Nutritional intake and growth until two years of age in moderate and late preterms.

BACKGROUND AND AIM: Moderate and late preterm infants (MLPTI) (gestational age 32 0/7-36 6/7 weeks), are at risk for suboptimal growth. This study evaluated adherence to nutritional recommendations until 6 months corrected age (CA), growth until 2 years CA, and associations between nutritional intake and growth until 2 years CA. METHODS: We prospectively collected nutritional intakes from 100 MLPTI during the first week of life and at 6 weeks, 3 months, and 6 months CA. Anthropometry was assessed at birth, discharge, term age, and at 6 weeks, 3 months, 6 months, 1 year, and 2 years CA. RESULTS: On day 7, <40% reached nutritional recommendations. Thereafter, >80% reached protein recommendations until 6 months of life, but <60% reached energy recommendations. Weight z-scores increased from -0.44 at term-age to 0.59 at 3 months CA, but declined to -0.53 at 2 years CA on the TNO curves. No significant associations were found between nutritional intake and growth until 2 years CA. CONCLUSION: No associations were demonstrated between nutritional intakes and growth until 2 years CA, despite not reaching recommended intakes. Despite high efforts to optimize growth, MLPTI find their own growth curve in the first 2 years of life. IMPACT: This research is pioneering in identifying how nutrition influences growth in moderate and late preterm infants (MLPTI) up to 2 years corrected age (CA). MLPTI often do not meet the recommended protein and energy intake in their first week of life, suggesting that current guidelines might be too high. No association was demonstrated between nutritional intake and growth of MLPTI in the first 2 years of life. Initially, MLPTI show an increase in weight z-scores from term age up to 3 months CA but experience a decline in weight z-scores at 2 years CA, according to TNO growth charts.

Long-Term Follow-Up of Daily Life Functioning After Pediatric Intensive Care Unit Admission.

OBJECTIVE: To investigate the long-term impact of pediatric intensive care unit (PICU) admission on daily life functioning while exploring the potential mediating role of neurocognitive outcome. STUDY DESIGN: This cross-sectional observational study compared children aged 6-12 years with previous PICU admission (age ≤1 year) for bronchiolitis requiring mechanical ventilation ("patient group," n = 65) to demographically comparable healthy peers ("control group," n = 76). The patient group was selected because bronchiolitis is not expected to affect neurocognitive functioning in itself. Assessed daily life outcome domains were behavioral and emotional functioning, academic performance, and health-related quality of life (QoL). The role of neurocognitive outcomes in the relationship between PICU admission and daily life functioning was assessed by mediation analysis. RESULTS: The patient group did not differ from the control group regarding behavioral and emotional functioning but performed poorer on academic performance and school-related QoL (Ps ≤ .04, d = -0.48 to -0.26). Within the patient group, lower full-scale IQ (FSIQ) was associated with poorer academic performance and school-related QoL (Ps ≤ .02). Poorer verbal memory was associated with poorer spelling performance (P = .002). FSIQ mediated the observed effects of PICU admission on reading comprehension and arithmetic performance. CONCLUSIONS: Children admitted to the PICU are at risk for long-term adverse daily life outcomes in terms of academic performance and school-related QoL. Findings suggest that lower intelligence may contribute to academic difficulties after PICU admission. Findings underline the importance of monitoring daily life and neurocognitive functioning after PICU admission.

Comparison of New Bronchopulmonary Dysplasia Definitions on Long-Term Outcomes in Preterm Infants.

OBJECTIVE: To compare the discriminative performances of the 2018 National Institutes of Health (NIH) and the 2019 Jensen definitions of bronchopulmonary dysplasia (BPD) with the 2001 NIH definition on adverse neurodevelopmental and respiratory outcomes at 2 years and 5 years corrected age. STUDY DESIGN: In this single-center retrospective cohort study, outcomes of infants born at <30 weeks of gestational age were collected. The 3 definitions of BPD were compared by adding the different definitions to the National Institute of Child Health and Human Development's outcome prediction model for neurodevelopmental impairment (NDI) or death. Discriminative performance was compared for both outcomes at 2 years and 5 years corrected age by calculating the areas under the receiver operating characteristic curve and z-statistics. RESULTS: The presence of BPD and its severity were determined in 584 infants. There were considerable shifts in BPD grading among the different definitions. At both time points, all BPD definition models had comparable discriminating power for NDI and respiratory morbidity, with one exception. Compared with the 2001 NIH definition, the 2018 NIH definition had less predictive power for the neurologic outcome at 2 years corrected age. CONCLUSIONS: Our comparison of the 3 BPD definitions shows similar discriminative performance on long term neurodevelopmental and respiratory outcomes at 2 years and 5 years corrected age.

