Abstract Background Omphalocele is a congenital defect of the abdominal wall with high morbidity and high practice variation. Evidence based guidance on its management is currently absent. The European Reference Network for Rare Inherited and Congenital Anomalies (ERNICA) developed this guideline to aid clinical decision-making. Methods This guideline was developed in accordance with the Guidelines 2.0 checklist and GRADE methodology. After a bottleneck analysis and prioritization, a systematic review of the literature and critical appraisal of the evidence was performed. Additionally, registry data from the European Pediatric Surgery Audit (EPSA) was provided in clinical questions for which published evidence was scarce. The Evidence to Decision framework was used as a guide to structure the consensus meetings and draft the recommendations. Results The panel developed 12 recommendations on the following topics: Genetic screening, mode of delivery, prognostic factors, enteral feeding and ventilation during staged reduction, type of closure and timing of surgery in giant and non-giant omphalocele. The panel weighed up the benefits and harms, informed by all relevant arguments and expert opinion, to decide on a recommendation. The supplementary data from the EPSA contributed to the panel’s decision on a recommendation in four topics. Conclusion This guideline provides recommendations for the perinatal care of patients with omphalocele. These recommendations support clinicians in making care decisions and help inform families about treatment options and relevant considerations. This guideline will be revised every five years to ensure it remains up to date.

INTRODUCTION:The validity of hypertensive disorders of pregnancy (HDP), including preeclampsia, gestational hypertension, and chronic hypertension, is essential for both clinical management and research. The Swedish Pregnancy Register automatically retrieves diagnostic codes based on the Swedish version of the International Classification of Diseases 10th revision (ICD-10), as recorded in antenatal, obstetric, and neonatal electronic medical records. The aim of the study was, for the first time, to assess the validity of HDP diagnoses within the Swedish Pregnancy Register in a contemporary population. MATERIAL AND METHODS:A multicenter validation study of women with deliveries from 2021 to 2023 who participated in the prospective Swedish study for Improving Maternal Pregnancy And Child ouTcomes (IMPACT) cohort. Women with a HDP diagnosis in the Swedish Pregnancy Register were retrospectively validated through standardized reviews of electronic medical records. The gold standard for classification followed the Swedish guidelines from the Swedish Society of Obstetrics and Gynecology (SFOG), updated in 2019. Incidence, sensitivity, and positive predictive value (PPV) were calculated and reported with 95% confidence intervals (CIs), using the Wilson score method. In addition, the study includes a descriptive analysis of preeclampsia disease characteristics and clinical diagnostic practices. RESULTS:Among 7443 women included in the validation study, 843 (11.3%, 95% CI 10.6-12.1) had a HDP diagnosis recorded in the Swedish Pregnancy Register and underwent validation. Within the study population, the register-based incidence of preeclampsia was 5.0% (95% CI 4.5-5.5%), while the minimum validated incidence was 5.1% (95% CI 4.6-5.6). The positive predictive value (PPV) of register diagnoses was 79.0% (95% CI 74.5-82.8%) for preeclampsia, 72.8% (95% CI 68.2-76.9%) for gestational hypertension, and 49.3% (95% CI 38.3-60.4%) for chronic hypertension, yielding an overall PPV for any hypertensive disorder of pregnancy diagnosis of 73.4% (95% CI 70.3-76.3%). Among validated cases of preeclampsia, 78% had proteinuria and the remaining cases were classified as preeclampsia based on other organ dysfunctions. CONCLUSIONS:In this contemporary Swedish cohort, a diagnosis of preeclampsia recorded in the Swedish Pregnancy Register demonstrated good validity, comparable to that reported in previous Nordic register validation studies.

We study the introduction of a noninvasive prenatal screening-cell-free DNA (cfDNA) screening-which is used to target a more costly invasive test that elevates miscarriage risk. Using Swedish administrative data, we document that coverage of cfDNA substantially increases cfDNA screening and reduces invasive testing. We develop and estimate a stylized model of prenatal choices and find that narrow targeting of cfDNA coverage can improve outcomes and reduce costs, while broader coverage also improves outcomes but with increased costs. These findings point to the potential gains from well-designed targeting of screening but at the same time highlight the importance of the targeting design.

