Congenital diaphragmatic hernia survival in an English regional ECMO center.

Introduction: Congenital diaphragmatic hernia (CDH) remains a cause of neonatal death. Our aims are to describe contemporary rates of survival and the variables associated with this outcome, contrasting these with our study of two decades earlier and recent reports. Materials and methods: A retrospective review of all infants diagnosed in a regional center between January 2000 and December 2020 was performed. The outcome of interest was survival. Possible explanatory variables included side of defect, use of complex ventilatory or hemodynamic strategies (inhaled nitric oxide (iNO), high-frequency oscillatory ventilation (HFOV), extracorporeal membrane oxygenation (ECMO), and Prostin), presence of antenatal diagnosis, associated anomalies, birth weight, and gestation. Temporal changes were studied by measuring outcomes in each of four consecutive 63-month periods. Results: A total of 225 cases were diagnosed. Survival was 60% (134 of 225). Postnatal survival was 68% (134 of 198 liveborn), and postrepair survival was 84% (134 of 159 who survived to repair). Diagnosis was made antenatally in 66% of cases. Variables associated with mortality were the need for complex ventilatory strategies (iNO, HFOV, Prostin, and ECMO), antenatal diagnosis, right-sided defects, use of patch repair, associated anomalies, birth weight, and gestation. Survival has improved from our report of a prior decade and did not vary during the study period. Postnatal survival has improved despite fewer terminations. On multivariate analysis, the need for complex ventilation was the strongest predictor of death (OR=50, 95% CI 13 to 224, p<0.0001), and associated anomalies ceased to be predictive. Conclusions: Survival has improved from our earlier report, despite reduced numbers of terminations. This may be related to increased use of complex ventilatory strategies.

Mosaicism in Hartsfield syndrome.

Hartsfield syndrome is a rare condition characterised by the co-occurrence of ectrodactyly and holoprosencephaly spectrum disorders; cleft lip and palate is a common associated feature. This is due to either monoallelic, or less commonly, biallelic variants in FGFR1 with a loss of function or dominant negative effect. To date 37 individuals have been reported, including two instances of germline mosaicism. We report a further family with Hartsfield syndrome due to a novel variant in FGFR1, with two affected fetuses, and somatic and germline mosaicism in the father detected on Sanger sequencing. The father had not come to medical attention prior to this finding. In light of our findings and those in the published literature, we suggest that mosaicism, either germline or germline and somatic, may be a relatively frequent finding, affecting 3 of 35 (9%) reported families, which has important implications for genetic counselling.

International Consensus Statement on the diagnosis, multidisciplinary management and lifelong care of individuals with achondroplasia.

Achondroplasia, the most common skeletal dysplasia, is characterized by a variety of medical, functional and psychosocial challenges across the lifespan. The condition is caused by a common, recurring, gain-of-function mutation in FGFR3, the gene that encodes fibroblast growth factor receptor 3. This mutation leads to impaired endochondral ossification of the human skeleton. The clinical and radiographic hallmarks of achondroplasia make accurate diagnosis possible in most patients. However, marked variability exists in the clinical care pathways and protocols practised by clinicians who manage children and adults with this condition. A group of 55 international experts from 16 countries and 5 continents have developed consensus statements and recommendations that aim to capture the key challenges and optimal management of achondroplasia across each major life stage and sub-specialty area, using a modified Delphi process. The primary purpose of this first International Consensus Statement is to facilitate the improvement and standardization of care for children and adults with achondroplasia worldwide in order to optimize their clinical outcomes and quality of life.

Epidemiology, natural history, progression, and postnatal outcome of severe fetal ventriculomegaly.

OBJECTIVE: To estimate the prevalence, associated anomalies, progression, and clinical outcome in fetuses prenatally diagnosed with severe ventriculomegaly. METHODS: This is a population-based study using prospectively collected data from the north of England. Data were obtained from the Northern Congenital Abnormality Survey for the period 1994-2008. Associated anomalies were categorized using the European Surveillance of Congenital Anomalies guidelines. Differences between isolated and nonisolated ventriculomegaly were examined using Fisher's exact test or Mann-Whitney U test. RESULTS: There were 157 cases of confirmed severe ventriculomegaly in singleton pregnancies among 441,247 eligible births, a prevalence of 3.6 per 10,000 births (95% confidence interval [CI] 3.0-4.2). Chromosomal anomalies were detected prenatally in five cases (3.2%, 95% CI 1.0-7.3) and associated structural anomalies in 67 (42.7%, 95% CI 34.8-50.8). One hundred one women (64.3%) elected to have a termination of pregnancy, more commonly in the presence of associated anomalies (76.9% compared with 51.9%, P=.001). Ultrasonographic follow-up data were available for 53 fetuses; in 13 cases (24.5%), atrium size decreased prenatally, whereas in the remainder, median atrium size increased by 4.1 mm over 3.5 weeks. Associated anomalies were detected postnatally in 22 of 79 cases suspected prenatally to be isolated (27.8%, 95% CI 18.3-39.1). Of 53 live births, there were 11 (20.8%) neonatal deaths, including six (16.2%) of the isolated group. Neonatal death was not predicted by atrial measurement progression. CONCLUSION: The prevalence of severe ventriculomegaly was 3.6 per 10,000 births. Although more than 50% opt to terminate, of those with live births, there were 21% neonatal deaths with nearly half in neonates with isolated ventriculomegaly.

Effect of tumour necrosis factor-α in combination with interferon-γ on first trimester extravillous trophoblast invasion.

Successful pregnancy is dependent upon invasion of the uterine tissues by extravillous trophoblast cells (EVT). The mechanisms that control trophoblast invasion are unclear, but several cytokines and growth factors appear to be involved. We have previously demonstrated that IFN-γ inhibits EVT invasion via a mechanism partially dependent on an increase in EVT apoptosis and decreased secretion of matrix metalloproteinase (MMP)-2. In the current study we show that TNF-α, both alone and in combination with IFN-γ, inhibits EVT invasion via a mechanism associated with increased trophoblast apoptosis, decreased trophoblast proliferation and/or altered production of active proteases. TNF-α and its receptors, TNF-αRI and TNF-αRII, were immunolocalised in the placental bed. Uterine natural killer (uNK) cells, EVT and villous cytotrophoblast were shown to all produce TNF-α, and TNF-α receptors were primarily immunolocalised to EVT in the placental bed. TNF-α increased EVT apoptosis, decreased villous cytotrophoblast proliferation and increased expression of pro-MMP-9 (but not active MMP-9), urokinase plasminogen activator (uPA) and plasminogen activator inhibitor (PAI)-1 by EVT. The combination of TNF-α and IFN-γ inhibited EVT via a mechanism associated with increased EVT apoptosis, reduced proliferation, reduced pro-MMP-2 secretion and increased secretion of uPA. TNF-α is one of several decidua-derived factors with the capacity to inhibit EVT invasion. The mode of activity of TNF-α was modified by the presence of IFN-γ, suggesting that the local cytokine milieu may be critical in determining spatial and/or temporal changes in EVT invasion.