Childhood outcomes after induction of labor or expectant management for preterm prelabor rupture of membranes: a 10-year follow-up of the PPROMEXIL trials.

BACKGROUND: Management of late preterm prelabor rupture of membranes between 34+0 and 36+6 weeks' gestation balances the risks of preterm birth with the risks of infection for both the mother and the neonate. Expectant management to prolong pregnancy showed similar risks of neonatal sepsis, but children at 2 years of age showed more neurodevelopmental delay when compared with induction of labor. Long-term outcomes on child development after 2 years of age are unknown. OBJECTIVE: This study aimed to assess the long-term outcomes of children born after singleton pregnancies complicated by late preterm prelabor rupture of membranes managed by induction of labor in comparison with expectant management. STUDY DESIGN: This was a follow-up study of the Preterm Prelabor Rupture of Membranes Expectant Management Versus Induction of Labor (PPROMEXIL) trials (randomized controlled trials between 2007 to 2011) evaluating children at 10 to 12 years of age (Netherlands Trial Register 6953). The primary outcomes were cognition, motor function, and behavior as assessed by the Wechsler Intelligence Scale for Children-V-NL, Movement Assessment Battery for Children-2, and Child Behavior Checklist, respectively. The secondary outcomes were sensory processing, respiratory problems, educational attainment, and general health. Mild delay was defined as -1 standard deviation or corresponding percentile. The relative risk and confidence intervals were calculated using standard methods. RESULTS: This follow-up study invited 711 surviving children of the 714 singleton pregnancies randomized in the original trials. In total, 248 (35%) children participated (127 induction of labor, 121 expectant management). Children born after induction of labor had no significant differences in the primary outcomes when compared with those born after expectant management. Mild cognitive delay was observed in 7 of 122 (5.7%) children born after induction of labor in comparison with in 12 of 120 (10.0%) children born after expectant management (relative risk, 0.57; 95% confidence interval, 0.23-1.41). A mild delay in motor function was observed in 42 of 122 (34.4%) children born after induction of labor vs in 55 of 120 (45.8%) children born after expectant management (relative risk, 0.75; 95% confidence interval, 0.55-1.03). Mild abnormal behavior was observed in 37 of 125 (29.6%) children born after induction of labor compared with in 33 of 118 (28.0%) children born after expectant management (relative risk, 1.05; 95% confidence interval, 0.71-1.57). Secondary outcomes were also comparable between the induction of labor and the expectant management groups except that more children born after expectant management had a hospital admission (relative risk, 0.68; 95% confidence interval, 0.52-0.89) or a surgery (relative risk, 0.58; 95% confidence interval, 0.41-0.82). CONCLUSION: In children born after pregnancies with late preterm prelabor rupture of membranes, expectant management did not improve long-term outcomes at 10 to 12 years when compared with induction of labor.

Structured Multidisciplinary Follow-Up After Pediatric Intensive Care: A Model for Continuous Data-Driven Health Care Innovation.

OBJECTIVES: Morbidity after PICU admission for critical illness is a growing concern. Sequelae may occur in various domains of functioning and can only appropriately be determined through structured follow-up. Here, we describe the process of designing and implementing a structured multidisciplinary follow-up program for patients and their parents after PICU admission and show the first results illustrating the significance of our program. DESIGN: Prospective observational cohort study. SETTING: Outpatient PICU follow-up clinic. PATIENTS: Patients 0-18 years old admitted to our PICU. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: In our structured multidisciplinary follow-up program, follow-up care is provided by a pediatric intensivist and psychologist and in addition, depending on patient's critical illness and received PICU treatment(s), by a pediatric pulmonologist, cardiologist, neurologist, and/or neuropsychologist. All consultations are scheduled consecutively. Collected data are stored in a hospital-wide data warehouse and used for yearly health care evaluation sessions as well as scientific research. Challenges in organizing this follow-up program include technological challenges, providing time-efficient care, participation rate, and completeness of questionnaires. In our experience, a dedicated team is essential to tackle these challenges. Our first results, obtained in 307 of 388 referred patients (79.1%), showed the diversity of problems arising after PICU discharge, including physical, neurocognitive, and psychosocial sequelae. In addition, our data also reflected the risk of psychosocial problems among parents. Within the limited operation time of our follow-up program, the program has evolved based on our experiences and the data collected. CONCLUSIONS: We successfully developed and implemented a structured multidisciplinary follow-up program for patients and their parents after PICU admission. This program may help to timely initiate appropriate interventions, improve the standard of care during and after PICU admission, and facilitate scientific research on outcome and prognosis after PICU admission.

