Neurodevelopmental Outcomes of Extremely Preterm Infants Fed Donor Milk or Preterm Infant Formula: A Randomized Clinical Trial.

Importance: Maternal milk feeding of extremely preterm infants during the birth hospitalization has been associated with better neurodevelopmental outcomes compared with preterm formula. For infants receiving no or minimal maternal milk, it is unknown whether donor human milk conveys similar neurodevelopmental advantages vs preterm formula. Objective: To determine if nutrient-fortified, pasteurized donor human milk improves neurodevelopmental outcomes at 22 to 26 months' corrected age compared with preterm infant formula among extremely preterm infants who received minimal maternal milk. Design, Setting, and Participants: Double-blind, randomized clinical trial conducted at 15 US academic medical centers within the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network. Infants younger than 29 weeks 0 days' gestation or with a birth weight of less than 1000 g were enrolled between September 2012 and March 2019. Intervention: Preterm formula or donor human milk feeding from randomization to 120 days of age, death, or hospital discharge. Main Outcomes and Measures: The primary outcome was the Bayley Scales of Infant and Toddler Development (BSID) cognitive score measured at 22 to 26 months' corrected age; a score of 54 (score range, 54-155; a score of ≥85 indicates no neurodevelopmental delay) was assigned to infants who died between randomization and 22 to 26 months' corrected age. The 24 secondary outcomes included BSID language and motor scores, in-hospital growth, necrotizing enterocolitis, and death. Results: Of 1965 eligible infants, 483 were randomized (239 in the donor milk group and 244 in the preterm formula group); the median gestational age was 26 weeks (IQR, 25-27 weeks), the median birth weight was 840 g (IQR, 676-986 g), and 52% were female. The birthing parent's race was self-reported as Black for 52% (247/478), White for 43% (206/478), and other for 5% (25/478). There were 54 infants who died prior to follow-up; 88% (376/429) of survivors were assessed at 22 to 26 months' corrected age. The adjusted mean BSID cognitive score was 80.7 (SD, 17.4) for the donor milk group vs 81.1 (SD, 16.7) for the preterm formula group (adjusted mean difference, -0.77 [95% CI, -3.93 to 2.39], which was not significant); the adjusted mean BSID language and motor scores also did not differ. Mortality (death prior to follow-up) was 13% (29/231) in the donor milk group vs 11% (25/233) in the preterm formula group (adjusted risk difference, -1% [95% CI, -4% to 2%]). Necrotizing enterocolitis occurred in 4.2% of infants (10/239) in the donor milk group vs 9.0% of infants (22/244) in the preterm formula group (adjusted risk difference, -5% [95% CI, -9% to -2%]). Weight gain was slower in the donor milk group (22.3 g/kg/d [95% CI, 21.3 to 23.3 g/kg/d]) compared with the preterm formula group (24.6 g/kg/d [95% CI, 23.6 to 25.6 g/kg/d]). Conclusions and Relevance: Among extremely preterm neonates fed minimal maternal milk, neurodevelopmental outcomes at 22 to 26 months' corrected age did not differ between infants fed donor milk or preterm formula. Trial Registration: ClinicalTrials.gov Identifier: NCT01534481.

Short Term Coping-Behaviors and Postpartum Health in a Population-Based Study of Women with a Live Birth, Stillbirth, or Neonatal Death.

OBJECTIVE: Responding to the National Institutes of Health Working Group's call for research on the psychological impact of stillbirth, we compared coping-related behaviors by outcome of an index birth (surviving live birth or perinatal loss - stillbirth or neonatal death) and, among individuals with loss, characterized coping strategies and their association with depressive symptoms 6-36 months postpartum. METHODS: We used data from the Stillbirth Collaborative Research Network follow-up study (2006-2008) of 285 individuals who experienced a stillbirth, 691 a livebirth, and 49 a neonatal death. We conducted a thematic analysis of coping strategies individuals recommended following their loss. We fit logistic regression models, accounting for sampling and inverse probability of follow-up weights to estimate associations between pregnancy outcomes and coping-related behaviors and, separately, coping strategies and probable depression (Edinburgh Postnatal Depression Scale > 12) for those with loss. RESULTS: Compared to those with a surviving live birth and adjusting for pre-pregnancy drinking and smoking, history of stillbirth, and age, individuals who experienced a loss were more likely to report increased drinking or smoking in the two months postpartum (adjusted OR: 2.7, 95% CI = 1.4-5.4). Those who smoked or drank more had greater odds of probable depression at 6 to 36 months postpartum (adjusted OR 6.4, 95% CI = 2.5-16.4). Among those with loss, recommended coping strategies commonly included communication, support groups, memorializing the loss, and spirituality. DISCUSSION: Access to a variety of evidence-based and culturally-appropriate positive coping strategies may help individuals experiencing perinatal loss avoid adverse health consequences.

