10.52) compared with no placental pathologic findings. This association was stronger among early preterm children. Maternal vascular malperfusion was associated with a 8.44 percentile higher childhood SBP among early preterm children (95% confidence interval: 1.54, 15.34) but the association was attenuated (6.25, 95% confidence interval: -0.76, 13.26) after additional adjustment for child standardized birthweight, a potential mediator of the association. These findings suggest that among children born preterm, especially those born early preterm, both placental histologic chorioamnionitis and vascular malperfusion may help to differentiate a child's risk of high BP.

P–406 Placental histopathology is different in specific subsets of ICSI singleton pregnancies with programmed cycles : a prospective study

Abstract Study question Does embryo vitrification or donor oocytes (DO) alter the histopathology of the placenta in ICSI singleton pregnancies with similar endometrial preparation? Summary answer Placentas from programmed cycles had significantly more immune/idiopathic-inflammation with vitrified-thawed embryos versus fresh transfer and significantly more maternal vascular-malperfusion(MVM) in DO versus autologous oocyte(AO) pregnancies. What is known already DO pregnancies and frozen embryo transfer(FET) pregnancies with programmed cycles are associated with hypertensive complications. As these complications are linked with abnormal placentation, comparing the placental histopathology in these pregnancies may point to a causative association. Studies of placental histopathology in DO in comparison to AO pregnancies show a dysregulated immune process and vasculopathy. The hormonal milieu during implantation remains an important confounder. Placental histopathology in fresh/ frozen cycles has recently shown variable results. To isolate the effect of embryo vitrification on placental histopathology, the donor oocyte model can provide valuable data, which till now is scarcely available. Study design, size, duration A prospective cohort study conducted in a tertiary center from 2018–2020. Placental histopathology, pregnancy-outcomes were studied in 116 ICSI singleton pregnancies≥28 weeks. Group1-Pregnancies with DO, by FET(n = 32) and freshET(n = 34) were compared to study the effect of embryo-vitrification. Group2-Pregnancies by DO FET(n = 32) were compared to AO FET(n = 50) to study the effect of DO. All patients had ICSI, cleavage embryo-transfer, programmed cycles and delivered at the same institute. The placentas were examined by pathologists (blinded to the ET type). Participants/materials, setting, methods 116 singleton pregnancies were followed for hypertensive disorders of pregnancy (HDP), preterm delivery(PTD&amp;lt;37weeks) and low birth-weight (LBW&amp;lt;2.5kg). Placentas were examined for cord mal-insertions Placental histopathology lesions were classified into 4 groups according to ‘Amsterdam criteria’ infectious-inflammatory, immune/ idiopathic-inflammatory, MVM, fetal vascular malperfusion (FVM). Chi-square and t-tests were used to compare outcomes across groups. Adjusted odds ratio were calculated using logistic regression. Statistical significance set at P &amp;lt;.05, two-tailed. Main results and the role of chance No patient had a history of chronic hypertension/smoking. Group 1 Patients conceived by DO, with FET and freshET were comparable with regards to age (34.1 vs 36.4years, P=.07),BMI(26.7 vs 27.1 kg/m2,P=.6),nulliparity(81%vs82%,P=.9) HDP(25%vs29.4%,P=0.69),birth-weight(2.48 vs 2.47kg,P=.93) LBW(31.3%vs41.2%,P=.41)respectively PTD was significantly less in donor FET versus donor freshET (6.3%vs47.1%P=.0002) Placental weight and cord mal-insertions were comparable for FET vs freshET (466 vs 486gms P=.03 12.5%vs23.5% P=.25)respectively. Amongst the placental histopathology lesions, immune/ idiopathic-inflammatory lesions were significantly more in the FET vs freshET group (37.5% vs 11.8%,P=.02)The other lesions were comparable infectious-inflammatory(6.3%vs17.6%,P=.16), MVM(75%vs58.8%, P=.16),FVM(18.8%vs17.6%,P=.9) Group 2 Patients conceived by DO compared to AO by FET were significantly older and had a higher BMI (34.1vs31.7years,P=.02 ,26.7vs25.5 kg/m2,P=.002) respectively. Nulliparity was comparable(81%vs92%,P=.15) Birth weight was significantly less in DO vs AO(2.4vs2.7kg,P=.02) HDP and LBW were significantly more in DO vs AO(25%vs8% ,P=.03, 31.3%vs 8%,P=.007),respectively. PTD was comparable(6.3%vs8.0%,P=.77). Placental weight was significantly less in DO vs AO (466 vs 513gms,P=.03) cord mal-insertions were comparable(12.5% vs 24%,P=.2) The MVM lesions were significantly more in the DO group compared to AO(75% vs 40%,P=.002) The difference remained after adjusting for age/BMI/HDP (AOR 4.31;95% CI 1.24–14.8;P=.02). The rest of placental lesions were comparable in DO vs AO, infectious-inflammatory lesions(6.3%vs16%,P=.19) immune/idiopathic-inflammatory lesions(37.5%vs28%,P=.37) FVM(18.8% vs 12%,P=.4)respectively. Limitations, reasons for caution These findings are based on a small number of patients. The results observed need to be confirmed using a larger study sample. Wider implications of the findings: Placentas in pregnancies by embryo-vitrification, in a DO-model, had significantly more immune/idiopathic-inflammation, the cause/significance of this needs to be explored. Placentas in DO-pregnancies had significantly more MVM-lesions and increased risk of HDP, emphasizing the clinical/histopathological link of DO with HDP and the need for counselling/preventive strategies for HDP in DO-pregnancie. Trial registration number Not applicable

