Exploring the association between haematological markers of iron and general movements in 4-month-old infants exposed to anaemia in-utero.

BACKGROUND: Iron is a vital micronutrient for brain development, influencing myelination, neurotransmitter balance, and the maturation of specific brain cells. Hence iron insufficiency in the foetal, neonatal and infancy period has the potential to influence the neuromotor development. AIMS: We aimed to describe haematological markers of iron at 4 months of age in infants exposed to prenatal anaemia and explore the association with their quality of general movements. STUDY DESIGN: Cross sectional study nested within the RAPIDIRON-KIDS trial. SUBJECTS: All infants whose mothers were part of RAPIDIRON-KIDS trial, were eligible to participate in this study when the infants were 4 months old. Children suffering from fever or acute illness on the day of assessment, or with a history of either surgery, or admission to hospital in the first month were excluded. OUTCOME MEASURES: Haematological markers of iron (Haemoglobin and Ferritin level) and quality of general movements in infants at 4 months of age. RESULTS: 120 infants were assessed with mean birth weight of 2685.5 g (±384.5) and median gestational age of 39 weeks [Q1, Q3:38,40]. There was no significant association between haemoglobin or ferritin levels with fidgety movements (p = 0.18 and p = 0.27, respectively). The combined effect of haemoglobin and ferritin estimates also did not show any significant association with the study groups (p = 0.21). CONCLUSION: A majority of infants still had low iron indices at 4 months of age and this was not associated with the quality of general movements. A prospective longitudinal study needs to be considered in infants exposed to prenatal anaemia rather than assessing the outcomes at a single time point.

Supplemental oxygen strategies in infants with bronchopulmonary dysplasia after the neonatal intensive care unit period: study protocol for a randomised controlled trial (SOS BPD study).

INTRODUCTION: Supplemental oxygen is the most important treatment for preterm born infants with established bronchopulmonary dysplasia (BPD). However, it is unknown what oxygen saturation levels are optimal to improve outcomes in infants with established BPD from 36 weeks postmenstrual age (PMA) onwards. The aim of this study is to compare the use of a higher oxygen saturation limit (≥95%) to a lower oxygen saturation limit (≥90%) after 36 weeks PMA in infants diagnosed with moderate or severe BPD. METHODS AND ANALYSIS: This non-blinded, multicentre, randomised controlled trial will recruit 198 preterm born infants with moderate or severe BPD between 36 and 38 weeks PMA. Infants will be randomised to either a lower oxygen saturation limit of 95% or to a lower limit of 90%; supplemental oxygen and/or respiratory support will be weaned based on the assigned lower oxygen saturation limit. Adherence to the oxygen saturation limit will be assessed by extracting oxygen saturation profiles from pulse oximeters regularly, until respiratory support is stopped. The primary outcome is the weight SD score at 6 months of corrected age. Secondary outcomes include anthropometrics collected at 6 and 12 months of corrected age, rehospitalisations, respiratory complaints, infant stress, parental quality of life and cost-effectiveness. ETHICS AND DISSEMINATION: Ethical approval for the trial was obtained from the Medical Ethics Review Committee of the Erasmus University Medical Centre, Rotterdam, the Netherlands (MEC-2018-1515). Local approval for conducting the trial in the participating hospitals has been or will be obtained from the local institutional review boards. Informed consent will be obtained from the parents or legal guardians of all study participants. TRIAL REGISTRATION NUMBER: NL7149/NTR7347.

CeRebrUm and CardIac Protection with ALlopurinol in Neonates with Critical Congenital Heart Disease Requiring Cardiac Surgery with Cardiopulmonary Bypass (CRUCIAL): study protocol of a phase III, randomized, quadruple-blinded, placebo-controlled, Dutch multicenter trial.

