OPtimal TIming of antenatal COrticosteroid administration in pregnancies complicated by early-onset fetal growth REstriction (OPTICORE): study protocol of a multicentre, retrospective cohort study.

INTRODUCTION: Early-onset fetal growth restriction (FGR) requires timely, often preterm, delivery to prevent fetal hypoxia causing stillbirth or neurologic impairment. Antenatal corticosteroids (CCS) administration reduces neonatal morbidity and mortality following preterm birth, most effectively when administered within 1 week preceding delivery. Optimal timing of CCS administration is challenging in early-onset FGR, as the exact onset and course of fetal hypoxia are unpredictable. International guidelines do not provide a directive on this topic. In the Netherlands, two timing strategies are commonly practiced: administration of CCS when the umbilical artery shows (A) a pulsatility index above the 95thh centile and (B) absent or reversed end-diastolic velocity (a more progressed disease state). This study aims to (1) use practice variation to compare CCS timing strategies in early-onset FGR on fetal and neonatal outcomes and (2) develop a dynamic tool to predict the time interval in days until delivery, as a novel timing strategy for antenatal CCS in early-onset FGR. METHODS AND ANALYSIS: A multicentre, retrospective cohort study will be performed including pregnancies complicated by early-onset FGR in six tertiary hospitals in the Netherlands in the period between 2012 and 2021 (estimated sample size n=1800). Main exclusion criteria are multiple pregnancies and fetal congenital or genetic abnormalities. Routinely collected data will be extracted from medical charts. Primary outcome for the comparison of the two CCS timing strategies is a composite of perinatal, neonatal and in-hospital mortality. Secondary outcomes include the COSGROVE core outcome set for FGR. A multivariable, mixed-effects model will be used to compare timing strategies on study outcomes. Primary outcome for the dynamic prediction tool is 'days until birth'. ETHICS AND DISSEMINATION: The need for ethical approval was waived by the Ethics Committee (University Medical Center Utrecht). Results will be published in open-access, peer-reviewed journals and disseminated by presentations at scientific conferences. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov: NCT05606497.

Expectant Management or Early Ibuprofen for Patent Ductus Arteriosus.

BACKGROUND: Cyclooxygenase inhibitors are commonly used in infants with patent ductus arteriosus (PDA), but the benefit of these drugs is uncertain. METHODS: In this multicenter, noninferiority trial, we randomly assigned infants with echocardiographically confirmed PDA (diameter, >1.5 mm, with left-to-right shunting) who were extremely preterm (<28 weeks' gestational age) to receive either expectant management or early ibuprofen treatment. The composite primary outcome included necrotizing enterocolitis (Bell's stage IIa or higher), moderate to severe bronchopulmonary dysplasia, or death at 36 weeks' postmenstrual age. The noninferiority of expectant management as compared with early ibuprofen treatment was defined as an absolute risk difference with an upper boundary of the one-sided 95% confidence interval of less than 10 percentage points. RESULTS: A total of 273 infants underwent randomization. The median gestational age was 26 weeks, and the median birth weight was 845 g. A primary-outcome event occurred in 63 of 136 infants (46.3%) in the expectant-management group and in 87 of 137 (63.5%) in the early-ibuprofen group (absolute risk difference, -17.2 percentage points; upper boundary of the one-sided 95% confidence interval [CI], -7.4; P<0.001 for noninferiority). Necrotizing enterocolitis occurred in 24 of 136 infants (17.6%) in the expectant-management group and in 21 of 137 (15.3%) in the early-ibuprofen group (absolute risk difference, 2.3 percentage points; two-sided 95% CI, -6.5 to 11.1); bronchopulmonary dysplasia occurred in 39 of 117 infants (33.3%) and in 57 of 112 (50.9%), respectively (absolute risk difference, -17.6 percentage points; two-sided 95% CI, -30.2 to -5.0). Death occurred in 19 of 136 infants (14.0%) and in 25 of 137 (18.2%), respectively (absolute risk difference, -4.3 percentage points; two-sided 95% CI, -13.0 to 4.4). Rates of other adverse outcomes were similar in the two groups. CONCLUSIONS: Expectant management for PDA in extremely premature infants was noninferior to early ibuprofen treatment with respect to necrotizing enterocolitis, bronchopulmonary dysplasia, or death at 36 weeks' postmenstrual age. (Funded by the Netherlands Organization for Health Research and Development and the Belgian Health Care Knowledge Center; BeNeDuctus ClinicalTrials.gov number, NCT02884219; EudraCT number, 2017-001376-28.).

Two-year neurodevelopmental outcome in children born extremely preterm: the EPI-DAF study.

OBJECTIVE: In 2010, the Dutch practice regarding initiation of active treatment in extremely preterm infants was lowered from 25 completed weeks' to 24 completed weeks' gestation. The nationwide Extremely Preterm Infants - Dutch Analysis on Follow-up Study was set up to provide up-to-date data on neurodevelopmental outcome at 2 years' corrected age (CA) after this guideline change. Design: National cohort study. PATIENTS: All live born infants between 240/7 weeks' and 266/7 weeks' gestational age who were 2 years' CA in 2018-2020. MAIN OUTCOME MEASURE: Impairment at 2 years' CA, based on cognitive score (Bayley-III-NL), neurological examination and neurosensory function. RESULTS: 651 of 991 live born infants (66%) survived to 2 years' CA, with data available for 554 (85%). Overall, 62% had no impairment, 29% mild impairment and 9% moderate-to-severe impairment (further defined as neurodevelopmental impairment, NDI). The percentage of survivors with NDI was comparable for infants born at 24 weeks', 25 weeks' and 26 weeks' gestation. After multivariable analysis, severe brain injury and low maternal education were associated with higher odds on NDI. NDI-free survival was 48%, 67% and 75% in neonatal intensive care unit (NICU)-admitted infants at 24, 25 and 26 weeks' gestation, respectively. CONCLUSIONS: Lowering the threshold has not been accompanied by a large increase in moderate-to-severely impaired infants. Among live-born and NICU-admitted infants, an increase in NDI-free survival was observed from 24 weeks' to 26 weeks' gestation. This description of a national cohort with high follow-up rates gives an accurate description of the range of outcomes that may occur after extremely preterm birth.