Placental growth factor as a diagnostic tool for placental mediated fetal growth restriction.

Placental growth factor (PlGF) has shown promise in identification of placental fetal growth restriction (FGR). We aimed to investigate the association between PlGF and sonographic markers of placental dysfunction and assess its ability to diagnose FGR secondary to maternal vascular malperfusion (MVM). A retrospective study of singleton pregnancies with small for gestational age (SGA) fetuses, who had PlGF testing at 16-36weeks. Fetuses with major chromosomal and/or structural anomalies and pregnancies with missing outcomes were excluded. Sonographic characteristics, perinatal outcomes and placental histopathology were compared between pregnancies with normal and low PlGF (<10th percentile for gestational age). The diagnostic accuracy of PlGF for prediction of MVM was calculated. 130 fetuses met inclusion criteria. Compared to normal PlGF (n=65), pregnancies with low PlGF (n=65) were associated with an estimated fetal weight<5th centile (73.8% (48) vs 53% (35), respectively, p=0.01), abnormal uterine, umbilical and MCA Dopplers (p=0.001 for all), fetal demise (18.8% (12) vs 0% respectively, p=0.01) and preterm delivery (100% (65) vs 39% (59), respectively, p<0.001) . Low PlGF had a 70.1% (58.6-80.0) sensitivity and a 79.6% (64.7-90.2) specificity for identifying MVM, with an AUC of 0.73 (0.63-0.84). Positive and negative predictive values were 85.7% (76.8-91.2) and 60.3% (51.2-68.9), respectively. PlGF outperformed other parameters of placental FGR (uterine, umbilical artery, middle cerebral artery and abdominal circumference<5th centile), in isolation and when combined. PlGF is a useful tool to aid in the diagnosis of placental FGR secondary to MVM.

SARS-CoV-2 and Placental Pathology: Malperfusion Patterns Are Dependent on Timing of Infection During Pregnancy.

The extent to which severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection at different points in the pregnancy timeline may affect maternal and fetal outcomes remains unknown. We sought to characterize the impact of SARS-CoV-2 infection proximate and remote from delivery on placental pathology. We performed a secondary analysis of placental pathology from a prospective cohort of universally tested SARS-CoV-2 positive women >20 weeks gestation at 1 institution. Subjects were categorized as having acute or nonacute SARS-CoV-2 based on infection <14 or ≥14 days from delivery admission, respectively, determined by nasopharyngeal swab, symptom history, and serologies, when available. A subset of SARS-CoV-2 negative women represented negative controls. Placental pathology was available for 90/97 (92.8%) of SARS-CoV-2 positive women, of which 26 were from women with acute SARS-CoV-2 infection and 64 were from women with nonacute SARS-CoV-2. Fetal vascular malperfusion lesions were significantly more frequent among the acute SARS-CoV-2 group compared with the nonacute SARS-CoV-2 group (53.8% vs. 18.8%; P=0.002), while frequency of maternal vascular malperfusion lesions did not differ by timing of infection (30.8% vs. 29.7%; P>0.99). When including 188 SARS-CoV-2 negative placentas, significant differences in frequency of fetal vascular malperfusion lesions remained between acute, nonacute and control cases (53.8% vs. 18.8% vs. 13.2%, respectively; P<0.001). No differences were noted in obstetric or neonatal outcomes between acutely and nonacutely infected women. Our findings indicate timing of infection in relation to delivery may alter placental pathology, with potential clinical implications for risk of thromboembolic events and impact on fetal health.

