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Maternal hepatitis virus has rarely been implicated in fetal meconium peritonitis (FMP), and its underlying mechanism is largely unknown. We describe a case of FMP presumably caused by maternal chronic hepatitis B virus (HBV). A 29-year-old primigravid woman was referred to our hospital at 35 weeks of gestation for the disappearance of fetal movements. The maternal prenatal history included HBV for more than 10 years. Her HBV DNA level was suppressed (<20 IU/mL) and she was taking oral tenofovir disoproxil fumarate (300 mg/day). At 21 +5 weeks, fetal ascites, echogenic bowel, and intra-abdominal calcifications were observed by abdominal ultrasound. These findings were confirmed by magnetic resonance imaging and were regarded as diagnostic for FMP. Cord blood and amniotic fluid were positive for hepatitis B e antigen and hepatitis B surface antigen. Ascites of the FMP was completely self-absorbed at 27 +3 weeks. At 35 weeks of gestation, fetal movements had vanished and male stillbirth was induced. A histopathological examination of the placenta showed meconium uptake by macrophages in the amniochorionic membranes. Our findings suggest that maternal HBV can cross the placenta and induce FMP. Close surveillance may allow an early diagnosis of FMP and prevent fetal mortality., Competing Interests: Declaration of conflicting interestThe authors declare that there is no conflict of interest.

Background: The available literature on intrauterine transfusion focuses largely on its application in fetal alloimmunization rather than hereditary red cell disorders, with limited illustration of its associated histopathologic findings. Case report: We present the histologic findings in a placenta associated with preterm delivery of an infant with autosomal SPTA1 mutation following multiple intrauterine transfusions, including appropriate villous maturation, subchorionic organizing hematomas, hemosiderin-laden macrophages, and dysmorphic fetal erythrocytes within villous capillaries. Conclusion: Intrauterine transfusion is associated with placental histologic findings that reflect procedural changes without significant disruption of placental membranes or villous maturation.

Objectives: Fetal and neonatal hyperthyroidism are most commonly seen in patients whose mothers have Graves' disease. Rarely, it can be caused by non-autoimmune conditions. As these conditions are rare, the workup and treatment is not uniform and can lead to persistent symptoms and long-term negative health effects., Case Presentation: This report describes a patient with congenital hyperthyroidism from a toxic adenoma presenting with fetal tachycardia. The patient was initially managed medically after birth, but was eventually treated with thyroidectomy., Conclusions: This case report highlights an additional, important, differential diagnosis for fetal hyperthyroidism when maternal Graves' disease has been ruled out., (© 2024 Walter de Gruyter GmbH, Berlin/Boston.)

Although widely known as a tumor suppressor, the breast cancer 1 susceptibility protein (BRCA1) is also important in development, where it regulates fetal DNA repair pathways that protect against DNA damage caused by physiological and drug-enhanced levels of reactive oxygen species (ROS). We previously showed that conditional heterozygous (+/-) knockout (cKO) mouse embryos with a minor 28% BRCA1 deficiency developed normally in culture, but when exposed to the ROS-initiating drug, alcohol (ethanol, EtOH), exhibited embryopathies not evident in wild-type (+/+) littermates. Herein, we characterized a directBrca1 +/- knockout (KO) model with a 2-fold greater (58%) reduction in BRCA1 protein vs. the cKO model. We also characterized and compared learning & memory deficits in both the cKO and KO models. Even saline-exposed Brca1 +/- vs. +/+ KO progeny exhibited enhanced oxidative DNA damage and embryopathies in embryo culture and learning & memory deficits in females in vivo, which were not observed in the cKO model, revealing the potential pathogenicity of physiological ROS levels. The embryopathic EtOH concentration for cultured direct KO embryos was half that for cKO embryos, and EtOH affected Brca1 +/+ embryos only in the direct KO model. The spectrum and severity of EtOH embryopathies in culture were greater in both Brca1 +/- vs. +/+ embryos, and direct KO vs. cKO +/- embryos. Motor coordination deficits were evident in both male and female Brca1 +/- KO progeny exposed in utero to EtOH. The results in our direct KO model with a greater BRCA1 deficiency vs. cKO mice provide the first evidence for BRCA1 protein dose-dependent susceptibility to developmental disorders caused by physiological and drug-enhanced oxidative stress., Competing Interests: Declaration of competing interest None., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Objectives: Studies suggest an association between placenta and congenital heart disease (CHD). We evaluated placental pathologies associated with major CHD. Methods: A prospective study included fetuses with major CHD, identified by fetal echocardiography. Fetal Doppler of umbilical artery (UA), middle cerebral artery (MCA), and placental histopathology were assessed. Outcome was measured by mortality at one month of age. Results: 21 cases were analyzed. Hypoplastic left heart syndrome was the commonest lesion (23.8%). Significant differences were detected among categories regarding MCA systolic/diastolic (S/D) ratio & pulsatility index ( p  = 0.023; 0.036), respectively. Placental histopathologies were demonstrated in 18(85.7%), predominately involved fetal malperfusion lesions 16/21(76.2%), especially chorangiosis (33.3%). No significant association was detected between placental histopathological abnormalities and Doppler parameter, diagnostic category, or mortality. Conclusion: The high prevalence of abnormal placental histopathological findings in major fetal CHD provides additional evidence of placental-cardiac interlinkage. No association was detected between abnormal placental histopathology and fetal Doppler measurements or neonatal outcome of CHD.

Objective: We evaluated what placental pathologies were associated with adverse preterm births., Materials and Methods: Placental findings, classified according to the Amsterdam criteria, were correlated with infant outcomes. The fetal vascular lesions, inflammatory responses other than histological chorioamnionitis (HCA), and placentas with combined maternal vascular malperfusion (MVM) and HCA were excluded., Results: A total of 772 placentas were evaluated. MVM was present in 394 placentas, HCA in 378. Early neonatal sepsis, retinopathy of prematurity, necrotizing enterocolitis, and neonatal death occurred more often in the MVM-only group than HCA-only group. The frequency of bronchopulmonary dysplasia (BPD) was 38.6% in the HCA-only group, and it was 20.3% in the MVM-only group ( p  < 0.001). HCA was the most important independent risk factor for BPD (OR 3.877, 95% CI 2.831-5.312)., Conclusion: Inflammation in the placenta influences fetal and neonatal outcomes. HCA is an independent risk factor for BPD.

Introduction: Placental morphology findings in SARS-CoV-2 infection are considered nonspecific, although the role of trimester and severity of infection are underreported. Therefore, we aimed to investigate abnormal placental morphology, according to these two criteria., Methods: This is an ancillary analysis of a prospective cohort study of pregnant women with suspected SARS-CoV-2 infection, managed in one maternity, from March 2020 to October 2021. Charting of clinical/obstetric history, trimester and severity of COVID-19 infection, and maternal/perinatal outcomes were done. Placental morphological findings were classified into maternal and fetal circulatory injury and acute/chronic inflammation. We further compared findings with women with suspected disease which tested negative for COVID-19. Diseases' trimester of infection and clinical severity guided the analysis of confirmed COVID-19 cases., Results: Ninety-one placental discs from 85 women were eligible as a COVID-19 group, and 42 discs from 41 women in negative COVID-19 group. SARS-CoV-2 infection occurred in 68.2% during third trimester, and 6.6% during first; 16.5% were asymptomatic, 61.5% non-severe and 22.0% severe symptomatic (two maternal deaths). Preterm birth occurred in 33.0% (one fetal death). Global maternal vascular malperfusion (MVM) were significant in COVID-19 group whether compared with negative COVID-19 tests group; however, fetal vascular malperfusion lesions and low-grade chronic villitis were not. Three placentas had COVID-19 placentitis. Decidual arteriopathy was associated with infection in first/mid trimester, and chorangiosis in asymptomatic infections., Discussion: Placental abnormalities after an infection by COVID-19 were more frequent after first/mid-trimester infections. Extensive placental lesions are rare, although they may be more common upon underlying medical conditions., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier Ltd.)