Adverse Metabolic Phenotypes in Parenterally Fed Neonatal Pigs Do Not Persist into Adolescence.

BACKGROUND: Nutrition during fetal and neonatal life is an important determinant for the risk of adult-onset diseases, especially type 2 diabetes and obesity. OBJECTIVES: We aimed to determine whether total parenteral nutrition (TPN) compared with enteral formula feeding [enteral nutrition (EN)] in term piglets during the first 2 wk after birth would increase the long-term (5-mo) development of metabolic syndrome phenotypes with adverse glucose homeostasis, fatty liver disease, and obesity. METHODS: Neonatal female pigs were administered TPN (n = 12) or fed enterally with a liquid enteral milk-replacer formula (EN, n = 12) for 14 d. After transitioning TPN pigs to enteral feeding of liquid formula (days 15-26), both groups were adapted to a solid high-fat diet (30% of the total diet) and sucrose (20% of the total diet) diet (days 27-33), which was fed until the end of the study (140 d). Body composition was measured by dual-energy X-ray absorptiometry at 14, 45, and 140 d. Serum biochemistry and glucose-insulin values (after a fasting intravenous glucose tolerance test) were obtained at 140 d. Liver and muscle were analyzed for insulin receptor signaling and triglycerides. RESULTS: Body weight was similar, but percent fat was higher, whereas percent lean and bone mineral density were lower in TPN than in EN pigs (P < 0.01) at 45 d of age but not at 140 d. At 140 d, there were no differences in serum markers of liver injury or lipidemia. Intravenous glucose tolerance test at 140 d showed a lower (P < 0.05) AUC for both glucose and insulin in TPN than in EN pigs, but the ratio of AUCs of insulin and glucose was not different between groups. CONCLUSIONS: Administration of TPN during the neonatal period increased adipose deposition that transiently persisted in early adolescence when challenged with a high-fat diet but was not sustained or manifested as glucose intolerance.

Pulsatile Leucine Administration during Continuous Enteral Feeding Enhances Skeletal Muscle Mechanistic Target of Rapamycin Complex 1 Signaling and Protein Synthesis in a Preterm Piglet Model.

BACKGROUND: Continuous feeding does not elicit an optimal anabolic response in skeletal muscle but is required for some preterm infants. We reported previously that intermittent intravenous pulses of leucine (Leu; 800 µmol Leu·kg-1·h-1 every 4 h) to continuously fed pigs born at term promoted mechanistic target of rapamycin complex 1 (mTORC1) activation and protein synthesis in skeletal muscle. OBJECTIVES: The aim was to determine the extent to which intravenous Leu pulses activate mTORC1 and enhance protein synthesis in the skeletal muscle of continuously fed pigs born preterm. METHODS: Pigs delivered 10 d preterm was advanced to full oral feeding >4 d and then assigned to 1 of the following 4 treatments for 28 h: 1) ALA (continuous feeding; pulsed with 800 µmol alanine·kg-1·h-1 every 4 h; n = 8); 2) L1× (continuous feeding; pulsed with 800 µmol Leu·kg-1·h-1 every 4 h; n = 7); 3) L2× (continuous feeding; pulsed with 1600 µmol Leu·kg-1·h-1 every 4 h; n = 8); and 4) INT (intermittent feeding every 4 h; supplied with 800 µmol alanine·kg-1 per feeding; n = 7). Muscle protein synthesis rates were determined with L-[2H5-ring]Phenylalanine. The activation of insulin, amino acid, and translation initiation signaling pathways were assessed by Western blot. RESULTS: Peak plasma Leu concentrations were 134% and 420% greater in the L2× compared to the L1× and ALA groups, respectively (P < 0.01). Protein synthesis was greater in the L2× than in the ALA and L1× groups in both the longissimus dorsi and gastrocnemius muscles (P < 0.05) but not different from the INT group (P > 0.10). Amino acid signaling upstream and translation initiation signaling downstream of mTORC1 largely corresponded to the differences in protein synthesis. CONCLUSIONS: Intravenous Leu pulses potentiate mTORC1 activity and protein synthesis in the skeletal muscles of continuously fed preterm pigs, but the amount required is greater than in pigs born at term.

