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It is under debate how preferential perfusion of the brain (brain-sparing) in fetal growth restriction (FGR) relates to long-term neurodevelopmental outcome. Epigenetic modification of neurotrophic genes by altered fetal oxygenation may be involved. To explore this theory, we performed a follow-up study of 21 FGR children, in whom we prospectively measured the prenatal cerebroplacental ratio (CPR) with Doppler sonography. At 4 years of age, we tested their neurodevelopmental outcome using the Wechsler Preschool and Primary Scale of Intelligence, the Child Behavior Checklist, and the Behavior Rating Inventory of Executive Function. In addition, we collected their buccal DNA to determine the methylation status at predefined genetic regions within the genes hypoxia-inducible factor-1 alpha (HIF1A), vascular endothelial growth factor A (VEGFA), erythropoietin (EPO), EPO-receptor (EPOR), brain-derived neurotrophic factor (BDNF), and neurotrophic tyrosine kinase, receptor, type 2 (NTRK2) by pyrosequencing. We found that FGR children with fetal brain-sparing (CPR n = 8) demonstrated a trend (0.05 < p < 0.1) toward hypermethylation of HIF1A and VEGFA at their hypoxia-response element (HRE) compared with FGR children without fetal brain-sparing. Moreover, in cases with fetal brain-sparing, we observed statistically significant hypermethylation at a binding site for cyclic adenosine monophophate response element binding protein (CREB) of BDNF promoter exon 4 and hypomethylation at an HRE located within the NTRK2 promoter (both p VEGFA was associated with a poorer Performance Intelligence Quotient, while hypermethylation of BDNF was associated with better inhibitory self-control (both p

Introduction: Understanding the course of stress during the neonatal intensive care unit stay may provide targets for interventions. Our aim was to describe the course of stress in preterm infants during the first 28 days of life, the influence of gestational age, and associations with clinical characteristics. Methods: In a single centre prospective cohort study, we included infants with a gestational age Results: We included 45 infants, with a median gestational age of 27 weeks. The mean daily NISS score was 66.5 (SD 8.7), with highest scores in the first 7 days of life. Scores decreased the slowest for the lowest gestational ages, in particular for nursing scores, rather than skin-breaking, monitoring and imaging, and medical morbidity-related scores. Adjusted for gestational age, infants with lower Apgar scores, sepsis, intraventricular haemorrhages, and on mechanical ventilation had significantly higher cumulative NISS scores at 7, 14, and 28 days. Conclusion: NISS scores varied greatly within infants and over time, with the highest mean scores in the first week after birth. The course of declining NISS scores in the first 28 days depended on gestational age at birth.

BACKGROUND: Changes in near-infrared spectroscopy-derived regional tissue oxygen saturation (StO2) during a vascular occlusion test (VOT; ischemic provocation of microcirculation by rapid inflation and deflation of a tourniquet) allow estimating peripheral tissue O2 consumption (desaturation slope; DS), vascular reactivity (recovery slope; RS) and post-ischemic hyperperfusion (AUC-H). The effects of isolated alterations in the inspiratory fraction of O2 (FiO2) and changes in expiratory CO2 remain to be elucidated. Therefore, in this secondary analysis we determined the effects of standardized isolated instances of hypoxia, hyperoxia, hypocapnia and hypercapnia on the VOT-induced StO2 changes in healthy volunteers (n = 20) to establish reference values for future physiological studies.METHODS: StO2 was measured on the thenar muscle. Multiple VOTs were performed in a standardized manner: i.e. at room air (baseline), during hyperoxia (FiO2 1.0), mild hypoxia (FiO2 ≈ 0.11), and after a second baseline, during hypocapnia (end-tidal CO2 (etCO2) 2.5-3.0 vol%) and hypercapnia (etCO2 7.0-7.5 vol%) at room air. Differences in DS, RS, and AUC-H were tested using repeated-measures ANOVA.RESULTS: DS and RS remained constant during all applied conditions. AUC-H after hypoxia was smaller compared to hyperoxia (963 %*sec vs hyperoxia 1702 %*sec, P = 0.005), while there was no difference in AUC-H duration between hypoxia and baseline. The StO2 peak (after tourniquet deflation) during hypoxia was lower compared to baseline and hyperoxia (92 % vs 94 % and 98 %, P < 0.001).CONCLUSION: We conclude that in healthy volunteers at rest, common situations observed during anesthesia and intensive care such as exposure to hypoxia, hyperoxia, hypocapnia, or hypercapnia, did not affect peripheral tissue O2 consumption and vascular reactivity as assessed by VOT-induced changes in StO2. These observations may serve as reference values for future physiological studies.TRIAL REGISTRATION: This study represents a secondary analysis of an original study which has been registered at ClinicalTrials.gov nr: NCT02561052.

Pulmonary hypertension (PH) is a frequent complication in extremely preterm born infants that seriously affects outcome. We aimed to describe the prevalence of PH in extremely preterm infants and the policy on screening and follow-up in the ten Dutch intensive care units (NICUs). We performed a retrospective cohort study at the University Medical Centre Groningen on infants with gestational age < 30 weeks and/or birthweight < 1000 g, born between 2012 and 2013. Additionally, we carried out a survey among the Dutch NICUs covering questions on the awareness of PH, the perceived prevalence, and policy regarding screening and following PH in extremely preterm infants. Prevalence of early-onset PH in our study was 26% and 5% for late-onset PH. PH was associated with poor survival and early-onset PH was associated with subsequent development of bronchopulmonary dysplasia (BPD). All the NICUs completed the questionnaire and we found that no standardized policy existed regarding screening and following PH in extremely preterm infants.Conclusion: Despite the frequent occurrence of PH and its clinically important consequences, (inter-)national standardized guidelines regarding screening and following of PH in extremely preterm infants are lacking. Standardizing screening and follow-up will enable early identification of infants with late-onset PH and allow for earlier treatment. Additionally, greater clarity is required regarding the prevalence of early PH as are new preventive treatment strategies to combat BPD. What is known? • Pulmonary hypertension (PH) substantially impairs the survival of extremely preterm infants. • PH is associated with bronchopulmonary dysplasia (BPD): Early-onset PH predicts the development of BPD. Late-onset PH is prevalent in infants with severe BPD. What is new? • Pulmonary hypertension (PH) is prevalent in preterm infants. Its consequences for morbidity and mortality justify a standardized policy aimed at early detection to improve prevention and treatment. • No structured policy exists in the Netherlands regarding screening/follow-up for PH in extremely preterm infants.

Persistent organic pollutants (POPs), such as polychlorinated biphenyls (PCBs), may interfere with hormonal processes. Knowledge about the effects of prenatal exposure to PCBs and their hydroxylated metabolites (OH-PCBs) on pubertal development is limited. Therefore, the aim of the current study was to determine whether prenatal environmental PCB and OH-PCB exposure are associated with reproductive hormone levels and pubertal characteristics in 13- to 15-year-old children. In this Dutch observational cohort study, 194 mother–infant pairs were included (1998–2002). Maternal pregnancy serum levels of PCBs, OH-PCBs, and other POPs were measured. At follow-up (2014–2016), we measured serum or plasma levels of reproductive hormones in their children. We assessed Tanner stages and testicular volume (by clinician or standardized self-assessment), and participants completed questionnaires on pubertal onset. In total, 101 adolescents (14.4 ± 0.8 years; 53.7% of invited) participated, and 55 were boys. In boys, higher prenatal PCB levels were associated with higher testosterone levels, higher pubic hair stage, larger testicular volume, and younger age at onset of growth spurt and voice break. In girls, higher prenatal PCB levels were associated with higher stages for breast development. In conclusion, higher prenatal PCB exposure could be associated with more advanced pubertal development in 13- to 15-year-old children.

ObjectiveTo determine the survival and evolution of pulmonary hypertension (PH) associated with bronchopulmonary dysplasia (BPD) in extremely premature born infants beyond 36 weeks postmenstrual age (PMA).DesignA single-centre retrospective cohort study from a university hospital.PatientsExtremely preterm (gestational age Main outcome measuresSurvival, mortality rate and PH resolution. Patient characteristics, treatment, presence and evolution of PH were collected from patient charts.ResultsTwenty-eight infants were included. All had BPD, while 23 (82%) had severe BPD and 11 infants (39%) died. Survival rates at 1, 3 and 7 months from 36 weeks PMA were 89%, 70% and 58%, respectively. In 16 of the 17 surviving infants, PH resolved over time, with a resolution rate at 1 and 2 years corrected age of 47% and 79%, respectively. At 2.5 years corrected age, the resolution rate was 94%.ConclusionsThese extremely preterm born infants with PH-BPD had a survival rate of 58% at 6 months corrected age. Suprasystemic pulmonary artery pressure was associated with poor outcome. In the current study, infants surviving beyond the corrected age of 6 months showed excellent survival and resolution of PH in almost all cases. Prospective follow-up studies should investigate whether resolution of PH in these infants can be improved by multi-modal therapies, including respiratory, nutritional and cardiovascular treatments.

