Neurodevelopmental outcome at 5.5 years in Dutch preterm infants born at 24-26 weeks' gestational age: the EPI-DAF study.

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 240/7 and 266/7 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.

Identifying effect modifiers of systemic hydrocortisone treatment initiated 7-14 days after birth in ventilated very preterm infants on long-term outcome: secondary analysis of a randomised controlled trial.

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.

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.

Risk Factors for Retinopathy of Prematurity in the Netherlands: A Comparison of Two Cohorts.

INTRODUCTION: Retinopathy of prematurity (ROP) remains an important cause for preventable blindness. Aside from gestational age (GA) and birth weight, risk factor assessment can be important for determination of infants at risk of (severe) ROP. METHODS: Prospective, multivariable risk-analysis study (NEDROP-2) was conducted, including all infants born in 2017 in the Netherlands considered eligible for ROP screening by pediatricians. Ophthalmologists provided data of screened infants, which were combined with risk factors from the national perinatal database (Perined). Clinical data and potential risk factors were compared to the first national ROP inventory (NEDROP-1, 2009). During the second period, more strict risk factor-based screening inclusion criteria were applied. RESULTS: Of 1,287 eligible infants, 933 (72.5%) were screened for ROP and matched with the Perined data. Any ROP was found in 264 infants (28.3% of screened population, 2009: 21.9%) and severe ROP (sROP) (stage ≥3) in 41 infants (4.4%, 2009: 2.1%). The risk for any ROP is decreased with a higher GA (odds ratio [OR] 0.59 and 95% confidence interval [CI] 0.54-0.66) and increased for small for GA (SGA) (1.73, 1.11-2.62), mechanical ventilation >7 days (2.13, 1.35-3.37) and postnatal corticosteroids (2.57, 1.44-4.66). For sROP, significant factors were GA (OR 0.37 and CI 0.27-0.50), SGA (OR 5.65 and CI 2.17-14.92), postnatal corticosteroids (OR 3.81 and CI 1.72-8.40), and perforated necrotizing enterocolitis (OR 7.55 and CI 2.29-24.48). CONCLUSION: In the Netherlands, sROP was diagnosed more frequently since 2009. No new risk factors for ROP were determined in the present study, apart from those already included in the current screening guideline.

Individual longitudinal neurodevelopmental trajectories of children treated with hypothermia for perinatal asphyxia from 3 months to 5 years of age.

BACKGROUND: Hypothermia for perinatal asphyxia is a common treatment to decrease morbidity. This study aims to describe a) individual longitudinal neurodevelopmental trajectories over 5 years in children with perinatal asphyxia treated with hypothermia and b) the correlation between movement quality at 3 months and motor developmental outcomes at 5 years of age. METHODS: In this longitudinal cohort study, 18 children (12 male) were assessed at 3 (t1), 6 (t2), 12 (t3), and 24 (t4) months, and at the age of 5 (t5) years, with standardized norm-referenced tests. RESULTS: Six children showed abnormal movement quality assessed with General Movements (t1) and all showed severe neurodevelopmental disabilities at t5. The 12 children without severe disabilities, showed a significant normalization of z-scores over the five assessment points (linear mixed model analysis). At t5, four of these children scored mildly delayed motor or cognitive development. CONCLUSION AND IMPLICATIONS: Children without anomalies on the MRI before hospital discharge and normal movement quality at 3 months of age showed normal neurodevelopment at the age of 5, however, individual motor trajectories showed variability over time. Presents of abnormal GMs tend to detect CP and developmental problems, advocating a developmental surveillance to determine need for early intervention.

Outcome of Infants with Therapeutic Hypothermia after Perinatal Asphyxia and Early-Onset Sepsis.

BACKGROUND: Animal models suggest that neuroprotective effects of therapeutic hypothermia (TH) after perinatal asphyxia are reduced in infants with early-onset sepsis. OBJECTIVES: To assess the outcome of infants with perinatal asphyxia, neonatal encephalopathy, and TH in the presence of early-onset sepsis. METHODS: In a retrospective cohort of 1,084 infants with perinatal asphyxia and TH, the outcome of 42 infants (gestational age 36.1-42.6 weeks and birth weight 2,280-5,240 g) with proven sepsis (n = 14) and probable sepsis (n = 28) was analyzed. Death, cerebral palsy, or a delayed development at 2 years was considered an adverse outcome. RESULTS: Sepsis was caused mostly by group B streptococci (n = 17), other Gram-positive bacteria (n = 5), and Candida albicans (n = 1). Of the 42 infants, 9 (21.4%) died, and 5 (11.9%) showed impairments on follow-up. The outcome is comparable to the previously reported outcome of infants with TH without early-onset sepsis. CONCLUSION: A good outcome was reported in the majority of infants with perinatal asphyxia, TH, and early-onset sepsis. Cooling should not be withheld from these infants.

