Henrietta S. Bada

Mean arterial blood pressure changes in premature infants and those at risk for intraventricular hemorrhage

Bedside microcomputer-derived, minute-to-minute mean arterial pressure (MAP) values during the first 48 hours of life were studied in 100 preterm babies with birth weight less than or equal to 1500 gm. In those babies (n = 72) with no periventricular-intraventricular hemorrhage (PV-IVH) or with grade 1 PV-IVH, the MAP values increased during the study period, with minute-to-minute variation and interval undulation. The MAP values in those with birth weight greater than 1000 gm were higher than in those of lower birth weight. Infants in whom grades 2 to 4 PV-IVH developed (n = 28) had consistently lower MAP values during the study period. Minute-to-minute variability, expressed as the average of the coefficients of variation at 15-minute intervals, did not differ between birth weight groups, nor did they differ between the PV-IVH group and their matched control subjects. However, those with PV-IVH spent a greater percentage of time, with a coefficient of variation greater than or equal to 13% or less than 3%, than their matched control subjects spent (p less than 0.005). This study provides reference data for MAP changes in premature babies. The observed MAP changes in those with PV-IVH lend support to a significant role for MAP alterations in the pathogenesis of PV-IVH.

Low birth weight and preterm births: Etiologic fraction attributable to prenatal drug exposure

OBJECTIVES:To determine the factors that would increase the likelihood of outcomes: low birth weight (LBW), preterm births and intrauterine growth restriction (IUGR).STUDY DESIGN:Secondary data analysis from a multi-center study. Risk factors for each outcome were derived from logistic regression models. Odds ratios (OR), 95% confidence intervals, and population-attributable risk proportions (PAR%) were estimated.RESULTS:Prenatal cocaine exposure increased the likelihood of LBW (OR: 3.59), prematurity (OR: 1.25), and IUGR (OR: 2.24). Tobacco, but not marijuana, significantly influenced these outcomes. Alcohol had an effect on LBW and IUGR. Etiologic fractions (PAR%) attributable to tobacco for LBW, prematurity, and IUGR were 5.57, 3.66, and 13.79%, respectively. With additional drug exposure including cocaine, estimated summary PAR% increased to 7.20% (LBW), 5.68% (prematurity), and 17.96% (IUGR).CONCLUSION:Disease burden for each outcome increases with each added drug exposure; however, etiologic fraction attributable to tobacco is greater than for cocaine.

Impact of prenatal cocaine exposure on child behavior problems through school age.

OBJECTIVE. We examined the trajectory of childhood behavior problems after prenatal cocaine exposure. METHODS. The Maternal Lifestyle Study, a longitudinal cohort study, enrolled children between 1993 and 1995 at 4 centers. Prenatal cocaine exposure was determined from mothers who admitted use and/or meconium results. Exposed children were matched with a group of nonexposed children within site and by gestational age, gender, race, and ethnicity. The study began at the 1-month corrected age with a total of 1388 children enrolled. A total of 1056 were assessed for internalizing, externalizing, and total behavior problems at ages 3, 5, and 7 years using the Child Behavior Checklist. Longitudinal hierarchical linear models were used to determine the effect of prenatal cocaine exposure on behavior problem trajectories while controlling for other prenatal exposures; time-varying covariates, including ongoing caregiver use of legal and illegal substances; demographic factors; family violence; and caregiver psychological distress. RESULTS. High prenatal cocaine exposure was associated with the trajectory of internalizing, externalizing, and total behavior problems; these effects were independent of and less than the significant combined effect of prenatal and postnatal tobacco and alcohol exposures. Caregiver depression and family violence had independent negative influence on all behavior outcomes. CONCLUSIONS. Prenatal cocaine exposure has a negative impact on the trajectories of childhood behavior outcomes. When they co-occur with prenatal cocaine exposure, prenatal and postnatal tobacco and alcohol exposures have added negative effects on behavior outcomes.

