Withholding or withdrawing life-sustaining treatment in extremely low gestational age neonates.

OBJECTIVE: To identify sociodemographic and clinical factors associated with withholding or withdrawing life-sustaining treatment (WWLST) for extremely low gestational age neonates. DESIGN: Observational study of prospectively collected registry data from 19 National Institute of Child Health and Human Development Neonatal Research Network centres on neonates born at 22-28 weeks gestation who died >12 hours through 120 days of age during 2011-2016. Sociodemographic and clinical factors were compared between infants who died following WWLST and without WWLST. RESULTS: Of 1168 deaths, 67.1% occurred following WWLST. Withdrawal of assisted ventilation (97.4%) was the primary modality. WWLST rates were inversely proportional to gestational age. Life-sustaining treatment was withheld or withdrawn more often for non-Hispanic white infants than for non-Hispanic black infants (72.7% vs 60.4%; 95% CI 1.00 to 1.92) or Hispanic infants (72.7% vs 67.2%; 95% CI 1.32 to 3.72). WWLST rates varied across centres (38.6-92.6%; p<0.001). The centre with the highest rate had adjusted odds 4.89 times greater than the average (95% CI 1.18 to 20.18). The adjusted odds of WWLST were higher for infants with necrotiing enterocolitis (OR 1.77, 95% CI 1.21 to 2.59) and severe brain injury (OR 1.98, 95% CI 1.44 to 2.74). CONCLUSIONS: Among infants who died, WWLST rates varied widely across centres and were associated with gestational age, race, ethnicity, necrotiing enterocolitis, and severe brain injury. Further exploration is needed into how race, centre, and approaches to care of infants with necrotiing enterocolitis and severe brain injury influence WWLST.

Association of prenatal opiate exposure with youth outcomes assessed from infancy through adolescence.

OBJECTIVE: This study examined acute findings and long-term outcome trajectories between birth and adolescence in children with prenatal opiate exposure. STUDY DESIGN: Ninety children (45 opiate-exposed, 45 non-exposed) completed assessments between 1 month and 15 years of age. Outcome variables (medical, anthropomorphic, developmental, and behavioral) were analyzed at individual time points and using longitudinal statistical modeling. RESULTS: Opiate-exposed infants displayed transient neurologic findings, but no substantial signs or symptoms long term. There were no group differences in growth, cognitive functioning, or behavior at individual time periods; however, the trajectories of outcomes using longitudinal analyses adjusting for variables known to impact outcome demonstrated increased deficits among opiate-exposed children over time with regards to weight, head circumference, cognitive functioning, and behavior. CONCLUSIONS: Findings support concerns that maternal opiate use during pregnancy may negatively impact a child's developmental trajectory, which in turn may impose concerns to society (e.g., increased need for social, medical, and/or educational services).

Genetic and behavioral modification of hemoglobin and iron status among first-time and high-intensity blood donors.

BACKGROUND: Some people rapidly develop iron deficiency anemia following blood donation, while others can repeatedly donate without becoming anemic. METHODS: Two cohorts of blood donors were studied. Participants (775) selected from a 2-year longitudinal study were classified into six analysis groups based on sex, donation intensity, and low hemoglobin deferral. Associations with iron supplement use, cigarette smoking, and four genetic variants of iron metabolism were examined at enrollment and with longitudinal regression models. An unbiased assessment of genetic variability and ability to repeatedly donate blood without experiencing low hemoglobin deferral was conducted on participants (13,403) in a cross-sectional study who were examined by genome wide association (GWA). RESULTS: Behaviors and genetic variants were associated with differences in hemoglobin and ferritin change following repeated donation. At least weekly iron supplement use was associated with improved status in first-time donors, while daily use was associated with improved status in high-intensity donors. Cigarette smoking was associated with 0.5 g/dL increased hemoglobin in high-intensity donors. A736V in TMPRSS6 was associated with a rapid drop in hemoglobin and ferritin in first-time females following repeated donation. Conversely, the protective TMPRSS6 genotype was not enriched among high-intensity donors. H63D in HFE was associated with increased hemoglobin in female high-intensity donors. However, no differences in genotype between first-time and high-intensity donors were found in GWA analyses. CONCLUSION: Behavioral and genetic modifiers contributed to first-time donor hemoglobin and iron status, while iron supplement use was more important than underlying genetics in high-intensity donors.

