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Background: Multiple pregnancy is a known predisposing factor for sagittal suture synostosis, and intrauterine constraint has been suggested as a potential cause. This study evaluates prenatal images of single and multiple pregnancies of children with sagittal suture synostosis to assess the possible pathogenesis. Materials and Methods: Prenatal ultrasound data of scaphocephaly twins treated at Erasmus MC was retrieved retrospectively. The head circumference, cephalic index (CI), and biparietal diameter (BPD) were analyzed. Data were compared with the nonaffected sibling, singletons with scaphocephaly, and to general fetal growth reference values. Results: Data of 8 twin pregnancies with 10 cases of scaphocephaly was gathered. For the head circumference no difference was found between affected fetuses and reference values throughout pregnancy. For the BPD a reduced growth was found, compared with control values. The growth curve for the CI of the affected twins is lower from the start and declines over time. When comparing affected fetuses to nonaffected fetuses, the same differences for the BPD and CI were found as compared with controls. No differences in growth parameters were found between the nonaffected siblings and reference values, nor between the affected scaphocephaly twins and singletons with scaphocephaly. Conclusions: Scaphocephaly in twin pregnancy develops early on in pregnancy, similar to singleton pregnancy, making the theory of constraint as a cause less likely. The development of scaphocephaly in twins is likely to be attributed to the same disturbed developmental processes in suture development as in singletons, and not to mechanical constraint.

Objectives: To describe the outcomes of preterm born infants with congenital diaphragmatic hernia (CDH; ≤32.0 weeks of gestation) and the associations between prenatal imaging markers and survival. Design: Retrospective cohort study. Setting: Multicentre study in large referral centres. Population: Infants with an isolated unilateral CDH, live born at 32.0 weeks or less of gestation, between January 2009 and January 2020. Methods: Neonatal outcomes were evaluated for infants that were expectantly managed during pregnancy and infants that underwent fetoscopic endoluminal tracheal occlusion (FETO) therapy, separately. We evaluated the association between prenatal imaging markers and survival to discharge. Prenatal imaging markers included observed to expected lung-to-head ratio (o/e LHR), side of the defect, liver position, stomach position grade, and observed to expected total fetal lung volume (o/e TFLV). Main Outcome Measure: Survival to discharge. Results: We included 53 infants born at 30 +4 (interquartile range 29 +1–31 +2) weeks. Survival in fetuses expectantly managed during pregnancy was 48% (13/27) in left-sided CDH and 33% (2/6) in right-sided CDH. Survival in fetuses that underwent FETO therapy was 50% (6/12) in left-sided CDH and 25% (2/8) in right-sided CDH. The o/e LHR at baseline was positively associated with survival in cases expectantly managed during pregnancy (odds ratio [OR] 1.20, 95% CI 1.07–1.42, p < 0.01), but not in cases that received FETO therapy (OR 1.01, 95% CI 0.88–1.15, p = 0.87). Stomach position grade (p = 0.03) and o/e TFLV were associated with survival (p = 0.02); liver position was not (p = 0.13). Conclusions: In infants with CDH born at or before 32 weeks of gestation, prenatal imaging markers of disease severity were associated with postnatal survival.

OBJECTIVE: To examine the association between prenatal stomach position (SP) grade and stomach volume (SV) and the need for pulmonary hypertension (PH) treatment after birth in prenatally diagnosed left-sided congenital diaphragmatic hernia (CDH), live born >34 weeks.METHODS: In retrospect, SP grade and SV were determined in fetuses with isolated left-sided CDH from 19 weeks gestational age (GA) onwards at three different time periods (≤24 weeks' GA: US1, 24-30 weeks' GA: US2; ≥30 weeks' GA: US3). Primary outcome was need for treatment of PH after birth. Secondary analyses included the predictive value of SP and SV for other respiratory outcomes and postnatal defect size.RESULTS: A total of 101 fetuses were included. SP grade was significantly associated with need for treatment of PH (US1, US2, and US3: p < 0.02). Also, prenatal SP grade was positively associated with defect size and development of chronic lung disease (CLD) in survivors. No association was found between SV and respiratory morbidities or postnatal defect size.CONCLUSION: SP grade in left-sided CDH fetuses is associated with an increased need for PH treatment, a larger postnatal defect size and CLD in survivors. We consider SP determination a valuable contribution to the prenatal assessment of left-sided CDH.