OBJECTIVE: To assess whether regional intestinal oxygen saturation (rintSO2) and regional cerebral oxygen saturation (rcSO2) measurements aid in estimating survival of preterm infants after surgery for NEC.SUMMARY OF BACKGROUND DATA: Predicting survival after surgery for NEC is difficult yet of the utmost importance for counseling parents.METHODS: We retrospectively studied prospectively collected data of preterm infants with surgical NEC who had available rintSO2 and rcSO2 values measured via near-infrared spectroscopy 0-24 hours preoperatively. We calculated mean rintSO2 and rcSO2 for 60-120 minutes for each infant. We analyzed whether preoperative rintSO2 and rcSO2 differed between survivors and non-survivors, determined cut-off points, and assessed the added value to clinical variables.RESULTS: We included 22 infants, median gestational age 26.9 weeks [interquartile range (IQR): 26.3-28.4], median birth weight 1088 g [IQR: 730-1178]. Eleven infants died postoperatively. Preoperative rintSO2, but not rcSO2, was higher in survivors than in non-survivors [median: 63% (IQR: 42-68) vs 29% (IQR: 21-43), P < 0.01), with odds ratio for survival 4.1 (95% confidence interval, 1.2-13.9, P = 0.02) per 10% higher rintSO2. All infants with rintSO2 values of >53% survived, whereas all infants with rintSO2 CONCLUSIONS: Measuring rintSO2, but not rcSO2, seems of added value to clinical variables in estimating survival of preterm infants after surgery for NEC. This may help clinicians in deciding whether surgery is feasible and to better counsel parents about their infants' chances of survival.

Persistent organic pollutants (POPs) may have obesogenic effects. Knowledge about the effects of prenatal exposure to POPs on anthropometric measurements and metabolic parameters into adolescence is limited. Therefore, the aim of the current study was to determine whether prenatal environmental exposure to several POPs is associated with indices of overweight and cardiovascular risk in 13–15-year-old children. In this Dutch observational cohort study, 194 mother–infant pairs were included (1998–2002). Maternal pregnancy serum levels of PCBs, OH-PCBs, PBDEs, and other POPs were measured. At follow-up (2014–2016), levels of cholesterol, HDL-C, LDL-C, triglycerides, fasting insulin, fasting glucose, leptin, and adiponectin were measured in their children. The children’s height, weight, waist circumference, hip circumference, and blood pressure were measured. In total, 101 adolescents (14.4 ± 0.8 years; 53.7% of invited) participated of which 55 were boys. Mean BMI was 19.1 ± 3.6 kg/m2 and mean BMI z-score 0.13 ± 1.14. Higher prenatal levels of PCBs were associated with lower levels of HDL-C and adiponectin in boys and higher levels of PBDEs with higher triglycerides in girls. We found significant differences by sex in the associations with OH-PCBs, with lower HDL-C and adiponectin, higher LDL-C/HDL-C ratio, fasting glucose, HOMA2-IR, height, and weight for boys. Our study indicates that higher prenatal exposure to PCBs, OH-PCBs, and PBDEs was associated with adolescent levels of some metabolic cardiovascular risk markers and hormones associated with the development of obesity and cardiovascular disease.

The detection of motor developmental problems, especially developmental coordination disorder, at age 5-6 contributes to early interventions. Here, we summarize evidence on (1) criterion validity of screening instruments for motor developmental problems at age 5-6, and (2) their applicability. We systematically searched seven databases for studies assessing criterion validity of these screening instruments using the M-ABC as reference standard. We applied COSMIN criteria for systematic reviews of screening instruments to describe the correlation between the tests and the M-ABC. We extracted information on correlation coefficients or area under the receiver operating curve, sensitivity and specificity, and applicability in practice. We included eleven studies, assessing eight instruments: three performance-based tests (MAND, MOT 4-6, BFMT) and five questionnaires (DCD-Q, PQ, ASQ-3, MOQ-T-FI, M-ABC-2-C). The quality of seven studies was fair, one was good, and three were excellent. Seven studies reported low correlation coefficients or AUC (

Problems in behavioural and emotional outcome are amongst the long-term sequelae of preterm birth. The exact prevalence and associations with perinatal risk factors are unknown. Minimal research has been performed in pre-school aged children, compared to school age. The primary aim of this study was to determine the prevalence of parent-reported behavioural and emotional problems at the age of two in children born at less than 30 weeks' gestational age and/or birth weight less than 1000 g. The secondary aim was to determine whether perinatal factors were associated with the behavioural and emotional outcome.Perinatal characteristics of 144 preterm-born children from the NeoLiFeS cohort were collected retrospectively. Of these children, 101 parents filled out a Childs Behaviour Checklist (CBCL) at the corrected age of two. The results of the CBCL tests were presented as Z-scores, a Z-score of 0 indicating the mean of behavioural scores in the norm population. A Z-score higher than zero indicates less behavioural problems than average, a negative Z-score indicates more problems. Associations between perinatal risk factors and CBCL-scores were analysed using linear regression analyses.Prevalences of clinically relevant CBCL scores were low, 4%, 2% and 5% for total score, internalizing score or externalizing score, respectively. Being part of a twin was associated with higher internalizing Z-scores, indicating less problems in emotional behaviour. Bronchopulmonary dysplasia was associated with lower Z-scores in total and externalizing behaviour. In conclusion, in our cohort generally very few problems in behavioural and emotional outcome were reported at the age of two.

Background The intestinal microbiome in preterm infants differs markedly from term infants. It is unclear whether the microbiome develops over time according to infant specific factors. Methods We analysed (clinical) metadata - to identify the main factors influencing the microbiome composition development - and the first meconium and faecal samples til the 4th week via 16 S rRNA amplican sequencing. Results We included 41 infants (gestational age 25–30 weeks; birth weight 430-990 g. Birth via Caesarean section (CS) was associated with placental insufficiency during pregnancy and lower BW. In meconium samples and in samples from weeks 2 and 3 the abundance of Escherichia and Bacteroides (maternal faecal representatives) were associated with vaginal delivery while Staphylococcus (skin microbiome representative) was associated with CS. Secondly, irrespective of the week of sampling or the mode of birth, a transition was observed as children children gradually increased in weight from a microbiome dominated by Staphylococcus (Bacilli) towards a microbiome dominated by Enterobacteriaceae (Gammaproteobacteria). Conclusions Our data show that the mode of delivery affects the meconium microbiome composition. They also suggest that the weight of the infant at the time of sampling is a better predictor for the stage of progression of the intestinal microbiome development/maturation than postconceptional age as it less confounded by various infant-specific factors.

CONTEXT An overview of the full range of neonatal stressors and the associated clinical, laboratory, and imaging outcomes regarding infants’ health and development may contribute to the improvement of neonatal care. OBJECTIVE To systematically review existing literature on the associations between all kinds of neonatal stressors and the health and development of preterm infants. DATA SOURCES Data sources included Embase, Medline, PsycINFO, the Cumulative Index to Nursing and Allied Health Literature, and reference lists. STUDY SELECTION Studies were eligible if they included a measure of neonatal stress during the NICU stay, reported clinical, laboratory, and/or imaging outcomes regarding health and/or development on discharge from the NICU or thereafter, included preterm infants, and were written in English or Dutch. DATA EXTRACTION Two reviewers independently screened the sources and extracted data on health and development. Study quality was assessed by using the Newcastle-Ottawa Quality Assessment Scale. RESULTS We identified 20 articles that reported on neonatal stress associated negatively with clinical outcomes, including cognitive, motor, and emotional development, and laboratory and imaging outcomes, including epigenetic alterations, hypothalamic-pituitary-adrenal axis functioning, and structural brain development. We found no evidence regarding associations with growth, cardiovascular health, parent-infant interaction, the neonatal immune system, and the neonatal microbiome. LIMITATIONS The studies were all observational and used different definitions of neonatal stress. CONCLUSIONS Neonatal stress has a profound impact on the health and development of preterm infants, and physicians involved in their treatment and follow-up should be aware of this fact.