Placental pathologic features in thyroid autoimmunity

IntroductionData on placental pathologic features associated with thyreoperoxidase antibodies (TPO Ab) and/or hypothyroidism are limited. The objective of the study was to analyze placental pathologic features of women with TPO Ab positivity. MethodsProspective case-control observational study of pregnancy outcome among women screened for TPO Ab positivity and/or isolated hypothyroidism (TSH>4mU/L) during the first trimester of pregnancy. Placenta pathologic findings were recorded according to standard classification. ResultsThe overall rates of TPO Ab positivity and isolated hypothyroidism with negative TPO Ab were 9.6% (86/899) and 2.7% (24/899), respectively. Among TPO Ab positive cases, 77.9% (67/86) and 22.1% (19/86) had TSH ≥2.5mU/L or <2.5mU/L, respectively. Compared to controls, mean first and second trimester uterine artery Doppler pulsatility indices (PI) were higher, placental volume and area were lower among cases with TSH≥2.5mU/L. The rates of fetal growth restriction (FGR)/small for gestational age (SGA) (20/67 versus 8/110, Adjusted Odds Ratio (AdjOR) = 10.8,95%CI = 2.7–44), placental pathological features suggesting decidual vasculopathy (37/67 versus 27/110, AdjOR = 2.7,95%CI = 1.1–6.8) or severe maternal vascular malperfusion (MVM) (22/67 versus 9/110, AdjOR = 5.8,95%CI = 1.6–20.1) were higher among cases with TSH ≥2.5mU/L than in controls. Similar results were obtained comparing overall TPO Ab positive subjects to controls. The increased risk of defective placentation and FGR associated with TPO Ab was independent of simultaneous presence of antinuclear antibodies (ANA) and TSH concentration. DiscussionFirst trimester TPO Ab positivity was associated with increased rates of abnormal uterine artery Doppler PI and placental features of MVM. This association was independent of TSH concentration and presence of ANA.

Acute and Chronic Placental Abnormalities in a Multicenter Cohort of Newborn Infants with Hypoxic–Ischemic Encephalopathy

To examine the frequency of placental abnormalities in a multicenter cohort of newborn infants with hypoxic-ischemic encephalopathy (HIE) and to determine the association between acuity of placental abnormalities and clinical characteristics of HIE. Infants born at ≥36weeks of gestation (n=500) with moderate or severe HIE were enrolled in the High-dose Erythropoietin for Asphyxia and Encephalopathy Trial. A placental pathologist blinded to clinical information reviewed clinical pathology reports to determine the presence of acute and chronic placental abnormalities using a standard classification system. Complete placental pathologic examination was available for 321 of 500 (64%) trial participants. Placental abnormalities were identified in 273 of 321 (85%) and were more common in infants ≥40weeks of gestation (93% vs 81%, P=.01). A combination of acute and chronic placental abnormalities (43%) was more common than either acute (20%) or chronic (21%) abnormalities alone. Acute abnormalities included meconium staining of the placenta (41%) and histologic chorioamnionitis (39%). Chronic abnormalities included maternal vascular malperfusion (25%), villitis of unknown etiology (8%), and fetal vascular malperfusion (6%). Infants with chronic placental abnormalities exhibited a greater mean base deficit at birth (-15.9 vs -14.3, P=.049) than those without such abnormalities. Patients with HIE and acute placental lesions had older mean gestational ages (39.1 vs 38.0, P<.001) and greater rates of clinically diagnosed chorioamnionitis (25% vs 2%, P<.001) than those without acute abnormalities. Combined acute and chronic placental abnormalities were common in this cohort of infants with HIE, underscoring the complex causal pathways of HIE. ClinicalTrials.gov: NCT02811263.

