Antenatal Steroids, Prophylactic Indomethacin, and the Risk of Spontaneous Intestinal Perforation.

OBJECTIVE: To estimate if the odds of spontaneous intestinal perforation (SIP) are increased when antenatal steroids (ANS) given close to delivery are combined with indomethacin on day 1 after birth (Indo-D1). STUDY DESIGN: A retrospective cohort study using the Neonatal Research Network (NRN) database of inborn infants, gestational age 220-286 weeks or birth weight of 401-1000 g, born between January 1, 2016 and December 31, 2019, and surviving >12 hours. The primary outcome was SIP through 14 days. Time of last ANS dose prior to delivery was analyzed as a continuous variable (using 169 hours for durations >168 hours or no steroid exposure). Associations between ANS, Indo-D1, and SIP were obtained from a multilevel hierarchical generalized linear mixed model after covariate adjustment. This yielded aOR and 95% CI. RESULTS: Of 6851 infants, 243 had SIP (3.5%). ANS exposure occurred in 6393 infants (93.3%) and IndoD1 was given to 1863 infants (27.2%). The time (median, IQR) from last dose of ANS to delivery was 32.5 hours (6-81) vs 37.1 hours (7-110) for infants with or without SIP, respectively (P = .10). Indo-D1 was given to 51.9 vs 26.3% of infants with SIP vs no SIP, respectively (P < .0001). Adjusted analysis indicated no interaction between time of last ANS dose and Indo-D1 for SIP (P = .7). Indo-D1 but not ANS was associated with increased odds of SIP (aOR: 1.73, 1.21-2.48, P = .003). CONCLUSION: The odds of SIP were increased after receipt of Indo-D1. Exposure to ANS prior to Indo-D1 was not associated with an increase in SIP.

The gut microbiome of extremely preterm infants randomized to the early progression of enteral feeding.

BACKGROUND: Early progression of feeding could influence the development of the gut microbiome. METHODS: We collected fecal samples from extremely preterm infants randomized to receive either early (feeding day 2) or delayed (feeding day 5) feeding progression. After study completion, we compared samples obtained at three different time points (week 1, week 2, and week 3) to determine longitudinal differences in specific taxa between the study groups using unadjusted and adjusted negative binomial and zero-inflated mixed models. Analyses were adjusted for a mode of delivery, breastmilk intake, and exposure to antibiotics. RESULTS: We analyzed 137 fecal samples from 51 infants. In unadjusted and adjusted analyses, we did not observe an early transition to higher microbial diversity within samples (i.e., alpha diversity) or significant differences in microbial diversity between samples (i.e., beta diversity) in the early feeding group. Our longitudinal, single-taxon analysis found consistent differences in the genera Lactococcus, Veillonella, and Bilophila between groups. CONCLUSIONS: Differences in single-taxon analyses independent of the mode of delivery, exposure to antibiotics, and breastmilk feeding suggest potential benefits of early progression of enteral feeding volumes. However, this dietary intervention does not appear to increase the diversity of the gut microbiome in the first 28 days after birth. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02915549. IMPACT: Early progression of enteral feeding volumes with human milk reduces the duration of parenteral nutrition and the need for central venous access among extremely preterm infants. Early progression of enteral feeding leads to single-taxon differences in longitudinal analyses of the gut microbiome, but it does not appear to increase the diversity of the gut microbiome in the first 28 days after birth. Randomization in enteral feeding trials creates appealing opportunities to evaluate the effects of human milk diets on the gut microbiome.

Indomethacin Prophylaxis in Preterm Infants: Changes over Time.