Neuropsychological Follow-up After Neonatal ECMO.

OBJECTIVE: To assess the longitudinal development of intelligence and its relation to school performance in a nationwide cohort of neonatal extracorporeal membrane oxygenation (ECMO) survivors and evaluate predictors of outcome at 8 years of age. METHODS: Repeated measurements assessed intelligence of neonatal ECMO survivors at 2, 5, and 8 years (n = 178) with the use of validated, standardized instruments. Selective attention (n = 148) and type of education were evaluated in the 8-year-olds. RESULTS: Intelligence remained stable and average across development (mean ± SD IQ: at 2 years, 102 ± 18; at 5 years, 100 ± 17; and at 8 years, 99 ± 17 [P = .15]). Children attending regular education without the need for help (n = 101; mean z score: -1.50 ± 1.93) performed significantly better on the selective attention task compared with those children who needed extra help (n = 65; mean z score: -2.54 ± 3.18) or those attending special education (n = 13; mean z score: -4.14 ± 3.63) (P = .03). However, only children attending special education had below-average intelligence (mean IQ: 76 ± 15), compared with average intelligence for those attending regular education, both with help (mean IQ: 95 ± 15) and without help (mean IQ: 105 ± 16). Compared with children with other diagnoses, children with congenital diaphragmatic hernia (CDH) scored significantly lower on both IQ (CDH, mean IQ: 93 ± 20; meconium aspiration syndrome, mean IQ: 100 ± 15; other diagnoses, mean IQ: 100 ± 19 [P = .04]) and selective attention (CDH, mean z score: -3.48 ± 3.46; meconium aspiration syndrome, mean z score: -1.60 ± 2.13; other diagnoses, mean z score: -1.65 ± 2.39 [P = .002]). CONCLUSIONS: For the majority of neonatal ECMO survivors, intelligence testing alone did not identify those at risk for academic problems. We propose internationally standardized follow-up protocols that focus on long-term, problem-oriented neuropsychological assessment.

High variability of individual longitudinal motor performance over five years in very preterm infants.

AIM: To determine longitudinal motor performance in very preterm (VPT) infants from 6 months to 5 years of age for the entire cohort of infants, according to gender and gestational age and at the individual level. METHOD: Single-center, prospective longitudinal study of 201 VPT infants (106 boys) without severe impairments. OUTCOMES: Motor performance was assessed with the Bayley Scales of Infant Development (BSID-II-MS: 6, 12, 24 months) and the Movement Assessment Battery for Children (MABC-2-NL: 5 years). RESULTS: At 6, 12, and 24 months and then at 5 years, 77%, 80%, 48%, and 22% of the infants, respectively, showed delayed motor performance (<-1SD). At 5 years, girls performed significantly better than boys in manual dexterity and balance. MIXED MODEL ANALYSES: that examined interactions between time and gender and time and gestational age, revealed no significant interactions. The variance at child level was 29%. Linear mixed model analysis revealed that mean z-scores of -1.46 at 6 months of age declined significantly to -0.52 at 5 years. Individual longitudinal motor performance showed high variability. IMPLICATIONS: Longitudinal motor performance improved almost 1 SD over five years. However, the variability of individual longitudinal motor performance hampers evaluation in clinical care and research.

The Ages and Stages Questionnaire and Neurodevelopmental Impairment in Two-Year-Old Preterm-Born Children.

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.

Motor performance after neonatal extracorporeal membrane oxygenation: a longitudinal evaluation.

