Special Issue "Physiology and Pathophysiology of Placenta 2.0".

We are pleased to present this Special Issue of the International Journal of Molecular Sciences, entitled "Physiology and Pathophysiology of Placenta 2 [...].

Maternal obesity and placental function: impaired maternal-fetal axis.

The prevalence of maternal obesity rapidly increases, which represents a major public health concern worldwide. Maternal obesity is characteristic by metabolic dysfunction and chronic inflammation. It is associated with health problems in both mother and offspring. Increasing evidence indicates that the placenta is an axis connecting maternal obesity with poor outcomes in the offspring. In this brief review, we have summarized the current data regarding deregulated placental function in maternal obesity. The data show that maternal obesity induces numerous placental defects, including lipid and glucose metabolism, stress response, inflammation, immune regulation and epigenetics. These placental defects affect each other and result in a stressful intrauterine environment, which transduces and mediates the adverse effects of maternal obesity to the fetus. Further investigations are required to explore the exact molecular alterations in the placenta in maternal obesity, which may pave the way to develop specific interventions for preventing epigenetic and metabolic programming in the fetus.

PPARγ-A Factor Linking Metabolically Unhealthy Obesity with Placental Pathologies.

Obesity is a known factor in the development of preeclampsia. This paper links adipose tissue pathologies with aberrant placental development and the resulting preeclampsia. PPARγ, a transcription factor from the ligand-activated nuclear hormone receptor family, appears to be one common aspect of both pathologies. It is the master regulator of adipogenesis in humans. At the same time, its aberrantly low activity has been observed in placental pathologies. Overweight and obesity are very serious health problems worldwide. They have negative effects on the overall mortality rate. Very importantly, they are also conducive to diseases linked to impaired placental development, including preeclampsia. More and more people in Europe are suffering from overweight (35.2%) and obesity (16%) (EUROSTAT 2021 data), some of them young women planning pregnancy. As a result, we will be increasingly encountering obese pregnant women with a considerable risk of placental development disorders, including preeclampsia. An appreciation of the mechanisms shared by these two conditions may assist in their prevention and treatment. Clearly, it should not be forgotten that health education concerning the need for a proper diet and physical activity is of utmost importance here.

Unique Severe COVID-19 Placental Signature Independent of Severity of Clinical Maternal Symptoms.

BACKGROUND: Although the risk for transplacental transmission of SARS-CoV-2 is rare, placental infections with adverse functional consequences have been reported. This study aims to analyse histological placental findings in pregnancies complicated by SARS-CoV-2 infection and investigate its correlation with clinical symptoms and perinatal outcomes. We want to determine which pregnancies are at-risk to prevent adverse pregnancy outcomes related to COVID-19 in the future. METHODS: A prospective, longitudinal, multicentre, cohort study. All pregnant women presenting between April 2020 and March 2021 with a nasopharyngeal RT-PCR-confirmed SARS-CoV-2 infection were included. Around delivery, maternal, foetal and placental PCR samples were collected. Placental pathology was correlated with clinical maternal characteristics of COVID-19. RESULTS: Thirty-six patients were included, 33 singleton pregnancies (n = 33, 92%) and three twin pregnancies (n = 3, 8%). Twenty-four (62%) placentas showed at least one abnormality. Four placentas (4/39, 10%) showed placental staining positive for the presence of SARS-CoV-2 accompanied by a unique combination of diffuse, severe inflammatory placental changes with massive perivillous fibrin depositions, necrosis of syncytiotrophoblast, diffuse chronic intervillositis, and a specific, unprecedented CD20+ B-cell infiltration. This SARS-CoV-2 placental signature seems to correlate with foetal distress (75% vs. 15.6%, p = 0.007) but not with the severity of maternal COVID-19 disease. CONCLUSION: We describe a unique placental signature in pregnant patients with COVID-19, which has not been reported in a historical cohort. We show that the foetal environment can be seriously compromised by disruption of placental function due to local, devastating SARS-CoV-2 infection. Maternal clinical symptoms did not predict the severity of the SARS-CoV-2-related placental signature, resulting in a lack of adequate identification of maternal criteria for pregnancies at risk. Close foetal monitoring and pregnancy termination in case of foetal distress can prevent adverse pregnancy outcomes due to COVID-19 related placental disease.