Protocol for the development of a core outcome set for neonatal sepsis (NESCOS).

Neonatal sepsis is a serious public health problem; however, there is substantial heterogeneity in the outcomes measured and reported in research evaluating the effectiveness of the treatments. Therefore, we aim to develop a Core Outcome Set (COS) for studies evaluating the effectiveness of treatments for neonatal sepsis. Since a systematic review of key outcomes from randomised trials of therapeutic interventions in neonatal sepsis was published recently, we will complement this with a qualitative systematic review of the key outcomes of neonatal sepsis identified by parents, other family members, parent representatives, healthcare providers, policymakers, and researchers. We will interpret the outcomes of both studies using a previously established framework. Stakeholders across three different groups i.e., (1) researchers, (2) healthcare providers, and (3) patients' parents/family members and parent representatives will rate the importance of the outcomes in an online Real-Time Delphi Survey. Afterwards, consensus meetings will be held to agree on the final COS through online discussions with key stakeholders. This COS is expected to minimize outcome heterogeneity in measurements and publications, improve comparability and synthesis, and decrease research waste.

Preterm Pigs Fed Donor Human Milk Have Greater Liver ß-Carotene Concentrations than Pigs Fed Infant Formula.

BACKGROUND: Milk carotenoids may support preterm infant health and neurodevelopment. Infants fed human milk often have higher blood and tissue carotenoid concentrations than infants fed carotenoid-containing infant formula (IF). Donor human milk (DHM) is a supplement to mother's own milk, used to support preterm infant nutrition. OBJECTIVES: We tested whether tissue and plasma ß-carotene concentrations would be higher in preterm pigs fed pasteurized DHM versus premature IF. METHODS: This is a secondary analysis of samples collected from a study of the effects of enteral diet composition on necrotizing enterocolitis incidence. Preterm pigs received partial enteral feeding of either DHM (n = 7) or premature IF (n = 7) from 2 to 7 d of age. The diets provided similar ß-carotene (32 nM), but DHM had higher lutein, zeaxanthin, and lycopene, whereas IF had higher total vitamin A. Plasma, liver, and jejunum carotenoid and vitamin A concentrations were measured by HPLC-PDA. Jejunal expression of 12 genes associated with carotenoid and lipid metabolism were measured. RESULTS: Liver ß-carotene concentrations were higher in DHM- than IF-fed piglets (23 ± 4 compared with 16 ± 2 µg/g, respectively, P = 0.0024), whereas plasma and jejunal ß-carotene concentrations were similar between diets. Liver vitamin A stores were higher in piglets fed IF than DHM (50.6 ± 10.1 compared with 30.9 ± 7.2 µg/g, respectively, P=0.0013); however, plasma vitamin A was similar between groups. Plasma, liver, and jejunum concentrations of lutein, zeaxanthin, and lycopene were higher with DHM than IF feeding. Relative to piglets fed DHM, jejunal low density lipoprotein receptor (Ldlr) expression was higher (61%, P = 0.018) and cluster determinant 36 (Cd36) expression (-27%, P = 0.034) was lower in IF-fed piglets. CONCLUSIONS: Preterm pigs fed DHM accumulate more liver ß-carotene than IF-fed pigs. Future studies should further investigate infant carotenoid bioactivity and bioavailability.

Use of term reference infants in assessing the developmental outcome of extremely preterm infants: lessons learned in a multicenter study.