Maternal and fetal vascular lesions of malperfusion in the placentas associated with fetal and neonatal death: results of a prospective observational study

Fetal death is one of the major adverse pregnancy outcomes and is common in low- and middle-income countries. Placental lesions may play an important role in the etiology of fetal and neonatal deaths. Previous research relating placental lesions to fetal death causation was hindered by a lack of agreement on a placental classification scheme. The Amsterdam consensus statement that was published in 2016 focused its attention on malperfusions in the maternal and fetal placental circulations. This study aimed to investigate the relationships of placental maternal and fetal vascular malperfusions in fetal and neonatal deaths, focusing on the most important maternal clinical conditions in the pathway to fetal and neonatal deaths, such as maternal hypertension, antepartum hemorrhage, and decreased fetal growth. This was a prospective, observational cohort study conducted at 2 Asian sites. The data collected included clinical history, gross and histologic evaluations of the placenta, and several other investigations and were used to determine the cause of death. The placenta was evaluated at both sites using the Amsterdam consensus framework. We estimated the risk of placental maternal and fetal vascular malperfusions in fetal and neonatal deaths. Between July 2018 and January 2020 in India and Pakistan, 1633 women with placentas available for the study provided consent. Of these women, 814 had fetal deaths, 618 had preterm live births and subsequent neonatal deaths, and 201 had term live births. The prevalence of maternal vascular malperfusion was higher in the placentas associated with fetal deaths (58.4%) and preterm neonatal deaths (31.1%) than in the placentas associated with term live births (15.4%). Adjusting for site, maternal vascular malperfusion had a relative risk of 3.88 (95% confidence interval, 2.70-5.59) in fetal deaths vs term live births and a relative risk of 2.07 (95% confidence interval, 1.41-3.02) in preterm neonatal deaths vs term live births. Infarcts and distal villous hypoplasia were the most common histologic components of maternal vascular malperfusion. Compared with maternal vascular malperfusion (58.4%), fetal vascular malperfusion was less common in the placentas associated with fetal deaths (19.0%). However, there were higher frequencies of fetal vascular malperfusion in the placentas associated with fetal deaths (19.0%) than in placentas associated with neonatal deaths (8.3%) or term live birth (5.0%). Adjusting for site, fetal vascular malperfusion had a relative risk of 4.09 (95% confidence interval, 2.15-7.75) in fetal deaths vs term live births and a relative risk of 1.77 (95% confidence interval, 0.90-3.49) in preterm neonatal deaths vs term live births. Furthermore, there was a higher incidence of maternal vascular malperfusion in cases of maternal hypertension (71.4%), small for gestational age (69.9%), and antepartum hemorrhage (59.1%) than in cases of fetal deaths with none of these conditions (43.3%). There was no significant difference in the occurrence of fetal vascular malperfusion in the 4 clinical categories. Histologic examination of the placenta, especially for malperfusion disorders, is crucial in elucidating pathways to fetal and neonatal deaths in preterm infants. In particular, focusing on placental maternal and fetal vascular malperfusions during pregnancy is a means to identify fetuses at risk of fetal death and is an important strategy to reduce the risk of fetal death early delivery. We hope that the increased risk of fetal and neonatal deaths in these pregnancies can be reduced by the development of an intervention that reduces the likelihood of developing maternal and fetal vascular malperfusion.

The association between maternal placental growth factor and placental maternal vascular malperfusion lesions