OBJECTIVE: Our objective was to examine changes in the use of indomethacin prophylaxis in the neonatal intensive care unit (NICU) between 2008 and 2018. STUDY DESIGN: The design of the study included cohort of 19,715 infants born between 220/7 and 266/7 weeks' gestation from 213 NICUs. A nonparametric trend test evaluated indomethacin prophylaxis and the percentage of sites using any prophylaxis over time. We evaluated the prevalence of indomethacin prophylaxis by the center and the correlation between indomethacin prophylaxis and severe intraventricular hemorrhage prevalence among 12 centers with the largest relative change in indomethacin prophylaxis prevalence. RESULTS: In total, 16% of infants received indomethacin prophylaxis. The use of indomethacin prophylaxis did not significantly decrease between 2008 and 2018 but it significantly decreased between 2014 and 2018 (p = 0.046). Among 74 centers with ≥10 infants included, 20% increased the use of indomethacin prophylaxis, while 57% decreased the use over the study period. Of the 12 centers with the largest relative change in indomethacin prophylaxis prevalence, 50% showed an inverse correlation between indomethacin prophylaxis prevalence and severe intraventricular hemorrhage, while 50% showed a positive correlation. CONCLUSION: Receipt of indomethacin prophylaxis remained similar until 2014, decreased from 2014 to 2018, and varied by the center.Key Points · The receipt of indomethacin prophylaxis decreased over time.. · Center change in the use of indomethacin prophylaxis does not correlate with the center prevalence of IVH.. · Variability in the use of indomethacin prophylaxis across centers persists..

Indomethacin Prophylaxis in Preterm Infants: Changes over Time.

OBJECTIVE: Our objective was to examine changes in the use of indomethacin prophylaxis in the neonatal intensive care unit (NICU) between 2008 and 2018. STUDY DESIGN: The design of the study included cohort of 19,715 infants born between 220/7 and 266/7 weeks' gestation from 213 NICUs. A nonparametric trend test evaluated indomethacin prophylaxis and the percentage of sites using any prophylaxis over time. We evaluated the prevalence of indomethacin prophylaxis by the center and the correlation between indomethacin prophylaxis and severe intraventricular hemorrhage prevalence among 12 centers with the largest relative change in indomethacin prophylaxis prevalence. RESULTS: In total, 16% of infants received indomethacin prophylaxis. The use of indomethacin prophylaxis did not significantly decrease between 2008 and 2018 but it significantly decreased between 2014 and 2018 (p = 0.046). Among 74 centers with ≥10 infants included, 20% increased the use of indomethacin prophylaxis, while 57% decreased the use over the study period. Of the 12 centers with the largest relative change in indomethacin prophylaxis prevalence, 50% showed an inverse correlation between indomethacin prophylaxis prevalence and severe intraventricular hemorrhage, while 50% showed a positive correlation. CONCLUSION: Receipt of indomethacin prophylaxis remained similar until 2014, decreased from 2014 to 2018, and varied by the center.Key Points · The receipt of indomethacin prophylaxis decreased over time.. · Center change in the use of indomethacin prophylaxis does not correlate with the center prevalence of IVH.. · Variability in the use of indomethacin prophylaxis across centers persists..

Growth Rates of Infants Randomized to Continuous Positive Airway Pressure or Intubation After Extremely Preterm Birth.

OBJECTIVE: To evaluate the effects of early treatment with continuous positive airway pressure (CPAP) on nutritional intake and in-hospital growth rates of extremely preterm (EPT) infants. STUDY DESIGN: EPT infants (240/7-276/7 weeks of gestation) enrolled in the Surfactant Positive Airway Pressure and Pulse Oximetry Trial (SUPPORT) were included. EPT infants who died before 36 weeks of postmenstrual age (PMA) were excluded. The growth rates from birth to 36 weeks of PMA and follow-up outcomes at 18-22 months corrected age of EPT infants randomized at birth to either early CPAP (intervention group) or early intubation for surfactant administration (control group) were analyzed. RESULTS: Growth data were analyzed for 810 of 1316 infants enrolled in SUPPORT (414 in the intervention group, 396 in the control group). The median gestational age was 26 weeks, and the mean birth weight was 839 g. Baseline characteristics, total nutritional intake, and in-hospital comorbidities were not significantly different between the 2 groups. In a regression model, growth rates between birth and 36 weeks of PMA, as well as growth rates during multiple intervals from birth to day 7, days 7-14, days 14-21, days 21-28, day 28 to 32 weeks PMA, and 32-36 weeks PMA did not differ between treatment groups. Independent of treatment group, higher growth rates from day 21 to day 28 were associated with a lower risk of having a Bayley-III cognitive score <85 at 18-22 months corrected age (P = .002). CONCLUSIONS: EPT infants randomized to early CPAP did not have higher in-hospital growth rates than infants randomized to early intubation.

Survival and Neurodevelopmental Outcomes among Periviable Infants.