Preterm Birth is Associated with Lower Academic Attainment at Age 12 Years: A Matched Cohort Study by Linkage of Population-Based Datasets.

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 250/7-296/7 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.

Severity of Bronchopulmonary Dysplasia and Neurodevelopmental Outcome at 2 and 5 Years Corrected Age.

OBJECTIVE: To evaluate the association between bronchopulmonary dysplasia (BPD) severity and risk of neurodevelopmental impairment (NDI) at 2 years and 5 years corrected age and to examine whether this association changes over time. STUDY DESIGN: This single-center retrospective cohort study included patients with a gestational age <30 weeks surviving to 36 weeks postmenstrual age, divided into groups according to BPD severity. NDI was defined as having cognitive or motor abilities below -1 SD, cerebral palsy, or a hearing or a visual impairment. The association was assessed using a multivariate logistic regression model analysis, adjusting for known confounders for NDI, and mixed-model analysis. RESULTS: Of the 790 surviving infants (15% diagnosed with mild BPD, 9% with moderate BPD, and 10% with severe BPD), 88% and 82% were longitudinally assessed at 2 years and 5 years corrected age, respectively. The mixed-model analysis showed a statistically significant increase in NDI at all levels of BPD severity compared with infants with no BPD, and a 5-fold increased risk in NDI was seen from 2 years to 5 years corrected age in all degrees of BPD severity. The strength of this association between NDI and BPD severity did not change over time. CONCLUSIONS: Increased BPD severity is associated with increased risk of NDI at both 2 years and 5 years corrected age. The absolute incidence of NDI increased significantly from 2 years to 5 years corrected age for all BPD severity categories, but this increased risk was similar at both time points in each category.

Executive function training in very preterm children: a randomized controlled trial.

Objective of the current study was to assess whether game-formatted executive function (EF) training, is effective in improving attention, EF and academic performance in very preterm and/or extremely low birthweight children aged 8-12 years. A multi-center, double-blind, placebo- and waitlist controlled randomized trial (NTR5365) in two academic hospitals in The Netherlands was performed. Eighty-five very preterm children with parent-rated attention problems on the Child Behavior Checklist were randomized to one of three treatment conditions: EF training, placebo training or waitlist condition. EF or placebo training was completed at home (6 weeks, 25 sessions of 30-45 min each). At baseline, 2 weeks after training or being on the waitlist, and five months after first follow-up visit, children underwent assessments of primary outcomes (parent and teacher ratings of attention) and secondary outcomes (parent and teacher ratings of daily-life EF, computerized EF tasks and academic performance). Linear mixed model analyses were performed for all outcome measures. There were no significant differences in improvement over time on parent- and teacher ratings of attention, parent- and teacher ratings of daily-life EF, computerized EF tasks, and academic performance (arithmetic and reading) between the EF training, placebo training and waitlist condition. In conclusion, game-formatted EF training does not improve attention, EF or academic performance in very preterm children with parent-rated attention problems.

Eight-year-old very and extremely preterm children showed more difficulties in performance intelligence than verbal intelligence.

AIM: This study determined possible discrepancies between verbal IQ and performance IQ in 8-year-old very preterm (VPT) and extremely preterm (EPT) children, and examined associations between verbal IQ and performance IQ, and sociodemographic factors, perinatal factors, early cognitive outcomes and also with school achievement scores. METHODS: This prospective cohort study included 120 eight-year-old VPT/EPT children. Cognitive development was assessed at the ages of 2, 5 and 8 years. Eight years' school achievement results in arithmetic, reading and spelling were collected. Multiple regression analyses were performed to determine predictors of verbal IQ and performance IQ at the age of 8 years and to determine associations with school achievement scores. RESULTS: Mean performance IQ (89.8) was significantly lower than mean verbal IQ (99.4; Cohen's d = 0.59) at the age of 8 years. Gestational age (GA), small for GA status, and cognitive scores at the ages of 2 and 5 years significantly predicted verbal IQ and performance IQ at the age of 8 years. Performance IQ at age 8 years was an important predictor for arithmetic scores (ß = 0.42). CONCLUSION: Performance IQ was more strongly affected than verbal IQ in 8-year-old VPT/EPT children and was strongly related to mathematical difficulties.