We aim to evaluate the clinical course and outcome of cases with a prenatal diagnosis of ectopia cordis in our center. In this retrospective study, we analyzed clinical variables including gestational age at diagnosis, maternal age, associated cardiac, extracardiac, genetic anomalies and, outcome in prenatally diagnosed ectopia cordis cases in our tertiary referral center. Eight ectopia cordis cases from seven pregnancies were included in the study. All fetuses had complete type of ectopia cordis and pentalogy of Cantrell. Five multiple pregnancies were found, four were twin pregnancies (three dichorionic diamniotic, one monochorionic monoamniotic) and one was triplet (trichorionic triamniotic). In the monochorionic monoamniotic twin pregnancy, both fetuses have pentalogy of Cantrell. Two cases had intracardiac structural defects including Tetralogy of Fallot and hypoplastic right heart syndrome. Three pregnancies were terminated, four cases delivered alive could not survive beyond the neonatal period. The striking feature in our study is its association with multiple pregnancies., (© 2023 Japanese Teratology Society.)

Objective: To determine the association of placental pathology with the severity of necrotizing enterocolitis (NEC) in preterm infants., Methods: This single-center matched case-control study included infants with NEC ( n  = 107) and gestational age and birth weight-matched controls ( n  = 130), born between 2013 and 2020. Placentas were evaluated according to the Amsterdam Placental Workshop Group Consensus Statement., Results: Acute histologic chorioamnionitis with the fetal response was significantly more common in infants with surgical NEC vs. medical NEC (35.4% vs. 15.3%; p  = 0.02). On regression model, infants with multiple placental pathologies (OR 2.16; 95% CI 1.01 - 4.73; p  = 0.04) and maternal vascular malperfusion (OR 2.2; 95% CI 1.12 - 4.51; p  = 0.02) had higher odds of either medical or surgical NEC than controls., Conclusion: Infants with multiple placental lesions, including placental inflammatory and vascular lesions, were at higher risk of medical or surgical NEC in the postnatal period.

Background: Pathogenic mutations in the smooth muscle myosin heavy chain gene, MYH11 , cause megacystis megacolon intestinal hypoperistalsis syndrome and other forms of chronic intestinal pseudo-obstruction. Evaluation of intestinal tissues from affected patients is often performed before mutational analysis, but the pathological findings of MYH11 -variant visceral myopathy have not been well defined., Methods: Light microscopic, immunohistochemical, and ultrastructural findings from multiple intestinal samples from 2 patients with MYH11-variant visceral myopathy were reviewed, including MYH11-specific immunohistochemistry. The findings were compared with intestinal samples from patients with gamma-smooth muscle actin ( ACTG2 )-variant visceral myopathy and non-pseudo-obstruction controls., Results: Apart from non-specific changes (e.g., muscle hypertrophy and distension-related muscularis propria necrosis), no alterations were identified by routine histopathological evaluation or electron microscopy. Immunohistochemistry with antibodies against a battery of smooth muscle proteins, including MYH11, revealed indistinguishable patterns of immunoreactivity in the muscularis propria of both patients and controls., Conclusions: Myopathic morphological or immunohistochemical changes may not be present in intestinal specimens from patients with MYH11 -variant visceral myopathy. Molecular genetic studies should be considered for patients with chronic intestinal pseudo-obstruction and normal or non-specific pathology findings.

Objectives: Fetal blood circulation may be modified in congenital heart disease (CHD). This retrospective analysis was performed to study whether the type of CHD is associated with specific placental pathology., Methods: Three types of CHD based on presumed proportion of placental and systemic blood distribution in fetal circulation were analyzed: Group 1: 89 cases with low placental blood content (hypoplastic left heart syndrome, transposition of great arteries, coarctation of aorta), Group 2: 71 placentas with intermediate placental and systemic blood content due to increased intracardiac blood mixing (tetralogy of Fallot, truncus arteriosus, double inlet/outlet ventricle), and Group 3: 24 placentas with high placental blood content (tricuspid or pulmonary atresia, Ebstein anomaly). Frequencies of 27 independent clinical and 47 placental phenotypes of 184 placentas in those three groups were statistically compared., Results: The most advanced gestational age at delivery, and large vessel (global) fetal vascular malperfusion (FVM) were most common in Group 1, while macerated stillbirths, neonatal mortality, abnormal amniotic fluid volume (oligohydramnios or polyhydramnios), other congenital anomalies, distal villous lesions of FVM, placental edema and amnion nodosum were most common in Groups 2 and 3, although the frequencies of placental lesions were statistically not significant., Conclusions: Left heart obstructive lesions potentially associated with brain maldevelopment show increase in lesions of global FVM (in aggregate and individually fetal vascular ectasia, stem vessel obliteration and intramural fibrin deposition) as may be seen in umbilical cord compromise. CHD with increased intracardiac blood mixing or with right heart defects is associated with average preterm gestational age at delivery and placental lesions of distal villous FVM, villous edema and amnion nodosum., (© 2022 Walter de Gruyter GmbH, Berlin/Boston.)

To study the relative importance of clinical and umbilical cord (UC) risk factors for placental fetal vascular malperfusion (FVM), 52 placentas with clinical UC compromise were compared with 204 placentas with other maternal/fetal conditions predisposing to FVM, 286 placentas with both factors, and 38 placentas with no clinical conditions or UC factors predisposing to FVM. FVM, both distal villous and global, was more common with UC compromise. Cases with isolated UC compromise were associated with more unfavorable clinical outcomes and histological distal FVM. Clinical conditions without umbilical cord compromise were not associated with increased rate of FVM., Competing Interests: Declaration of competing interest None declared., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: Congenital heart defects(CHDs) are an important cause of neonatal mortality and morbidity. With advances in diagnosis and treatment, many defects are now amenable to correction. There is a need for individualized approach to prenatally detected lesions to predict the likely prognosis. Assigning them into risk category helps in prenatal counseling, decision making, referrals and formulation of management plan to improve the outcome., Objective: To grade the fetal CHDs according to severity and study its usefulness in decision making., Methods: A prospective study at a tertiary care institute between 2016 and 18, including pregnant women with antenatal diagnosis of fetal CHD. Detailed fetal echocardiography was followed by classification of lesions into four risk categories using modified grading system: (A) extremely high risk; (B) high risk (C) moderate risk (D) low risk. Appropriate counseling was provided to facilitate decision making and further management. The grading was reviewed and revised again postpartum/post-mortem for correlation., Results: Of the total 137 cases, almost half (45.53%) were Category B, while Category D, C and A had 24.1%, 20.4% and 10.2% of cases respectively. The mean gestation age at diagnosis was 26.5 weeks. Termination of pregnancy was done in 21 cases, mostly in Category B (71.4%) and of the 116 continued pregnancies, there were 16 intrauterine deaths. Prenatal and postnatal findings were available in 109 cases and kappa analysis for agreement between antenatal and postnatal grading showed good agreement (0.82)., Conclusion: Prenatal grading of congenital heart disease is a reliable, structured and simplified tool that can be used for providing counseling and facilitate decision making.