Previous studies have frequently reported neurocognitive deficits in children born with congenital diaphragmatic hernia (CDH) at school age, which may contribute to academic difficulties. Yet, age at onset of these deficits is currently unknown. We evaluated neurocognitive skills with possible determinants in preschool children born with CDH. Eligible 5-year-old children born with CDH (2010-2015) who participated in our prospective structural follow-up program were included. We used the WPPSI-III to assess intelligence, subtests of the Kaufman-ABC for memory, and NEPSY-II to assess inhibition and attention. We included 63 children. Their test scores generally were within or significantly above normal range: total IQ = 103.4 (15.7) (p = 0.13); Verbal memory = 10.2 (2.8) (p = 0.61); Visuospatial memory = 11.4 (2.6) (p 0.01); Inhibition = 10.5 (2.2), (p = 0.10). In univariable analyses, length of ICU-stay was negatively associated with IQ, and maximum vasoactive inotropic score and open repair were negatively associated with inhibition skills. In multivariable regression analysis, the latter association remained (B = 5.52, p = 0.04 (CI 0.32-10.72)). Conclusions: In these tested 5-year-old children born with CDH, neuropsychological outcome was normal on average. While problems in 8-year-olds are common, we did not detect onset of these problems at age 5. Yet, we cannot rule out that this cohort had a relatively mild level of disease severity; therefore, conclusions should be interpreted with caution. However, given the growing-into-deficit hypothesis, meaning that deviant brain development in early life is revealed once higher cognitive brain functions are demanded, follow-up should be conducted up to school age, and preferably beyond. What is Known: • Children born with CDH are at risk for academic difficulties at school age. • Whether these difficulties can be detected already before school age is unknown. What is New: • At age 5 years, intelligence, inhibition, attention, and memory skills were all within normal range, or even above, in children with CDH. This is supportive of the growing-into-deficit hypothesis in this patient population. • Those who underwent open surgical correction had poorer inhibition skills than those who were corrected with minimal access surgery.

Congenital diaphragmatic hernia (CDH) is a congenital structural anomaly in which the diaphragm has not developed properly. It may occur either as an isolated anomaly or with additional anomalies. It is thought to be a multifactorial disease in which genetic factors could either substantially contribute to or directly result in the developmental defect. Patients with aneuploidies, pathogenic variants or de novo Copy Number Variations (CNVs) impacting specific genes and loci develop CDH typically in the form of a monogenetic syndrome. These patients often have other associated anatomical malformations. In patients without a known monogenetic syndrome, an increased genetic burden of de novo coding variants contributes to disease development. In early years, genetic evaluation was based on karyotyping and SNP-array. Today, genomes are commonly analyzed with next generation sequencing (NGS) based approaches. While more potential pathogenic variants are being detected, analysis of the data presents a bottleneck—largely due to the lack of full appreciation of the functional consequence and/or relevance of the detected variant. The exact heritability of CDH is still unknown. Damaging de novo alterations are associated with the more severe and complex phenotypes and worse clinical outcome. Phenotypic, genetic—and likely mechanistic—variability hampers individualpatient diagnosis, short and long-term morbidity prediction and subsequent care strategies. Detailed phenotyping, clinical follow-up at regular intervals and detailed registries are needed to find associations between long-term morbidity, genetic alterations, and clinical parameters. Since CDH is a relatively rare disorder with only a few recurrent changes large cohorts of patients are needed to identify genetic associations. Retrospective whole genome sequencing of historical patient cohorts using will yield valuable data from which today's patients and parents will profit Trio whole genome sequencing has an excellent potential for future re-analysis and data-sharing increasing the chance to provide a genetic diagnosis and predict clinical prognosis. In this review, we explore the pitfalls and challenges in the analysis and interpretation of genetic information, present what is currently known and what still needs further study, and propose strategies to reap the benefits of genetic screening.

