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Necrotizing enterocolitis (NEC) is associated with significant morbidity and mortality in preterm infants. Early recognition and treatment of NEC are critical to improving outcomes. Enteric nervous system (ENS) immaturity has been proposed as a key factor in NEC pathophysiology. Gastrointestinal dysmotility is associated with ENS immaturity and may serve as a predictive factor for the development of NEC. In this case-control study, preterm infants (gestational age (GA) < 30 weeks) were included in two level-IV neonatal intensive care units. Infants with NEC in the first month of life were 1:3 matched to controls based on GA (± 3 days). Odds ratios for NEC development were analyzed by logistic regression for time to first passage of meconium (TFPM), duration of meconial stool, and mean daily defecation frequency over the 72 h preceding clinical NEC onset (DF < T0). A total of 39 NEC cases and 117 matched controls (median GA 27 + 4 weeks) were included. Median TFPM was comparable in cases and controls (36 h [IQR 13-65] vs. 30 h [IQR 9-66], p = 0.83). In 21% of both cases and controls, TFPM was ≥ 72 h (p = 0.87). Duration of meconial stool and DF < T0 were comparable in the NEC and control group (median 4 and 3, resp. in both groups). Odds of NEC were not significantly associated with TFPM, duration of meconial stools, and DF < T0 (adjusted odds ratio [95% confidence interval]: 1.00 [0.99-1.03], 1.16 [0.86-1.55] and 0.97 [0.72-1.31], resp.)., Conclusion: In this cohort, no association was found between TFPM, duration of meconium stool, and DF < T0 and the development of NEC., What Is Known: • Necrotizing enterocolitis (NEC) is a life-threatening acute intestinal inflammatory disease of the young preterm infant. Early clinical risk factors for NEC have been investigated in order to facilitate early diagnosis and treatment. • Signs of disrupted gastrointestinal mobility, such as gastric retention and paralytic ileus, have been established to support the diagnosis of NEC. Nevertheless, defecation patterns have insufficiently been studied in relation to the disease., What Is New: • Defecation patterns in the three days preceding NEC did not differ from gestational age-matched controls of corresponding postnatal age. Additionally, the first passage of meconium and the duration of meconium passage were comparable between cases and controls. Currently, defecation patterns are not useful as early warning signs for NEC. It remains to be elucidated whether these parameters are different based on the location of intestinal necrosis., (© 2023. The Author(s).)

The threshold to initiate empiric antibiotics for suspicion of early-onset sepsis (EOS) is low in preterm infants. Antibiotics' effects on short-term outcomes have recently been debated. We aimed at exploring the extent of early empiric antibiotic exposure (EEAE) in preterm infants and the association between the duration of EEAE with necrotizing enterocolitis (NEC) and late-onset sepsis (LOS) within different EEAE groups. EEAE practice for suspicion of EOS was evaluated in all included infants (gestational age < 30 weeks) born in 9 centers in the Netherlands and Belgium between Oct. 2014 and Jan. 2019. EEAE association with NEC and LOS development was analyzed by multivariate regression. After excluding 56 EOS cases, 1259 infants were included. A total of 1122 infants (89.1%) were exposed to empirical antibiotics for the suspicion of EOS of whom 802 (63.7%) had short (≤ 72 h) and 320 (25.4%) prolonged EEAE (> 72 h). Infants with EEAE ≤ 72 h had a lower incidence of NEC compared to both infants without EEAE (adjusted odds ratio (aOR) 0.39; 95% confidence interval (CI) [0.19-0.80]; p = 0.01) and with prolonged EEAE (> 72 h) (aOR [95%CI]: 0.58 [0.35-0.96]; p = 0.03). With every additional day of EEAE, LOS incidence decreased (aOR [95%CI]: 0.90 [0.85-0.97]; p = 0.003)., Conclusion: Almost 90% of preterm infants who have negative blood culture results in the first 72 h of life are exposed to EEAE under suspicion of EOS. One-fourth has prolonged EEAE. Duration of EEAE was differently associated with NEC and LOS incidence. The effects of antibiotics, and potentially induced microbial dysbiosis related to development of NEC and LOS, should further be explored., What Is Known: • Preterm infants often receive antibiotics empirically directly after birth for suspicion of early-onset sepsis. • The effects of the duration of early empirical antibiotic exposure on the risk for necrotizing enterocolitis and late-onset sepsis are debated., What Is New: • Almost 90% of preterm infants with a gestational age below 30 weeks are exposed to antibiotics empirically after birth despite negative culture results. In a quarter of these culture-negative infants, empirical antibiotics are prolonged. • A short course of empirical antibiotics (≤72h) is associated with decreased odds for necrotizing enterocolitis compared to both prolonged (>72h) or no empirical antibiotics after birth. Furthermore, every additional day of empirical antibiotic exposure is associated with decreased risk for late-onset sepsis in the first month of life., (© 2022. The Author(s).)