Approximately 200 genetic skeletal disorders can present prenatally, detectable through ultrasound abnormalities during pregnancy. Severe forms are typically identified during the first or second trimester, whereas milder phenotypes are recognized later, in the third trimester. Diagnosing skeletal dysplasia prenatally is challenging due to the large number of disorders and the overlapping clinical findings that can be detected by ultrasound. This study, conducted at Karolinska University Hospital between 2015 and 2022, examines the genetic and radiographic findings in 32 fetuses (14 female and 18 male, from unrelated families) with skeletal abnormalities detected on prenatal ultrasound and confirmed by radiographs at birth or after pregnancy termination. Fetal DNA samples from all 32 fetuses underwent singleton genome sequencing using an in silico skeletal dysplasia gene panel. As a second step, for six fetuses with molecularly unsolved diagnoses, trio genome sequencing analysis involving the fetus and both parents was performed. The diagnostic yield of genome sequencing was 72%, with pathogenic or likely pathogenic variants identified in 23 of the 32 fetuses. Additionally, four variants of uncertain significance, strongly suspected to be causative based on clinical and radiographic features, as well as structural protein analyses, were identified in four fetuses with autosomal recessive conditions. The diagnoses of five fetuses remain molecularly unsolved. In conclusion, by combining detailed phenotypic data with singleton genome sequencing we were able to reach a genetic diagnosis in 72% of 32 fetal genetic skeletal disorder cases investigated at the Karolinska University Hospital.

The European Reference Network for rare Inherited Congenital Anomalies, ERNICA, guidelines for gastroschisis cover perinatal period to help teams to improve care. A systematic literature search including 136 publications was conducted. Research findings were assessed following the GRADE methodology. The evidence to decision framework was used to determine the strength and direction of recommendations. The mode or timing of delivery do not impact neonatal mortality, risk of NEC or time on parenteral nutrition (PN). Intra or extra abdominal bowel dilatation predict complex gastroschisis and longer length of hospital stay but not increased perinatal mortality. Outcomes after Bianchi procedure and primary fascia closure under anesthesia are similar. Sutureless closure decreases the rate of surgical site infections and duration of ventilation compared to surgical closure. Silo-staged closure with or without intubation results in similar outcomes. Outcomes of complex gastroschisis (CG) undergoing early or delayed surgical repair are similar. Early enteral feeds starting within 14 days is associated with lower risk of surgical site infection. The panel suggests vaginal birth between 37 and 39 w in cases of uncomplicated gastroschisis. Bianchi’s approach is an option in simple gastroschisis. Sutureless closure is suggested when general anesthesia can be avoided, sutured closure. If anesthesia is required. Silo treatment without ventilation and general anesthesia can be considered. In CG with atresia primary intestinal repair can be attempted if the condition of patient and intestine allows. Enteral feeds for simple gastroschisis should start within 14 days.

Objective Congenital Diaphragmatic Hernia (CDH) associated with hydrops is rare. The aim of this study was to describe the incidence of this combination of anomalies and the postnatal outcomes from a large database for CDH.Study design Data from the multicenter, multinational database on infants with prenatally diagnosed CDH (CDHSG Registry) born from 2015 to 2021 were analyzed.Results A total of 3985 patients were entered in the registry during the study period, 3156 were prenatally diagnosed and 88 were reported to have associated fluid in at least 1 compartment, representing 2.8% of all prenatally diagnosed CDH cases in the registry. The overall survival to discharge for CDH patients with hydrops was 43%. The hydropic CDH group had lower birth weight and gestational age at birth, and increased incidence of right-sided CDH (55%), and rate of non-repair (45%). However, the survival rate for hydropic infants with CDH undergoing surgical repair was 80%. Other associated anomalies were more common in hydropic CDH (50% vs 37%, p = 0.001).Conclusion Hydropic CDH is rare, only 2.8% of all prenatally diagnosed cases, and more commonly occurring in right-sided CDH. Survival rates are low, with higher rates of non-repair. However, decision-making regarding goals of care and an aggressive surgical approach in selected cases may result in survival rates comparable to non-hydropic cases.