OBJECTIVE: Extremely preterm (EP) impairment rates are likely underestimated using the Bayley III norm-based thresholds scores and may be better assessed relative to concurrent healthy term reference (TR) infants born in the same hospital. STUDY DESIGN: Blinded, certified examiners in the Neonatal Research Network (NRN) evaluated EP survivors and a sample of healthy TR infants recruited near the 2-year assessment age. RESULTS: We assessed 1452 EP infants and 183 TR infants. TR-based thresholds showed higher overall EP impairment than Bayley norm-based thresholds (O.R. = 1.86; [95% CI 1.56-2.23], especially for severe impairment (36% vs. 24%; p ≤ 0.001). Difficulty recruiting TR patients at 2 years extended the study by 14 months and affected their demographics. CONCLUSION: Impairment rates among EP infants appear to be substantially underestimated from Bayley III norms. These rates may be best assessed by comparison with healthy term infants followed with minimal attrition from birth in the same centers. GOV ID: Term Reference (under the Generic Database Study): NCT00063063.

Probiotics and Human Milk Differentially Influence the Gut Microbiome and NEC Incidence in Preterm Pigs.

Necrotizing enterocolitis (NEC) is the leading cause of death caused by gastrointestinal disease in preterm infants. Major risk factors include prematurity, formula feeding, and gut microbial colonization. Microbes have been linked to NEC, yet there is no evidence of causal species, and select probiotics have been shown to reduce NEC incidence in infants. In this study, we evaluated the effect of the probiotic Bifidobacterium longum subsp. infantis (BL. infantis), alone and in combination with a human milk oligosaccharide (HMO)-sialylactose (3'SL)-on the microbiome, and the incidence of NEC in preterm piglets fed an infant formula diet. We studied 50 preterm piglets randomized between 5 treatments: (1) Preterm infant formula, (2) Donor human milk (DHM), (3) Infant formula + 3'SL, (4) Infant formula + BL. infantis, and (5) Infant formula and BL. infantis + 3'SL. NEC incidence and severity were assessed through the evaluation of tissue from all the segments of the GI tract. The gut microbiota composition was assessed both daily and terminally through 16S and whole-genome sequencing (WGS) of rectal stool samples and intestinal contents. Dietary BL. infantis and 3'SL supplementation had no effect, yet DHM significantly reduced the incidence of NEC. The abundance of BL. infantis in the gut contents negatively correlated with disease severity. Clostridium sensu stricto 1 and Clostridium perfringens were significantly more abundant in NEC and positively correlated with disease severity. Our results suggest that pre- and probiotics are not sufficient for protection from NEC in an exclusively formula-based diet. The results highlight the differences in microbial species positively associated with both diet and NEC incidence.

Generalizability of the Necrotizing Enterocolitis Surgery Trial to the Target Population of Eligible Infants.

OBJECTIVE: The objective of this study was to evaluate whether infants randomized in the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network Necrotizing Enterocolitis Surgery Trial differed from eligible infants and whether differences affected the generalizability of trial results. STUDY DESIGN: Secondary analysis of infants enrolled in Necrotizing Enterocolitis Surgery Trial (born 2010-2017, with follow-up through 2019) at 20 US academic medical centers and an observational data set of eligible infants through 2013. Infants born ≤1000 g and diagnosed with necrotizing enterocolitis or spontaneous intestinal perforation requiring surgical intervention at ≤8 weeks were eligible. The target population included trial-eligible infants (randomized and nonrandomized) born during the first half of the study with available detailed preoperative data. Using model-based weighting methods, we estimated the effect of initial laparotomy vs peritoneal drain had the target population been randomized. RESULTS: The trial included 308 randomized infants. The target population included 382 (156 randomized and 226 eligible, non-randomized) infants. Compared with the target population, fewer randomized infants had necrotizing enterocolitis (31% vs 47%) or died before discharge (27% vs 41%). However, incidence of the primary composite outcome, death or neurodevelopmental impairment, was similar (69% vs 72%). Effect estimates for initial laparotomy vs drain weighted to the target population were largely unchanged from the original trial after accounting for preoperative diagnosis of necrotizing enterocolitis (adjusted relative risk [95% CI]: 0.85 [0.71-1.03] in target population vs 0.81 [0.64-1.04] in trial) or spontaneous intestinal perforation (1.02 [0.79-1.30] vs 1.11 [0.95-1.31]). CONCLUSION: Despite differences between randomized and eligible infants, estimated treatment effects in the trial and target population were similar, supporting the generalizability of trial results. TRIAL REGISTRATION: ClinicalTrials.gov ID: NCT01029353.