Interferon lambda (IFN-λ) (type III IFN) is constitutively secreted from human placental cells in culture and reduces Zika virus (ZIKV) transplacental transmission in mice. However, the roles of IFN-λ during healthy pregnancy and in restricting congenital infection remain unclear. Here, we used mice lacking the IFN-λ receptor ( Ifnlr1 -/- ) to generate pregnancies lacking either maternal or fetal IFN-λ responsiveness and found that the antiviral effect of IFN-λ resulted from signaling exclusively in maternal tissues. This protective effect depended on gestational stage, as infection earlier in pregnancy (E7 rather than E9) resulted in enhanced transplacental transmission of ZIKV. In Ifnar1 -/- dams, which sustain robust ZIKV infection, maternal IFN-λ signaling caused fetal resorption and intrauterine growth restriction. Pregnancy pathology elicited by poly(I·C) treatment also was mediated by maternal IFN-λ signaling, specifically in maternal leukocytes, and also occurred in a gestational stage-dependent manner. These findings identify an unexpected effect of IFN-λ signaling, specifically in maternal (rather than placental or fetal) tissues, which is distinct from the pathogenic effects of IFN-αβ (type I IFN) during pregnancy. These results highlight the complexity of immune signaling at the maternal-fetal interface, where disparate outcomes can result from signaling at different gestational stages. IMPORTANCE Pregnancy is an immunologically complex situation, which must balance protecting the fetus from maternal pathogens with preventing maternal immune rejection of non-self fetal and placental tissue. Cytokines, such as interferon lambda (IFN-λ), contribute to antiviral immunity at the maternal-fetal interface. We found in a mouse model of congenital Zika virus infection that IFN-λ can have either a protective antiviral effect or cause immune-mediated pathology, depending on the stage of gestation when IFN-λ signaling occurs. Remarkably, both the protective and pathogenic effects of IFN-λ occurred through signaling exclusively in maternal immune cells rather than in fetal or placental tissues or in other maternal cell types, identifying a new role for IFN-λ at the maternal-fetal interface.

Background: Neonatal myocardial infarction (MI) in a structurally normal heart is frequently an obscure event that remains undiagnosed until autopsy. Causal attributions usually cite underlying maternal or fetal conditions. Refinement in understanding of pathogenic mechanisms underlying neonatal MI is key to advancements in diagnosis, prevention, treatments and prognosis., Objective: This study presents a 36-week gestational age female with perinatal asphyxia, congenital hemolytic anemia and umbilical vein thrombosis who sustained catastrophic MI with reperfusion injury; and it reviews pertinent literature., Results: We propose a pathogenic sequence that links maternal vascular malperfusion, fetal vascular malperfusion, hemolytic anemia, umbilical venous thrombosis, and paradoxical thromboemboli., Conclusion: This case highlights the importance of placental examination in connecting complex neonatal events with adverse maternal/placental conditions. A high index of suspicion is essential for early diagnosis of neonatal MI.

Children with congenital heart disease (CHD) are living longer due to effective medical and surgical management. However, the majority have neurodevelopmental delays or disorders. The role of the placenta in fetal brain development is unclear and is the focus of an emerging field known as neuroplacentology. In this review, we summarize neurodevelopmental outcomes in CHD and their brain imaging correlates both in utero and postnatally. We review differences in the structure and function of the placenta in pregnancies complicated by fetal CHD and introduce the concept of a placental inefficiency phenotype that occurs in severe forms of fetal CHD, characterized by a myriad of pathologies. We propose that in CHD placental dysfunction contributes to decreased fetal cerebral oxygen delivery resulting in poor brain growth, brain abnormalities, and impaired neurodevelopment. We conclude the review with key areas for future research in neuroplacentology in the fetal CHD population, including (1) differences in structure and function of the CHD placenta, (2) modifiable and nonmodifiable factors that impact the hemodynamic balance between placental and cerebral circulations, (3) interventions to improve placental function and protect brain development in utero, and (4) the role of genetic and epigenetic influences on the placenta-heart-brain connection. IMPACT: Neuroplacentology seeks to understand placental connections to fetal brain development. In fetuses with CHD, brain growth abnormalities begin in utero. Placental microstructure as well as perfusion and function are abnormal in fetal CHD., (© 2021. The Author(s).)

Background: Fetal cell-derived exosomes (extracellular vesicles, 40-160 nm) are communication channels that can signal parturition by inducing inflammatory changes in maternal decidua and myometrium. Little is known about maternal cell-derived exosomes and their functional roles on the fetal side. This study isolated and characterized exosomes from decidual and myometrial cells grown under normal and inflammatory/oxidative stress conditions and determined their impact on fetal membrane cells., Methods: Decidual and myometrial cells were grown under standard culture conditions (control) or exposed for 48 h to cigarette smoke extract or tumor necrosis factor-α, as proxies for oxidative stress and inflammation, respectively. Exosomes were isolated from media (differential ultra-centrifugation followed by size exclusion chromatography), quantified (nano particle tracking analysis), and characterized in terms of their size and morphology (cryo-electron microscopy), markers (dot blot), and cargo contents (proteomics followed by bioinformatics analysis). Maternal exosomes (10 9 /mL) were used to treat amnion epithelial cells and chorion trophoblast cells for 24 h. The exosome uptake by fetal cells (confocal microscopy) and the cytokine response (enzyme-linked immunosorbent assays for IL-6, IL-10, and TNF-α) was determined., Results: Exosomes from both decidual and myometrial cells were round and expressed tetraspanins and endosomal sorting complexes required for transport (ESCRT) protein markers. The size and quantity was not different between control and treated cell exosomes. Proteomic analysis identified several common proteins in exosomes, as well as unique proteins based on cell type and treatment. Compared to control exosomes, pro-inflammatory cytokine release was higher in both amnion epithelial cell and chorion trophoblast cell media when the cells had been exposed to exosomes from decidual or myometrial cells treated with either cigarette smoke extract or tumor necrosis factor-α. In chorion trophoblast cells, anti-inflammatory IL-10 was increased by exosomes from both decidual and myometrial cells., Conclusion: Various pathophysiological conditions cause maternal exosomes to carry inflammatory mediators that can result in cell type dependent fetal inflammatory response. Video Abstract., (© 2021. The Author(s).)

Introduction: Trophoblast inclusions (TIs) are associated with aneuploidy and pregnancy loss and have thus been considered to be a marker of genetic abnormality. However, to date, no study has specifically explored whether TIs are a manifestation of fetal genetics or, rather, the result of the intrauterine environment. The goal of this study was to compare the frequency of TIs in the placentas of monozygotic (MZ) and dizygotic (DZ) twin pairs in order to determine whether the formation of TIs is genetically driven or not., Methods: We performed a retrospective case series of placentas from 48 twin pairs. The placentas were grouped based on zygosity: MZ, DZ, or unknown (UZ). The average number of total TIs per slide was calculated for each twin individual and the mean absolute difference in the total TIs per slide between the twin pairs was calculated for each zygosity group and compared., Results: The mean difference in the total TIs per slide for DZ twins was significantly greater than the mean difference in the total TIs per slide for MZ twins (p = 0.003). The mean difference in the total TIs per slide for the UZ group was also significantly greater than the mean difference in total TIs per slide between MZ twin pairs (p = 0.028)., Discussion: Our finding that MZ twins were significantly more concordant than DZ twins for the average number of TIs per slide supports the conclusion that TIs are intrinsic to the genetics of the fetus, not the uterine environment., Competing Interests: Declaration of competing interest All the authors declare no conflicts of interest., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Achondrogenesis type II (ACG2) is a lethal skeletal dysplasia caused by dominant pathogenic variants in COL2A1 . Most of the variants found in patients with ACG2 affect the glycine residue included in the Gly-X-Y tripeptide repeat that characterizes the type II collagen helix. In this study, we reported a case of a novel splicing variant of COL2A1 in a fetus with ACG2. An NGS analysis of fetal DNA revealed a heterozygous variant c.1267-2&#95;1269del located in intron 20/exon 21. The variant occurred de novo since it was not detected in DNA from the blood samples of parents. We generated an appropriate minigene construct to study the effect of the variant detected. The minigene expression resulted in the synthesis of a COL2A1 messenger RNA lacking exon 21, which generated a predicted in-frame deleted protein. Usually, in-frame deletion variants of COL2A1 cause a phenotype such as Kniest dysplasia, which is milder than ACG2. Therefore, we propose that the size and position of an in-frame deletion in COL2A1 may be relevant in determining the phenotype of skeletal dysplasia.