In this study, we aimed to (a) evaluate postnatal changes in bone development in relation to growth and (b) to determine factors associated with bone development, from birth to 24 months of corrected age. The metacarpal speed of sound (mcSOS) and metacarpal bone transmission time (mcBTT) were used to evaluate bone development in 98 preterm infants, during hospitalization and follow-up. The mcSOS and mcBTT values not only declined in the first 6 weeks of hospitalization but also during follow-up. The mcSOS reached its lowest point at 12 months (β=-34.64), while the mcBTT reached a plateau between 12 and 24 months (β=0.06). Univariable analysis showed that gender (p=0.28), time (p<0.001), and growth parameters (p<0.001) were significant negative associated factors with mcSOS, whereas with mcBTT, time (p=0.009), length (p=0.063), length standard deviation scores (SDS) (p=0.027), head circumference (p=0.005), and head circumference SDS (p=0.007) were significant positive. The multivariable model revealed that time (β= -3.364, p=<0.001), weight (β=-0.007, p<0.001) and length (β=1.163, p<0.001) for mcSOS and length (β=-0.021, p<0.001), and length SDS (β= 0.066, p<0.001) and head circumference (β=0.049, p<0.001) for mcBTT remained highly significant associated factors.Conclusion: The most important finding is that mcSOS decreased and the mcBTT reached a plateau to 24 months. In both mcSOS and mcBTT, the growth parameters were significant factors.Clinical Trial Registration: N/A What is known: • Metabolic bone disease is one of the possible long term adverse outcomes after preterm birth. • Metacarpal speed of sound (mcSOS) and metacarpal bone transmission time (mcBTT) decline in the early postnatal period. What is new: • During follow-up, mcSOS further decreased and reached its lowest point at 12 months, while the mcBTT reached a plateau up to 24 months. • Postnatal nutrition in relation to comorbidity does not meet the optimal mineralization rate of the developing preterm bone., (© 2021. The Author(s).)

The aim of this study was to compare whole body composition, generated by air displacement plethysmography (ADP) and dual-energy X-ray absorptiometry (DXA), and to evaluate the potential predictive value of the sum of skinfolds (∑SFT) for whole body composition, in preterm infants at term equivalent age. A convenience sample of sixty-five preterm infants with a mean (SD) gestational age of 29 (1.6) weeks was studied at term equivalent age. Fat mass measured by DXA and ADP were compared and the ability of the ∑SFT to predict whole body fat mass was investigated. There was poor agreement between fat mass percentage measured with ADP compared with DXA (limits of agreement: - 4.8% and 13.7%). A previously modeled predictive equation with the ∑SFT as a predictor for absolute fat mass could not be validated. Corrected for confounders, the ∑SFT explained 42% (ADP, p = 0.001) and 75% (DXA, p = 0.001) of the variance in fat mass percentage.Conclusions: The ∑SFT was not able to accurately predict fat mass and ADP and DXA did not show comparable results. It remains to be elucidated whether or not DXA provides more accurate assessment of whole body fat mass than ADP in preterm infants.Trial registration: NTR5311 What is Known: • Diverse methods are used to assess fat mass in preterm infants. What is New: • This study showed that there is poor agreement between dual-energy X-ray absorptiometry, air displacement plethysmography, and skinfold thickness measurements. • Our results affirm the need for consensus guidelines on how to measure fat mass in preterm infants, to improve the assimilation of data from different studies and the implementation of the findings from those studies.

