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Contains fulltext : 305092.pdf (Publisher’s version ) (Closed access), OBJECTIVE: To explore clinical effect modifiers of systemic hydrocortisone in ventilated very preterm infants for survival and neurodevelopmental outcome at 2 years' corrected age (CA). DESIGN: Secondary analysis of a randomised placebo-controlled trial. SETTING: Dutch and Belgian neonatal intensive care units. PATIENTS: Infants born <30 weeks' gestational age (GA), ventilator-dependent in the second week of postnatal life. INTERVENTION: Infants were randomly assigned to systemic hydrocortisone (cumulative dose 72.5 mg/kg; n=182) or placebo (n=190). MAIN OUTCOME MEASURES: The composite of death or neurodevelopmental impairment (NDI) at 2 years' CA and its components. Candidate effect modifiers (GA, small for GA, respiratory index, sex, multiple births, risk of moderate/severe bronchopulmonary dysplasia or death) were analysed using regression models with interaction terms and subpopulation treatment effect pattern plots. RESULTS: The composite outcome was available in 356 (96.0%) of 371 patients (one consent withdrawn). For this outcome, treatment effect heterogeneity was seen across GA subgroups (<27 weeks: hydrocortisone (n=141) vs placebo (n=156), 54.6% vs 66.2%; OR 0.61 (95% CI 0.38 to 0.98); ≥27 weeks: hydrocortisone (n=30) vs placebo (n=31), 66.7% vs 45.2%; OR 2.43 (95% CI 0.86 to 6.85); p=0.02 for interaction). This effect was also found for the component death (<27 weeks: 20.1% vs 32.1%; OR 0.53 (95% CI 0.32 to 0.90); ≥27 weeks: 28.1% vs 16.1%; OR 2.04 (95% CI 0.60 to 6.95); p=0.049 for interaction) but not for the component NDI. No differential treatment effects were observed across other subgroups. CONCLUSION: This secondary analysis suggests that in infants <27 weeks' GA, systemic hydrocortisone may improve the outcome death or NDI, mainly driven by its component death. There was insufficient evidence for other selected candidate effect modifiers.

Contains fulltext : 294367.pdf (Publisher’s version ) (Open Access), Over 90% of preterm neonates are, often empirically, exposed to antibiotics as a potentially life-saving measure against sepsis. Long-term outcome in association with antibiotic exposure (NABE) has insufficiently been studied after preterm birth. We investigated the association of NABE-duration with early-childhood developmental and health outcomes in preterm-born children and additionally assessed the impact of GA on outcomes. Preterm children (GA < 30 weeks) participating in a multicenter cohort study were approached for follow-up. General expert-reviewed health questionnaires on respiratory, atopic and gastrointestinal symptoms were sent to parents of children > 24 months' corrected age (CA). Growth and developmental assessments (Bayley Scales of Infant and Toddler Development (BSID) III) were part of standard care assessment at 24 months' CA. Uni- and multivariate regressions were performed with NABE (per 5 days) and GA (per week) as independent variables. Odds ratios (OR) for health outcomes were adjusted (aOR) for confounders, where appropriate. Of 1079 infants whose parents were approached, 347 (32%) responded at a mean age of 4.6 years (SD 0.9). In children with NABE (97%), NABE duration decreased by 1.6 days (p < 0.001) per week of gestation. Below-average gross-motor development (BSID-III gross-motor score < 8) was associated with duration of NABE (aOR = 1.28; p = 0.04). The aOR for constipation was 0.81 (p = 0.04) per gestational week. Growth was inversely correlated with GA. Respiratory and atopic symptoms were not associated with NABE, nor GA. We observed that prolonged NABE after preterm birth was associated with below-average gross-motor development at 24 months' CA, while a low GA was associated with lower weight and stature Z-scores and higher odds for constipation.

Contains fulltext : 283154.pdf (Publisher’s version ) (Open Access), 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.