BACKGROUND: Data reported during the past 5 years indicate that rates of survival have increased among infants born at the borderline of viability, but less is known about how increased rates of survival among these infants relate to early childhood neurodevelopmental outcomes. METHODS: We compared survival and neurodevelopmental outcomes among infants born at 22 to 24 weeks of gestation, as assessed at 18 to 22 months of corrected age, across three consecutive birth-year epochs (2000-2003 [epoch 1], 2004-2007 [epoch 2], and 2008-2011 [epoch 3]). The infants were born at 11 centers that participated in the National Institute of Child Health and Human Development Neonatal Research Network. The primary outcome measure was a three-level outcome - survival without neurodevelopmental impairment, survival with neurodevelopmental impairment, or death. After accounting for differences in infant characteristics, including birth center, we used multinomial generalized logit models to compare the relative risk of survival without neurodevelopmental impairment, survival with neurodevelopmental impairment, and death. RESULTS: Data on the primary outcome were available for 4274 of 4458 infants (96%) born at the 11 centers. The percentage of infants who survived increased from 30% (424 of 1391 infants) in epoch 1 to 36% (487 of 1348 infants) in epoch 3 (P<0.001). The percentage of infants who survived without neurodevelopmental impairment increased from 16% (217 of 1391) in epoch 1 to 20% (276 of 1348) in epoch 3 (P=0.001), whereas the percentage of infants who survived with neurodevelopmental impairment did not change significantly (15% [207 of 1391] in epoch 1 and 16% [211 of 1348] in epoch 3, P=0.29). After adjustment for changes in the baseline characteristics of the infants over time, both the rate of survival with neurodevelopmental impairment (as compared with death) and the rate of survival without neurodevelopmental impairment (as compared with death) increased over time (adjusted relative risks, 1.27 [95% confidence interval {CI}, 1.01 to 1.59] and 1.59 [95% CI, 1.28 to 1.99], respectively). CONCLUSIONS: The rate of survival without neurodevelopmental impairment increased between 2000 and 2011 in this large cohort of periviable infants. (Funded by the National Institutes of Health and others; ClinicalTrials.gov numbers, NCT00063063 and NCT00009633 .).

Enteral High Fat-Polyunsaturated Fatty Acid Blend Alters the Pathogen Composition of the Intestinal Microbiome in Premature Infants with an Enterostomy.

OBJECTIVE: To determine the effect of enteral fish oil and safflower oil supplementation on the intestinal microbiome in infants with an enterostomy born premature. STUDY DESIGN: Infants with an enterostomy born premature were randomized to receive early enteral supplementation with a high-fat polyunsaturated fatty acid (HF-PUFA) blend of fish oil and safflower oil vs standard nutritional therapy. We used 16S rRNA gene sequencing for longitudinal profiling of the microbiome from the time of study entry until bowel reanastomosis. We used weighted gene coexpression network analysis to identify microbial community modules that differed between study groups over time. We performed imputed metagenomic analysis to determine metabolic pathways associated with the microbial genes. RESULTS: Sixteen infants were randomized to receive enteral HF-PUFA supplementation, and 16 infants received standard care. The intestinal microbiota of infants in the treatment group differed from those in the control group, with greater bacterial diversity and lower abundance of Streptococcus, Clostridium, and many pathogenic genera within the Enterobacteriaceae family. We identified 4 microbial community modules with significant differences between groups over time. Imputed metagenomic analysis of the microbial genes revealed metabolic pathways that differed between groups, including metabolism of amino acids, carbohydrates, fatty acids, and secondary bile acid synthesis. CONCLUSION: Enteral HF-PUFA supplementation was associated with decreased abundance of pathogenic bacteria, greater bacterial diversity, and shifts in the potential metabolic functions of intestinal microbiota. TRIAL REGISTRATION: ClinicalTrials.gov:NCT01306838.

Novel pathogenic variants in FOXP3 in fetuses with echogenic bowel and skin desquamation identified by ultrasound.

