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This report summarizes a meeting sponsored by the National Institute of Child Health and Development to review important scientific contributions over the past several years that addressed the causes and consequences of intrauterine growth restriction (IUGR). IUGR contributes significantly to perinatal morbidity and mortality. Considerable research has focused on various aspects of fetal growth, particularly with respect to the epidemiology of IUGR, the regulation of fetal growth by intrinsic growth factors and extrinsic nutrient supply, the role of the placenta in fetal growth, and diagnosis and treatment of IUGR. In addition to summarizing many of the advances in each of these important areas of research, a major purpose of the meeting was to consider future directions for research into the causes, consequences, diagnosis, and treatment of IUGR. At the onset of the meeting, Dr William Hay provided a broad overview of IUGR. Much of the impetus for studying IUGR began with the observation by pediatricians and neonatologists that when classified according to birth weight and gestational age, newborn infants were shown to be small, average, or large for gestational age (SGA, AGA, and LGA, respectively), and that specific morbidities and rates of death were unique to each of these birth weight-gestational age classifications.1 SGA infants, for example, were recognized as having more frequent problems with hypoglycemia, hypothermia, polycythemia, and neurodevelopmental handicaps, as well as a higher mortality rate.2 With the advent of improved fetal diagnosis, infants who were small at birth were increasingly recognized as representing a variety of fetal growth patterns. For example, infants who were considered constitutionally small simply grew parallel to, but less than, the 10th percentile for normal rates of fetal growth. Infants with genetic abnormalities or acquired diseases, particularly infections occurring in the first trimester, also grew slowly, and many of these infants …

A neonatal bilirubin workshop took place at The Rockefeller University on June 20 through 22, 1993 to consider controversial issues in the field of neonatal jaundice and bilirubin neurotoxicity, particularly as they relate to management. The conference was sponsored by the National Institute of Child Health and Human Development (Pregnancy and Perinatology Branch, Center for Mothers and Children), The Rockefeller University, and the Consiglio Nazionale delle Richerche (Italy). tk;4Presentations and discussion emphasized diagnosis, biochemistry, and mechanisms of bilirubin toxicity, the definition and consequences of kernicterus, and the appropriateness and safety of the various therapies currently in use. Identification of future research needs was an important agenda item. The conferees agreed that conventional management of jaundice in the newborn with phototherapy and exchange transfusion, as well as with phenobarbital in certain situations, had significantly reduced the occurrence of "traditional" kernicterus. However, the conferees acknowledged that the classical definition of kernicterus was in need of re-examination in view of the potential of bilirubin as a CNS toxin. Early discharge of newborns from the hospital has significantly altered diagnostic and therapeutic management of neonatal jaundice, transforming it into an outpatient problem. This transformation raises new questions regarding the best time to ascertain the cause(s) of jaundice and to identify risk factors to insure optimal management of the infant. Review of the current state of knowledge of bilirubin metabolism focused on new methods for measurement of unconjugated and conjugated bilirubin, measurement of bilirubin synthesis rates, the molecular biology of bilirubin conjugation and the developmental role of the family of enzymes known as glucuronyl transferase(s), and the role of genetic and other host factors in determining the safety or toxicity of bilirubin in the newborn.

The National Institute of Child Health and Human Development and the Agency for Health Care Policy and Research convened a workshop addressing the issues related to early discharge and hyperbilirubinemia on March 28, 1995. Recent reports have suggested that a high proportion of hospital readmissions in the neonatal period are related to hyperbilirubinemia.1-3 In addition, a growing number of anecdotal reports have raised concern about a resurgence of kernicterus and other hyperbilirubinemia-related morbidity, much of which may be preventable with improved neonatal discharge practices, monitoring technologies, and/or new pharmacologic therapies.4 Cost-containment strategies, such as managed care, have resulted in a continued trend toward shorter lengths of stay for all hospitalizations in all age groups. As a part of this trend, early discharge of neonates has also become common. The potential effects of these policies on subsequent outcomes for neonates and their mothers have generated concern. (In fact, Maryland has recently passed, and other states have introduced, legislation mandating at least 2 days postnatal hospital care.5) In addition to hyperbilirubinemia, other health issues related to early discharge that have been identified were discussed. These are reviewed in this issue of Pediatrics.6 They include potential adverse effects on newborn screening, poor preparation for breast-feeding, inadequate surveillance of mothers and neonates for health problems in the postpartum/neonatal period, reduced opportunities for parent training in "at-risk" populations, disruption of immunization practices, and shifting of economic burdens to families and nonhospital-based providers. The objectives of this workshop were: a) to review the present status of knowledge regarding hyperbilirubinemia requiring clinical intervention in the newborn and its prevention, and b) in the context of current practices, to begin outlining an agenda for research needs, practice guidance, and policy formulation related to morbidity and mortality associated with early discharge and neonatal jaundice.

