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Background: Early-onset fetal growth restriction as consequence of placental insufficiency frequently requires iatrogenic preterm birth. Administration of antenatal corticosteroids reduces risks of neonatal morbidity and mortality following preterm birth and is most beneficial if the neonate is delivered within 2 weeks following treatment. International guidelines on fetal growth restriction pregnancies do not provide directives regarding the timing of antenatal corticosteroids, resulting in practice variation., Objective: This study compared the 2 main timing strategies of antenatal corticosteroids administration in the Netherlands for early-onset fetal growth restriction pregnancies: administration when the umbilical artery shows a pulsatility index above the 95th centile with (A) positive end-diastolic flow vs (B) absent or reversed end-diastolic velocity., Study Design: A multicenter retrospective cohort study was performed in 6 tertiary hospitals in the Netherlands between 2012 and 2021. Three hospitals practiced timing strategy A and 3 strategy B. The primary outcome was defined as a composite of perinatal and in-hospital mortality. Secondary outcomes were in line with the core outcome set for fetal growth restriction. Mixed effects analyses were performed adjusted for birthweight z-score and gestational age at birth to compare the 2 timing strategies., Results: A total of 1453 patients were included, of whom 871 and 582 were treated according to timing strategy A and B, respectively. Corticosteroids were administered at a mean gestational age of 28 weeks and 3 days (standard deviation 16.0 days) in timing strategy A and 28 weeks and 4 days (standard deviation 15.8 days) in timing strategy B. The median birthweights were 1050 (range 795, 1350) and 1060 (range 801, 1339) in timing strategy A and B, respectively. Although not statistically significant, rates of perinatal and in-hospital mortality were increased in timing strategy B infants (7.2% vs 9.8%; adjusted odds ratio 1.47; 95% confidence interval 0.97-2.22, reference A). 52.8% and 53.6% of patients in strategy A and B, respectively, delivered within the corticosteroids therapeutic window of 2 to 14 days (P value .663), with a median time between corticosteroid administration and delivery of 6 days for strategy A and 6 days for strategy B. Timing strategy B was associated with more necrotizing enterocolitis (3.7% vs 7.6%; adjusted odds ratio 2.18; 95% confidence interval 1.29-3.69), but less respiratory distress syndrome (39.6% vs 34.5%; adjusted odds ratio 0.63; 95% confidence interval 0.45-0.88) and bronchopulmonary dysplasia (18.9% vs 17.4%; adjusted odds ratio 0.69; 95% confidence interval 0.50-0.96). Other outcomes were similar between groups., Conclusion: Timing strategy B seemed to be associated with higher rates of the composite of perinatal and in-hospital mortality, which could not be explained by a difference in time intervals between corticosteroid administration and delivery. Importantly, most pregnant women delivered outside the presumed therapeutic corticosteroid window. Future research should focus on the improvement of the timing of antenatal corticosteroids in pregnancies complicated by early-onset fetal growth restriction and the identification of other differences in ante- and/or postnatal management to explain differences in outcomes, given the high risk for neonatal morbidity and mortality in this setting., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: After lowering the Dutch threshold for active treatment from 25 to 24 completed weeks' gestation, survival to discharge increased by 10% in extremely preterm live born infants. Now that this guideline has been implemented, an accurate description of neurodevelopmental outcome at school age is needed., Design: Population-based cohort study., Setting: All neonatal intensive care units in the Netherlands., Patients: All infants born between 24 0/7 and 26 6/7 weeks' gestation who were 5.5 years' corrected age (CA) in 2018-2020 were included., Main Outcome Measures: Main outcome measure was neurodevelopmental outcome at 5.5 years. Neurodevelopmental outcome was a composite outcome defined as none, mild or moderate-to-severe impairment (further defined as neurodevelopmental impairment (NDI)), using corrected cognitive score (Wechsler Preschool and Primary Scale of Intelligence Scale-III-NL), neurological examination and neurosensory function. Additionally, motor score (Movement Assessment Battery for Children-2-NL) was assessed. All assessments were done as part of the nationwide, standardised follow-up programme., Results: In the 3-year period, a total of 632 infants survived to 5.5 years' CA. Data were available for 484 infants (77%). At 5.5 years' CA, most cognitive and motor (sub)scales were significantly lower compared with the normative mean. Overall, 46% had no impairment, 36% had mild impairment and 18% had NDI. NDI-free survival was 30%, 49% and 67% in live born children at 24, 25 and 26 weeks' gestation, respectively (p<0.001)., Conclusions: After lowering the threshold for supporting active treatment from 25 to 24 completed weeks' gestation, a considerable proportion of the surviving extremely preterm children did not have any impairment at 5.5 years' CA., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

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 95th h 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., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

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.)., (Copyright © 2022 Massachusetts Medical Society.)

