Parenting style impacts cognitive and behavioural outcomes of former preterm infants: A systematic review.

We sought to evaluate published evidence in aggregate regarding the impact of parenting style on the cognitive and behavioural outcomes of former preterm infants. We searched 5 databases using germane MeSH terms. Parenting style was defined as any descriptor of parenting using ≥2 dimensions on published parenting axes. We evaluated studies for quality of evidence and strength of recommendations using standardized tools and categorized summative recommendations by parenting axis and child outcome. Twenty-seven articles met our inclusion criteria. Parental responsivity is the only parenting axis strongly associated with both improved child cognition and behaviour. Parental demandingness is associated only with improved child cognition, and parental warmth and rejection are associated only with child behaviour. Parental coercion is not associated with subsequent child outcomes. Parental responsivity may be essential in optimizing neurodevelopment in former preterm infants. More targeted studies are needed to inform this relationship and identify opportunities for intervention.

Increasing F2-isoprostanes in the first month after birth predicts poor respiratory and neurodevelopmental outcomes in very preterm infants.

OBJECTIVE: This study examined the association between increased early oxidative stress, measured by F2-isoprostanes (IsoPs), and respiratory morbidity at term equivalent age and neurological impairment at 12 months of corrected age (CA). STUDY DESIGN: Plasma samples were collected from 136 premature infants on days 14 and 28 after birth. All participants were infants born at ⩽28 weeks of gestational age enrolled into the Prematurity and Respiratory Outcomes Program (PROP) study. Respiratory morbidity was determined at 40 weeks of postmenstrual age (PMA) by the Respiratory Severity Index (RSI), a composite measure of oxygen and pressure support. Neurodevelopmental assessment was performed using the Developmental Assessment of Young Children (DAYC) at 12 months of CA. Multivariable logistic regression models estimated associations between IsoP change, RSI and DAYC scores. Mediation analysis was performed to determine the relationship between IsoPs and later outcomes. RESULTS: Developmental data were available for 121 patients (90% of enrolled) at 12 months. For each 50-unit increase in IsoPs, regression modeling predicted decreases in cognitive, communication and motor scores of -1.9, -1.2 and -2.4 points, respectively (P<0.001). IsoP increase was also associated with increased RSI at 40 weeks of PMA (odds ratio=1.23; P=0.01). RSI mediated 25% of the IsoP effect on DAYC motor scores (P=0.02) and had no significant impact on cognitive or communication scores. CONCLUSIONS: In the first month after birth, increases in plasma IsoPs identify preterm infants at risk for respiratory morbidity at term equivalent age and worse developmental outcomes at 12 months of CA. Poor neurodevelopment is largely independent of respiratory morbidity.

Adverse neurodevelopmental outcomes after exposure to phenobarbital and levetiracetam for the treatment of neonatal seizures.

OBJECTIVE: Compare neurodevelopment after levetiracetam (LEV) and phenobarbital (PB) for neonatal seizures. STUDY DESIGN: Retrospective study of infants who received antiepileptic drugs (AEDs) for neonatal seizures. Effect of cumulative exposure to LEV and PB on outcomes of death, cerebral palsy (CP) and Bayley Scales of Infant Development (BSID) scores were evaluated at 24 months corrected age. Analyses were adjusted for number of electrographic seizures and gestational age. RESULT: In 280 infants with comparable seizure etiology and cranial imaging results, increased exposure to PB was associated with worse BSID cognitive and motor scores (8.1- and 9-point decrease per 100 mg kg(-1); P=0.01). The effect was less with LEV (2.2- and 2.6-point decrease per 300 mg kg(-1) LEV (P=0.01)). CP probability increased by 2.3-fold per 100 mg kg(-1) PB and was not associated with increasing LEV. CONCLUSION: Increased exposure to PB is associated with worse neurodevelopmental outcomes than LEV. Prospective studies of outcomes of neonatal exposure to AEDs are essential.

Should we screen newborns for glucose-6-phosphate dehydrogenase deficiency in the United States?