Outcomes of Preterm Infants following Discussions about Withdrawal or Withholding of Life Support.

OBJECTIVES: To describe the frequency of postnatal discussions about withdrawal or withholding of life-sustaining therapy (WWLST), ensuing WWLST, and outcomes of infants surviving such discussions. We hypothesized that such survivors have poor outcomes. STUDY DESIGN: This retrospective review included registry data from 18 centers of the National Institute of Child Health and Human Development Neonatal Research Network. Infants born at 22-28 weeks of gestation who survived >12 hours during 2011-2013 were included. Regression analysis identified maternal and infant factors associated with WWLST discussions and factors predicting ensuing WWLST. In-hospital and 18- to 26-month outcomes were evaluated. RESULTS: WWLST discussions occurred in 529 (15.4%) of 3434 infants. These were more frequent at 22-24 weeks (27.0%) compared with 27-28 weeks of gestation (5.6%). Factors associated with WWLST discussion were male sex, gestational age (GA) of ≤24 weeks, birth weight small for GA, congenital malformations or syndromes, early onset sepsis, severe brain injury, and necrotizing enterocolitis. Rates of WWLST discussion varied by center (6.4%-29.9%) as did WWLST (5.2%-20.7%). Ensuing WWLST occurred in 406 patients; of these, 5 survived to discharge. Of the 123 infants for whom intensive care was continued, 58 (47%) survived to discharge. Survival after WWLST discussion was associated with higher rates of neonatal morbidities and neurodevelopmental impairment compared with babies for whom WWLST discussions did not occur. Significant predictors of ensuing WWLST were maternal age >25 years, necrotizing enterocolitis, and days on a ventilator. CONCLUSIONS: Wide center variations in WWLST discussions occur, especially at ≤24 weeks GA. Outcomes of infants surviving after WWLST discussions are poor. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00063063.

Outcome trajectories in extremely preterm infants.

OBJECTIVE: Methods are required to predict prognosis with changes in clinical course. Death or neurodevelopmental impairment in extremely premature neonates can be predicted at birth/admission to the ICU by considering gender, antenatal steroids, multiple birth, birth weight, and gestational age. Predictions may be improved by using additional information available later during the clinical course. Our objective was to develop serial predictions of outcome by using prognostic factors available over the course of NICU hospitalization. METHODS: Data on infants with birth weight ≤ 1.0 kg admitted to 18 large academic tertiary NICUs during 1998-2005 were used to develop multivariable regression models following stepwise variable selection. Models were developed by using all survivors at specific times during hospitalization (in delivery room [n = 8713], 7-day [n = 6996], 28-day [n = 6241], and 36-week postmenstrual age [n = 5118]) to predict death or death/neurodevelopmental impairment at 18 to 22 months. RESULTS: Prediction of death or neurodevelopmental impairment in extremely premature infants is improved by using information available later during the clinical course. The importance of birth weight declines, whereas the importance of respiratory illness severity increases with advancing postnatal age. The c-statistic in validation models ranged from 0.74 to 0.80 with misclassification rates ranging from 0.28 to 0.30. CONCLUSIONS: Dynamic models of the changing probability of individual outcome can improve outcome predictions in preterm infants. Various current and future scenarios can be modeled by input of different clinical possibilities to develop individual "outcome trajectories" and evaluate impact of possible morbidities on outcome.

PGE2 EP1 receptor exacerbated neurotoxicity in a mouse model of cerebral ischemia and Alzheimer's disease.

