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Introduction: Congenital CMV infection is the first worldwide cause of congenital viral infection but systematic screening of pregnant women and newborns for CMV is still debated in many countries., Objectives: This systematic review aims to provide the state of the art on current practices concerning management of maternal and congenital CMV infection during pregnancy, after maternal primary infection (PI) in first trimester of pregnancy., Data Sources: Electronically searches on databases and hand searches in grey literature., Study Eligibility Criteria and Participants: Primary outcome was listing biological, imaging, and therapeutic management interventions in two distinct populations: population 1 are pregnant women with PI, before or without amniocentesis; population 2 are pregnant women with congenitally infected fetuses (after positive amniocentesis). Secondary outcome was pregnancy outcome in population 2., Results: Out of 4,134 studies identified, a total of 31 studies were analyzed, with 3,325 pregnant women in population 1 and 1,021 pregnant women in population 2, from 7 countries (Belgium, France, Germany, Israel, Italy, Spain and USA). In population 1, ultrasound (US) examination frequency was 0.75/month, amniocentesis in 82% cases, maternal viremia in 14% and preventive treatment with hyperimmune globulins (HIG) or valaciclovir in respectively 14% and 4% women. In population 2, US examination frequency was 1.5/month, magnetic resonance imaging (MRI) in 44% cases at 32 weeks gestation (WG), fetal blood sampling (FBS) in 24% at 28 WG, and curative treatment with HIG or valaciclovir in respectively 9% and 8% patients., Conclusions: This systematic review illustrates management of maternal and congenital CMV during pregnancy in published and non-published literature, in absence of international consensus., Systematic Review Registration: PROSPERO CRD42019124342., Competing Interests: The authors have declared that no competing interests exist.

The transmission of chronic wasting disease (CWD) has largely been attributed to contact with infectious prions shed in excretions (saliva, urine, feces, blood) by direct animal-to-animal exposure or indirect contact with the environment. Less-well studied has been the role that mother-to-offspring transmission may play in the facile transmission of CWD, and whether mother-to-offspring transmission before birth may contribute to the extensive spread of CWD. We thereby focused on a population of free-ranging white-tailed deer from West Virginia, USA, in which CWD has been detected. Fetal tissues, ranging from 113 to 158 days of gestation, were harvested from the uteri of CWD+ dams in the asymptomatic phase of infection. Using serial protein misfolding amplification (sPMCA), we detected evidence of prion seeds in 7 of 14 fetuses (50%) from 7 of 9 pregnancies (78%), with the earliest detection at 113 gestational days. This is the first report of CWD detection in free ranging white-tailed deer fetal tissues. Further investigation within cervid populations across North America will help define the role and impact of mother-to-offspring vertical transmission of CWD.

Introduction: Distended fetal bladder, also known as fetal megacystis, usually points to lower urinary tract obstruction (LUTO) which is most commonly caused by posterior urethral valves (PUV) in the male fetus. We present a short case-series of fetal megacystis without oligohydramnion where primary vesicoureteral reflux (VUR) was the leading aetiology. These cases also displayed a high rate of kidney dysplasia with early-onset renal dysfunction. By contrast, late-onset diagnosis of isolated megacystis, i.e without significant renal parenchymal or upper urinary tract abnormalities, had a surprisingly benign postnatal course with spontaneous resolution after birth. Our case series also display the associated risk for extra-renal malformations and specifically neuro-cognitive developmental abnormalities which should be sought on genetic and imaging evaluation.

The field of fetal medicine has evolved significantly over the past several decades. Our ability to identify and treat the unborn patient has been shaped by advancements in imaging technology, genetic diagnosis, an improved understanding of fetal physiology, and the development and optimization of in utero surgical techniques. The future of the field will be shaped by medical innovators pushing for the continued refinement of minimally invasive surgical technique, the application of pioneering technologies such as robotic surgery and in utero stem cell and gene therapies, and the development of innovative ex utero fetal support systems., Competing Interests: Disclosure The authors have nothing to disclose., (Published by Elsevier Inc.)

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.)

