Human Ontogeny of Drug Transporters: Review and Recommendations of the Pediatric Transporter Working Group.

The critical importance of membrane-bound transporters in pharmacotherapy is widely recognized, but little is known about drug transporter activity in children. In this white paper, the Pediatric Transporter Working Group presents a systematic review of the ontogeny of clinically relevant membrane transporters (e.g., SLC, ABC superfamilies) in intestine, liver, and kidney. Different developmental patterns for individual transporters emerge, but much remains unknown. Recommendations to increase our understanding of membrane transporters in pediatric pharmacotherapy are presented.

Obstetric clinical pharmacology: coming of age.

Little is known about changes in drug disposition and effect during pregnancy. In this issue, which is devoted to maternal and child health, Andrew and colleagues from the University of Washington present research describing significant changes in the disposition of amoxicillin during pregnancy. The clinical significance is the potential for inadequate dosing during pregnancy of compounds that are renally cleared. Further research is needed to guide the appropriate, safe, and effective medical treatment of pregnant women. In 2003, the National Institute of Child Health and Human Development (NICHD) formed the Obstetric Pharmacology Research Units Network. This network serves in part as a proof-of-concept platform, to demonstrate that clinical investigations can be performed in pregnant women.

Incentive to study drugs in children and other governmental initiatives: will patients with asthma benefit?

This article summarizes current regulations that have been developed to facilitate the performance of pediatric drug trials and their impact on children, particularly those children affected with asthma. In addition, other initiatives that have been developed by the federal government in response to the unexplained increase of asthma occurrence during the last 15 years will be reviewed. In the face of an asthma epidemic, a comprehensive approach is needed to determine the causes for the increase in the prevalence rate and the role of aeroallergens and other environmental and genetic factors and to identify effective preventive measures. Clearly, facilitating drug trials to prove the safety and effectiveness of drugs is of paramount importance.

Severe fetomaternal hemorrhage: a review.

The etiology, clinical presentation, obstetrical antecedents, and outcome of pregnancies complicated by large fetomaternal hemorrhage (FMH) were reviewed by doing a MEDLINE search from 1966 to the present and manual search before 1966. One hundred thirty-four infants with FMH > 50 dl were reported in the literature. The primary variables: birth weight, gestational age, presence of sinusoidal fetal heart rate pattern, decrease or absent fetal body movements (FBM) estimated the amount of fetomaternal bleeding and the pretransfusion hemoglobin. Other variables included the condition of the infants at birth, erythroblasts, and reticulocyte blood counts at birth, as well as the year of publication. Thirty-five of the 134 cases were preterm. Twenty infants born to mothers reporting decreased or absent FBM survived. FBM was absent in 17 cases for a period ranging between 24 hours and 7 days. In this group, six infants survived, five were stillborn, and five died in the neonatal period. A sinusoidal heart rate (SHR) pattern was reported in 21 cases. A SHR pattern was associated with decreased FBM in 13 cases (39.3 percent). Fifteen cases with sinusoidal fetal heart rate pattern survived (71.4 percent). Both decreased or absent FBM and SHR patterns were reported more often in 1990 or later than before 1990 (P < .0017 and P < .008, respectively). The cause of FMH was not known in 82 percent of the cases. The most common presenting symptoms of FMH were anemia at birth (35.2 percent), decreased or absent FBM (26.8 percent), and unexpected stillbirths (12.5 percent). Seventeen intrauterine transfusions were performed in nine cases (eight survived). A negative correlation was found between pretransfusion hemoglobin and FMH (r = -0.35; P = .0019). No significant difference was found between the cases with FMH of > 200 ml or < 200 ml. Thus, decreased or absent FBM, SHR pattern, or hydrops fetalis are late signs of FMH. Other means of early detection are needed. The role of intrauterine transfusion (IUT) needs to be better defined. The inadequate outcome data indicate the need to follow infants born with large FMH into childhood to document the effect on the central nervous system.

Follow-up of school-age children with bronchopulmonary dysplasia.