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

OBJECTIVE: 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). METHODS: 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. RESULTS: 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). CONCLUSIONS: 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.

Is endothelial function impaired among women with placenta-mediated fetal growth restriction? Evidence from a prospective cohort study using peripheral artery tonometry.

INTRODUCTION: Women with pregnancies complicated by IUGR are at increased risk for future cardiovascular disease. Nevertheless, it is unknown whether endothelial function of women with pregnancies complicated by IUGR is already impaired during pregnancy. Hence, we evaluated maternal endothelial function in pregnancies complicated by IUGR due to placental dysfunction. METHODS: Prospective cohort study assessing systemic endothelial function of women with singleton pregnancies and estimated fetal weight (EFW) below 10th percentile and abnormal umbilical artery flow (n = 15). Control group included women with singleton pregnancies and normal EFW (n = 22). Endothelial function was assessed using EndoPAT™ device which evaluates the change in peripheral vascular tone in reaction to temporal ischemia, a process called reactive hyperemia. The ratio of the readings before and after ischemia is used to assess endothelial function and called reactive hyperemia index (RHI). Low RHI values indicate endothelial dysfunction. RESULTS: The median gestational age at endoPAT examination was comparable between the IUGR and control groups (32; IQR 31,33; p = 0.18). The median RHI was significantly lower in the IUGR group compared to the control group (1.3 vs 1.5, p = 0.02). Median gestational age at delivery and mean neonatal birth weight were lower in the IUGR group compared to the control group (36.7 (35.6,37.2) vs 37.7 (35.3, 39.3), p = 0.04 and 1647 ± 414 g vs 2785 ± 587 g, p < 0.001). DISCUSSION-: Pregnant women with IUGR due to placental dysfunction are characterized by impaired systemic endothelial function.

Placental Histological Features and Neurodevelopmental Outcomes at Two Years in Very-Low-Birth-Weight Infants.

BACKGROUND: We evaluated the rates of placental pathologic lesions and their relationship with two-year neurodevelopmental outcomes in very-low-birth-weight (VLBW) infants. METHODS: This is a cohort observational study comprising 595 VLBW infants during 2007 to 2015. Neurodevelopmental assessment was carried out at 24 months corrected age. RESULTS: In univariate analysis the rates of survival with normal neurodevelopmental outcomes were lower in pregnancies with severe histologic chorioamnionitis (38 of 43, 88.4% when compared with 305 of 450, 67.8%), severe maternal vascular malperfusion (MVM) (17 of 37, 45.9% when compared with 326/492, 66.3%), and intravillous hemorrhage (37 of 82, 45.1% when compared with 306 of 449, 68.1%). In logistic models, severe MVM (adjusted odds ratio [adj. OR] = 0.45, 95% confidence interval [CI] = 0.22 to 0.92), severe fetal vascular malperfusion (FVM) (adj. OR = 0.46, 95% CI = 0.22 to 0.45), and intravillous hemorrhage (adj. OR = 0.38, 95% CI = 0.22 to 0.62) were associated with lower rates of infant survival with normal neurodevelopmental outcome. FVM (adj. OR = 0.46, 95% CI = 0.21 to 0.97) and intravillous hemorrhage (adj. OR = 0.37, 95% CI = 0.22 to 0.62) were also the only placental lesions that were independent predictors of a lower rate of intact survival in stepwise analysis for prognostic factors of the entire cohort. CONCLUSIONS: Placental pathologic findings such as severe MVM, FVM, and intravillous hemorrhage are significant predictors of neonatal survival and subsequent adverse neurodevelopmental outcomes. Data on the placental pathology could be useful in the neurodevelopmental follow-up of VLBW infants.

COVID-19 as an independent risk factor for subclinical placental dysfunction.