Necrotizing enterocolitis (NEC) is one of the most common and lethal gastrointestinal diseases in preterm infants. Early recognition of infants in need for surgical intervention might enable early intervention. In this multicenter case-control study, performed in nine neonatal intensive care units, preterm born infants (< 30 weeks of gestation) diagnosed with NEC (stage ≥ IIA) between October 2014 and August 2017 were divided into two groups: (1) medical (conservative treatment) and (2) surgical NEC (sNEC). Perinatal, clinical, and laboratory parameters were collected daily up to clinical onset of NEC. Univariate and multivariate logistic regression analyses were applied to identify potential predictors for sNEC. In total, 73 preterm infants with NEC (41 surgical and 32 medical NEC) were included. A low gestational age (p value, adjusted odds ratio [95%CI]; 0.001, 0.91 [0.86-0.96]), no maternal corticosteroid administration (0.025, 0.19 [0.04-0.82]), early onset of NEC (0.003, 0.85 [0.77-0.95]), low serum bicarbonate (0.009, 0.85 [0.76-0.96]), and a hemodynamically significant patent ductus arteriosus for which ibuprofen was administered (0.003, 7.60 [2.03-28.47]) were identified as independent risk factors for sNEC.Conclusions: Our findings may support the clinician to identify infants with increased risk for sNEC, which may facilitate early decisive management and consequently could result in improved prognosis. What is Known: • In 27-52% of the infants with NEC, a surgical intervention is indicated during its disease course. • Absolute indication for surgical intervention is bowel perforation, whereas fixed bowel loop or clinical deterioration highly suggestive of bowel perforation or necrosi, is a relative indication. What is New: • Lower gestational age, early clinical onset, and no maternal corticosteroids administration are predictors for surgical NEC. • Low serum bicarbonate in the 3 days prior clinical onset and patent ductus arteriosus for which ibuprofen was administered predict surgical NEC.

Late-onset sepsis is associated with impaired neurodevelopmental outcome in preterm infants. This prospective cohort study aims to establish the effect of sepsis after 72 h of life on cognitive, psychomotor, and language development of preterm infants (below 32 weeks gestational age and/or below 1500 g). At 2 years corrected age, neurodevelopmental outcome was tested using Bayley's Scales of Infant Development-II, Lexilijst (lexical development questionnaire), and behavior checklists. Of 117 patients included, 85 experienced blood culture-proven infection. Coagulase-negative staphylococci were responsible for 55% of the episodes. No significant differences were found in cognitive, motor, and behavioral scores or lexiquotient comparing patients with versus no proven infection. When comparing three groups (coagulase-negative staphylococci, other, and negative blood culture), a significant difference was found in composite cognitive scores (p = 0.016), in favor of the coagulase-negative staphylococci group versus other causal agent group (p = 0.007). No significant differences were found in other subscales.Conclusion: In this cohort, no differences were found in neurodevelopmental outcome at 2 years corrected age between proven and no proven infection groups; confirmation in larger cohorts with a control group is needed. Patients encountering coagulase-negative staphylococci sepsis showed a significant better cognitive outcome compared to other causal agents. What is Known: • Late-onset sepsis is associated with impaired neurodevelopmental outcome in preterm infants. What is New: • Preterm infants encountering late-onset sepsis by coagulase-negative staphylococci show a better cognitive outcome in comparison to other causal infectious agents in this cohort. • No differences were found in neurodevelopment at 2 years of age in preterm infants with suspected lateonset sepsis, between proven and no proven infection groups. Confirmation is needed in larger cohorts with a substantial control group.