OBJECTIVE: To assess longitudinally children's motor performance 5 to 12 years after neonatal extracorporeal membrane oxygenation (ECMO) and to evaluate associations between clinical characteristics and motor performance. METHODS: Two hundred fifty-four neonatal ECMO survivors in the Netherlands were tested with the Movement Assessment Battery for Children at 5, 8, and/or 12 years. Percentile scores were transformed to z scores for longitudinal evaluation (norm population mean = 0 and SD = 1). Primary diagnoses: meconium aspiration syndrome (n = 137), congenital diaphragmatic hernia (n = 49), persistent pulmonary hypertension of the newborn (n = 36), other diagnoses (n = 32). RESULTS: Four hundred fifty-six tests were analyzed. At 5, 8, and 12 years motor performance was normal in 73.7, 74.8, and 40.5%, respectively (vs 85% expected based on reference values; P < .001 at all ages). In longitudinal analyses mean (95% confidence interval [CI]) z scores were -0.42 (-0.55 to -0.28), -0.25 (-0.40 to -0.10) and -1.00 (-1.26 to -0.75) at 5, 8, and 12 years, respectively. Mean score at 8 years was significantly higher than at 5 years (difference 0.16, 95% CI 0.02 to 0.30), and mean score at 12 years was significantly lower than at both other ages (differences -0.59 and -0.75; 95% CI -0.33 to -0.84 and -0.49 to -1.00, respectively). Children with congenital diaphragmatic hernia encountered problems at all ages. The presence of chronic lung disease was negatively related with outcome. CONCLUSIONS: Motor problems in neonatal ECMO survivors persist throughout childhood and become more obvious with time.

A comparison of perinatal outcomes in singletons and multiples born after in vitro fertilization or intracytoplasmic sperm injection stratified for neonatal risk criteria.

OBJECTIVE: To compare perinatal singleton and multiple outcomes in a large Dutch in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI) population and within risk subgroups. Newborns were assigned to a risk category based on gestational age, birthweight, Apgar score and congenital malformation. DESIGN: Register-based retrospective cohort study. SETTING: Netherlands Perinatal Registry data. SAMPLE: A total of 3041 singletons and 1788 multiple children born from IVF/ICSI in 2003-2005. METHODS: Student's t-test or Mann-Whitney U-test was used to analyze continuous data, chi-squared analyses were used for categorical data. Multivariate logistic and linear regression analysis was performed to analyze whether the risk stratification criteria were associated with neonatal hospital admission and length of stay. MAIN OUTCOME MEASURES: Start of labor, mode of delivery, gestational age, birthweight, 5-min Apgar score, congenital malformation, neonatal hospital admission, neonatal intensive care unit admission and mortality. RESULTS: IVF/ICSI-conceived multiples had considerably poorer outcomes than singletons in terms of cesarean section rate, preterm birth, birthweight, being small-for-gestational-age, Apgar score, neonatal hospital admission, neonatal intensive care unit admission and neonatal mortality. As opposed to the results found in the total study population and the low-risk and moderate-risk populations, high-risk multiples showed better outcomes than high-risk singletons regarding cesarean section rate, birthweight and Apgar score. All risk stratification variables were associated with being hospitalized after birth. Length of stay was associated with all risk stratification criteria except Apgar score. CONCLUSIONS: Perinatal outcomes in IVF/ICSI-conceived multiples are considerably poorer than in singletons. This finding mainly pertains to low-risk children. High-risk multiples had significantly better perinatal outcomes than high-risk singletons.

Neurodevelopmental, educational and behavioral outcome at 8 years after neonatal ECMO: a nationwide multicenter study.

PURPOSE: Reporting neurodevelopmental outcome of 8-year-old children treated with neonatal extracorporeal membrane oxygenation (ECMO). METHODS: In a follow-up study in 135 8-year-old children who received neonatal ECMO between 1996 and 2001 we assessed intelligence (Revised Amsterdam Intelligence Test), concentration (Bourdon-Vos test), eye-hand coordination (Developmental Test of Visual-Motor Integration) and behavior (Child Behavior Checklist and Teacher Report Form). RESULTS: Intelligence fell within normal range (mean IQ 99.9, SD 17.7, n = 125) with 91 % of the children following regular education. Significantly more children attended special education (9 %) or received extra support in regular education (39 %) compared with normative data. Slower working speed (χ(2) = 132.36, p < 0.001) and less accuracy (χ(2) = 12.90, p < 0.001) were found on the Bourdon-Vos test (n = 123) compared with normative data. Eye-hand coordination fell within the normal range (mean 97.6, SD 14.3, n = 126); children with congenital diaphragmatic hernia scored lowest but still normally (mean 91.0, SD 16.4, n = 28). Mothers (n = 117) indicated more somatic and attention behavior problems; teachers (n = 115) indicated more somatic, social, thought, aggression and total problems compared with normative data. Mothers indicated more somatic problems than teachers (p = 0.003); teachers reported more attention problems than mothers (p = 0.036; n = 111). CONCLUSIONS: Eight-year-old children treated with neonatal ECMO fall in the normal range of intelligence with problems with concentration and behavior. Long-term follow-up for children treated with neonatal ECMO should focus on early detection of (subtle) learning deficits.