Background and Aim: Prenatal diagnosis of fetal abnormalities is a critical and stressful event for women. Most pregnant women are concerned about fetal abnormalities and screening tests. Due to the importance of anxiety reduction in pregnant women, this study was conducted to determine the effect of short-term psychological intervention on the anxiety of pregnant women with positive screening results for chromosomal disorders., Methods: A randomized clinical trial was performed on women referred to Akbarabadi Hospital in Tehran, Iran, who had positive screening results for chromosomal abnormalities. Participants were selected from eligible individuals by a continuous method and were assigned to two groups of cognitive-behavioral training (n = 46) and control (n = 46), using the block balanced randomization method. Participants in the cognitive-behavioral training group received 4 sessions of individual counseling. The control group received routine pregnancy visits. The Spielberger State-Trait Anxiety Inventory was completed before the intervention and immediately at the end of the intervention (before receiving the amniocentesis result). The analysis of intervention effects was performed as intention-to-treat and per-protocol analysis., Results: There was a statistically significant difference in post-intervention state anxiety scores and trait anxiety scores (p <  0.001) between the intervention and control groups, when their means were adjusted for pre-intervention scores for both intention-to-treat and per-protocol analysis. Also, there was a large effect size between the groups in terms of state (ITT: η p 2  = 0.63, PP: η p 2  = 0.71) and trait (ITT: η p 2  = 0.72, PP: η p 2  = 0.75) anxiety scores clinically for both intention-to-treat and per-protocol analysis. The intervention group had a statistically significant and large decrease in state and trait anxiety scores from pretrial to post-trial. In contrast, the control group had a statistically significant and medium increase in state and trait anxiety scores from pretrial to post-trial., Conclusion: The results showed that cognitive-behavioral training reduced the anxiety of pregnant women with positive screening results for chromosomal disorders. According to the results, it is recommended to hold cognitive-behavioral training classes to reduce the anxiety of pregnant women with a positive screening result for chromosomal disorders., Trial Registration: IRCT.ir: IRCT20180427039436N7 ; date of registration: 24/08/2020 2020-08-24., (© 2021. The Author(s).)

Objective: To compare redox imbalance and inflammation biomarkers in umbilical cords from pregnancies with and without preeclampsia (PE) and to analyse their relationships with perinatal outcomes., Methods: A controlled cross-sectional study was conducted in Maceió, Alagoas, Brazil, that involved pregnant women with PE and a group of women without the disease, through the application of a standardized questionnaire. After delivery, umbilical cord samples were collected to measure antioxidant defense, products from oxidative damage, and inflammation biomarkers such as myeloperoxidase (MPO), interleukin- (IL-) 6, IL-8, IL-10, and tumor necrosis factor-alpha (TNF- α ). Statistical analyses were performed using Stata version 13.0 software and IBM Statistical Package for the Social Sciences (SPSS) 20.0, adopting a 95% confidence level ( α = 0.05), with the chi-square test, the Wilcoxon-Mann-Whitney test, and the multinomial and Poisson regression tests., Results: One hundred PE pregnant women and 50 women without the disease were studied. The umbilical cords from PE pregnancies showed higher levels of reduced glutathione (GSH) ( p ≤ 0.001), glutathione peroxidase (GPx) ( p = 0.016), and malondialdehyde (MDA) ( p = 0.028) and lower levels of IL-6 ( p = 0.030) and TNF- α ( p ≤ 0.001) than the other group, with some associations among these biomarkers with perinatal outcomes., Conclusion: The higher levels of GSH and GPx, in addition to the lower levels of IL-6 and TNF- α , found in the PE umbilical cord, may result from adaptive mechanisms to maintain the oxidative and inflammatory balance; however, despite these changes, the damage to the cell membranes was not minimized, as the MDA level was higher in women with PE than in women without the disease. This implies that a redox imbalance is present, confirming that other physiological and adaptive mechanisms are being activated to preserve foetal health. Therefore, the present work unveils an important role of the umbilical cord in controlling redox imbalance and inflammation in PE pregnancies. Our results reinforce the necessity for continuous research on GSH as a protective compound for the perinatal outcome, especially in PE women., Competing Interests: The authors declare that they have no conflict of interest., (Copyright © 2021 Marilene Brandão Tenório Fragoso et al.)

Introduction: Clinical prediction of foetal inflammatory response syndrome (FIRS) is highly necessary. We have previously reported that miR-4535 and miR-1915-5p are potential biomarkers for severe chorioamnionitis based on the results of microRNA array analysis. Therefore, we evaluated the relationship between foetal morbidity of infection and miR-4535, miR-1915-5p, interleukin (IL)-6, or 16S rDNA copy number levels in amniotic fluid from pregnant women with chorioamnionitis., Methods: Amniotic fluid from 57 pregnant women with preterm premature membrane rupture or threatened premature labour were collected. Infants with WBC counts <5000/μL or >20,000/μL, CRP >0.5 mg/mL, or IgM >20 mg/mL at birth received a diagnosis of suspicious foetal infection, and those requiring antibiotic administration for >5 days were considered infected newborns. miR-4535, miR-1915-5p, and IL-6 levels and 16S rDNA copy number were evaluated. Mann-Whitney U test and Dunn's test were used for comparison. The area under the curve (AUC) and Youden index were calculated to examine the diagnostic accuracy of foetal morbidity of infection., Results: miR-4535, miR-1915-5p, 16S rDNA, and IL-6 were significantly higher in patients with severe chorioamnionitis than in patients with chorionitis or sub-chorionitis (P < 0.05). miR-4535 and miR-1915-5p levels were significantly associated with WBC counts <5000/μL or >20,000/μL, CRP >0.5 mg/mL, or IgM >20 mg/mL (P < 0.05). AUC values of miR-4535 and miR-1915-5p indicated moderate or low accuracy for foetal morbidity of infection, while those of IL-6 and 16S rDNA seemed unreliable., Discussion: MiR-4535 and miR-1915-5p levels in amniotic fluid may be considered clinically predictive for foetal morbidity of infection., 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 © 2021. Published by Elsevier Ltd.)