Incidence of brain lesions in moderate-late preterm infants assessed by cranial ultrasound and MRI: The BIMP-study.

PURPOSE: To evaluate the incidence and characteristics of brain lesions in moderate-late preterm (MLPT) infants, born at 32-36 weeks' gestation using cranial ultrasound (cUS) and magnetic resonance imaging (MRI). METHODS: Prospective cohort study carried out at Isala Women and Children's Hospital between August 2017 and November 2019. cUS was performed at postnatal day 3-4 (early-cUS), before discharge and repeated at term equivalent age (TEA) in MLPT infants born between 32+0 and 35+6 weeks' gestation. At TEA, MRI was also performed. Several brain lesions were assessed e.g. hemorrhages, white matter and deep gray matter injury. Brain maturation was visually evaluated. Lesions were classified as mild or moderate-severe. Incidences and confidence intervals were calculated. RESULTS: 166 MLPT infants were included of whom 127 underwent MRI. One or more mild lesions were present in 119/166 (71.7 %) and moderate-severe lesions in 6/166 (3.6 %) infants on cUS and/or MRI. The most frequent lesions were signs suggestive of white matter injury: inhomogeneous echogenicity in 50/164 infants (30.5 %) at early-cUS, in 12/148 infants (8.1 %) at TEA-cUS and diffuse white matter signal changes (MRI) in 27/127 (23.5 %) infants. Cerebellar hemorrhage (MRI) was observed in 16/127 infants (12.6 %). Delayed maturation (MRI) was seen in 17/117 (13.4 %) infants. Small hemorrhages and punctate white matter lesions were more frequently detected on MRI than on cUS. CONCLUSIONS: In MLPT infants mild brain lesions were frequently encountered, especially signs suggestive of white matter injury and small hemorrhages. Moderate-severe lesions were less frequently seen.

A systematic review on brain injury and altered brain development in moderate-late preterm infants.

OBJECTIVES: To provide a systematic review of brain injury and altered brain development in moderate-late preterm (MLPT) infants as compared to very preterm and term infants. STUDY DESIGN: A systematic search in five databases was performed in January 2020. Original research papers on incidence of brain injury and papers using quantitative data on brain development in MLPT infants were selected. The Johanna Briggs Institute 'Critical Appraisal Checklist for Studies Reporting Prevalence Data' was used for quality appraisal. Data extraction included: imaging modality, incidences of brain injury, brain volumes, 2D-measurements and diffusivity values. RESULTS: In total, 24 studies were eligible. Most studies had a moderate quality. Twenty studies reported on the incidence of brain injury in MLPT infants. The incidence of intraventricular hemorrhage (IVH) ranged from 0.0% to 23.5% and of white matter injury (WMI) from 0.5% to 10.8%. One study reported the incidence of arterial infarction (0.3%) and none of cerebellar hemorrhage. Eleven studies compared incidences of brain injury between MLPT infants and very preterm or term infants. Five studies reported signs of altered brain development in MLPT infants. CONCLUSIONS: The incidences of IVH and WMI in MLPT infants varied widely between studies. Other abnormalities were sparsely reported. Evidence regarding a higher or lower incidence of brain injury in MLPT infants compared to very preterm or term infants is weak due to moderate methodological quality of reported studies. There is limited evidence suggesting a difference in brain development between MLPT and term infants.

Development of Nationwide Recommendations to Support Prenatal Counseling in Extreme Prematurity.

OBJECTIVES: To develop a nationwide, evidence-based framework to support prenatal counseling in extreme prematurity, focusing on organization, decision-making, content, and style aspects. METHODS: A nationwide multicenter RAND-modified Delphi method study was performed between November 2016 and December 2017 in the Netherlands. Firstly, recommendations were extracted from literature and previous studies. Secondly, an expert panel (n = 21) with experienced parents, obstetricians, and neonatologists rated the recommendations on importance for inclusion in the framework. Thirdly, ratings were discussed in a consensus meeting. The final set of recommendations was approved and transformed into a framework. RESULTS: A total of 101 recommendations on organization, decision-making, content, and style were included in the framework, including tools to support personalization. The most important recommendations regarding organization were to have both parents involved in the counseling with both the neonatologist and obstetrician. The shared decision-making model was recommended for deciding between active support and comfort care. Main recommendations regarding content of conversation were explanation of treatment options, information on survival, risk of permanent consequences, impossibility to predict an individual course, possibility for multiple future decision moments, and a discussion on parental values and standards. It was considered important to avoid jargon, check understanding, and provide a summary. The expert panel, patient organization, and national professional associations (gynecology and pediatrics) approved the framework. CONCLUSIONS: A nationwide, evidence-based framework for prenatal counseling in extreme prematurity was developed. It contains recommendations and tools for personalization in the domains of organization, decision-making, content, and style of prenatal counseling.