OBJECTIVE: To investigate the outcome of school-age children with bronchopulmonary dysplasia (BPD) in terms of nutrition, pulmonary function, and intelligence, and to compare the results with a preterm cohort matched for gestational age and birth weight, and with a term control group. DESIGN: Cross-sectional. SETTING: Follow-up clinic at level III neonatal intensive care unit, university-affiliated hospital, Children's Hospital. SUBJECTS: Twelve children who had BPD as infants and 2 control groups of 12 children each. MAIN OUTCOME VARIABLES: Anthropometric measurements, dietary intake, resting energy expenditure, pulmonary function, body composition measurements by dual energy x-ray absorptiometry, and Weschler intelligence test scores. RESULTS: Children with BPD had decreased forced expiratory volume at 1 second, decreased forced expiratory flow between 25% and 75% of vital capacity, and decreased maximal expiratory flow velocity at 50% of vital capacity compared with age-matched normal inborn subjects (p = 0.025, p = 0.005, and p = 0.0013, respectively). Both children with BPD and matched preterm control children were shorter than infants in the term control group (p = 0.018). There were no significant differences in the other anthropometric parameters studied. The groups did not differ in resting energy expenditure. Lean body mass was lower in the BPD group compared with the term control groups (p = 0.017). Bone mineral content was lower in the BPD group compared with both the preterm and term control infants (p = 0.050 and p = 0.059, respectively). The mean performance intelligence quotient (IQ) and full-scale IQ scores in the BPD group were lower than in the term control group (p = 0.011 and p = 0.029, respectively). The proportion of children with borderline or intellectually deficient scores was significantly higher in the preterm group compared with the term group for verbal, performance, and full-scale IQ scales (p = 0.046, p = 0.018, and p = 0.048 respectively). The proportion of children with BPD who had borderline or deficient performance IQ scores was higher than for the term group (p = 0.046). CONCLUSIONS: The lower height and intelligence scores in children with BPD may be related to prematurity and perinatal events rather than pulmonary disease. Subclinical pulmonary dysfunction in children with BPD persists at school age. The lower amount of lean body mass and possible decrease in bone mineral content in children with BPD may be related to their smaller size.

Vitamin B-6 adequacy in neonatal nutrition: associations with preterm delivery, type of feeding, and vitamin B-6 supplementation.

Concerns about vitamin B-6 adequacy in neonatal nutrition relate to critical functions of the vitamin in development. Vitamin B-6 status was assessed in six groups of neonates: two groups each of breast-fed term and preterm infants whose mothers were supplemented with 2 or 27 mg pyridoxine-hydrochloride (PN-HCl); a subgroup of term infants (2-mg maternal group) supplemented with 0.4 mg PN-HCl/d; and a formula-fed preterm group. During the 28-d experimental period, weekly assessments showed lower concentrations of total vitamin B-6 and percentages of pyridoxal in milk from mothers of preterm infants than in milk from mothers of term infants, even when maternal PN-HCl supplementation was 27 mg/d. The vitamin B-6 concentration of milk and estimated intakes of the vitamin by breast-fed infants paralleled maternal supplements (ie, 2 and 27 mg). Plasma and erythrocyte measurements of infants correlated with their vitamin B-6 intakes; values were highest for infants given vitamin B-6 supplements and those that wee formula-fed. Vitamin B-6 adequacy was questionable for unsupplemented breast-fed infants of mothers in the 2-mg supplemented groups.

Tracheal TDx fetal lung maturity test for assessing lung maturity in newborns with respiratory distress.

We evaluated a modified TDx-fetal lung maturity (FLM) test for estimating surfactant in small volume tracheal aspirates in 140 infants requiring mechanical ventilation. Respiratory distress syndrome was present in 75 infants, and 68 had TDx FLM less than 60 mg/dL (sensitivity, 90.6%). Respiratory distress was absent in 65 infants, 56 had TDx FLM more than 60 mg/dL (specificity, 86.1%). The modified TDx-FLM assay is highly automated, has a fast turn-around time (less than 30 minutes), has high reproducibility, and is less expensive than other available methods. This method has potential routine application in the diagnosis of surfactant deficiency, and the assessment of surfactant replacement and mechanical ventilation therapies.

Rectal bleeding due to nonspecific colitis in premature infants.

Rectal bleeding is not uncommon in newborn infants. Anal fissures are regarded as the most common cause. We report two cases in which the presence of an anal fissure delayed the diagnosis of nonspecific colitis in premature infants. Rectosigmoidoscopic and biopsy findings are discussed with regard to the heterogeneous group of disorders associated with isolated rectal bleeding in young infants. These procedures may be helpful in ruling out necrotizing enterocolitis in premature infants.

Nitric oxide: a selective pulmonary vasodilator.

Nitric oxide (NO) has recently been found to be the endothelium-derived factor that produces profound relaxation of the vascular smooth muscle. This discovery has led to the experimental use of inhaled NO as a selective pulmonary vasodilator without concomitant systemic vasodilation. Currently, clinical trials of inhaled NO in persistent pulmonary hypertension of the newborn (PPHN) are in progress. Inhaled NO has also been used in the adult respiratory distress syndrome (ARDS). The therapeutic role, if any, of inhaled NO in other diseases featuring pulmonary hypertension remains unknown. Further research is needed to determine potential toxic effects of NO, development of delivery systems, and monitoring techniques applicable to routine clinical care.

Nitric oxide: an environmental pollutant as a therapeutic agent.