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 24 0/7 weeks' and 26 6/7 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., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

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., (Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.)

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., Competing Interests: POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose., (Copyright © 2019 by the American Academy of Pediatrics.)

Although bilateral injury to the thalami is often seen in (near)term infants with hypoxic ischemic encephalopathy (HIE), symmetrical thalamic lesions (STL) is a different, very rare condition, seen both in full-term and preterm infants often after an antenatal insult, although the history is not always clear. These lesions are usually first detected using cranial ultrasound (cUS). They may not always be seen on the first (admission) scan, but become apparent in the course of the 1st week after birth. Clinically, these infants present with hypo- or hypertonia, absence of sucking and swallowing reflexes, and they may have contractures and facial diplegia. Neuropathology commonly demonstrates a thalamic lesion with additional and variable involvement of basal ganglia and brainstem. The prognosis is very poor, the condition often leads to severe disabilities and/or death within the first years of life. The clinical course and neuroimaging findings of 13 patients with symmetrical thalamic lesions (STL) are reported., Competing Interests: None., (Georg Thieme Verlag KG Stuttgart · New York.)

Objective: The objective of this study is to explore developmental outcomes at five years after early-onset fetal growth restriction (FGR)., Study Design: Retrospective data analysis of prospective follow-up of patients of three Dutch centres, who participated in a twenty centre European randomized controlled trial on timing of delivery in early-onset FGR. Developmental outcome of very preterm infants born after extreme FGR is assessed at (corrected) age of five., Results: Seventy-four very preterm FGR children underwent follow-up at the age of five. Mean gestational age at birth was 30 weeks and birth weight was 910 g, 7% had a Bayley score <85 at two years. Median five years' FSIQ was 97, 16% had a FSIQ < 85, and 35% had one or more IQ scores <85. Motor score ≤ 7 on movement ABC-II (M-ABC-II-NL) was seen in 38%. Absent or reversed end-diastolic flow, gestational age at delivery, birthweight and neonatal morbidity were related to an FSIQ < 85. Any abnormal IQ scale score was related to birthweight, male sex and severity of FGR, and abnormal motor score to male sex and bronchopulmonary dysplasia (BPD)., Conclusions: Overall, median cognitive outcome at five years was within normal range, but 35% of the children had any abnormal IQ score at age five, depending on the IQ measure, and motor impairment was seen in 38% of the children. GA at delivery, birthweight, EDF prior to delivery and neonatal morbidity were the most important risk factors for cognitive outcomes., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: Much controversy exists about the optimal management of a patent ductus arteriosus (PDA) in preterm infants, especially in those born at a gestational age (GA) less than 28 weeks. No causal relationship has been proven between a (haemodynamically significant) PDA and neonatal complications related to pulmonary hyperperfusion and/or systemic hypoperfusion. Although studies show conflicting results, a common understanding is that medical or surgical treatment of a PDA does not seem to reduce the risk of major neonatal morbidities and mortality. As the PDA might have closed spontaneously, treated children are potentially exposed to iatrogenic adverse effects. A conservative approach is gaining interest worldwide, although convincing evidence to support its use is lacking., Methods: This multicentre, randomised, non-inferiority trial is conducted in neonatal intensive care units. The study population consists of preterm infants (GA < 28 weeks) with an echocardiographic-confirmed PDA with a transductal diameter > 1.5 mm. Early treatment (between 24 and 72 h postnatal age) with the cyclooxygenase inhibitor (COXi) ibuprofen (IBU) is compared with an expectative management (no intervention intended to close a PDA). The primary outcome is the composite of mortality, and/or necrotising enterocolitis (NEC) Bell stage ≥ IIa, and/or bronchopulmonary dysplasia (BPD) defined as the need for supplemental oxygen, all at a postmenstrual age (PMA) of 36 weeks. Secondary outcome parameters are short term sequelae of cardiovascular failure, comorbidity and adverse events assessed during hospitalization and long-term neurodevelopmental outcome assessed at a corrected age of 2 years. Consequences regarding health economics are evaluated by cost effectiveness analysis and budget impact analysis., Discussion: As a conservative approach is gaining interest, we investigate whether in preterm infants, born at a GA less than 28 weeks, with a PDA an expectative management is non-inferior to early treatment with IBU regarding to the composite outcome of mortality and/or NEC and/or BPD at a PMA of 36 weeks., Trial Registration: This trial is registered with the Dutch Trial Register NTR5479 (registered on 19 October 2015), the registry sponsored by the United States National Library of Medicine Clinicaltrials.gov NCT02884219 (registered May 2016) and the European Clinical Trials Database EudraCT 2017-001376-28 .