Abstract: Vomiting in young infants is a common presentation to the pediatric emergency department with a broad differential diagnosis. We present 2 cases seen in our emergency department of infant females with symptomatic complex ovarian cysts who presented with vomiting. The first case study describes a patient with a prenatally diagnosed ovarian cyst that was being followed with serial ultrasounds by general surgery. The second case study describes a patient with reportedly normal prenatal ultrasounds with a subsequent diagnosis of a large complex ovarian cyst. These cases were selected to review pertinent imaging findings, discuss management decisions, and expand the differential of vomiting in the young female infants., Competing Interests: Disclosure: The authors declare no conflict of interest., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Fetal inflammatory response syndrome (FIRS) is strongly associated with neonatal morbidity and mortality and can be classified as type I or type II. Clinically, FIRS type I and type II are considered as distinct syndromes, yet the molecular underpinnings of these fetal inflammatory responses are not well understood because of their low prevalence and the difficulty of postdelivery diagnosis. In this study, we performed RNA sequencing of human cord blood samples from preterm neonates diagnosed with FIRS type I or FIRS type II. We found that FIRS type I was characterized by an upregulation of host immune responses, including neutrophil and monocyte functions, together with a proinflammatory cytokine storm and a downregulation of T cell processes. In contrast, FIRS type II comprised a mild chronic inflammatory response involving perturbation of HLA transcripts, suggestive of fetal semiallograft rejection. Integrating single-cell RNA sequencing-derived signatures with bulk transcriptomic data confirmed that FIRS type I immune responses were mainly driven by monocytes, macrophages, and neutrophils. Last, tissue- and cell-specific signatures derived from the BioGPS Gene Atlas further corroborated the role of myeloid cells originating from the bone marrow in FIRS type I. Collectively, these data provide evidence that FIRS type I and FIRS type II are driven by distinct immune mechanisms; whereas the former involves the innate limb of immunity consistent with host defense, the latter resembles a process of semiallograft rejection. These findings shed light on the fetal immune responses caused by infection or alloreactivity that can lead to deleterious consequences in neonatal life., (Copyright © 2021 The Authors.)

We studied a family in which the first-born child, a girl, had developmental delay, facial dysmorphism, and agenesis of the corpus callosum (ACC). The subsequent pregnancy was interrupted as the fetus was found to be also affected by ACC. Both cases were heterozygous for two KDM5B variants predicting p (Ala635Thr) and p (Ser1155Ala fs Ter4) that were shown to be in trans . KDM5B variants have been previously associated with moderate to severe developmental delay/intellectual disability (DD/ID), autism spectrum disorders (ASD), and dysmorphism in a few individuals, but the pathogenetic mechanisms are not clear yet as patients with both monoallelic and biallelic variants have been observed. Interestingly, one individual has previously been reported with ACC and severe ID in association with biallelic KDM5B variants. Together with the observations in this family, this suggests that agenesis of the corpus callosum may be part of the phenotypic spectrum associated with KDM5B variants and that the KDM5B gene should be included in gene panels to clarify the etiology of ACC both in the prenatal and postnatal setting.

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.

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.

Background: To examine disparities by maternal place of birth in the opportunity to make an informed choice about Down syndrome screening, in France, where the national guidelines recommend that physicians offer it to all pregnant women., Methods: We used population-based data from the nationally representative French Perinatal Surveys in 2010 and 2016 (N=24,644 women) to analyze the opportunity for an informed choice for prenatal screening, measured by a composite indicator., Results: Among the 24 644 women in the study, 20 612 (83.6%) were born in France, 861 (3.5%) elsewhere in Europe, 1550 (6.3%) in North Africa, and 960 (3.9%) in sub-Saharan Africa. The probability of screening was lower for women born outside France. After adjustment for survey year, maternal age, parity, education level, and the maternity unit's level of perinatal care, women born outside France had the opportunity to make an informed choice less often than women born in France. This association remained essentially the same even after excluding women without adequate prenatal care., Conclusions: Women born outside France, including those with adequate prenatal care, had less opportunity than women born in France to make an informed choice about prenatal screening for Down syndrome., (© 2021. The Author(s).)

