Neonatal outcomes for women at risk of preterm delivery given half dose versus full dose of antenatal betamethasone: a randomised, multicentre, double-blind, placebo-controlled, non-inferiority trial.

BACKGROUND: Antenatal betamethasone is recommended before preterm delivery to accelerate fetal lung maturation. However, reports of growth and neurodevelopmental dose-related side-effects suggest that the current dose (12 mg plus 12 mg, 24 h apart) might be too high. We therefore investigated whether a half dose would be non-inferior to the current full dose for preventing respiratory distress syndrome. METHODS: We designed a randomised, multicentre, double-blind, placebo-controlled, non-inferiority trial in 37 level 3 referral perinatal centres in France. Eligible participants were pregnant women aged 18 years or older with a singleton fetus at risk of preterm delivery and already treated with the first injection of antenatal betamethasone (11·4 mg) before 32 weeks' gestation. We used a computer-generated code producing permuted blocks of varying sizes to randomly assign (1:1) women to receive either a placebo (half-dose group) or a second 11·4 mg betamethasone injection (full-dose group) 24 h later. Randomisation was stratified by gestational age (before or after 28 weeks). Participants, clinicians, and study staff were masked to the treatment allocation. The primary outcome was the need for exogenous intratracheal surfactant within 48 h after birth. Non-inferiority would be shown if the higher limit of the 95% CI for the between-group difference between the half-dose and full-dose groups in the primary endpoint was less than 4 percentage points (corresponding to a maximum relative risk of 1·20). Four interim analyses monitoring the primary and the secondary safety outcomes were done during the study period, using a sequential data analysis method that provided futility and non-inferiority stopping rules and checked for type I and II errors. Interim analyses were done in the intention-to-treat population. This trial was registered with ClinicalTrials.gov, NCT02897076. FINDINGS: Between Jan 2, 2017, and Oct 9, 2019, 3244 women were randomly assigned to the half-dose (n=1620 [49·9%]) or the full-dose group (n=1624 [50·1%]); 48 women withdrew consent, 30 fetuses were stillborn, 16 neonates were lost to follow-up, and 9 neonates died before evaluation, so that 3141 neonates remained for analysis. In the intention-to-treat analysis, the primary outcome occurred in 313 (20·0%) of 1567 neonates in the half-dose group and 276 (17·5%) of 1574 neonates in the full-dose group (risk difference 2·4%, 95% CI -0·3 to 5·2); thus non-inferiority was not shown. The per-protocol analysis also did not show non-inferiority (risk difference 2·2%, 95% CI -0·6 to 5·1). No between-group differences appeared in the rates of neonatal death, grade 3-4 intraventricular haemorrhage, stage ≥2 necrotising enterocolitis, severe retinopathy of prematurity, or bronchopulmonary dysplasia. INTERPRETATION: Because non-inferiority of the half-dose compared with the full-dose regimen was not shown, our results do not support practice changes towards antenatal betamethasone dose reduction. FUNDING: French Ministry of Health.

Patent ductus arteriosus, tracheal ventilation, and the risk of bronchopulmonary dysplasia.

BACKGROUND: An increased risk for bronchopulmonary dysplasia (BPD) exists when moderate-to-large patent ductus arteriosus shunts (hsPDA) persist beyond 14 days. GOAL: To examine the interaction between prolonged exposures to tracheal ventilation (≥10 days) and hsPDA on the incidence of BPD in infants <28 weeks gestation. STUDY DESIGN: Predefined definitions of prolonged ventilation (≥10 days), hsPDA (≥14 days), and BPD (room air challenge test at 36 weeks) were used to analyze deidentified data from the multicenter TRIOCAPI RCT in a secondary analysis of the trial. RESULTS: Among 307 infants who survived >14 days, 41 died before 36 weeks. Among survivors, 93/266 had BPD. The association between BPD and hsPDA depended on the length of intubation. In multivariable analyses, prolonged hsPDA shunts were associated with increased BPD (odds ratio (OR) (95% confidence interval (CI)) = 3.00 (1.58-5.71)) when infants required intubation for ≥10 days. In contrast, there was no significant association between hsPDA exposure and BPD when infants were intubated <10 days (OR (95% CI) = 1.49 (0.98-2.26)). A similar relationship between prolonged hsPDA and length of intubation was found for BPD/death (n = 307): infants intubated ≥10 days: OR (95% CI) = 2.41 (1.47-3.95)); infants intubated <10 days: OR (95% CI) = 1.37 (0.86-2.19)). CONCLUSIONS: Moderate-to-large PDAs were associated with increased risks of BPD and BPD/death-but only when infants required intubation ≥10 days. IMPACT: Infants with a moderate-to-large hsPDA that persist beyond 14 days are only at risk for developing BPD if they also receive prolonged tracheal ventilation for ≥10 days. Infants who receive less ventilatory support (intubation for <10 days) have the same incidence of BPD whether the ductus closes shortly after birth or whether it persists as a moderate-to-large shunt for several weeks. Early PDA closure may be unnecessary in infants who require short durations of intubation since the PDA does not seem to alter the incidence of BPD in infants who require intubation for <10 days.