Objective: Since 2010 the guideline 'Guideline for perinatal policy in cases of extreme prematurity' has advised an active policy in infants born at 24 weeks gestation. We investigated how infants born at 24 and 25 weeks gestation in the first year following the implementation of the guideline had developed by the age of 2 years., Design: Retrospective national cohort study., Method: The study population consisted of all surviving infants born in the Netherlands at 24 or 25 weeks gestation in the period from 1 October 2010 to 1 October 2011. At a corrected age of 2 years the children underwent a general physical and neurological examination, and their cognitive scores were determined on the 'Bayley scales of infant and toddler development' (Bayley III). Examinations took place in the 10 neonatal intensive care units (NICU's) in the Netherlands., Results: Of 185 extremely premature infants, 166 were admitted to a NICU. A total of 95 survived to a corrected age of 2 years; 78 (82%) children were examined. Their average cognitive score on the Bayley III scale was 88 (SD: 16). Among the children born at 24 weeks gestation, 20% had mild disabilities and 20% had moderate to severe disabilities. Among the children born at 25 weeks gestation, 17% had mild disabilities and 12% had moderate to severe disabilities., Conclusion: Of the children born at 24 weeks gestation in the first year after the introduction of active policy in the Netherlands and surviving to 2 years of age (46%), more than half had developed without disabilities. This was comparable to children born at 25 weeks gestation. Of all children born at 24 weeks gestation, 25% survived to 2 years of age without disabilities.

Background: Preterm-born or asphyxiated term-born children who received neonatal intensive care show more emotional and behavioral problems than term-born children without a medical condition. It is uncertain whether regular parenting intervention programs to which the parents of these children are usually referred, are effective in reducing child problem behavior in this specific population. Our objective was to investigate whether a regular, brief parenting intervention, Primary Care Triple P, is effective in decreasing emotional and behavioral problems in preterm-born or asphyxiated term-born preschoolers., Methods: For this pragmatic, open randomized clinical trial, participants were recruited from a cohort of infants admitted to the neonatal intensive care units (NICU) of two Dutch hospitals. Children born with a gestational age <32 weeks or birth weight <1500 g and children born at a gestational age 37-42 weeks with perinatal asphyxia were included. After screening for a t-score ≥60 on the Child Behavior Checklist (CBCL), children were randomly assigned to Primary Care Triple P (n = 34) or a wait-list control group (n = 33). The primary outcome was child emotional and behavioral problems reported by parents on the CBCL, 6 months after the start of the trial., Results: There was no effect of the intervention on the CBCL at the trial endpoint (t64 = 0.54, P = .30). On secondary measurements of child problem behavior, parenting style, parenting stress, and parent perceived child vulnerability, groups either did not differ significantly or the intervention group showed more problems. In both the intervention and control group there was a significant decrease in emotional and behavioral problems during the trial., Conclusions: Primary Care Triple P, a brief parenting intervention, is not effective in reducing child emotional and behavioral problems in preterm-born children or term-born children with perinatal asphyxia., Trial Registration: Netherlands National Trial Register (NTR): NTR2179.

Maneb, manganese ethylene-bis-dithiocarbamate, is a fungicide pesticide used in the agriculture and bulb flower culture sector. Toxicological effects for humans have been reported in literature and are diverse. They vary from allergic reactions (dermatitis, conjunctivitis, and bronchitis), central nervous system effects (muscarinic, nicotinic, central and extrapyramidal) and renal toxicity (acute renal failure).A 7-year old girl was admitted to the pediatric intensive care unit because of status epilepticus. Physical examination showed respiratory insufficiency, convulsions, and severe hypothermia (32.5 degrees C). The patient was intubated and her convulsions were successfully treated with benzodiazepines. Except for a combined metabolic and respiratory acidosis and hyperglycemia, diagnostic investigations on admission (full blood count, electrolytes, liver and renal functions, cerebrospinal fluid investigation, toxicology screening of blood and urine for barbiturates and benzodiazepines, blood culture, herpes PCR, and a CT scan of the brain) were normal. Within 24 hours, there was a complete recovery of all neurological signs. Within 72 hours, the patient was discharged from the hospital. Liquid chromatography-mass spectrometric investigation of her blood showed amounts of maneb, which can explain all symptoms and signs. However, effects of this magnitude on the central nervous system have not previously been reported in humans.