Camilia R. Martin

Early Intervention in Low Birth Weight Premature Infants: Results at 18 Years of Age for the Infant Health and Development Program

OBJECTIVE. To assess whether improvements in cognitive and behavioral development seen in preschool educational programs persist, we compared those in a multisite randomized trial of such a program over the first 3 years of life (INT) to those with follow-up only (FUO) at 18 months of age. METHODS. This was a prospective follow-up of the Infant Health and Development Program at 8 sites heterogeneous for sociodemographic characteristics. Originally 985 children were randomized to the INT (n = 377) or FUO (n = 608) groups within 2 birth weight strata: heavier low birth weight (HLBW; 2001–2499 g) and lighter low birth weight (LLBW; ≤2000 g). Primary outcome measures were the Peabody Picture Vocabulary Test (PPVT-III), reading and mathematics subscales of the Woodcock-Johnson Tests of Achievement, youth self-report on the Total Behavior Problem Index, and high-risk behaviors on the Youth Risk Behavior Surveillance System (YRBSS). Secondary outcomes included Weschler full-scale IQ, caregiver report on the Total Behavior Problem Index, and caregiver and youth self-reported physical health using the Medical Outcome Study measure. Assessors were masked as to study status. RESULTS. We assessed 636 youths at 18 years (64.6% of the 985, 72% of whom had not died or refused at prior assessments). After adjusting for cohort attrition, differences favoring the INT group were seen on the Woodcock-Johnson Tests of Achievement in math (5.1 points), YRBSS (−0.7 points), and the PPVT-III (3.8 points) in the HLBW youth. In the LLBW youth, the Woodcock-Johnson Tests of Achievement in reading was higher in the FUO than INT group (4.2). CONCLUSIONS. The findings in the HLBW INT group provide support for preschool education to make long-term changes in a diverse group of children who are at developmental risk. The lack of observable benefit in the LLBW group raises questions about the biological and educational factors that foster or inhibit sustained effects of early educational intervention.

Probiotics: Role in Pathophysiology and Prevention in Necrotizing Enterocolitis

Necrotizing enterocolitis (NEC) is an inflammatory bowel disease largely affecting low birth weight, premature infants. Once acquired, NEC is accompanied by significant mortality and morbid sequelae. Our understanding of the pathophysiology of NEC continues to evolve, and the development of NEC is likely multifactorial with resultant bowel injury mediated through a final, common inflammatory pathway. The predisposition for NEC appears to involve the interplay between intestinal integrity and function, enteral feeding and bacterial colonization, and regulation of the gastrointestinal and systemic inflammatory response. Commensal organisms or probiotics have been shown to be crucial in the development and modulation of each of these factors within the intestinal epithelium. As a result, probiotic supplementation has been proposed as a promising new intervention for the prevention of NEC. To understand the potential utility of probiotics in NEC, we will discuss: the components of gut defense; the role of the intestinal ecosystem in modulating immunity and inflammation; bacterial colonization patterns in the preterm infant compared with patterns seen in the healthy, full-term infant; the evidence for probiotic use in other populations and diseases; and finally, the evidence of probiotic use specific to the preterm infant and NEC.

Two-Year Neurodevelopmental Outcomes of Ventilated Preterm Infants Treated with Inhaled Nitric Oxide

OBJECTIVE In a randomized multi-center trial, we demonstrated that inhaled nitric oxide begun between 7 and 21 days and given for 24 days significantly increased survival without bronchopulmonary dysplasia (BPD) in ventilated premature infants weighing <1250 g. Because some preventative BPD treatments are associated with neurodevelopmental impairment, we designed a follow-up study to assess the safety of nitric oxide. STUDY DESIGN Our hypothesis was that inhaled nitric oxide would not increase neurodevelopmental impairment compared with placebo. We prospectively evaluated neurodevelopmental and growth outcomes at 24 months postmenstrual age in 477 of 535 surviving infants (89%) enrolled in the trial. RESULTS In the treated group, 109 of 243 children (45%) had neurodevelopmental impairment (moderate or severe cerebral palsy, bilateral blindness, bilateral hearing loss, or score <70 on the Bayley Scales II), compared with 114 of 234 (49%) in the placebo group (relative risk, 0.92; 95% CI, 0.75-1.12; P = .39). No differences on any subcomponent of neurodevelopmental impairment or growth variables were found between inhaled nitric oxide or placebo. CONCLUSIONS Inhaled nitric oxide improved survival free of BPD, with no adverse neurodevelopmental effects at 2 years of age.