BACKGROUND: Neonates with critical congenital heart disease (CCHD) undergoing cardiac surgery with cardiopulmonary bypass (CPB) are at risk of brain injury that may result in adverse neurodevelopment. To date, no therapy is available to improve long-term neurodevelopmental outcomes of CCHD neonates. Allopurinol, a xanthine oxidase inhibitor, prevents the formation of reactive oxygen and nitrogen species, thereby limiting cell damage during reperfusion and reoxygenation to the brain and heart. Animal and neonatal studies suggest that allopurinol reduces hypoxic-ischemic brain injury and is cardioprotective and safe. This trial aims to test the hypothesis that allopurinol administration in CCHD neonates will result in a 20% reduction in moderate to severe ischemic and hemorrhagic brain injury. METHODS: This is a phase III, randomized, quadruple-blinded, placebo-controlled, multicenter trial. Neonates with a prenatal or postnatal CCHD diagnosis requiring cardiac surgery with CPB in the first 4 weeks after birth are eligible to participate. Allopurinol or mannitol-placebo will be administered intravenously in 2 doses early postnatally in neonates diagnosed antenatally and 3 doses perioperatively of 20 mg/kg each in all neonates. The primary outcome is a composite endpoint of moderate/severe ischemic or hemorrhagic brain injury on early postoperative MRI, being too unstable for postoperative MRI, or mortality within 1 month following CPB. A total of 236 patients (n = 188 with prenatal diagnosis) is required to demonstrate a reduction of the primary outcome incidence by 20% in the prenatal group and by 9% in the postnatal group (power 80%; overall type 1 error controlled at 5%, two-sided), including 1 interim analysis at n = 118 (n = 94 with prenatal diagnosis) with the option to stop early for efficacy. Secondary outcomes include preoperative and postoperative brain injury severity, white matter injury volume (MRI), and cardiac function (echocardiography); postnatal and postoperative seizure activity (aEEG) and regional cerebral oxygen saturation (NIRS); neurodevelopment at 3 months (general movements); motor, cognitive, and language development and quality of life at 24 months; and safety and cost-effectiveness of allopurinol. DISCUSSION: This trial will investigate whether allopurinol administered directly after birth and around cardiac surgery reduces moderate/severe ischemic and hemorrhagic brain injury and improves cardiac function and neurodevelopmental outcome in CCHD neonates. TRIAL REGISTRATION: EudraCT 2017-004596-31. Registered on November 14, 2017. ClinicalTrials.gov NCT04217421. Registered on January 3, 2020.

Criterion Validity and Applicability of Motor Screening Instruments in Children Aged 5-6 Years: A Systematic Review.

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 (<0.70), four did not report these. Sensitivities ranged from 21-87% and specificities from 50-96%, with the MOT4-6 having the highest sensitivity and specificity. The DCD-Q, PQ, ASQ-3, MOQ-T-FI, and M-ABC-2-C scored highest on applicability. In conclusion, none of the instruments were sufficiently valid for motor screening at age 5-6. More research is needed on screening instruments of motor delay at age 5-6.

Altered neurodevelopmental DNA methylation status after fetal growth restriction with brain-sparing.

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 <1, 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 <0.05). Hypermethylation of VEGFA was associated with a poorer Performance Intelligence Quotient, while hypermethylation of BDNF was associated with better inhibitory self-control (both p <0.05). These results led us to formulate the hypothesis that early oxygen-dependent epigenetic alterations due to hemodynamic alterations in FGR may be associated with altered neurodevelopmental outcome in later life. We recommend further studies to test this hypothesis.

Intestinal Oxygenation and Survival After Surgery for Necrotizing Enterocolitis: An Observational Cohort Study.

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 <35% died. Median C-reactive protein [138 mg/L (IQR: 83-179) vs 73 mg/L (IQR: 12-98), P < 0.01), lactate [1.1 mmol/L (IQR: 1.0-1.6) vs 4.6 mmol/L (IQR: 2.8-8.0), P < 0.01], and fraction of inspired oxygen [25% (IQR: 21-31) vs 42% (IQR: 30-80), P < 0.01] differed between survivors and non-survivors. Only rintSO2 remained significant in the multiple regression model. 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.

Favorable parental perception of behaviour at two years' corrected age in very preterm-born children.

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.

Blood group AB is associated with poor outcomes in infants with necrotizing enterocolitis.

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.

Pulmonary hypertension in extremely preterm infants: a call to standardize echocardiographic screening and follow-up policy.

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.

Fate of pulmonary hypertension associated with bronchopulmonary dysplasia beyond 36 weeks postmenstrual age.

OBJECTIVE: To 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). DESIGN: A single-centre retrospective cohort study from a university hospital. PATIENTS: Extremely preterm (gestational age <30 weeks and/or birth weight <1000 g) infants, born between 2012 and 2017, in the University Medical Center Groningen with confirmed PH at/beyond 36 weeks PMA. MAIN OUTCOME MEASURES: Survival, mortality rate and PH resolution. Patient characteristics, treatment, presence and evolution of PH were collected from patient charts. RESULTS: Twenty-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%. CONCLUSIONS: These 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.

Plasma citrulline during the first 48 h after onset of necrotizing enterocolitis in preterm infants.

