Mortality and Neurodevelopmental Outcomes in the Heart Rate Characteristics Monitoring Randomized Controlled Trial.

OBJECTIVE: To test whether the composite outcome of death or neurodevelopmental impairment (NDI) at 18-22 months corrected age for infants ≤1000 g at birth is decreased by continuous monitoring of heart rate characteristics during neonatal intensive care. STUDY DESIGN: We studied a subset of participants enrolled in a multicenter randomized trial of heart rate characteristics monitoring. Survivors were evaluated at 18-22 months corrected age with a standardized neurologic examination and the Bayley Scales of Infant Development-III (BSID-III). NDI was defined as Gross Motor Function Classification System of >2 (moderate or severe cerebral palsy), BSID-III language or cognitive scores of <70, severe bilateral hearing impairment, and/or bilateral blindness. RESULTS: The composite outcome, death or NDI, was obtained for 628 of 884 study infants (72%). The prevalence of this outcome was 44.4% (136/306) among controls (infants randomized to heart rate characteristics monitored but not displayed) and 38.9% (125/322) among infants randomized to heart rate characteristics monitoring displayed (relative risk, 0.87; 95% CI, 0.73-1.05; P = .17). Mortality was reduced from 32.0% (99/307) among controls to 24.8% (81/326) among monitoring displayed infants (relative risk, 0.75; 95% CI, 0.59 to 0.97; P = .028). The composite outcomes of death or severe CP and death or mildly low Bayley cognitive score occurred less frequently in the displayed group (P < .05). CONCLUSIONS: We found no difference in the composite outcome of death or NDI for extremely preterm infants whose heart rate characteristics were and were not displayed during neonatal intensive care. Two outcomes that included mortality or a specific NDI were less frequent in the displayed group.

Dose-Response Effects of Early Vitamin D Supplementation on Neurodevelopmental and Respiratory Outcomes of Extremely Preterm Infants at 2 Years of Age: A Randomized Trial.

BACKGROUND: Many extremely preterm infants have low vitamin D concentrations at birth, but early childhood outcomes after vitamin D supplementation have not been reported. OBJECTIVE: To determine a dose-response relationship between increasing doses of enteral vitamin D in the first 28 days after birth and cognitive scores at 2 years of age. METHODS: In this phase II double-blind dose-response randomized trial, infants with gestational ages between 23 and 27 weeks were randomly assigned to receive placebo or a vitamin D dose of 200 or 800 IU/day from day 1 of enteral feeding to postnatal day 28. The primary outcome of this follow-up study was Bayley III cognitive score at 22-26 months of age. RESULTS: Seventy of 80 survivors had a follow-up evaluation at 2 years of age (88%). There were no significant differences in cognitive scores between supplementation groups (p = 0.47). Cognitive scores did not differ between the higher vitamin D dose group and the placebo group (median difference favoring the 800 IU group: +5 points; 95% CI: -5 to 15; p = 0.23). The linear trend between increasing doses of vitamin D and reduction of neurodevelopmental impairment (placebo group: 54%; 200 IU group: 43%; 800 IU group: 30%; p = 0.08) or language impairment (placebo group: 64%; 200 IU group: 57%; 800 IU group: 45%; p = 0.15) was not statistically significant. Respiratory outcomes at 2 years of age (need for supplemental oxygen or asthma medications) did not differ between groups. CONCLUSION: In extremely preterm infants, early vitamin D supplementation did not significantly improve cognitive scores. Though underpowered for clinically meaningful differences in early childhood outcomes, this trial may help determine dosing for further investigation of vitamin D supplementation.

Short versus Extended Duration of Trophic Feeding to Reduce Time to Achieve Full Enteral Feeding in Extremely Preterm Infants: An Observational Study.

BACKGROUND: Trophic feeding compared to no enteral feeding prevents atrophy of the gastrointestinal tract. However, the practice of extending the duration of trophic feeding often delays initiation of full enteral feeding in extremely preterm infants. We hypothesized that a short duration of trophic feeding (3 days or less) is associated with early initiation of full enteral feeding. METHODS: A total of 192 extremely preterm infants (23-28 weeks' gestation) born between 2013 and 2015 were included. Infants were divided into 2 groups according to the duration of trophic feeding (short vs. extended). The primary outcome was time to achieve full enteral feeding and the safety outcome was necrotizing enterocolitis (NEC) and/or death. RESULTS: A short duration of trophic feeding was associated with a reduction in time to achieve full enteral feeding after adjustment for birth weight, gestational age, race, sex, type of enteral nutrition, and day of initiation of trophic feeding (mean difference favoring a short duration of trophic feeding: -4.1 days; 95% CI: -2.3 to -5.8; p < 0.001). A short duration of trophic feeding was not associated with a higher risk of NEC and/or death after achieving full enteral feeding (AOR: 0.91; 95% CI: 0.30-2.77; p = 0.87). CONCLUSIONS: A short duration of trophic feeding is associated with early initiation of full enteral feeding. A short duration of trophic feeding is not associated with a higher risk of NEC, but our study was underpowered for this safety outcome. Randomized trials are needed to test this study hypothesis.