Contains fulltext : 282941.pdf (Publisher’s version ) (Open Access), INTRODUCTION: Vaginal progesterone and a cervical pessary are both interventions that are investigated for the prevention of preterm birth (PTB). Thus far, beneficial or harmful effects of these interventions on long-term child health and development are described, but evidence is not robust enough to draw firm conclusions. With this follow-up study, we intent to investigate if progesterone or a pessary is superior for the prevention of PTB considering the child's health at 4-6 years of corrected age. METHODS AND ANALYSIS: This study is a follow-up study of the Quadruple-P trial; a multicentre, randomised clinical trial (NL42926.018.13, Eudractnumber 2013-002884-24) which randomises women with an asymptomatic midtrimester short cervix to daily progesterone or a pessary for the prevention of PTB. All children born to mothers who participated in the Quadruple-P study (n=628 singletons and n=332 multiples) will be eligible for follow-up at 4-6 years of corrected age. Children will be assessed using parental questionnaires. Main outcomes are child (neuro)development and behaviour. Other outcomes include child mortality, growth and general health. A composite of adverse child outcomes will be compared between the progesterone and pessary groups reporting OR and the corresponding 95% CI. Analyses will be performed separately for singletons and multiples and using the intention-to-treat approach. ETHICS AND DISSEMINATION: The Medical Research Ethics Committee from Amsterdam UMC confirmed that de Medical Research Involving Human Subjects Act (WMO) did not apply to our study (W20_481 #20.531). Results will be published in a peer-reviewed journal and shared with stakeholders and participants. This protocol is published before analysis of the results. TRIAL REGISTRATION NUMBER: Dutch Trial Register (NL9646).

OBJECTIVE: To compare academic attainment at age 12 years in preterm children born below 30 weeks of gestation with matched term-born peers, using standardized, nationwide and well-validated school tests.STUDY DESIGN: This population-based, national cohort study was performed by linking perinatal data from the nationwide Netherlands Perinatal Registry with educational outcome data from Statistics Netherlands and included 4677 surviving preterm children born at 25 0/7-29 6/7 weeks of gestational age and 366 561 controls born at 40 weeks of gestational age in 2000-2007. First, special education participation rate was calculated. Subsequently, all preterm children with academic attainment test data derived at age 12 years were matched to term-born children using year and month of birth, sex, parity, socioeconomic status, and maternal age. Total, language, and mathematics test scores and secondary school level advice were compared between these 2 groups. RESULTS: Children below 30 weeks of gestation had a higher special education participation rate (10.2% vs 2.7%, P < .001) than term-born peers. Preterm children had lower total (-0.37 SD; 95% CI -0.42 to -0.31), language (-0.21 SD; 95% CI -0.27 to -0.15), and mathematics (-0.45 SD; 95%CI -0.51 to -0.38) z scores, and more often a prevocational secondary school level advice (62% vs 46%, P < .001).CONCLUSIONS: A substantial proportion of children born before 30 weeks of gestation need special education at the end of elementary schooling. These children have significant deficits on all measures of academic attainment at age 12 years, especially mathematics, compared with matched term-born peers.

Contains fulltext : 235722.pdf (Publisher’s version ) (Open Access), OBJECTIVE: To assess the effect of transabdominal amnioinfusion or no intervention on long-term outcomes in children born after second-trimester prelabour rupture of the membranes (PROM between 16(+0/7) -24(+0/7) weeks) and oligohydramnios. POPULATION: Follow up of infants of women who participated in the randomised controlled trial: PPROMEXIL-III (NTR3492). METHODS: Surviving infants were invited for neurodevelopmental assessment up to 5 years of corrected age using a Bayley Scales of Infant and Toddler Development or a Wechsler Preschool and Primary Scale of Intelligence. Parents were asked to complete several questionnaires. MAIN OUTCOME MEASURES: Neurodevelopmental outcomes were measured. Mild delay was defined as -1 standard deviation (SD), severe delay as -2 SD. Healthy long-term survival was defined as survival without neurodevelopmental delay or respiratory problems. RESULTS: In the amnioinfusion group, 18/28 children (64%) died versus 21/28 (75%) in the no intervention group (relative risk 0.86; 95% confidence interval [CI] 0.60-1.22). Follow-up data were obtained from 14/17 (82%) children (10 amnioinfusion, 4 no intervention). In both groups, 2/28 (7.1%) had a mild neurodevelopmental delay. No severe delay was seen. Healthy long-term survival occurred in 5/28 children (17.9%) after amnioinfusion versus 2/28 (7.1%) after no intervention (odds ratio 2.50; 95% CI 0.53-11.83). When analysing data for all assessed survivors, 10/14 (71.4%) survived without mild neurodevelopmental delay and 7/14 (50%) were classified healthy long-term survivor. CONCLUSIONS: In this small sample of women suffering second-trimester PROM and oligohydramnios, amnioinfusion did not improve long-term outcomes. Overall, 71% of survivors had no neurodevelopmental delay. TWEETABLE ABSTRACT: Healthy long-term survival was comparable for children born after second-trimester PROM and treatment with amnioinfusion or no intervention.