Background: Neonatal anemia may compromise oxygen transport to the brain. The effects of anemia and cerebral oxygenation on neurological functioning in the early neonatal period are largely unknown. Objective: This study aimed to determine the association between initial hemoglobin levels (Hb) and early neurological functioning in preterm infants by assessing their general movements (GMs). Methods: A retrospective analysis of prospectively collected data on preterm infants born before 32 weeks of gestation was conducted. We excluded infants with intraventricular hemorrhage > grade II. On day 8, we assessed infants’ GMs, both generally as normal/abnormal and in detail using the general movement optimality score (GMOS). We measured cerebral tissue oxygen saturation (rcSO2) on day 1 using near-infrared spectroscopy. Results: We included 65 infants (median gestational age 29.9 weeks [IQR 28.2–31.0]; median birth weight 1,180 g [IQR 930–1,400]). Median Hb on day 1 was 10.3 mmol/L (range 4.2–13.7). Lower Hb on day 1 was associated with a higher risk of abnormal GMs (OR = 2.3, 95% CI: 1.3–4.1) and poorer GMOSs (B = 0.9, 95% CI: 0.2–1.7). Hemoglobin strongly correlated with rcSO2 (rho = 0.62, p < 0.01). Infants with lower rcSO2 values tended to have a higher risk of abnormal GMs (p = 0.06). After adjusting for confounders, Hb on day 1 explained 44% of the variance of normal/abnormal GMs and rcSO2 explained 17%. Regarding the explained variance of the GMOS, this was 25% and 16%, respectively. Conclusions: In preterm infants, low Hb on day 1 is associated with impaired neurological functioning on day 8, which is partly explained by low cerebral oxygenation.

BACKGROUND AND OBJECTIVES Children born very preterm ( METHODS Of 118 infants born RESULTS Seventy-eight (80%) infants with early motor repertoire data had neurodevelopmental assessments at 8 years. A higher MOS-R, and favorable components of the individual subscales of the MOS-R, including the presence of normal FMs, were associated with better performance for general cognition, attention, working memory, executive function and motor function at 8 years; eg, presence of normal FMs was associated with a 21.6 points higher general conceptual ability score (95% confidence interval: 12.8–30.5; P < .001) compared with absent FMs. CONCLUSIONS Favorable early motor repertoire of infants born

Introduction: Magnesium sulfate (MgSO4) is frequently administered for maternal and fetal neuroprotection in preeclampsia (PE) and imminent preterm birth, respectively. Objective: To assess whether MgSO4 affects neonatal cerebral oxygenation, blood flow, and cerebral autoregulation (CAR) during the first postnatal days independently from PE. Methods: 148 neonates 0.5) was determined. Linear mixed models were applied. Results: MgSO4 exposure was recorded in 77 neonates. Twenty-nine neonates were born following PE. MgSO4 independently lowered cFTOE (B: –0.026, 95% CI: –0.050 to 0.002, p < 0.05) but did not affect PSV and RI. PE was associated with a lower cFTOE (B: –0.041, 95% CI: –0.067 to –0.015, p < 0.05) and a tendency towards both lower PSV (B: –4.285, 95% CI: –9.067 to 0.497, p < 0.1) and more impaired CAR (B: 4.042, 95% CI: –0.028 to 8.112, p < 0.1), which seemed to be strongly mediated by fetal brain sparing. MgSO4 did not alter CAR. Conclusions: In contrast to fetal brain sparing in PE, MgSO4 seems to lower cFTOE by lowering cerebral oxygen demands in preterm neonates without affecting the cerebrovasculature.

Objective Migration of umbilical venous catheters (UVCs) after initial correct position has been described. The aim of this study was to assess the incidence of malposition of the tip of the UVCs at 24 to 36 hours postinsertion. Study Design Retrospective analysis of all neonates who had UVC placement in a 14-month period. The primary outcome was the rate of UVCs incorrectly positioned 24 to 36 hours after initial correct placement, defined as the UVC tip below or more than 5 mm above the level of the right diaphragm on a thoracoabdominal X-ray. Results We included 86 neonates with a median (range) birth weight of 1,617 (535–5,000) grams, and gestational age of 31 (24–42) weeks. Of the 80 UVCs that were further analyzed, only in 38 (48%) of 80 patients, the tip of the UVC still had a correct position 24 to 36 hours after initial placement. In 22 (28%) of 80 patients, the UVCs had a position that was too high and in 20 (25%) that was too low. Conclusion More than half of UVCs migrated at 24 to 36 hours postinsertion to positions known to have higher complication rates. We, therefore, recommend follow-up evaluation at 24 to 36 hours postinsertion, to prevent complications from malposition.

Background: High arterial oxygen saturation (SaO2) is associated with the development of retinopathy of prematurity (ROP), but difficult to avoid. Objective: To assess the association between severe ROP and a burden of cerebral and arterial hyperoxia. Methods: We retrospectively analyzed 225 preterm infants born ≤30 weeks’ gestation. The cerebral oxygen saturation (rcSO2) and SaO2 were measured within the first 96 h after birth. We determined the burden of both cerebral and arterial hyperoxia, which was defined as the percentage of time spent at saturation thresholds exceeding 85 and 90%, respectively. Their association with severe ROP (prethreshold disease type 1) was tested using logistic regression analyses. Results: Median gestational age (GA) was 28.0 weeks (interquartile range 26.7–29.0) and mean birth weight 1,032 g (±281 SD). Eight infants developed severe ROP. Infants with severe ROP spent more time at cerebral hyperoxic levels than infants without severe ROP (medians 30 vs. 16%). Adjusted for GA, for every 10% increase in burden of cerebral hyperoxia, the OR for developing ROP was 1.50 (95% CI 1.09 – 2.06, p = 0.013). A burden of arterial hyperoxia was not associated with ROP. Infants with severe ROP experienced even less arterial hyperoxia, although not statistically significant. Conclusions: Cerebral hyperoxia may be a better early predictor of severe ROP than arterial hyperoxia. Moreover, under strict oxygen management, cerebral hyperoxia in these infants may result from cerebral immaturity rather than a high SaO2. Whether reducing cerebral hyperoxia is feasible and might prevent ROP needs to be further examined.

Purpose: To investigate postural effects of the family-centered program, COPing with and CAring for infants with special needs (COPCA), applied at 3 to 6 months' corrected age in infants at high risk of cerebral palsy. Previously, we reported postural differences between the infants at risk of CP in the control group of the current study and a group of infants developing typically. Now we focus on differences between 2 intervention groups.Methods: We explored postural adjustments during reaching in seated infants at 4, 6, and 18 months using surface electromyography of arm, neck, and trunk muscles. Infants randomly received the family-centered program or another infant physical therapy. Using videotaped intervention sessions, we investigated correlations between time spent on specific physical therapeutic actions and direction specificity, recruitment order, and anticipatory activation at 18 months.Results: Postural adjustments in both groups were similar, but development of direction specificity and anticipatory activation in COPCA infants better mimicked typical development. These 2 parameters were associated with COPCA-type physical therapeutic actions.Conclusions: Postural control was similar after both interventions. Positive outcomes were associated with fewer intervening actions of the therapist and greater allowance of spontaneous movements.

Increasing evidence recognizes the harm of excess oxygen to lungs, eyes, and brain of preterm infants, but not yet to the intestine. We assessed changes in splanchnic oxygenation during reoxygenation with 21% compared to 100% OWe randomized 25 piglets to control or intervention. Intervention groups underwent global hypoxia until acidosis and hypotension occurred. Piglets were reoxygenated for 30 min with 21% or 100% OReoxygenation after global hypoxia restored rReoxygenation after global hypoxia improves splanchnic oxygenation, but is associated with reduced variability of rSplanchnic oxygenation improves during reoxygenation after global hypoxia, though reoxygenation with 100% O

Interventions such as kangaroo care (KC) and live-performed music therapy (LPMT), are increasingly used to facilitate stress reduction in neonates. This study aims to investigate the effect of combining the two on physiological responses and neurological functioning in very preterm infants. Infants received six sessions of LPMT. KC was added to one LPMT session. Physiological responses included heart rate, respiratory rate and oxygen saturation. We videotaped infants for 30 min before and after two sessions to assess general movements (GMs). We included 17 infants, gestational age median 26.0 weeks (IQR 25.6–30.6 weeks), of whom six were males. Combined interventions showed a decrease in heart rate from mean 164 bpm before to 157 bpm during therapy, p = 0.001. Oxygen saturation levels increased during combination therapy from median 91.4% to 94.5%, p = 0.044. We found no effects of LPMT or combined interventions on GMs. Infants with a postnatal age (PNA) &lt, 7 days generally seem to display less optimal GMs after therapy compared with infants with a PNA &gt, 7 days. In conclusion, combining interventions is equally beneficial for physiological stability and neurological functioning as LPMT alone. Future studies should focus on the effects of this combination on parent-infant bonding.