Pediatric Swine Model of Methicillin-Resistant Staphylococcus aureus Sepsis-Induced Coagulopathy, Disseminated Microvascular Thrombosis, and Organ Injuries.

Sepsis-induced coagulopathy leading to disseminated microvascular thrombosis is associated with high mortality and has no existing therapy. Despite the high prevalence of Gram-positive bacterial sepsis, especially methicillin-resistant Staphylococcus aureus (MRSA), there is a paucity of published Gram-positive pediatric sepsis models. Large animal models replicating sepsis-induced coagulopathy are needed to test new therapeutics before human clinical trials. HYPOTHESIS: Our objective is to develop a pediatric sepsis-induced coagulopathy swine model that last 70 hours. METHODS AND MODELS: Ten 3 weeks old piglets, implanted with telemetry devices for continuous hemodynamic monitoring, were IV injected with MRSA (n = 6) (USA300, Texas Children's Hospital 1516 strain) at 1 × 109 colony forming units/kg or saline (n = 4). Fluid resuscitation was given for heart rate greater than 50% or mean arterial blood pressure less than 30% from baseline. Acetaminophen and dextrose were provided as indicated. Point-of-care complete blood count, prothrombin time (PT), activated thromboplastin time, d-dimer, fibrinogen, and specialized coagulation assays were performed at pre- and post-injection, at 0, 24, 48, 60, and 70 hours. Piglets were euthanized and necropsies performed. RESULTS: Compared with the saline treated piglets (control), the septic piglets within 24 hours had significantly lower neurologic and respiratory scores. Over time, PT, d-dimer, and fibrinogen increased, while platelet counts and activities of factors V, VII, protein C, antithrombin, and a disintegrin and metalloproteinase with thrombospondin-1 motifs (13th member of the family) (ADAMTS-13) decreased significantly in septic piglets compared with control. Histopathologic examination showed minor focal organ injuries including microvascular thrombi and necrosis in the kidney and liver of septic piglets. INTERPRETATIONS AND CONCLUSIONS: We established a 70-hour swine model of MRSA sepsis-induced coagulopathy with signs of consumptive coagulopathy, disseminated microvascular thrombosis, and early organ injuries with histological minor focal organ injuries. This model is clinically relevant to pediatric sepsis and can be used to study dysregulated host immune response and coagulopathy to infection, identify potential early biomarkers, and to test new therapeutics.

Trends and Racial and Geographic Differences in Infant Mortality in the United States Due to Necrotizing Enterocolitis, 1999 to 2020.

This cohort study analyzes yearly trends in necrotizing enterocolitis­related infant mortality rates (NEC-IMR) from 1999 to 2020, overall and by Black and White race, and described Black-to-White NEC-IMR ratios and NEC-IMR for US states.

Regulation of skeletal muscle protein synthesis in the preterm pig by intermittent leucine pulses during continuous parenteral feeding.

BACKGROUND: Extrauterine growth restriction is a common complication of preterm birth. Leucine (Leu) is an agonist for the mechanistic target of rapamycin (mTOR) complex 1 (mTORC1) signaling pathway that regulates translation initiation and protein synthesis in skeletal muscle. Previously, we showed that intermittent intravenous pulses of Leu to neonatal pigs born at term receiving continuous enteral nutrition increases muscle protein synthesis and lean mass accretion. Our objective was to determine the impact of intermittent intravenous pulses of Leu on muscle protein anabolism in preterm neonatal pigs administered continuous parenteral nutrition. METHODS: Following preterm delivery (on day 105 of 115 gestation), pigs were fitted with umbilical artery and jugular vein catheters and provided continuous parenteral nutrition. Four days after birth, pigs were assigned to receive intermittent Leu (1600 µmol kg-1 h-1 ; n = 8) or alanine (1600 µmol kg-1 h-1 ; n = 8) parenteral pulses every 4 h for 28 h. Anabolic signaling and fractional protein synthesis were determined in skeletal muscle. RESULTS: Leu concentration in the longissimus dorsi and gastrocnemius muscles increased in the leucine (LEU) group compared with the alanine (ALA) group (P < 0.0001). Despite the Leu-induced disruption of the Sestrin2·GATOR2 complex, which inhibits mTORC1 activation, in these muscles (P < 0.01), the abundance of mTOR·RagA and mTOR·RagC was not different. Accordingly, mTORC1-dependent activation of 4EBP1, S6K1, eIF4E·eIF4G, and protein synthesis were not different in any muscle between the LEU and ALA groups. CONCLUSION: Intermittent pulses of Leu do not enhance muscle protein anabolism in preterm pigs supplied continuous parenteral nutrition.

