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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: Pregnancies with prenatally diagnosed congenital heart disease (CHD) have increased cesarean delivery (CD) rates, with no outcome improvement., Objective: We aim to examine indications for delivery, indications for CD and risk factors associated with CD., Study Design: Retrospective cohort of 322 singleton pregnancies prenatally diagnosed with moderate to severe CHD. We compared maternal and fetal factors correlated with delivery route., Results: CD rate was 46% (95% CI 40, 51%). Of all CD, 31.3% (95% CI 23.8, 38.7) were secondary to urgent fetal indications. However, 79.7% of inductions resulted in vaginal delivery (VD). Factors associated with CD include morbid obesity (RR 3.0, 95% CI 1.5, 6.1), diabetes (RR 3.9, 95% CI 2.0, 7.3) and severe pre-eclampsia (6.0, 95% CI 1.7, 21.4). Of the 10 most frequent CHD diagnoses, only hypoplastic-left-heart was associated with CD (OR 1.9, 95% CI 1.02, 3.4)., Conclusions: Although the CD rate is higher in fetal CHD, most indications for CD are maternal., (© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Objective: To investigate the clinical characteristics of children with early-onset necrotizing enterocolitis (NEC) undergoing enterostomy and analyze the risk factors for postoperative complications. Methods: Retrospective analysis was conducted on the clinical data (perinatal conditions, clinical characteristics, clinical outcomes, etc.) of NEC patients who underwent enterostomy at Beijing Children's Hospital from May 2016 to May 2023. The patients were divided into two groups based on the age of onset: an early-onset enterostomy group (<14 days) and a late-onset enterostomy group (≥14 days). Furthermore, the children with NEC were categorized into complication group and non-complication group based on whether there were complications after enterostomy. The differences in clinical data between these groups were analyzed, and the clinical characteristics of children with early-onset NEC and enterostomy were summarized. Multivariate logistic regression model was employed to analyze the risk factors for postoperative complications in NEC children with enterostomy. Results: A total of 68 cases were enrolled, including 43 cases in the early-onset enterostomy group [26 males and 17 females, aged (6.5±3.0) days] and 25 cases in the late-onset enterostomy group [15 males and 10 females, aged (21.0±3.0) days]. There were 28 cases (17 males and 11 females), age [ M ( Q 1 , Q 3 )] 9 (5, 14) days in the complication group and 33 cases (22 males and 11 females), aged of 14 (6, 21) days in the non-complication group. Compared to the late-onset enterostomy group, the early-onset enterostomy group had significantly higher rates of intraventricular hemorrhage [30.2% (13/43) vs 8.0% (2/25)], hemodynamically significant patent ductus arteriosus [37.2% (16/43) vs 12.0% (3/25)], mechanical ventilation≥72 hours after birth [39.5% (17/43) vs 16.0% (4/25)], stage Ⅲ NEC [(69.8% (30/43) vs 40.0% (10/25)], extensive NEC [27.9% (12/43) vs 8.0% (2/25)], and short-term postoperative complications [56.8% (21/37) vs 29.2% (7/24)] (all P <0.05).Multivariate logistic regression model analysis revealed that residual length of proximal small intestine was a protective factor for postoperative complications after enterostomy in NEC infants ( OR =0.764, 95% CI : 0.648-0.901, P =0.001), but stage Ⅲ NEC was a risk factor ( OR =1.042, 95% CI : 1.004-5.585, P =0.017). Conclusions: The incidence of postoperative complications is high, and the prognosis is poor in children with early-onset NEC enterostomy. The residual length of proximal enterostomy is a protective factor for postoperative complications of NEC enterostomy, but stage Ⅲ NEC is a risk factor.

Importance: Early anhydramnios during pregnancy, resulting from fetal bilateral renal agenesis, causes lethal pulmonary hypoplasia in neonates. Restoring amniotic fluid via serial amnioinfusions may promote lung development, enabling survival., Objective: To assess neonatal outcomes of serial amnioinfusions initiated before 26 weeks' gestation to mitigate lethal pulmonary hypoplasia., Design, Setting, and Participants: Prospective, nonrandomized clinical trial conducted at 9 US fetal therapy centers between December 2018 and July 2022. Outcomes are reported for 21 maternal-fetal pairs with confirmed anhydramnios due to isolated fetal bilateral renal agenesis without other identified congenital anomalies., Exposure: Enrolled participants initiated ultrasound-guided percutaneous amnioinfusions of isotonic fluid before 26 weeks' gestation, with frequency of infusions individualized to maintain normal amniotic fluid levels for gestational age., Main Outcomes and Measures: The primary end point was postnatal infant survival to 14 days of life or longer with dialysis access placement., Results: The trial was stopped early based on an interim analysis of 18 maternal-fetal pairs given concern about neonatal morbidity and mortality beyond the primary end point despite demonstration of the efficacy of the intervention. There were 17 live births (94%), with a median gestational age at delivery of 32 weeks, 4 days (IQR, 32-34 weeks). All participants delivered prior to 37 weeks' gestation. The primary outcome was achieved in 14 (82%) of 17 live-born infants (95% CI, 44%-99%). Factors associated with survival to the primary outcome included a higher number of amnioinfusions (P = .01), gestational age greater than 32 weeks (P = .005), and higher birth weight (P = .03). Only 6 (35%) of the 17 neonates born alive survived to hospital discharge while receiving peritoneal dialysis at a median age of 24 weeks of life (range, 12-32 weeks)., Conclusions and Relevance: Serial amnioinfusions mitigated lethal pulmonary hypoplasia but were associated with preterm delivery. The lower rate of survival to discharge highlights the additional mortality burden independent of lung function. Additional long-term data are needed to fully characterize the outcomes in surviving neonates and assess the morbidity and mortality burden., Trial Registration: ClinicalTrials.gov Identifier: NCT03101891.

Background: Massive fetomaternal hemorrhage (FMH) is a rare event during pregnancy that may cause severe fetal anemia or death., Case Presentation: This paper reports two cases of fetomaternal hemorrhage with unexplained reasons. Both cases required emergency caesarean sections for non-reassuring fetal status and were treated with neonatal blood transfusion. Fetomaternal hemorrhage was confirmed via maternal Kleihauer-Betke test., Conclusion: We found parenchymal pallor, increased nucleated red blood cells (nRBCs), and syncytial knots (SKs) in the placentas, which are compatible with fetal anemia. Immunohistochemical staining indicated VEGF, CD34, and CD31 expression in the endothelial cells of the capillaries, characteristic of massive FMH placenta. This article also reviews the particular histopathological changes in FHM placenta according to the placental lesion classification system., (© 2023. The Author(s).)