Having an infant in the neonatal intensive care unit (NICU) elicits maternal anxiety, which may hamper parent−child bonding. We performed a prospective cohort study to describe anxiety in mothers of infants born before 30 weeks of gestation during NICU stay in The Netherlands, and investigated the influence of infant stress and gestational age. Second, we performed a randomized-controlled live-performed music therapy trial (LPMT trial) to investigate whether music therapy applied to the infant alleviated maternal anxiety. The relation between infant stress, gestational age, and maternal anxiety was measured in 45 mother−infant dyads, using the Neonatal Infant Stressor Scale and the State-Trait Anxiety Inventory (STAI). The effect of LPMT on anxiety was assessed in 21 mothers whose infants were assigned to either LPMT (n = 12) or waitlist (n = 9). Mothers completed the STAI before and after this period. Maternal anxiety decreased over time in all mothers, and was strongly related with infant stress (r = 0.706, p &lt, 0.001), but not with gestational age. Anxiety scores decreased by 12% after LMPT, and increased by 1% after a waitlist period (p = 0.30). Our results indicate that LPMT in the weeks after birth may accelerate the reduction of maternal anxiety. Further research should focus on the effects on mother−child bonding.

BACKGROUND: Accurate prediction of persistent and emerging developmental problems in preterm-born children may lead to targeted interventions.AIMS: To determine whether specific perinatal and social factors were associated with persistent, emerging, and resolving developmental problems of early-preterm (EPs) and moderately-and-late-preterm children (MLPs) from before to after school entry.STUDY DESIGN: Observational longitudinal cohort study, part of the LOLLIPOP cohort-study.SUBJECTS: 341 EPs and 565 MLPs.OUTCOME MEASURES: Developmental problems using the Ages and Stages Questionnaire at ages 4 and 5. We collected data on perinatal and social factors from medical records. Using logistic regression analyses we assessed associations between 48 factors and persistent, emerging, and resolving problems.RESULTS: Of EPs, 8.7% had persistent and 5.1% emerging problems; this was 4.3% and 1.9% for MLPs, respectively. Predictors for persistent problems included chronic mental illness of the mother, odds ratio (95% confidence interval) 8.01 (1.85-34.60), male sex 4.96 (2.28-10.82), being born small-for-gestational age (SGA) 2.39 (1.15-4.99), and multiparity 3.56 (1.87-6.76). Predictors for emerging problems included MLP birth with prolonged premature rupture of membranes (PPROM) 5.01 (1.38-18.14). Including all predictors in a single prediction model, the explained variance (Nagelkerke R2) was 21.9%, whereas this was 3.0% with only EP/MLP birth as predictor.CONCLUSIONS: Only few perinatal and social factors had associations with persistent and emerging developmental problems for both EPs and MLPs. For children with specific neonatal conditions such as SGA, and PPROM in MLPs, problems may persist. Insight in risk factors largely improved the prediction of developmental problems among preterm children.

OBJECTIVES The aim of the study was to assess the neurological status in infants with biliary atresia (BA) at time of diagnosis, using Prechtl's validated General Movement Assessment. METHODS Infants diagnosed with BA were prospectively included in a nationwide cohort study. From birth to approximately 46 weeks of postmenstrual age (PMA), general movements (GMs) are defined as "writhing movements." At 46 to 49 weeks PMA, "'fidgety movements" emerge. The infant's early motor repertoire was recorded on video before Kasai portoenterostomy. We scored GM optimality scores (min-max 5-42) or motor optimality scores (MOS, min-max 5-28) as appropriate. We defined GM optimality scores

BACKGROUND: Necrotizing enterocolitis (NEC) is a neonatal disease associated with necrosis and perforation of the bowel. We investigated the association between blood group and NEC outcomes and the potential contribution of fetal-maternal blood group incompatibility.METHODS: Retrospective study including all preterm-born infants with NEC (≥ Bell's stage IIa) admitted to our NICU between January 2008 and October 2019. We analyzed the association between infants' blood groups and fetal-maternal blood group incompatibility with Bell stage severity, need for surgery, and mortality due to NEC.RESULTS: We included 237 NEC patients. In univariable analyses both AB blood group and fetal-maternal blood group incompatibility increased infants' risk of severe outcomes, with odds ratios (OR) ranging from 6.57 to 12.06 and 1.97 to 2.38, respectively. When adjusted for gestational age only AB blood group remained significant with OR 7.47 (95% confidence interval, 1.95-28.53, P = 0.003), 12.37 (2.63-58.20, P = 0.001), and 8.16 (2.28-29.14, P = 0.001) for NEC Bell's stage III, need for surgery, and NEC related mortality, respectively. Blood group incompatibility adjusted for gestational age was not related to worse outcomes with OR 1.84 (0.87-3.89, P = 0.11, 2.08 (0.98-4.41, P = 0.06) 1.52 (0.68-3.42, P = 0.31), for NEC Bell's stage III, need for surgery, and NEC related mortality, respectively.CONCLUSION: Our data confirm an association between blood group AB and worse outcomes in NEC infants, but this is not based on fetal-maternal blood group incompatibility.

BackgroundThe incidence of retinopathy of prematurity (ROP) is higher in Indonesia than in high-income countries. In order to reduce the incidence of the disease, a protocol on preventing, screening and treating ROP was published in Indonesia in 2010. To assist the practical implementation of the protocol, meetings were held in all Indonesia regions, calling attention to the high incidence of ROP and the methods to reduce it. In addition, national health insurance was introduced in 2014, making ROP screening and treatment accessible to more infants.ObjectiveTo evaluate whether the introduction of both the guideline drawing attention to the high incidence of ROP and national health insurance may have influenced the incidence of the disease in Indonesia.SettingData were collected from 34 hospitals with different levels of care: national referral centres, university-based hospitals, and public and private hospitals.MethodsA survey was administered with questions on admission numbers, mortality rates, ROP incidence, and its stages for 2016–2017 in relation to gestational age and birth weight.ResultsWe identified 12 115 eligible infants with a gestational age of less than 34 weeks. Mortality was 24% and any stage ROP 6.7%. The mortality in infants aged less than 28 weeks was 67%, the incidence of all-stage ROP 18% and severe ROP 4%. In the group aged 28–32 weeks, the mortality was 24%, all-stage ROP 7% and severe ROP 4%–5%. Both mortality and the incidence of ROP were highest in university-based hospitals.ConclusionsIn the 2016–2017 period, the infant mortality rate before 32 weeks of age was higher in Indonesia than in high-income countries, but the incidence of ROP was comparable. This incidence is likely an underestimation due to the high mortality rate. The ROP incidence in 2016–2017 is lower than in surveys conducted before 2015. This decline is likely due to a higher practitioner awareness about ROP and national health insurance implementation in Indonesia.

Background Preterm infants are at risk for functional impairments in motor, cognitive, and behavioral development that may persist into childhood. The aim of this study was to determine the co-occurrence of cognitive impairments in multiple cognitive domains at school age in very preterm born children compared to term-born children. Methods Comparative study including 60 very preterm-born children (gestational age ≤ 32 weeks) and 120 term-born controls. At school age, we assessed intelligence with the WISC-III, and visuomotor integration with the NEPSY-II, verbal memory with the AVLT, attention with the TEA-ch, and executive functioning with the BRIEF. We investigated co-occurrence of various abnormal ( Results At mean age 8.8 years, 15% of preterm children had abnormal outcomes in multiple cognitive functions (≥2), versus 3% of the controls (odds ratio, OR 4.65, 95%-confidence interval, CI 1.33–16.35). For multiple suspect-abnormal cognitive outcomes, rates were 55% versus 25% (OR 3.02, 95%-CI 1.49–6.12). We found no pattern of co-occurrence of cognitive impairments among preterm children that deviated from term-born controls. However, low performance IQ was more frequently accompanied by additional cognitive impairments in preterms than in controls (OR 5.43, 95%-CI 1.75–16.81). Conclusions A majority of preterm children showed co-occurrence of impairments in multiple cognitive domains, but with no specific pattern of impairments. The occurrence of multi-domain cognitive impairments is higher in preterms but this seems to reflect a general increase, not one with a pattern specific for preterm-born children.