Immunodysregulation, Polyendocrinopathy, Enteropathy, X-linked (IPEX) syndrome is a rare, X-linked recessive disease that affects regulatory T cells (Tregs) resulting in diarrhea, enteropathy, eczema, and insulin-dependent diabetes mellitus. IPEX syndrome is caused by pathogenic alterations in FOXP3 located at Xp11.23. FOXP3 encodes a transcription factor that interacts with several partners, including NFAT and NF-κB, and is necessary for the proper cellular differentiation of Tregs. Although variable, the vast majority of IPEX syndrome patients have onset of disease during infancy with severe enteropathy. Only five families with prenatal presentation of IPEX syndrome have been reported. Here, we present two additional prenatal onset cases with novel inherited frameshift pathogenic variants in FOXP3 that generate premature stop codons. Ultrasound findings in the first patient identified echogenic bowel, echogenic debris, scalp edema, and hydrops. In the second patient, ultrasound findings included polyhydramnios with echogenic debris, prominent fluid-filled loops of bowel, and echogenic bowel. These cases further broaden the phenotypic spectrum of IPEX syndrome by describing previously unappreciated prenatal ultrasound findings associated with the disease.

Neonatal Necrotizing Enterocolitis: An Update on Pathophysiology, Treatment, and Prevention.

Necrotizing enterocolitis (NEC) is a life-threatening disease predominantly affecting premature and very low birth weight infants resulting in inflammation and necrosis of the small bowel and colon and potentially leading to sepsis, peritonitis, perforation, and death. Numerous research efforts have been made to better understand, treat, and prevent NEC. This review explores a variety of factors involved in the pathogenesis of NEC (prematurity, low birth weight, lack of human breast milk exposure, alterations to the microbiota, maternal and environmental factors, and intestinal ischemia) and reports treatment modalities surrounding NEC, including pain medications and common antibiotic combinations, the rationale for these combinations, and recent antibiotic stewardship approaches surrounding NEC treatment. This review also highlights the effect of early antibiotic exposure, infections, proton pump inhibitors (PPIs), and H2 receptor antagonists on the microbiota and how these risk factors can increase the chances of NEC. Finally, modern prevention strategies including the use of human breast milk and standardized feeding regimens are discussed, as well as promising new preventative and treatment options for NEC including probiotics and stem cell therapy.

A pilot study of fecal pH and redox as functional markers in the premature infant gut microbiome.

The infant gut microbiome is a crucial factor in health and development. In preterm infants, altered gut microbiome composition and function have been linked to serious neonatal complications such as necrotizing enterocolitis and sepsis, which can lead to long-term disability. Although many studies have described links between microbiome composition and disease risk, there is a need for biomarkers to identify infants at risk of these complications in practice. In this pilot study, we obtained stool samples from preterm infant participants longitudinally during the first postnatal months, and measured pH and redox, as well as SCFA content and microbiome composition by 16S rRNA gene amplicon sequencing. These outcomes were compared to clinical data to better understand the role of pH and redox in infant gut microbiome development and overall health, and to assess the potential utility of pH and redox as biomarkers. We found that infants born earlier or exposed to antibiotics exhibited increased fecal pH, and that redox potential increased with postnatal age. These differences may be linked to changes in SCFA content, which was correlated with pH and increased with age. Microbiome composition was also related to birth weight, age, pH, and redox. Our findings suggest that pH and redox may serve as biomarkers of metabolic state in the preterm infant gut.

Risk factors and epidemiology of spontaneous intestinal perforation among infants born at 22-24 weeks' gestational age.

OBJECTIVE: To describe the epidemiology, risk factors, and timing of spontaneous intestinal perforation (SIP) among infants born at 22-24 weeks' gestational age (GA). STUDY DESIGN: Observational cohort study among infants born at 22-24 weeks' GA in 446 neonatal intensive care units. RESULTS: We identified 9712 infants, of whom 379 (3.9%) developed SIP. SIP incidence increased with decreasing GA (P < 0.001). Antenatal magnesium (odds ratio (OR) 1.42; 95% confidence interval (CI), 1.09-1.85), antenatal indomethacin (OR 1.40; 95% CI, 1.06-1.85), postnatal indomethacin (OR 1.61; 95% CI, 1.23-2.11), and postnatal hydrocortisone exposure (OR 2.02; 95% CI 1.50-2.73) were associated with SIP. Infants who lost 15-20% (OR 1.77; 95% CI, 1.28-2.44) or >20% (OR 2.04; 95% CI, 1.46-2.85) of birth weight had higher odds of SIP than infants with weight loss <10%. CONCLUSIONS: Antenatal magnesium exposure, antenatal indomethacin exposure, postnatal hydrocortisone exposure, postnatal indomethacin exposure, and weight loss ≥15% were associated with SIP.