There is no effective treatment for patients with pulmonary hypertension because of the lack of a selective pulmonary vasodilator. Recently, nitric oxide (NO) has been found to be the endothelium-derived factor that produces relaxation of the vascular smooth muscle. This discovery has led to the experimental use of inhaled NO as the first selective pulmonary vasodilator. This review summarizes the development of NO inhalation for pulmonary hypertension, including the essential aspects of basic research, which identified NO as a potent endogenous vasodilator. The use of inhaled NO in animal studies of experimental pulmonary hypertension, as well as in the clinical experience so far reported in newborns, children, and adults are summarized. It is concluded that inhaled NO remains experimental and that controlled clinical trials and further studies on potential toxicity are needed before this new therapy can be accepted for routine clinical use.

Uncommon pathogens in newborn infants.

Newborns, especially premature newborns, are immunocompromised and have increased susceptibility to infections by opportunistic organisms. Experience with these uncommon pathogens is limited to a handful of case reports and to several reports of neonatal intensive care nursery outbreaks. Many of these infections are misdiagnosed or diagnosed at autopsy because of the nonspecific features of their clinical presentation, difficulties in recovering the pathogen from body fluids, or because the microorganism is considered either a contaminant or nonpathogenic. This review summarizes the clinical characteristics of these uncommon pathogens and emphasizes the existence of dual and polymicrobial infections. The limited experience with many of these infections precludes the formulation of an optimal therapeutic approach.

Right-sided diaphragmatic hernia associated with superior vena cava syndrome.

The term "hydrops fetalis" denotes generalized fetal edema, a condition that differs from localized edema confined to head, extremities, or body cavities. This report illustrates a case of right-sided diaphragmatic hernia associated with severe edema of the head, polyhydramnios, small hydrothorax, and ascites with an antenatal diagnosis of hydrops fetalis. At autopsy, edema was confined to the head and neck and the peritoneal sac. The mechanisms responsible for these forms of localized edema were obstruction of the superior vena cava and hepatic veins, respectively. Localized fetal edema may be confused with hydrops fetalis. Fetal edema of the head and neck may result from obstruction of the superior vena cava by abnormal mediastinal structures.

Acrodermatitis enteropathica-like syndrome secondary to isoleucine deficiency during treatment of maple syrup urine disease.

We describe a patient with maple syrup urine disease in whom an acrodermatitis enteropathica-like syndrome developed while he was receiving a branched-chain amino acid-free formula. Iatrogenically induced isoleucine deficiency developed and resulted in a decreased protein accretion and persistent increase in the plasma concentrations of leucine. A rapid clinical response to isoleucine supplementation was noted. This observation underscores the risks of using amino acid-free formulas without adequate supplementation of deficient amino acids.

Indomethacin and recurrent ileal perforations in a preterm infant.

This article reports a case of a very low birth weight infant who was given intravenous indomethacin for a symptomatic patent ductus arteriosus and subsequently had two isolated ileal perforations several days apart. Spontaneous or indomethacin-related ileal perforation appears to constitute a separate clinical and pathologic entity, different from necrotizing enterocolitis, with a benign clinical picture and good prognosis when promptly recognized.

Asphyxial brain damage in the newborn: new insights into pathophysiology and possible pharmacologic interventions.

New insights into the pathophysiology of the hypoxic-ischemic insult have opened the possibility of pharmacologic intervention in neonatal hypoxic-ischemic encephalopathy. It is now known that many neurons survive a hypoxic-ischemic insult but remain dysfunctional for hours, with profound alterations in cell function. A cascade of biochemical alterations occurs as a consequence of cellular ionic shifts, energy depletion, degradation of cell membrane phospholipids, and increased release of neurotransmitters. In addition, there are alterations in the metabolism of arachidonic acid and prostanoids and an excessive production of oxygen free radicals. The new therapeutic modalities are aimed at preventing or arresting the biochemical changes that occur in the period after hypoxia-ischemia. This review details the biochemical alterations associated with neonatal hypoxic-ischemic encephalopathy and discusses the possible use in newborns of pharmacologic agents currently undergoing extensive investigations in experimental animals and adult humans.

Congenital herpes infection: placental and umbilical cord findings.

BACKGROUND: Herpes simplex virus (HSV) fetal infections are rare, and the routes through which the virus reaches the fetus are insufficiently documented. CASE: We describe a case of congenital HSV ascending infection in an infant whose membranes were intact until cesarean delivery. The pathologic findings were remarkable for a mild lymphoplasmocytic funisitis and the presence of positive viral staining of cells in the subamniotic connective tissue, amniotic epithelium, and umbilical cord. Antigen-positive cells within the extraplacental membranes were mostly located in an area presumably adjacent to the cervix before birth. In the umbilical cord, positive viral staining was confined to cells in the subamniotic mesenchyma away from the perivascular mesenchyma of the central portion of the cord. CONCLUSION: Immunohistochemistry using herpes-specific antibodies, coupled with routine histologic examination, allows early diagnosis of congenital HSV infection and documentation of the ascending route of infection when the membranes are intact.