Brain-Type Natriuretic Peptide in the Diagnosis and Management of Persistent Pulmonary Hypertension of the Newborn

Objective. The diagnosis of persistent pulmonary hypertension (PPHN) can often be difficult to make, especially in a clinical setting in which pediatric echocardiography is not readily available. A noninvasive test that could differentiate PPHN from other cardiorespiratory disease would be very useful in the early management of the disease, because it would allow rapid identification of those infants at greatest risk of requiring the services of a level 3 nursery. Brain-type natriuretic peptide (BNP) is an endogenous peptide hormone secreted by the cardiac ventricles in response to increased wall stress and related ventricular filling pressures. The purpose of this study was to determine if BNP levels are elevated in newborns with PPHN and therefore may be used as a marker for differentiating PPHN from other forms of respiratory disease during the early newborn period. Method. We used a prospective cohort design with 3 groups. One group was diagnosed with PPHN by clinical and echocardiographic criteria (PPHN group: n = 15). The second group had been diagnosed with respiratory disease; however, PPHN had been ruled out by having no evidence of elevated pulmonary pressure by echocardiography (RD group: n = 17). The third group had no respiratory disease and was breathing room air (RA group: n = 15). BNP levels were measured with a point-of-care fluorescence immunoassay at various time intervals between birth and 150 hours of life. Results. There were no differences between groups for birth weight, gestational age, gender, race, Apgar scores at 1 minute, or age at time of initial blood sampling. Initial BNP levels (pg/mL) were elevated in the PPHN group relative to both the RA and RD groups (median [25%, 75%]: PPHN group = 1610 [1128, 1745]; RD group = 132 [76, 327]; RA group = 248 [127, 395]). There was no difference in the initial BNP level between the RA and RD groups. BNP levels remained elevated in the PPHN group over both groups for the first 4 days of life. BNP levels correlated with the gradient of the tricuspid regurgitation jet and with the ratio of tricuspid regurgitation jet gradient to mean blood pressure. BNP levels were not affected by administration of dopamine or dobutamine. BNP weakly correlated with the oxygenation index but not with the alveolar-arterial oxygenation gradient. Conclusions. Our findings indicate that BNP levels are elevated in infants with PPHN but not in infants with other forms of respiratory distress not associated with PPHN. Elevated BNP levels in term or near-term infants with respiratory distress should increase the suspicion of PPHN. Serial determination may also be helpful in monitoring the clinical course of such infants.

C-Reactive Protein in the Diagnosis, Management, and Prognosis of Neonatal Necrotizing Enterocolitis

Objective. In this prospective, observational study, we determined whether serum C-reactive protein (CRP) correlated with necrotizing enterocolitis (NEC) stages II and III. We hypothesized that serial CRP measurement if used as an adjunct to abdominal radiographs would improve the identification of infants with NEC. Methods. Serum CRP level was measured every 12 hours for 3 measurements and, when abnormal, once daily. When clinical signs persisted and the initial abdominal radiographs were abnormal, follow-up radiographs were obtained. Results. Of 241 infants who were evaluated for gastrointestinal signs, 11 had ileus or benign pneumatosis intestinalis with persistently normal CRP; gastrointestinal manifestations resolved within 48 hours, antibiotics were discontinued in <48 hours, and feedings were restarted early without complications. Fifty-five infants had NEC stages II and III; all had abnormal CRP regardless of their blood culture results. In infants with stage II NEC, CRP returned to normal at a mean of 9 days except in those who developed complications such as stricture or abscess formation. Conclusions. In infants with suspected NEC, normal serial CRP values would favor aborted antibiotic therapy and early resumption of feedings. CRP becomes abnormal in both stage II and stage III NEC. In infants with NEC, persistently elevated CRP after initiation of appropriate medical management suggests associated complications, which may require surgical intervention.

Brain superoxide anion generation in asphyxiated piglets and the effect of indomethacin at therapeutic dose.