Objective: To evaluate whether patients with obesity who undergo scheduled cesarean delivery under neuraxial anesthesia are at increased risk for umbilical artery pH less than 7.1 and base deficit 12 mmol or greater., Methods: We conducted a multicenter, retrospective cohort study of individuals who delivered a term, singleton, nonanomalous neonate at one of four academic medical centers in New York City from 2013 to 2019 by scheduled cesarean under neuraxial anesthesia for whom fetal cord blood gas results were available. The primary study outcome was rate of fetal acidosis , defined as umbilical artery pH less than 7.1. This was compared between patients with obesity (body mass index [BMI] 30 or higher) and those without obesity (BMI lower than 30). Base deficit 12 mmol or greater and a composite of fetal acidosis and base deficit 12 mmol or greater were also compared. Secondary outcomes included neonatal intensive care unit admission rate, 5-minute Apgar score less than 7, and neonatal morbidity. Associations between maternal BMI and study outcomes were assessed using multivariable logistic or linear regression and adjusted for age, race and ethnicity, insurance type, cesarean delivery order number, and neuraxial anesthesia type., Results: Of the 6,264 individuals who met inclusion criteria during the study interval, 3,098 had obesity and 3,166 did not. The overall rate of umbilical artery cord pH less than 7.1 was 2.5%, and the overall rate of umbilical artery base deficit 12 mmol or greater was 1.5%. Patients with obesity were more likely to have umbilical artery cord pH less than 7.1 (adjusted odds ratio [aOR] 2.7, 95% CI 1.8-4.2) and umbilical artery base deficit 12 mmol or greater (aOR 3.2, 95% CI 1.9-5.3). This association was not significantly attenuated after additional adjustments for potential mediators, including maternal medical comorbidities. We found no differences in secondary outcomes between groups., Conclusion: Maternal obesity is associated with increased odds of arterial pH less than 7.1 and base deficit 12 mmol or greater at the time of scheduled cesarean delivery under neuraxial anesthesia., Competing Interests: Financial Disclosure The authors did not report any potential conflicts of interest., (Copyright © 2022 by the American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. All rights reserved.)

Introduction: Hemolytic disease of the fetus and newborn (HDFN) is a condition caused by maternal alloantibodies against fetal red blood cells (RBCs) that can cause severe morbidity and mortality in the fetus and newborn. Adequate screening programs allow for timely prevention and intervention resulting in significant reduction of the disease over the last decades. Nevertheless, HDFN still occurs and with current treatment having reached an optimum, focus shifts toward noninvasive therapy options., Areas Covered: This review focusses on the timely identification of high risk cases and antenatal management. Furthermore, we elaborate on future perspectives including improvement of screening, identification of high risk cases and promising treatment options., Expert Opinion: In high-income countries mortality and morbidity rates due to HDFN have drastically been reduced over the last decades, yet worldwide anti-D mediated HDFN still accounts for 160,000 perinatal deaths and 100,000 patients with disabilities every year. Much of these deaths and disabilities could have been avoided with proper identification and prophylaxis. By implementing sustainable prevention, screening, and disease treatment measures in all countries this will systemically reduce unnecessary perinatal deaths. There is a common responsibility to engage in this cause.

Diabetic embryopathy is defined as congenital anomalies that are linked to maternal diabetes. The association between diabetes and fetal, neonatal, and long-term complications is well-established. These complications include organ or structural maldevelopment, fetal growth abnormalities, and learning/psychiatric comorbidities. Recent studies have elucidated the pathophysiology behind these conditions and outlined new management approaches. Caudal regression syndrome, also known as sacral agenesis, is a well-known but less described complication of maternal diabetes. The purpose of this review is to summarize existing research on common neonatal morbidities in infants of mothers with diabetes with a focus on caudal regression syndrome and its long-term associations., (Copyright © 2022 by the American Academy of Pediatrics.)

Background: Necrotizing enterocolitis (NEC) is one of serious gastrointestinal inflammatory diseases in newborn infants, with a high morbidity and mortality. Red blood cell transfusion (RBCT) plays a controversial and doubtful role in the treatment of NEC. In present study, we aim to analyze the association between RBCT and the deterioration of NEC., Methods: This was a retrospective cohort study of near-term and full-term infants with a confirmed diagnosis of Bell's stage II NEC between Jan 1, 2010 and Jan 31, 2020. The maternal and infant baseline characteristics, treatment information and laboratory test for each case were collected. The eligible subjects were divided into two groups based on receiving RBCT post NEC diagnosis or not. The propensity score was used to eliminate potential bias and baseline differences. A multivariate logistic regression model was used to adjust the propensity score and calculate the odds ratio (OR) and 95% confidential interval (CI) of RBCT for the deterioration of NEC., Results: A total of 242 infants were included in this study, 60 infants had a history of RBCT post NEC diagnosis, and 40 infants deteriorated from Bell's stage II to stage III. By adjusting the propensity score, RBCT post NEC diagnosis was associated with an increased risk for NEC deteriorating from stage II to III (adjusted OR 6.06, 95%CI 2.94-12.50, P = 0.000)., Conclusions: NEC infants who required RBCT post NEC diagnosis were more likely to deteriorate from stage II to III in full-term and near-term infants., (© 2022. The Author(s).)

Background: Permanent progression of paternal age and development of reproductive medicine lead to increase in number of children conceived with assisted reproductive techniques (ART). Although it is uncertain if ARTs have direct influence on offspring health, advanced paternal age, associated comorbidities and reduced fertility possess significant risks of genetic disorders to the offspring. With a broad implementation of a non-invasive prenatal testing (NIPT), more cases of genetic disorders, including sex discordance are revealed. Among biological causes of sex discordance are disorders of sexual development, majority of which are associated with the SRY gene., Case Presentation: We report a case of a non-invasive prenatal testing and ultrasound sex discordance in a 46,XY karyotype female fetus with an SRY pathogenic variant, who was conceived through an intracytoplasmic sperm injection (ICSI) due to severe oligozoospermia of the father. Advanced mean age of ICSI patients is associated with risk of de novo mutations and monogenic disorders in the offspring. Additionally, ICSI patients have higher risk to harbour infertility-predisposing mutations, including mutations in the SRY gene. These familial and de novo genetic factors predispose ICSI-conceived children to congenital malformations and might negatively affect reproductive health of ICSI-patients' offspring., Conclusions: Oligozoospermic patients planning assisted reproduction are warranted to undergo genetic counselling and testing for possible inherited and mosaic mutations, and risk factors for de novo mutations., (© 2022. The Author(s).)

Background: Prenatal ultrasonography allows for timely identification of fetal abnormalities that can have an effect on securing the neonatal airway at delivery. We illustrate the role of antenatal three-dimensional printing in cases with fetal airway obstruction., Case: We present two cases that highlight the utility of a three-dimensional printing technique to aid in ex utero intrapartum treatment procedures during cesarean delivery., Conclusion: Three-dimensional printing plays a complementary role to standard imaging options in optimizing presurgical planning, prenatal parental counseling, personalized patient care, and education of the multidisciplinary team in cases of fetal congenital airway obstruction., Competing Interests: Financial Disclosure The authors did not report any potential conflicts of interest., (Copyright © 2022 by the American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. All rights reserved.)