IntroductionPlacental Growth Factor (PlGF) is used for the prediction of preeclampsia (PE), a syndrome associated with maternal vascular malperfusion (MVM). Our goal is to determine the correlation between PlGF and MVM. Material and methodsWe performed a secondary analysis of the PEARL study that included nulliparous women with PE (cases), and low-risk nulliparous women recruited in early pregnancy (controls). All participants provided blood samples at diagnosis of PE (cases), or between 26 and 34 weeks (controls) for measurement of PlGF (B·R·A·H·M·S plus KRYPTOR automated assays), that was transformed into multiple of median (MoM). Placental examination was performed for the diagnosis of MVM based on the Amsterdam Placental Workshop Group Consensus Statement. Nonparametric tests and receiver operating characteristic (ROC) curves were used to compare PlGF in pregnancies with, and without PE, stratified by the presence of MVM. ResultsThird trimester PlGF was lower in PE cases with MVM (N = 20; median: 0.04 MoM; interquartile: 0.03–0.09; p<0.0001), and in controls with MVM (N = 4; 0.30MoM; 0.07–0.52; p = 0.002) compared to controls without MVM (N = 29; 0.99 MoM; 0.67–1.52). PlGF in PE cases without MVM (N = 5; 0.18 MoM; 0.17–1.64) was not significantly different than in controls without MVM but the sample size was small. ROC curve demonstrated a greater predictability of PlGF for PE with MVM than PE without MVM (AUC: 0.99 vs. 0.38; p<0.0001). DiscussionThird trimester PlGF is a better predictor of PE associated with MVM than a predictor of PE without MVM. We hypothesize that PlGF is a stronger marker of MVM than PE.

Chronic Inflammatory Placental Lesions Correlate With Bronchopulmonary Dysplasia Severity in Extremely Preterm Infants.

Correlation of BPD with placental pathology is important for clarification of the multifactorial pathogenesis of BPD; however, previous reports have yielded varying results. We report placental findings in no/mild BPD compared to moderate/severe BPD, and with and without pulmonary hypertension (PH). Eligible infants were 230/7-276/7 weeks gestational age. BPD was defined by the need for oxygen at ≥28 days with severity based on need for respiratory support at ≥36 weeks. Acute and chronic inflammatory placental lesions and lesions of maternal and fetal vascular malperfusion were examined. Of 246 eligible infants, 146 (59%) developed moderate/severe BPD. Thirty-four (23%) infants developed PH, all but 1 being in the moderate/severe BPD group. Chronic deciduitis (32% vs 16%, P = .003), chronic chorioamnionitis (23% vs 12%, P = .014), and ≥ 2 chronic inflammatory lesions (13% vs 3%, P = .007) were more frequent in the moderate/severe BPD group. Development of PH was associated with placental villous lesions of maternal vascular malperfusion (30% vs 15%, P = .047). The association of chronic inflammatory placental lesions with BPD severity has not been previously reported. This supports the injury responsible for BPD as beginning before birth in some neonates, possibly related to cytokines associated with these chronic inflammatory lesions.

Pregnancy Outcome, Antibodies, and Placental Pathology in SARS-CoV-2 Infection during Early Pregnancy.

There are reports that pregnant women infected with SARS-CoV-2 not only have increased morbidity but also increased complications and evidence of maternal and fetal vascular malperfusion on placental pathology. This was a retrospective study of pregnant women diagnosed with SARS-CoV-2 infection after March 2020. The results of reverse transcription polymerase chain reaction testing and IgM and IgG antibody testing of the amniotic fluid, cord blood, placenta, and maternal blood were confirmed at delivery. Placentas were evaluated histopathologically. The study included seven pregnant women diagnosed with SARS-CoV-2 infection during pregnancy at a mean gestational age of 14.5 weeks. Out of the seven women, five were infected during the first trimester. The mean gestational age at delivery was 38.4 weeks. The reverse transcription polymerase chain reaction results for maternal plasma, cord blood, placenta, and amniotic fluid were negative and IgG antibodies were detected in maternal plasma and cord blood. On placental pathology, maternal vascular malperfusion was found in only one case, fetal vascular malperfusion in four cases, and inflammatory changes were found in two cases. Pregnancy outcomes for women diagnosed with SARS-CoV-2 infection during early pregnancy are positive and it is likely that maternal antibodies are passed to the fetus, which results in a period of immunity.

Association Between COVID-19 Pregnant Women Symptoms Severity and Placental Morphologic Features.