Objective To assess the predictive value of observed-to-expected lung-to-head ratio (O/E LHR) for survival and chronic lung disease (CLD) in survivors of left-sided congenital diaphragmatic hernia (CDH) in an era of standardized neonatal treatment, and to evaluate the predictive value of the O/E LHR trajectory for survival. Methods This retrospective cohort study was performed in two high-volume CDH centers in the Netherlands in prenatally detected, isolated left-sided CDH patients born between 2008 and 2014. O/E LHR and liver position were determined using 2D-ultrasonography at three time points during gestation from 19 weeks onwards. Ultrasound measurements were performed on stored ultrasound data by one single experienced operator blinded to postnatal outcome. Results Of the 122 included cases, 77.9% survived of whom 38.9% developed CLD. A significant association was found between the first measured O/E LHR and survival and development of CLD in survivors. Prenatal liver position did not have additional predictive value. No significant association was found between the trajectory of the O/E LHR and survival. Conclusion In an era of standardized neonatal treatment for neonates with CDH, the first measured O/E LHR per patient significantly predicts survival and development of CLD in survivors in isolated left-sided CDH infants. © 2017 The Authors. Prenatal Diagnosis published by John Wiley & Sons, Ltd.

BACKGROUND: Congenital diaphragmatic hernia (CDH) is a rare congenital anomaly with a mortality of ∼27%. The Congenital Diaphragmatic Hernia Study Group (CDHSG) developed a simple postnatal clinical prediction rule to predict mortality in newborns with CDH. Our aim for this study is to externally validate the CDHSG rule in the European population and to improve its prediction of mortality by adding prenatal variables. METHODS: We performed a European multicenter retrospective cohort study and included all newborns diagnosed with unilateral CDH who were born between 2008 and 2015. Newborns born from November 2011 onward were included for the external validation of the rule (n = 343). To improve the prediction rule, we included all patients born between 2008 and 2015 (n = 620) with prenatally diagnosed CDH and collected pre- and postnatal variables. We build a logistic regression model and performed bootstrap resampling and computed calibration plots. RESULTS: With our validation data set, the CDHSG rule had an area under the curve of 79.0%, revealing a fair predictive performance. For the new prediction rule, prenatal herniation of the liver was added, and absent 5-minute Apgar score was taken out. The new prediction rule revealed good calibration, and with an area under the curve of 84.6%, it had good discriminative abilities. CONCLUSIONS: In this study, we externally validated the CDHSG rule for the European population, which revealed fair predictive performance. The modified rule, with prenatal liver herniation as an additional variable, appears to further improve the model’s ability to predict mortality in a population of patients with prenatally diagnosed CDH.

Objective To determine the predictive value of the fetal omphalocele circumference/abdominal circumference (OC/AC) ratio for type of surgical closure and survival and to describe the trajectory of OC/AC ratio throughout gestation. Methods This cohort study included all live‐born infants prenatally diagnosed with an omphalocele in our tertiary centre (2000–2017) with an intention to treat. The OC/AC ratio and liver position were determined using 2D ultrasound at three periods during gestation (11–16, 17–26, and/or 30–38 weeks). Primary outcome was type of closure; secondary outcome was survival. In the secondary analyses, the predictive value of the OC/AC‐ratio trend for type of closure and survival was assessed. Results Primary closure was performed in 37/63 (59%) infants, and 54/63 (86%) survived. The OC/AC ratio was predictive for type of closure and survival in all periods. Optimal cut‐off values for predicting closure decreased throughout gestation from 0.69 (11–16 weeks) to 0.63 (30–38 weeks). Repeated OC/AC‐ratio measurements were available in 33 (73%) fetuses. The trend of the OC/AC ratio throughout gestation was not significantly associated with type of closure. All infants without liver herniation underwent primary closure. Conclusion Type of omphalocele surgical closure and survival can be predicted prenatally on the basis of the OC/AC ratio and liver herniation independent of associated anomalies. Learning objective The reader will be able to use the OC/AC ratio throughout gestation in all omphalocele cases for prediction of type of closure and survival and thus patient counselling., What's already known about this topic? In fetuses with an isolated omphalocele, the OC/AC ratio is less than 24 weeks; gestation is of predictive value for postnatal type of closure. What does this study add? The OC/AC ratio is predictive for type of surgical closure and survival in all fetuses with an omphalocele.This report is the first concerning the trend of the OC/AC ratio throughout gestation.The OC/AC ratio best predicts type of closure and survival in the third trimester of pregnancy.