BACKGROUND: The pandemic of the severe acute respiratory distress syndrome-associated Coronavirus-2 (SARS-CoV-2) has affected millions around the world. In pregnancy the dangers to the mother and fetus are still being explored. SARS-CoV2 can potentially compromise maternal and neonatal outcomes and this may be dependent on the pregnancy stage during which the infection occurs. OBJECTIVE: The present study was done to find the histopathological alterations in the placenta of SARS-CoV-2 positive pregnancies with either no symptoms or mild coronavirus disease (COVID)-19 related symptoms and its association with neonatal outcomes. STUDY DESIGN: This was a prospective analytical study. Twenty seven asymptomatic or mildly symptomatic SARS-CoV-2 positive pregnant women with a singleton pregnancy delivered between 1st July 2020 and 15th September 2020, were included as cases. An equal number of SARS-CoV-2 negative singleton pregnancies matched for maternal and gestational age during the same period were included as controls. After delivery the histopathological examination of the placenta of these women was done and the findings recorded on a predesigned proforma based on the Amsterdam consensus criteria for evidence of maternal and fetal vascular malperfusion changes. RESULTS: The baseline characteristics were comparable between the cases and controls. The following features of maternal vascular malperfusion (MVM) were significantly higher in the placentae of COVID-19 positive pregnancies: retroplacental hematomas (RPH), accelerated villous maturation (AVM), distal villous hyperplasia (DVH), atherosis, fibrinoid necrosis, mural hypertrophy of membrane arterioles (MHMA), vessel ectasia and persistence of intramural endovascular trophoblast (PIEVT). Fetal vascular malperfusion (FVM) significantly associated with the positive pregnancies were chorioangiosis, thrombosis of the fetal chorionic plate (TFCP), intramural fibrin deposition (IMFD) and vascular ectasia. Additionally, perivillous fibrin deposition was also significantly higher in the placentae of cases. The percentage of spontaneously delivered women was comparable in the two groups. The sex and weight of the newborn and the number of live births were comparable between the two groups. CONCLUSIONS: Asymptomatic or mildly symptomatic SARS-CoV-2 positive pregnant women, with otherwise uncomplicated pregnancies, show evidence of placental injury at a microscopic level. Similar findings have been demonstrated in other studies too. This placental injury apparently does not lead to poor pregnancy outcomes. The extent of this injury in symptomatic cases of COVID-19 pregnancies and its consequences on the outcomes need to be analysed.

Disorders of placental villous maturation are present in one-third of cases with spontaneous preterm labor.

OBJECTIVES: Spontaneous preterm labor is an obstetrical syndrome accounting for approximately 65-70% of preterm births, the latter being the most frequent cause of neonatal death and the second most frequent cause of death in children less than five years of age worldwide. The purpose of this study was to determine and compare to uncomplicated pregnancies (1) the frequency of placental disorders of villous maturation in spontaneous preterm labor; (2) the frequency of other placental morphologic characteristics associated with the preterm labor syndrome; and (3) the distribution of these lesions according to gestational age at delivery and their severity. METHODS: A case-control study of singleton pregnant women was conducted that included (1) uncomplicated pregnancies (controls, n=944) and (2) pregnancies with spontaneous preterm labor (cases, n=438). All placentas underwent histopathologic examination. Patients with chronic maternal diseases (e.g., chronic hypertension, diabetes mellitus, renal disease, thyroid disease, asthma, autoimmune disease, and coagulopathies), fetal malformations, chromosomal abnormalities, multifetal gestation, preeclampsia, eclampsia, preterm prelabor rupture of the fetal membranes, gestational hypertension, gestational diabetes mellitus, and HELLP (hemolysis, elevated liver enzymes and low platelet count) syndrome were excluded from the study. RESULTS: Compared to the controls, the most prevalent placental lesions among the cases were the disorders of villous maturation (31.8% [106/333] including delayed villous maturation 18.6% [62/333] vs. 1.4% [6/442], q<0.0001, prevalence ratio 13.7; and accelerated villous maturation 13.2% [44/333] vs. 0% [0/442], q<0.001). Other lesions in decreasing order of prevalence included hypercapillarized villi (15.6% [68/435] vs. 3.5% [33/938], q<0.001, prevalence ratio 4.4); nucleated red blood cells (1.1% [5/437] vs. 0% [0/938], q<0.01); chronic inflammatory lesions (47.9% [210/438] vs. 29.9% [282/944], q<0.0001, prevalence ratio 1.6); fetal inflammatory response (30.1% [132/438] vs. 23.2% [219/944], q<0.05, prevalence ratio 1.3); maternal inflammatory response (45.5% [195/438] vs. 36.1% [341/944], q<0.01, prevalence ratio 1.2); and maternal vascular malperfusion (44.5% [195/438] vs. 35.7% [337/944], q<0.01, prevalence ratio 1.2). Accelerated villous maturation did not show gestational age-dependent association with any other placental lesion while delayed villous maturation showed a gestational age-dependent association with acute placental inflammation (q-value=0.005). CONCLUSIONS: Disorders of villous maturation are present in nearly one-third of the cases of spontaneous preterm labor.