Objective: To determine whether bladder size is associated with an unfavorable neonatal outcome, in the case of first-trimester megacystis., Materials and Methods: This was a retrospective observational study between 2009 and 2019 in two prenatal diagnosis centers. The inclusion criterion was an enlarged bladder (> 7 mm) diagnosed at the first ultrasound exam between 11 and 13+6 weeks of gestation. The main study endpoint was neonatal outcome based on bladder size. An adverse outcome was defined by the completion of a medical termination of pregnancy, the occurrence of in utero fetal death, or a neonatal death. Neonatal survival was considered as a favorable outcome and was defined by a live birth, with or without normal renal function, and with a normal karyotype., Results: Among 75 cases of first-trimester megacystis referred to prenatal diagnosis centers and included, there were 63 (84%) adverse outcomes and 12 (16%) live births. Fetuses with a bladder diameter of less than 12.5 mm may have a favorable outcome, with or without urological problems, with a high sensitivity (83.3%) and specificity (87.3%), area under the ROC curve = 0.93, 95% CI (0.86-0.99), p< 0.001. Fetal autopsy was performed in 52 (82.5%) cases of adverse outcome. In the 12 cases of favorable outcome, pediatric follow-up was normal and non-pathological in 8 (66.7%)., Conclusion: Bladder diameter appears to be a predictive marker for neonatal outcome. Fetuses with smaller megacystis (7-10 mm) have a significantly higher chance of progressing to a favorable outcome. Urethral stenosis and atresia are the main diagnoses made when first-trimester megacystis is observed. Karyotyping is important regardless of bladder diameter., Competing Interests: The authors have declared that no competing interests exist.

This study includes previous reports of four affected individuals from two unrelated families with hedgehog acyl-transferase (HHAT)-related multiple congenital anomaly syndrome. Microcephaly, small cerebellar vermis, holoprosencephaly, agenesis of corpus callosum, intellectual disability, short stature, skeletal dysplasia, microphthalmia-anophthalmia, and sex reversal constitute the phenotypic spectrum of this condition with variable expression. We report an additional family with three affected conceptuses: two abortuses and one living proband. We did proband-parents trio exome sequencing and identified a biallelic in-frame deletion c.365&#95;367del; (p.Thr122del) in exon 5 of HHAT. With this report, we delineate the phenotype and allelic heterogeneity of the HHAT-related multiple congenital anomaly syndrome., (© 2021 Wiley Periodicals LLC.)

Introduction: Angiotensin-Converting Enzyme Inhibitors and Angiotensin II Receptor Blockers (AAs) are used for several indications, with cessation recommended in pregnancy due to toxic effects. AA fetopathy phenotype is similar to renal tubular dysgenesis including reduced proximal convoluted tubules (PCTs). Our study aimed to quantify the reduction of PCTs in fetuses and infants with prenatal exposure to AAs., Materials and Methods: We identified 5 fetal AA exposure cases that underwent autopsy at our institution between 2011 and 2018 and compared with 5 gestational age-matched controls. Immunohistochemistry with CD10 and epithelial membrane antigen (EMA) was utilized., Results: CD10 and EMA identified a median PCT density of 19.0% ± 12.3% in AA fetopathy patients, significantly less than controls (52.8% ± 4.4%; p < 0.0001). One case with in utero cessation had a PCT density of 34.2% ± 0.2%. Among other AA fetopathy findings, 1 case demonstrated unilateral renal vein thrombosis and 4 had hypocalvaria., Conclusions: We have quantified the reduction in AA fetopathy PCT density, and demonstrated in utero cessation may recover PCT differentiation. Future studies may benefit from calculating PCT percentage as a potential biomarker to correlate with post-natal renal function and maternal factors including medication type, dosage, duration, and time from medication cessation.

Introduction: Translational models of myelomeningocele (MMC) are needed to test novel in utero interventions. An ideal animal model for MMC has locomotor function at birth and is low cost enough to allow for high throughput. The rat MMC model is limited by immature locomotor function at birth. The ovine MMC model is a costly surgical model. Guinea pigs are uniquely suited for an MMC model being a small animal model with locomotor function at birth. We aimed to develop a retinoic acid (RA) model of MMC in the guinea pig and to evaluate if pregnant guinea pigs could tolerate uterine manipulation., Methods: Time-mated Dunkin Hartley guinea pig dams were dosed with 60 mg/kg of RA between gestation age (GA) 12 and 15 days in the development of an RA model. Fetuses were grossly evaluated for MMC lesions at Cesarean section after GA 31 days. Evaluation of the ability of pregnant guinea pig dams to tolerate uterine surgical intervention was performed by hysterotomy of a separated group of time-mated guinea pigs at GA 45, 50, and 55., Results: Forty-two pregnant guinea pigs were dosed with RA, with a total of 189 fetuses. The fetal demise rate was 38% ( n = 71). A total of 118 fetuses were viable, 83% ( n = 98) were normal fetuses, 8% ( n = 10) had a neural tube defect, and 8% ( n = 10) had a hematoma or other anomalies. No fetuses developed an MMC defect. None of the fetuses that underwent hysterotomy survived to term., Conclusion: RA dosed at 60 mg/kg in guinea pigs between GA 12 and 15 did not result in MMC. Dunkin Hartley guinea pigs did not tolerate a hysterotomy near term in our surgical model. Further work is needed to determine if MMC can be induced in guinea pigs with alternate RA dosing., Competing Interests: The authors have no conflicts of interest to declare., (Copyright © 2021 Sarah C. Stokes et al.)

Early life is a period of considerable plasticity and vulnerability and insults during that period can disrupt the homeostatic equilibrium of the developing organism, resulting in adverse developmental programming and enhanced susceptibility to disease. Fetal exposure to prenatal stress can impede optimum brain development and deranged mother's hypothalamic-pituitary-adrenal axis (HPA axis) stress responses can alter the neurodevelopmental trajectories of the offspring. Corticotropin-releasing hormone (CRH) and glucocorticoids, regulate fetal neurogenesis and while CRH exerts neuroprotective actions, increased levels of stress hormones have been associated with fetal brain structural alterations such as reduced cortical volume, impoverishment of neuronal density in the limbic brain areas and alterations in neuronal circuitry, synaptic plasticity, neurotransmission and G-protein coupled receptor (GPCR) signalling. Emerging evidence highlight the role of epigenetic changes in fetal brain programming, as stress-induced methylation of genes encoding molecules that are implicated in HPA axis and major neurodevelopmental processes. These serve as molecular memories and have been associated with long term modifications of the offspring's stress regulatory system and increased susceptibility to psychosomatic disorders later in life. This review summarises our current understanding on the roles of CRH and other mediators of stress responses on fetal neurodevelopment., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Kassotaki, Valsamakis, Mastorakos and Grammatopoulos.)

Necrotizing enterocolitis (NEC) and focal intestinal perforation (FIP) are two of the most common emergencies of the gastrointestinal tract in preterm infants with very low birth weight (VLBW, birth weight < 1500 g). Identification of risk factors among these children is crucial for earlier diagnosis and prompt intervention. In this study, we investigated a relationship between ABO blood groups and the risk for surgical NEC/FIP. We genotyped the ABO locus (rs8176746 and rs8176719) in VLBW infants enrolled in a prospective, population-based cohort study of the German Neonatal Network (GNN). Of the 10,257 VLBW infants, 441 (4.3%) had surgical NEC/FIP. In univariate analyses, the blood group AB was more prevalent in VLBW infants with surgical NEC/FIP compared to non-AB blood groups (OR 1.51, 95% CI 1.07-2.13, p = 0.017; absolute risk difference 2.01%, 95% CI 0.06-3.96%). The association between blood group AB and surgical NEC/FIP was observed in a multivariable logistic regression model (OR of 1.58, 95% CI 1.10-2.26, p = 0.013) as well. In summary, our study suggests that the risk of surgical NEC and FIP is higher in patients with blood group AB and lower in those having non-AB blood groups.

Fetal urinoma is defined as an encapsulated accumulation of extravasated urine within the perirenal space or retroperitoneum. It is an uncommon finding in prenatal practice, and the vast majority of known cases are strongly associated with the existence of a urinary obstruction, such as posterior urethral valves, ureteropelvic junction obstruction, or ureterocele. We report a unique case of prenatally detected fetal bladder urinoma that occurred in the absence of an apparent obstructive uropathy, but was associated with extensive ischemic necrosis and calcifications of adjacent bladder wall, coexistent with signs of vascular supply decompensation.