Infections are a major threat to human reproductive health, and infections in pregnancy can cause prematurity or stillbirth, or can be vertically transmitted to the fetus leading to congenital infection and severe disease. The acronym 'TORCH' (Toxoplasma gondii, other, rubella virus, cytomegalovirus, herpes simplex virus) refers to pathogens directly associated with the development of congenital disease and includes diverse bacteria, viruses and parasites. The placenta restricts vertical transmission during pregnancy and has evolved robust mechanisms of microbial defence. However, microorganisms that cause congenital disease have likely evolved diverse mechanisms to bypass these defences. In this Review, we discuss how TORCH pathogens access the intra-amniotic space and overcome the placental defences that protect against microbial vertical transmission., (© 2021. Springer Nature Limited.)

Background: One of the most common fetal complications in pregnant women with cardiovascular disease is a small for gestational age (SGA) neonate, which is associated with a higher risk of perinatal morbidity/mortality and poor long-term health outcomes. The objective of this study was to identify cardiac determinants and derive a risk score for clinically relevant SGA < 5th percentile (SGA-5th)., Methods: A prospective cohort of 1812 pregnancies in women with heart disease were studied. SGA-5th was the outcome of interest, defined as birth weight < 5th percentile for gestational age and sex. Multivariable logistic regression analysis was used to identify predictors for SGA-5th. Based on the regression coefficients, a weighted risk score was created., Results: SGA-5th complicated 10% of pregnancies, 11 predictors of SGA-5th were identified, and each was assigned a weighted score: maternal cyanosis (8), Fontan palliation (7), smoking (3), moderate or severe valvular regurgitation (3), β-blocker use throughout pregnancy (4) or only in the 2nd and 3rd trimesters (2), high baseline β-blocker dose (4), body mass index < 18.5 kg/m 2 (3) or 18.5-24.9 kg/m 2 (1), Asian/other ethnicity (2), and significant outflow tract obstruction (1). In the absence of these identified risk factors, the risk of SGA-5th was approximately 4%. Pregnancies with risk scores of 1 had a rate of 5%; 2, 7%; 3, 9%; 4, 12%; 5, 14%; 6, 18%; 7, 23%; 8, 28%; and ≥ 9, 34%., Conclusions: There are a number of cardiac predictors that are associated with increased risk of SGA-5th. This is a prognostically important outcome, and consideration should be given to routinely predicting and modifying the risk whenever possible., (Copyright © 2021 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.)

Objective: To describe the etiology of isolated fetal ascites and associated perinatal outcomes, and to assess the progression of isolated fetal ascites to fetal hydrops., Data Sources: PubMed, Cochrane Library, Scopus, and ClinicalTrials.gov databases were searched using the following keywords: "fetus" OR "foetal" OR "fetal" OR "foetus" AND "ascites" from inception to February 2020. The search was limited to the English language., Methods of Study Selection: A total of 1,983 articles were identified through the search strategy. All studies containing five or more cases of isolated fetal ascites were included., Tabulation, Integration, and Results: Eleven studies, involving 315 cases of isolated fetal ascites, were eligible for inclusion in this systematic review. All included studies were evaluated using the tool for evaluating the methodologic quality of case reports and case series described by Murad et al. Data were summarized using narrative review and descriptive statistics. Two-tailed Fisher exact P values calculated from hypergeometric distribution were used to compare outcome by etiology. CIs were calculated with Clopper-Pearson exact binomial interval. The etiologies of isolated fetal ascites are genitourinary (24%), gastrointestinal (20%), viral or bacterial infections (9%), cardiac (9%), genetic disorders not otherwise categorized (8%), chylous ascites (6%), metabolic storage disorders (3%), other structural disorders (4%), other causes (4%) and idiopathic (13%). Survival is most favorable for cases of isolated fetal ascites as a result of chylous (100%), idiopathic (90%), gastrointestinal (77%) and genitourinary (77%) etiologies. Survival is least favorable for fetuses with isolated fetal ascites as a result of structural disorders (25%), cardiac etiology (32%) and metabolic storage disorders (33.3%). When pregnancy terminations were excluded, survival rates were similar between fetuses diagnosed at or after 24 weeks of gestation compared with those diagnosed at less than 24 weeks (74% vs 61%, P=.06). Progression of fetal ascites to fetal hydrops occurred in 6.6% (95% CI 3.6-9.6%) (17/259) of cases when pregnancies that were terminated were excluded., Conclusion: Isolated fetal ascites has a diverse etiology. Outcome is related to the etiology of isolated fetal ascites. In the majority of cases, fetal ascites does not progress to fetal hydrops., Systematic Review Registration: PROSPERO, CRD42020213930., Competing Interests: Financial Disclosure The authors did not report any potential conflicts of interest., (Copyright © 2021 by the American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. All rights reserved.)

Intrauterine inflammation affects fetal development of the nervous system and may cause prenatal brain injury in offspring. Previously, neural stem cells have been extensively used as a therapeutic choice for nervous system diseases. Recently, the therapeutic ability of conditioned medium, harvested from cultured stem cells, has captured the attention of researchers in the field. Our study aimed to compare the therapeutic effect of neural stem cells (NSCs) or NSC-conditioned medium (NSC-CM) after prenatal brain injury. The animal model was induced by intraperitoneal injection of lipopolysaccharide into the pregnant mice and NSCs or NSC-CM were transplanted into the lateral ventricle of embryos in treatment groups. Inflammation and apoptosis were evaluated postpartum in offspring via measuring the expression of NLRP3 gene and protein, the expression and the activity of caspase-3, and the expression of pro-inflammatory cytokines by real-time PCR, immunohistochemistry, western blotting, ELISA, and colorimetric assay kit. A rotarod test was performed for motor function evaluation. Data showed that although NSC-CM fought against the inflammation and apoptosis and improved the motor function, NSCs acted more efficiently. In conclusion, the results of our study contend that NSCs have a better therapeutic effect than CM in prenatal brain injury., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Recognizing the importance of placental features and their unique functions can provide insight into maternal health, the uterine environment during the course of pregnancy, birth outcomes and neonatal health. In the context of HIV and antiretroviral therapy (ART), there have been great strides in the prevention of mother to child transmission of HIV. However, there is still paucity of data on the impact of HIV/ART exposure on placental pathology and studies available only examine specific patterns of placental injury, further justifying the need for a more defined and comprehensive approach to the differential diagnoses of HIV/ART-exposed placentae. The purpose of this review is to consolidate findings from individual studies that have been reported on patterns of placental injury in the context of HIV/ART exposure. In both the pre- and post-ART eras HIV and/or ART has been associated with placental injury including maternal vascular malperfusion as well as acute and chronic inflammation. These patterns of injury are further associated with adverse birth outcomes including preterm birth and current evidence suggests an association between poor placental function and compromised fetal development. With the ever increasing number of pregnant women with HIV on ART, there is a compelling need for full incorporation of placental diagnoses into obstetric disease classification. It is also important to take into account key elements of maternal clinical history. Lastly, there is a need to standardize the reporting of placental pathology in order to glean additional insight into the elucidation of HIV/ART associated placental injury., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Gestational diabetes mellitus (GDM) affects one in four Saudi women and is associated with high risks of cardiovascular diseases in both the mother and foetus. It is believed that endothelial cells (ECs) dysfunction initiates these diabetic complications. In this study, differences in the transcriptome profiles, cell cycle distribution, and mitochondrial superoxide (MTS) between human umbilical vein endothelial cells (HUVECs) from GDM patients and those from healthy (control) subjects were analysed. Transcriptome profiles were generated using high-density expression microarray. The selected four altered genes were validated using qRT-PCR. MTS and cell cycle were analysed by flow cytometry. A total of 84 altered genes were identified, comprising 52 upregulated and 32 downregulated genes in GDM.HUVECs. Our selection of the four interested altered genes (TGFB2, KITLG, NEK7, and IGFBP5) was based on the functional network analysis, which revealed that these altered genes are belonging to the highest enrichment score associated with cellular function and proliferation; all of which may contribute to ECs dysfunction. The cell cycle revealed an increased percentage of cells in the G2/M phase in GDM.HUVECs, indicating cell cycle arrest. In addition, we found that GDM.HUVECs had increased MTS generation. In conclusion, GDM induces persistent impairment of the biological functions of foetal ECs, as evidenced by analyses of transcriptome profiles, cell cycle, and MTS even after ECs culture in vitro for several passages under normal glucose conditions.