ABSTRACT: We have previously shown that generation of superoxide anion occurs in cerebral cortex during asphyxia/reventilation in newborn pigs and that a high dose of indornethacin (5 mg/kg i.v.) abolishes superoxide anion production. The purposes of this study were 1) to determine whether the generation of superoxide anion occurs primarily during asphyxia or whether reventilation must take place, 2) to investigate the effects of indornethacin pretreatment at a therapeutic dose of 0.2 mg/kg i.v. on superoxide anion generation, and 3) to investigate the effects of oxypurinol, an oxygen free radical scavenger, on superoxide anion production during asphyxia/reventilation. Superoxide anion production on cerebral cortex was determined by superoxide dismutase-inhibitable nitroblue tetrazolium (NBT) reduction using closed cranial windows. Superoxideanion generation during asphyxia without reventilation was 4 ± 2 pmol NBT/mm2 per 20 min, which was significantly lower than during asphyxia/reventilation (16 ± 4 pmol NBT/mm2 per 20 min) but comparable to the control group (3 ± 1 pmol NBT/mm2 per 20 min). Indomethacin given at therapeutic dosage before asphyxia/reventilation decreased superoxide anion production to 3 ± 1 pmol NBT/mm2 per 20 min, values not significantly different from the control group and from piglets pretreated with oxypurinol at a dose of 50 mg/kg i.v. (4 ± 2 pmol NBT/mm2 per 20 min). We conclude that in newborn pigs 1) superoxide anions are generated largely during reventilation rather than during asphyxia; 2) the therapeutic dose of indomethacin (0.2 mg/kg) is effective in inhibiting the superoxide anion generation during asphyxia/reventilation; and 3) oxypurinol reduces the superoxide anion accumulation on cerebral cortex during asphyxia/reventilation.

Indomethacin reduces the risks of severe intraventricular hemorrhage

A prospective, random selection, double-blind clinical trial was carried out to determine the efficacy of indomethacin in preventing periventricular-intraventricular hemorrhage (PV-IVH). Babies who were born in our institution, had birth weights less than or equal to 1500 gm, and had no PV-IVH or grade 1 PV-IVH were given either placebo (n = 70) or indomethacin (n = 71), 0.2 mg/kg intravenously at 6 hours of age and 0.1 mg/kg at 18 and 30 hours. Two major outcomes were determined: the development of grades 2 to 4 PV-IVH and the development of severe PV-IVH (i.e., hemorrhages with blood filling greater than 50% of the ventricles and in some cases with associated parenchymal echodensities). Grades 2 to 4 PV-IVH occurred in 16 (23%) of the indomethacin group and 27 (39%) of the placebo group (p less than 0.03). The incidence of severe PV-IVH was 3% in the indomethacin-treated babies and 14% in the control group (p less than 0.02). The influence of other perinatal factors on the incidence of grades 2 to 4 or severe PV-IVH was determined by stepwise logistic regression. Placebo use, early grade 1 PV-IVH, lower birth weight, and higher fraction of inspired oxygen at 6 hours of life were associated with higher estimated odds of the development of grades 2 to 4 PV-IVH. Placebo use, male gender, lower 5-minute Apgar score, and a large base deficit were predictive of severe PV-IVH. Estimated odds ratios of severe PV-IVH with placebo use and male gender were 11.25:1 and 9:1, respectively. Thus indomethacin prophylaxis reduced the relative risk of grades 2 to 4 PV-IVH and severe PV-IVH, but other perinatal variables contributed significantly to the overall risk of PV-IVH.

Prenatal drug exposure and maternal and infant feeding behaviour.