Introduction: There is little evidence to guide the timing of delivery of women with early-onset severe preeclampsia. We hypothesize that immediate delivery is not inferior for neonatal outcome but reduces maternal complications compared with temporizing management. Material and methods: This Dutch multicenter open-label randomized clinical trial investigated non-inferiority for neonatal outcome of temporizing management as compared with immediate delivery (TOTEM NTR 2986) in women between 27+5 and 33+5 weeks of gestation admitted for early-onset severe preeclampsia with or without HELLP syndrome. In participants allocated to receive immediate delivery, either induction of labor or cesarean section was initiated at least 48 hours after admission. Primary outcomes were adverse perinatal outcome, defined as a composite of severe respiratory distress syndrome, bronchopulmonary dysplasia, culture proven sepsis, intraventricular hemorrhage grade 3 or worse, periventricular leukomalacia grade 2 or worse, necrotizing enterocolitis stage 2 or worse, and perinatal death. M

Importance: Severe early onset fetal growth restriction caused by placental dysfunction leads to high rates of perinatal mortality and neonatal morbidity. The phosphodiesterase 5 inhibitor, sildenafil, inhibits cyclic guanosine monophosphate hydrolysis, thereby activating the effects of nitric oxide, and might improve uteroplacental function and subsequent perinatal outcomes. Objective: To determine whether sildenafil reduces perinatal mortality or major morbidity. Design, Setting, and Participants: This placebo-controlled randomized clinical trial was conducted at 10 tertiary referral centers and 1 general hospital in the Netherlands from January 20, 2015, to July 16, 2018. Participants included pregnant women between 20 and 30 weeks of gestation with severe fetal growth restriction, defined as fetal abdominal circumference below the third percentile or estimated fetal weight below the fifth percentile combined with Dopplers measurements outside reference ranges or a maternal hypertensive disorder. The trial was stopped early owing to safety concerns on July 19, 2018, whereas benefit on the primary outcome was unlikely. Data were analyzed from January 20, 2015, to January 18, 2019. The prespecified primary analysis was an intention-to-treat analysis including all randomized participants. Interventions: Participants were randomized to sildenafil, 25 mg, 3 times a day vs placebo. Main Outcomes and Measures: The primary outcome was a composite of perinatal mortality or major neonatal morbidity until hospital discharge. Results: Out of 360 planned participants, a total of 216 pregnant women were included, with 108 women randomized to sildenafil (median gestational age at randomization, 24 weeks 5 days [interquartile range, 23 weeks 3 days to 25 weeks 5 days]; mean [SD] estimated fetal weight, 458 [160] g) and 108 women randomized to placebo (median gestational age, 25 weeks 0 days [interquartile range, 22 weeks 5 days to 26 weeks 3 days]; mean [SD] estimated fetal weig

Objectives: To explore whether, in early fetal growth restriction (FGR), the longitudinal pattern of fetal heart rate (FHR) short-term variation (STV) can be used to identify imminent fetal distress and whether abnormalities of FHR recordings are associated with 2-year infant outcome. Methods: The original TRUFFLE study assessed whether, in early FGR, delivery based on ductus venosus (DV) Doppler pulsatility index (PI), in combination with safety-net criteria of very low STV on cardiotocography (CTG) and/or recurrent FHR decelerations, could improve 2-year infant survival without neurological impairment in comparison with delivery based on CTG monitoring only. This was a secondary analysis of women who delivered before 32 weeks and had consecutive STV data recorded > 3 days before delivery and known infant outcome at 2 years of age. Women who received corticosteroids within 3 days of delivery were excluded. Individual regression line algorithms of all STV values, except the last one before delivery, were calculated. Life tables and Cox regression analysis were used to calculate the daily risk for low STV or very low STV and/or FHR decelerations (below DV group safety-net criteria) and to assess which parameters were associated with this risk. Furthermore, it was assessed whether STV pattern, last STV value or recurrent FHR decelerations were associated with 2-year infant outcome. Results: One hundred and forty-nine women from the original TRUFFLE study met the inclusion criteria. Using the individual STV regression lines, prediction of a last STV below the cut-off used by the CTG monitoring group had sensitivity of 42% and specificity of 91%. For each day after study inclusion, the median risk for low STV (CTG group cut-off) was 4% (interquartile range (IQR), 2–7%) and for very low STV and/or recurrent FHR decelerations (below DV group safety-net criteria) was 5% (IQR, 4–7%). Measures of STV pattern, fetal Doppler (arterial or venous), birth-weight multiples of the