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.)

Introduction: Neonatal hyperthyroidism is a disease that can cause mortality and sequelae. To date, there is no clinical series of cases that allows us to know the local reality of this condition., Objective: to charac terize the children of mothers with Graves' disease (GD) from a clinical and biochemical point of view., Subjects and Method: A prospective follow-up of all newborns (NB) of mothers with history of GD was performed in two public hospitals in Santiago, during 5 years. Clinical and laboratory variables of mother-child pairs and thyroid-stimulating hormone receptor antibodies (TRAbs) le vels were analyzed looking for associations between these variables and the development of neonatal hyperthyroidism., Results: Seventy-six mother-child pairs were included (0.2% of all deliveries). Five neonates (6.6%) presented biochemical hyperthyroidism, and 3 of them developed clinical disease and required treatment. All 5 NBs who developed hyperthyroidism had mothers with positive or indeterminate TRAbs. No child of TRAbs-negative mothers developed the disease. TRAbs could be determined in only 65% of the mothers and 72% of the NBs. There was a significant correlation bet ween maternal TRAbs titers (p < 0.03), neonatal TRAbs titers (p < 0.008), and neonatal TSH between days 2-6 (p < 0.006), with the subsequent development of hyperthyroidism. All cases of neonatal hyperthyroidism were transient. There was no mortality in our series., Conclusions: This is the first national case series of children of mothers with GD. Maternal and neonatal TRAbs and TSH between days 2-6 of life were predictors of neonatal hyperthyroidism.

Background: Chorioamnionitis is associated with increased rates of bronchopulmonary dysplasia (BPD) in ventilated preterm infants. Budesonide when added to surfactant decreased lung and systemic inflammation from mechanical ventilation in preterm lambs and decreased the rates and severity of BPD in preterm infants. We hypothesized that the addition of budesonide to surfactant will decrease the injury from mechanical ventilation in preterm lambs exposed to intra-amniotic (IA) lipopolysaccharide (LPS)., Methods: Lambs at 126 ± 1 day GA received LPS 10 mg IA 48 h prior to injurious mechanical ventilation. After 15 min, lambs received either surfactant mixed with: (1) saline or (2) Budesonide 0.25 mg/kg, then ventilated with normal tidal volumes for 4 h. Injury markers in the lung, liver, and brain were compared., Results: Compared with surfactant alone, the addition of budesonide improved blood pressures, dynamic compliance, and ventilation, while decreasing mRNA for pro-inflammatory cytokines in the lung, liver, and multiple areas of the brain. LPS caused neuronal activation and structural changes in the brain that were not altered by budesonide. Budesonide was not retained within the lung beyond 4 h., Conclusions: In preterm lambs exposed to IA LPS, the addition of budesonide to surfactant improved physiology and markers of lung and systemic inflammation., Impact: The addition of budesonide to surfactant decreases the lung and systemic responses to injurious mechanical ventilation preterm lambs exposed to fetal LPS. Budesonide was present in the plasma by 15 min and the majority of the budesonide is no longer in the lung at 4 h of ventilation. IA LPS and mechanical ventilation caused structural changes in the brain that were not altered by short-term exposure to budesonide. The budesonide dose of 0.25 mg/kg being used clinically seems likely to decrease lung inflammation in preterm infants with chorioamnionitis., (© 2020. International Pediatric Research Foundation, Inc.)

Intrauterine inflammation is shown to be associated with preterm birth, fetal inflammatory response syndrome, and other pregnancy-related comorbidities such as central nervous system diseases including cerebral palsy and periventricular leukomalacia, pulmonary diseases such as bronchopulmonary dysplasia and respiratory distress syndrome, and necrotizing enterocolitis, to name a few. Many animal studies on intrauterine inflammation demonstrate that ascending infection of reproductive organs or the production of proinflammatory cytokines by some stimuli in utero results in such manifestations. Melatonin, known for its primary function in maintaining circadian rhythm, is now recognized as one of the most potent antioxidant and anti-inflammatory drugs. In some studies, melatonin injection in pregnant animals with intrauterine inflammation significantly reduced the number of preterm births, the severity of structural disintegration of the fetal lungs observed in bronchopulmonary dysplasia, and perinatal brain injuries with improvement in neuromotor function. These implicated benefits of melatonin in pregnant women with intrauterine inflammation seem promising in many research studies, strongly supporting the hypothesis that melatonin has antioxidative and anti-inflammatory properties that can potentially be taken by pregnant women who are at risk of having intrauterine inflammation. In this review, the potential of melatonin for improving outcomes of the pregnancies with intrauterine inflammation will be discussed., (© 2021 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Introduction: Maternal Cytomegalovirus (CMV) infection in the first trimester (T1) of pregnancy is a public health concern, as it increases the risk of severe neurodevelopmental outcomes associated with congenital infection compared to infections occurring later during pregnancy., Objectives: To determine CMV seroprevalence in T1 of pregnancy, its trend, risk factors and the incidence rate of primary infection during pregnancy., Methods: Using the biobank of the prospective cohort "Grossesse en Santé de Québec" collected between April 2005 and March 2010 at the Québec-Laval Hospital, Québec, Canada, maternal CMV serology was determined using Abbott Architect Chemiluminescence microparticle immunoassays for immunoglobulin G(IgG), immunoglobulin M(IgM) titration and IgG avidity testing. Changepoint detection analysis was used to assess temporal trends. Risk factors associated with seropositivity were determined by multivariable logistic regression., Results: CMV seroprevalence in T1 of pregnancy was 23.4% (965/4111, 95% CI, 22.1-24.7%). The incidence rate for CMV primary infection during pregnancy was 1.8 (95% CI, 1.2-2.6) per 100 person-years. No changepoint was identified in the maternal CMV-seroprevalence trend. Multivariable analyses showed that T1 maternal CMV seropositivity was associated with having one child OR 1.3 (95% CI, 1.10-1.73) or two or more children OR 1.5 (95%CI, 1.1-2.1), ethnicity other than Caucasian OR 2.1 (95% CI, 1.1-3.8) and country of birth other than Canada and the USA OR 2.8 (95% CI, 1.5-4.9)., Conclusions: In this cohort, maternal seroprevalence in T1 of pregnancy and seroconversion rate were low. This information and identified risk factors could help guide the development and implementation of preventive actions and evidence-based health policies to prevent CMV infection during pregnancy., Competing Interests: The authors have no conflicts of interest to disclose.