Objective: To evaluate feeding difficulties and maternal behaviour during a feeding session with 1 month old infants prenatally exposed to cocaine and/or opiates. Methods: The study is part of the maternal lifestyle study, which recruited 11 811 subjects at four urban hospitals, then followed 1388 from 1 to 36 months of age. Exposure to cocaine and opiates was determined by maternal interview and meconium assay. At the 1 month clinic visit, biological mothers were videotaped while bottle feeding their infants. This sample included 364 exposed to cocaine, 45 exposed to opiates, 31 exposed to both drugs, and 588 matched comparison infants. Mothers were mostly black, high school educated, and on public assistance. Videotapes were coded without knowledge of exposure status for frequency, duration and quality of infant sucking, arousal, feeding problems, and maternal feeding activity and interaction. Results: No cocaine effects were found on infant feeding measures, but cocaine-using mothers were less flexible (6.29 v 6.50), less engaged (5.77 v 6.22), and had shorter feeding sessions (638 v 683 seconds). Opiate exposed infants showed prolonged sucking bursts (29 v 20 seconds), fewer pauses (1.6 v 2.2 per minute), more feeding problems (0.55 v 0.38), and increased arousal (2.59 v 2.39). Their mothers showed increased activity (30 v 22), independent of their infants’ feeding problems. Conclusions: Previous concerns about feeding behaviour in cocaine exposed infants may reflect the quality of the feeding interaction rather than infant feeding problems related to prenatal exposure. However, opiate exposed infants and their mothers both contributed to increased arousal and heightened feeding behaviour.

The Combined Effects of Prenatal Drug Exposure and Early Adversity on Neurobehavioral Disinhibition in Childhood and Adolescence

The negative effects of prenatal substance exposure on neurobiological and psychological development and of early adversity are clear, but little is known about their combined effects. In this study, multilevel analyses of the effects of prenatal substance exposure and early adversity on the emergence of neurobehavioral disinhibition in adolescence were conducted. Neurobehavioral disinhibition has previously been observed to occur frequently in multiproblem youth from high-risk backgrounds. In the present study, neurobehavioral disinhibition was assessed via behavioral dysregulation and poor executive function composite measures. Data were drawn from a prospective longitudinal investigation of prenatal substance exposure that included 1,073 participants followed from birth through adolescence. The results from latent growth modeling analyses showed mean stability but significant individual differences in behavioral dysregulation and mean decline with individual differences in executive function difficulties. Prior behavioral dysregulation predicted increased executive function difficulties. Prenatal drug use predicted the emergence and growth in neurobehavioral disinhibition across adolescence (directly for behavioral dysregulation and indirectly for executive function difficulties via early adversity and behavioral dysregulation). Prenatal drug use and early adversity exhibited unique effects on growth in behavioral dysregulation; early adversity uniquely predicted executive function difficulties. These results are discussed in terms of implications for theory development, social policy, and prevention science.

Prenatal Cocaine Exposure Related to Cortisol Stress Reactivity in 11-Year-Old Children

OBJECTIVE Determine the association between prenatal cocaine exposure and postnatal environmental adversity on salivary cortisol stress reactivity in school-aged children. STUDY DESIGN Subjects included 743 11-year-old children (n = 320 cocaine-exposed; 423 comparison) followed since birth in a longitudinal prospective multisite study. Saliva samples were collected to measure cortisol at baseline and after a standardized procedure to induce psychological stress. Children were divided into those who showed an increase in cortisol from baseline to post stress and those who showed a decrease or blunted cortisol response. Covariates measured included site, birthweight, maternal pre and postnatal use of alcohol, tobacco or marijuana, social class, changes in caretakers, maternal depression and psychological symptoms, domestic and community violence, child abuse, and quality of the home. RESULTS With adjustment for confounding variables, cortisol reactivity to stress was more likely to be blunted in children with prenatal cocaine exposure. Children exposed to cocaine and who experienced domestic violence showed the strongest effects. CONCLUSIONS The combination of prenatal cocaine exposure and an adverse postnatal environment could downregulate the hypothalamic-pituitary-adrenal axis resulting in the blunted cortisol response to stress possibly increasing risk for later psychopathology and adult disease.