Safety issues of maternal drug therapy during breastfeeding.

Two goals when counseling breastfeeding mothers taking medication are protecting the infant from adverse events and permitting necessary maternal therapy. Madadi et al. report a case-control study of neonatal and maternal opioid toxicity after codeine administration. Therapeutic considerations in counseling breastfeeding mothers include susceptibility to drug toxicity of the very young and/or premature infant, significant interindividual variations in drug response, the dose-response relationship with respect to drug toxicity, and the role of pharmacogenetics in both the mother and the infant. These host factors may combine in a particular patient to act synergistically to produce an adverse reaction.

Advances in pediatric pharmacology, therapeutics, and toxicology.

This chapter reviews published studies in the field of pediatric therapeutics between July 1998 and July 2000. The most important area discussed in the first part of the chapter concerns the significant advances made in the labeling of drugs for children in the United States. Dr Harry Shirkey coined the term "therapeutic orphan" in 1968 to describe the state of children who were not being considered in either drug development or in drug clinical trials. This explains why about 80% of drugs listed in each edition of the Physicians' Desk Reference do not have labeling for the pediatric age group, especially children younger than 12 years. The recent legislative, regulatory, and pharmaceutical company activities to change this situation are summarized. These changes are current and promise to make significant contributions to the availability of drugs with adequate pediatric indications to the practicing physician. Another important change in recent years has been the appreciation of the importance of placebo-controlled clinical trials for psychotropic medications in children. Trials with one of the selective serotonin reuptake inhibitors, as well as further studies involving the appropriate dosing and preparation of stimulant drugs for attention-deficit/hyperactivity disorder (ADHD), are also discussed. Several new areas that promise significant knowledge in therapeutics are in the treatment of osteoporosis (a neglected condition in pediatrics), arthritis (a condition for which drugs are used to treat the disease rather than the symptoms), and acquisition of data concerning transplacental transfer of human immunodeficiency virus (HIV) and use of multiple anti-HIV drugs for treatment of this virus in the pediatric population.

Infant exposure to chemicals in breast milk in the United States: what we need to learn from a breast milk monitoring program.

The presence of environmental chemicals in breast milk has gained increased attention from regulatory agencies and groups advocating women's and children's health. As the published literature on chemicals in breast milk has grown, there remains a paucity of data on parameters related to infant exposure via breast-feeding, particularly those with a time-dependent nature. This information is necessary for performing exposure assessments without heavy reliance on default assumptions. Although most experts agree that, except in unusual situations, breast-feeding is the preferred nutrition, a better understanding of an infant's level of exposure to environmental chemicals is essential, particularly in the United States where information is sparse. In this paper, we review extant data on two parameters needed to conduct realistic exposure assessments for breast-fed infants: a) levels of chemicals in human milk in the United States (and trends for dioxins/furans); and b) elimination kinetics (depuration) of chemicals from the mother during breast-feeding. The limitations of the existing data restrict our ability to predict infant body burdens of these chemicals from breast-feeding. Although the data indicate a decrease in breast milk dioxin toxic equivalents over time for several countries, the results for the United States are ambiguous. Whereas available information supports the inclusion of depuration when estimating exposures from breast-feeding, the data do not support selection of a specific rate of depuration. A program of breast milk monitoring would serve to provide the information needed to assess infant exposures during breast-feeding and develop scientifically sound information on benefits and risks of breast-feeding in the United States.

Challenges in conducting pediatric drug trials.

For many decades, and with the exception of the treatment of infections, drug use in children has been confined to symptom relief. But the emphasis in asthma treatment has now shifted to the use of antiinflammatory agents that prevent the process resulting in bronchoconstriction, thus removing a symptom's cause. Newer understanding from the use of antiinflammatory agents in adults has led to an appreciation of preventative therapy and a growing understanding that effective drug therapy during childhood could prevent changes in the disease process that lead to chronic symptoms during adulthood. Alongside these developments, and while the debate over conducting drug trials in children continues, a persistent gap remains in the knowledge about drug use in children. Challenges remain not only in the regulatory environment but also in research and in the identifying, recruiting, and fostering of pediatric investigators.

Methodology for characterizing distributions of incremental body burdens of 2,3,7,8-TCDD and DDE from breast milk in North American nursing infants.

A clear picture of ranges of doses of breast-milk contaminants experienced by nursing infants in North America has not yet been described, resulting in a significant gap in our understanding of potential health risks to infants from those contaminants. While point estimates of incremental dose have appeared in the published literature, these do not account for the wide variability in exposures experienced by nursing infants. This research expands on the current state of understanding of breast-milk contaminant exposure by characterizing distributions, rather than point estimates, of dose. Distributions of milk intake by nursing infants were characterized to examine intake of 2,3,7,8-tetrachlorodibenzo-p-dioxin (2,3,7,8-TCDD) and dichlorodiphenyl dichloroethane (DDE). The results indicate that, despite the uncertainties inherent in modeling incremental body burdens of chemicals from nursing, estimating incremental infant body burdens of lipophilic chemicals from breastfeeding using point estimates may result in overly conservative estimates of the contribution of breastfeeding to long-term body burdens of those chemicals in children. To develop reliable estimates of incremental body burden from nursing, depuration via lactation and half-life in the infant should be considered. Further, incremental infant body burdens of lipophilic chemicals increase rapidly at the start of lactation, but decrease after approximately 5 to 6 mo; by 2 yr postpartum, incremental body burdens have decreased substantially. Given the benefits afforded to infants who breastfeed, and because breastfeeding does not necessarily lead to significantly increased long-term body burdens in infants, breastfeeding should be encouraged and promoted.