Aim: To analyze the effectiveness of amniotic fluid neutrophil gelatinase-associated lipocalin and L-type fatty acid-binding protein as predictive factors for fetal inflammatory response syndrome., Methods: We classified single pregnancy cases into the fetal inflammatory response syndrome and nonfetal inflammatory response syndrome groups. We collected amniotic fluid at vaginal delivery and cesarean section and compared the patient characteristics, maternal white blood cell count, C-reactive protein level, and amniotic fluid interleukin-6; neutrophil gelatinase-associated lipocalin; and L-type fatty acid-binding protein levels between the groups. We further analyzed the relationship between L-type fatty acid-binding protein levels and neonatal clinical outcomes., Results: We analyzed 129 pregnancies, of which 36 and 93 (27.9% and 72.1%, respectively) were classified into the fetal inflammatory response syndrome and nonfetal inflammatory response syndrome groups, respectively. We observed significant differences in the maternal white blood cell counts and amniotic fluid interleukin-6 and neutrophil gelatinase-associated lipocalin levels. On the multivariate analysis, the useful predictive factors were maternal white blood cell count and amniotic fluid interleukin-6 and neutrophil gelatinase-associated lipocalin levels. Furthermore, the level of L-type fatty acid-binding protein was significantly higher in the transient tachypnea of the newborn and postnatal respiratory support group than in the control group., Conclusions: The maternal white blood cell count and amniotic interleukin-6 and neutrophil gelatinase-associated lipocalin levels were effective predictors of fetal inflammatory response syndrome. Amniotic fluid L-type fatty acid-binding protein level was an effective predictor of neonatal respiratory support., (© 2021 Japan Society of Obstetrics and Gynecology.)

Competing Interests: Declaration of Competing Interest The authors have indicated they have no potential conflicts of interest to disclose.

Objective: To investigate the predictive value of pre-induction digital examination, sonographic measurements and parity for the prediction of non-reassuring fetal status and cord arterial pH < 7.2 prior to the induction of labor (IOL)., Method: This was a prospective observational study, including 384 term pregnancies undergoing IOL. Before the IOL, the Bishop score (BS) by digital examination, sonographic Doppler parameters and the estimated fetal weight (EFW) was assessed. The fetal cord arterial was sampled to measure the pH at delivery. Multivariate logistic regression analysis was performed to identify independent predictors of non-reassuring fetal status and low cord arterial pH., Results: Forty four cases (11.5%) had non-reassuring fetal status, and 76 cases (19.8%) had fetal cord arterial pH < 7.2. In the non-reassuring fetal status group, the incidence of cord arterial pH < 7.2 was significantly higher than that in the normal fetal heart rate group (χ 2  = 6.401, p = 0.011). Multivariate analysis indicated that significant independent predictors of non-reassuring fetal status were nulliparity (adjusted odds ratio [AOR]: 3.746, p = 0.003), EFW < 10 th percentile (AOR: 3.764, p = 0.003) and cerebroplacental ratio (CPR) < 10 th centile (AOR:4.755, p < 0.001). In the prediction of non-reassuring fetal status, the performance of the combination of nulliparity and EFW < 10th percentile was improved by the addition of CPR < 10th percentile (AUC: 0.681, (95%CI: 0.636 to 0.742) vs 0.756, (95%CI:0.713 to 0.795)), but the difference was not significant (DeLong test: z = 1.039, p = 0.053).. None of the above variables were predictors of cord arterial pH < 7.2., Conclusion: The risk of fetal acidosis has increased in cases of non-reassuring fetal status. Nulliparity, small for gestational age and CPR < 10th centile are independent predictors for non-reassuring fetal status in term fetuses, though the addition of CPR < 10th centile could not significantly improve the screening accuracy.

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: Since 2011, screening maternal blood for cell-free foetal DNA (cffDNA) fragments has offered a robust clinical tool to classify pregnancy as low or high-risk for Down, Edwards, and Patau syndromes. With recent advances in molecular biology and improvements in data analysis algorithms, the screening's scope of analysis continues to expand. Indeed, screening now encompassess additional conditions, including aneuploidies for sex chromosomes, microdeletions and microduplications, rare autosomal trisomies, and, more recently, segmental deletions and duplications called copy number variations (CNVs). Yet, the ability to detect CNVs creates a new challenge for cffDNA analysis in couples in which one member carries a structural rearrangement such as a translocation or inversion., Case Presentation: We report a segmental duplication of the long arm of chromosome 3 and a segmental deletion of the short arm of chromosome 5 detected by cffDNA analysis in a 25-year-old pregnant woman. The blood sample was sequenced on a NextSeq 550 (Illumina) using the VeriSeq NIPT Solution v1 assay. G-band karyotyping in amniotic fluid only detected an abnormality in chromosome 5. Next-generation sequencing in amniocytes confirmed both abnormalities and identified breakpoints in 3q26.32q29 and 5p13.3p15. The foetus died at 21 weeks of gestation due to multiple abnormalities, and later G-band karyotyping in the parents revealed that the father was a carrier of a balanced reciprocal translocation [46,XY,t(3;5)(q26.2;p13)]. Maternal karyotype appeared normal., Conclusion: This case provides evidence that extended cffDNA can detect, in addition to aneuploidies for whole chromosomes, large segmental aneuploidies. In some cases, this may indicate the presence of chromosomal rearrangements in a parent. Such abnormalities are outside the scope of standard cffDNA analysis targeting chromosomes 13, 18, 21, X, and Y, potentially leading to undiagnosed congenital conditions.

