Jayant P. Shenai

Vitamin A Status of Neonates with Bronchopulmonary Dysplasia

ABSTRACT: We prospectively assessed and compared the vitamin A status of two groups of preterm neonates (<1500 g birth weight, <32 wk gestation), one who developed clinical and radiographic evidence of bronchopulmonary dysplasia (BPD) (n = 10), and the other (control) who developed no significant lung disease (n = 8). The infants with BPD in this study required prolonged mechanical ventilation and supplemental O2 therapy, and had a higher incidence of cardiorespiratory complications when compared to controls. Their mean plasma vitamin A concentrations were significantly lower than those of controls at four sampling times in the 1st postnatal month. In contrast to the controls, infants with BPD showed a substantial decline in their plasma vitamin A concentrations from the initial values, and a high percentage of individual values of plasma vitamin A concentration in these infants were <10 μg/dl during the 8-wk postnatal period of observation. Delayed establishment of gastrointestinal feeding and a lower vitamin A intake in these infants relative to controls may have accounted for this decline. Our data show that preterm neonates who develop BPD have suboptimal plasma vitamin A concentrations for extended periods of time postnatally. We speculate that the necrotizing bronchiolitis and squamous metaplasia of conducting airways associated with vitamin A deficiency could influence the orderly repair of lung injury in susceptible neonates who are mechanically ventilated and could contribute to the pathophysiology of BPD in these infants. Further studies are needed to determine whether more efficient management of these neonates with regard to their vitamin A nutrition and early achievement of vitamin A sufficiency could result in a decrease in the incidence and severity of BPD.

Liver Vitamin A Reserves of Very Low Birth Weight Neonates

ABSTRACT: This study assessed the liver vitamin A concentrations at birth in a group of very low birth weight neonates (n = 25) (<1500 g birth weight, <32 wk gestation), dying within 24 h of birth, prior to possiblechanges in vitamin A status induced by postnatal intervention. Serum concentrations of vitamin A and retinol-binding protein were also measured in 16 of these neonates. The mean (± SD) liver vitamin A concentration was 30.0 ± 12.9 Mg/g (range 2.0-49.0 μg/g)- The mean (± SD) serum vitamin A concentration was 13.0 ± 4.7 μg/dl (range 6.7-22.8 μg/dl). The mean (± SD) serum retinol-binding protein concentration was 2.2 ± 0.8 mg/dl (range 1.5–4.8 mg/ dl). Liver vitamin A, serum vitamin A, and serum retinolbinding protein concentrations did not correlate significantly with gestational age or birth weight. Linear regression analysis did not show a significant correlation between liver vitamin A, and serum vitamin A or retinol-binding protein concentrations. This study provides reference values for vitamin A concentrations at birth in very low birth weight neonates, which may be helpful in future studies designed to evaluate postnatal changes in the vitamin A status of these high-risk neonates.

Vitamin A Storage in Lungs during Perinatal Development in the Rat

We examined the ontogeny of vitamin A storage in fetal and neonatal lungs during perinatal development in the rat. High-performance liquid chromatography was used to measure concentrations of vitamin A and its esters, retinyl palmitate and stearate, in various fetal and neonatal tissues at times ranging from gestational day 14 through 21, and from postnatal day 1 through 21. The data show that significant vitamin A storage occurs in the fetal lung during the latter one-third of prenatal life. Depletion of these stores that begins before birth and continues into the early postnatal period suggests that the developing lung may be dependent on these local vitamin A stores during active growth and differentiation. The utilization of vitamin A stores in the developing lung appears to be independent of the liver stores of vitamin A.

Plasma retinol-binding protein response to vitamin A administration in infants susceptible to bronchopulmonary dysplasia

We hypothesized that changes in plasma retinol-binding protein (RBP) concentration in response to vitamin A administration might be useful for evaluating vitamin A status of very low birth weight infants susceptible to bronchopulmonary dysplasia. We prospectively studied 24 consecutively admitted neonates (birth weight less than 1350 gm, gestational age less than 31 weeks, ventilator dependent for greater than 24 hours after birth), who were eligible to receive 2000 IU supplemental vitamin A by intramuscular injection on postnatal day 1 and on alternate days thereafter for 28 days. In addition to serial assessment of vitamin A status, we measured plasma RBP just before and 1, 3, and 6 hours after an intramuscular injection of vitamin A (2000 IU/kg retinyl palmitate) on days 1 and 28. The percent increase in plasma RBP (delta-RBP) was high (mean +/- SD: 61 +/- 37%) and plasma vitamin A and RBP values were low on day 1, indicative of vitamin A deficiency. Supplemental vitamin A improved vitamin A status of all infants as shown by low delta-RBP (mean +/- SD: 8 +/- 9%) and normal plasma vitamin A and RBP values on day 28. Bronchopulmonary dysplasia was diagnosed in 12 of 24 infants. Infants with bronchopulmonary dysplasia had a higher mean (+/- SD) delta-RBP on day 28 than those without bronchopulmonary dysplasia (13 +/- 10% vs 3 +/- 3%, p less than 0.01), indicative of persistence of low vitamin A status in infants with lung disease despite supplementation. We conclude that the plasma RBP response to vitamin A is a useful indicator of vitamin A status in very low birth weight infants. Although vitamin A supplementation at the dosage used in this study normalizes conventional plasma indexes of vitamin A in very low birth weight infants, the plasma RBP response to vitamin A may continue to reflect persistence of low vitamin A status in the more immature infants with significant lung disease. We suggest that the plasma RBP response to vitamin A may be a useful functional test in such infants.