COVID-19 has affected patients of all ages and demographics, not excluding pregnant women. The effects of COVID-19 on pregnant women are still largely unknown. Several adverse perinatal outcomes have been reported in COVID-19-positive pregnant women, including pre-eclampsia, miscarriage, pre-term labor, and stillbirth. Histopathological examination of COVID-19 placentas can contribute significant data regarding maternal and fetal health and can elucidate more findings in this novel disease. A 23-year-old female with morbid obesity and scant antenatal care presented to the emergency department complaining of shortness of breath and fever; she was found to be positive for COVID-19. Grossly, her placenta showed no abnormalities. Histological examination of her placenta showed chronic lymphoplasmacytic deciduitis, villous fibrosis, loss of capillarization, extravasation of erythrocytes, chorangiosis, and thrombosis of upstream stem vessels, including large fetal vessels on the chorionic plate. These changes were deemed to be consistent with fetal thrombotic vasculopathy (FTV). In conclusion, this case of FTV in the placenta of a patient with COVID-19 is a significant finding, as it can be critical to clinicians in the management of prenatal care for expecting mothers during this pandemic.This case was presented at the annual meeting of the Association of Clinical Scientists (ACS) on May 13, 2021., (© 2021 by the Association of Clinical Scientists, Inc.)

Fragile perinatal and fetal brains are the rule rather than the exception for developmental neuropathologists. Retrieving the fresh brain from the skull and examining early fetal, macerated or severely hydrocephalic brains after fixation can be a challenge. Textbooks on neurodevelopmental pathology mention these challenges to macroscopic examination of the developing central nervous system only in passing, but many perinatal pathologists recognize this diagnostic problem. We reviewed protocols and publications on the removal, fixation, slicing and sampling of these fetal- and perinatal brains. In addition, we describe a technique to facilitate the removal of severely hydrocephalic brains with very thin cerebral walls from the skull by replacing the intraventricular fluid with agar in-situ . Furthermore, we present a method for post-fixation pre-embedding in agar to facilitate slicing, macroscopic examination and sampling of fragile and macerated brains.

Background: Canine leishmaniosis (CanL) is a zoonotic disease caused by Leishmania infantum. Although usually transmitted by phlebotomine sand flies, infection by vertical transmission and by blood transfusion have also been reported., Methods: We describe the very early onset of clinical leishmaniosis, starting from 2 months of age, in a litter of pups born to an infected dam and sire. Seven pups from the litter of nine living in different households showed alopecic, exfoliative dermatitis and ulcerative cutaneous lesions. All pups and both parents were tested on at least one occasion both serologically, by enzyme-linked immunosorbent assay (ELISA), and by polymerase chain reaction (PCR) targeting the Leishmania ribosomal operon internal transcribed spacer 1 region and a short fragment of the kinetoplast minicircle; positive amplicons were sequenced., Results: All nine pups were PCR positive for L. infantum verified by DNA sequencing, seven were positive by conjunctival, five by blood, four by lymph node, and one by skin PCR from an ulcerative lesion. Both pups with no clinical signs were seronegative, while five of the seven pups with dermatologic abnormalities were seropositive by ELISA. The sire had typical clinical dermatologic and visceral findings of CanL, was seropositive and PCR positive for L. infantum in the lymph node and fluid from the vas deferens tested after the testes were removed by castration. The dam was sub-clinically infected and seronegative, but positive by blood, lymph node and conjunctival PCR for L. infantum. Allopurinol administered to all clinically affected dogs resulted in clinical recovery., Conclusions: Infection with L. infantum in both parents, the very early age of clinical onset among most of the pups, and the fact that the puppies were born and detected with signs of leishmaniosis in the winter, which is a season without sand fly activity in Israel, strongly suggest vertical transmission. Awareness of the possibility of vertical transmission of L. infantum and infection in littermates should be increased. It is recommended that littermates of young dogs with clinical leishmaniosis should be tested for sub-clinical infection as they may also be infectious to sand flies and thus to other dogs and to humans. Restricting the mating of infected bitches should also be considered to prevent the vertical transmission of the infection.

Background: The fetal hypothalamic-pituitary-adrenal (HPA) axis plays a key role in the control of parturition and maturation of organ systems in preparation for birth. In hypothyroid fetuses, gestational length may be prolonged and maturational processes delayed. The extent to which the effects of thyroid hormone deficiency in utero on the timing of fetal maturation and parturition are mediated by changes to the structure and function of the fetal HPA axis is unknown. Methods: In twin sheep pregnancies where one fetus was thyroidectomized and the other sham-operated, this study investigated the effect of hypothyroidism on circulating concentrations of adrenocorticotrophic hormone (ACTH) and cortisol, and the structure and secretory capacity of the anterior pituitary and adrenal glands. The relative population of pituitary corticotrophs and the masses of the adrenal zones were assessed by immunohistochemical and stereological techniques. Adrenal mRNA abundances of key steroidogenic enzymes and growth factors were examined by quantitative polymerase chain reaction. Results: Hypothyroidism in utero reduced plasma concentrations of ACTH and cortisol. In thyroid-deficient fetuses, the mass of corticotrophs in the anterior pituitary gland was unexpectedly increased, while the mass of the zona fasciculata and its proportion of the adrenal gland were decreased. These structural changes were associated with lower adrenocortical mRNA abundances of insulin-like growth factor (IGF)-I and its receptor, and key steroidogenic enzymes responsible for glucocorticoid synthesis. The relative mass of the adrenal medulla and its proportion of the adrenal gland were increased by thyroid hormone deficiency in utero , without any change in expression of phenylethanolamine N -methyltransferase or the IGF system. Conclusions: Thyroid hormones are important regulators of the structure and secretory capacity of the pituitary-adrenal axis before birth. In hypothyroid fetuses, low plasma cortisol may be due to impaired adrenocortical growth and steroidogenic enzyme expression, secondary to low circulating ACTH concentration. Greater corticotroph population in the anterior pituitary gland of the hypothyroid fetus indicates compensatory cell proliferation and that there may be abnormal corticotroph capacity for ACTH synthesis and/or impaired hypothalamic input. Suppression of the development of the fetal HPA axis by thyroid hormone deficiency may contribute to the delay in fetal maturation and delivery observed in hypothyroid offspring.

Maternal consumption of polyphenol-rich foods has been associated with fetal ductus arteriosus constriction (DAC), but safety of chocolate exposure in fetal life has not been studied. This experimental study tested the hypothesis that maternal cocoa consumption in late pregnancy causes fetal DAC, with possible associated antioxidant effects. Pregnant Wistar rats, at the 21st gestational day, received by orogastric tube cocoa (720 mg/Kg) for 12 h, indomethacin (10 mg/Kg), for 8 h, or only water, before cesaren section. Immediately after withdrawal, every thorax was obtained and tissues were fixed and stained for histological analysis. The ratio of the narrowest part of the pulmonary artery to the fetal ductus inner diameter and increased ductal inner wall thickness characterized ductal constriction. Substances reactive to thiobarbituric acid were quantified. Statistical analysis used ANOVA and Tukey test. Cocoa (n = 33) and indomethacin (n = 7) reduced fetal internal ductus diameter when compared to control (water, n = 25) (p < 0.001) and cocoa alone increased ductus wall thickness (p < 0.001), but no change was noted in enzymes activity. This pharmacological study shows supporting evidences that there is a cause and effect relationship between maternal consumption of cocoa and fetal ductus arteriosus constriction. Habitual widespread use of chocolate during gestation could account for undetected ductus constriction and its potentially severe consequences, such as perinatal pulmonary hypertension, cardiac failure and even death. For this reason, dietary guidance in late pregnancy to avoid high chocolate intake, to prevent fetal ductal constriction, may represent the main translational aspect of this study.