The article presents current views on maternal hyperhomocysteinemia (HHcy) as an important factor causing prenatal stress and impaired nervous system development in fetuses and newborns in early ontogenesis, as well as complications in adulthood. Experimental data demonstrate that prenatal HHcy (PHHcy) affects the morphological maturation of the brain and activity of its neurotransmitter systems. Cognitive deficit observed in the offspring subjected to PHHcy in experimental studies can presumably cause the predisposition to various neurodegenerative diseases, as the role of maternal HHcy in the pathogenesis such diseases has been proven in clinical studies. The review also discusses molecular mechanisms of the HHcy neurotoxic action on the nervous system development in the prenatal and early postnatal periods, which include oxidative stress, apoptosis activation, changes in the DNA methylation patterns and microRNA levels, altered expression and processing of neurotrophins, and neuroinflammation induced by an increased production of pro-inflammatory cytokines. Special attention is given to the maternal HHcy impact on the placenta function and its possible contribution to the brain function impairments in the offspring. Published data suggest that some effects of PHHcy on the developing fetal brain can be due to the disturbances in the transport functions of the placenta resulting in an insufficient supply of nutrients necessary for the proper formation and functioning of brain structures.

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.

Objectives: To analyze and compare, using ultrasound-based radiomics technology, fetal-lung texture in pregnancies affected by gestational diabetes mellitus (GDM) and/or pre-eclampsia (PE) and in normal pregnancies, overall and at different gestational ages., Methods: In this retrospective study, 430 high-throughput features per fetal-lung image were extracted from 548 fetal-lung ultrasound images (obtained at the level of the four-chamber view of the heart) in 548 pregnant women who delivered between July 2018 and August 2019 at the Obstetrics and Gynecology Hospital of Fudan University. Images had been obtained during ultrasound examinations between 28 and 41 weeks of gestation. The data were divided randomly into training set (80% of fetal-lung images) and independent test set (20% of images), and 20% of the images in the training set were then selected as the validation set. A standard machine-learning model based on ultrasound-based radiomics technology was created using features of fetal-lung texture extracted from the images, and a regression model was used to evaluate the relationship between lung-texture features, GDM and/or PE and gestational age., Results: Of the 548 pregnancies included, 108 were affected by GDM alone, 71 by PE alone and 25 by both GDM and PE, and 344 were normal. The overall performance of the GDM and PE prediction model was superior to that of the gestational-age prediction model, with an area under the receiver-operating-characteristics curve of 0.95-0.99, sensitivity of 78.8-97.1% in the validation set and 74.5-91.3% in the independent test set, specificity of 79.8-94.3% in the validation set and 75.7-88.4% in the independent test set and accuracy of 81.0-95.3% in the validation set and 80.6-86.4% in the independent test set., Conclusions: Using ultrasound-based radiomics technology, fetal lungs from pregnancies grouped according to whether they were affected by GDM and/or PE could be distinguished from each other and from fetal lungs of normal pregnancies, and lungs from pregnancies at different gestational ages could be distinguished. These findings support further research to explore the use of this non-invasive technology to predict neonatal respiratory complications in women with PE, GDM or their combination. © 2020 International Society of Ultrasound in Obstetrics and Gynecology., (© 2020 International Society of Ultrasound in Obstetrics and Gynecology.)

Fetal anemia is common in malaria-endemic areas and a risk factor for anemia as well as mortality during infancy. Placental malaria (PM) and red cell abnormalities have been proposed as possible etiologies, but the relationship between PM and fetal anemia has varied in earlier studies, and the role of red cell abnormalities has not been studied in malaria-endemic areas. In a Tanzanian birth cohort study designed to elucidate the pathogenesis of severe malaria in young infants, we performed a cross-sectional analysis of risk factors for fetal anemia. We determined PM status, newborn red cell abnormalities, and maternal and cord blood levels of iron regulatory proteins, erythropoietin (EPO), cytokines and cytokine receptors. We examined the relationship between these factors and fetal anemia. Fetal anemia was present in 46.2% of the neonates but was not related to PM. Maternal iron deficiency was common (81.6%), most frequent in multigravidae, and interacted with parity to modify risk of fetal anemia, but it was not directly related to risk. Among offspring of iron-deficient women, the odds of fetal anemia increased with fetal α + -thalassemia, as well as these patterns of cord blood cytokines: increased cord IL-6, decreased TNF-RI, and decreased sTfR. The EPO response to fetal anemia was low or absent and EPO levels were significantly decreased in newborns with the most severe anemia. This study from an area of high malaria transmission provides evidence that 1) fetal α + -thalassemia and cytokine balance, but not PM at delivery, are related to fetal anemia; 2) maternal iron deficiency increases the risk that other factors may cause fetal anemia; and 3) fetal anemia has a multifactorial etiology that may require a variety of interventions, although measures that reduce maternal iron deficiency may be generally beneficial., 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 Kabyemela, Fried, Kurtis, Moses, Gorres, Muehlenbachs and Duffy.)

Fetal thyroid complications in pregnancy are uncommon, and are commonly related to the passage of substances through the placenta. The excessive iodine intake during the pregnancy is a well-known mechanism of fetal thyroid enlargement or goiter, and invasive procedures have been proposed for the treatment of fetal thyroid pathologies. In the present report, we demonstrate two cases from different centers of prenatal diagnosis of fetal thyroid enlargement and/or goiter in three fetuses (one pair of twins, wherein both fetuses were affected, and one singleton pregnancy). The anamnesis revealed the ingestion of iodine by the patients, prescribed from inadequate vitamin supplementation. In both cases, the cessation of iodine supplement intake resulted in a marked reduction of the volume of the fetal thyroid glands, demonstrating that conservative treatment may be an option in those cases. Also, clinicians must be aware that patients may be exposed to harmful dosages or substances during pregnancy., Competing Interests: The authors have no conflict of interests to declare., (Federação Brasileira de Ginecologia e Obstetrícia. This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. (https://creativecommons.org/licenses/by/4.0/).)