Effect of edaravone on pregnant mice and their developing fetuses subjected to placental ischemia.

Growing evidence indicates that reduced uterine perfusion pressure (RUPP) triggers the cascade of events leading to preeclampsia. Edaravone is a powerful free radical scavenger used for the treatment of ischemia/reperfusion diseases due to its anti-oxidative stress and anti-inflammatory properties. Here we investigate the effect of edaravone (3 mg/kg) on different maternal and fetal outcomes of RUPP-induced placental ischemia mice model. RUPP surgery was performed on gestation day (GD) 13 followed by edaravone injection from GD14 to GD18, sacrifice day. The results showed that edaravone injection significantly decreased the maternal blood pressure (113.2 ± 2.3 mmHg) compared with RUPP group (131.5 ± 1.9 mmHg). Edaravone increased fetal survival rate (75.4%) compared with RUPP group (54.4%), increased fetal length, weights, and feto-placental ratio (7.2 and 5.7 for RUPP and RUPP-Edaravone groups, respectively) compared with RUPP group. In addition, RUPP resulted in many fetal morphological abnormalities as well as severe delayed ossification, however edaravone decreased the morphological abnormalities and increased the ossification of the fetal endoskeleton. Edaravone improved the histopathological structure of the maternal kidney and heart as well as decreased the elevated blood urea and creatinine levels (31.5 ± 0.15 mg/dl (RUPP), 25.6 ± 0.1 mg/dl (RUPP+edaravone) for urea and 5.4 ± 0.1 mg/dl (RUPP), 3.5 ± 0.1 mg/dl (RUPP+edaravone) for creatinine) and decreased cleaved caspase-3 expression in the maternal kidney. In conclusion, this study demonstrated that our RUPP mice model recapitulated preeclampsia symptoms and edaravone injection ameliorated most of these abnormalities suggesting its effectiveness and potential application in preeclampsia treatment regimes.

Temporal heterogeneity of placental segmental fetal vascular malperfusion: timing but not etiopathogenesis.

Clinicopathologic correlations of segmental villous avascularity and other histological lesions of segmental fetal vascular malperfusion (SFVM) were analyzed retrospectively to determine whether lesions of various durations reflect different etiopathogeneses. The frequencies of 25 independent clinical and 43 placental phenotypes were statistically compared by ANOVA or Chi-square among 3 groups containing a total of 378 placentas with SFVM: group 1 contained 44 cases of recent SFVM (endothelial fragmentation, villous hypovascularity by CD34 immunostain, and/or stromal vascular karyorrhexis); group 2 contained 264 cases of established SFVM (clusters of avascular villi); and group 3 contained 70 cases of remote SFVM (villous mineralization). Statistically significant differences among the three study groups (p Bonferroni < 0.002) were found in four clinical variables (gestational age, frequencies of macerated stillbirth, induction of labor, and cesarean section) and in five placental variables (frequencies of fetal vascular ectasia, stem vessel luminal vascular abnormalities, diffusely increased extracellular matrix in chorionic villi, chorionic disk extravillous trophoblast microcysts, and excessive extravillous trophoblasts in the chorionic disc). In summary, the absence of statistically significant differences between the study groups regarding the most common causes of SFVM (hypertensive conditions of pregnancy, diabetes mellitus, fetal anomalies, and clinical and pathological features of umbilical cord compromise) is evidence that the three types of SFVM reflect temporal heterogeneity rather than etiopathogenesis. This evidence can be used to date the onset of fetal vascular malperfusion before delivery or stillbirth. The coexistence of different SVFM lesions of various durations indicates ongoing or repeat occurrences of FVM rather than single episodes.