ABSTRACT Objective To investigate the diagnostic yield of trio whole‐genome sequencing (WGS) in fetuses with various congenital malformations referred to a tertiary center for prenatal diagnosis. Methods In this prospective study, 50 pregnancies with different congenital malformations, negative for trisomies and causative copy‐number variants, were analyzed further with fetal–parental trio WGS analysis. Parents were eligible for inclusion if they accepted further investigation following the detection of isolated or multiple malformations on prenatal ultrasound. Cases with isolated increased nuchal translucency, gamete donation or multiple pregnancy were excluded. WGS with the Illumina Inc. 30× polymerase‐chain‐reaction‐free short‐read sequencing included analysis of single‐nucleotide variants, insertions and deletions, structural variants, short tandem repeats and copy‐number identification of SMN1 and SMN2 genes. Results A molecular diagnosis was achieved in 13/50 (26%) cases. Causative sequence variants were identified in 12 genes: FGFR3 ( n = 2), ACTA1 ( n = 1), CDH2 ( n = 1), COL1A2 ( n = 1), DHCR7 ( n = 1), EYA1 ( n = 1), FBXO11 ( n = 1), FRAS1 ( n = 1), L1CAM ( n = 1), OFD1 ( n = 1), PDHA1 ( n = 1) and SOX9 ( n = 1). The phenotypes of the cases were divided into different groups, with the following diagnostic yields: skeletal malformation (4/9 (44%)), multisystem malformation (3/7 (43%)), central nervous system malformation (5/15 (33%)) and thoracic malformation (1/10 (10%)). Additionally, two cases carried variants that were considered potentially clinically relevant, even though they were assessed as variants of uncertain significance, according to the guidelines provided by the American College of Medical Genetics and Genomics. Overall, we identified a causative or potentially clinically relevant variant in 15/50 (30%) cases. Conclusions We demonstrate a diagnostic yield of 26% with clinical WGS in prenatally detected congenital malformations. This study emphasizes the benefits that WGS can bring to the diagnosis of fetal structural anomalies. It is important to note that causative chromosomal aberrations were excluded from our cohort before WGS. As chromosomal aberrations are a well‐known cause of prenatally detected congenital malformations, future studies using WGS as a primary diagnostic test, including assessment of chromosomal aberrations, may show that the detection rate exceeds the diagnostic yield of this study. WGS can add clinically relevant information, explaining the underlying cause of the fetal anomaly, which will provide information concerning the specific prognosis of the condition, as well as estimate the risk of recurrence. A genetic diagnosis can also provide more reproductive choice for future pregnancies. © 2024 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Congenital diaphragmatic hernia (CDH) is a severe birth defect frequently associated with pulmonary hypoplasia, pulmonary hypertension, and heart failure. Since amniotic fluid comprises proteins of both fetal and maternal origin, its analysis could provide insights on mechanisms underlying CDH and provide biomarkers for early diagnosis, severity of pulmonary changes and treatment response. The study objective was to identify proteomic changes in amniotic fluid consistently associated with CDH. Amniotic fluid was obtained at term (37–39 weeks) from women with normal pregnancies (n = 5) or carrying fetuses with CDH (n = 5). After immuno-depletion of the highest abundance proteins, off-line fractionation and high-resolution tandem mass spectrometry were performed and quantitative differences between the proteomes of the groups were determined. Of 1036 proteins identified, 218 were differentially abundant. Bioinformatics analysis showed significant changes in GP6 signaling, in the MSP–RON signaling in macrophages pathway and in networks associated with cardiovascular system development and function, connective tissue disorders and dermatological conditions. Differences in selected proteins, namely pulmonary surfactant protein B, osteopontin, kallikrein 5 and galectin-3 were validated by orthogonal testing using ELISA in larger cohorts and showed statistically significant differences aiding in the diagnosis and prediction of CDH. The findings provide potential tools for clinical management of CDH.

Background The aim of this study was to describe the incidence of Congenital Diaphragmatic Hernia, CDH, associated with known or clinically suspected syndromes, and the postnatal outcomes from a large database for CDH.Methods Data from the multicenter, multinational database on infants with CDH (Congenital Diaphragmatic Hernia Study Group Registry) born from 1996 to 2020 were analyzed. Patients with known or suspected syndromes were grouped and outcome data were analyzed and compared to those without syndromic features.Results A total of 12,553 patients were entered in the registry during the study period, and 421 had reported known syndromes, representing 3.4% of all CDH cases in the registry. A total of 50 different associated syndromes were reported. In addition to those with clinically suspected genetic conditions, a total rate of genetic syndromes with CDH was 8.2%. The overall survival to discharge for syndromic CDH was 34% and for non-syndromic CDH was 76.7%. The most common were syndromes Fryns syndrome (19.7% of all syndromes, 17% survival), trisomy 18 or Edward syndrome (17.5%, 9% survival), trisomy 21 or Down syndrome (9%, 47% survival), trisomy 13 or Patau syndrome (6.7%, 14% survival), Cornelia de Lange syndrome (6.4% of all syndromes, 22% survival) and Pallister-Killian syndrome (5.5% of all syndromes, 39.1% survival). In addition, 379 cases had reported chromosomal anomalies and 233 cases had clinically suspected syndromes, based on two more dysmorphic features or malformations in addition to CDH, but without molecular diagnosis.Conclusion Syndromic CDH is rare and only 3.4% of the reported cases of CDH have a known syndrome or association, but, if including patients with two dysmorphic features malformations, in addition to CDH, altogether as many as 8.2% have a diagnosed or suspected genetic condition. These children have with lower survival rates. Given higher rates of non-repair and decreased extracorporeal life support use, along with a high early mortality, decision-making regarding goals of care clearly influences outcomes. Survival varies depending on the genetic cause. Early genetic diagnosis is important and may influence the decision-making.

