A randomised controlled trial of amnioexchange for fetal gastroschisis.

OBJECTIVE: Morbidity in fetuses affected by gastroschisis is mainly the result of bowel ischaemic and inflammatory processes. Experimental studies on animal models show that clearing amniotic fluid from the digestive secretions by amnioexchange procedures reduces the inflammatory process. We evaluated the benefit of the amnioexchange procedure for fetal gastroschisis in humans. DESIGN: Prospective, interventional, randomised study. SETTING: Eight referral centres for fetal medicine. POPULATION: Pregnant women carrying a fetus with gastroschisis. METHODS: We compared, in utero, amnioexchange with a sham procedure. The protocol included, in both arms, steroid injections at 30 weeks of gestation and the use of postnatal minimal enteral feeding. MAIN OUTCOME MEASURES: The primary outcome was a composite variable based on the duration of ventilation and parenteral nutrition. Secondary outcomes were the effectiveness and safety of the amnioexchange procedure, including the rate of perinatal death, time to full enteral feeding, primary closure, and late feeding disorders. RESULTS: Sixty-four patients were randomised. There was no difference in the composite criteria between the amnioexchange and control groups. Based on an intention-to-treat analysis, there were no significant between-group differences in pregnancy outcome or complications. When studying the relationship between digestive compounds and amniotic fluid inflammatory markers, a clear correlation was found between bile acid and both ferritin and interleukin 1ß (IL1ß). CONCLUSIONS: In humans, amnioexchange, as described in our protocol, is not an option for fetal care; however, we provide supplementary proof of the involvement of inflammation in the pathogenicity of gastroschisis and suggest that future research should aim at reducing inflammation. ClinicalTrials.gov: NCT00127946. TWEETABLE ABSTRACT: A prospective, interventional, randomised study shows no benefit of amnioexchange for fetal gastroschisis in humans.

Maintenance of methylation profile in imprinting control regions in human induced pluripotent stem cells.

BACKGROUND: Parental imprinting is an epigenetic mechanism that leads to monoallelic expression of a subset of genes depending on their parental origin. Imprinting disorders (IDs), caused by disturbances of imprinted genes, are a set of rare congenital diseases that mainly affect growth, metabolism and development. To date, there is no accurate model to study the physiopathology of IDs or test therapeutic strategies. Human induced pluripotent stem cells (iPSCs) are a promising cellular approach to model human diseases and complex genetic disorders. However, aberrant hypermethylation of imprinting control regions (ICRs) may appear during the reprogramming process and subsequent culture of iPSCs. Therefore, we tested various conditions of reprogramming and culture of iPSCs and performed an extensive analysis of methylation marks at the ICRs to develop a cellular model that can be used to study IDs. RESULTS: We assessed the methylation levels at seven imprinted loci in iPSCs before differentiation, at various passages of cell culture, and during chondrogenic differentiation. Abnormal methylation levels were found, with hypermethylation at 11p15 H19/IGF2:IG-DMR and 14q32 MEG3/DLK1:IG-DMR, independently of the reprogramming method and cells of origin. Hypermethylation at these two loci led to the loss of parental imprinting (LOI), with biallelic expression of the imprinted genes IGF2 and DLK1, respectively. The epiPS™ culture medium combined with culturing of the cells under hypoxic conditions prevented hypermethylation at H19/IGF2:IG-DMR (ICR1) and MEG3/DLK1:IG-DMR, as well as at other imprinted loci, while preserving the proliferation and pluripotency qualities of these iPSCs. CONCLUSIONS: An extensive and quantitative analysis of methylation levels of ICRs in iPSCs showed hypermethylation of certain ICRs in human iPSCs, especially paternally methylated ICRs, and subsequent LOI of certain imprinted genes. The epiPS™ culture medium and culturing of the cells under hypoxic conditions prevented hypermethylation of ICRs in iPSCs. We demonstrated that the reprogramming and culture in epiPS™ medium allow the generation of control iPSCs lines with a balanced methylation and ID patient iPSCs lines with unbalanced methylation. Human iPSCs are therefore a promising cellular model to study the physiopathology of IDs and test therapies in tissues of interest.