Glucose-6-phosphate dehydrogenase (G6PD) deficiency, a common X-linked enzymopathy can lead to severe hyperbilirubinemia, acute bilirubin encephalopathy and kernicterus in the United States. Neonatal testing for G6PD deficiency is not yet routine and the American Academy of Pediatrics recommends testing only in jaundiced newborns who are receiving phototherapy whose family history, ethnicity, or geographic origin suggest risk for the condition, or for infants whose response to phototherapy is poor. Screening tests for G6PD deficiency are available, are suitable for use in newborns and have been used in birth hospitals. However, US birth hospitals experience is limited and no national consensus has emerged regarding the need for newborn G6PD testing, its effectiveness or the best approach. Our review of current state of G6PD deficiency screening highlights research gaps and informs specific operational challenges to implement universal newborn G6PD testing concurrent to bilirubin screening in the United States.

Formal selection of measures for a composite index of NICU quality of care: Baby-MONITOR.

OBJECTIVE: To systematically rate measures of care quality for very low birth weight infants for inclusion into Baby-MONITOR, a composite indicator of quality. STUDY DESIGN: Modified Delphi expert panelist process including electronic surveys and telephone conferences. Panelists considered 28 standard neonatal intensive care unit (NICU) quality measures and rated each on a 9-point scale taking into account pre-defined measure characteristics. In addition, panelists grouped measures into six domains of quality. We selected measures by testing for rater agreement using an accepted method. RESULT: Of 28 measures considered, 13 had median ratings in the high range (7 to 9). Of these, 9 met the criteria for inclusion in the composite: antenatal steroids (median (interquartile range)) 9(0), timely retinopathy of prematurity exam 9(0), late onset sepsis 9(1), hypothermia on admission 8(1), pneumothorax 8(2), growth velocity 8(2), oxygen at 36 weeks postmenstrual age 7(2), any human milk feeding at discharge 7(2) and in-hospital mortality 7(2). Among the measures selected for the composite, the domains of quality most frequently represented included effectiveness (40%) and safety (30%). CONCLUSION: A panel of experts selected 9 of 28 routinely reported quality measures for inclusion in a composite indicator. Panelists also set an agenda for future research to close knowledge gaps for quality measures not selected for the Baby-MONITOR.

Variation among institutional review boards in evaluating the design of a multicenter randomized trial.

OBJECTIVE: The objective of the study was to examine the variation among institutional review boards (IRBs) in evaluation of the study design of a multicenter trial. STUDY DESIGN: We assessed the first written response of local IRBs to each site investigator for a multicenter trial of vitamin A supplementation in extremely low birth weight (ELBW) infants performed by the National Institute of Child Health and Human Development Neonatal Research Network. Each author of this paper independently reviewed and categorized IRB concerns as major, minor or none, according to the predefined criteria. RESULT: Initially, 9 of 18 IRBs withheld approval because of at least one major concern. These concerns reflected difficulties in evaluating specific scientific issues for the design of the trial, including its justification, enrollment criteria, control and experimental therapies, co-interventions, toxicity assessment, outcome monitoring and informed consent. CONCLUSION: The difficulty in assessing appropriate trial design for the specific hypothesis under investigation resulted in considerable variability in the evaluation by local IRBs.

Hospital neonatal services in the United States: variation in definitions, criteria, and regulatory status, 2008.

OBJECTIVE: The purpose of this study was to describe variation among states in designations of hospital neonatal services levels. STUDY DESIGN: We systematically searched all 50 states and District of Columbia governmental web sites and extracted definitions and levels terminology, functional and utilization criteria, regulatory compliance and funding measures, and citation of American Academy of Pediatrics (AAP) documents on levels of neonatal care. RESULT: Thirty-three states designate multiple graduated levels of neonatal services. Two to six levels were designated by numbers, titles, or both. Regulatory sources include hospital licensure, Certificate of Need or State Health Plan (CON/SHP), State Health Department, or an affiliated non-governmental entity (SHD/affiliate). Twenty-four states have a single source and nine have two or more. Functional criteria include population characteristics, respiratory care capabilities, and neonatal and cardiac surgery in 25 states. Utilization criteria include capacity, volume, occupancy, or case mix. Compliance mechanisms include license renewal, CON/SHP approval, and/or SHD/affiliate certification. Thirteen states link funding for the highest level of care through Medicaid, Maternal Child Health Title V funds or regional programs. AAP documents are cited or incorporated by reference in 22 states. CONCLUSION: All states regulate health care services and facilities. Definitions, criteria, compliance mechanisms, and regulatory source and status of neonatal levels of service vary widely. A consistent national approach would facilitate comparisons in neonatal outcomes and resource use and be informative to parents, providers, and policy makers. AAP documents could serve as a mechanism to foster such consistency.

Systems changes to prevent severe hyperbilirubinemia and promote breastfeeding: pilot approaches.