Over the past decade many exciting advances have been made with regard to the survival, medical care, and outcome of extremely low birth weight (ELBW) infants (those who weigh

The apparent volume of distribution (Vd) of salicylate was determined in 11 children, 4 months to 16 years old, who had ingested from about 36 to over 340 mg of salicylic acid (mainly as aspirin) per kilogram of body weight. Vd was calculated from the amount of salicylate in the body at a given time (as determined by the amount of total salicylates excreted in the urine and, where applicable, removed in peritoneal dialysis fluid after that time) and the concentration of salicylate in the plasma at the same time. This method of calculation is ideal for the nonlinearly eliminated salicylic acid and does not require any assumptions with respect to the nature of the pharmacokinetic model for salicylate distribution. The Vd for salicylate in the children ranged from 162 to 345 ml/kg and was larger at the higher doses. Plots of salicylate concentration in plasma versus amount of drug in the body were usually linear for a given patient, showing that Vd remained relatively constant over the time course of elimination of the drug in the patients studied. This indicates that a given plasma salicylate concentration in children who have ingested large doses reflects a larger amount of salicylate in the body than the same plasma concentration in children who ingested smaller doses of the drug. These observations help to rationalize and emphasize the usefulness of the Done nomogram (which involves estimation of the theoretical zero time plasma salicylate concentration by back extrapolation) for assessing the severity of salicylate intoxication.

During the first half of this decade, much new information about the acquired immunodeficiency syndrome (AIDS) became available, including landmark reports of the syndrome in children from Oleske et al, Rubinstein et al, and Scott et al; descriptions of AIDS in pregnancy by Wetli et al, Rawlinson et al, and Minkoff et al; and discovery of the agent that causes AIDS, the human immunodeficiency virus (HIV, formerly called HTLV-III/LAV). The first sets of health guidelines pertaining to HIV-infected children and adolescents in school, day-care and foster care settings were published by the American Academy of Pediatrics' Committee on Infectious Diseases in March 1986 and 1987. In 1987, the Surgeon General's Workshop on Children With HIV Infection and Their Families provided the first comprehensive set of recommendations relevant to the provision of pediatric and obstetrical care to infected mothers, infants, children, and adolescents. Most recently, during February 1988, the Secretary of Health and Human Services formed the Secretary's Work Group on Pediatric HIV Infection and Disease that consisted of members from each of the health and human services agencies, including the Social Security Administration and the Health Care Financing Administration. The broad mandate of this group was to make recommendations to facilitate the removal of barriers to care, treatment, and financial burdens of children and adolescents with HIV infection and their families. In contrast, HIV infection has not received sufficiently widespread attention from the obstetric, pediatric, or adolescent research communities. The uneven geographic distribution of the disease; its associated social, legal, and ethical complexities; and the lack of sufficient research monies all have contributed to this problem.

Although infrequently an antibiotic of first choice for neonates, chloramphenicol (CL) may be indicated in selected instances of infection caused by aminoglycoside-resistant enterobacteriaciae, anaerobes, and ampicillin-resistant Haemophilus influenzae. Use of CL in neonates has been limited since the recognition that vascular collapse may occur as a consequence of dosage regimens tolerated by adults. With an assay that detects only active CL, we studied drug disposition in 13 low birth weight infants, eight between 1 and 8 days of age (group I), and five between 11 days and 8 weeks of age (group II). Peak serum CL concentrations ranged from 11.2 to 36.2 microgram/ml in group I and from 10.0 to 36.2 microgram/ml in group II, at doses ranging from 15 to 50 mg/kg/day, and 25 to 50 mg/kg/day, in groups I and II, respectively. Serum CL half-lives (T1/2) ranged from 10 to 36 hours in four of the eight group I patients; three of the remaining patients had T1/2 greater than 48 hours and the fourth patient accumulated CL in the interval between doses. T1/2 in group II ranged from 5.5 to 15.7 hours. Observed differences in T1/2 between groups I and II were statistically significant (P = .05) and could not be accounted for by factors other than postnatal age. These preliminary data suggest that although there appears to be an inverse relationship between CL T1/2 and postnatal age, there is sufficient variability in serum levels that monitoring must be performed in low birth weight infants treated with this drug.

The Committee on Drugs has reviewed the pharmacology of marihuana with special emphasis on effects in man because of the enormous impact of this drug on society. Much of modern day society's reaction to and attitudes about this psychoactive agent does not reflect its pharmacology, and it is only recently that pertinent biologic facts about marihuana have become known. The Committee reports these facts here, in part, to inform the Academy membership of these facts and, in part, to provide a perspective with which to consider the various societal controls (i.e., laws) on the use of marihuana. COMPOSITION Marihuana is a mixture of leaves and flowering tops of the plant Cannabis sativa L. It contains approximately 1% Δ-9-tetrahydrocannabinol (THC), the principal psychoactive substance in marihuana. Street preparations tend to vary in Δ-9-THC content; the range is 0% to 5%. An average marihuana cigarette contains 500 mg of marihuana and, therefore, about 5 mg of Δ-9-THC. Hashish, usually used in Eastern (Asiatic) countries and in North Africa, is the resinous substance of the flowers and leaves of Cannabis sativa L in which Δ-9-THC is found. Hashish contains 5% to 15% Δ-9-THC and is usually smoked as a mixture of the resin and tobacco. Generally, marihuana cigarettes do not contain tobacco, although some street preparations do. USERS In considering adverse effects of marihuana, it is important to appreciate some pertinent epidemiologic facts. It is estimated that 24,000,000 Americans have tried marihuana at least once and that there are 8,300,000 current users in this country.1 Approximately 70% of adults and youth (12 through 17 years) who were found by the National Commission on Marihuana and Drug Abuse1 to use marthuana used it so infrequently as to be considered experimental users.