How can we improve perinatal care in isolated multiple intestinal atresia? A retrospective study with a 30-year literature review.

INTRODUCTION: Multiple intestinal atresia (MIA) is a rare cause of neonatal intestinal obstruction. To provide an overview of the current prenatal, surgical, and nutritional management of MIA, we report our experience and a literature review of papers published after 1990. METHODS: All cases of isolated MIA (non-hereditary, not associated with apple-peel syndrome or gastroschisis) treated at our institution between 2005 and 2016 were reviewed and compared with cases found in the literature. RESULTS: Seven patients were prenatally suspected of having intestinal obstruction and were postnatally diagnosed with MIA, with a mean 1.7 (1-2) resections-anastomoses (RA) and 6 (1-10) strictureplasties performed, resulting in a mean resected bowel length of 15.1cm (15-25 cm). Median time to full oral feed was 46 days (14-626 days). All patients were alive and none had orality disorder after a mean follow-up of 3.1 years (0.2-8.1 years). Three surgical strategies were found in the literature review: multiple RA (68%, 34/50) including Santulli's technique in four of 34 (12%) and anastomoses over a transanastomotic tube (32%, 16/50), with a 98% survival rate, and short-bowel syndrome for only two patients. CONCLUSION: Bowel-sparing surgery and appropriate medical management are key to ensuring a favorable nutritional and gastrointestinal outcome and a good prognosis. Prenatal assessment and standardization of the surgical course of treatment remain challenging.

[Repeat doses of prenatal corticosteroids for women at risk of preterm birth: a difficult consensus]. / Répétition des cures de corticoïdes chez les femmes à risque d'accouchement prématuré: un consensus difficile.

A single course of antenatal corticosteroids in women at risk of preterm delivery reduces the risk of neonatal mortality and morbidity. Recent experimental and clinical studies have stated early, medium and long term consequences of single or repeated courses of antenatal corticosteroids. Betamethasone and dexamethasone are the two molecules usually used. Benefits are observed until the first 24 hours after the first injection. Single-course corticosteroids are not effective in babies born more than 7 days after initial treatment. Benefits of corticosteroids were evaluated between 22 and 35 weeks of gestation. Antenatal exposure to single-course betamethasone might result in disruption on glucose metabolism in adult offspring. Weekly courses of prenatal corticosteroids therapy are not recommended. Repeat prenatal corticosteroids given to women at continuing risk of preterm birth 7 or more days after an initial course reduced the inherent respiratory complications of prematurity and improved health outcomes of preterm infants. However, adverse outcomes have been reported concerning cognitive development. Although repeat course may have short term benefits, whether there are effects on health into childhood and beyond must await later assessment. Long term data are needed to recommend repeated courses.

[Ontogenesis of glucose regulation in neonate and consequences in neonatal management]. / Ontogenèse de la régulation glycémique et conséquences pour la prise en charge du nouveau-né.