Stroke and Alzheimer's disease (AD) are major age-related neurodegenerative diseases that may worsen the prognosis of each other. Our study was designed to delineate the prostaglandin E(2) EP1 receptor role in AD and in the setting of cerebral ischemia. Genetic deletion of the prostaglandin EP1 receptor significantly attenuated the more severe neuronal damage (38.5 ± 10.6%) and memory loss induced by ischemic insult observed in AD transgenic mice (percentage of viable hippocampal CA1 neurons: 11.2 ± 2.9%) when compared with wild type mice (45.1 ± 9.1%). In addition, we found that the amyloid plaques were reduced in EP1 deleted AD mice. ß-amyloid-induced toxicity (18.0 ± 7.1%) and Ca(2+) response (91.8 ± 12.9%) were also reduced in EP1(-/-) neurons compared with control neurons in in vitro. Hence, EP1 might mediate most of the toxicity associated with cyclooxygenase-2 and contribute substantially to the cell death pathways in AD and stroke. Exploring potential therapeutic agent targeting EP1 receptor could potentially benefit treatments for stroke and AD patients.

Prediction of bronchopulmonary dysplasia by postnatal age in extremely premature infants.

RATIONALE: Benefits of identifying risk factors for bronchopulmonary dysplasia in extremely premature infants include providing prognostic information, identifying infants likely to benefit from preventive strategies, and stratifying infants for clinical trial enrollment. OBJECTIVES: To identify risk factors for bronchopulmonary dysplasia, and the competing outcome of death, by postnatal day; to identify which risk factors improve prediction; and to develop a Web-based estimator using readily available clinical information to predict risk of bronchopulmonary dysplasia or death. METHODS: We assessed infants of 23-30 weeks' gestation born in 17 centers of the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network and enrolled in the Neonatal Research Network Benchmarking Trial from 2000-2004. MEASUREMENTS AND MAIN RESULTS: Bronchopulmonary dysplasia was defined as a categorical variable (none, mild, moderate, or severe). We developed and validated models for bronchopulmonary dysplasia risk at six postnatal ages using gestational age, birth weight, race and ethnicity, sex, respiratory support, and Fi(O(2)), and examined the models using a C statistic (area under the curve). A total of 3,636 infants were eligible for this study. Prediction improved with advancing postnatal age, increasing from a C statistic of 0.793 on Day 1 to a maximum of 0.854 on Day 28. On Postnatal Days 1 and 3, gestational age best improved outcome prediction; on Postnatal Days 7, 14, 21, and 28, type of respiratory support did so. A Web-based model providing predicted estimates for bronchopulmonary dysplasia by postnatal day is available at https://neonatal.rti.org. CONCLUSIONS: The probability of bronchopulmonary dysplasia in extremely premature infants can be determined accurately using a limited amount of readily available clinical information.

Compact wave functions for the beryllium isoelectronic series, Li- to Ne6+: a standard Hylleraas approach.

Variational calculations have been carried out for the ground states of several members of the beryllium isoelectronic series using a standard Hylleraas approach involving Slater-type basis functions. The species examined are Li(-), Be, B(+), C(2+), N(3+), O(4+), F(5+), and Ne(6+). For each species, the nonrelativistic energy, the electronic density at the nucleus, the expectation value <∇(i)·∇(j)>, the moments for n = -1, 1, 2, and 3, and for n = -1, 1, and 2, are reported. With relatively compact basis sets, the ground state energies are obtained with uncertainties ranging from 50 parts per million to just under 4 parts per million.

Hypocarbia and adverse outcome in neonatal hypoxic-ischemic encephalopathy.