Influence of infant microbiome on health and development.

The microbiome is a complex ecosystem comprising microbes, their genomes, and the surrounding environment. The microbiome plays a critical role in early human development, including maturation of the host immune system and gastrointestinal tract. Multiple factors, including diet, antibiotic use, and other environmental exposures, influence the establishment of the microbiome during infancy. Numerous studies have identified associations between the microbiome and neonatal diseases, including necrotizing enterocolitis, sepsis, and malnutrition. Furthermore, there is compelling evidence that perturbation of the microbiome in early life can have lasting developmental effects that increase an individual's risk for immune and metabolic diseases in later life. Supplementation of the microbiome with probiotics reduces the risk of necrotizing enterocolitis and sepsis in at-risk infants. This review focuses on the structure and function of the infant microbiome, the environmental and clinical factors that influence its assembly, and its impact on infant health and development.

Hormonal Determinants of Growth and Weight Gain in the Human Fetus and Preterm Infant.

The factors controlling linear growth and weight gain in the human fetus and newborn infant are poorly understood. We review here the changes in linear growth, weight gain, lean body mass, and fat mass during mid- and late gestation and the early postnatal period in the context of changes in the secretion and action of maternal, placental, fetal, and neonatal hormones, growth factors, and adipocytokines. We assess the effects of hormonal determinants on placental nutrient delivery and the impact of preterm delivery on hormone expression and postnatal growth and metabolic function. We then discuss the effects of various maternal disorders and nutritional and pharmacologic interventions on fetal and perinatal hormone and growth factor production, growth, and fat deposition and consider important unresolved questions in the field.

Human milk fortification and use of infant formulas to support growth in the neonatal intensive care unit.

Newborn infants require adequate nutrition to achieve full potential growth and development. Early life nutrition and health impacts long-term outcomes through adulthood. Human milk is the optimal source of nutrition during the first 6 months of life. However, infants admitted to the neonatal intensive care unit (NICU) often have comorbidities that create more or different nutrition demands than healthy newborns. There are different strategies to meet the nutrition needs of sick newborns, including use of parenteral nutrition, human milk fortifiers (HMFs), and infant formulas. Multinutrient HMFs are frequently used to achieve the higher nutrition demands of preterm infants. They are available in various presentations, such as human milk- or cow milk-derived, liquid or powder, and acidified or nonacidified, each of which has different risks and benefits associated with its use. Infant formulas are available to meet a demand when mother's own milk or donor breast milk is not available or sufficient, and there are also specialty formulas for infants with certain diseases that present unique nutrition needs. This review is focused on the use of HMFs to support the unique nutrition requirements of preterm infants for healthy growth, as well as the indications for the use of formulas among infants in the NICU.

Fecal pH and redox as functional markers in the premature infant gut microbiome.

The infant gut microbiome is a crucial factor in health and development. In preterm infants, altered gut microbiome composition and function have been linked to serious neonatal complications such as necrotizing enterocolitis and sepsis, which can lead to long-term disability. Although many studies have described links between microbiome composition and disease risk, there is a need for biomarkers to identify infants at risk of these complications in practice. In this study, we obtained stool samples from preterm infant participants longitudinally during the first postnatal months, and measured pH and redox, as well as SCFA content and microbiome composition by 16S rRNA gene amplicon sequencing. These outcomes were compared to clinical data to better understand the role of pH and redox in infant gut microbiome development and overall health, and to assess the potential utility of pH and redox as biomarkers. We found that infants born earlier or exposed to antibiotics exhibited increased fecal pH, and that redox potential increased with postnatal age. These differences may be linked to changes in SCFA content, which was correlated with pH and increased with age. Microbiome composition was also related to birth weight, age, pH, and redox. Our findings suggest that pH and redox may serve as biomarkers of metabolic state in the preterm infant gut.

The gestational membrane microbiome in the presence or absence of intraamniotic infection.