Since the beginning of the pandemic, few papers describe the placenta’s morphological and morphometrical features in SARS-CoV-2–positive pregnant women. Alterations, such as low placental weight, accelerated villous maturation, decidual vasculopathy, infarcts, thrombosis of fetal placental vessels, and chronic histiocytic intervillositis (CHI), have been described.ObjectiveTo analyze clinical data and the placental morphological and morphometric changes of pregnant women infected with SARS-CoV-2 (COVID-19 group) in comparison with the placentas of non-infected pregnant women, matched for maternal age and comorbidities, besides gestational age of delivery (Control group).MethodThe patients in the COVID-19 and the Control group were matched for maternal age, gestational age, and comorbidities. The morphological analysis of placentas was performed using Amsterdam Placental Workshop Group Consensus Statement. The quantitative morphometric evaluation included perimeter diameter and number of tertiary villi, number of sprouts and knots, evaluation of deposition of villous fibrin, and deposition of intra-villous collagen I and III by Sirius Red. Additionally, Hofbauer cells (HC) were counted within villi by immunohistochemistry with CD68 marker.ResultsCompared to controls, symptomatic women in the COVID-19 group were more likely to have at least one comorbidity, to evolve to preterm labor and infant death, and to have positive SARS-CoV-2 RNA testing in their concepts. Compared to controls, placentas in the COVID-19 group were more likely to show features of maternal and fetal vascular malperfusion. In the COVID-19 group, placentas of symptomatic women were more likely to show CHI. No significant results were found after morphometric analysis.ConclusionPregnant women with symptomatic SARS-CoV-2 infection, particularly with the severe course, are more likely to exhibit an adverse fetal outcome, with slightly more frequent histopathologic findings of maternal and fetal vascular malperfusion, and CHI. The morphometric changes found in the placentas of the COVID-19 group do not seem to be different from those observed in the Control group, as far as maternal age, gestational age, and comorbidities are paired. Only the deposition of villous fibrin could be more accentuated in the COVID-19 group (p = 0.08 borderline). The number of HC/villous evaluated with CD68 immunohistochemistry did not show a difference between both groups.

Reflections illuminate antenatal detection of placental pathology.

Most human pregnancies have a relatively uneventful progression to birth, but a proportion are accompanied by vascular pathologies affecting either the maternal or fetal sides of the placenta, now respectively categorized as maternal vascular malperfusion (MVM) [1] and fetal vascular malperfusion (FVM) [2]. These pathologies may compromise fetal well-being and predispose to complications that include fetal growth restriction, stillbirth, perinatal stroke and postnatal cerebral palsy. Current antenatal detection of placental pathology with routine ultrasound screening is only moderately successful for MVM, and difficult to attain for FVM.

HIV, Placental Pathology, and Birth Outcomes-a Brief Overview.

The spectrum of placental pathology in human immunodeficiency virus (HIV) is vast. Features observed are not only limited to the effects of the virus itself but may include that of coinfections such as tuberculosis and syphilis. The presence of other comorbidities and changes as a result of antiretroviral therapy may further confound the histologic findings. There is a paucity of unbiased information of the effects of maternal HIV on the placenta and how these changes relate to birth outcomes. Antiretroviral therapy, now in widespread use, has altered the course of maternal HIV disease and it is unknown whether this has altered the pathophysiology of HIV on the placenta. HIV-associated placental findings that have been most well described include acute chorioamnionitis, low placental weight, and maternal vascular malperfusion, with a tendency towards lower rates of chronic villitis.

Cognition and Cerebrovascular Reactivity in Midlife Women With History of Preeclampsia and Placental Evidence of Maternal Vascular Malperfusion.

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.

Wave reflections in the umbilical artery measured by Doppler ultrasound as a novel predictor of placental pathology.

BackgroundThe 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.MethodsStandard 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.FindingsCompared to controls, wave reflections were significantly elevated in women with either MVM (p<0.0001) or FVM pathology (p = 0.02). In contrast, the umbilical and uterine artery pulsatility indices were only elevated in the MVM group (p<0.0001) and there were no differences between women with FVM and the controls.InterpretationThe measurement of wave reflections in the UA, combined with standard clinical ultrasound parameters, has the potential to improve the diagnostic performance of UA Doppler to detect placental vascular pathology. Identifying women with FVM pathology is particularly challenging prenatally and future investigations will determine if women at risk of this specific placental disease could benefit from this novel diagnostic technique.

Placental Decidual Arteriopathy and Vascular Endothelial Growth Factor A Expression Among Women With or Without Human Immunodeficiency Virus.