Rationale: Fetal alloimmune thrombocytopenia (FAIT) is a serious life-threatening disease caused by platelet-antigen incompatibility between the mother and fetus. FAIT can lead to fetal thrombocytopenia, intracranial hemorrhage (ICH), fetal death and severe neurological disorders after birth. Noninvasive prenatal diagnosis technology has not been widely used in China, and thus few cases of FAIT can be diagnosed prenatally. In this study, we report a case of prenatal diagnosis and treatment of FAIT., Patient Concerns: A 29-year-old female was admitted at 32 weeks' gestational age (GA). Fetal ultrasound at 32 weeks' GA showed a hemorrhagic focus area in the left lateral ventricle and the sign of severe fetal anemia. Hence, fetal umbilical cord puncture was ordered to identify the etiology., Diagnoses: The fetal cord blood test revealed a normal hemoglobin level but severe fetal thrombocytopenia (platelet count, 23 × 109/L). Antibodies of human platelet antigens and human leukocyte antigens between mother and fetus were positive, and thus the diagnosis of FAIT was confirmed., Interventions: The patient refused intravenous immunoglobulin (IVIG) therapy owing to financial consideration. She was treated with dexamethasone acetate tablets (Xianju Company, China) 0.75 mg twice a day until delivery and cesarean section was performed at 34 weeks' GA. The newborn received postnatal anti-platelet antibody treatment., Outcomes: The platelet count of the newborn progressively decreased until the third day after birth and it increased to normal level after postnatal treatment. The neonatal cerebral ultrasound showed the area of hemorrhage was in the process of absorption. During the postnatal one-year follow-up, the neonate showed normal developmental milestones and had no abnormal signs of neurological symptoms., Lessons: For FAIT, the fetal umbilical cord puncture can be carried out by skilled fetal medical teams. Dexamethasone acetate tablets can be an alternative choice for patients from underdeveloped areas., Competing Interests: The authors have no conflicts of interests to disclose., (Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.)

Introduction: The aim of this retrospective cohort study was to determine the potential diagnostic yield of prenatal whole exome sequencing in fetuses with structural anomalies on expert ultrasound scans and normal chromosomal microarray results., Material and Methods: In the period 2013-2016, 391 pregnant women with fetal ultrasound anomalies who received normal chromosomal microarray results, were referred for additional genetic counseling and opted for additional molecular testing pre- and/or postnatally. Most of the couples received only a targeted molecular test and in 159 cases (40.7%) whole exome sequencing (broad gene panels or open exome) was performed. The results of these molecular tests were evaluated retrospectively, regardless of the time of the genetic diagnosis (prenatal or postnatal)., Results: In 76 of 391 fetuses (19.4%, 95% CI 15.8%-23.6%) molecular testing provided a genetic diagnosis with identification of (likely) pathogenic variants. In the majority of cases (91.1%, 73/76) the (likely) pathogenic variant would be detected by prenatal whole exome sequencing analysis., Conclusions: Our retrospective cohort study shows that prenatal whole exome sequencing, if offered by a clinical geneticist, in addition to chromosomal microarray, would notably increase the diagnostic yield in fetuses with ultrasound anomalies and would allow early diagnosis of a genetic disorder irrespective of the (incomplete) fetal phenotype., (© 2020 The Authors. Acta Obstetricia et Gynecologica Scandinavica published by John Wiley & Sons Ltd on behalf of Nordic Federation of Societies of Obstetrics and Gynecology (NFOG).)

The normal fetal heart rate ranges between 110 und 180 beats per minute (bpm). Intrauterine arrhythmias are not an uncommon finding. Fetal echocardiography (ECG) allows for correct diagnosis of the arrhythmia, which is prerequisite for decision making and treatment. Most fetal rhythm disturbances are the result of premature atrial contractions and are of little clinical significance. Intrauterine bradycardias (heart rate < 110 bpm) result from sinus node dysfunction, complete AV block and nonconducted atrial bigeminy. Isolated complete heart block related to maternal anti-SSA/Ro or SSB/La auto-antibodies is irreversible in almost all fetuses. Anti-inflammatory therapy and chronotropic medication may improve outcome. Newborn babies often require pacemaker implantation to augment cardiac output. Intrauterine tachycardias (heart rate > 180 bpm) are most commonly related to supraventricular tachycardia and atrial flutter. Specific antiarrhythmic medication is available to stop the arrhythmia and to prevent hemodynamic deterioration.