BACKGROUND: Levels of plasma citrulline (citrulline-P), a biomarker for enterocyte function, might be useful for the monitoring the course of necrotizing enterocolitis (NEC). Our aim was to evaluate whether citrulline-P levels during the first 48 h (h) after NEC onset were associated with need for surgery, survival, and intestinal recovery. METHODS: In preterm infants with NEC (Bell's stage ≥2) we measured citrulline-P levels during the first 48 h after NEC onset. Categorizing the measurements into 0-8 h, 8-16 h, 16-24 h, 24-36 h, and 36-48 h, we determined the course of citrulline-P using linear regression analyses. Next, we analyzed whether citrulline-P levels measured at 0-24 h and 24-48 h differed between conservative and surgical treatment, survivors and nonsurvivors, and equal/below and above total group's median time to full enteral feeding (FEFt). RESULTS: We included 48 infants, median gestational age 28.3 [IQR:26.0-31.4] weeks, birth weight 1200 [IQR:905-1524] grams. Citrulline-P levels decreased the first 48 h (B per time interval: -1.40 µmol, 95% CI, -2.73 to -0.07, p = 0.04). Citrulline-P was not associated with treatment, nor with survival. Citrulline-P at 0-24 h, but not 24-48 h, was higher in infants with FEFt ≤20 days than in infants with FEFt >20 days (20.7 [IQR:19.9-25.3] µmol/L (n = 13) vs. 11.1 [IQR:8.4-24.0] µmol/L (n = 11), p = 0.049), with a citrulline-P cut-off value of 12.3 µmol/L. CONCLUSION: Citrulline-P levels decreased the first 48 h after NEC onset, suggesting on-going intestinal injury. In survivors, measuring citrulline-P in the first 24 h after NEC onset may provide an indication for intestinal recovery rate.

Onset of brain injury in infants with prenatally diagnosed congenital heart disease.

BACKGROUND: The 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. METHODS: Prenatally, 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 (rcSO2) 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). RESULTS: Thirty-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, rcSO2 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 rcSO2 and FTOE were not associated with short-term neurological outcome. CONCLUSION: In 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.

Differential placental DNA methylation of VEGFA and LEP in small-for-gestational age fetuses with an abnormal cerebroplacental ratio.

BACKGROUND: In Fetal Growth Restriction 'fetal programming' may take place via DNA methylation, which has implications for short-term and long-term health outcomes. Small-for-gestational age fetuses are considered fetal growth restricted, characterized by brain-sparing when fetal Doppler hemodynamics are abnormal, expressed as a cerebroplacental ratio (CPR) <1. We aimed to determine whether brain-sparing is associated with altered DNA methylation of selected genes. METHODS: We compared DNA methylation of six genes in 41 small-for-gestational age placentas with a normal or abnormal CPR. We selected EPO, HIF1A, VEGFA, LEP, PHLDA2, and DHCR24 for their role in angiogenesis, immunomodulation, and placental and fetal growth. DNA methylation was analyzed by pyrosequencing. RESULTS: Growth restricted fetuses with an abnormal CPR showed hypermethylation of the VEGFA gene at one CpG (VEGFA-309, p = .001) and an overall hypomethylation of the LEP gene, being significant at two CpGs (LEP-123, p = .049; LEP-51, p = .020). No differences in methylation were observed for the other genes. CONCLUSIONS: VEGFA and LEP genes are differentially methylated in placentas of small-for-gestational age fetuses with brain-sparing. Hypermethylation of VEGFA-309 in abnormal CPR-placentas could indicate successful compensatory mechanisms. Methylation of LEP-51 is known to suppress LEP expression. Hypomethylation in small-for-gestational age placentas with abnormal CPR may result in hyperleptinemia and predispose to leptin-resistance later in life.

Risk factors for emotional and behavioral problems in moderately-late preterms.

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 (p<0.01). Perinatal infection, maternal smoking, and male gender increased the risk of CBCL externalizing problem scores with ORs between 1.64 and 2.46 (all p<0.05). Multiple birth decreased the risk of CBCL internalizing problem scores with an OR 0.63 (p<0.05). CONCLUSIONS: 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.

Functional outcome at school age of preterm-born children treated with low-dose dexamethasone in infancy.

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.

Serial fecal calprotectin in the prediction of necrotizing enterocolitis in preterm neonates.

PURPOSE: To investigate whether serial measurements of fecal calprotectin concentrations enable us to identify infants who will develop NEC prior to development of symptoms. METHODS: Prospective matched case-control study including 100 high-risk neonates. High risk includes 1) gestational age (GA) ≤30 weeks, 2) birth-weight (BW) ≤1000 g, 3) GA 30-32 weeks and BW ≤1250 g, 4) born from a mother who received indomethacin for tocolysis. We matched every NEC subject with three controls for birth weight and gestational age. Fecal calprotectin was measured twice a week from day one until five weeks after birth or until NEC development. We analyzed differences in fecal calprotectin between NEC subjects and controls in the week preceding NEC onset and course of fecal calprotectin within subjects who developed NEC. RESULTS: Of 100 included patients, ten (median GA 27.5 weeks [24.6-29.4], BW 1010 g [775-1630]) developed NEC. The median calprotectin concentration in all samples combined was 332 µg/g [<40-8230] µg/g feces. There were no differences between NEC subjects and controls, with a wide variation in both groups. In NEC subjects, there was no intraindividual rise in calprotectin before clinical symptoms occurred. CONCLUSIONS: There are high concentrations and wide interindividual variations in calprotectin in preterm infants during the first weeks of life. Wide intraindividual variation further precludes the serial use of fecal calprotectin in the early detection or prediction of NEC in high risk infants. LEVEL OF EVIDENCE: III.