Nursery epidemic due to multiply-resistant Klebsiella pneumoniae: epidemiologic setting and impact on perinatal health care delivery.

Gram-negative bacilli frequently cause epidemics in high-risk newborn intensive care units. Recently, an epidemic caused by a multiply-resistant K. pneumoniae, serotype 21, occurred in the Vanderbilt University intensive care nursery. The background of this outbreak included an increasing endemic nosocomial sepsis rate, operation of the facility in excess of rated capacity, and increasingly inadequate nurse-to-patient staffing ratios. The epidemic lasted 11 weeks; 26 (12%) of the 232 infants at risk in the unit became colonized. Five infants developed systemic illness and one died. Cohorting, reinforcement of strict handwashing and isolation procedures, and closure of the unit to outborn admissions resulted in rapid termination of the outbreak. Followup studies performed on infants colonized with the epidemic bacterium demonstrated persistent fecal shedding up to 13 months following discharge from the hospital. This epidemic had a detrimental influence on high-risk newborn and obstetric health care delivery in an area encompassing portions of three states. Under a system of progressively more sophisticated referral units, nosocomial infections occurring at a tertiary center can have an impact on other hospitals within the network.

Effect of maternal vitamin-A administration on fetal lung vitamin-A stores in the perinatal rat.

Vitamin A (retinol) is essential for normal differentiation and integrity of developing respiratory epithelium and its deficiency has been linked to an increased susceptibility to lung injury. Because significant vitamin-A storage occurs in the fetal lung near term in the perinatal rat, prematurely born animals deprived of adequate stores in their lungs may be susceptible to the adverse effects of vitamin-A deficiency. It would be desirable if lung vitamin-A stores could be augmented with maternal administration, but the feasibility of this strategy has not been reported. We therefore conducted this study in rats to determine whether maternal administration of vitamin A could increase the lung stores of vitamin A in the offspring. Vitamin-A-sufficient pregnant rats were given a single dose of either vitamin A (50,000 IU retinyl palmitate) or 0.9% saline solution on gestational day 16 (term = 21 days) by the intragastric route. High-performance liquid chromatography was used to measure concentrations of vitamin A and its esters in fetal and neonatal lungs and livers at times ranging from gestational day 17 through 21, and from postnatal day 1 through 14. The concentrations of vitamin-A esters in the lungs of fetuses and newborn pups of the vitamin-A-treated animals were significantly (1.7- to 7.1-fold) higher than those of the control group. This increase in the lung vitamin-A ester concentrations was seen within 24 h of maternal administration and persisted throughout the 14-day postnatal period.(ABSTRACT TRUNCATED AT 250 WORDS)

Deletions in chromosome 6p22.3-p24.3, including ATXN1, are associated with developmental delay and autism spectrum disorders

Interstitial deletions of the short arm of chromosome 6 are rare and have been associated with developmental delay, hypotonia, congenital anomalies, and dysmorphic features. We used array comparative genomic hybridization in a South Carolina Autism Project (SCAP) cohort of 97 subjects with autism spectrum disorders (ASDs) and identified an ~ 5.4 Mb deletion on chromosome 6p22.3-p23 in a 15-year-old patient with intellectual disability and ASDs. Subsequent database queries revealed five additional individuals with overlapping submicroscopic deletions and presenting with developmental and speech delay, seizures, behavioral abnormalities, heart defects, and dysmorphic features. The deletion found in the SCAP patient harbors ATXN1, DTNBP1, JARID2, and NHLRC1 that we propose may be responsible for ASDs and developmental delay.

Postnatal Dexamethasone Treatment and Retinopathy of Prematurity in Very-Low-Birth-Weight Neonates

Whether postnatal dexamethasone treatment for bronchopulmonary dysplasia (BPD) increases the risk of retinopathy of prematurity (ROP) in very-low-birth-weight (VLBW) neonates is uncertain. We performed a retrospective cohort study to determine the association between dexamethasone administered postnatally and the development of ROP in VLBW (≤1,250 g birth weight, ≤32 weeks’ gestational age at birth) neonates. The incidence of severe ROP (stage 2 or higher) was 26% among 72 infants who received no dexamethasone postnatally, 61% among 23 infants who received a low cumulative dexamethasone dose (≤1.8 mg/kg body weight), and 85% among 20 infants who received a high cumulative dexamethasone dose (>1.8 mg/kg body weight). However, after adjustment for confounding covariates of prematurity and severity of lung disease by logistic regression analysis, we found no independent association between postnatal dexamethasone treatment and the incidence of severe ROP.