Providing safe and effective care requires coordination among the multiple levels of the health care system. These levels comprise the newborn (patient, family and community), nursery or primary care practice (microsystem), hospital or managed care organization (macro-organization) and policy, payment or regulatory issues (environmental context). Contemporary care practices associated with childbirth and early newborn care often reflect disruptions in coordination of these processes and place newborns at risk for poor outcomes. For example, with routine early postpartum discharge, often at less than 48 h after vaginal birth, the peak of serum bilirubin at 3 to 5 days of age typically occurs at home, rather than observed by clinicians in a newborn nursery. In addition, lactation is rarely well established by early discharge and support is often inadequate, increasing the risk of hyperbilirubinemia and discontinuation of breastfeeding. Also, late preterm infants are frequently cared for in the newborn nursery, although they often have difficulty establishing oral feeding and are at substantially higher risk for severe hyperbilirubinemia than infants born at term. Finally, pediatric follow-up is often delayed beyond the first week, after the optimal time for continued assessment of jaundice and lactation. The American Academy of Pediatrics Safe and Healthy Beginnings Initiative, a pilot quality improvement project, will target newborn nurseries, primary care practices and coordination between these sites using a systems-based approach to facilitate implementation of the 2004 guideline for management of hyperbilirubinemia.

Effects of early erythropoietin therapy on the transfusion requirements of preterm infants below 1250 grams birth weight: a multicenter, randomized, controlled trial.

OBJECTIVES: Infants of

Detection of neonatal carnitine palmitoyltransferase II deficiency by expanded newborn screening with tandem mass spectrometry.

The introduction of tandem mass spectrometry to newborn screening has substantially expanded our ability to diagnose metabolic diseases in the newborn period. We report the first case of neonatal carnitine palmitoyltransferase deficiency II detected by expanded newborn screening with tandem mass spectrometry. The neonate presented with dysmorphic facial features, structural malformations, renal failure, seizures, and cardiac arrythmias and died on the third day of life. This experience illustrates the importance of expanded newborn screening to avoid missing a metabolic diagnosis in early infantile death.

Adverse effects of early dexamethasone treatment in extremely-low-birth-weight infants. National Institute of Child Health and Human Development Neonatal Research Network.

BACKGROUND: Early administration of high doses of dexamethasone may reduce the risk of chronic lung disease in premature infants but can cause complications. Whether moderate doses would be as effective but safer is not known. METHODS: We randomly assigned 220 infants with a birth weight of 501 to 1000 g who were treated with mechanical ventilation within 12 hours after birth to receive dexamethasone or placebo with either routine ventilatory support or permissive hypercapnia. The dexamethasone was administered within 24 hours after birth at a dose of 0.15 mg per kilogram of body weight per day for three days, followed by a tapering of the dose over a period of seven days. The primary outcome was death or chronic lung disease at 36 weeks' postmenstrual age. RESULTS: The relative risk of death or chronic lung disease in the dexamethasone-treated infants, as compared with those who received placebo, was 0.9 (95 percent confidence interval, 0.8 to 1.1). Since the effect of dexamethasone treatment did not vary according to the ventilatory approach, the two dexamethasone groups and the two placebo groups were combined. The infants in the dexamethasone group were less likely than those in the placebo group to be receiving oxygen supplementation 28 days after birth (P=0.004) or open-label dexamethasone (P=0.01), were more likely to have hypertension (P<0.001), and were more likely to be receiving insulin treatment for hyperglycemia (P=0.02). During the first 14 days, spontaneous gastrointestinal perforation occurred in a larger proportion of infants in the dexamethasone group (13 percent, vs. 4 percent in the placebo group; P=0.02). The dexamethasone-treated infants had a lower weight (P=0.02) and a smaller head circumference (P=0.04) at 36 weeks' postmenstrual age. CONCLUSIONS: In preterm infants, early administration of dexamethasone at a moderate dose has no effect on death or chronic lung disease and is associated with gastrointestinal perforation and decreased growth.

Inhaled nitric oxide reduces the need for extracorporeal membrane oxygenation in infants with persistent pulmonary hypertension of the newborn.