Use of maternal oxygen for intrauterine resuscitation is contentious because of the lack of evidence for its efficacy and the possibility of fetal harm through oxidative stress. Because the developing brain is rich in lipids and low in antioxidants, it remains vulnerable to oxidative stress. Here, we tested this hypothesis in a term pregnant rat model with oxytocin-induced fetal distress followed by treatment with either room air or 100% oxygen for 6 h. Fetal brains from both sexes were subjected to assays for biomarkers of oxidative stress (4-hydroxynonenal, protein carbonyl, or 8-hydroxy-2'-deoxyguanosine), expression of genes mediating oxidative stress, and mitochondrial oxidative phosphorylation. Contrary to our hypothesis, maternal hyperoxia was not associated with increased biomarkers of oxidative stress in the fetal brain. However, there was significant upregulation of the expression of select genes mediating oxidative stress, of which some were male-specific. These observations, however, were not accompanied by changes in the expression of proteins from the mitochondrial electron transport chain. In summary, maternal hyperoxia in the setting of acute uteroplacental ischemia-hypoxia does not appear to cause oxidative damage to the developing brain.

Objective: Detection of fetal airway compromise through imaging raises the possible need for ex utero intrapartum treatment (EXIT) procedures. Despite EXIT procedures involving massive resource utilization and posing increased risk to the mother, decisions for EXIT are usually based on anecdotal experience. Our objectives were to analyze prenatal consultations with potential fetal airway obstruction for imaging and obstetric findings used to determine management strategy., Methods: Retrospective chart review was performed for prenatal abnormal fetal airway consults between 2004-2019 at a quaternary pediatric facility. Data collected included demographics, imaging characteristics, delivery information, and airway management. Our primary outcome was EXIT performance and the secondary outcome was postnatal airway management. Fisher's exact test was used to compare management decisions, outcomes, and imaging findings., Results: Thirty-seven patients met inclusion criteria. The most common diagnoses observed were lymphatic malformation, teratoma, and micrognathia. Of the imaging findings collected, only midline neck mass location was associated with EXIT procedure performance. Factors associated with invasive airway support at birth were mass-induced in-utero neck extension and neck vessel compression, polyhydramnios, and micrognathia., Conclusions: Multidisciplinary input and interpretation of prenatal imaging can guide management of fetal airway-related pathology. EXIT is an overall safe procedure and can decrease risk due to airway obstruction at birth. We identified in-utero neck extension, neck vessel compression, micrognathia, and polyhydramnios as better indicators of a need for invasive airways measures at birth and suggest use of these criteria in combination with clinical judgement when recommending EXIT., Level of Evidence: 4 Laryngoscope, 131:E1357-E1362, 2021., (© 2020 The American Laryngological, Rhinological and Otological Society, Inc.)

Introduction: Recent reports suggest SARS-CoV-2, the virus causing COVID-19, may be transmittable from pregnant mother to placenta and fetus, albeit rarely. The efficacy of vertical transmission of SARS-CoV-2 critically depends on the availability of its receptor, ACE2, in the placenta. In the present study, we tested the hypothesis that placental ACE2 expression is oxygenation-dependent by studying the expression of ACE2 and associated cell entry regulators in the monochorionic twin anemia-polycythemia (TAPS) placenta, a model of discordant placental oxygenation., Methods: We performed a retrospective comparative immunohistochemical, immunofluorescence and Western blot analysis of ACE2, TMPRSS2 and Cathepsin B expression in anemic and polycythemic territories of TAPS placentas (N = 14)., Results: ACE2 protein levels were significantly higher in the anemic twin territories than in the corresponding polycythemic territories, associated with upregulation of the key ACE2-related cell entry regulators, TMPRSS2 and Cathepsin B, immunolocalized to villous trophoblastic and stromal cells. Cellular colocalization of ACE2 and TMPRSS2, suggestive of functionality of this cell entry axis, was demonstrated by double immunofluorescence studies., Discussion: Placental hypoxia is associated with upregulation of ACE2 expression, concomitant with increased expression of its key cell entry proteases. ACE2-regulated placental functions, both infection- and non-infection related, may be highly oxygenation-dependent., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Objective: To analyze adverse fetal and neonatal outcomes of Zika virus infection by the timing of infection during pregnancy. Method: Cohort study of 190 pregnancies with 193 offspring with a positive RT-PCR test for Zika virus (March/2016 to April/2017)., Results: Death or defects related to congenital Zika virus infection were identified in 37.3% of fetuses and newborns, and microcephaly in 21.4% of the newborns. The proportion of small for gestational age newborns was 21.9%. Maternal symptoms in the first trimester were significantly associated with the birth of newborns with microcephaly/cerebral atrophy, small for gestational age and with the deaths (one abortion, one stillbirth and the two neonatal deaths). Maternal infection during the second trimester was further associated with asymptomatic newborns at birth. The study showed that 58.5% of the offspring with microcephaly and / or cortical atrophy were small for gestational age, with an evident decrease in symptomatic offspring without microcephaly, 24.1%, and with only 9.1% in the asymptomatic group., Conclusion: This study showed that the earlier the symptoms appear during gestation, the more severe the endpoints. We found a higher percentage of small for gestational age newborns exposed to Zika virus early in gestation. We also found a group of apparently asymptomatic newborns with proven Zika infection, which highlights the importance of follow up studies in this population., Competing Interests: The authors have declared that no competing interests exist.

Background: Severe fetal anemias can cause high output cardiac failure. Mitochondria are key regulators of cardiac function. However, the effects of an early phase of fetal anemia on the fetal heart and cardiac mitochondrial function are not known., Objective: The aim of this study is to compare mitochondrial function and cardiac biochemical alterations in the fetal cardiac tissue between anemic and non-anemic fetuses., Materials and Methods: A cross-sectional study was conducted in Fetuses affected by Hb Bart's disease (n=18) and non-anemic fetuses (n=10) at 17-20 weeks. Echocardiograms had been carried out in all cases to assess prenatal cardiac function. Cardiac tissues were collected after pregnancy termination for the determination of cardiac iron accumulation, mitochondrial function, including mitochondrial ROS production, mitochondrial depolarization and mitochondrial swelling, mitochondrial dynamics, inflammation, and apoptosis., Results: Prenatal cardiac function evaluated by ultrasound was comparable between the Hb Bart's and non-anemic groups. In Bart's group, the levels of cardiac mitochondrial depolarization and swelling, and the TNF-α level were significantly higher, compared to the non-anemic group. On the contrary, anti-inflammatory (IL-10) levels were significantly lower in the Hb Bart's group. Additionally, active caspase-3 and Bcl-2 expression were also significantly higher (P= 0.001, P=0.035) in Bart's group. The mitochondrial fission protein expression, including p-DRP1/total DRP1, was significantly higher in Bart's group. However, there was no difference in cardiac iron accumulation levels between these two groups., Conclusion: Despite equivalent prenatal cardiac function and comparable cardiac iron accumulation in the Bart's and non-anemic groups, fetal anemia is significantly associated with cardiac mitochondrial dysfunction, increased mitochondrial fission, and increased inflammation and apoptosis. These findings indicate that an early phase of fetal anemia without cardiac iron overload can lead to cardiac mitochondrial dysfunction in fetuses with Hb Bart's., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Objective: Approximately 10% of stillbirths are attributed to fetal anomalies, but anomalies are also common in live births. We aimed to assess the relationship between anomalies, by system and stillbirth., Design: Secondary analysis of a prospective, case-control study., Setting: Multicentre, 59 hospitals in five regional catchment areas in the USA., Population or Sample: All stillbirths and representative live birth controls., Methods: Standardised postmortem examinations performed in stillbirths, medical record abstraction for stillbirths and live births., Main Outcome Measures: Incidence of major anomalies, by type, compared between stillbirths and live births with univariable and multivariable analyses using weighted analysis to account for study design and differential consent., Results: Of 465 singleton stillbirths included, 23.4% had one or more major anomalies compared with 4.3% of 1871 live births. Having an anomaly increased the odds of stillbirth; an increasing number of anomalies was more highly associated with stillbirth. Regardless of organ system affected, the presence of an anomaly increased the odds of stillbirth. These relationships remained significant if stillbirths with known genetic abnormalities were excluded. After multivariable analyses, the adjusted odds ratio (aOR) of stillbirth for any anomaly was 4.33 (95% CI 2.80-6.70) and the systems most strongly associated with stillbirth were cystic hygroma (aOR 29.97, 95% CI 5.85-153.57), and thoracic (aOR16.18, 95% CI 4.30-60.94) and craniofacial (aOR 35.25, 95% CI 9.22-134.68) systems., Conclusions: In pregnancies affected by anomalies, the odds of stillbirth are higher with increasing numbers of anomalies. Anomalies of nearly any organ system increased the odds of stillbirth even when adjusting for gestational age and maternal race., Tweetable Abstract: Stillbirth risk increases with anomalies of nearly any organ system and with number of anomalies seen., (© 2020 John Wiley & Sons Ltd.)