Introduction of hypothermia for neonates with perinatal asphyxia in the Netherlands and Flanders.

BACKGROUND: Therapeutic hypothermia was introduced in the Netherlands and Flanders, Belgium, in 2008. Since then, an increasing number of patients has been treated - up to 166 in 2010. Complications and outcome were registered in an online database. OBJECTIVES: The aim of this study was to analyse complications and outcome after implementation. METHODS: Data were retrieved from an online database to which all centres had contributed. RESULTS: In 3 years, 332 patients were treated. Excluding 24 patients with congenital abnormalities or metabolic disorders, mortality was 31.8%. Of the 210 survivors without congenital malformations, 21 had cerebral palsy, another 19 a developmental delay of more than 3 months at the age of at least 24 months, and 2 had severe hearing loss. The total adverse outcome, combining death and adverse neurodevelopment, in 308 patients without congenital malformations is 45.5%, which is similar to that of the large trials. CONCLUSIONS: The introduction of therapeutic hypothermia for neonates with perinatal asphyxia in the Netherlands and Flanders has been rapid and successful, with results similar to findings in the randomised controlled trials.

Unstable longitudinal motor performance in preterm infants from 6 to 24 months on the Bayley Scales of Infant Development--Second edition.

Preterm birth increases the risk for neurologic and developmental disabilities and therefore long-term follow-up is important. This prospective follow-up study aims to describe longitudinal motor performance in preterm infants from 6 to 24 months and to detect the influence of risk factors on motor performance trajectories. We included preterm infants (n=348) with a gestational age of ≤32 weeks. The Bayley Scales of Infant Development, 2nd edition (BSID-II) Motor Scale and the Behaviour Rating Scale were recorded at the corrected ages of 6, 12 and 24 months. The Motor Scale raw score was the dependent variable in random coefficient analysis for risk factors in the cohort if infants with cerebral damage were in- and excluded. The raw score increased, showed the highest correlation (rp=0.48-0.67) and was more stable than the PDI and its classification. Fifteen percent of the infants had a stable classification, while 45% changed one class. Male sex and intra-ventricular haemorrhage (IVH) lowered the raw scores. Higher motor quality scores and height increased the raw scores, while the influence of maternal education varied at different time points. Removal of infants with cerebral damage from the cohort did not change the risk factors. The results showed that the raw score trajectories were more stable, but after corrections for norm data, the measurements became highly unstable. This is clinically important when reporting results to parents, guiding intervention and in randomised trials. The risk factors predominantly influenced the level of motor performance raw scores. Maternal education additionally influenced the trajectory and should be included in randomisation procedures.

Long term costs and effects of reducing the number of twin pregnancies in IVF by single embryo transfer: the TwinSing study.

BACKGROUND: Pregnancies induced by in vitro fertilisation (IVF) often result in twin gestations, which are associated with both maternal and perinatal complications. An effective way to reduce the number of IVF twin pregnancies is to decrease the number of embryos transferred from two to one. The interpretation of current studies is limited because they used live birth as outcome measure and because they applied limited time horizons. So far, research on long-term outcomes of IVF twins and singletons is scarce and inconclusive. The objective of this study is to investigate the short (1-year) and long-term (5 and 18-year) costs and health outcomes of IVF singleton and twin children and to consider these in estimating the cost-effectiveness of single embryo transfer compared with double embryo transfer, from a societal and a healthcare perspective. METHODS/DESIGN: A multi-centre cohort study will be performed, in which IVF singletons and IVF twin children born between 2003 and 2005 of whom parents received IVF treatment in one of the five participating Dutch IVF centres, will be compared. Data collection will focus on children at risk of health problems and children in whom health problems actually occurred. First year of life data will be collected in approximately 1,278 children (619 singletons and 659 twin children). Data up to the fifth year of life will be collected in approximately 488 children (200 singletons and 288 twin children). Outcome measures are health status, health-related quality of life and costs. Data will be obtained from hospital information systems, a parent questionnaire and existing registries. Furthermore, a prognostic model will be developed that reflects the short and long-term costs and health outcomes of IVF singleton and twin children. This model will be linked to a Markov model of the short-term cost-effectiveness of single embryo transfer strategies versus double embryo transfer strategies to enable the calculation of the long-term cost-effectiveness. DISCUSSION: This is, to our knowledge, the first study that investigates the long-term costs and health outcomes of IVF singleton and twin children and the long-term cost-effectiveness of single embryo transfer strategies versus double embryo transfer strategies.