To investigate prenatal and postnatal outcomes of atrial flutter and its association with the development of a second tachycardia, following restoration of sinus rhythm, in the fetus or newborn. This study is a retrospective review of all fetuses that presented with atrial flutter from January 2001 to December 2019 at the University Hospital of Wales, Cardiff, UK. The specific type of arrhythmia, its time of appearance and clinical characteristics, echocardiographic findings, medical management, and postnatal outcomes were evaluated. Sixteen fetuses were diagnosed with atrial flutter (AFL). Thirteen fetuses had persistent AFL and three fetuses had intermittent AFL. Seven patients had hydrops, of which one had Ebstein's anomaly and the other six had normal hearts. Three of the fetuses that presented with AFL were diagnosed at 20, 21, and 23 weeks' gestation and the remainder were diagnosed in the third trimester. Thirteen patients with AFL received antiarrhythmic drugs and three were delivered without any treatment. Five fetuses with AFL developed atrioventricular reciprocating tachycardia following DC cardioversion after birth, and four of them exhibited pre-excitation on the ECG. These five patients (31.3%) required postnatal antiarrhythmic treatment for up to 2 years. Pre-excitation disappeared in two patients during follow-up and two asymptomatic patients with neonatal pre-excitation required accessory pathway ablation. Fetal atrial flutter has a strong association with atrioventricular reciprocating tachycardia and ventricular pre-excitation in the neonatal period. Therefore, electrocardiograms should be carefully reviewed in newborns following the initial resolution of atrial flutter.

Advanced imaging techniques are enhancing research capacity focussed on the developmental origins of adult health and disease (DOHaD) hypothesis, and consequently increasing awareness of future health risks across various subareas of DOHaD research themes. Understanding how these advanced imaging techniques in animal models and human population studies can be both additively and synergistically used alongside traditional techniques in DOHaD-focussed laboratories is therefore of great interest. Global experts in advanced imaging techniques congregated at the advanced imaging workshop at the 2019 DOHaD World Congress in Melbourne, Australia. This review summarizes the presentations of new imaging modalities and novel applications to DOHaD research and discussions had by DOHaD researchers that are currently utilizing advanced imaging techniques including MRI, hyperpolarized MRI, ultrasound, and synchrotron-based techniques to aid their DOHaD research focus.

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.)

Optimal placental function is critical for fetal development, and therefore a crucial consideration for understanding the developmental origins of health and disease (DOHaD). The structure of the fetal side of the placental vasculature is an important determinant of fetal growth and cardiovascular development. There are several imaging modalities for assessing feto-placental structure including stereology, electron microscopy, confocal microscopy, micro-computed tomography, light-sheet microscopy, ultrasonography and magnetic resonance imaging. In this review, we present current methodologies for imaging feto-placental vasculature morphology ex vivo and in vivo in human and experimental models, their advantages and limitations and how these provide insight into placental function and fetal outcomes. These imaging approaches add important perspective to our understanding of placental biology and have potential to be new tools to elucidate a deeper understanding of DOHaD.

In-utero vesica-amniotic shunting for fetal lower urinary obstruction (LUTO) is known to improve perinatal survival. More recently, studies including centres performing fetal cystoscopy, have suggested benefit on longer-term survival and renal outcome - within the limitations of small numbers and limited follow-up. These interventions carry significant risk, and therefore patient selection, and optimal timing, are key. The aim of this article is to explore ways of improving the accuracy of prenatal diagnosis, and of identifying risk factors for fetal and postnatal renal failure. The next step is that of using established staging and classification systems to select the patient group that may benefit from intervention, based on published outcomes. Several factors come into play when selecting the timing of intervention, especially if the aim is that of renal, and not only pulmonary, preservation. Lastly, current technologies and their shortfalls are discussed., (Copyright © 2021 Journal of Pediatric Urology Company. Published by Elsevier Ltd. All rights reserved.)