Urothelial Cancer Associated 1 (UCA1) and miR-193 Are Two Non-coding RNAs Involved in Trophoblast Fusion and Placental Diseases.

A bioinformatics screen for non-coding genes was performed from microarrays analyzing on the one hand trophoblast fusion in the BeWo cell model, and on the other hand, placental diseases (preeclampsia and Intra-Uterine Growth Restriction). Intersecting the deregulated genes allowed to identify two miRNA (mir193b and miR365a) and one long non-coding RNA (UCA1) that are pivotal for trophoblast fusion, and deregulated in placental diseases. We show that miR-193b is a hub for the down-regulation of 135 cell targets mainly involved in cell cycle progression and energy usage/nutrient transport. UCA1 was explored by siRNA knock-down in the BeWo cell model. We show that its down-regulation is associated with the deregulation of important trophoblast physiology genes, involved in differentiation, proliferation, oxidative stress, vacuolization, membrane repair and endocrine production. Overall, UCA1 knockdown leads to an incomplete gene expression profile modification of trophoblast cells when they are induced to fuse into syncytiotrophoblast. Then we performed the same type of analysis in cells overexpressing one of the two major isoforms of the STOX1 transcription factor, STOX1A and STOX1B (associated previously to impaired trophoblast fusion). We could show that when STOX1B is abundant, the effects of UCA1 down-regulation on forskolin response are alleviated.

Diagnosis of Neonatal Late-Onset Infection in Very Preterm Infant: Inter-Observer Agreement and International Classifications.

BACKGROUND: The definition of late-onset bacterial sepsis (LOS) in very preterm infants is not unified. The objective was to assess the concordance of LOS diagnosis between experts in neonatal infection and international classifications and to evaluate the potential impact on heart rate variability and rate of "bronchopulmonary dysplasia or death". METHODS: A retrospective (2017-2020) multicenter study including hospitalized infants born before 31 weeks of gestation with intention to treat at least 5-days with antibiotics was performed. LOS was classified as "certain or probable" or "doubtful" independently by five experts and according to four international classifications with concordance assessed by Fleiss's kappa test. RESULTS: LOS was suspected at seven days (IQR: 5-11) of life in 48 infants. Following expert classification, 36 of them (75%) were considered as "certain or probable" (kappa = 0.41). Following international classification, this number varied from 13 to 46 (kappa = -0.08). Using the expert classification, "bronchopulmonary dysplasia or death" occurred less frequently in the doubtful group (25% vs. 78%, p < 0.001). Differences existed in HRV changes between the two groups. CONCLUSION: The definition of LOS is not consensual with a low international and moderate inter-observer agreement. This affects the evaluation of associated organ dysfunction and prognosis.

Effect of Early Targeted Treatment of Ductus Arteriosus with Ibuprofen on Survival Without Cerebral Palsy at 2 Years in Infants with Extreme Prematurity: A Randomized Clinical Trial.

OBJECTIVE: To examine the effects of early echocardiography-targeted ibuprofen treatment of large patent ductus arteriosus (PDA) on survival without cerebral palsy at 24 months of corrected age. STUDY DESIGN: We enrolled infants born at <28 weeks of gestation with a large PDA on echocardiography at 6-12 hours after birth to ibuprofen or placebo by 12 hours of age in a multicenter, double blind, randomized-controlled trial. Open-label ibuprofen was allowed for prespecified criteria of a hemodynamically significant PDA. The primary outcome was survival without cerebral palsy at 24 months of corrected age. RESULTS: Among 337 enrolled infants, 109 had a small or closed ductus and constituted a reference group; 228 had a large PDA and were randomized. The primary outcome was assessed at 2 years in 108 of 114 (94.7%) and 102 of 114 (89.5%) patients allocated to ibuprofen or placebo, respectively. Survival without cerebral palsy occurred in 77 of 108 (71.3%) after ibuprofen, 73 of 102 (71.6%) after placebo (adjusted relative risk 0.98, 95% CI 0.83-1.16, P = .83), and 77 of 101 (76.2%) in reference group. Infants treated with ibuprofen had a lower incidence of PDA at day 3. Severe pulmonary hemorrhage during the first 3 days occurred in 2 of 114 (1.8%) infants treated with ibuprofen and 9 of 114 (7.9%) infants treated with placebo (adjusted relative risk 0.22, 95% CI 0.05-1.00, P = .05). Open-label rescue treatment with ibuprofen occurred in 62.3% of infants treated with placebo and 17.5% of infants treated with ibuprofen (P < .001), at a median (IQR) age of 4 (3, 5) and 4 (4, 12) days, respectively. CONCLUSIONS: Early echocardiography-targeted ibuprofen treatment of a large PDA did not change the rate of survival without cerebral palsy. TRIAL REGISTRATION: Eudract 2011-003063-30 and ClinicalTrials.gov: NCT01630278.