Objective: Evaluate the effectiveness and safety of application of oral glucose to neonates with an increased risk of neonatal hypoglycaemia., Background: Neonatal hypoglycaemia is a common problem in neonates with potential permanent neurological damage. Recent studies show that the use of oral glucose to prevent and treat neonatal hypoglycaemia leads to a decrease in intravenous glucose administration and fewer clinical admissions. However, oral glucose administration is still rarely used. In 2019 Isala hospital implemented the use of oral glucose in neonates with an increased risk of neonatal hypoglycaemia., Method: Retrospective evaluation study in Isala hospital between November 1, 2018 and December 31. Neonates with one of the following risk factors for neonatal hypoglycaemia: prematurity (gestational age between 34+0-37+0), maternal diabetes requiring medication, asphyxia with an Apgar score <7 at five minutes and/or a birthweight <2500 grams. The frequency of glucose infusions, the lowest glucose value and the type of food were compared between neonates treated before and after the use of oral glucose., Results: The number of glucose infusions decreased after introduction of oral glucose (14.0% versus 5.9%, -8.1% [-14.1, -2.1]). The lowest measured glucose value (2.2 mmol/l versus 2.5 mmol/l, 0.3 mmol/l [0.15, 0.47]) was significantly higher after introduction of oral glucose. Mild complications (vomiting and food refusal) occurred in 3.8% of neonates receiving oral glucose, all without clinical consequence., Conclusion: The use of oral glucose administration in neonates with an increased risk of hypoglycaemia reduces the number of intravenous glucose by half and is safe to use.

Aim: To determine how the severity of antenatally diagnosed germinal matrix-intraventricular hemorrhage (GMH-IVH) relates to morbidity and mortality, and to explore potential risk factors., Method: We conducted a systematic review and individual patient data meta-analysis of antenatally diagnosed fetal GMH-IVH. The primary outcomes were mortality and morbidity. Potential associations with clinical factors during pregnancy were explored. Analysis employed Fisher's exact test and logistic regression., Results: We included 240 cases from 80 studies. Presence of venous infarction was associated with mortality (odds ratio [OR] 4.3, 95% confidence interval [CI] 1.4-13.25), motor impairment (OR 103.2, 95% CI 8.6-1238), epilepsy (OR 6.46, 95% CI 2.64-16.06), and developmental delay (OR 8.55, 95% CI 2.12-48.79). Shunt placement was associated with gestational age at GMH-IVH diagnosis and in utero progression. Many cases had uncomplicated pregnancies but possible co-occurring conditions included twin gestation, small for gestational age, and congenital anomalies., Interpretation: Severity of fetal GMH-IVH, specifically venous infarction, is associated with overall mortality and morbidity. Risk factors for fetal GMH-IVH are poorly understood and controlled studies are required., What This Paper Adds: Preterm germinal matrix-intraventricular hemorrhage (GMH-IVH) grading can be applied to fetuses. Many fetal germinal matrix hemorrhages occur in otherwise typical pregnancies. Half of fetuses with post-hemorrhagic ventricular dilatation receive a shunt after delivery. Fetuses with grade I or II GMH-IVH have few sequelae. Fetuses with periventricular hemorrhagic infarction have a high burden of motor impairment., (© 2020 Mac Keith Press.)

Craniofacial development requires extremely fine-tuned developmental coordination of multiple specialized tissues. It has been evidenced that a folate deficiency (vitamin B 9 ), or its synthetic form, folic acid (FA), in maternal diet could trigger multiple craniofacial malformations as oral clefts, tongue, or mandible abnormalities. In this study, a folic acid-deficient (FAD) diet was administered to eight-week-old C57/BL/6J female mouse for 2-16 weeks. The head symmetry, palate and nasal region were studied in 24 control and 260 experimental fetuses. Our results showed a significant reduction in the mean number of fetuses per litter according to maternal weeks on FAD diet ( p < 0.01). Fetuses were affected by cleft palate (3.8%) as well as other severe congenital abnormalities, for the first time related to maternal FAD diet, as head asymmetries (4.6%), high arched palate (3.5%), nasal septum malformed (7.3%), nasopharynx duct shape (15%), and cilia and epithelium abnormalities (11.2% and 5.8%). Dysmorphologies of the nasal region were the most frequent, appearing at just four weeks following a maternal FAD diet. This is the first time that nasal region development is experimentally related to this vitamin deficiency. In conclusion, our report offers novel discoveries about the importance of maternal folate intake on midface craniofacial development of the embryos. Moreover, the longer the deficit lasts, the more serious the consequent effects appear to be.

Umbilical vein varix is associated with a high incidence of fetal anomalies and perinatal complications. There are two types of umbilical vein varix: fetal intra-abdominal and extra-abdominal. Herein, a case is reported of severe fetal anemia with extra-abdominal umbilical vein varix. A 33-year-old primigravida was referred to our hospital for fetal growth restriction, fetal cardiomegaly, and decreased fetal movements at 26 weeks' gestation. A Doppler assessment showed an elevated middle cerebral artery peak systolic velocity at 2.2 MoM, suggesting fetal anemia. Umbilical vein varix had caused intermittent turbulent flow, provoking hemolytic anemia. Intrauterine transfusion improved fetal circulatory failure and anemia and prolonged gestational period. At 33 weeks' gestation, the patient underwent cesarean delivery due to nonreassuring fetal status. Pathological analysis revealed focal loss of vascular smooth muscle of the umbilical vein. Extra-abdominal umbilical vein varix has been reported in 14 cases including this case. The antenatal diagnosis rate is reported to be 79%; fetal heartbeat abnormalities and fetal deaths were reported as 50% and 14%, respectively. Eighty-six percent of patients had intra-umbilical cord thrombosis, but currently this is the only case of hemolytic anemia. Furthermore, extra-abdominal umbilical vein varix may present as fetal hydrops with anemia. During ultrasound examination of fetal anemia, umbilical cord screening should be performed with caution., (© 2020 Japanese Teratology Society.)