Incidence of and Neurodevelopmental Outcomes After Late-Onset Meningitis Among Children Born Extremely Preterm.

Importance: Late-onset meningitis (LOM) has been associated with adverse neurodevelopmental outcomes in children born extremely preterm. Objective: To report the incidence of LOM during birth hospitalization and neurodevelopmental outcomes at 18 to 26 months' corrected age. Design, Setting, and Participants: This cohort study is a secondary analysis of a multicenter prospective cohort of children born at 22 to 26 weeks' gestation between 2003 and 2017 with follow-up from 2004 to 2021. The study was conducted at 25 Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network centers. Exposures: Culture-confirmed LOM. Main Outcomes and Measures: Incidence and microbiology of LOM (2003-2017); lumbar puncture (LP) performance in late-onset sepsis (LOS) evaluations (2011-2017); composite outcome of death or neurodevelopmental impairment (NDI; 2004-2021). Results: Among 13 372 infants (median [IQR] gestational age, 25.4 [24.4-26.1] weeks; 6864 [51%] boys), LOM was diagnosed in 167 (1%); LOS without LOM in 4564 (34%); and neither LOS nor LOM in 8641 (65%). The observed incidence of LOM decreased from 2% (95% CI, 1%-3%) in 2003 to 0.4% (95% CI, 0.7%-1.0%) in 2017 (P < .001). LP performance in LOS evaluations decreased from 36% (95% CI, 33%-40%) in 2011 to 24% (95% CI, 21%-27%) in 2017 (P < .001). Among infants with culture-confirmed LOS, LP performance decreased from 58% (95% CI, 51%-65%) to 45% (95% CI, 38%-51%; P = .008). LP performance varied by center among all LOS evaluations (10%-59%, P < .001) and among those with culture-confirmed LOS (23%-79%, P < .001). LOM occurred in the absence of concurrent LOS in 27 of 167 cases (16%). The most common LOM isolates were coagulase-negative Staphylococcus (98 [59%]), Candida albicans (38 [23%]), and Escherichia coli (27 [16%]). Death or NDI occurred in 22 of 46 children (48%) with LOM due to coagulase-negative Staphylococcus, 43 of 67 (64%) due to all other bacterial pathogens, and 26 of 33 (79%) due to fungal pathogens. The adjusted relative risk of death or NDI was increased among children with LOM (aOR, 1.53; 95% CI, 1.04-2.25) and among those with LOS without LOM (aOR, 1.41; 95% CI, 1.29-1.54) compared with children with neither infection. Conclusions and Relevance: In this cohort study, LP was performed with decreasing frequency, and the observed incidence of LOM also decreased. Both LOM and LOS were associated with increased risk of death or NDI; risk varied by LOM pathogen. The full association of LOM with outcomes of children born extremely preterm may be underestimated by current diagnostic practices.

Increased Circulating Cortisol After Vaginal Birth Is Associated With Increased FGF19 Secretion in Neonatal Pigs.