Women with human immunodeficiency virus (HIV) (WHIV) are at higher risk of adverse birth outcomes. Proposed mechanisms for the increased risk include placental arteriopathy (vasculopathy) and maternal vascular malperfusion (MVM) due to antiretroviral therapy and medical comorbid conditions. However, these features and their underlying pathophysiologic mechanisms have not been well characterized in WHIV. We performed gross and histologic examination and immunohistochemistry staining for vascular endothelial growth factor A (VEGF-A), a key angiogenic factor, on placentas from women with ≥1 MVM risk factors including: weight below the fifth percentile, histologic infarct or distal villous hypoplasia, nevirapine-based antiretroviral therapy, hypertension, and preeclampsia/eclampsia during pregnancy. We compared pathologic characteristics by maternal HIV serostatus. Twenty-seven of 41 (placentas 66%) assessed for VEGF-A were from WHIV. Mean maternal age was 27 years. Among WHIV, median CD4 T-cell count was 440/µL, and the HIV viral load was undetectable in 74%. Of VEGF-A-stained placentas, both decidua and villous endothelium tissue layers were present in 36 (88%). VEGF-A was detected in 31 of 36 (86%) with decidua present, and 39 of 40 (98%) with villous endothelium present. There were no differences in VEGF-A presence in any tissue type by maternal HIV serostatus (P = .28 to >.99). MVM was more common in placentas selected for VEGF-A staining (51 vs 8%; P < .001). VEGF-A immunostaining was highly prevalent, and staining patterns did not differ by maternal HIV serostatus among those with MVM risk factors, indicating that the role of VEGF-A in placental vasculopathy may not differ by maternal HIV serostatus.

SARS-CoV-2 and Placenta: New Insights and Perspectives.

The study of SARS-CoV-2 positive pregnant women is of some importance for gynecologists, obstetricians, neonatologists and women themselves. In recent months, new works have tried to clarify what happens at the fetal–placental level in women positive for the virus, and different pathogenesis mechanisms have been proposed. Here, we present the results of a large series of placentas of Coronavirus disease (COVID) positive women, in a reference center for COVID-positive pregnancies, on which we conducted histological, immunohistochemical and electron microscopy investigations. A case–control study was conducted in order to highlight any histopathological alterations attributable to SARS-CoV-2. The prevalence of maternal vascular malperfusion was not significantly different between cases and controls (54.3% vs. 43.7% p = 0.19), whereas the differences with regard to fetal vascular malperfusion (21.1% vs. 4.2% p < 0.001) were significant. More frequent in cases with respect to controls were decidual arteriopathy (40.9% vs. 1.4% p < 0.0001), decidual inflammation (32.4% vs. 0.7% p < 0.0001), perivillous fibrin deposition (36.6% vs. 3.5% p < 0.0001) and fetal vessel thrombi (22.5% vs. 0.7% p < 0.0001). No significant differences in the percentage of terminal villous hyperplasia and chorioamnionitis were observed between the two groups. As the pandemic continues, these studies will become more urgent in order to clarify the possible mechanism of maternal–fetal transmission of the virus.

Formulating a Meaningful and Comprehensive Placental Phenotypic Classification.

While many placental lesions have been identified and defined, the significance of multiple overlapping lesions has not been addressed. The purpose of our analysis was to evaluate overlapping patterns of placental pathology and determine meaningful phenotypes associated with adverse birth outcomes. Placental pathology reports were obtained from a single hospital between 2009 and 2018. Placental lesions were grouped into four major categories: acute inflammation (AI), chronic inflammation (CI), maternal vascular malperfusion (MVM), and fetal vascular malperfusion (FVM). Within each category, lesions were classified as not present, low grade or high grade. Combinations of pathologies were evaluated in relation to preterm birth (<37 weeks) and small for gestational age (SGA) infant (birthweight <10th percentile). During the study period, 19,027 placentas were reviewed by pathologists. Results from interaction models indicate that MVM and MVM in combination with CI and/or FVM are associated with the greatest odds of SGA infant and PTB. When incorporating grade, we identified 21 phenotype groups, each with characteristic associations with the SGA infant and patterns of PTB. We have developed a comprehensive and meaningful placental phenotype that incorporates severity and multiplicity of placental lesions. We have also developed a web application to facilitate phenotype determination (https://placentaexpression.shinyapps.io/phenotype).