Prenatal exposure to persistent organic pollutants and cognition and motor performance in adolescence.

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.

Behavioral and neurodevelopmental outcome of children after maternal allopurinol administration during suspected fetal hypoxia: 5-year follow up of the ALLO-trial.

OBJECTIVE: To evaluate the long-term neurodevelopmental and behavioral outcome of antenatal allopurinol treatment during suspected fetal hypoxia. STUDY DESIGN: We studied children born from women who participated in a randomized double-blind placebo controlled multicenter study (ALLO-trial). Labouring women in whom the fetus was suspected to have fetal hypoxia were randomly allocated to receive allopurinol or placebo. At 5 years of age, the children were assessed with 2 parent reported questionnaires, the Ages and Stages Questionnaire (ASQ) and the Child Behavior Checklist (CBCL). A child was marked abnormal for ASQ if it scored below 2 standard deviation under the normative mean of a reference population in at least one domain. For CBCL, a score above the cut-off value (95th percentile for narrowband scale, 85th percentile for broadband scale) in at least one scale was marked as abnormal. RESULTS: We obtained data from 138 out of the original 222 mildly asphyxiated children included in the ALLO-trial (response rate 62%, allopurinol n = 73, placebo n = 65). At 5 years of age, the number of children that scored abnormal on the ASQ were 11 (15.1%) in the allopurinol group versus 11 (9.2%) in the placebo group (relative risk (RR) 1.64, 95% confidence interval (CI): 0.64 to 4.17, p = 0.30). On CBCL 21 children (30.4%) scored abnormal in de allopurinol group versus 12 children (20.0%) in the placebo group (RR 1.52, 95% CI: 0.82 to 2.83, p = 0.18). CONCLUSION: We found no proof that allopurinol administered to labouring women with suspected fetal hypoxia improved long-term developmental and behavioral outcome. These findings are limited due to the fact that the study was potentially underpowered. TRIAL REGISTRATION: NCT00189007 Dutch Trial Register NTR1383.

Preterm infants undergoing laparotomy for necrotizing enterocolitis or spontaneous intestinal perforation display evidence of impaired cerebrovascular autoregulation.

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 < .05. We used logistic regression analyses to determine factors associated with impaired CAR. 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 < .01). A higher PCO2 level was associated with impaired CAR during surgery (OR 3.04, 95% CI, 1.11-8.12 for every 1 kPa increase). 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.

Identification of gaps in the current knowledge on pulmonary hypertension in extremely preterm infants: A systematic review and meta-analysis.

BACKGROUND: Pulmonary hypertension complicates the clinical course of extremely preterm infants and is associated with bronchopulmonary dysplasia (BPD). However, prevalence, risk factors, and outcome of pulmonary hypertension in these infants are insufficiently known. This systematic review and meta-analysis aims to provide an up-to-date overview of available data on prevalence, risk factors, and outcome of pulmonary hypertension and to identify current knowledge gaps. METHODS: Medline, EMBASE, and the Cochrane Library databases were searched in July 2017. Two authors reviewed titles/abstracts and full-texts. Eligible studies reported prevalence, patient characteristics or mortality of infants with/without pulmonary hypertension. Studies were excluded if they did not include extremely preterm infants. Only similar study samples (selected infants with BPD or infants both with/without BPD) were compared in the meta-analyses. RESULTS: Of 1829 unique articles identified, 25 were eligible for inclusion. Pulmonary hypertension was observed in infants with BPD (20%, 95% confidence interval [CI] 14, 25), but also in those without BPD (2%, 95% CI 0, 8). Infants with severe BPD were most at risk of pulmonary hypertension (risk ratio [RR] 2.7, 95% CI 1.7, 4.2). Infants with pulmonary hypertension were more at risk of mortality (RR 4.7, 95% CI 2.7, 8.3). CONCLUSIONS: Pulmonary hypertension occurs in particularly in infants with severe BPD, and increases risk of mortality. Due to selected study populations, heterogeneous pulmonary hypertension-definitions and poorly reported timing of pulmonary hypertension assessments, however, data available in current reports are insufficient to allow accurate assessment of true prevalence, risk factors, and time-related outcome. Prospective studies, with standardised methodology and follow-up are needed to determine these factors.