Behavioral Problems and Socioemotional Competence at 18 to 22 Months of Extremely Premature Children.

BACKGROUND: Behavior and socioemotional development are crucial aspects of child development . METHODS: A total of 2505 children born at <27 weeks' gestation was evaluated at 18 to 22 months' corrected age between January 1, 2008 and December 12, 2012 (86% follow-up). The Brief Infant and Toddler Social and Emotional Assessment was used to evaluate behavioral and socioemotional problems. Cognition and language were evaluated by using the Bayley Scales of Infant and Toddler Development, Third Edition (Bayley-III). Logistic regression analysis was used to evaluate for perinatal and demographic factors associated with behavioral problems (≥75th percentile) and delayed socioemotional competence (≤15th percentile). Structural equation modeling with bootstrapping was used to identify possible associated risk factors and Bayley-III scores as mediators. RESULTS: Thirty-five percent (873) of children had behavioral problems, and 26% (637) displayed deficits in socioemotional competence. Male sex, public insurance, mothers with less than a high school education, and lower maternal age were associated with behavioral problems. Deficits in competence were associated with lower birth weight, public insurance, mothers with less than a high school education, and abnormal neuromotor exam. Bayley-III language and cognitive scores were significant mediators of the relationships between risk factors and both behavioral and competence scores (P < .05). CONCLUSIONS: Extremely premature children are at risk for behavioral problems and deficits in socioemotional competence. Sociodemographic factors were associated with both socioemotional competence and behavioral problems. Deficits in socioemotional competence were also associated with neuromotor abnormalities and cognitive and language function.

Associations Between Hormonal Biomarkers and Cognitive, Motor, and Language Developmental Status in Very Low Birth Weight Infants.

BACKGROUND: Male infants are more prone to health problems and developmental delays than female infants. OBJECTIVES: On the basis of theories of gender differences in brain development and social relationships, we explored associations between testosterone and cortisol levels with infant cognitive, motor, and language development ("infant development") in very low birth weight (VLBW) infants, controlling for mother-infant interactions, characteristics of mothers and infants, and days of saliva collection after birth. METHODS: A total of 62 mother-VLBW infant pairs were recruited from the newborn intensive care unit of a tertiary medical center in the Southeast United States. Data were collected through infant medical record review, biochemical measurement, observation of mother-infant interactions, and standard questionnaires. Infant development was assessed at 6 months corrected age (CA), and mother-infant interactions were observed at 3 and 6 months CA. RESULTS: General linear regression with separate analyses for each infant gender showed that high testosterone levels were positively associated with language development of male infants after controlling for mother-infant interactions and other covariates, whereas high cortisol levels were negatively associated with motor development of female infants after controlling for mother-infant interactions. CONCLUSIONS: Steroid hormonal levels may well be more fundamental factors for assessing infant development than infant gender or mother-infant interactions at 6 months CA.

Associations of Maternal and Infant Testosterone and Cortisol Levels With Maternal Depressive Symptoms and Infant Socioemotional Problems.

This study examined the associations of testosterone and cortisol levels with maternal depressive symptoms and infant socioemotional (SE) problems that are influenced by infant gender. A total of 62 mothers and their very-low-birth weight (VLBW) infants were recruited from a neonatal intensive care unit at a tertiary medical center in the southeast United States. Data were collected at three time points (before 40 weeks' postmenstrual age [PMA] and at 3 months and 6 months of age corrected for prematurity). Measures included infant medical record review, maternal interview, biochemical assays of salivary hormone levels in mother-VLBWinfant pairs, and standard questionnaires. Generalized estimating equations with separate analyses for boys and girls showed that maternal testosterone level was negatively associated with depressive symptoms in mothers of boys, whereas infant testosterone level was negatively associated with maternal report of infant SE problems in girls after controlling for characteristics of mothers and infants and number of days post birth of saliva collection. Not surprisingly, the SE problems were positively associated with a number of medical complications. Mothers with more depressive symptoms reported that their infants had more SE problems. Mothers with higher testosterone levels reported that girls, but not boys, had fewer SE problems. In summary, high levels of testosterone could have a protective role for maternal depressive symptoms and infant SE problems. Future research need to be directed toward clinical application of these preliminary results.

Association of Maternal and Infant Salivary Testosterone and Cortisol and Infant Gender With Mother-Infant Interaction in Very-Low-Birthweight Infants.