Background: Routine third-trimester ultrasound is frequently offered to pregnant women to identify fetuses with abnormal growth. Infrequently, a congenital anomaly is incidentally detected., Objective: To establish the prevalence and type of fetal anomalies detected during routine third-trimester scans using a systematic review and meta-analysis., Search Strategy: Electronic databases (MEDLINE, Embase and the Cochrane library) from inception until August 2019., Selection Criteria: Population-based studies (randomised control trials, prospective and retrospective cohorts) reporting abnormalities detected at the routine third-trimester ultrasound performed in unselected populations with prior screening. Case reports, case series, case-control studies and reviews without original data were excluded., Data Collection and Analysis: Prevalence and type of anomalies detected in the third trimester. We calculated pooled prevalence as the number of anomalies per 1000 scans with 95% confidence intervals. Publication bias was assessed., Main Results: The literature search identified 9594 citations: 13 studies were eligible representing 141 717 women; 643 were diagnosed with an unexpected abnormality. The pooled prevalence of a new abnormality diagnosed was 3.68 per 1000 women scanned (95% CI 2.72-4.78). The largest groups of abnormalities were urogenital (55%), central nervous system abnormalities (18%) and cardiac abnormalities (14%)., Conclusion: Combining data from 13 studies and over 140 000 women, we show that during routine third-trimester ultrasound, an incidental fetal anomaly will be found in about 1 in 300 scanned women. This information should be taken into account when taking consent from women for third-trimester ultrasound and when designing and assessing cost of third-trimester ultrasound screening programmes., Tweetable Abstract: One in 300 women attending a third-trimester scan will have a finding of a fetal abnormality., (© 2020 John Wiley & Sons Ltd.)

Objective: We aimed to compare obstetric and neonatal outcomes of deliveries complicated by meconium stained amniotic fluid (MSAF), according to placental histology of continuous vs. acute meconium associated changes., Methods: This was a retrospective cohort study of singleton deliveries complicated by MSAF at a single university-affiliated medical center during 2008-2018. Obstetric and neonatal outcomes were compared between cases with placental acute vs. continuous meconium exposure associated changes (columnar epithelial changes and meconium-laden macrophages, respectively). Regression analysis was used to identify independent associations with adverse neonatal outcomes., Results: The medical records of 294 deliveries at our institution were reviewed, along with medical records of the neonates and the histopathological reports of their placentas. Ninety-two cases were classified as an acute placental reaction to meconium (acute exposure group) and 200 as continuous placental exposure (continuous exposure group). Patient demographics did not differ between groups. Placentas from the continuous exposure to meconium were associated with a higher rate of placental weight <10th percentile (p = 0.03) while the acute exposure group was associated with a shorter time between rupture of membranes and delivery (p = 0.02). and higher rates of non-reassuring fetal heart rate in labor (p = 0.003), and of adverse neonatal outcome (p = 0.02). In multivariable analysis adverse neonatal outcome was associated with acute histologic exposure to meconium independent of background confounders (aOR = 1.51, 95% CI 1.12-3.67)., Conclusions: Acute histological changes of MSAF were independently associated with adverse neonatal outcomes as compared to continuous histologic MSAF., Competing Interests: Declaration of competing interest The authors declare no conflict of interest, including any financial, personal or professional interests., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Objectives: (1) To compare brain findings between large and non-large neural tube defect (NTD); (2) to evaluate the impact of large lesion on the surgical parameters; (3) to study any associations between the size of the lesions and brain findings 6 weeks postoperatively and neurological short-term outcomes., Design: Retrospective cohort study., Setting: Texas Children's Hospital, between 2011 and 2018., Population: Patients who underwent prenatal NTD repair., Methods: Large lesion was defined when the lesion's surface was >75th centile of our cohorts' lesions., Main Outcome Measures: Time of referral: ventriculomegaly and anatomical level of the lesion; surgery: duration and need for relaxing incisions. 6 weeks postoperative: hindbrain herniation (HBH) and ventriculomegaly. After delivery: dehiscence, need for hydrocephalus treatment and motor function., Results: A total of 99 patients were included, 25 of whom presented with large lesions. Type of lesion and ventriculomegaly were comparable between individuals with large and non-large lesions. Individuals with large lesions were associated with increased need for relaxing incisions by 5.4 times (95% CI 1.3-23.2, P = 0.02). Six weeks postoperatively, having a large lesion decreased by ten times the likelihood of having a postoperative reversal of HBH (odds ratio = 0.1, 95% CI 0.1-0.4, P < 0.01). At birth, larger lesions increased the risk for repair dehiscence by 6.1 times (95% CI 1.6-22.5, P < 0.01) and the risk of dehiscence or leakage of cerebrospinal fluid at birth by 5.5 times (95% CI 1.6-18.9, P < 0.01)., Conclusion: Prenatal repair of patients with large NTD presents a lower proportion of HBH reversal 6 weeks after the surgery, a higher risk of dehiscence and a higher need for postnatal repair., Tweetable Abstract: Evaluation of the size of fetal NTD can predict adverse neurological outcomes after prenatal NTD repair., (© 2020 Royal College of Obstetricians and Gynaecologists.)

Antenatal hydronephrosis (AHN) is the most frequently detected abnormality by prenatal ultrasonography. Differential diagnosis of AHN includes a wide variety of congenital abnormalities of the kidney and urinary tract ranging from mild abnormalities such as transient or isolated AHN to more important ones as high-grade congenital vesicoureteral reflux or ureteropelvic junction obstruction. It is well known that the outcome depends on the underlying etiology. Various grading systems have been proposed for the classification of AHN on prenatal and postnatal ultrasonography. Mild isolated AHN represents up to 80% of cases, is considered to be benign, and majority of them resolve, stabilize, or improve during follow-up. Controversies exist regarding the diagnosis and management of some important and severe causes of AHN such as high-grade vesicoureteral reflux and ureteropelvic junction obstruction. Current approach is becoming increasingly conservative during diagnosis and follow-up of these patients with less imaging and close follow-up. However, there is still no consensus regarding the clinical significance, postnatal evaluation, and management of infants with AHN. The aim of this review is to discuss the controversies and provide an overview on the management of AHN.

Kinase D-interacting substrate of 220 kDa (KIDINS220) is a transmembrane protein playing integral role in growth mediating pathways in the nervous and cardiovascular systems. KIDINS220 heterozygous truncating variants that affect the protein's C-terminus have been associated with a phenotype, so far described only in few unrelated children, including spastic paraplegia, intellectual disability, nystagmus, and obesity. More recently, a homozygous, more N-terminal truncating variant in KIDINS220 gene was suggested to be associated with enlarged cerebral ventricles and limb contractures in three fetuses from a consanguineous family. We confirm the latter finding by presenting the first detailed prenatal identification of a fetal phenotype associated with novel homozygous deleterious frameshift variant in KIDINS220 gene in a consanguineous healthy Egyptian couple. History of unexplained seven miscarriages and a similar stillbirth were recorded. Prenatal ultrasonography revealed limb contractions and ventriculomegaly; in addition to previously unreported cerebellar anomalies, cardiac anomalies and hydrops fetalis. These findings represent an expansion of clinical and molecular spectrum associated with KIDINS220 variants and broaden our understanding of genotype-phenotype relationships in lethal congenital contractures syndromes and associated severe abnormal embryological development. More generally, our study adds KIDINS220 to the rare group of genes which may cause disease by either of two distinct mutational mechanisms., (© 2020 Wiley Periodicals LLC.)