Aim: Cardiotocography is used worldwide to evaluate fetal well-being during pregnancy and labor. In past guidelines, the management plan was determined based on the assessment of the most severe waveform. There are no guidelines for evaluating the integrated recurrent decelerations; however, we believe their assessment to be essential for predicting the status of the fetus. The objective of this study was to propose an indicator for performing medical interventions during labor by creating a scoring system that reflects integrated recurrent decelerations., Methods: In this retrospective cohort study, we included data for only full-term single fetus births from vaginal deliveries. The score named the iPREFACE score (integrated score index to predict fetal acidemia by intrapartum fetal heart rate monitoring) was calculated using cardiotocography findings from continuing 30 min before delivery. We examined the iPREFACE score and fetal acidemia association and calculated the cut-off iPREFACE scores for acidemia using receiver operating characteristic curves., Results: The study included 469 delivery cases. Their iPREFACE scores exhibited a significant negative correlation with the umbilical artery blood pH (correlation coefficient; -0.43). The cut-off iPREFACE scores for the umbilical artery blood with pH <7.20, <7.10 and <7.0 were 44, 46 and 67, respectively (the areas under the curve were 0.776, 0.962 and 0.996, respectively)., Conclusion: The iPREFACE score may predict fetal acidemia and could be used as an indicator for timely medical interventions during labor. Because assessments using a cardiotocography are quick and easy to perform, the iPREFACE score could be a valuable tool in clinical practice., (© 2021 The Authors. Journal of Obstetrics and Gynaecology Research published by John Wiley & Sons Australia, Ltd on behalf of Japan Society of Obstetrics and Gynecology.)

Ruptured diverticula and ventricular aneurysms are rare in the fetus, with a limited number of case reports published previously. Additional fetal complications secondary to these ventricular wall abnormalities can be seen. Interventional measures can be considered and attempted either in utero or postnatally to improve the chance of survival. We present a case of a ruptured diverticulum in a fetus and the clinical course.

Hemophilia is an X-linked recessive bleeding disorder. In pregnant women carrier of hemophilia, the fetal sex can be determined by non-invasive analysis of fetal DNA circulating in the maternal blood. However, in case of a male fetus, conventional invasive procedures are required for the diagnosis of hemophilia. Fetal cells, circulating in the maternal bloodstream, are an ideal target for a safe non-invasive prenatal diagnosis. Nevertheless, the small number of cells and the lack of specific fetal markers have been the most limiting factors for their isolation. We aimed to develop monoclonal antibodies (mAbs) against the ribosomal protein RPS4Y1 expressed in male cells. By Western blotting, immunoprecipitation and immunofluorescence analyses performed on cell lysates from male human hepatoma (HepG2) and female human embryonic kidney (HEK293) we developed and characterized a specific monoclonal antibody against the native form of the male RPS4Y1 protein that can distinguish male from female cells. The availability of the RPS4Y1-targeting monoclonal antibody should facilitate the development of novel methods for the reliable isolation of male fetal cells from the maternal blood and their future use for non-invasive prenatal diagnosis of X-linked inherited disease such as hemophilia.

Introduction: The aim of the present study was to identify possible associations of fetal heart rate (FHR) patterns during the last 2 hours of labor with fetal asphyxia expressed by umbilical artery acidemia at birth and with neonatal complications in a large obstetric cohort., Material and Methods: Cardiotocographic recordings from 4988 singleton term childbirths over 1 year were evaluated retrospectively and blinded to the pregnancy and neonatal outcomes in a university teaching hospital in Helsinki, Finland. Umbilical artery pH, base excess and pO 2 , low Apgar scores at 5 minutes, need for intubation and resuscitation, early neonatal hypoglycemia, and neonatal encephalopathy were used as outcome variables. According to the severity of the neonatal complications at birth, the cohort was divided into three groups: no complications (Group 1), moderate complications (Group 2) and severe complications (Group 3)., Results: Of the 4988 deliveries, the ZigZag pattern (FHR baseline amplitude changes of >25 bpm with a duration of 2-30 minutes) occurred in 11.7%, late decelerations in 41.0%, bradycardia episodes in 52.9%, reduced variability in 36.7%, tachycardia episodes in 13.9% and uterine tachysystole in 4.6%. No case of saltatory pattern (baseline amplitude changes of >25 bpm with a duration of >30 minutes) was observed. The presence of the ZigZag pattern or late decelerations, or both, was associated with cord blood acidemia (odds ratio [OR] 3.3, 95% confidence interval [CI] 2.3-4.7) and severe neonatal complications (Group 3) (OR 3.3, 95% CI 2.4-4.9). In contrast, no significant associations existed between the other FHR patterns and severe neonatal complications. ZigZag pattern preceded late decelerations in 88.7% of the cases. A normal FHR preceded the ZigZag pattern in 90.4% of the cases, whereas after ZigZag episodes, a normal FHR pattern was observed in only 0.9%., Conclusions: ZigZag pattern and late decelerations during the last 2 hours of labor are significantly associated with cord blood acidemia at birth and neonatal complications. The ZigZag pattern precedes late decelerations, and the fact that normal FHR pattern precedes the ZigZag pattern in the majority of the cases suggests that the ZigZag pattern is an early sign of fetal hypoxia, which emphasizes its clinical importance., (© 2020 The Authors. Acta Obstetricia et Gynecologica Scandinavica published by John Wiley & Sons Ltd on behalf of Nordic Federation of Societies of Obstetrics and Gynecology (NFOG).)