Background: Phaeochromocytoma or paraganglioma (collectively known as PPGL) in pregnant women can lead to severe complications and death due to associated catecholamine excess. We aimed to identify factors associated with maternal and fetal outcomes in women with PPGL during pregnancy., Methods: We did a multicentre, retrospective study of patients with PPGL and pregnancy between Jan 1, 1980, and Dec 31, 2019, in the International Pheochromocytoma and Pregnancy Registry and a systematic review of studies published between Jan 1, 2005, and Dec 27, 2019 reporting on at least five cases. The inclusion criteria were pregnancy after 1980 and PPGL before or during pregnancy or within 12 months post partum. Eligible patients from the retrospective study and systematic review were included in the analysis. Outcomes of interest were maternal or fetal death and maternal severe cardiovascular complications of catecholamine excess. Potential variables associated with these outcomes were evaluated by logistic regression., Findings: The systematic review identified seven studies (reporting on 63 pregnancies in 55 patients) that met the eligibility criteria and were of adequate quality. A further 197 pregnancies in 186 patients were identified in the International Pheochromocytoma and Pregnancy Registry. After excluding 11 pregnancies due to potential overlap, the final cohort included 249 pregnancies in 232 patients with PPGL. The diagnosis of PPGL was made before pregnancy in 37 (15%) pregnancies, during pregnancy in 134 (54%), and after delivery in 78 (31%). Of 144 patients evaluated for genetic predisposition for phaeochromocytoma, 95 (66%) were positive. Unrecognised PPGL during pregnancy (odds ratio 27·0; 95% CI 3·5-3473·1), abdominal or pelvic tumour location (11·3; 1·5-1440·5), and catecholamine excess at least ten-times the upper limit of the normal range (4·7; 1·8-13·8) were associated with adverse outcomes. For patients diagnosed during pregnancy, α-adrenergic blockade therapy was associated with fewer adverse outcomes (3·6; 1·1-13·2 for no α-adrenergic blockade vs α-adrenergic blockade), whereas surgery during pregnancy was not associated with better outcomes (0·9; 0·3-3·9 for no surgery vs surgery)., Interpretation: Unrecognised and untreated PPGL was associated with a substantially higher risk of either maternal or fetal complications. Appropriate case detection and counselling for premenopausal women at risk for PPGL could prevent adverse pregnancy-related outcomes., Funding: US National Institutes of Health., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

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: 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.)

Introduction: Umbilical cord prolapse is a major obstetric emergency associated with significant perinatal complications. However, there is no consensus on the optimal decision-to-delivery interval, as many previous studies have shown poor correlation between the interval and umbilical cord arterial blood gas or perinatal outcomes. We aim to investigate whether bradycardia-to-delivery or decision-to-delivery interval was related to poor cord arterial pH or adverse perinatal outcome in umbilical cord prolapse., Material and Methods: This was a retrospective study conducted at a university tertiary obstetric unit in Hong Kong. All women with singleton pregnancy complicated by cord prolapse during labor between 1995 and 2018 were included. Women were categorized into three groups. Group 1: persistent bradycardia; Group 2: any type of decelerations without bradycardia; and Group 3: normal fetal heart rate. The main outcome was cord arterial blood gas results of the newborns in different groups. Maternal demographic data and perinatal outcomes were reviewed. Correlation analysis between cord arterial blood gas result and time intervals including bradycardia-to-delivery, deceleration-to-delivery, and decision-to-delivery were performed for the different groups with Spearman test., Results: There were 34, 30, and 50 women in Groups 1, 2, and 3, respectively. Cord arterial pH and base excess did not correlate with decision-to-delivery interval in any of the groups, but they were inversely correlated with bradycardia-to-delivery interval in Group 1 (Spearman's ρ = -.349; P = .043 and Spearman's ρ = -.558; P = .001, respectively). The cord arterial pH drops at 0.009 per minute with bradycardia-to-delivery interval in Group 1 (95% CI 0.0180-0.0003). The risk of significant acidosis (pH < 7) was 80% when bradycardia-to-delivery interval was >20 minutes, and 17.2% when the interval was <20 minutes., Conclusions: There is significant correlation between bradycardia-to-delivery interval and cord arterial pH in umbilical cord prolapse with fetal bradycardia but not in cases with decelerations or normal heart rate. The drop of cord arterial pH is rapid and urgent delivery is essential in such situations., (© 2020 Nordic Federation of Societies of Obstetrics and Gynecology (NFOG). Published by John Wiley & Sons Ltd.)

Objective: To investigate cerebral anomalies other than Chiari type 2 malformation in fetuses with myelomeningocele (MMC)., Design: A retrospective cohort study in a single tertiary centre., Setting: A review of associated cerebral anomalies in cases with prenatal diagnosis of myelomeningocele., Population: Seventy cases of fetal myelomeningocele., Methods: Ultrasound and MRI images were blindly reviewed. Postnatal imaging and results of the postmortem results were also reviewed. The association between cerebral anomalies and the following ultrasound findings was measured: level of the defect, ventriculomegaly, microcephaly and fetal talipes., Main Outcome Measures: A microcephaly was observed in 32/70 cases (46%) and a ventriculomegaly was observed in 39/70 cases (56%). Other cerebral anomalies were diagnosed in 47/70 (67%)., Results: Other cerebral anomalies were represented by 42/70 cases with abnormal CC (60%), 8/70 cases with perinodular heterotopia (PNH; 11%), 2/70 cases with abnormal gyration (3%). MRI performed only in fetal surgery cases confirmed the ulltrasound findings in all cases and provided additional findings in two cases (PNH). Risk ratios of fetal cerebral anomalies associated with MMC did not reach significance for microcephaly, ventriculomegaly, talipes or the level of the defect There was an overall good correlation between pre- and postnatal findings with a Kappa value of 0.79 [95% CI 0.57-1] and 82% agreement., Conclusion: Fetal brain anomalies other than Chiari type 2 malformation are frequently observed in fetuses with myelomeningocele, predominantly represented by CC anomalies. Whether these associated cerebral anomalies have an impact on selecting cases eligible for fetal surgery needs further evaluation., Tweetable Abstract: Fetal cerebral anomalies other than Chiari type 2 malformation, microcephaly, and ventriculomegaly may be associated with MMC in up to 67% of the cases., (© 2020 Royal College of Obstetricians and Gynaecologists.)

Perinatal stroke ranks second only to that of adult stroke in the overall stroke incidence. It is a major contributor to long-term neurological morbidity, which includes cognitive dysfunction, cerebral palsy and seizures. Risk factors for stroke in the perinatal period differ from those in children and tend to be multifactorial. Differences in territorial predilection, response to injury, and stroke evolution exist when compared with childhood and adult stroke, and also among differing gestation age groups in the perinatal period (i.e., extreme preterm versus preterm versus term). The role of imaging is to diagnose stroke, exclude stroke mimics, establish the nature of stroke (arterial versus venous), and aid in prognostication. Magnetic resonance imaging is the mainstay of neuroimaging in perinatal stroke. Advanced imaging techniques such as diffusion tensor imaging and perfusion-weighted imaging are emerging as useful supplements to conventional imaging sequences. Here we describe the neuroimaging of perinatal arterial ischemic stroke with emphasis on imaging techniques, imaging phenotypes, stroke evolution, role of advanced imaging, and differences between stroke in preterm and term neonates. We also briefly describe the emerging role of fetal magnetic resonance imaging in the diagnosis of in utero stroke., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Animal studies indicate that suboptimal conditions during pregnancy adversely impact both maternal health and offspring phenotype, predisposing offspring to development of later-life diseases including obesity, diabetes, cardiovascular diseases, and behavioral and reproductive dysfunction. Effective interventions during pregnancy and/or lactation are needed to improve both maternal and offspring health. This review addresses the relationship between adverse perinatal insults and its negative impact on offspring development and presents some maternal intervention studies in animal models, such as maternal nutrition (diet modification, antioxidants, omega-3-6 (n-3-6), probiotics) or physical activity, which can prevent or alleviate negative outcomes in both mother and offspring., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

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.)