Fetal vascular malperfusion includes a continuum of placental histologic abnormalities increasingly associated with perinatal brain injury, namely arterial ischemic stroke. Here, we describe the clinical-neuroimaging features of 5 neonates with arterial ischemic stroke and histologically proved fetal vascular malperfusion. All infarcts involved the anterior territories and were multiple in 2 patients. In 2 neonates, there were additional signs of marked dural sinus congestion, thrombosis, or both. A mixed pattern of chronic hypoxic-ischemic encephalopathy and acute infarcts was noted in 1 patient at birth. Systemic cardiac or thrombotic complications were present in 2 patients. These peculiar clinical-radiologic patterns may suggest fetal vascular malperfusion and should raise the suspicion of this rare, underdiagnosed condition carrying important implications in patient management, medicolegal actions, and future pregnancy counseling., (© 2020 by American Journal of Neuroradiology.)

Recombinant chromosome 8 (Rec8) syndrome (San Luis Valley [SLV] syndrome; OMIM #179613) is a rare chromosome disorder associated with intellectual disability, congenital heart defects, variable skeletal and urogenital anomalies, and dysmorphic features. It is characterized by a partial terminal deletion of 8p and a partial terminal duplication of 8q, which is usually due to meiotic recombination of a pericentric inversion of chromosome 8 of a healthy carrier parent. There are only few reports of cases with breakpoints defined at the molecular level by molecular karyotyping. We report on a case of Rec8 syndrome with previously unreported breakpoints in a male fetus with intrauterine growth restriction, hypogenesis of the corpus callosum, bilateral cleft lip/palate, and congenital heart defect. Cytogenetic analysis revealed a recombinant chromosome 8 [46,XY,rec(8)(qter→q21.11::p23.3→qter)] secondary to a paternal pericentric inversion [46,XY,inv(8)(p23.3q21.11)]. Molecular karyotyping correspondingly showed a terminal copy number loss of 1.4 Mb (arr[hg19] 8p23.3(158048&#95;1514749)×1) and a terminal copy number gain of chromosome band 8q21.11q24.3 of 69.8 Mb (arr[hg19] 8q21.11q24.3(76477367&#95;146295771)×3). To our knowledge, this is the fourth reported case diagnosed prenatally. We describe the postnatal clinical course of the male newborn. Furthermore, we review and compare the phenotypic features and breakpoints of 74 reported Rec8/SLV cases., (© 2020 Wiley Periodicals LLC.)

We sought to assess chronic inflammatory responses in patients who achieved pregnancy by oocyte donation and non-oocyte donation-assisted reproductive technology and delivered at The Ottawa Hospital. Data describing maternal health, obstetrical outcomes, neonatal outcomes, and placental pathology were collected and analyzed from electronic medical records. An increased frequency of adverse obstetrical outcomes was observed. In the oocyte donation-assisted reproductive technology group, placental pathology data demonstrated increased frequency of fetal vascular malperfusion (p = 0.02) and placenta accreta (p < 0.001), representing a chronic inflammatory response. Placental pathology reflecting dysregulated immune processes and vasculopathy is associated with oocyte donation., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: Birthweight is a critical predictor of congenital heart disease (CHD) surgical outcomes. Hypoplastic left heart syndrome (HLHS) is cyanotic CHD with known fetal growth restriction and placental abnormalities. Transposition of the great arteries (TGA) is cyanotic CHD with normal fetal growth. Comparison of the placenta in these diagnoses may provide insights on the fetal growth abnormality of CHD., Methods: Clinical data and placental histology from placentas associated with Transposition of the Great Arteries (TGA) were analyzed for gross pathology, morphology, maturity and vascularity and compared to both control and previously analyzed HLHS placentas [1]. RNA was isolated from HLHS, TGA and control placentas and sequenced by Illumina HiSeq.Transcriptome analysis was performed using AltAnalyze. Immunohistochemistry was utilized to assess placental nutrient transporter expression in all three groups., Results: Placental weight was reduced in TGA cases, and demonstrated reduced villous vasculature, immature terminal villi in the parenchyma compared to controls and reflected our previous data from HLHS placentas. However, birth weight was not reduced in TGA cases compared to controls in contrast to the HLHS cohort and birthweight:placental weight ratio was significantly increased in TGA cases but not HLHS compared to control. Transcriptomic and histologic analysis demonstrates reduced cell activity and nutrient transport capability in HLHS but not TGA placentas which appear to increase/maintain these mechanisms., Conclusions: Despite common vascular disturbances in placentas from HLHAs and TGA, these do not account for the disparities in birthweights frequently seen between these CHD subtypes, in contrast our transcriptomic and histologic analyses reveal differentially regulated mechanisms between the subtypes that may explain these disparities., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Objectives: To describe placental findings on prenatal ultrasound and anatomopathological examination in women with Zika virus (ZIKV) infection, and to assess their association with congenital ZIKV infection and severe adverse outcome, defined as fetal loss or congenital Zika syndrome (CZS)., Methods: This was a prospective study of pregnancies undergoing testing for maternal ZIKV infection at a center in French Guiana during the ZIKV epidemic. In ZIKV-positive women, congenital infection was defined as either a positive reverse transcription polymerase chain reaction result or identification of ZIKV-specific immunoglobulin-M in at least one placental, fetal or neonatal sample. Placental ZIKV-infection status was classified as non-exposed (placentae from non-infected women), exposed (placentae from ZIKV-infected women without congenital infection) or infected (placentae from ZIKV-infected women with proven congenital infection). Placentae were assessed by monthly prenatal ultrasound examinations, measuring placental thickness and umbilical artery Doppler parameters, and by anatomopathological examination after live birth or intrauterine death in women with ZIKV infection. The association of placental thickness during pregnancy and anatomopathological findings with the ZIKV status of the placenta was assessed. The association between placental findings and severe adverse outcome (CZS or fetal loss) in the infected group was also assessed., Results: Among 291 fetuses/neonates/placentae from women with proven ZIKV infection, congenital infection was confirmed in 76 cases, of which 16 resulted in CZS and 11 resulted in fetal loss. The 215 remaining placentae from ZIKV-positive women without evidence of congenital ZIKV infection represented the exposed group. A total of 334 placentae from ZIKV-negative pregnant women represented the non-exposed control group. Placentomegaly (placental thickness > 40 mm) was observed more frequently in infected placentae (39.5%) than in exposed placentae (17.2%) or controls (7.2%), even when adjusting for gestational age at diagnosis and comorbidities (adjusted hazard ratio (aHR), 2.02 (95% CI, 1.22-3.36) and aHR, 3.23 (95% CI, 1.86-5.61), respectively), and appeared earlier in infected placentae. In the infected group, placentomegaly was observed more frequently in cases of CZS (62.5%) or fetal loss (45.5%) than in those with asymptomatic congenital infection (30.6%) (aHR, 5.43 (95% CI, 2.17-13.56) and aHR, 4.95 (95% CI, 1.65-14.83), respectively). Abnormal umbilical artery Doppler was observed more frequently in cases of congenital infection resulting in fetal loss than in those with asymptomatic congenital infection (30.0% vs 6.1%; adjusted relative risk (aRR), 4.83 (95% CI, 1.09-20.64)). Infected placentae also exhibited a higher risk for any pathological anomaly than did exposed placentae (62.8% vs 21.6%; aRR, 2.60 (95% CI, 1.40-4.83))., Conclusions: Early placentomegaly may represent the first sign of congenital infection in ZIKV-infected women, and should prompt enhanced follow-up of these pregnancies. Copyright © 2019 ISUOG. Published by John Wiley & Sons Ltd., (Copyright © 2019 ISUOG. Published by John Wiley & Sons Ltd.)