Male very-low-birthweight (VLBW) infants are more prone than females to health and developmental problems and less positive mother-infant interactions. Because gender differences in brain development and social relationships suggest hormonal influences on quality of mother-infant interaction, the authors explored the associations of maternal and infant salivary testosterone and cortisol levels with mother-infant interactions in the sample as a whole and by gender, after controlling for covariates. Data were collected prospectively from 62 mothers and their VLBW infants through infant record review, maternal interview, biochemical measurement of both mothers and infants, and observation of mother-infant interactions at 40 weeks postmenstrual age and at three and six months corrected age. Infants' positive interactions increased and mothers' decreased from three to six months. In generalized estimating equation (GEE) analyses, after controlling for covariates, higher maternal testosterone and infant cortisol were associated with more positive and more frequent maternal interactive behaviors. In GEE analyses by infant gender, after controlling for covariates, effects of maternal and infant hormone levels became more significant, especially on infants' interactive behaviors. Based on these preliminary findings, among VLBW infants, males with high testosterone are expected to have less positive mother-infant interactions than males with low testosterone or female infants.

Seasonal Variation in Solar Ultra Violet Radiation and Early Mortality in Extremely Preterm Infants.

BACKGROUND: Vitamin D production during pregnancy promotes fetal lung development, a major determinant of infant survival after preterm birth. Because vitamin D synthesis in humans is regulated by solar ultraviolet B (UVB) radiation, we hypothesized that seasonal variation in solar UVB doses during fetal development would be associated with variation in neonatal mortality rates. METHODS: This cohort study included infants born alive with gestational age (GA) between 23 and 28 weeks gestation admitted to a neonatal unit between 1996 and 2010. Three infant cohort groups were defined according to increasing intensities of solar UVB doses at 17 and 22 weeks gestation. The primary outcome was death during the first 28 days after birth. RESULTS: Outcome data of 2,319 infants were analyzed. Mean birth weight was 830 ± 230 g and median gestational age was 26 weeks. Mortality rates were significantly different across groups (p = 0.04). High-intensity solar UVB doses were associated with lower mortality when compared with normal intensity solar UVB doses (hazard ratio: 0.70; 95% confidence interval: 0.54-0.91; p = 0.01). CONCLUSION: High-intensity solar UVB doses during fetal development seem to be associated with risk reduction of early mortality in preterm infants. Prospective studies are needed to validate these preliminary findings.

Both extremes of arterial carbon dioxide pressure and the magnitude of fluctuations in arterial carbon dioxide pressure are associated with severe intraventricular hemorrhage in preterm infants.

OBJECTIVE: The goal was to test the hypothesis that extremes of PaCO2 during the first 4 days after birth are associated with severe intraventricular hemorrhage (grades 3 and 4). METHODS: A single-center retrospective review of clinical and blood gas data in the first 4 postnatal days for 849 infants with birth weights of 401 to 1250 g was performed. The univariate and multivariate relationships of severe intraventricular hemorrhage with maximal and minimal PaCO2, PaCO2 averaged over time (time-weighted PaCO2), and measures of PaCO2 fluctuation (SD of PaCO2 and difference in PaCO2 [maximum minus minimum]) were assessed. RESULTS: Birth weight (mean +/- SD) was 848 +/- 212 g, and the median gestational age was 26 weeks. Infants with severe intraventricular hemorrhage had higher maximal PaCO2 (median: 72 vs 59 mm Hg) and time-weighted PaCO2 (mean: 49 vs 47 mm Hg) values but lower minimal PaCO2 values (32 vs 37 mm Hg). High PaCO2, low PaCO2, SD of PaCO2, and difference in PaCO2 predicted severe intraventricular hemorrhage, but time-weighted average PaCO2 was not as predictive. CONCLUSIONS: Both extremes and fluctuations of PaCO2 are associated with severe intraventricular hemorrhage. It may be prudent to avoid extreme hypocapnia and hypercapnia during the period of risk for intraventricular hemorrhage.

Estimating blood needs for very-low-birth-weight infants.

BACKGROUND: Red blood cell (RBC) transfusions are crucial for the care of very-low-birth-weight (VLBW) infants. These infants frequently require multiple, small-volume RBC transfusions, with potential exposure to multiple donors. Optimal protocols provide dedicated RBC units to reduce exposures and avoid RBC wastage. STUDY DESIGN AND METHODS: This study was a retrospective, single-institution review of RBC transfusions in VLBW infants. The RBC volume transfused during the entire hospitalization (VTH) and that transfused at 35 days were determined for all infants, 401 to 1250 g at birth, admitted to a Level III neonatal intensive care unit from January 1, 2000, through December 31, 2002. Multivariable models identified perinatal factors associated with volume transfused. RESULTS: The 640-infant cohort had a median birth weight (BW) of 818 g and gestational age (GA) of 26 weeks. Most infants (546 or 85%) required at least one RBC transfusion. Median number of RBC transfusions was 3 (range, 0-30) and median volume transfused was 82 mL (range, 9-737 mL). Of 328 infants who received all transfusions within a 35-day period, only 5 (1.5%) required at least 200 mL. VTH was inversely related to BW and GA. Multivariable models identified BW, GA, age at first transfusion, and use of inotropes as variables associated with higher volume transfused. CONCLUSION: Few VLBW infants use an entire RBC unit. One dedicated unit shared by two or more infants should meet their transfusion needs. GA, BW, and markers of illness severity predict increased RBC volume requirements.