BackgroundNecrotizing enterocolitis (NEC) is a devastating disease that is relatively frequently diagnosed in term infants with congenital heart disease (CHD), compared with term infants without CHD, in whom NEC is rare. The exact pathogenesis of NEC in term infants with CHD is unknown, but it is hypothesized that ischemia of the intestines plays a pivotal role. We aimed to explore whether (near) term CHD infants, who develop NEC, exhibit more clinical signs of hypoxia/ischemia and low body perfusion directly after birth and during the first 48 hours after admission to the neonatal intensive care unit, when compared with (near) term CHD infants who did not develop NEC.Methods956 infants with CHD born after ≥ 35 weeks of gestational age were retrospectively reviewed for this case-control study between January 1999 and February 2020. We included infants with radiographically confirmed pneumatosis intestinalis and controls matched by type of CHD. Seven infants were diagnosed with transposition of the great arteries, six with left and four with right ventricular outflow tract obstruction. Several parameters suggestive of (relative) hypoxia/ischemia were used for analyses.ResultsWe included sixteen CHD infants with NEC and selected sixteen controls. There were no significant demographic differences between both groups. Apgar score at one and five minutes (median [IQR]) were lower in infants who developed NEC compared with control infants (8 [7-8]) vs. (9 [8-9],P = .011) and (8 [8-9]) vs. (9 [9-10],P = .009). A higher proportion of infants with NEC required respiratory support in the delivery room (11(69) vs. 2(13),P = .001). The (median [IQR]) diastolic blood pressure on the second day after admission (39 mmHg [34–42], vs. 43 mmHg [37–51],P = .112) and lowest (median [IQR]) pH in the 48 hours after admission (7.24 [7.17–7.35] vs. 7.38 ([7.27–7.43],P = .157) were not significantly lower in NEC infants but both demonstrated a similar direction towards (relative) hypoxia/ischemia in NEC infants.ConclusionsOur clinical results support a hypoxic/ischemic pathophysiology of NEC in (near) term CHD infants, with lower Apgar scores, more respiratory support in the delivery room and a tendency towards a lower diastolic blood pressure and pH in CHD infants who develop NEC.

Background: Early intervention after perinatal brain insults requires early detection of infants with cerebral palsy (CP). General Movements Assessments (GMA) in the fidgety movement period has a high predictive value for CP. Aim: To investigate the NeuroMotionTM apps usability regarding film quality and user experience and to assess the inter-rater reliability of GMA in a neonatal risk group. Methods: GMA, inter-rater reliability and film quality was assessed in a cohort consisting of 37 infants enrolled in a multicentre study of GMA as part of the Swedish neonatal follow-up program for high-risk infants. Some of these infants were filmed twice. For evaluation of user experience 95 parents of 52 infants were addressed with a web-based questionnaire. A GMA expert assessed film quality and performed GMA and three on-site assessors, individually performed GMA. Inter-rater reliability was computed using Krippendorffs alpha (k-alpha). Results: In all, 45 films showed good or excellent quality. The response rate of the questionnaire survey was 40% and revealed predominantly positive perceptions of the NeuroMotionTM app. GMA in 36 infants resulted in substantial agreement (k-alpha = 0.72, 95%CI = 0.3-1.0) between the three on-site assessors consensus and the GMA expert. Inter-rater reliability for GMA between the on-site assessors was moderate (k-alpha = 0.48, 0.18-0.74). Conclusion: The NeuroMotionTM app produces good technical quality films and the app user experience was overall positive. High agreement was observed between the on-site assessors and the GMA expert. The study design is feasible for more extensive GMA studies in cohorts of infants at risk of CP. (c) 2021 The Authors. Published by Elsevier Ltd on behalf of European Paediatric Neurology Society. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). Funding Agencies|Knut and Alice Wallenberg Foundation for research on stroke; Region Ostergotland Research Council; Medical Reaserch Council of Southeast Sweden [FORSS-859871]

Background Severe hyperbilirubinemia is more frequent in low- and middle-income countries such as Indonesia than in high-income countries. One of the contributing factors might be the lack of adherence to existing guidelines on the diagnosis and treatment of hyperbilirubinemia. We developed a new national guideline for hyperbilirubinemia management in Indonesia. To help healthcare workers use this guideline, a web-based decision support tool application may improve both the adherence to the guideline and the care for infants with hyperbilirubinemia. Methods We developed a web-based application (BiliNorm) to be used on a smartphone that displays the bilirubin level of the patient on the nomogram and advises about the treatment that should be started. Healthcare workers of two teaching hospitals in East Java, Indonesia, were trained on the use of BiliNorm. At 6 months after the introduction, a questionnaire was sent to those who worked with the application enquiring about their experiences. An observational study was conducted in two time epochs. A chart review of infants with hyperbilirubinemia in the two hospitals was sent. The appropriateness of hyperbilirubinemia management during a 6-month period before BiliNorm introduction was compared to that during a 7-month period after its introduction. Results A total of 43 participants filled in the questionnaire, the majority (72%) of them indicated that BiliNorm was well received and easy to use. Moreover, 84% indicated that BiliNorm was helpful for the decision to start phototherapy. Chart review of 255 infants before BiliNorm introduction and that of 181 infants after its introduction indicated that significantly more infants had received treatment according to the guideline (38% vs 51%, p = 0.006). Few infants received phototherapy, but bilirubin level was not measured (14% vs 7%, p = 0.024). There was no difference in the proportion of infants who were over- and under-treated (34% vs 32% and 14% vs 10%, respectively). Conclusions The web-based decision tool BiliNorm appears to be a valuable application. It is easy to use for healthcare workers and helps them adhere to the guideline. It improves the care for infants with hyperbilirubinemia and may help reduce the incidence of severe hyperbilirubinemia in Indonesia.

Background: Hyperbilirubinemia commonly occurs in neonates, with a higher prevalence among preterm neonates, which can lead to severe hyperbilirubinemia. Assessment of total serum bilirubin (TSB) and the use of transcutaneous bilirubinometry (TcB) are existing methods which can identify and predict hyperbilirubinemia. This study aimed to determine TcB cut-off values during the first day for preterm neonates, in order to predict hyperbilirubinemia at 48 and 72 hours. Methods: This cohort study was conducted at Dr. Soetomo General Hospital from September 2018 to January 2019, studying a total of 90 neonates born at ≤35 weeks. They were divided into two groups (Group I: 1000-1500 grams; Group II: 1501-2000 grams). The bilirubin levels were measured at the sternum, using TcB at the ages of 12, 24, and 72 hours. TSB measurements were taken on the third day or if the TcB level reached phototherapy threshold ± 1.24 mg/dL and if TcB showed abnormal results (Group I: 5.76-8.24 mg/dL; Group II: 8.76-11.24 mg/dL). Hyperbilirubinemia was defined as TSB ≥7 mg/dL for Group I and >10 mg/dL for Group II. Results: In total, 38 Group I neonates and 48 Group II neonates were observed. Approximately onehalf of the neonates in Group I (45%) suffered from hyperbilirubinemia at 48 hours, along with 46% of Group II at 72 hours. The best 24-hour-old TcB cut-off values to predict hyperbilirubinemia at 48 hours were calculated to be 4.5 mg/dL for Group I and 5.8 mg/dL for Group II. The determined 24-hour-old TcB value to predict hyperbilirubinemia at 72 hours was 5.15 mg/dL for Group II. Conclusion: TcB values on the first day of life can be used as hyperbilirubinemia predictors on the following days for preterm neonates. Close monitoring should be managed for those with TcB values higher than the calculated cut-off values.

Background: Selective serotonin reuptake inhibitors (SSRIs) are prescribed in 2-8% during pregnancy. Whether prenatal exposure to SSRIs has long-term effects on the children's development is unknown.Aim: The aim of this study was to determine the effect of prenatal exposure to SSRIs on children's cognitive, motor, and behavioral outcomes at 2.5 years, adjusted for maternal depression and anxiety.Methods: In a prospective, longitudinal cohort-study we included 111 pregnant women treated either or not with an SSRI. We examined cognitive and motor development of their children at 2.5 years, using the Bayley Scale of Infant and Toddler Development, 3rd Edition, and measured emotional and behavioral problems using the parent-rated Child Behavior Checklist (CBCL). Maternal depression and anxiety was determined during pregnancy and at the children's assessment. Differences of normed cognitive, motor, and behavioral scores between SSRI-exposed and non-SSRI-exposed children were tested using multiple linear regression analyses.Results: We examined 102 children. SSRI-exposed children had lower scaled scores on cognition and gross motor development than non-SSRI-exposed children: 9.0 +/- 1.4 (mean +/- SD) versus 9.9 +/- 1.7 [P = 0.004], and 7.9 +/- 2.2 versus 9.0 +/- 2.5 [P = 0.01], respectively. Differences remained significant after adjusting for maternal depression and anxiety and other confounders in various models (mean difference for cognition 0.8 to 0.9 points, for gross motor 1.1 to 1.2 points). Only after adjusting for severity of maternal anxiety, differences in gross motor scores lost significance.Conclusions: Prenatal exposure to SSRIs is associated with poorer cognitive and gross motor development of the children at 2.5 years. Effects on gross motor development disappeared after correction for severity of maternal anxiety.