Correction to: Clinical Practice Guidelines for Childbearing Female Candidates for Bariatric Surgery, Pregnancy, and Post-Partum Management after Bariatric Surgery.

In the original article, due to an XML tagging error the name of Véronique Taillard was omitted from the list of members of the French Study Group for Bariatric Surgery and Maternity (the BARIA-MAT Group). The correct list is as follows.

Neonatal and neurodevelopmental outcomes in preterm infants according to maternal body mass index: A prospective cohort study.

OBJECTIVE: Maternal obesity is associated with an increase in maternal, foetal and neonatal morbidity and mortality. The aim of our study was to evaluate the relationships between maternal pre-pregnancy body mass index and (1) neonatal outcome in preterm infants, and (2) neurodevelopmental outcome at 2 years of corrected age. METHOD: We conducted a single-centre cohort study. Infants born between 24+0 and 33+6 weeks of gestation between January 2009 and December 2013, hospitalised in the neonatal intensive care unit of Angers University Hospital, and with available data regarding maternal pre-pregnancy body mass index were eligible. Three groups were defined according to maternal body mass index: normal (n = 418), overweight (n = 136) and obese (n = 89). The primary outcome was neurodevelopment at 2 years of corrected age. Children with a non-optimal neuromotor and/or psychomotor assessment and/or a sensory disability were regarded as having a "non-optimal neurodevelopmental outcome". Neuromotor function was regarded as non-optimal when cerebral palsy was present or when the clinical examination revealed neurological signs of abnormal muscular tone. Psychomotor assessment was regarded as non-optimal if the revised Brunet-Lézine test was < 85 or when the overall score in the parental Ages and Stages Questionnaire (ASQ) was < 185. Finally, sensory disabilities such as blindness and children who required a hearing aid were taken into account. The secondary outcome was the composite criteria of neonatal complications. Multivariable analysis included the following variables: mother's age, gestational age, smoking during pregnancy, magnesium sulphate and steroid treatment during pregnancy, twin status, gender, socioeconomic status and social security benefits for those with low incomes. RESULTS: The study population was composed of 643 preterm infants. Among them, 520 were assessed at 2 years. There was no difference in the proportion of infants with non-optimal neurodevelopmental outcomes between the three groups (16.6% for obese, 13.5% for overweight, 16.9% for normal body mass index mothers; p = 0.73). According to multivariable analysis, being born from an overweight or obese mother was not associated with an increased risk of non-optimal neuro-development at 2 years (adjusted OR = 0.84 [0.40-1.76] for obese, adjusted OR = 0.83 [0.43-1.59] for overweight mothers). There was no difference in the proportion of preterm infants with a non-optimal composite criterion of neonatal complications between the three groups. In the multivariable analysis, being born from an overweight or obese mother was not associated with an increased risk of non-optimal neonatal outcomes (adjusted OR = 0.95 [0.49-1.83] for obese, adjusted OR = 1.18 [0.69-2.01] for overweight mothers). CONCLUSION: In this large prospective cohort of preterm infants born before 34 weeks of gestation, we found no relationship between maternal body mass index and neurodevelopmental outcomes at 2 years of corrected age and no relationship between maternal body mass index and neonatal outcomes. Other prematurity-related factors may be more relevant for neurodevelopmental outcome than the mother's pre-pregnancy BMI.

Clinical Practice Guidelines for Childbearing Female Candidates for Bariatric Surgery, Pregnancy, and Post-partum Management After Bariatric Surgery.

Emerging evidence suggests that bariatric surgery improves pregnancy outcomes of women with obesity by reducing the rates of gestational diabetes, pregnancy-induced hypertension, and macrosomia. However, it is associated with an increased risk of a small-for-gestational-age fetus and prematurity. Based on the work of a multidisciplinary task force, we propose clinical practice recommendations for pregnancy management following bariatric surgery. They are derived from a comprehensive review of the literature, existing guidelines, and expert opinion covering the preferred type of surgery for women of childbearing age, timing between surgery and pregnancy, contraception, systematic nutritional support and management of nutritional deficiencies, screening and management of gestational diabetes, weight gain during pregnancy, gastric banding management, surgical emergencies, obstetrical management, and specific care in the postpartum period and for newborns.