OBJECTIVE: To evaluate the association between early hypocarbia and 18- to 22-month outcome among neonates with hypoxic-ischemic encephalopathy. STUDY DESIGN: Data from the National Institute of Child Health and Human Development Neonatal Research Network randomized, controlled trial of whole-body hypothermia for neonatal hypoxic-ischemic encephalopathy were used for this secondary observational study. Infants (n = 204) had multiple blood gases recorded from birth to 12 hours of study intervention (hypothermia versus intensive care alone). The relationship between hypocarbia and outcome (death/disability at 18 to 22 months) was evaluated by unadjusted and adjusted analyses examining minimum PCO(2) and cumulative exposure to PCO(2) <35 mm Hg. The relationship between cumulative PCO(2) <35 mm Hg (calculated as the difference between 35 mm Hg and the sampled PCO(2) multiplied by the duration of time spent <35 mm Hg) and outcome was evaluated by level of exposure (none-high) using a multiple logistic regression analysis with adjustments for pH, level of encephalopathy, treatment group (± hypothermia), and time to spontaneous respiration and ventilator days; results were expressed as odds ratios and 95% confidence intervals. Alternative models of CO(2) concentration were explored to account for fluctuations in CO(2). RESULTS: Both minimum PCO(2) and cumulative PCO(2) <35 mm Hg were associated with poor outcome (P < .05). Moreover, death/disability increased with greater cumulative exposure to PCO(2) <35 mm Hg. CONCLUSIONS: Hypocarbia is associated with poor outcome after hypoxic-ischemic encephalopathy.

Prediction of death for extremely premature infants in a population-based cohort.

OBJECTIVE: Although gestational age (GA) is often used as the primary basis for counseling and decision-making for extremely premature infants, a study of tertiary care centers showed that additional factors could improve prediction of outcomes. Our objective was to determine how such a model could improve predictions for a population-based cohort. METHODS: From 2005 to 2008, data were collected prospectively for the California Perinatal Quality Care Collaborative, which encompasses 90% of NICUs in California. For infants born at GAs of 22 to 25 weeks, we assessed the ability of the Eunice Kennedy Shriver National Institute of Child Health and Human Development 5-factor model to predict survival rates, compared with a model using GA alone. RESULTS: In the study cohort of 4527 infants, 3647 received intensive care. Survival rates were 53% for the whole cohort and 66% for infants who received intensive care. In multivariate analyses of data for infants who received intensive care, prenatal steroid exposure, female sex, singleton birth, and higher birth weight (per 100-g increment) were each associated with a reduction in the risk of death before discharge similar to that for a 1-week increase in GA. The multivariate model increased the ability to group infants in the highest and lowest risk categories (mortality rates of >80% and <20%, respectively). CONCLUSIONS: In a population-based cohort, the addition of prenatal steroid exposure, sex, singleton or multiple birth, and birth weight to GA allowed for improved prediction of rates of survival to discharge for extremely premature infants.

Impact of postnatal corticosteroid use on neurodevelopment at 18 to 22 months' adjusted age: effects of dose, timing, and risk of bronchopulmonary dysplasia in extremely low birth weight infants.

OBJECTIVE: Postnatal steroid use decreases lung inflammation but increases impairment. We hypothesized that increased dose is associated with increased neurodevelopmental impairment, lower postmenstrual age at exposure increases impairment, and risk of bronchopulmonary dysplasia modifies the effect of postnatal corticosteroid. METHODS: Steroid dose and timing of exposure beyond 7 days was assessed among 2358 extremely low birth weight infants nested in a prospective trial, with 1667 (84%) survivors examined at 18 to 22 months' postmenstrual age. Logistic regression tested the relationship between impairment (Bayley Mental Developmental Index/Psychomotor Developmental Index of <70, disabling cerebral palsy, or sensory impairment), total dose (tertiles: <0.9, 0.9-1.9, and >/=1.9 mg/kg), and postmenstrual age at first dose. Separate logistic regression tested effect modification according to bronchopulmonary dysplasia severity (Romagnoli risk > 0.5 as high risk, n = 2336 (99%) for days of life 4-7). RESULTS: Three hundred sixty-six (16%) neonates were steroid-treated (94% dexamethasone). Treated neonates were smaller and less mature; 72% of those treated were at high risk for bronchopulmonary dysplasia. Exposure was associated with neurodevelopmental impairment/death. Impairment increased with higher dose; 71% dead or impaired at highest dose tertile. Each 1 mg/kg dose was associated with a 2.0-point reduction on the Mental Developmental Index and a 40% risk increase for disabling cerebral palsy. Older age did not mitigate the harm. Treatment after 33 weeks' postmenstrual age was associated with greatest harm despite not receiving the highest dose. The relationship between steroid exposure and impairment was modified by the bronchopulmonary dysplasia risk, with those at highest risk experiencing less harm. CONCLUSIONS: Higher steroid dose was associated with increased neurodevelopmental impairment. There is no "safe" window for steroid use in extremely low birth weight infants. Neonates with low bronchopulmonary dysplasia risk should not be exposed. A randomized trial of steroid use in infants at highest risk is warranted.