OBJECTIVE: We previously reported improved oxygenation, but no change, in rates of extracorporeal membrane oxygenation (ECMO) use or death among infants with persistent pulmonary hypertension of the newborn who received inhaled nitric oxide (NO) with conventional ventilation, irrespective of lung disease. The goal of our study was to determine whether treatment with inhaled NO improves oxygenation and clinical outcomes in infants with persistent pulmonary hypertension of the newborn and associated lung disease who are ventilated with high-frequency oscillatory ventilation (HFOV). DESIGN: Single-center, prospective, randomized, controlled trial. SETTING: Newborn intensive care unit of a tertiary care teaching hospital. PATIENTS: We studied infants with a gestational age of > or =34 wks who were receiving mechanical ventilatory support and had echocardiographic and clinical evidence of pulmonary hypertension and hypoxemia (PaO2 < or =100 mm Hg on FIO2 = 1.0), despite optimal medical management Infants with congenital heart disease, diaphragmatic hernia, or other major anomalies were excluded. INTERVENTIONS: The treatment group received inhaled NO, whereas the control group did not. Adjunct therapies and ECMO criteria were the same in the two groups of patients. Investigators and clinicians were not masked as to treatment assignment, and no crossover of patients was permitted. MEASUREMENTS AND MAIN RESULTS: Primary outcome variables were mortality and use of ECMO. Secondary outcomes included change in oxygenation and duration of mechanical ventilatory support and supplemental oxygen therapy. Forty-two patients were enrolled. Baseline oxygenation and clinical characteristics were similar in the two groups of patients. Infants in the inhaled NO group (n = 21) had improved measures of oxygenation at 15 mins and 1 hr after enrollment compared with infants in the control group (n = 20). Fewer infants in the inhaled NO group compared with the control group were treated with ECMO (14% vs. 55%, respectively; p = .007). Mortality did not differ with treatment assignment. CONCLUSIONS: Among infants ventilated by HFOV, those receiving inhaled NO had a reduced need for ECMO. We speculate that HFOV enhances the effectiveness of inhaled NO treatment in infants with persistent pulmonary hypertension of the newborn and associated lung disease.

Computer-assisted adjustment of inspired oxygen concentration improves control of oxygen saturation in newborn infants requiring mechanical ventilation.

Open-loop computer control of inspired oxygen concentration was evaluated in 16 newborn infants requiring mechanical ventilation. FIO2 and oxygen saturation were compared for 2-hour periods of computer versus routine manual FIO2 adjustment. During computer-assisted FIO2 adjustment, patients spent more time at the target SaO2 and less time with SaO2 < 90%.

Apnea frequently persists beyond term gestation in infants delivered at 24 to 28 weeks.

BACKGROUND: Apnea of prematurity remains among the most commonly diagnosed conditions in the Newborn Intensive Care Unit and may prolong hospital stays in some infants. Because survival of extremely premature infants has improved markedly, the natural history of apnea in this population needs to be reassessed. OBJECTIVE: To document the natural history of recurrent apnea and/or bradycardia events in infants delivered at 24 to 28 weeks' gestation. METHODS: Medical records of all infants delivered at 24 to 28 weeks' gestation admitted to the Brigham and Women's Hospital Newborn Intensive Care Unit between January 1989 and March 1994 were reviewed to document the clinical course of apnea of prematurity. Subjects were included in the study sample if they were discharged home from the Brigham and Women's Hospital or after transfer to an affiliated hospital. Recordings of apnea and/or bradycardia events were based on nursing observations of monitor alarms and assessment of the infant's condition. RESULTS: Of 457 eligible infants, 226 were included in the study sample and stratified by gestational age at birth assigned by the attending neonatologist. The time to resolution of recurrent apnea/bradycardia events was longer with lower gestational age at birth. Apnea/bradycardia events were frequently observed beyond 36 weeks' postconceptional age in all gestational age groups. The incidence of apnea persisting beyond 38 weeks postconceptional age was significantly higher in the 24- to 27-week infants combined compared with the 28-week infants. CONCLUSIONS: Apnea of prematurity frequently persists beyond term gestation in infants delivered at 24 to 28 weeks' gestational age. These persistent apnea and/or bradycardia events may contribute to prolonged hospitalization. Programs to promote earlier discharge of premature infants should take into account the variability in resolution of apnea and specifically address management of persistent apnea.

Effect of inhaled nitric oxide on endothelin-1 and cyclic guanosine 5'-monophosphate plasma concentrations in newborn infants with persistent pulmonary hypertension.