Glucose homeostasis during fetal life depends entirely on continuous placental glucose transfer. Fetal endocrine milieu is characterized by high insulin which has mainly anabolic action. During third trimester, insulin promotes energetic stores as glycogen and fat deposition. At birth, constant maternal supply is interrupted and this is accompanied by a surge in glucagon and catecholamine levels and a decrease in insulin level. These hormonal changes induce hepatic glucose production provided by glycogenolysis during the first hours of life and then by gluconeogenesis. They also promote lipolysis which generates glycerol, a gluconeogenic substrate and free fatty acids. Free fatty acids provide gluconeogenesis activating factors and ketone bodies which represent alternative fuels for brain metabolism. Equilibrium between tissue consumption of glucose, hepatic glucose production and exogenous glucose supply maintains blood glucose level. If one of these mechanisms fails, hypoglycaemia may occur. Hypoglycaemia is predictable in three situations: depletion of energetic stores (prematurity and intra-uterine growth restriction), increase tissue energetic consumption and fetal hyperinsulinism. Blood glucose levels at which clinical interventions should be considered depend on operational thresholds. Therapeutic goal in case of hypoglycaemia is to increase blood glucose enhancing gluconeogenesis and providing continuous brain supply with glucose and ketone bodies. Paradoxically, many preterm infants less than 30 gestational weeks develop hyperglycaemia. There is evidence that processing of proinsulin in beta-cells is deficient and that preterm infants are partially resistant to insulin. Exogenous insulin infusion is efficient and may be used with caution.

[Antenatal treatment of congenital diaphragmatic hernia: an update]. / Traitement anténatal de la hernie de coupole diaphragmatique: le point en 2008.

Despite advances in neonatal care, the associated mortality in isolated congenital diaphragmatic hernia remains in the order of 30%. Death is mainly due to consecutive pulmonary hypoplasia and severe associated pulmonary hypertension. This statement led to the implement of fetal therapy in order to improve fetal lung development. The first phase of fetal surgery consisted in open repair with one-stage surgical correction of the anatomic defect. It was followed by tracheal occlusion technique based on the decrease egress of lung fluid in order to improve lung growth. Initial approach of tracheal occlusion used clips on the trachea. It is now performed with intra-tracheal inflatable balloon. The challenge of such prenatal treatment is to establish accurate prenatal prognosis factors in order to offer this therapeutic in the subgroup of patients in whom outcome of postnatal treatment remains dismal. Current factors used for prenatal prognosis evaluation are thoracic liver position and lung-to-head ratio (LHR). The balloon is inserted at 26 to 28 weeks and removed at 34 weeks. First results are encouraging. However, many patients developed premature prelabour rupture of the membrane and paediatric data are sparse. Only few patients were currently treated and long term evaluation is needed. A powered multicentric study is needed to determine the value of fetal tracheal occlusion in the management of fetuses with isolated severe congenital diaphragmatic hernia.

Antenatal antipsychotic exposure induces multigenerational and gender-specific programming of adiposity and glucose tolerance in adult mouse offspring.

Second-generation antipsychotics (SGAs) are well known for their metabolic side effects in humans, including obesity and diabetes. These compounds are maintained during pregnancy to prevent the relapse of psychoses, but they readily diffuse across the placenta to the fetus, as documented with the widely-prescribed drug olanzapine (OLZ). However, observational studies have provided conflicting results on the potential impact of SGAs on fetal growth and body weight, and their effects on metabolic regulation in the offspring. For this reason, our study has tested whether antenatal exposure of CD1 mice to OLZ influenced metabolic outcomes in the offspring of the first (F1) and second (F2) generations. In F1 mice, OLZ antenatal treatment caused a decrease in neonatal body weight in both genders, an effect that persisted throughout life only in male animals. Interestingly, F1 female mice also displayed altered glucose homoeostasis. F2 mice, generated by mating normal males with F1 female mice exposed to OLZ during antenatal life, exhibited higher neonatal body weights which persisted only in F2 female animals. This was associated with expansion of fat mass and a concordant pattern of adipose tissue gene expression. Moreover, male and female F2 mice were glucose-intolerant. Thus, our study has demonstrated that antenatal OLZ exposure induces multigenerational and gender-specific programming of glucose tolerance in the offspring mice as adults, and points to the need for careful monitoring of children exposed to SGAs during pregnancy.

[Premedication before tracheal intubation in French neonatal intensive care units and delivery rooms]. / Sédation-analgésie avant intubation trachéale en réanimation néonatale et en salle de naissance: pratiques en France métropolitaine.