The influence of birth modality (scheduled cesarean or spontaneous vaginal) on the development of the newborn has been a source of controversy in neonatology. The impact of cesarean vs vaginal birth on the development of bile acid and fibroblast growth factor 19 (FGF19) signaling is unknown. Our aim was to determine the effect of birth modality and gestational age (preterm vs term) on plasma hormone levels, bile acid pool distribution, expression of genes in the bile acid-FXR-FGF19 pathway, and plasma levels of FGF19 at birth and on day 3 of life in neonatal pigs. Four sows underwent cesarean delivery on gestation day 105 (n = 2) and 114 (n = 2; term = 115 days), and 2 additional sows were allowed to farrow at term (gestation days 112 and 118). Piglets were euthanized at birth (Term-Vaginal n = 6; Term-Cesarean n = 8; Preterm n = 10) for tissue and blood collection, and the remaining pigs received total parenteral nutrition then were fed enterally on day 3 (Term-Vaginal n = 8; Term-Cesarean n = 10; Preterm n = 8), before blood and tissue were collected. Piglets born vaginally had a markedly (30-fold) higher plasma FGF19 at birth than term pigs born via cesarean delivery, and 70-fold higher than preterm pigs (P < 0.001). However, distal ileum FGF19 gene expression was similar in all groups (P > 0.05). Plasma FGF19 positively correlated with plasma cortisol (r = 0.58; P < 0.05) and dexamethasone treatment increased ileal FGF19 expression in cultured pig tissue explants and human enteroids. Our findings suggest that exposure to maternal or endogenous glucocorticoids in the perinatal period may upregulate the development of the bile acid-FGF19 pathway.

Contributions of the NICHD neonatal research network's generic database to documenting and advancing the outcomes of extremely preterm infants.

The Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network (NRN) maintains a database of extremely preterm infants known as the Generic Database (GDB). Begun in 1987, this database now includes more than 91,000 infants, most of whom are extremely preterm (<29 weeks gestation). The GDB has been the backbone of the NRN, providing high quality, prospectively collected data to study the changing epidemiology of extreme prematurity and its outcomes over time. In addition, GDB data have been used to generate hypotheses for prospective studies and to develop new clinical trials by providing information about the numbers and characteristics of available subjects and the expected event rates for conditions and complications to be studied. Since its inception, the GDB has been the basis of more than 200 publications in peer-reviewed journals, many of which have had a significant impact on the field of neonatology.

Neonatal infections: Insights from a multicenter longitudinal research collaborative.

For more than 30 years, the Neonatal Research Network (NRN) has conducted studies addressing the epidemiology of neonatal infections, including incidence, microbiology, maternal and neonatal risk factors, associated clinical findings, and outcomes. These studies have provided clinicians and policymakers critical data needed to inform national guidance for infection risk assessment and support daily practice. Further, NRN studies have prompted research into optimal approaches to infection diagnosis, treatment, and antimicrobial stewardship. In this article, we summarize the key findings of NRN infection-related studies, with an emphasis on those published in 2000 or later.

DLK1: A Novel Biomarker of Placental Insufficiency in Stillbirth and Live Birth.

OBJECTIVE: Delta-like homolog 1 (DLK1) is a growth factor that is reduced in maternal sera in pregnancies with small for gestational age neonates. We sought to determine if DLK1 is associated with stillbirth (SB), with and without placental insufficiency. STUDY DESIGN: A nested case-control study was performed using maternal sera from a multicenter case-control study of SB and live birth (LB). SB and LB were stratified as placental insufficiency cases (small for gestational age <5% or circulatory lesions on placental histopathology) or normal placenta controls (appropriate for gestational age and no circulatory lesions). Enzyme-linked immunosorbent assay (ELISA) was used to measure DLK1. The mean difference in DLK1 was compared on the log scale in an adjusted linear regression model with pairwise differences, stratified by term/preterm deliveries among DLK1 results in the quantifiable range. In exploratory analysis, geometric means were compared among all data and the proportion of "low DLK1" (less than the median value for gestational age) was compared between groups and modeled using linear and logistic regression, respectively. RESULTS: Overall, 234 SB and 234 LB were analyzed; 246 DLK1 values were quantifiable within the standard curve. Pairwise comparisons of case and control DLK1 geometric means showed no significant differences between groups. In exploratory analysis of all data, adjusted analysis revealed a significant difference for the LB comparison only (SB: 71.9 vs. 99.1 pg/mL, p = 0.097; LB: 37.6 vs. 98.1 pg/mL, p = 0.005). In exploratory analysis of "low DLK1," there was a significant difference between the odds ratio of having "low DLK1" between preterm cases and controls for both SB and LB. There were no significant differences in geometric means nor "low DLK1" between SB and LB. CONCLUSION: In exploratory analysis, more placental insufficiency cases in preterm SB and LB had "low DLK1." However, low DLK1 levels were not associated with SB. KEY POINTS: · Maternally circulating DLK1 is correlated with placental insufficiency.. · Maternally circulating DLK1 is not correlated with SB.. · DLK1 is a promising marker for placental insufficiency..