BACKGROUND: Surviving preterm born children, postnatally exposed to high doses of dexamethasone, show an increased risk of neurodevelopmental impairments. Regarding treatment with low doses of dexamethasone, no data exist on outcomes at school age.AIM: To assess the functional outcome at school age of preterm-born children treated with low-dose dexamethasone.STUDY DESIGN: In this cohort study, twenty-seven very preterm-born infants treated with dexamethasone from eight days after birth, underwent neuropsychological assessments at age 6-13 years. Their scores were compared with those of the norm population, and scores on total IQ and motor functioning also with those of a preterm reference group, using one-sample-chi-square and student's t-tests.RESULTS: Compared with the norm population, performance of dexamethasone-treated children was poorer, particularly in the motor domain (mean z-score - 1.81). Dexamethasone-treated children also had lower scores on IQ (-0.29 to -1.12), verbal memory (-0.41 to -0.56), attention (-0.90 to -1.28), and word generation (-0.75). Their parents reported behavioral problems more often. Compared with preterm peers, motor skills remained poor, but total IQs were similar. Adjustment for bronchopulmonary dysplasia did not change our results, because all surviving children had bronchopulmonary dysplasia.CONCLUSIONS: At school age, the prevalence of adverse motor, cognitive, and behavioral outcomes of preterm-born children treated with low-dose dexamethasone is increased. This could be the consequence of either dexamethasone or BPD.

Near-infrared spectroscopy is used in the assessment of regional splanchnic oxygen saturation (rWe included infants with gestational age (GA)32 weeks and/or birth weight1200 g. We excluded infants who developed necrotizing enterocolitis or sepsis or who died. In the first week after birth, we determined a daily 2-h mean of rWe included 220 infants. On day 1, the mean ± SD rWe established reference values of rRegional splanchnic oxygen saturation is lower in infants with a lower gestational age and in small-for-gestational age infants. Regional splanchnic oxygen saturation decreases with a higher postnatal age until day 4 after birth and then increases until day 7 after birth. Gestational age, postnatal age, and small-for-gestational age status affect regional splanchnic oxygen saturation and need to be taken into account when interpreting regional splanchnic oxygen saturations using NIRS. Reference values for infant regional splanchnic oxygen saturation can be computed with a formula based on these variables, as provided by this study.

We aimed to investigate whether splanchnic tissue oxygen saturation (rWe retrospectively included infants with suspected NEC, gestational age32 weeks and/or birth weight1200 g in the first 3 weeks after birth. We calculated mean rOf the 75 infants, 21 (28%) had NEC (Bell's stage ≥2). Characteristics of infants with and without NEC differed only on mechanical ventilation and nil-per-os status. RUsing NIRS, high SCOR may confirm NEC and high variability of rNear-infrared spectroscopy may contribute to the diagnosis of necrotizing enterocolitis. When clinical signs are present a high splanchnic-cerebral oxygenation may indicate necrotizing enterocolitis. A low splanchnic-cerebral oxygenation ratio and high variability of splanchnic tissue oxygen saturation may rule out necrotizing enterocolitis. Whether a bedside real-time availability of the splanchnic-cerebral oxygenation ratio and variability of splanchnic tissue oxygen saturation improves NEC diagnosis needs to be further investigated.

BackgroundThe exact onset of brain injury in infants with congenital heart disease (CHD) is unknown. Our aim was, therefore, to assess the association between prenatal Doppler flow patterns, postnatal cerebral oxygenation and short-term neurological outcome.MethodsPrenatally, we measured pulsatility indices of the middle cerebral (MCA-PI) and umbilical artery (UA-PI) and calculated cerebroplacental ratio (CPR). After birth, cerebral oxygen saturation (r(c)SO(2)) and fractional tissue oxygen extraction (FTOE) were assessed during the first 3 days after birth, and during and for 24 hours after every surgical procedure within the first 3 months after birth. Neurological outcome was determined preoperatively and at 3 months of age by assessing general movements and calculating the Motor Optimality Score (MOS).ResultsThirty-six infants were included. MOS at 3 months was associated with MCA-PI (rho 0.41, P = 0.04), UA-PI (rho -0.39, P = 0.047, and CPR (rho 0.50, P = 0.01). Infants with abnormal MOS had lower MCA-PI (P = 0.02) and CPR (P = 0.01) and higher UA-PI at the last measurement (P = 0.03) before birth. In infants with abnormal MOS, r(c)SO(2) tended to be lower during the first 3 days after birth, and FTOE was significantly higher on the second day after birth (P = 0.04). Intraoperative and postoperative r(c)SO(2) and FTOE were not associated with short-term neurological outcome.ConclusionIn infants with prenatally diagnosed CHD, the prenatal period may play an important role in developmental outcome. Additional research is needed to clarify the relationship between preoperative, intra-operative and postoperative cerebral oxygenation and developmental outcome in infants with prenatally diagnosed CHD.

BACKGROUND: Anemia is associated with decreased tissue oxygenation in preterm infants and may contribute to developing necrotizing enterocolitis (NEC). We aimed to investigate whether hemoglobin level is associated with intestinal injury, by comparing anemic infants 10 days prior to red blood cell (RBC) transfusion with non-anemic controls.METHODS: A nested case-control study in which we matched anemic preterms (gestational age (GA) < 32 weeks) with non-anemic controls (1:1), based on GA, birth weight (BW), and postnatal age. We measured urinary intestinal fatty acid-binding protein, I-FABP, marker for intestinal injury, twice weekly. Simultaneously, we assessed splanchnic oxygen saturation (rsSO2) and rsSO2 variability.RESULTS: Thirty-six cases and 36 controls were included (median GA 27.6 weeks, BW 1020 grams). Median I-FABP level was higher in cases from 6 days to 24-h before transfusion (median ranging: 4749-8064 pg/ml versus 2194-3751 pg/ml). RsSO2 and rsSO2 variability were lower in cases than controls shortly before transfusion. Hemoglobin levels correlated negatively with rsSO2 and rsSO2 variability in cases, and negatively with I-FABP in cases and controls together.CONCLUSIONS: Urinary I-FABP levels were higher in anemic infants before RBC transfusion than in non-anemic matched controls, suggesting intestinal injury associated with anemia. This may predispose to NEC in some anemic preterm infants.IMPACT: Anemia is a common comorbidity in preterm infants and may lead to impaired splanchnic oxygen saturation and intestinal tissue hypoxia, a proposed mechanism for NEC. Lower hemoglobin level is associated with higher urinary I-FABP levels, a marker for intestinal injury, both in anemic preterm infants and in cases and controls together. Lower splanchnic oxygen saturation and reduction of its variability are associated with higher urinary I-FABP levels in anemic preterm infants before their first RBC transfusion. These results support the hypothesis that anemia in very preterm infants results in intestinal cell injury, which may precede NEC development in some.

Background: Prenatal exposure to persistent organic pollutants (POPs), such as polychlorinated biphenyls (PCBs), was found to be associated with poorer neurological development in children. Knowledge about the effects on outcomes until adolescence is limited. Objectives: To determine whether prenatal exposure to POPs, particularly hydroxylated PCBs (OH-PCBs), is associated with cognitive and motor development in 13- to 15-year-old children. Methods: This prospective observational cohort study is part of the Development at Adolescence and Chemical Exposure (DACE)-study, a follow-up of two Dutch birth cohorts. Maternal pregnancy serum levels of PCB-153 and three OH-PCBs were measured, in part of the cohort also nine other PCBs and three OH-PCBs, and in another part five polybrominated diphenyl ethers (PBDEs), dichloroethene (DDE), pentachlorophenol (PCP) and hexabroomcyclododecane (HBCDD). Of the 188 invited adolescents, 101 (53.7%) participated, 55 were boys. Cognition (intelligence, attention, verbal memory) and motor performance (fine motor, ball skills, balance) were assessed. Scores were classified into ‘normal’ (IQ > 85; scores > P15) and ‘(sub)clinical’ (IQ ≤ 85; scores ≤ P15). We used linear and logistic regression analyses, and adjusted for maternal education, maternal smoking, maternal alcohol use, breast feeding, and age at examination. Results: Several OH-PCBs were associated with more optimal sustained attention and balance. PCB-183 was associated with lower total intelligence (OR: 1.29; 95%CI:0.99–1.68; P = .060), and HBCDD with lower performance intelligence (OR: 3.62; 95%CI:0.97–13.49; P = .056). PCBs, OH-PCBs and PBDEs were negatively associated with verbal memory. Conclusions: Prenatal background exposure to several POPs can influence neuropsychological outcomes in 13- to 15-year-old Dutch adolescents, although exposure to most compounds does not have clinically relevant consequences at adolescence. Keywords: Persistent organic pollutant, Prenatal exposure, Adolescent, Cognitive function, Motor skills