Risk evaluation for preeclampsia in early pregnancy allows identification of women at high risk. Prediction models for preeclampsia often include circulating concentrations of placental growth factor (PlGF); however, the models are usually limited to a specific PlGF method of analysis. The aim of this study was to compare three different PlGF methods of analysis in a Swedish cohort to assess their convergent validity and appropriateness for use in preeclampsia risk prediction models in the first trimester of pregnancy.

ABSTRACTObjectiveTo investigate the diagnostic yield of clinical whole‐genome sequencing (WGS) in prenatally diagnosed non‐immune hydrops fetalis (NIHF).MethodsThis was a retrospective study of 23 fetuses with prenatally diagnosed NIHF, negative for trisomies and copy‐number variants, referred for analysis by WGS with an in‐silico panel of 281 genes associated with hydrops fetalis. Due to identification of a high proportion of causative variants in the HRAS gene in the main cohort, Sanger sequencing of HRAS was performed in a replication cohort, consisting of 24 additional fetuses with NIHF that were negative for trisomies and copy‐number variants and had not undergone WGS.ResultsOf the 23 fetuses in the main cohort, a molecular diagnosis was achieved in 12 (52.2%). Pathogenic or likely pathogenic variants were identified in seven genes: HRAS (n = 5), RIT1 (n = 2), FOXP3 (n = 1), GLB1 (n = 1), MAP2K1 (n = 1), PTPN11 (n = 1) and RASA1 (n = 1). The inheritance pattern of the 12 causative variants was autosomal dominant in 10 cases (HRAS, MAP2K1, PTPN11, RASA1, RIT1), autosomal recessive in one (GLB1) and X‐linked recessive in one (FOXP3). Of the 24 fetuses in the replication cohort, a pathogenic variant in HRAS was identified in one, resulting in an overall frequency of causative HRAS variants of 12.8% (6/47) in our two cohorts.ConclusionsWe demonstrate a diagnostic yield of 52% with clinical WGS in NIHF using an in‐silico panel of 281 genes. However, the high diagnostic yield may be attributed to the small sample size and possible over‐representation of severe phenotypes in the included fetuses. Bearing in mind that chromosomal abnormalities were excluded in our cohorts, a detection rate of up to 75% is possible in prenatally diagnosed NIHF when WGS analysis includes calling of chromosomal aberrations. © 2022 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Linked article: This Correspondence comments on Westenius et al. Click here to view the article.

Background: The natural history of congenital pulmonary airway malformations (CPAM) and bronchopul-monary sequestrations (BPS) is not fully understood, and the management of the newborn with an asymptomatic lesion is a controversial issue. We aimed to study the natural history and outcome of CPAM/BPS at our institution with a policy of watchful waiting, and to investigate if any prognostic factors in the pre-and/or postnatal-period may predict the need for surgery.Material and methods: A retrospective review study was conducted of children prenatally diagnosed with CPAM and/or BPS during the 18-year period, from 2002 to 2020. Data from the pre and postnatal period was collected and analysed.Results: Sixty-six patients with prenatally observed lung lesions were entered in the study, with an overall survival rate of 94%. Fifty-six percent of the lesions decreased in size during gestation. Thirty-one percent had surgery and 69% could be managed conservatively with a median follow-up of 4 years. Nineteen percent developed symptoms after the neonatal period. Children with a presence of mediasti-nal shift on postnatal imaging ( p = 0.003), with a high CVR ( p = 0.005) and a large lesion size during gestation ( p = 0.014) were significantly more likely to require surgery.Conclusion: Prenatal regression is common among prenatally diagnosed CPAM/BPS and the majority of children that are asymptomatic beyond the neonatal period will remain asymptomatic throughout their childhood. Future analysis with a longer follow-up might give new insights in order to identify children at risk of developing symptoms. Level of evidence: III (c) 2022 Published by Elsevier Inc.