UNLABELLED: Tracheal intubation is a painful procedure commonly used in the neonatal intensive care units and in the delivery rooms. It can be complicated by changes in vital signs. OBJECTIVE: To ascertain the use of sedatives and/or analgesics before tracheal intubation in French neonatal intensive care units and delivery rooms. METHODS: A survey by questionnaire sent to 58 neonatal intensive care units and 58 maternities. RESULTS: We obtained 46 responses (79,3%) from the neonatal intensive care units and 38 (65,5%) from the delivery rooms. In neonatal intensive care units, 74% of the newborns received a sedative and/or an analgesic before being intubated, and 60% of the units had specific written guidelines. Opioïds and benzodiazepines were the main drugs used. In the delivery rooms, sedatives or analgesics were only used in 21% of the centres. CONCLUSION: The use of sedation-analgesia seems to improve in neonatology but is still insufficient in the delivery rooms. The development of specific guidelines and a best learning about the different drugs are necessary.

[Determinants of diphemanil methylsulfate (Prantal) utilization: a survey of practice in the French neonatal and intensive care units]. / Enquête française sur l'utilisation du diphémanil méthylsulfate (Prantal) dans les unités de néonatologie.

UNLABELLED: Diphemanil methylsulfate (Prantal) is a quaternary ammonium with parasympathicolytic properties. It is used in premature and term neonates with bradycardias related to vagal hyper reflectivity (HRV). OBJECTIVES: To assess the use of Prantal in the French neonatal and intensive care units: its indications, its modalities of use, its side effects and the number of patients treated during 1 year (2004) in France. METHODS: A questionnaire was electronically sent to all neonatology units and all neonatal intensive care units in France. RESULTS: Among 202 units, 121 (60%) answered the questionnaire. Prantal was reported to be used in 51 (42.1%) units. Among them, 38 (31.4%) actually treated 169 patients in 2004 with a mean number of patients treated by unit of 4. The diagnostic of HRV was supported by: a history of malaise (84.3%), bradycardia (94.1%), oculocardiac reflex (74.5%), cardiac Holter (76.4%), cardiorespirographic recording (19.6%), esophageal pHmetry (35.2%) and esophageal fibroscopy (21.5%). The mean starting dosing was 4.7 mg/kg/d, the mean maximal dosing was 9 mg/kg/d and the mean daily intakes were initially 2.3 and secondary 2.9. Prantal dosing was adjusted to weight in 54.9%, every month in 85.7%. Treatment was stopped at the mean post-natal age of 6 months, mostly in a progressive manner and without monitoring help. CONCLUSION: Prantal was seldom used in 2004 in France for different reasons: HRV is an uncertain entity, the efficacy of Prantal has not been validated and atropinic side effects can be encountered.

[G6PD deficiency in females with neonatal revelation. Report of four cases]. / Déficit en G6PD chez la fille à révélation néonatale. Revue de 4 cas cliniques.

Glucose-6-phosphate dehydrogenase (G6PD) deficiency is the most common human erythrocyte enzyme defect, estimated to affect approximately 4 million people worldwide. It is associated with severe neonatal hyperbilirubinemia, which may lead to bilirubin encephalopathy and kernicterus, and with hemolytic crisis. G6PD deficiency is an X-linked enzymopathy affecting hemizygous males, homozygous females, and also a subset of heterozygous females via chromosome X inactivation. We report four cases of female newborns with neonatal hyperbilirubinemia related to a G6PD deficiency and followed by the Centre national de référence en hémobiologie périnatale (CNRHP) from November 2013 to July 2014. Clinical and biological characteristics suggested G6PD deficiency (jaundice observed within the first 24h, severe hyperbilirubinemia, associated with regenerative hemolytic anemia, low response to phototherapy, ethnic origin of the parents from high-incident geographical regions). The family investigations revealed a deficit in G6PD in one of the parents who was unaware of this deficit until then. This article aims to make neonatologists and pediatricians aware of the need to search for an etiology for any severe hyperbilirubinemia and to raise G6PD deficiency in male and female newborns in case of hyperbilirubinemia with hemolysis.