Intensive care for extreme prematurity--moving beyond gestational age.

BACKGROUND: Decisions regarding whether to administer intensive care to extremely premature infants are often based on gestational age alone. However, other factors also affect the prognosis for these patients. METHODS: We prospectively studied a cohort of 4446 infants born at 22 to 25 weeks' gestation (determined on the basis of the best obstetrical estimate) in the Neonatal Research Network of the National Institute of Child Health and Human Development to relate risk factors assessable at or before birth to the likelihood of survival, survival without profound neurodevelopmental impairment, and survival without neurodevelopmental impairment at a corrected age of 18 to 22 months. RESULTS: Among study infants, 3702 (83%) received intensive care in the form of mechanical ventilation. Among the 4192 study infants (94%) for whom outcomes were determined at 18 to 22 months, 49% died, 61% died or had profound impairment, and 73% died or had impairment. In multivariable analyses of infants who received intensive care, exposure to antenatal corticosteroids, female sex, singleton birth, and higher birth weight (per each 100-g increment) were each associated with reductions in the risk of death and the risk of death or profound or any neurodevelopmental impairment; these reductions were similar to those associated with a 1-week increase in gestational age. At the same estimated likelihood of a favorable outcome, girls were less likely than boys to receive intensive care. The outcomes for infants who underwent ventilation were better predicted with the use of the above factors than with use of gestational age alone. CONCLUSIONS: The likelihood of a favorable outcome with intensive care can be better estimated by consideration of four factors in addition to gestational age: sex, exposure or nonexposure to antenatal corticosteroids, whether single or multiple birth, and birth weight. (ClinicalTrials.gov numbers, NCT00063063 [ClinicalTrials.gov] and NCT00009633 [ClinicalTrials.gov].).

Importance of stability of early living arrangements on behavior outcomes of children with and without prenatal drug exposure.

OBJECTIVE: We evaluated whether living arrangements of children with or without prenatal drug exposure would be associated with their behavior outcomes and adaptive functioning. METHODS: A total of 1388 children with or without prenatal cocaine or opiate exposure were enrolled in a longitudinal cohort study at 1 month of age, were seen at intervals, tracked over time for their living situation, and evaluated for behavior problems and adaptive functioning at 3 years of age. The Child Behavior Checklist and Vineland Adaptive Behavior Scales were administered. Using multiple regression models, we determined the factors that would predict behavior problems and adaptive functioning. RESULTS: Of the children enrolled, 1092 children were evaluated. Total and externalizing behavior problems T scores of children in relative care were lower (better) than those in parental care; externalizing behavior scores were lower than those in nonrelative care (p < .05). Total behavior problem scores increased 2.3 and 1.3 points, respectively, with each move per year and each year of Child Protective Services involvement. Compared to children in nonrelative care, those in parental or relative care had higher (better) scores in the Vineland Adaptive Behavior Scales total composite (p < .023), communication (p < .045), and daily living (p < .001). Each caretaker change was associated with a decrease of 2.65 and 2.19 points, respectively, in communication and daily living scores. CONCLUSION: Children's living arrangements were significantly associated with childhood behavior problems and adaptive functioning. The instability of living situation was also a significant predictor of these outcomes. While family preservation continues to be the goal of the child welfare system, expediting decision toward permanency remains paramount once children are placed in foster care.

Persistent beneficial effects of breast milk ingested in the neonatal intensive care unit on outcomes of extremely low birth weight infants at 30 months of age.