Executive function deficits in children born preterm or at low birthweight: a meta-analysis.

AIM: To investigate the magnitude of executive function deficits and their dependency on gestational age, sex, age at assessment, and year of birth for children born preterm and/or at low birthweight. METHOD: PubMed, PsychINFO, Web of Science, and ERIC were searched for studies reporting on executive functions in children born preterm/low birthweight and term controls born in 1990 and later, assessed at a mean age of 4 years or higher. Studies were included if five or more studies reported on the same executive function measures. RESULTS: Thirty-five studies (3360 children born preterm/low birthweight, 2812 controls) were included. Children born preterm/low birthweight performed 0.5 standardized mean difference (SMD) lower on working memory and cognitive flexibility and 0.4 SMD lower on inhibition. SMDs for these executive functions did not significantly differ from each other. Meta-regression showed that heterogeneity in SMDs for working memory and inhibition could not be explained by study differences in gestational age, sex, age at assessment, or year of birth. INTERPRETATION: Children born preterm/low birthweight since 1990 perform half a SMD below term-born peers on executive function, which does not seem to improve with more recent advances in medical care or with increasing age. WHAT THIS PAPER ADDS: Children born preterm/low birthweight perform below term-born children on core executive functions. Lower gestational age or male sex are not risk factors for poorer executive functions. Executive function difficulties in children born preterm/low birthweight remain stable across childhood. Executive function difficulties are similar for children born recently and children born in earlier eras.

Maternal psychological distress after severe pregnancy hypertension was associated with increased child behavioural problems at the age of 12.

AIM: We examined the association between early maternal psychological distress after severe hypertensive disorders of pregnancy (HDP) and behavioural issues in their 12-year-old offspring. METHODS: This secondary analyses of a prospective mother-child birth cohort focused on 95 women with severe HDP and their singleton offspring. The mothers were recruited during pregnancy from 2000 to 2003 in Amsterdam, the Netherlands. Maternal distress at child term age and three months post-term was measured using the Symptom Checklist-90. The Child Behaviour Checklist for six years to 18 years was used to quantify social and attention problems in their offspring at 12 years of age. Perinatal and neonatal risk factors were also analysed. RESULTS: The children were born at a mean age of just under 32 weeks and 90% weighed below the 10th percentile. High psychological distress (score ≥133) affected 45% of the mothers at term age and 44% three months post-term. Child social problems were significantly associated with maternal distress at three months and were highest in cases of high maternal distress in combination with major neonatal morbidity. Child attention problems were associated with maternal anxiety at three months post-term. CONCLUSION: Early maternal psychological distress after severe maternal HDP was associated with childhood behavioural issues at the age of 12.

Fetal Growth Restriction with Brain Sparing: Neurocognitive and Behavioral Outcomes at 12 Years of Age.

OBJECTIVE: To study neurocognitive functions and behavior in children with a history of fetal growth restriction (FGR) with brain sparing. We hypothesized that children with FGR would have poorer outcomes on these domains. STUDY DESIGN: Subjects were 12-year-old children with a history of FGR born to mothers with severe early-onset hypertensive pregnancy disorders (n = 96) compared with a normal functioning full term comparison group with a birth weight ≥2500 g (n = 32). Outcome measures were neurocognitive outcomes (ie, intelligence quotient, executive function, attention) and behavior. RESULTS: For the FGR group, the mean ratio of the pulsatility index for the umbilical artery/middle cerebral artery (UC-ratio = severity of brain sparing) was 1.42 ± 0.69. The mean gestational age was 31-6/7 ± 2-2/7 weeks. The mean birth weight was 1341 ± 454 g, and the mean birth weight ratio 0.68 ± 0.12. Neurocognitive outcomes were comparable between groups. Parents of children with FGR reported more social problems (mean T-score 56.6 ± 7.7; comparison 52.3 ± 4.3, P < .001, effect size = 1, 95% CI 0.52-1.46) and attention problems (mean T-score 57.3 ± 6.9; comparison 53.6 ± 4.2, P = .004, effect size = 0.88, 95% CI 0.42-1.33). UC-ratio was not associated with any of the outcomes, but low parental education and lower birth weight ratio were. CONCLUSIONS: In this prospective follow-up study of 12-year-old children with a history of FGR and confirmed brain sparing, neurocognitive functions were comparable with the comparison group, but parent-reported social and attention problem scores were increased.