[Congenital cytomegalovirus infection manifesting as neonatal respiratory distress in an HIV-exposed uninfected newborn]. / Pneumopathie congénitale à cytomégalovirus chez un nouveau-né à terme né de mère séropositive pour le VIH.

BACKGROUND: Cytomegalovirus (CMV) is one of the most common intrauterine infections, affecting approximately 1% of all live births. There are few reports on congenital CMV infections manifesting as isolated pneumonitis. CASE REPORT: We report a case of congenital CMV with neonatal respiratory distress affecting an HIV-exposed uninfected infant. This infant required noninvasive ventilation beginning within the first 15min of life. The initial chest X-ray showed diffuse bilateral ground-glass opacifications. Bacterial infection, meconium aspiration and hyaline membrane disease were excluded. Salivary quantitative CMV PCR was positive (2,342,261IU/mL) and serum viral load for CMV was low (476IU/mL). Bronchoalveolar lavage (BAL) performed on day 12 for quantitative CMV PCR was significantly positive (1,045,942IU/mL). Intravenous ganciclovir treatment was started on day 14 (7.5mg/kg/12h) for 2 weeks and oral valganciclovir (15mg/kg/12h) was given for 4 weeks afterwards. Ventilatory support was stopped on day 18. HIV serum viral load was negative on day 30. DISCUSSION: Congenital CMV infection can present as isolated pneumonitis with persistent neonatal respiratory symptoms, emphysematous lung disease, or persistent pulmonary hypertension. If this diagnosis is suspected, and even if CMV viremia remains low, BAL with quantitative CMV PCR must be performed to ascertain the diagnosis and indicate antiviral treatment. HIV-exposed uninfected infants have higher rates of congenital CMV infection when the mother's CD4 rate is<200/mm3. Most cases of CMV transmission in HIV-exposed uninfected infants have occurred by maternal endogenous reactivation or reinfection.

Endothelial dysfunction in individuals born after fetal growth restriction: cardiovascular and renal consequences and preventive approaches.

Individuals born after intrauterine growth restriction (IUGR) have an increased risk of perinatal morbidity/mortality, and those who survive face long-term consequences such as cardiovascular-related diseases, including systemic hypertension, atherosclerosis, coronary heart disease and chronic kidney disease. In addition to the demonstrated long-term effects of decreased nephron endowment and hyperactivity of the hypothalamic-pituitary-adrenal axis, individuals born after IUGR also exhibit early alterations in vascular structure and function, which have been identified as key factors of the development of cardiovascular-related diseases. The endothelium plays a major role in maintaining vascular function and homeostasis. Therefore, it is not surprising that impaired endothelial function can lead to the long-term development of vascular-related diseases. Endothelial dysfunction, particularly impaired endothelium-dependent vasodilation and vascular remodeling, involves decreased nitric oxide (NO) bioavailability, impaired endothelial NO synthase functionality, increased oxidative stress, endothelial progenitor cells dysfunction and accelerated vascular senescence. Preventive approaches such as breastfeeding, supplementation with folate, vitamins, antioxidants, L-citrulline, L-arginine and treatment with NO modulators represent promising strategies for improving endothelial function, mitigating long-term outcomes and possibly preventing IUGR of vascular origin. Moreover, the identification of early biomarkers of endothelial dysfunction, especially epigenetic biomarkers, could allow early screening and follow-up of individuals at risk of developing cardiovascular and renal diseases, thus contributing to the development of preventive and therapeutic strategies to avert the long-term effects of endothelial dysfunction in infants born after IUGR.

Delayed surgery in pericardial teratoma with neonatal hydrops.