Review of Infant Feeding: Key Features of Breast Milk and Infant Formula

Mothers’ own milk is the best source of nutrition for nearly all infants. Beyond somatic growth, breast milk as a biologic fluid has a variety of other benefits, including modulation of postnatal intestinal function, immune ontogeny, and brain development. Although breastfeeding is highly recommended, breastfeeding may not always be possible, suitable or solely adequate. Infant formula is an industrially produced substitute for infant consumption. Infant formula attempts to mimic the nutritional composition of breast milk as closely as possible, and is based on cow’s milk or soymilk. A number of alternatives to cow’s milk-based formula also exist. In this article, we review the nutritional information of breast milk and infant formulas for better understanding of the importance of breastfeeding and the uses of infant formula from birth to 12 months of age when a substitute form of nutrition is required.

Resolvin D1 and Lipoxin A4 Improve Alveolarization and Normalize Septal Wall Thickness in a Neonatal Murine Model of Hyperoxia-Induced Lung Injury

Background The critical fatty acids Docosahexaenoic Acid (DHA) and Arachidonic Acid (AA) decline in preterm infants within the first postnatal week and are associated with neonatal morbidities, including bronchopulmonary dysplasia (BPD). DHA and AA are precursors to downstream metabolites that terminate the inflammatory response. We hypothesized that treatment with Resolvin D1 and/or Lipoxin A4 would prevent lung injury in a murine model of BPD. Objective To determine the effect of Resolvin D1 and/or Lipoxin A4 on hyperoxia-induced lung injury. Methods C57/BL6 pups were randomized at birth to Room Air, Hyperoxia (>90% oxygen), Hyperoxia + Resolvin D1, Hyperoxia + Lipoxin A4, or Hyperoxia + Resolvin D1/Lipoxin A4. Resolvin D1 and/or Lipoxin A4 (2 ng/g) were given IP on days 0, 3, 6, and 9. On day 10, mice were sacrificed and lungs collected for morphometric analyses including Mean Linear Intercept (MLI), Radial Alveolar Count (RAC), and Septal Thickness (ST); RT-PCR analyses of biomarkers of lung development and inflammation; and ELISA for TGFβ1 and TGFβ2. Result The increased ST observed with hyperoxia exposure was normalized by both Resolvin D1 and Lipoxin A4; while, hyperoxia-induced alveolar simplification was attenuated by Lipoxin A4. Relative to hyperoxia, Resolvin D1 reduced the gene expression of CXCL2 (2.9 fold), TIMP1 (6.7 fold), and PPARγ (4.8 fold). Treatment with Lipoxin A4 also led to a reduction of CXCL2 (2.4 fold) while selectively increasing TGFβ2 (2.1 fold) and Smad3 (1.58 fold). Conclusion The histologic and biochemical changes seen in hyperoxia-induced lung injury in this murine model can be reversed by the addition of DHA and AA fatty acid downstream metabolites that terminate the inflammatory pathways and modulate growth factors. These fatty acids or their metabolites may be novel therapies to prevent or treat lung injury in preterm infants.

Impact of clinical and histologic correlates of maternal and fetal inflammatory response on gestational age in preterm births

Objective. To evaluate the impact of clinical and histopathologic correlates related to maternal and fetal inflammatory responses (MIR and FIR) on degree of preterm birth. Methods. Pathology reports and clinical data from 577 singleton preterm births (<37 weeks of gestation) that took place between 1998 and 2004 were analyzed according to decreasing gestational age (≥33 weeks, 29–32 weeks, and <29 weeks). MIR was defined by presence of subchorionitis, chorioamnionitis, deciduitis, or free membranitis; FIR was defined by presence of funisitis or chorionic plate vasculitis. The associations between MIR alone and MIR with FIR and gestational age subgroups were assessed using logistic regression. Results. The presence of FIR in addition to MIR was more strongly associated with degree of prematurity than the presence of MIR alone, especially for those born at <29 weeks (OR = 10.1 (95% CI 4.3–23.7) and OR = 5.3 (95% CI 2.3–12.5), respectively). These associations remained significant after adjusting for maternal race, clinical signs of chorioamnionitis, medically indicated birth, and intrapartum corticosteroid, tocolysis and antibiotic use, and after stratification by clinical signs of chorioamnionitis and medically indicated birth. Conclusions. The combined presence of MIR and FIR is associated with a higher risk of extreme preterm birth (<29 weeks) than MIR alone, suggesting a contributory role of FIR in the pathophysiology of preterm birth.