BACKGROUND: We previously reported beneficial effects of breast milk ingestion by infants with extremely low birth weight in the NICU on developmental outcomes at 18 months' corrected age. The objective of this study was to determine whether these effects of breast milk in infants with extremely low birth weight persisted at 30 months' corrected age. METHODS: Nutrition data, including enteral and parenteral feeds, were prospectively collected, and 30 months' corrected age follow-up assessments were completed on 773 infants with extremely low birth weight who participated in the National Institute of Child Health and Human Development Neonatal Research Network Glutamine Trial. A total of 593 ingested some breast milk during the neonatal hospitalization, and 180 ingested none. Neonatal feeding characteristics and morbidities and 30-month interim history, neurodevelopmental outcomes, and growth parameters were analyzed. Children were divided into quintiles of breast milk volume to evaluate the effects of volume of human milk ingested during the NICU hospitalization. RESULTS: At 30 months, increased ingestion of breast milk was associated with higher Bayley Mental Developmental Index scores, higher Bayley behavior score percentiles for emotional regulation, and fewer rehospitalizations between discharge and 30 months. There were no differences in growth parameters or cerebral palsy. For every 10 mL/kg per day increase in breast milk, the Mental Developmental Index increased by 0.59 points, the Psychomotor Developmental Index by 0.56 points, and the total behavior percentile score by 0.99 points, and the risk of rehospitalization between discharge and 30 months decreased by 5%. CONCLUSIONS: Beneficial effects of ingestion of breast milk in the NICU persist at 30 months' corrected age in this vulnerable extremely low birth weight population. Continued efforts must be made to offer breast milk to all extremely low birth weight infants both in the NICU and after discharge.

Role of Nrf2 in protection against intracerebral hemorrhage injury in mice.

Nrf2 is a key transcriptional factor for antioxidant response element (ARE)-regulated genes. While its beneficial role has been described for stroke, its contribution to intracerebral hemorrhage (ICH)-induced early brain injury remains to be determined. Using wild-type (WT) and Nrf2 knockout (Nrf2(-/-)) mice, the role of Nrf2 in ICH induced by intracerebral injection of collagenase was investigated. The results showed that injury volume was significantly larger in Nrf2(-/-) mice than in WT controls 24 h after induction of ICH (P<0.05), an outcome that correlated with neurological deficits. This exacerbation of brain injury in Nrf2(-/-) mice was also associated with an increase in leukocyte infiltration, production of reactive oxygen species, DNA damage, and cytochrome c release during the critical early phase of the post-ICH period. In combination, these results suggest that Nrf2 reduces ICH-induced early brain injury, possibly by providing protection against leukocyte-mediated free radical oxidative damage.

Human milk intake and retinopathy of prematurity in extremely low birth weight infants.

OBJECTIVES: Our goal was to analyze the association between human milk intake and severe retinopathy of prematurity in extremely low birth weight infants. PATIENTS AND METHODS: This study is a secondary analysis of data collected for a trial of glutamine supplementation in extremely low birth weight infants (birth weight <1000 g). Among the 1433 participants in that trial, data are available regarding human milk intake and the occurrence of severe retinopathy of prematurity (defined in this study as retinopathy of prematurity treated surgically) for 1057 infants. The volume of human milk intake was expressed as the mean volume (milliliters per kilogram per day) and the mean proportional volume (proportion of total nutritional intake) from birth to discharge or transfer. Using logistic regression, we estimated odds ratios and 95% confidence intervals for any human milk intake and, among infants who received human milk, for each 10 mL/kg per day and each 10% increase in volume. RESULTS: Of the 1057 infants included in this cohort, 788 infants (75%) received at least some human milk. Among these milk-fed infants, the median volume of human milk intake was 30 mL/kg per day (interquartile range: 6-83 mL/kg per day), and the median proportional volume of human milk intake was 0.18 (interquartile range: 0.03-0.66). One hundred sixty-three infants (15%) developed severe retinopathy of prematurity. CONCLUSIONS: In extremely low birth weight infants, human milk intake was not associated with a decreased risk of severe retinopathy of prematurity.