Impact of mode of conception on neonatal and neurodevelopmental outcomes in preterm infants.

STUDY QUESTION: Is assisted conception associated with neonatal morbidity and mortality and with neurodevelopmental impairment at 2 years of corrected age in preterm infants born before 34 weeks of gestational age? SUMMARY ANSWER: Assisted conception is not associated with an increase in neonatal morbidity and mortality and is even significantly associated with a better 2-year neurodevelopmental outcome in preterm infants. WHAT IS KNOWN ALREADY: Assisted conception appears to increase the rate of preterm births, though few studies have analysed outcomes for these preterm infants. STUDY DESIGN, SIZE, DURATION: This prospective observational study included 703 preterm infants born between January 2009 and December 2013 and 573 of them were assessed at 2 years of corrected age. PARTICIPANTS/MATERIALS, SETTING, METHODS: All infants born alive between 24+0 and 33+6 weeks of gestational age and hospitalised at the Angers University Hospital were eligible as long as the mode of conception was known for neonatal outcome assessment. They were enroled in the Loire Infant Follow-up Team (LIFT) prospective longitudinal cohort and included for neurodevelopmental outcome assessment. Neonatal morbidity and mortality were evaluated during hospitalisation based on a composite score including death, intraventricular haemorrhage Grade ≥3, periventricular leukomalacia, treated patent ductus arteriosus and bronchopulmonary dysplasia at 36 weeks of gestational age. The neurodevelopmental outcome at 2 years of corrected age was determined by a physical examination, a neuropsychological test and a parental questionnaire. In order to ensure comparability, infants were matched 1:1 according to maternal age, twin status and propensity score,calculated from variables usually associated (positively or negatively) with assisted conception, including gestational age, z-score of birth weight, antenatal corticosteroids and magnesium sulphate treatments, gender, parity, maternal body mass index, tobacco consumption, outborn delivery (i.e. not at a tertiary-care medical centre) and maternal socio-economic status. MAIN RESULTS AND THE ROLE OF CHANCE: There were 703 preterm infants included in the analysis of neonatal morbidity and mortality, including 137 born after assisted conception. After matching, 184 preterm infants were included for neonatal morbidity and mortality analysis. There was no significant association between assisted conception and neonatal morbidity and mortality (aOR 0.67, 95% CI [0.25, 1.77], P = 0.422). 573 infants were assessed at 2 years, including 121 born after assisted conception. After matching, 154 preterm infants were included for neurodevelopmental outcome analysis. Assisted conception was significantly associated with a reduction in the probability of non-optimal neurological development at 2 years (aOR 0.26, 95% CI [0.09, 0.80], P = 0.019). LIMITATION, REASONS FOR CAUTION: Further studies remain necessary to fully confirm these results. This was a monocentric study and 14% of enroled infants were lost to follow up at 2 years of corrected age. WIDER IMPLICATIONS OF THE FINDINGS: These findings are relevant for providing appropriate information to parents considering assisted conception, and more importantly for those with a preterm infant following a pregnancy achieved by assisted conception. STUDY FUNDING/COMPETING INTEREST(S): The authors report external funding and no conflicts of interest for this work. TRIAL REGISTRATION NUMBER: N/A.

Risk of low birth weight and micronutrient deficiencies in neonates from mothers after gastric bypass: a case control study.

BACKGROUND: An increased risk of small-for-gestational-age infants after maternal bariatric surgery has been shown. The risk of micronutrients deficiencies in these neonates is unclear. OBJECTIVE: To screen for micronutrients deficiencies in newborns of mothers with gastric bypass. SETTINGS: University hospital in Angers, France. METHODS: This study compared the clinical and cord blood biological characteristics of 56 newborns of mothers with prior Roux-en-Y gastric bypass (RYGB) and 56 newborns of nonobese healthy mothers after normal pregnancy (controls), followed between January 3, 2008 and October 31, 2012. Cord blood micronutrients concentrations from controls were used for establishing normative data. After RYGB, the women took daily micronutrients supplements. RESULTS: RYGB mothers lost 18.1±6.3 kg/m2 of body mass index (BMI) in the 11-69 months between surgery and pregnancy onset (percentage of excess weight loss 79±20%), reaching BMI of 30.1±6.0 kg/m2 compared with 22.3±4.0 kg/m2 in the controls (P<.05). Neonates born to RYGB mothers were small-for-gestational-age in 23% of cases versus 3.6% in the control group (P<.01). A higher percentage of RYGB neonates had cord blood concentrations below the 2.5 percentile for calcium (19% versus 2%), zinc (13% versus 3%,), iron (19% versus 2%), and vitamin A (13% versus 3%), and over the 97.5 percentile for magnesium (13% versus 3%), vitamin E (16% versus 3%), 25-hydroxy-vitamin D (13% versus 2%), and vitamin B12 (14% versus 2%) (P<.05 for all comparisons). CONCLUSION: Neonates from RYGB mothers showed cord blood micronutrient differences compared with neonates from healthy mothers. The comparison with neonates from morbidly obese women is still to be done.