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Background: Severe, early-onset fetal growth restriction due to placental insufficiency is associated with a high risk of perinatal mortality and morbidity with long-lasting sequelae. Placental insufficiency is the result of abnormal formation and function of the placenta with inadequate remodelling of the maternal spiral arteries. There is currently no effective therapy available. Some evidence suggests sildenafil citrate may improve uteroplacental blood flow, fetal growth, and meaningful infant outcomes. The objective of the Sildenafil TheRapy In Dismal prognosis Early onset fetal growth Restriction (STRIDER) collaboration is to evaluate the effectiveness of sildenafil versus placebo in achieving healthy perinatal survival through the conduct of randomised clinical trials and systematic review including individual patient data meta-analysis. Methods: Five national/bi-national multicentre randomised placebo-controlled trials have been launched. Women with a singleton pregnancy between 18 and 30 weeks with severe fetal growth restriction of likely placental origin, and where the likelihood of perinatal death/severe morbidity is estimated to be significant are included. Participants will receive either sildenafil 25 mg or matching placebo tablets orally three times daily from recruitment to 32 weeks gestation. Discussion: The STRIDER trials were conceived and designed through international collaboration. Although the individual trials have different primary outcomes for reasons of sample size and feasibility, all trials will collect a standard set of outcomes including survival without severe neonatal morbidity at time of hospital discharge. This is a summary of all the STRIDER trial protocols and provides an example of a prospectively planned international clinical research collaboration. All five individual trials will contribute to a pre-planned systematic review of the topic including individual patient data meta-analysis.

Item does not contain fulltext, OBJECTIVE: To evaluate long-term effects of maintenance tocolysis with nifedipine on neurodevelopmental outcome of the infant. DESIGN, SETTING AND POPULATION: Follow up of infants of women who participated in a multicentre randomised controlled trial on maintenance tocolysis with nifedipine versus placebo. METHODS: Two years after the APOSTEL II trial on maintenance tocolysis with nifedipine versus placebo, we asked participants to complete the Ages and Stages Questionnaire. MAIN OUTCOME MEASURES: Infant development was measured in five domains. Developmental delay was defined as a score of

Item does not contain fulltext, INTRODUCTION: We investigated the predictive capacity of mid-trimester cervical length (CL) measurement for spontaneous and iatrogenic preterm birth. MATERIAL AND METHODS: We performed a prospective observational cohort study in nulliparous women and low-risk multiparous women with a singleton pregnancy between 16(+0) and 21(+6) weeks of gestation. We assessed the prognostic capacity of transvaginally measured mid-trimester CL for spontaneous and iatrogenic preterm birth (<37 weeks) using likelihood ratios (LR) and receiver-operating-characteristic analysis. We calculated numbers needed to screen to prevent one preterm birth assuming different treatment effects. Main outcome measures were preterm birth <32, <34 and <37 weeks. RESULTS: We studied 11 943 women, of whom 666 (5.6%) delivered preterm: 464 (3.9%) spontaneous and 202 (1.7%) iatrogenic. Mean CL was 44.1 mm (SD 7.8 mm). In nulliparous women, the LRs for spontaneous preterm birth varied between 27 (95% CI 7.7-95) for a CL

Contains fulltext : 154101.PDF (publisher's version ) (Open Access), OBJECTIVE: To test the ability of the Ages and Stages Questionnaire, Third Edition (ASQ3) to help identify or exclude neurodevelopmental impairment (NDI) in very preterm-born children at the corrected age of two. METHODS: We studied the test results of 224 children, born at <32 postmenstrual weeks, who had scores on ASQ3 and Bayley Scales of Infant and Toddler Development, Third Edition (BSIDIII) and neurological examination at 22-26 months' corrected age. We defined NDI as a score of <70 on the cognitive--or motor composite scale of BSIDIII, or impairment on neurological examination or audiovisual screening. We compared NDI with abnormal ASQ3 scores, i.e., < -2SDs on any domain, and with ASQ3 total scores. To correct for possible overestimation of BSIDIII, we also analyzed the adjusted BSIDIII thresholds for NDI, i.e., scores <80 and <85. RESULTS: We found 61 (27%) children with abnormal ASQ3 scores, and 10 (4.5%) children who had NDI with original BSIDIII thresholds (<70). Twelve children had NDI at BSIDIII thresholds at <80, and 15 had <85. None of the 163 (73%) children who passed ASQ3 had NDI. The sensitivity of ASQ3 to detect NDI was excellent (100%), its specificity was acceptable (76%), and its negative predictive value (NPV) was 100%. Sensitivity and NPV remained high with the adjusted BSIDIII thresholds. CONCLUSION: The Ages and Stages Questionnaire is a simple, valid and cost-effective screening tool to help identify and exclude NDI in very preterm-born children at the corrected age of two years.