Cumulative index of exposure to hypocarbia and hyperoxia as risk factors for periventricular leukomalacia in low birth weight infants.

BACKGROUND: Hypocarbia and hyperoxia are risk factors for periventricular leukomalacia in low birth weight infants. The association of a cumulative index of exposure to hypocarbia and hyperoxia and periventricular leukomalacia has not been evaluated. OBJECTIVE: Our goal was to examine the relationship between cumulative index of exposure to hypocarbia and hyperoxia and periventricular leukomalacia during the first 7 days of life in low birth weight infants. METHODS: Blood gas results were recorded in 6-hour intervals among low birth weight infants in a prospective data registry. Cumulative index of exposure to hypocarbia was calculated as the difference between arterial carbon dioxide level and 35 mmHg multiplied by the time interval in hours for each 6-hour block in a 24-hour day for the first 7 days of life. Cumulative index of exposure to hyperoxia was calculated in the same manner for arterial oxygen level >80 mm Hg. The relationship between exposure to hypocarbia, hyperoxia, and periventricular leukomalacia was examined in 778 infants with blood gas and cranial sonography data. RESULTS: Twenty-one infants had periventricular leukomalacia. Hypocarbia occurred in 489 infants and hyperoxia in 502 infants. Infants with periventricular leukomalacia were more likely to have a lower gestational age and to require delivery room resuscitation than those without periventricular leukomalacia. More infants in the highest quartile of exposure to hypocarbia had periventricular leukomalacia compared to those with no hypocarbia. Risk of periventricular leukomalacia was increased in infants with the highest quartile of exposure to hypocarbia after adjusting for maternal and neonatal variables, none to be associated with periventricular leukomalacia. Cumulative index exposure to hyperoxia was not related to periventricular leukomalacia. CONCLUSIONS: Cumulative exposure to hypocarbia and not hyperoxia was independently related to risk of periventricular leukomalacia in low birth weight infants.

Beneficial effects of breast milk in the neonatal intensive care unit on the developmental outcome of extremely low birth weight infants at 18 months of age.