Objective: To determine the association between potential neonatal risk factors and the quality of general movements (GMs) in preterm infants.Study design: Prospective cohort study in 67 preterm infants. From video recordings made on Days 8 and 15, we scored the GMs as normal/abnormal and detailed aspects using the general movement optimality score (GMOS). Risk factors included respiratory insufficiency requiring mechanical ventilation, patent ductus arteriosus (PDA), and abnormal blood glucose levels. We used multiple regression analyses.Result: On Day 8 after birth, the presence of a PDA remained in the multivariable model, explaining 17.1% of the variance in GMOS (beta, -0.414). On Day 15, duration of mechanical ventilation and frequency of hypoglycemic episodes explained 38.8% of the variance (betas, -0.382 and -0.466, respectively).Conclusion: In preterm infants, PDA, duration of mechanical ventilation, and frequency of hypoglycemic episodes were associated with poorer neurological functioning during the first 2 weeks after birth.

BACKGROUND: Little is known on the motor development of moderately preterm born (MPT) children, in comparison with early preterm born (EPT) children and fullterm born (FT), for children with normal motor outcomes at school entry.AIMS: To compare attainment rates of gross motor milestones reached between ages 1-24 months for MPT, EPT, and FT children, all with normal development upon school entry.STUDY DESIGN: Prospective cohort study.SUBJECTS: We included 1247 preterm (PT) children (gestational age [GA] 24.0-35.6 weeks) and 488 FT children (GA 38.0-41.6 weeks), with normal gross motor development at 4 years according to the Ages and Stages Questionnaire.OUTCOME MEASURES: We assessed 11 gross motor milestones assessed in preventive child healthcare during six standardized visits at calendar age.RESULTS: During the first six months, all PT categories had lower milestone attainment-rates than FTs children (differences 9-60% for PTs compared with FTs children). For all PT categories attainment rates gradually increased during toddlerhood. For PT children with higher GA, differences in attainment rates compared with FTs children were smaller and attainment rates became comparable to FT children at an earlier age. At age 24 months only attainment rates for PT children born CONCLUSION: Milestone attainment rates are highly dependent on GA during the first two years. Differences between PT and FT children are larger and persist longer with lower GA. For PT children

BackgroundLittle is known on amplitude-integrated electroencephalography (aEEG) during the first few days after birth in neonates with congenital heart disease (CHD). Our aim was, therefore, to assess electrocortical activity using aEEG within the first 72 h after birth in neonates diagnosed prenatally with CHD, and to define independent prenatal and postnatal predictors for abnormal aEEG.MethodsNeonates with CHD who were admitted to the neonatal intensive care unit between 2010 and 2017 were retrospectively included. We assessed aEEG background patterns, sleep-wake cycling, and epileptic activity during the first 72 h after birth and defined prenatal and postnatal clinical parameters associated with aEEG patterns.ResultsSeventy-two neonates were included. Twenty-six (36%) had mildly abnormal and six (8%) had severely abnormal aEEG background patterns at some point during the study period. Sleep-wake cycling was present in 97% of the neonates. Subclinical seizures were common (15%), whereas none of the neonates had clinical seizures. Only treatment with sedatives was a significant predictor for abnormal aEEG background patterns, explaining 56% of the variance.ConclusionAbnormal aEEG background patterns are common and are strongly associated with treatment with sedatives in neonates with prenatally diagnosed CHD. Future studies should assess the association between early postnatal aEEG abnormalities and neurodevelopmental outcome.

Objective To assess intestinal and cerebral oxygenation during and after red blood cell (RBC) transfusions in preterms with or without subsequent transfusion-associated necrotizing enterocolitis (TANEC). Study Design In preterms of Results In TANEC infants, rcSO2 was lower during and after RBC transfusions than in controls, median (interquartile range) 55% (50–62) versus 72% (65–75), p Conclusion In preterm infants lower rcSO2, but not rintSO2, values during and after RBC transfusions are associated with TANEC. Lower rintSO2 and rcSO2 variabilities after RBC transfusions may represent a diminished capacity for vascular adaptation, possibly leading to TANEC.

BACKGROUND: Preterm infants requiring surgery are at risk of impaired neurocognitive development caused, possibly, by cerebral ischemia associated with impaired cerebrovascular autoregulation (CAR). We evaluated CAR before, during, and after laparotomy.STUDY DESIGN: This was a hypothesis generating prospective observational cohort study.SUBJECTS: We included preterm infants requiring surgery for necrotizing enterocolitis (NEC) or spontaneous intestinal perforation (SIP). Before, during, and after surgery we measured cerebral oxygen saturation using NIRS and calculated cerebral fractional tissue oxygen extraction (cFTOE).OUTCOME MEASURES: Impaired CAR was defined if correlation coefficients (rho) between mean cFTOE and mean arterial blood pressure values were ≤-0.30 with P RESULTS: Nineteen infants with median (IQR) GA 27.6 weeks (26.6-31.0), birth weight 1090 g (924-1430), and postnatal age 9 days (7-12) were included. CAR was impaired more often during surgery than before (12 versus 3, P = .02) or after (12 versus 0, P CONCLUSIONS: More than half of preterm infants with NEC or SIP displayed evidence of impaired CAR during laparotomy. Further research should focus on mechanisms contributing to impaired CAR in preterm infants during surgery.

Infants experience multiple stressors in the neonatal intensive care unit (NICU), which may have adverse effects on brain development. Non-invasive interventions that reduce stress may improve neurodevelopmental functioning.1 This pilot study assessed whether live music therapy, performed by a certified neonatal music therapist,2 had beneficial effects on neurodevelopment.

Background: Amplitude-integrated electroencephalography (aEEG) is used increasingly in neonatal intensive care and seems helpful in predicting outcomes at the age of 2 years. Objectives: To determine whether early aEEG patterns in preterm infants are equally useful in predicting outcomes at early school age. Methods: We recorded aEEG in 41 preterms (gestational age 26.0–32.9 weeks) at a median postnatal age of 9.7 h (IQR 7.0–25.3) and in 43 preterms on median day 8 (IQR 7–9). We assessed aEEG by pattern recognition and calculated the means of the aEEG amplitude centiles. At a median of 7.39 years, i.e., early school age, we assessed their motor, cognitive, and behavioral outcomes. Results: Depressed aEEG patterns were not associated with poorer outcomes. Cyclicity directly after birth was associated with a higher total IQ (mean 104 vs. 97, p = 0.05) and higher scores on visual perception (mean percentile 57.1 vs. 40.1, p = 0.049) and visual memory (mean percentile 34.5 vs. 19.1, p = 0.090). We found some associations between the aEEG amplitude centiles and cognitive outcomes, but none for motor or behavioral outcomes. There was an increased risk of abnormal scores on long-term verbal memory in cases of the lower 5th and 50th aEEG amplitude centiles directly after birth. The odds ratios were 0.65 (95% CI 0.42–0.99, p = 0.040) and 0.71 (95% CI 0.52–0.96, p = 0.025), respectively. Conclusions: In relatively healthy preterm infants the value of aEEG in predicting neuropsychological outcomes at early school age is limited. The presence of cyclicity directly after birth tends to be associated with better cognition.