Skeletal ciliopathies are a heterogenous group of disorders with overlapping clinical and radiographic features including bone dysplasia and internal abnormalities. To date, pathogenic variants in at least 30 genes, coding for different structural cilia proteins, are reported to cause skeletal ciliopathies. Here, we summarize genetic and phenotypic features of 34 affected individuals from 29 families with skeletal ciliopathies. Molecular diagnostic testing was performed using massively parallel sequencing (MPS) in combination with copy number variant (CNV) analyses and in silico filtering for variants in known skeletal ciliopathy genes. We identified biallelic disease-causing variants in seven genes: DYNC2H1, KIAA0753, WDR19, C2CD3, TTC21B, EVC, and EVC2. Four variants located in non-canonical splice sites of DYNC2H1, EVC, and KIAA0753 led to aberrant splicing that was shown by sequencing of cDNA. Furthermore, CNV analyses showed an intragenic deletion of DYNC2H1 in one individual and a 6.7 Mb de novo deletion on chromosome 1q24q25 in another. In five unsolved cases, MPS was performed in family setting. In one proband we identified a de novo variant in PRKACA and in another we found a homozygous intragenic deletion of IFT74, removing the first coding exon and leading to expression of a shorter message predicted to result in loss of 40 amino acids at the N-terminus. These findings establish IFT74 as a new skeletal ciliopathy gene. In conclusion, combined single nucleotide variant, CNV and cDNA analyses lead to a high yield of genetic diagnoses (90%) in a cohort of patients with skeletal ciliopathies.

To investigate the natural history and need for postnatal surgery in pregnancies and children with congenital pulmonary airway malformation (CPAM). A retrospective review of all children with a diagnosis of CPAM evaluated at the Department of Pediatric Surgery from 2002–2020. Data from pre- and postnatal variables were assessed to determine the natural history of the condition and to predict the need for postnatal surgery. Median follow-up time of children was 39 (3–144) months. A total of 74 cases of CPAM were identified. The cohort consisted of 60 CCAMs, nine bronchopulmonary sequestrations and five hybrid lesions. There was one intrauterine death and one neonatal and infant death respectively resulting in an overall survival of 96%. There were 65 children (88%) with a prenatal diagnosis and nine (12%) detected postnatally. In the prenatal group, 35 (54%) lesions decreased in size during pregnancy and in 18 (28%) the malformation was not detectable on ultrasound in the third trimester. 4/74 (5%) children had associated anomalies, 3/65 (7%) polyhydramniosis and one child developed hydrops. A mediastinal shift was observed in 42% of cases and 11/65 (17%) were given steroids to avoid progression to hydrops. Only symptomatic children, in total 28 (38%) with respiratory distress, pneumothorax or infections were managed surgically at a median age of 3.5 months. A large lesion pre- or postnatally and mediastinal shift postnatally were significantly associated with the need for surgery. 25% of children born with CPAM developed symptoms or the lesion expanded following the neonatal period. No malignancies were observed. A majority of CPAM lesions will undergo regression during pregnancy and 75% will remain asymptomatic after the neonatal period. Only a third will require surgery but require long-term follow-up. Further studies are warranted to identify predictive factors and identify children at risk of symptom development to reduce complications and avoid overtreatment.

Objectives To determine the detection rates of all types of chromosome aberrations and the residual risk for postnatal diagnosis of an atypical chromosome aberration depending on the strategy for further investigation with either noninvasive prenatal testing (NIPT) or invasive testing in pregnancies with increased risk following combined first-trimester screening (cFTS). Methods A review of all pregnancies examined with cFTS during 2010 to 2017. Results The cohort consisted of 129 493 pregnancies. There were 852 (0.7%) clinically significant chromosome aberrations, including aberrations detected later on or after birth. A total of 12% were atypical chromosome aberrations. Considering that 40% were detected due to a miscarriage/intrauterine fetal death or a malformation on ultrasound there is a 0.05% (1:2000) background risk of a postnatal diagnosis of a liveborn child with an atypical chromosome aberration if no further invasive test is performed during pregnancy. If all women with an increased risk (>= 1:200) had an invasive test and NIPT was performed up to a risk of 1:1000, 95% of common trisomies/sex chromosome aberrations and 55% of atypical aberrations would be detected. Conclusions If NIPT was offered to all women with an increased risk following cFTS it would imply that three times as many children would be born with an atypical chromosome aberration.