Consequences of Correcting Intelligence Quotient for Prematurity at Age 5 Years.

OBJECTIVES: To determine the effects of correcting for prematurity on full scale IQ (FSIQ), verbal IQ (VIQ), performance IQ (PIQ), and processing speed quotient (PSQ) scores, and to investigate whether differences between corrected and uncorrected FSIQ are associated with gestational age (GA), FSIQ, and age at assessment. STUDY DESIGN: Single-center consecutive cohort study. Data were analyzed from 275 very preterm children (GA <30 weeks), born between January 2006 and December 2009 and assessed at 5 years corrected age as part of the neonatal long-term follow-up program, at the Emma Children's Hospital in Amsterdam, The Netherlands. Outcome measures were FSIQ, VIQ, PIQ, and PSQ, calculated for uncorrected and corrected age. Paired sample t tests, repeated measures ANOVA, and ANCOVA were performed to explore differences between corrected and uncorrected IQ. RESULTS: Differences between corrected and uncorrected FSIQ, VIQ, PIQ, and PSQ ranged from 0-15 IQ points. All corrected IQ scores were significantly higher than uncorrected IQ scores (all P values <.001). Differences were larger at lower GAs, for higher IQ scores, and if time of assessment lay near the starting point of a 3-month age band of the Wechsler Preschool and Primary Scale of Intelligence-Third Edition-Dutch Version. CONCLUSIONS: Given the great variation observed in differences between corrected and uncorrected IQ scores, an international standard as to what age correction is appropriate should be pursued.

Risk Factors for Neurodevelopmental Impairment at 2- and 5-Years Corrected Age in Preterm Infants with Established Bronchopulmonary Dysplasia.

INTRODUCTION: The objective of this study was to identify risk factors for neurodevelopmental impairment (NDI) at 2- and 5-years corrected age (CA) in a cohort of preterm infants with established bronchopulmonary dysplasia (BPD). METHODS: This single-center retrospective cohort study included infants born between 2009 and 2016 at a gestational age (GA) <30 weeks with moderate or severe BPD at 36 weeks' postmenstrual age. Perinatal characteristics, (social) demographics, and comorbidities were collected from the electronic patient records. Odds ratios for NDI were calculated with univariate and multivariate logistic regression analyses adjusting for potential confounders. RESULTS: Of the 602 eligible infants, 123 infants were diagnosed with BPD. NDI was present in 30.3% and 56.1% at 2- and 5-years CA, respectively. The only independent risk factors associated with NDI in the multivariate analyses were birthweight (adjusted odds ratio [aOR] 0.74, 95% CI 0.57-0.95; aOR 0.70, 95% CI 0.54-0.91, respectively), small for GA (SGA) (aOR 3.25, 95% CI 1.09-9.61; aOR 5.44, 95% CI 1.62-18.2, respectively) at both time points, and male gender at 5-years CA (OR 2.49, 95% CI 1.11-5.57). CONCLUSION: Birthweight and SGA are independent risk factors for NDI at 2- and 5-years CA and male gender at 5-years CA in preterm infants with BPD. In contrast, well-known other risk factors for NDI in the general population of preterm infants, such as GA, maternal education, and neonatal comorbidities were not independently associated with NDI.

Association between bronchopulmonary dysplasia severity and its risk factors and long-term outcomes in three definitions: a historical cohort study.