OBJECTIVE: Beneficial effects of breast milk on cognitive skills and behavior ratings have been demonstrated previously in term and very low birth weight infants. Extremely low birth weight infants are known to be at increased risk for developmental and behavior morbidities. The benefits of breast milk that is ingested in the NICU by extremely low birth weight infants on development and behavior have not been evaluated previously. METHODS: Nutrition data including enteral and parenteral feeds were collected prospectively, and follow-up assessments of 1035 extremely low birth weight infants at 18 months' corrected age were completed at 15 sites that were participants in the National Institute of Child Health and Human Development Neonatal Research Network Glutamine Trial between October 14, 1999, and June 25, 2001. Total volume of breast milk feeds (mL/kg per day) during hospitalization was calculated. Neonatal characteristics and morbidities, interim history, and neurodevelopmental and growth outcomes at 18 to 22 months' corrected age were assessed. RESULTS: There were 775 (74.9%) infants in the breast milk and 260 (25.1%) infants in the no breast milk group. Infants in the breast milk group were similar to those in the no breast milk group in every neonatal characteristic and morbidity, including number of days of hospitalization. Mean age of first day of breast milk for the breast milk infants was 9.3 +/- 9 days. Infants in the breast milk group began to ingest non-breast milk formula later (22.8 vs 7.3 days) compared with the non-breast milk group. Age at achieving full enteral feeds was similar between the breast milk and non-breast milk groups (29.0 +/- 18 vs 27.4 +/- 15). Energy intakes of 107.5 kg/day and 105.9 kg/day during the hospitalization did not differ between the breast milk and non-breast milk groups, respectively. At discharge, 30.6% of infants in the breast milk group still were receiving breast milk. Mothers in the breast milk group were significantly more likely to be white (42% vs 27%), be married (50% vs 30%), have a college degree (22% vs 6%), and have private health insurance (34% vs 18%) compared with the no breast milk group. Mothers who were black, had a low household income (< or = dollar 20000), or had higher parity were less likely to provide breast milk feeds. The analysis of outcomes between the any human milk and no human milk groups were adjusted for maternal age, maternal education, marital status, race/ethnicity, and the other standard covariates. Children in the breast milk group were more likely to have a Bayley Mental Development Index > or = 85, higher mean Bayley Psychomotor Development Index, and higher Bayley Behavior Rating Scale percentile scores for orientation/engagement, motor regulation, and total score. There were no differences in the rates of moderate to severe cerebral palsy or blindness or hearing impairment between the 2 study groups. There were no differences in the mean weight (10.4 kg vs 10.4 kg), length (80.5 cm vs 80.5 cm), or head circumference (46.8 cm vs 46.6 cm) for the breast milk and no breast milk groups, respectively, at 18 months. Multivariate analyses, adjusting for confounders, confirmed a significant independent association of breast milk on all 4 primary outcomes: the mean Bayley (Mental Development Index, Psychomotor Development Index, Behavior Rating Scale, and incidence of rehospitalization). For every 10-mL/kg per day increase in breast milk ingestion, the Mental Development Index increased by 0.53 points, the Psychomotor Development Index increased by 0.63 points, the Behavior Rating Scale percentile score increased by 0.82 points, and the likelihood of rehospitalization decreased by 6%. In an effort to identify a threshold effect of breast milk on Bayley Mental Development Index and Psychomotor Development Index scores and Behavior Rating Scale percentile scores, the mean volume of breast milk per kilogram per day during the hospitalization was calculated, and infants in the breast milk group were divided into quintiles of breast milk ingestion adjusted for confounders. Overall, the differences across the feeding quintiles of Mental Development Index and Psychomotor Development Index were significant. There was a 14.0% difference in Behavior Rating Scale scores between the lowest and highest quintiles. For the outcomes (Mental Development Index, Psychomotor Development Index, Behavior Rating Scale, and Rehospitalization <1 year), only the values for the >80th percentile quintile of breast milk feeding were significantly different from the no breast milk values. In our adjusted regression analyses, every 10 mL/kg per day breast milk contributed 0.53 points to the Bayley Mental Development Index; therefore, the impact of breast milk ingestion during the hospitalization for infants in the highest quintile (110 mL/kg per day) on the Bayley Mental Development Index would be 10 x 0.53, or 5.3 points. CONCLUSIONS: An increase of 5 points potentially would optimize outcomes and decrease costs by decreasing the number of very low birth weight children who require special education services. The societal implications of a 5-point potential difference (one third of an SD) in IQ are substantial. The potential long-term benefit of receiving breast milk in the NICU for extremely low birth weight infants may be to optimize cognitive potential and reduce the need for early intervention and special education services.

Early provision of parenteral amino acids in extremely low birth weight infants: relation to growth and neurodevelopmental outcome.

OBJECTIVE: To determine if postnatal growth failure exerts an adverse effect on subsequent growth and neurodevelopment. STUDY DESIGN: A secondary analysis of 1018 infants who were enrolled in a randomized, clinical trial of glutamine supplementation was performed to determine whether early provision of parenteral amino acids (AA) is associated with better growth and neurodevelopmental outcomes. Infants were stratified by whether they were provided > or =3 g/kg per day of AA at < or =5 days of life (early; n = 182) or not (late; n = 836). RESULTS: At 36 weeks' postmenstrual age, significant differences were found in weight, length, and head circumference in favor of the infants who received early AA; the odds of having weight less than the 10(th) percentile for age was 4-fold higher for infants in the late group. At 18 months' CA, there were no differences in weight, length, or measures of neurodevelopment between the groups; however, male infants in the late group were twice as likely to have head circumference less than the 10(th) percentile. CONCLUSIONS: Early AA were associated with significantly better growth outcomes at 36 weeks' postmenstrual age, and fewer infants who received early AA were found to have suboptimal head growth at 18 months' CA.