Group B Streptococcus Infection in Extremely Preterm Neonates and Neurodevelopmental Outcomes at 2 Years.

BACKGROUND: This study was performed to determine the incidence of group B Streptococcus (GBS) disease among extremely preterm infants and assess to risk of death or neurodevelopmental impairment (NDI) at a corrected age of 18-26 months. METHODS: In this observational cohort study of infants enrolled in a multicenter registry, the incidence of GBS disease was assessed in infants born in 1998-2016 at 22-28 weeks' gestation and surviving for >12 hours. The composite outcome, death or NDI, was assessed in infants born in 1998-2014 at 22-26 weeks' gestation. Infection was defined as GBS isolation in blood or cerebrospinal fluid culture at ≤72 hours (early-onset disease [EOD]) or >72 hours (late-onset disease [LOD]) after birth. Using Poisson regression models, the outcome was compared in infants with GBS disease, infants infected with other pathogens, and uninfected infants. RESULTS: The incidence of GBS EOD (2.70/1000 births [95% confidence interval (CI), 2.15-3.36]) and LOD (8.47/1000 infants [7.45-9.59]) did not change significantly over time. The adjusted relative risk of death/NDI was higher among infants with GBS EOD than in those with other infections (adjusted relative risk, 1.22 [95% CI, 1.02-1.45]) and uninfected infants (1.44 [1.23-1.69]). Risk of death/NDI did not differ between infants with GBS LOD and comparator groups. GBS LOD occurred at a significantly later age than non-GBS late-onset infection. Among infants surviving >30 days, the risk of death was higher with GBS LOD (adjusted relative risk, 1.90 [95% CI, 1.36-2.67]), compared with uninfected infants. CONCLUSIONS: In a cohort of extremely preterm infants, the incidence of GBS disease did not change during the study period. The increased risk of death or NDI with GBS EOD, and of death among some infants with GBS LOD, supports the need for novel preventive strategies for disease reduction. CLINICAL TRIALS REGISTRATION: NCT00063063.

Preeclampsia at delivery is associated with lower serum vitamin D and higher antiangiogenic factors: a case control study.

BACKGROUND: Preeclampsia is characterized by decreased trophoblastic angiogenesis leading to abnormal invasion of spiral arteries, shallow implantation and resulting in compromised placentation with poor uteroplacental perfusion. Vitamin D plays an important role in pregnancy influencing implantation, angiogenesis and placental development. The objective of this study was to determine whether there is an association between serum vitamin D levels, and anti-angiogenic factors at the time of delivery and the occurrence of preeclampsia. METHODS: This nested case control study analyzed frozen serum samples at the time of delivery and related clinical data from women with singleton liveborn pregnancies who had participated in studies of the NICHD Stillbirth Collaborative Research Network. Women with a recorded finding of preeclampsia and who had received magnesium sulfate treatment prior to delivery were considered index cases (N = 56). Women without a finding of preeclampsia were controls (N = 341). RESULTS: Women with preeclampsia had 14.5% lower serum vitamin D levels than women in the control group (16.5 ng/ml vs. 19 ng/ml, p = 0.014) with 64.5% higher sFlt-1 levels (11,600 pg/ml vs. 7050 pg/ml, p < 0.001) and greater than 2 times higher endoglin levels (18.6 ng/ml vs. 8.7 ng/ml, < 0.001). After controlling for gestational age at delivery and maternal BMI, vitamin D levels were 0.88 times lower (P = 0.051), while endoglin levels were 2.5 times higher and sFlt-1 levels were 2.1 times higher than in control pregnancies (P < 0.001). CONCLUSIONS: Women with preeclampsia at time of delivery have higher maternal antiangiogenetic factors and may have lower maternal serum vitamin D levels. These findings may lead to a better understanding of the underlying etiology of preeclampsia as well as possible modifiable treatment options which could include assuring adequate levels of maternal serum vitamin D prior to pregnancy.