Incidence of Hypertriglyceridemia in Critically Ill Neonates Receiving Lipid Injectable Emulsions in Glass Versus Plastic Containers: A Retrospective Analysis

OBJECTIVE To evaluate plasma clearance of lipid injectable emulsions packaged in either glass or plastic containers in neonates from 2 7-month periods, 1 year apart. STUDY DESIGN Clinical records from June 1 to December 31, 2003 (glass [G] period) and the same months in 2004 (plastic [P] period) were assessed. Neonates who received lipid injectable emulsions were studied. Lipid container (glass vs plastic) was the independent variable. RESULTS Of the 197 patients studied, 122 (G, 50/81; P, 72/116) had evaluable triglyceride (TG) levels, for an overall rate of 62%. Only birth weight (G, 1.09 +/- 0.32 kg vs P, 1.23 +/- .45 kg) and birth length (G, 36.4 +/- 3.5 cm vs P, 37.9 +/- 3.5 cm) were significantly different between the 2 groups (P = .047 and .028, respectively). There were no differences in the day of life on which lipid injection was started, the lipid dose, or the timing of TG measurements. The incidence of hypertriglyceridemia was significantly higher in the P period (G, 3/50 vs P, 19/72; P = .004). CONCLUSIONS Administration of the same lipid formulation in plastic bags compared with glass containers is associated with higher rates of hypertriglyceridemia. The poorer clearance of lipids could be due to a higher proportion of large-diameter fat globules in plastic bags compared with those in glass containers.

Early Nutrition and Weight Gain in Preterm Newborns and the Risk of Retinopathy of Prematurity

Objective To identify nutritional and weight gain limitations associated with retinopathy of prematurity (ROP) severity among very preterm newborns. Patients and Methods 1180 infants <28 weeks GA at birth with ROP examination results were grouped and analyzed by quartile of weekly total calorie, carbohydrate, protein, and lipid intake, as well as growth velocity between postnatal days 7 and 28 (adjusted for GA and birth weight Z-score). ROP was categorized by development of no, mild (<prethreshold), type 2, or type 1 ROP, as well as markers of ROP severity including stage 3 ROP, zone 1 disease, and plus disease. Associations between nutritional intake and ROP severity were compared. Results Greater risk for Type 1 ROP (risk/95% confidence intervals) was found for infants with lowest quartile receipt of lipids (2.1/1.1, 3.8), total calories (2.2/1.4, 3.6), and carbohydrates (1.7/1.1, 2.9). Development of zone 1 ROP was associated with lipid or total calorie intake in the lowest quartile, and development of stage 3 ROP was associated with lowest quartile of total calorie intake. Growth velocity in the lowest quartile was associated with increased risk of any ROP, including type 1 ROP. Conclusion The risk of developing severe ROP in extremely premature infants might be reduced by improving nutritional support, specifically targeting lipids and total calories, and perhaps by improving weight gain.

Cooling for Newborns with Hypoxic Ischemic Encephalopathy

adverse effects of cooling and ‘early’ indicators of neurodevelopmental outcome. Data Collection and Analysis: Four review authors independently selected, assessed the quality of and extracted data from the included studies. Study authors were contacted for further information. Meta-analyses were performed using risk ratios (RR) and risk differences (RD) for dichotomous data, and weighted mean difference for continuous data with 95% confidence intervals (CI). Main Results: We included 11 randomized controlled trials in this updated review, comprising 1,505 term and late preterm infants with moderate/severe encephalopathy and evidence of intrapartum asphyxia. Therapeutic hypothermia resulted in a statistically significant and clinically important reduction in the combined outcome of mortality or major neurodevelopmental disability to 18 months of age (typical RR 0.75 (95% CI 0.68–0.83); typical RD –0.15, 95% CI –0.20 to –0.10); number needed to treat for an additional beneficial outcome (NNTB) 7 (95% CI 5–10) (8 studies, 1,344 infants). Cooling also resulted in statistically significant reductions in mortality (typical RR 0.75 (95% CI 0.64–0.88), typical RD –0.09 (95% CI –0.13 to –0.04); NNTB 11 (95% CI 8–25) (11 studies, 1,468 infants) and in neurodevelopmental disability in survivors (typical RR 0.77 (95% CI 0.63–0.94), typical RD –0.13 (95% CI –0.19 to –0.07); NNTB 8 (95% CI 5–14) (8 studies, 917 infants). Some adverse effects of hypothermia included an increase sinus bradycardia and a significant increase in thrombocytopenia. Cochrane Abstract

Systemic inflammation associated with severe intestinal injury in extremely low gestational age newborns

To define the role of systemic inflammation in infants with intestinal perforation (IP) and necrotizing enterocolitis (NEC), we measured 25 blood protein concentrations on days 1, 7 and 14 in 939 infants born before 28 weeks’ gestation. On days 7 and 14, infants with NEC had elevated levels of C-reactive protein (CRP), serum amyloid A (SAA), IL-6 and IL-8. Infants with IP had elevated levels of CRP and insulin growth factor binding protein-1 on day 7 and elevated CRP, SAA, TNF-receptor-2 and matrix metalloproteinase-9 levels on day 14. A better understanding of systemic inflammation might help prevent and treat these disorders.