OBJECTIVE: To compare the association of the severity categories of the 2001-National Institutes of Health (NIH), the 2018-NIH and the 2019-Jensen bronchopulmonary dysplasia (BPD) definitions with neurodevelopmental and respiratory outcomes at 2 and 5 years' corrected age (CA), and several BPD risk factors. DESIGN: Single-centre historical cohort study with retrospective data collection. SETTING: Infants born between 2009 and 2015 at the Amsterdam University Medical Centers, location Amsterdam Medical Center. PATIENTS: Preterm infants born at gestational age (GA) <30 weeks and surviving up to 36 weeks' postmenstrual age. INTERVENTIONS: Perinatal characteristics, (social) demographics and comorbidities were collected from the electronic patient records. MAIN OUTCOME MEASURES: The primary outcomes were neurodevelopmental impairment (NDI) or late death, and respiratory morbidity at 2 and 5 years' CA. Using logistic regression and Brier scores, we investigated if the ordinal grade severity is associated with incremental increase of adverse long-term outcomes. RESULTS: 584 preterm infants (median GA: 28.1 weeks) were included and classified according to the three BPD definitions. None of the definitions showed a clear ordinal incremental increase of risk for any of the outcomes with increasing severity classification. No significant differences were found between the three BPD definitions (Brier scores 0.169-0.230). Respiratory interventions, but not GA, birth weight or small for GA, showed an ordinal relationship with BPD severity in all three BPD definitions. CONCLUSION: The severity classification of three BPD definitions showed low accuracy of the probability forecast on NDI or late death and respiratory morbidity at 2 and 5 years' CA, with no differences between the definitions.

Effect of systemic hydrocortisone in ventilated preterm infants on parent-reported behavioural outcomes at 2 years' corrected age: follow-up of a randomised clinical trial.

OBJECTIVE: To report the parent-reported behavioural outcomes of infants included in the Systemic Hydrocortisone To Prevent Bronchopulmonary Dysplasia in preterm infants study at 2 years' corrected age (CA). DESIGN: Randomised placebo-controlled trial. SETTING: Dutch and Belgian neonatal intensive care units. PATIENTS: Infants born <30 weeks' gestation and/or birth weight <1250 g, and ventilator dependent in the second week of life. INTERVENTION: Infants were randomly assigned to a 22-day course of systemic hydrocortisone (cumulative dose 72.5 mg/kg; n=182) or placebo (n=190). MAIN OUTCOME MEASURES: Parent-reported behavioural outcomes at 2 years' CA assessed with the Child Behavior Checklist (CBCL 1½-5). RESULTS: Parents completed the CBCL of 183 (70% (183/262)) infants (hydrocortisone group, n=96; placebo group, n=87). Multiple imputation was used to account for missing data. Infants with critically elevated T-scores (>55) were found in 22.9%, 19.1% and 29.4% of infants for total, internalising and externalising problems, respectively; these scores were not significantly different between groups (mean difference -1.52 (95% CI -4.00 to 0.96), -2.40 (95% CI -4.99 to 0.20) and -0.81 (95% CI -3.40 to 1.77), respectively). In the subscales, we found a significantly lower T-score for anxiety problems in the hydrocortisone group (mean difference -1.26, 95% CI -2.41 to -0.12). CONCLUSION: This study found high rates of behaviour problems at 2 years' CA following very preterm birth, but these problems were not associated with hydrocortisone treatment initiated between 7 and 14 days after birth in ventilated preterm infants. TRIAL REGISTRATION NUMBER: NTR2768; EudraCT 2010-023777-19.

Duration of Neonatal Antibiotic Exposure in Preterm Infants in Association with Health and Developmental Outcomes in Early Childhood.

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.

The profile of executive function in very preterm children at 4 to 12 years.

AIM: To examine executive functioning in very preterm (gestational age ≤30 wks) children at 4 to 12 years of age. METHOD: Two-hundred very preterm (106 males, 94 females; mean gestational age 28.1wks, SD 1.4; mean age 8y 2mo, SD 2y 6mo) and 230 term children (106 males, 124 females; mean gestational age 39.9wks, SD 1.2; mean age 8y 4mo, SD 2y 3mo) without severe disabilities, born between 1996 and 2004, were assessed on an executive function battery comprising response inhibition, interference control, switching, verbal fluency, verbal and spatial working memory, and planning. Multiple regression analyses examined group differences while adjusting for effects of parental education, age, sex, and speed indices. RESULTS: Relative to children born at term, very preterm children had significant (p(s) <0.02; where p(s) represents p-values) deficits in verbal fluency (0.5 standardized mean differences [SMD]), response inhibition (0.4 SMD), planning (0.4 SMD), and verbal and spatial working memory (0.3 SMD), independent of slow and highly fluctuating processing speed. A significant group by age interaction indicated that group differences for response inhibition decreased between 4 and 12 years. INTERPRETATION: Very preterm birth is associated with a profile of affected and non-affected executive functions independent of impaired speed. Deficits are of small to moderate magnitude and persist over time, except for response inhibition for which very preterm children catch up with peers.