Lead poisoning in children.

Increased lead exposure and increased body burden of lead remains a significant problem for children in the United States. With the increased use of blood level screening methods, a large percentage of children in many industrialized countries are being tested as a being at risk. A controversy continues over the definition of what population to screen and at what age to screen. There are parts of the United States, especially rural areas and health maintenance organization populations, where screening for lead exposure has not been productive. A new drug, DMSA (meso 2,3-dimercaptosuccinic acid) has been approved for oral chelation of children with increased body burden of lead. At the present time it is labeled for use in children with blood lead concentrations in excess of 45 micrograms/dL. Evidence exists that DMSA is effective in lowering the blood lead concentrations in children with levels between 25 and 45 micrograms/dL. The long-term effectiveness of chelation at lower levels is at present uncertain. There remains no substitution for strict environmental decontamination in the home environment of children and the workplace environment of their parents.

Mutation analysis in families with discordant phenotypes of phenylalanine hydroxylase deficiency. Inheritance and expression of the hyperphenylalaninaemias.

Neonatal hyperphenylalaninaemia caused by mutations in the gene encoding phenylalanine hydroxylase (PAH) represents a wide spectrum of metabolic phenotypes, ranging from classical phenylketonuria (PKU) to mild hyperphenylalaninaemia (MHP). The marked interindividual heterogeneity is due to the expression of multiple PAH mutations in genetic compounds. We have investigated four unusual families in which both PKU and MHP were present. In each family three different mutations in the PAH gene were identified, including two associated with PKU and one associated with MHP. The unexpected outcome of discordant phenotypes within the families described is explained by previously unrecognized parental MHP. By mutation analysis we have also predicted the phenotypical outcome in a hyperphenylalaninaemic infant born to a mother who before pregnancy had been diagnosed as having MHP. Our results demonstrate the utility of nucleic acid analysis in follow-up in PKU screening programmes.

Effect of dietary aspartame on plasma concentrations of phenylalanine and tyrosine in normal and homozygous phenylketonuric patients.

Six normal subjects each ingested a single 12-oz can of a diet cola (Diet Coke) providing 184 mg aspartame (APM), of which 104 mg is phenylalanine (Phe), and, on another occasion, a single 12-oz can of regular cola (Coke Classic). Neither cola significantly affected plasma concentrations of Phe or tyrosine over the three-hour postingestion study period. Each of five homozygous phenylketonuric (PKU) subjects (ages 11, 16, 17, 21, and 23 years) ingested a single 12-oz can of the same diet cola. In these five subjects (three with classic PKU and two with hyperphenylalinemia), the increase in plasma Phe concentrations varied from 0.26 mg/dL to 1.77 mg/dL two or three hours after ingestion (baseline levels, 5.04 to 17.2 mg/dL). Tyrosine concentrations did not differ significantly from baseline levels. The data indicate that ingestion of dietary Phe, as supplied in a single can of diet cola, is readily handled in both normal and PKU subjects. The small increases in plasma Phe concentrations in the homozygous PKU patients are not considered clinically significant.

Hepatic granulomata. Presenting with prolonged fever. Resolution with anti-inflammatory treatment.

A patient is described who presented with a 1-month history of daily fever to 38.8 degrees C. There was no sign of joint pain or swelling and no skin rash. The patient had impressive hepatomegaly without splenomegaly. The only abnormal laboratory test was a sedimentation rate of 120 mm/hr. Ultrasound examination showed hypoechoic foci throughout the liver. These foci were confirmed by CT scan, which showed multiple well-marginated lesions of decreased attenuation and variable size throughout the right and left lobes of the liver. A liver biopsy specimen showed large nodules that were yellow and gritty in texture. Microscopic examination of biopsy specimens of these nodules showed extensive areas of necrotizing granulomatous inflammation with palisading histiocytes and occasional giant cells surrounded by necrotic foci. There was an associated fibroinflammatory infiltrate. The patient was treated with a nonsteroidal anti-inflammatory agent with prompt cessation of fever. A repeat CT examination of the liver after 14 months of treatment showed only mild hepatomegaly and a normal liver parenchyma. The focal lesions had disappeared. This is a case of hepatic granulomata in a child showing features of necrotizing inflammation.

Drugs and chemicals: exposure of the nursing mother.

Over half of newborn infants begin life breastfeeding. Nearly all drugs ingested by nursing mothers appear in their milk; amount is 1 to 2 per cent of the mother's dose. Drugs for most maternal conditions are safe for the nursing infant. Information is presented to permit nursing mothers who need medication to nurse safely.

Caffeine pharmacokinetics in preterm infants older than 2 weeks.

We studied 17 preterm infants receiving caffeine, and measured their plasma levels of caffeine and the theophylline metabolite by high-pressure liquid chromatography. The half-life was calculated by computer analysis using the least-square method. The mean gestational age of our patients was 29.7 +/- 1.9 weeks (mean +/- SD) and they were studied at 20.7 +/- 6.6 days (mean +/- SD) postnatal age. The caffeine half-life was 52.03 +/- 23.87 h (means +/- SD) and the theophylline half-life was 77.04 +/- 65.01 h (mean +/- SD).