The application of in utero magnetic resonance imaging in the study of the metabolic and cardiovascular consequences of the developmental origins of health and disease.

Observing fetal development in utero is vital to further the understanding of later-life diseases. Magnetic resonance imaging (MRI) offers a tool for obtaining a wealth of information about fetal growth, development, and programming not previously available using other methods. This review provides an overview of MRI techniques used to investigate the metabolic and cardiovascular consequences of the developmental origins of health and disease (DOHaD) hypothesis. These methods add to the understanding of the developing fetus by examining fetal growth and organ development, adipose tissue and body composition, fetal oximetry, placental microstructure, diffusion, perfusion, flow, and metabolism. MRI assessment of fetal growth, organ development, metabolism, and the amount of fetal adipose tissue could give early indicators of abnormal fetal development. Noninvasive fetal oximetry can accurately measure placental and fetal oxygenation, which improves current knowledge on placental function. Additionally, measuring deficiencies in the placenta's transport of nutrients and oxygen is critical for optimizing treatment. Overall, the detailed structural and functional information provided by MRI is valuable in guiding future investigations of DOHaD.

Estimating umbilical cord flow resistance from measurements of the whole cord.

Measuring umbilical blood pressure in utero is challenging and for this reason non-invasive methods are required. However, the total vessel blood pressure drop can be estimated using numerical and empirical results by studying the mechanics of fluids in coiled and straight tubes. Two key findings emerge from such an analysis. Firstly, the total pressure drop along a vessel at a given blood flow-rate depends on both the tightness of the coils and the total cord length. Relatively short and straight cords exhibit low pressure, while long, tightly coiled cords with large width exhibit high pressure. It follows that an estimate of the pressure requires three measurements: the full cord length, its average width and number of coils. Using this result we propose two prototype indices for clinical testing that estimate umbilical cord flow resistance. The umbilical pressure index (PX) and flow index (QX) quantify the deviation of a cord geometry from defined typical conditions by considering the steady pressure drop and flow-rate, respectively. These indices can be quickly calculated, and require only a single additional measurement to the conventional umbilical coiling index (UCI); namely the cord coiling width. Unlike the UCI, these indices are derived from blood-flow properties and provide a measure of the relative flow-resistance inherent to a cord geometry. Furthermore, the pressure index can be applied to irregularities, including loose true knots, which we show must be accounted for.

The association between first trimester placental biomarkers and placental lesions of maternal vascular malperfusion.

INTRODUCTION: Abnormal levels of first trimester placental biomarkers are associated with the development of placental syndrome (PS). However, prediction performance is moderate, possibly explained by the clinical heterogeneity of PS. Aim of this study is to investigate the association between first trimester biomarkers and the presence of maternal vascular malperfusion (MVM), as a marker for placental insufficiency. METHODS: This retrospective study included 195 women with available first trimester blood sample and placenta histological sections for examination at the Maastricht University Medical Centre. Women were divided into 4 groups, based on the presence of having MVM lesions and/or PS. Levels of PAPP-A, PlGF and sFlt-1 were measured and MVM lesions were classified according to the Amsterdam Placental Workshop Group Consensus Statement. RESULTS: MVM occurrence was observed in 32% of the uncomplicated pregnancies. Women with MVM (regardless of the PS) had lower levels of PAPP-A (p = 0.038) and sFLt-1 (p = 0.006), and a non-significant trend for lower PlGF and sFlt-1/PlGF ratio compared to women without MVM. Low PAPP-A levels individually and in combination with the presence of PS was significantly associated with MVM lesions (aOR = 3.0 and 6.1, respectively), as did the combination of low PlGF levels and PS (aOR = 4.6). In women with PS, having MVM increased the incidence of fetal growth restriction, small for gestational age neonates, lower birthweight and adverse neonatal outcome. DISCUSSION: Our findings suggest that MVM lesions were found to be associated with increased obstetric risks due to early placental dysfunction that can potentially be predicted by the use of first trimester biomarkers.