Long-term follow-up of children exposed in-utero to progesterone treatment for prevention of preterm birth: study protocol of the AMPHIA follow-up.

INTRODUCTION: Preterm birth is one of the main problems in obstetrics, and the most important cause of neonatal mortality, morbidity and neurodevelopmental impairment. Multiple gestation is an important risk factor for preterm birth, with up to 50% delivering before 37 weeks. Progesterone has a role in maintaining pregnancy and is frequently prescribed to prevent (recurrent) preterm birth and improve pregnancy outcomes in high-risk patients. However, little is known about its long-term effects in multiple gestations. The objective of this follow-up study is to assess long-term benefits and harms of prenatal exposure to progesterone treatment in multiple gestations on child development. METHODS AND ANALYSIS: This is a follow-up study of a multicentre, double-blind, placebo-controlled randomised trial (AMPHIA trial, ISRCTN40512715). Between 2006 and 2009 women with a multiple gestation were randomised at 16-20 weeks of gestation to weekly injections 250 mg 17α-hydroxyprogesterone caproate or placebo, until 36 weeks of gestation or delivery. The current long-term follow-up will assess all children (n=1355) born to mothers who participated in the AMPHIA trial, at 11-14 years of age, with internationally validated questionnaires, completed by themselves, their parents and their teachers. MAIN OUTCOMES ARE CHILD COGNITION AND BEHAVIOUR: Additional outcomes are death (perinatal and up to age 14), gender identity, educational performance and health-related problems. We will use intention-to-treat analyses comparing experimental and placebo group. To adjust for the correlation between twins, general linear mixed-effects models will be used. ETHICS AND DISSEMINATION: Amsterdam UMC MEC provided a waiver for the Medical Research Involving Human Subjects Act (W20_234#20.268). Results will be disseminated through peer-reviewed journals and summaries shared with stakeholders, patients and participants. This protocol is published before analysis of the results. TRIAL REGISTRATION NUMBER: NL8933.

Child outcomes after induction of labour or expectant management in women with preterm prelabour rupture of membranes between 34 and 37 weeks of gestation: study protocol of the PPROMEXIL Follow-up trial. A long-term follow-up study of the randomised controlled trials PPROMEXIL and PPROMEXIL-2.

INTRODUCTION: Late preterm prelabour rupture of membranes (PROM between 34+0 and 36+6 weeks gestational age) is an important clinical dilemma. Previously, two large Dutch randomised controlled trials (RCTs) compared induction of labour (IoL) to expectant management (EM). Both trials showed that early delivery does not reduce the risk of neonatal sepsis as compared with EM, although prematurity-related risks might increase. An extensive, structured long-term follow-up of these children has never been performed. METHODS AND ANALYSIS: The PPROMEXIL Follow-up trial (NL6623 (NTR6953)) aims to assess long-term childhood outcomes of the PPROMEXIL (ISRCTN29313500) and PPROMEXIL-2 trial (ISRCTN05689407), two multicentre RCTs using the same protocol, conducted between 2007 and 2010 evaluating IoL versus EM in women with late preterm PROM. The PPROMEXIL Follow-up will analyse children of mothers with a singleton pregnancy (PPROMEXIL trial n=520, PPROMEXIL-2 trial n=191, total IoL n=359; total EM n=352). At 10-12 years of age all surviving children will be invited for a neurodevelopmental assessment using the Wechsler Intelligence Scale for Children-V, Color-Word Interference Test and the Movement Assessment Battery for Children-2. Parents will be asked to fill out questionnaires assessing behaviour, motor function, sensory processing, respiratory problems, general health and need for healthcare services. Teachers will fill out the Teacher Report Form and answer questions regarding school attainment. For all tests means with SDs will be compared, as well as predefined cut-off scores for abnormal outcome. Sensitivity analyses consisting of different imputation techniques will be used to deal with lost to follow-up. ETHICS AND DISSEMINATION: The study has been granted approval by the Medical Centre Amsterdam (MEC) of the AmsterdamUMC (MEC2016_217). Results will be disseminated through peer-reviewed journals and summaries shared with stakeholders. This protocol is published before analysis of the results. TRIAL REGISTRATION NUMBER: NL6623 (NTR6953).