Abstention or intervention for isolated hypotension in the first 3†days of life in extremely preterm infants: association with short-term outcomes in the EPIPAGE 2 cohort study.

OBJECTIVE: To compare outcomes at hospital discharge for preterm infants born before 29 weeks of gestation who had at least one episode of isolated hypotension during their first 72 hours of life for which they did or did not receive antihypotensive treatment. DESIGN: Etude Epidémiologique sur les Petits Ages Gestationnels 2 (EPIPAGE 2) French national prospective population-based cohort study in 2011. SETTING: 60 neonatal intensive care units. PATIENTS: All infants with a minimum mean arterial blood pressure less than gestational age (in weeks) (minMAP

Neonatal EEG and neurodevelopmental outcome in preterm infants born before 32†weeks.

OBJECTIVE: To assess the value of neonatal EEG for predicting non-optimal neurodevelopmental outcomes in very preterm infants, using a multimodal strategy of evaluation comprising brain imaging and clinical assessment. DESIGN AND SETTING: Between 2003 and 2009, we performed an observational, population-based study. Out of 2040 eligible preterm infants born before 32 weeks, 1954 were enrolled in the French regional Loire Infant Follow-Up Team (LIFT) cohort. 1744 (89%) of these completed the follow-up. Neonatal EEGs were recorded prospectively as two EEGs during the first 2 weeks of life and then one every 2 weeks up to 33 weeks. MAIN OUTCOME MEASURES: The neurodevelopmental outcome was assessed by physical examination, the Brunet-Lézine Test and/or the Age and Stages Questionnaire at 2 years of corrected age. RESULTS: Of the 1744 infants assessed at 2 years, 422 had a non-optimal outcome. A total of 4804 EEGs were performed, and 1345 infants had at least one EEG. EEG abnormalities were predictive of non-optimal outcomes after controlling for confounding factors such as severe intracranial lesions detected by brain imaging. Transient moderate and severe abnormalities were independent predictors of non-optimal outcomes with an OR and 95% CI of 1.49 (1.08 to 2.04) and 2.38 (1.49 to 3.81), respectively. In the validation group, the predictive risk stratification tree identified severe abnormalities as a factor contributing to the prognosis of two subgroups: infants with severe cranial lesions and infants with a normal examination at discharge and without severe cranial lesions.

Usefulness of parent-completed ASQ for neurodevelopmental screening of preterm children at five years of age.

INTRODUCTION: Preterm children are at greater risk of developmental impairment and require close follow-up for early and optimal medical care. Our goal was to examine use of the parent-completed Ages and Stages Questionnaire (ASQ) as a screening tool for neurodevelopmental disabilities in preterm infants at five years of age. PATIENTS AND METHODS: A total of 648 preterm children (<35 weeks gestational age) born between 2003 and 2004 and included in the regional Loire Infant Follow-up network were evaluated at five years of age. ASQ was compared with two validated tools (Intelligence Quotient and Global School Adaptation Score) and the impact of maternal education on the accuracy of this questionnaire was assessed. RESULTS: Overall ASQ scores for predicting full-scale IQ<85 and GSA score produced an area under the receiver operating characteristic curve of 0.73±0.03 and 0.77±0.03, respectively. An ASQ cut-off value of 285 had optimal discriminatory power for identifying children with IQ scores<85 and GSA scores in the first quintile. ASQ values<285 were significantly associated with a higher risk of non-optimal neurologic outcomes (sensitivity of 0.80, specificity of 0.54 for IQ<85). ASQ values>285 were not distinctive for mild delay or normal development. In children with developmental delay, no difference was found when ASQ scores according to maternal education levels were analyzed. CONCLUSIONS: ASQ at five years is a simple and cost-effective tool that can detect severe developmental delay in preterm children regardless of maternal education level, while its capacity to identify children with mild delay appears to be more limited.