Timing of neonatal surgery in cases of pericardial teratoma with hydrops is not standardised. We report two cases of hydropic premature newborns with pericardial teratoma in which surgery was delayed until respiratory and haemodynamic stabilisation. Mature teratoma was removed on day 3. The newborns were weaned from the ventilator on postoperative day 5 and 10, respectively. Both infants were doing well at 18 months, suggesting delayed surgery may be feasible and effective.

The offspring of the diabetic mother--short- and long-term implications.

In the 1980s, David Barker and Colleagues proposed that the major causes of cardiovascular and metabolic diseases have their roots in early development. There is now robust evidence that an hyperglycemic intrauterine environment is responsible not only for significant short-term morbidity in the fetus and the neonate but also for an increased risk of developing diabetes as well as other chronic, noncommunicable diseases at adulthood. The risk is higher in pregestational diabetes, but unrecognized and/or poorly managed gestational diabetes (GDM) may have similar consequences. Although a relatively clear picture of the pathogenesis of the fetal and neonatal complications of maternal diabetes and of their interrelationship is available today, the intimate molecular mechanisms involved in the long term are far from being understood. While the rate of GDM is sharply increasing in association with the pandemic of obesity and of type 2 diabetes over the world, we review here the current understanding of short- and long-term outcomes of fetuses exposed to a diabetic environment.

[Oxidative stress after preterm birth: origins, biomarkers, and possible therapeutic approaches]. / Stress oxydant chez l'enfant prématuré : causes, biomarqueurs et possibilités thérapeutiques.

The survival of preterm babies has increased over the last few decades. However, disorders associated with preterm birth, known as oxygen radical diseases of neonatology, such as retinopathy, bronchopulmonary dysplasia, periventricular leukomalacia, and necrotizing enterocolitis are severe complications related to oxidative stress, which can be defined by an imbalance between oxidative reactive species production and antioxidant defenses. Oxidative stress causes lipid, protein, and DNA damage. Preterm infants have decreased antioxidant defenses in response to oxidative challenges, because the physiologic increase of antioxidant capacity occurs at the end of gestation in preparation for the transition to extrauterine life. Therefore, preterm infants are more sensitive to neonatal oxidative stress, notably when supplemental oxygen is being delivered. Furthermore, despite recent advances in the management of neonatal respiratory distress syndrome, controversies persist concerning the oxygenation saturation targets that should be used in caring for preterm babies. Identification of adequate biomarkers of oxidative stress in preterm infants such as 8-iso-prostaglandin F2α, and adduction of malondialdehyde to hemoglobin is important to promote specific therapeutic approaches. At present, no therapeutic strategy has been validated as prevention or treatment against oxidative stress. Breastfeeding should be considered as the main measure to improve the antioxidant status of preterm infants. In the last few years, melatonin has emerged as a protective molecule against oxidative stress, with antioxidant and free-radical scavenger roles, in experimental and preliminary human studies, giving hope that it can be used in preterm infants in the near future.

Regulated expression of mature human insulin in the liver of transgenic mice.

Transgenic mice expressing either human proinsulin cDNA or mutated proinsulin cDNA in the liver were created. The human proinsulin cDNA was mutated to generate a protein cleavable by the ubiquitous prohormone convertase furin, thus leading to mature insulin peptide. All transgenic lines expressed human C-peptide in the blood, whose level varied according to nutritional conditions. High performance liquid chromatography fractionation of mouse serum revealed that mutant proinsulin was effectively processed into mature insulin in vivo. This transgenic mouse model provides a useful tool for further prospects of gene therapy of insulin-dependent diabetes mellitus.

[Enteral nutrition for the preterm infant: which maternal milk supplement?]. / Nutrition entérale du préterme: quelle(s) supplémentation(s) pour le lait de femme?

Different types of human milks are given to preterm newborns (mother and bank milk). Their effect on neonatal growth is recalled. The usefulness and justification of dietetic supplements as well as appropriate quantities and practical aspects are discussed.