Diffuse Subamniotic Calcification: A Novel Pattern of Placental Calcification.

Two primary patterns of placental calcification have been described, each with distinctive pathophysiology and clinical relevance. We report a novel pattern of diffuse subamniotic calcification. It occurred in a 25-week placenta involved by recurrent chronic histiocytic intervillositis (CHI) associated with severe intrauterine growth restriction (IUGR) and intrauterine fetal demise (IUFD). This was the mother's third stillbirth related to CHI, despite treatment with intravenous immunoglobulin (IVIG), prednisone, low-molecular-weight heparin, and acetylsalicylic acid (ASA). On placental examination, the majority of the fetal surface was calcified. This variably formed a continuous band or dispersed calcium microparticles. Electron microscopy demonstrated associated electron dense deposits highly suggestive of immune complex deposition. CHI explains recurrent IUGR and stillbirth, but has not been associated with calcification or immune complex deposition. We hypothesize IVIG therapy may have caused immune complex deposition and subsequent dystrophic calcification, supported by its rare association with immune complex deposition disorders in the kidney. Identification of additional cases with this pattern of calcification, with additional studies on fresh tissue including immunofluorescence, electron microscopy and mass spectrometry, may aid in elucidating the underlying pathophysiology and clinical significance of this unusual lesion.

Tracking placental development in health and disease.

Pre-eclampsia and fetal growth restriction arise from disorders of placental development and have some shared mechanistic features. Initiation is often rooted in the maldevelopment of a maternal-placental blood supply capable of providing for the growth requirements of the fetus in later pregnancy, without exerting undue stress on maternal body systems. Here, we review normal development of a placental bed with a safe and adequate blood supply and a villous placenta-blood interface from which nutrients and oxygen can be extracted for the growing fetus. We consider disease mechanisms that are intrinsic to the maternal environment, the placenta or the interaction between the two. Systemic signalling from the endocrine placenta targets the maternal endothelium and multiple organs to adjust metabolism for an optimal pregnancy and later lactation. This signalling capacity is skewed when placental damage occurs and can deliver a dangerous pathogenic stimulus. We discuss the placental secretome including glycoproteins, microRNAs and extracellular vesicles as potential biomarkers of disease. Angiomodulatory mediators, currently the only effective biomarkers, are discussed alongside non-invasive imaging approaches to the prediction of disease risk. Identifying the signs of impending pathology early enough to intervene and ameliorate disease in later pregnancy remains a complex and challenging objective.

Maternal and neonatal response to COVID-19.

The risk of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) to maternal and newborn health has yet to be determined. Several reports suggest pregnancy does not typically increase the severity of maternal disease; however, cases of preeclampsia and preterm birth have been infrequently reported. Reports of placental infection and vertical transmission are rare. Interestingly, despite lack of SARS-CoV-2 placenta infection, there are several reports of significant abnormalities in placenta morphology. Continued research on pregnant women infected with SARS-CoV-2 and their offspring is vitally important.

Maternal Sildenafil vs Placebo in Pregnant Women With Severe Early-Onset Fetal Growth Restriction: A Randomized Clinical Trial.