Item does not contain fulltext, Objective The objective of this study was to evaluate the effectiveness of vaginal progesterone in reducing adverse neonatal outcome due to preterm birth (PTB) in low-risk pregnant women with a short cervical length (CL). Study Design Women with a singleton pregnancy without a history of PTB underwent CL measurement at 18 to 22 weeks. Women with a CL grade II, necrotizing enterocolitis > stage 1, proven sepsis, or death before discharge. Secondary outcomes included time to delivery, PTB before 32, 34, and 37 weeks of gestation. Analysis was by intention to treat. Results Between 2009 and 2013, 20,234 women were screened. A CL of 30 mm or less was seen in 375 women (1.8%). In 151 women, a CL

Item does not contain fulltext, OBJECTIVE: We recently reported that induction of labour does not improve short term neonatal outcome in women with late preterm premature rupture of membranes (PPROM) as compared to expectant management (PPROMEXIL trial). In this study the neurodevelopmental and behavioural outcome of the children from this trial at 2 years of age was studied. STUDY DESIGN: We studied outcome of offspring of women randomised in the PPROMEXIL study. These women had >24h of ruptured membranes and were between 34 and 37 weeks of pregnancy when they were randomised to induction of labour (IoL) or expectant management (EM). Two years after delivery, the parents received the ages and stages questionnaire (ASQ), the child behaviour checklist (CBCL) and a general questionnaire. RESULTS: Follow-up data were obtained from 234 children (121 after IoL, 113 after EM, response rate 59% (44% of the original 532 randomised women)). In the IoL group 16 children (14%) had an abnormal score in >/=1 domains of the ASQ, versus 27 (26%) in the EM group (difference in percentage -11.4 (95% CI -21.9 to -0.98; p=0.033)). For the CBCL, an abnormal score was found in 13% (n=15) in the IoL group and in 15% (n=16) in the EM group (difference in percentage -2.13 (95% CI -11.2 to 6.94; p=0.645)). CONCLUSION: Although a policy of induction of labour in women with late PPROM does not improve short term neonatal outcome, it might be associated with a decrease in neurodevelopmental difficulties at the age of two years as compared to expectant management. Expectant management did not lead to a difference in behavioural problems.

Objective: To test the ability of the Ages and Stages Questionnaire, Third Edition (ASQ3) to help identify or exclude neurodevelopmental impairment (NDI) in very preterm-born children at the corrected age of two. Methods: We studied the test results of 224 children, born at <32 postmenstrual weeks, who had scores on ASQ3 and Bayley Scales of Infant and Toddler Development, Third Edition (BSIDIII) and neurological examination at 22-26 months' corrected age. We defined NDI as a score of <70 on the cognitive-or motor composite scale of BSIDIII, or impairment on neurological examination or audiovisual screening. We compared NDI with abnormal ASQ3 scores, i.e., < -2SDs on any domain, and with ASQ3 total scores. To correct for possible overestimation of BSIDIII, we also analyzed the adjusted BSIDIII thresholds for NDI, i.e., scores <80 and <85. Results: We found 61 (27%) children with abnormal ASQ3 scores, and 10 (4.5%) children who had NDI with original BSIDIII thresholds (<70). Twelve children had NDI at BSIDIII thresholds at <80, and 15 had <85. None of the 163 (73%) children who passed ASQ3 had NDI. The sensitiv

Background and Objective: High bilirubin/albumin (B/A) ratios increase the risk of bilirubin neurotoxicity. The B/A ratio may be a valuable measure, in addition to the total serum bilirubin (TSB), in the management of hyperbilirubinemia. We aimed to assess whether the additional use of B/A ratios in the management of hyperbilirubinemia in preterm infants improved neurodevelopmental outcome. Methods: In a prospective, randomized controlled trial, 615 preterm infants of 32 weeks' gestation or less were randomly assigned to treatment based on either B/A ratio and TSB thresholds (consensus-based), whichever threshold was crossed first, or on the TSB thresholds only. The primary outcome was neurodevelopment at 18 to 24 months' corrected age as assessed with the Bayley Scales of Infant Development III by investigators unaware of treatment allocation. Secondary outcomes included complications of preterm birth and death. Results: Composite motor (100±13 vs. 101±12) and cognitive (101±12 vs. 101±11) scores did not differ between the B/A ratio and TSB groups. Demographic characteristics, maximal TSB levels, B/A ratios, and other secondary outcomes were similar. The rates of death and/or severe neurodevelopmental impairment for the