Neonatal Transport: Outreach Educational Program

Neonatal transport is an integral part of a regionalized system of perinatal health care delivery. An effective outreach educational program promotes early identification of high-risk neonates, consultation, communication, and referral. The education offered in several formats also promotes optimal pretransport and intratransport stabilization of referred neonates. This improved stabilization may favorably influence the overall neonatal outcome. The impact of education in the region can be determined by a systematic review of referral patterns, standard of care during stabilization, and neonatal outcome. An organized outreach educational effort is therefore an essential aspect of any neonatal transport program.

Developmental origins of health and disease

Events during embryonic and fetal life as well as during early infancy may be a harbinger of disease in adulthood. Numerous examples can be cited to validate this contention. A fetus who fails to grow as a result of an adverse intrauterine environment may show a deficit of nephrons, predisposition of the nephrons to sclerosis from increased pressure in glomerular capillaries, and consequent development of hypertension in adult life. A fetus who has growth restriction with relative sparing of cranial growth may have an altered blood flow through the liver, possibly causing disruptions in cholesterol metabolism and coagulation, which may raise the risk of atherosclerosis and related cardiovascular disease in adult life. The same fetus may have a deficit of pancreatic b cells and be predisposed to insulin deficiency and type I diabetes mellitus as an adult. A low-birth-weight, small-for-gestational-age neonate whose nutrition is compromised may show metabolic adaptation by reducing dependence on glucose and using alternate fuels such as amino acids for survival, and in the process may develop insulin resistance and type II diabetes mellitus in adult life. A preterm neonate who has poor bone mineral content from deficient mineral intake and/or excessive mineral loss resulting from chronic use of diuretics may be at increased risk of osteoporosis as an adult. A preterm neonate with bronchopulmonary dysplasia may have alterations in alveolar number and size that may place the infant at risk for chronic obstructive pulmonary disease as an adult. The cases cited above raise an important hypothesis that many an adult disease may have its origin during development in periconceptional, embryonic, fetal and early neonatal life. Adult disease is probably a complex interplay of genotypic variation and environmental factors. One of the well-characterized adult diseases of developmental origin is termed metabolic syndrome, which comprises a pentad of hypertension, hyperinsulinism, dyslipidemia, obesity and cardiovascular disease. Insulin resistance, the hallmark of the metabolic syndrome, may be from genetic alterations such as angiotensin-converting enzyme gene-deletion polymorphism or from intrauterine and extrauterine environmental factors that lead to growth failure. If these concepts are important in our understanding of the management of a high-risk mother, fetus or neonate with regard to its consequences in adult life, we may be best served by reading a sentinel book entitled Developmental Origins of Health and Disease, edited by Peter Gluckman and Mark Hanson. With 84 authors from 12 countriesFamong them are maternal–fetal medicine specialists, neonatologists, epidemiologists, developmental biologists, nutritionists, endocrinologists, pathologists and physiologistsFthis book truly represents an international endeavor and a landmark contribution to the subject of human development in relation to its long-term effects. The in-depth coverage of many developmental perturbations causing adult disease introduces the reader to a unique lexicon relevant to the subject. For example, ‘critical window of developmental plasticity’ refers to a specific period during which an organ system may be most vulnerable to change, while being spared of an analogous effect of the genetic or the environmental factor during other times. The classic example of the window of plasticity is the development of a neural-tube defect attributed to folic acid deficiency, specifically during the periconceptional period. ‘Biologic adaptation’ is the adaptive response of a species to an environmental influence. The best example of the adaptive response is provided by observations in the desert locust. When the population density is high, the wing shape in the offspringFyielded by pheromonic signals from the mother at egg layingFis such that migration is possible, important for survival. Conversely, when the population is sparse, the wing shape is non-migratory, allowing the offspring to remain at the protective site of birth. ‘Thrifty genotype’ is an example of how low birth weight can promote genesFglucokinase as the probable candidate geneFthat protect the fetus from excess insulin during the intrauterine period of nutritional deprivation, but raising the specter of insulin resistance and type II diabetes mellitus during the period of surplus nutrition in later life. ‘Thrifty phenotype’ is an example of how low birth weight represents a phenotypic adaptation to a poor intrauterine environment in which a small size confers a survival benefit, but becomes deleterious in a postnatal environment of surplus energy. ‘Epigenetic’ is a term used to signify changes in gene expression in response to an environmental influence. Whether or not a gene is actively expressed within a particular cell is determined not only by the primary nucleotide sequence of the gene and its regulatory elements, but also by changes in the manner the DNA is modified and packaged within the nucleus. Epigenetic changes include Journal of Perinatology (2007) 27, 732–733 r 2007 Nature Publishing Group All rights reserved. 0743-8346/07