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.)

Objectives: Clinical chorioamnionitis at term is considered the most common infection-related diagnosis in labor and delivery units worldwide. The syndrome affects 5-12% of all term pregnancies and is a leading cause of maternal morbidity and mortality as well as neonatal death and sepsis. The objectives of this study were to determine the (1) amniotic fluid microbiology using cultivation and molecular microbiologic techniques; (2) diagnostic accuracy of the clinical criteria used to identify patients with intra-amniotic infection; (3) relationship between acute inflammatory lesions of the placenta (maternal and fetal inflammatory responses) and amniotic fluid microbiology and inflammatory markers; and (4) frequency of neonatal bacteremia., Methods: This retrospective cross-sectional study included 43 women with the diagnosis of clinical chorioamnionitis at term. The presence of microorganisms in the amniotic cavity was determined through the analysis of amniotic fluid samples by cultivation for aerobes, anaerobes, and genital mycoplasmas. A broad-range polymerase chain reaction coupled with electrospray ionization mass spectrometry was also used to detect bacteria, select viruses, and fungi. Intra-amniotic inflammation was defined as an elevated amniotic fluid interleukin-6 (IL-6) concentration ≥2.6 ng/mL., Results: (1) Intra-amniotic infection (defined as the combination of microorganisms detected in amniotic fluid and an elevated IL-6 concentration) was present in 63% (27/43) of cases; (2) the most common microorganisms found in the amniotic fluid samples were Ureaplasma species, followed by Gardnerella vaginalis ; (3) sterile intra-amniotic inflammation (elevated IL-6 in amniotic fluid but without detectable microorganisms) was present in 5% (2/43) of cases; (4) 26% of patients with the diagnosis of clinical chorioamnionitis had no evidence of intra-amniotic infection or intra-amniotic inflammation; (5) intra-amniotic infection was more common when the membranes were ruptured than when they were intact (78% [21/27] vs. 38% [6/16]; p=0.01); (6) the traditional criteria for the diagnosis of clinical chorioamnionitis had poor diagnostic performance in identifying proven intra-amniotic infection (overall accuracy, 40-58%); (7) neonatal bacteremia was diagnosed in 4.9% (2/41) of cases; and (8) a fetal inflammatory response defined as the presence of severe acute funisitis was observed in 33% (9/27) of cases., Conclusions: Clinical chorioamnionitis at term, a syndrome that can result from intra-amniotic infection, was diagnosed in approximately 63% of cases and sterile intra-amniotic inflammation in 5% of cases. However, a substantial number of patients had no evidence of intra-amniotic infection or intra-amniotic inflammation. Evidence of the fetal inflammatory response syndrome was frequently present, but microorganisms were detected in only 4.9% of cases based on cultures of aerobic and anaerobic bacteria in neonatal blood., (© 2020 Walter de Gruyter GmbH, Berlin/Boston.)

Prior to 1970, maternal alloimmunization was the leading cause of perinatal death. Currently, it has become rarer thanks to screening and monitoring in high-risk pregnancies. The advent of transcranial doppler has been a turning point in the monitoring of these pregnancies, as it is a reliable, non-invasive method for the diagnosis of fetal anemia. This helps clinicians decide whether or not to perform intrauterine transfusion. Anti-D immunoprophylaxis has also played an important role in preventing fetal and neonatal hemolytic anemia and its administration is currently well codified. Adequate management helps to avoid the effects of alloimmunization on the fetus and newborn as well as to reduce the risks of alloimmunization in subsequent pregnancies. We here report a case of severe fetomaternal rhesus (Rh) alloimmunization during unmonitored pregnancy complicated by fetoplacental anasarca., Competing Interests: Les auteurs ne déclarent aucun conflit d'intérêts., (Copyright: Sara Ait Souabni et al.)

Bardet-Biedl syndrome (BBS) is a rare ciliopathic human genetic disorder with mainly an autosomal recessive inheritance. BBS phenotype develops over the years and diagnosis is usually made in late childhood or early adulthood. Prenatal diagnosis is rare in the absence of family history or consanguinity. We present a prenatal case without a family history of inherited diseases or consanguinity. Mid-trimester ultrasound revealed hyperechogenic kidneys and postaxial polydactyly putting us on track of BBS. The fetopathology supported this diagnosis and the whole-exome sequencing confirmed the hypothesis. Our case illustrates how high-resolution obstetric scan, detailed observation of fetal features and application of gene sequencing technology contribute to elucidate the aetiology of rare, yet disabling and incurable disease, with the particular setting of negative family history., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Competing Interests: Competing interests: None declared.

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.