OBJECTIVE: To examine the role of endogenous nitric oxide (NO) and endothelin-1 (ET-1) in the pathogenesis of persistent pulmonary hypertension of the newborn (PPHN) and to determine whether inhaled NO, currently under investigation as a new therapy for PPHN, affects plasma concentrations of these vasoactive mediators. METHODS: Circulating ET-1 and cyclic guanosine monophosphate (cGMP) concentrations were measured by radioimmunoassay in 15 healthy term newborn infants and 46 newborn infants with PPHN enrolled in a randomized, controlled trial of inhaled NO. These concentrations were followed up longitudinally and compared between the NO and the conventionally treated group. RESULTS: Concentrations of ET-1 were significantly higher and cGMP concentrations significantly lower in infants with PPHN compared with healthy newborn infants (median ET-1, 28 vs 11 pmol/L; p = 0.0001; median cGMP, 35 vs 61 pmol/ml; p = 0.0001, respectively). ET-1 concentrations showed an upward trend at 1 and 24 hours of treatment and a subsequent decline at recovery in both subgroups of patients, with the most pronounced decrease in the NO group. cGMP concentrations increased significantly only in the NO group, with a peak at 1 hour of treatment (median, 61 pmol/ml). As the dose of NO decreased, cGMP concentrations declined. In contrast, conventionally treated infants manifested no change in cGMP concentrations from baseline until recovery, when a significant decrease was noted (median decrease of 13 pmol/ml; p = 0.002). We did not find a significant difference between ET-1 and cGMP concentrations in infants who required extracorporeal membrane oxygenation compared with those who did not. CONCLUSIONS: PPHN is associated with increased ET-1 and decreased cGMP plasma concentrations, which may contribute to the pathogenesis of the disease. Inhaled NO appears to modulate these mediators during the disease process, suggesting an interaction between ET-1 and NO in vivo.

Improved oxygenation in a randomized trial of inhaled nitric oxide for persistent pulmonary hypertension of the newborn.

OBJECTIVE: To determine the effect of inhaled nitric oxide (NO) on clinical outcome in newborns with persistent pulmonary hypertension (PPHN). DESIGN: A prospective, randomized trial of patients referred to a level 3 nursery in a single large center. Clinicians were not masked to group assignment. Crossover of patients from control to NO treatment was not permitted. METHODS: We randomized 49 mechanically ventilated newborns, transferred to our center with clinical and echocardiographic evidence of severe PPHN (arterial oxygen tension [PaO2] <100; fractional inspired oxygen = 1) to treatment with or without NO. Patients with gestational age <34 weeks or with congenital heart disease or diaphragmatic hernia were excluded. High-frequency oscillatory ventilation was used but not allowed concomitantly with NO. Primary outcome variables were oxygenation, mortality, and use of extracorporeal membrane oxygenation (ECMO). RESULTS: Meconium aspiration syndrome and isolated PPHN were the most common diagnoses (32/49) and were distributed equally between groups. The median age at the time of entry into the study was similar between groups, 25 hours for control patients and 18 hours for NO patients. Median baseline oxygenation index (OI) was similar in 23 control (OI = 29) and 26 NO (OI = 30) patients. Mortality (8%), use of ECMO (33%), median days on mechanical ventilation (9 days), and duration of supplemental oxygen (13 days) were not different between treatment groups. PaO2, oxygen saturation, and OI improved in the NO group compared with baseline and to control patients at 15 minutes. The median percent change in OI (-31%) in the NO group was significantly different from baseline and from the control group. The difference in oxygenation between treatment groups was still apparent 12 hours after baseline. Before cannulation for ECMO, oxygenation was better in the NO group compared with control patients. Among patients who were placed on ECMO, the median time from baseline to ECMO cannulation was 2.4 hours (range, 1 to 12 hours) among control patients and 3.3 hours (range, 2 to 68 hours) for those randomized to receive NO. There was a tendency to observe fewer adverse neurologic events (seizure and intracranial hemorrhage) in the NO group (4/26 vs 8/23). One child with alveolar capillary dysplasia confirmed by postmortem examination could not be weaned from 80 parts per million of NO and transiently developed methemoglobinemia (peak methemoglobin level = 17%). No other side effects were observed. CONCLUSIONS: Although mortality and ECMO use were similar for both treatment groups using this study size and design, sustained improvement in oxygenation with NO and better oxygenation at initiation of ECMO may have important clinical benefits. We speculate that modification of treatment to include specific lung expansion strategies with NO treatment and recognition that early improvement of oxygenation may be sustained with NO may lead to reduced use of ECMO in NO treated patients compared with controls.