BACKGROUND: Data regarding the microbiome of the gestational membranes are emerging and conflicting. Shifts in the microbial communities in the setting of labor, rupture of membranes, and intraamniotic infection are yet to be understood. OBJECTIVE: This study aimed to characterize the microbiome of the gestational membranes of women in labor or with ruptured membranes, including those with and without intraamniotic infection. STUDY DESIGN: Women with a singleton pregnancy at ≥28 weeks' gestation undergoing unscheduled cesarean delivery in the setting of labor or rupture of membranes were included. Demographic and clinical variables were collected. We defined suspected intraamniotic infection by standard clinical criteria; placentae and gestational membranes were also reviewed for histologic evidence of infection. Sterile swabs were collected from membranes at the time of delivery. Bacteria were cultured from the swabs, and the isolates were sequenced. DNA extraction and 16S sequencing of the swabs were also performed. Bacterial taxonomy was assigned to each sequence. Alpha diversity indices and beta-diversity metrics were calculated to test for differences in microbial community diversity and composition between uninfected and infected groups. Differential abundance of bacteria between infected and uninfected groups was tested at the class, family, and genus level. RESULTS: Samples were collected from 34 participants. Clinical intraamniotic infection was diagnosed in 38% of participants, although 50% of placentae and membranes demonstrated histologic signs of infection. Of all samples, 68% grew bacteria on culture; this included 62% of the uninfected samples and 77% of the infected samples (P=.83). Multiple measures of alpha diversity were not significantly different between uninfected and infected groups. Similarly, analysis of beta diversity revealed that the microbial community was not significantly different between the uninfected and infected group. Several bacteria traditionally characterized as pathogenic, including Actinomyces and Streptococcus agalactiae, were identified in both infected and uninfected samples. CONCLUSION: The pathogenesis and clinical implications of intraamniotic infection remain poorly understood. Diverse bacteria are present in both infected and uninfected gestational membranes. A unique microbiologic signature may exist among the gestational membranes following labor or rupture of membranes, and further characterization of the pathogens specifically implicated in intraamniotic infection may allow for targeted therapy.

The effect of sex on retinopathy of prematurity severity among premature mixed-sex multiple gestation infants.

This retrospective study of 68 premature infants examined whether there was a difference between male and female mixed-sex multiple gestation infants with regard to stage of retinopathy of prematurity (ROP) developed or need for ROP treatment. We found that among mixed-sex twin infants there was no statistically significant difference between sexes in most severe ROP stage developed or need for ROP treatment, but males were treated at an earlier postmenstrual age (PMA) than females, despite females having a lower mean birthweight and slower mean growth velocity compared to males.

Associations between systemic health and retinal nerve fibre layer thickness in preterm infants at 36 weeks postmenstrual age.

BACKGROUND/AIMS: Neonatal insults from systemic diseases have been implicated in the pathway of impaired neurodevelopment in preterm infants. We aimed to investigate the associations between systemic health factors and retinal nerve fibre layer (RNFL) thickness in preterm infants. METHODS: We prospectively enrolled infants and imaged both eyes at 36±1 weeks postmenstrual age (PMA) using a hand-held optical coherence tomography system at the bedside in the Duke intensive care nurseries. We evaluated associations between RNFL thickness and 29 systemic health factors using univariable and multivariable regression models. RESULTS: 83 infants with RNFL thickness measures were included in this study. Based on the multivariable model, RNFL thickness was positively associated with infant weight at imaging and was negatively associated with sepsis/necrotising enterocolitis (NEC). RNFL thickness was 10.4 µm (95% CI -15.9 to -4.9) lower in infants with than without sepsis/NEC in the univariable analysis (p<0.001). This difference remained statistically significant after adjustment for confounding variables in various combinations (birth weight, birthweight percentile, gestational age, infant weight at imaging and growth velocity). A 250 g increase in infant weight at imaging was associated with a 3.1 µm (95% CI 2.1 to 4.2) increase in RNFL thickness in the univariable analysis (p<0.001). CONCLUSIONS: Low infant weight and sepsis/NEC were independently associated with thinner RNFL in preterm infants at 36 weeks PMA. To our knowledge, this study is the first to suggest that sepsis/NEC may affect retinal neurodevelopment. Future longitudinal studies are needed to investigate this relationship further.