Background The factors that determine the effect of enteral feeding on intestinal perfusion after preterm birth remain largely unknown. We aimed to determine the effect of enteral feeding on intestinal oxygen saturation (rintSO2) in preterm infants and evaluated whether this effect depended on postnatal age (PNA), postmenstrual age (PMA), and/or feeding volumes. We also evaluated whether changes in postprandial rintSO2 affected cerebral oxygen saturation (rcSO2). Methods In a longitudinal observational pilot study using near-infrared spectroscopy we measured rintSO2 and rcSO2 continuously for two hours on postnatal Days 2 to 5, 8, 15, 22, 29, and 36. We compared preprandial with postprandial values over time using multi-level analyses. To assess the effect of PNA, PMA, and feeding volumes, we performed Wilcoxon signed-rank tests or logistic regression analyses. To evaluate the effect on rcSO2, we also used logistic regression analyses. Results We included 29 infants: median (range) gestational age 28.1 weeks (25.1–30.7) and birth weight 1025 g (580–1495). On Day 5, rintSO2 values decreased postprandially: mean (SE) 44% (10) versus 35% (7), P = .01. On Day 29, rintSO2 values increased: 44% (11) versus 54% (7), P = .01. Infants with a PMA ≥ 32 weeks showed a rintSO2 increase after feeding (37% versus 51%, P = .04) whereas infants with a PMA intSO2 (per 10 mL/kg: OR 1.63, 95% CI, 1.02–2.59). We did not find an effect on rcSO2 when rintSO2 increased postprandially. Conclusions Our study suggests that postprandial rintSO2 increases in preterm infants only from the fifth week after birth, particularly at PMA ≥ 32 weeks when greater volumes of enteral feeding are tolerated. We speculate that at young gestational and postmenstrual ages preterm infants are still unable to increase intestinal oxygen saturation after feeding, which might be essential to meet metabolic demands. Trial registration For this prospective longitudinal pilot study we derived patients from a larger observational cohort study: CALIFORNIA-Trial, Dutch Trial Registry NTR4153.

Intestinal recovery after NEC is difficult to predict in individuals. We evaluated whether several biomarkers predict intestinal recovery after NEC in preterm infants.We measured intestinal tissue oxygen saturation (rWe included 27 preterm infants who survived NEC (Bell's stage ≥ 2). Median FEFt was 14 [IQR: 12-23] days. Biomarkers only predicted intestinal recovery after the first re-feed. Mean rThe r

Objectives Congenital heart disease (CHD) has been associated with reduced fetal head circumference (HC), although the underlying pathophysiology remains undetermined. We aimed to define trends in fetal growth and cerebroplacental Doppler flow, and to investigate their relationship, in fetuses with CHD. Methods This was a retrospective study in two fetal medicine units in The Netherlands. We included all fetuses with CHD in whom Doppler flow patterns (middle cerebral artery (MCA) pulsatility index (PI), umbilical artery (UA) PI and cerebroplacental ratio (CPR)) and biometry (HC and abdominal circumference (AC)) had been measured serially after 19 weeks' gestation between January 2010 and November 2016. Fetuses were categorized into three groups based on the expected cerebral arterial oxygen saturation of their particular type of CHD: normal; mild to moderately reduced; severely reduced. Trends over time in Z‐scores were analyzed using a linear mixed‐effects model. Results A total of 181 fetuses fulfilled the inclusion criteria. Expected cerebral arterial oxygen saturation in CHD was classified as normal in 44 cases, mild to moderately reduced in 84 and severely reduced in 53. In the cohort overall, average trends over time were significant for both HC and AC Z‐scores. HC Z‐scores showed a tendency to decrease until 23 weeks, then to increase until 33 weeks, followed by another decrease in the late third trimester. AC Z‐scores increased progressively with advancing gestation. MCA‐PI and UA‐PI Z‐scores showed significant trends throughout pregnancy, but CPR Z‐scores did not. There were no associations between expected cerebral arterial oxygen saturation and fetal growth. Average trends in MCA‐PI Z‐scores were significantly different between the three subgroups, whereas those in UA‐PI Z‐scores and in CPR Z‐scores were similar between the subgroups. There was no significant association between MCA‐PI and HC Z‐scores. Conclusions Fetal biometry and Doppler flow patterns are within normal range in fetuses with CHD, but show trends over time. Head growth in fetuses with CHD is not associated with cerebral blood flow pattern or placental function and HC is not influenced by the cerebral arterial oxygen saturation. © 2018 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of the International Society of Ultrasound in Obstetrics and Gynecology.

OBJECTIVE: To assess which factors, including maternal, lifestyle, pregnancy- and delivery-related, fetal and neonatal factors adjusted for socio-economic status, are related to emotional and behavioral problems in moderately-late preterm born children (MLPs; gestational age 32.0-35.9 weeks) at 4 years of age. MLPs are at greater risk of emotional and behavioral problems than full-term born children. Especially for MLPs, knowledge about factors that increase or decrease the risk of emotional and behavioral problems is scarce.DESIGN AND SETTING: We assessed emotional and behavioral problems in 809 MLPs between ages 41 and 49 months from the prospective community-based Longitudinal Preterm Outcome Project (LOLLIPOP), using the parent-reported Child Behavior Checklist (CBCL). We collected potential risk factors from hospital records and parental questionnaires. Univariable and multiple logistic regression analyses were applied.MAIN OUTCOME MEASURES: (Sub)clinical CBCL scores.RESULTS: Perinatal infection increased the risk of CBCL total problem scores with an OR 2.22 (pCONCLUSIONS: Risk factors for behavioral problems in MLPs are male gender, perinatal infection and maternal smoking, the latter two being potentially modifiable. Multiple birth is a protective factor for emotional problems in MLPs. These results suggest potential factors for targeting preventive intervention in MLPs, comprising the large majority of all preterm born children.

BACKGROUND: Organohalogen compounds (OHCs), i.e. polychlorinated biphenyls (PCBs, are wide-spread environmental pollutants known to be neurotoxic for the developing brain. The hydroxylated metabolites of PCBs, OH-PCBs, might be even more toxic due to their structure and interference with thyroid hormone metabolism. We found that prenatal exposure to OH-PCBs was associated with thyroid hormone metabolism at toddler age. Little, however, is known about the neurotoxicity of OH-PCBs in humans.OBJECTIVES: To determine whether prenatal background exposure to OHCs has an effect on mental and motor development in children at the age of 18 and 30 months.METHODS: One hundred and eighty-one healthy mother-infant pairs were included in this observational study performed in the Netherlands. We measured maternal pregnancy levels of PCB-153 and three OH-PCBs. In one part of the cohort we measured another nine PCBs and three OH-PCBs and in the other part we measured five brominated diphenyl ethers (BDEs), dichloro-diphenyldichloroethylene (p,p'-DDE), pentachlorophenol (PCP), and hexabromocyclododecane (HBCDD). We used the mental development index (MDI) and the motor development index (PDI) of the Bayley Scales of Infant Development II (BSID-II) to assess children's mental and motor development (mean = 100; delayed score RESULTS: Higher prenatal PCB-153 levels were associated with a delayed MDI score at 18 months. None of the other compounds were associated with a delayed score, but several associations were found between OHC levels and BSID-II scores. The sum of all six OH-PCBs and three individual OH-PCBs, 4-OH-PCB-107, 3-OH-PCB-153, and 4'-OH-PCB-172, correlated positively with MDI at 30 months. The compound 3'-OH-PCB-138 showed a similar trend. A higher 4-OH-PCB-187 was associated with a lower MDI at 18 months. We found a similar trend for higher BDE-99. Higher BDE levels were associated with higher PDI at 18 months. The levels of p,p'-DDE-, PCP, and HBCDD were not associated with BSID-II scores at 18 months.CONCLUSIONS: Higher prenatal levels of PCB-153 were associated with a delayed MDI score at 18 months. None of the other compounds were associated with a delayed score, but several associations were found between OHC levels and BSID-II scores. Prenatal OH-PCBs were positively associated with mental development at 30 months, whereas one OH-PCB was negatively associated at 18 months. BDE levels were positively associated with psychomotor development. Prenatal p,p'-DDE, PCP, and HBCDD levels were not associated with neurodevelopment at 18 months.

Background and aim: Predicting necrotizing enterocolitis (NEC) might help in preventing its devastating consequences. We aimed to investigate whether early cerebral and intestinal tissue oxygen saturation (rSO(2)) and fractional tissue oxygen extraction (FTOE) predict the onset of NEC.Study design: Prospective observational case-control study.Subjects: Infants with gestational age (GA) Outcome measures: Cerebral oxygenation and intestinal oxygenation were prospectively monitored two-hours daily during the first five days after birth and once a week thereafter until five weeks after birth or until NEC developed. We used Kaplan-Meier analyses to determine the ability of near-infrared spectroscopy (NIRS) measurements, including their variability, to predict the development of NEC.Results: We included ten infants (median (range) GA 27.1 (24.6-29.4) weeks, BW 903 (560-1630) grams) who developed NEC at median postnatal day 13 (range: 4-43 days), and 20 matched controls. Infants with cerebral rSO(2) = 70% (odds ratio 9.00 (95% CI 1.33-61.14). Intestinal FTOE was higher in infants who developed NEC compared to controls during the last NIRS measurement at median 2 days (range: 1-7) before NEC onset (median 0.65 vs. 0.44).Conclusions: Cerebral oxygenation monitoring early after birth might be valuable in the risk assessment of NEC development. Additionally, our results suggest that intestinal oxygenation is impaired before the onset of clinical NEC.