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: Autophagy is highly active in neuroepithelial cells of the developing neuroepithelium, and impairment of autophagy leads to neural tube defects. In this study, we have found that maternal diabetes suppresses autophagy that leads to neural tube defects and consequent cellular imbalance in the endoplasmic reticulum where critical events occur, leading to the induction of diabetic embryopathy. Because the mammalian target of rapamycin pathway suppresses autophagy, we hypothesized that 70 kDa ribosomal protein S6 kinase 1 (p70S6K1), a major downstream effector of mammalian target of rapamycin, mediates the inhibitory effect of maternal diabetes on autophagy in the developing neuroepithelium., Objective: We investigated whether p70S6K1 mediates the inhibitory effect of maternal diabetes on autophagy during neurulation. We also examined whether p70S6K1 deficiency restores autophagy and therefore relieves endoplasmic reticulum stress and inhibits maternal diabetes-induced apoptosis, which leads to reduction in neural tube defect incidence in diabetic embryopathy., Study Design: Female p70S6K1 heterogeneous knockout (p70S6K1 +/- ) mice were bred with male p70S6K1 heterogeneous knockout (p70S6K1 +/- ) mice to generate wild-type (WT), p70S6K1 +/- and p70S6K1 knockout (p70S6K1 -/- ) embryos. Embryos at embryonic day 8.5 were harvested for the assessment of indices of autophagy, endoplasmic reticulum stress, and apoptosis. Neural tube defect incidence in embryos was determined at embryonic day 10.5. For in vitro studies, small interfering RNA knockdown of p70S6K1 in C17.2 mouse neural stem cells was used to determine the effect of p70S6K1 deficiency on autophagy impairment and endoplasmic reticulum stress under high glucose conditions., Results: Knockout of the Rps6kb1 gene, which encodes for p70S6K1, ameliorated maternal diabetes-induced NTDs and restored autophagosome formation in neuroepithelial cells suppressed by maternal diabetes. Maternal diabetes-suppressed conversion of LC3-I (microtubule-associated protein 1A/1B-light chain 3) to LC3-II, an index of autophagic activity, in neurulation stage embryos was abrogated in the absence of p70S6K1. p70S6K1 knockdown in neural stem cells also restored autophagosome formation and the conversion of LC3-I to LC3-II. The activation of the major unfolded protein response, indicated by phosphorylation of inositol-requiring enzyme 1 alpha, and protein kinase R-like endoplasmic reticulum kinase, and eukaryotic translation initiation factor 2α, and the increase of the endoplasmic reticulum stress marker, C/EBP homologous protein, were induced by maternal diabetes in vivo and high glucose in vitro. Unfolded protein response and endoplasmic reticulum stress induced by maternal diabetes or high glucose were reduced by Rps6kb1 deletion or p70S6K1 knockdown, respectively. Rps6kb1 knockout blocked maternal diabetes-induced caspase cleavage and neuroepithelial cell apoptosis. The superoxide dismutase mimetic Tempol abolished high glucose-induced p70S6K1 activation., Conclusion: The study revealed the critical involvement of p70S6K1 in the pathogenesis of diabetic embryopathy., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Aims: To compare the effects of maternal subclinical hypothyroidism (SCH) diagnosed by the 2011 or 2017 "Guidelines of the American Thyroid Association (ATA) for the diagnosis and management of thyroid disease during pregnancy and the postpartum" during the first trimester on adverse pregnancy outcomes in thyroid peroxidase antibody (TPOAb)-negative pregnant women. Methods: There were 1,556 Chinese singleton pregnant women with negative TPOAb diagnosed with either SCH or euthyroidism who were investigated, and the prevalence and risk of obstetric outcomes were compared between the two groups using 2011 and 2017 ATA standards, respectively. The effects of a mildly elevated thyroid-stimulating hormone (TSH) concentration on adverse pregnancy outcomes were evaluated by binary logistic regression. Results: Maternal SCH identified by the 2011 ATA guidelines correlated with higher rates and risks of pregnancy-induced hypertension (PIH), preeclampsia, and low-birth-weight infants, while maternal SCH diagnosed by the 2017 ATA guidelines was more likely to develop PIH, preeclampsia, cesarean delivery, preterm delivery, placenta previa, and total adverse maternal and neonatal outcomes. Moreover, a mildly elevated TSH level was significantly associated with PIH after adjustment for confounding factors. Conclusions: Compared with the 2011 ATA guidelines, the 2017 ATA guidelines could be more applicable to Chinese pregnant women to screen the effects of SCH on the majority of adverse pregnancy outcomes., (Copyright © 2020 Li, Ma, Feng, Zhu, Yu, Ke, Zhang, Liu and Li.)

Objectives: EXIT (ex-utero intrapartum treatment) procedure is a fetal survival-increasing modification of cesarean section. Previously we found an increase incidence of fetal vascular malperfusion (FVM) in placentas from EXIT procedures which indicates the underlying stasis of fetal blood flow in such cases. This retrospective analysis analyzes the impact of the recently introduced CD34 immunostain for the FVM diagnosis in placentas from EXIT procedures., Methods: A total of 105 placentas from EXIT procedures (48 to airway, 43 to ECMO and 14 to resection) were studied. In 73 older cases, the placental histological diagnosis of segmental FVM was made on H&E stained placental sections only (segmental villous avascularity) (Group 1), while in 32 most recent cases, the CD34 component of a double E-cadherin/CD34 immunostain slides was also routinely used to detect the early FVM (endothelial fragmentation, villous hypovascularity) (Group 2). Twenty-three clinical and 47 independent placental phenotypes were compared by χ 2 or ANOVA, where appropriate., Results: There was no statistical significance between the groups in rates of segmental villous avascularity (29 vs. 34%), but performing CD34 immunostain resulted in adding and/or upgrading 12 more cases of segmental FVM in Group 2, thus increasing the sensitivity of placental examination for FVM by 37%. There were no other statistically significantly differences in clinical (except for congenital diaphragmatic hernias statistically significantly more common in Group 2, 34 vs. 56%, p=0.03) and placental phenotypes, proving the otherwise comparability of the groups., Conclusions: The use of CD34 immunostain increases the sensitivity of placental examination for FVM by 1/3, which may improve the neonatal management by revealing the increased likelihood of the potentially life-threatening neonatal complications., (© 2020 Walter de Gruyter GmbH, Berlin/Boston.)