The aim of this study was to assess the prevalence of congenital heart defects (CHDs) and persistent pulmonary hypertension of the neonate (PPHN) in children with Down syndrome (DS) and to assess its impact on neonatal factors. It was a prospective study of a birth cohort of children with DS born between 2003 and 2006 registered by the Dutch Paediatric Surveillance Unit (DPSU). A CHD occurred in 43% of 482 children with trisomy 21. Atrioventricular septal defect was found in 54%, ventricular septal defect in 33.3% and patent ductus arteriosus in 5.8%. The incidence of PPHN in DS was 5.2%, which is significantly higher than the general population (p < 0.001). The reported mortality in newborns with DS was overall 3.3% and was still significant higher in children with a CHD versus no CHD (5.8% versus 1.5%) (p = 0.008). The presence of CHD in children with DS had no influence on their birth weight, mean gestational age and Apgar score. In neonates with DS, we found not only a 43% prevalence of CHD, but also a high incidence of PPHN at 5.2%. Early recognition of the cardiac condition of neonates with DS seems justified.

The aim of this study was to examine the school functioning of 8- to 18-year-old children born after in vitro fertilization (IVF). We compared 233 children born after IVF to 233 matched control children born spontaneously from parents with fertility problems on measures of education level, general cognitive ability, school performance (need for extra help, repeating a grade, special education), and rates of learning and developmental disorders. No differences were found between IVF and control children on these measures of school functioning. More than 60% of adolescents at secondary school attended high academic levels (with access to high school or university). We conclude that children and adolescents born after IVF show good academic achievement and general cognitive ability. They do not experience any more educational limitations than the naturally conceived children and adolescents of the control group. The tendency of reassuring school functioning already found in younger IVF children has been shown to continue at secondary school age.

Unlabelled: Short-term oxandrolone treatment is used to stimulate growth in boys with constitutional delay of growth and puberty (CDGP). Oxandrolone stimulates growth, but a beneficial effect on final height has not been established. In our study, we report the effect of long-term treatment (30-57 months) with oxandrolone in 18 boys with CDGP, compared with nine puberty-matched, untreated controls (group 1). The oxandrolone-treated boys were divided into two groups: four boys who received oxandrolone before onset of puberty (group 2), and 14 boys who started oxandrolone therapy during Tanner stage 2 (group 3). Height standard deviation scores for calender age (HSDSCA) between the three groups of patients at Tanner stage 2 (G2) were not different: -2.86 (SD 0.56) in the controls and -2.60 (SD 0.52) in group 2 and -2.81 (SD 0.59) in group 3. Age at G2 was 15.1 (SD 1.4) years (controls), 14.6 (SD 0.5) years (group 2) and 14.0 (SD 0.9) years (group 3). Height velocity in the time span from G2 to G5 was more pronounced in the oxandrolone-treated boys: 7.7 (SD 0.5) cm/year in group 2 and 7.7 (SD 1.4) cm/year in group 3 versus 5.1 (SD 0.9) cm/year in the controls. Height gain was significantly increased in the oxandrolone treated groups: 25.8 (SD 3.8) in group 2 and 25.2 (SD 3.7) in group 3 versus 19.8 (SD 4.9) in the controls (P < 0.05). Final height did not differ significantly among the three groups: 168.5 (SD 7.0) cm in the controls and 173.0 (SD 4.0) cm in group 2 and 167.8 (SD 5.3) cm in group 3. HSDSCA increased during puberty in all three groups. At final height, HSDSCA (calculated at age = 20 years) was -2.01 (SD 1.05), -1.34 (SD 0.59) and -2.12 (SD 0.79) respectively in groups 1, 2 and 3. An effect of oxandrolone on HSDSCA was not found. Target height was neither reached by the controls nor by the treated groups. Tempo of pubertal development was not different in the three groups, and delta BA/delta CA did not alter after start of oxandrolone treatment in groups 2 and 3., Conclusion: Boys with CDGP may benefit from oxandrolone treatment in terms of increased height gain. Starting treatment before the onset of puberty may be favourable.