Importance: Severe early onset fetal growth restriction caused by placental dysfunction leads to high rates of perinatal mortality and neonatal morbidity. The phosphodiesterase 5 inhibitor, sildenafil, inhibits cyclic guanosine monophosphate hydrolysis, thereby activating the effects of nitric oxide, and might improve uteroplacental function and subsequent perinatal outcomes. Objective: To determine whether sildenafil reduces perinatal mortality or major morbidity. Design, Setting, and Participants: This placebo-controlled randomized clinical trial was conducted at 10 tertiary referral centers and 1 general hospital in the Netherlands from January 20, 2015, to July 16, 2018. Participants included pregnant women between 20 and 30 weeks of gestation with severe fetal growth restriction, defined as fetal abdominal circumference below the third percentile or estimated fetal weight below the fifth percentile combined with Dopplers measurements outside reference ranges or a maternal hypertensive disorder. The trial was stopped early owing to safety concerns on July 19, 2018, whereas benefit on the primary outcome was unlikely. Data were analyzed from January 20, 2015, to January 18, 2019. The prespecified primary analysis was an intention-to-treat analysis including all randomized participants. Interventions: Participants were randomized to sildenafil, 25 mg, 3 times a day vs placebo. Main Outcomes and Measures: The primary outcome was a composite of perinatal mortality or major neonatal morbidity until hospital discharge. Results: Out of 360 planned participants, a total of 216 pregnant women were included, with 108 women randomized to sildenafil (median gestational age at randomization, 24 weeks 5 days [interquartile range, 23 weeks 3 days to 25 weeks 5 days]; mean [SD] estimated fetal weight, 458 [160] g) and 108 women randomized to placebo (median gestational age, 25 weeks 0 days [interquartile range, 22 weeks 5 days to 26 weeks 3 days]; mean [SD] estimated fetal weight, 464 [186] g). In July 2018, the trial was halted owing to concerns that sildenafil may cause neonatal pulmonary hypertension, whereas benefit on the primary outcome was unlikely. The primary outcome, perinatal mortality or major neonatal morbidity, occurred in the offspring of 65 participants (60.2%) allocated to sildenafil vs 58 participants (54.2%) allocated to placebo (relative risk, 1.11; 95% CI, 0.88-1.40; P = .38). Pulmonary hypertension, a predefined outcome important for monitoring safety, occurred in 16 neonates (18.8%) in the sildenafil group vs 4 neonates (5.1%) in the placebo group (relative risk, 3.67; 95% CI, 1.28-10.51; P = .008). Conclusions and Relevance: These findings suggest that antenatal maternal sildenafil administration for severe early onset fetal growth restriction did not reduce the risk of perinatal mortality or major neonatal morbidity. The results suggest that sildenafil may increase the risk of neonatal pulmonary hypertension. Trial Registration: ClinicalTrials.gov Identifier: NCT02277132.

Placental growth disorders and perinatal adverse outcomes in Brazilian HIV-infected pregnant women.

Fetal and placental growth disorders are common in maternal human immunodeficiency virus (HIV) infection and can be attributed to both the infection and comorbidities not associated with HIV. We describe placental growth disorders and adverse reproductive outcomes in HIV-infected pregnant women whose delivery occurred between 2001-2014 in Vitoria, Brazil. Cases with gestational age (GA) ≥ than 22 weeks validated by ultrasonography, with placental and fetal weight dimensions at birth, were studied. Outcomes were summarized as proportions of small (SGA), appropriate (AGA), and large (LGA) for GA when the z-score values were below -1.28, between -1.28 and +1.28, or above +1.28, respectively. Of 187 fetal attachment requisitions, 122(65.2%) women and their newborns participated in the study. The median maternal age was 28 years and 81(66.4%) underwent ≥ 6 prenatal visits. A total of 81(66.4%) were diagnosed before current pregnancy; 68(55.7%) exhibited criteria for acquired immunodeficiency syndrome (AIDS); 64(52.4%) had detectable viral load; 25(20.5%) cases presented SGA placental weight and 6(4.9%) SGA placental thickness. SGA placental area was observed in 41(33.6%) cases, and among the SGA placental weight cases 12(48%) were also SGA fetal weight. Preterm birth (PTB) occurred in 15.6%(19/122) of cases; perinatal death in 4.1%(5/122) and HIV vertical transmission in 6 of 122 (4.9%). Women, ≥36 years old, were 5.7 times more likely to have PTB than those under 36. Also, patients with AIDS-defining criteria were 3.7 times more likely to have PTB. Prenatal care was inversely associated with PTB. Statistically significant associations were observed between AGA placental area and Protease Inhibitor usage and between SGA placental weight and SGA area. We found a prevalence of placental growth disorders in HIV-infected pregnant women and values higher than international reference values. The restriction of placental growth was a common disorder, possibly attributed to virus effects or a combination of antiretroviral regimens.