ObjectivesTo compare the prenatal frame of reference of omphalocele (ie, survival of fetuses) with that after birth (ie, survival of liveborn neonates), and to assess physical growth and neurodevelopment in children with minor or giant omphalocele up to 2 years of age.DesignWe included fetuses and neonates diagnosed in 2000–2012. Physical growth (SD scores, SDS) and mental and motor development at 12 and 24 months were analysed using general linear models, and outcomes were compared with reference norms. Giant omphalocele was defined as defect ≥5 cm, with liver protruding.ResultsWe included 145 fetuses and neonates. Of 126 (87%) who were diagnosed prenatally, 50 (40%) were liveborn and 35 (28%) survived at least 2 years. Nineteen (13%) neonates were diagnosed after birth. Of the 69 liveborn neonates, 52 (75%) survived and 42 children (81% of survivors) were followed longitudinally. At 24 months, mean (95% CI) height and weight SDS were significantly below 0 in both minor (height: −0.57 (−1.05 to –0.09); weight: −0.86 (−1.35 to –0.37)) and giant omphalocele (height: −1.32 (−2.10 to –0.54); weight: −1.58 (−2.37 to –0.79)). Mental development was comparable with reference norms in both groups. Motor function delay was found significantly more often in children with giant omphalocele (82%) than in those with minor omphalocele (21%, P=0.002).ConclusionsThe prenatal and postnatal frames of reference of omphalocele differ considerably; a multidisciplinary approach in parental counselling is recommended. As many children with giant omphalocele had delayed motor development, we recommend close monitoring of these children and early referral to physical therapy.

Introduction: To evaluate differences between consultants of different disciplines in the prenatal prediction of the type of postnatal surgical closure of an omphalocele. Material and Methods: Twenty-one images of prenatally detected omphaloceles prior to 24 weeks of gestation were included. A standardized form provided known prenatal information and an ultrasound image for each case. Nineteen consultants were asked to assess the probability of primary closure of an omphalocele and to state which information was the most important for their assessment. Results: Primary closure (13/21 images) was predicted correctly in 5/13 images. The number of correct predictions per image ranged from 63 to 89%. The type of closure was predicted correctly in 7/8 images of cases which were not closed primarily, ranging from 58 to 84% correct predictions per image. There was no significant difference between consultants of different disciplines. Individual accuracy ranged from 10 to 62%. The consultants regarded omphalocele content as the most important information (34%) for counseling. Discussion: The consultants did not differ in their prenatal judgment of the primary closure of an omphalocele. The consultants tended to be too negative in their assessment, since 75% assessed the probability of primary closure overall to be

Objective To assess the predictive value of observed‐to‐expected lung‐to‐head ratio (O/E LHR) for survival and chronic lung disease (CLD) in survivors of left‐sided congenital diaphragmatic hernia (CDH) in an era of standardized neonatal treatment, and to evaluate the predictive value of the O/E LHR trajectory for survival. Methods This retrospective cohort study was performed in two high‐volume CDH centers in the Netherlands in prenatally detected, isolated left‐sided CDH patients born between 2008 and 2014. O/E LHR and liver position were determined using 2D‐ultrasonography at three time points during gestation from 19 weeks onwards. Ultrasound measurements were performed on stored ultrasound data by one single experienced operator blinded to postnatal outcome. Results Of the 122 included cases, 77.9% survived of whom 38.9% developed CLD. A significant association was found between the first measured O/E LHR and survival and development of CLD in survivors. Prenatal liver position did not have additional predictive value. No significant association was found between the trajectory of the O/E LHR and survival. Conclusion In an era of standardized neonatal treatment for neonates with CDH, the first measured O/E LHR per patient significantly predicts survival and development of CLD in survivors in isolated left‐sided CDH infants. © 2017 The Authors. Prenatal Diagnosis published by John Wiley & Sons, Ltd.