Anaphylaxis* is an acute reaction, which may range from mild self-limited symptoms to a grave medical emergency. It is caused by a variety of agents, usually occurs unexpectedly, frequently is iatrogenic, and can be fatal if not treated promptly and appropriately. Every physician's and dentist's office, pediatric outpatient clinic, hospital emergency room, allergy clinic or allergy testing laboratory, and radiology department should be equipped to treat this potential disaster.1 The Committee on Drugs of the American Academy of Pediatrics has reviewed the equipment and procedures necessary to treat this emergency, and offers this guide to physicians. CLINICAL PICTURE Anaphylaxis is usually characterized by the following sequence of signs and symptoms: generalized flush, urticaria, paroxysmal coughing, severe anxiety, dyspnea, wheezing, orthopnea, vomiting, cyanosis, and shock. The sooner symptoms develop after the initiating stimulus the more intense the reaction. Symptoms beginning within 15 minutes after administration of the inciting agent require the most expedient management. The primary cause of death in the child is laryngeal edema. In the adult, cardiac arrhythmais may be superimposed on acute upper airway edema.2 MAJOR CAUSES OF ANAPHYLAXIS Table I lists the most common agents associated with anaphylaxis in children. The severity and acuteness of onset will depend upon both the type of agent and the route of administration. Generally, agents administered parenterally are more apt to result in severe life-threatening or fatal anaphylactic reactions than those ingested orally or administered topically to mucus membranes. Medications administered orally, such as aspirin or penicillin, however, have been associated with fatal reactions so that the oral route cannot be utilized with impunity.

The abuse of amphetamines has become a problem of international significance. Japan was the first country to recognize this problem, and by 1954 there were an estimated 500,000 to 600,000 abusers in Japan. More than ten years ago Japan banned the use of amphetamines. The United Kingdom restricted distribution of amphetamines to hospital pharmacies in 1968. Sweden categorized amphetamine as a narcotic in 1944 because of abuse; and in 1965 phenmetrazine (Preludin) and in 1968 methylphenidate (Ritalin) were removed from the market. Patients now requiring amphetamines are registered with the government. Sweden has about 10,000 drug addicts (almost all between 15 and 30 years of age) using central stimulants intravenously; this is about the same percentage of their population as the estimated percentage of heroin addicts in New York City.1 In contrast, the number of heroin and opiate addicts in Sweden is estimated to be less than 500. In 1970, the Food and Drug Administration (FDA) responded to the problem of amphetamine abuse in the United States by limiting the package insert labeling for amphetamines to three indications: narcolepsy, hyperkinesis in children, and the short-term treatment of obesity. Currently, the latter indication is being reviewed and may no longer be valid. Among the related agents there is some specificity in labeling, e.g., methylphenidate is approved for use in adults with mild depression, narcolepsy at any age, and children with minimal brain dysfunction but not obesity; phenmetrazine for use only in obesity, etc. However, in the broad view there is a similarity in the pharmacologic properties, side effects, and abuse liability of dextro-amphetamine, methamphetamine, methylphenidate, and phenmetrazine.

The absorption, apparent volumes of distribution, serum concentrations, serum half-lives, and urinary excretion of ampicillin, methicillin, oxacillin, neomycin, and colistin were studied in premature infants by means of a micro-diffusion technique. Marked changes in serum half-lives and urinary excretion of the penicillins occurred during the first month of life. The serum half-lives of ampicillin and methicillin declined from 4.0 and 2.4 hours to 1.6 and 1.2 hours, respectively, as postnatal age increased from 1 week to 1 month. The serum half-life of oxacillin declined from 1.6 hours in 1 to 2-week-old infants to 1.2 hours in those 3 weeks of age. Concomitantly, urinary excretion rate of the penicillins increased approximately twofold as the age of infants increased from 1 week to 1 month, suggesting that immature renal function was partially responsible for the elevated serum half-lives of the penicillins in the younger premature infants. The serum half-life of neomycin was 6.5 hours in premature infants less than 2 weeks of age. It declined progressively to 3.3 hours in 3-week-old infants. The age-related changes in serum half-life were independent of birth weight. In contrast to the findings with the penicillins and neomycin, the serum half-life of colistin was not prolonged in premature infants, nor did it change with postnatal age. The mean serum half-life of colistin in premature infants was 2.4 hours. A method for using these data to calculate ampicillin, methicillin, oxacillin, neomycin, and colistin dosages appropriate for premature infants has been presented.

The developmental pattern of activities of several enzymes in mammalian (mouse) liver concerned with sulfate cleavage and transfer is presented. Maximum arylsulfatase activity occurred at 14 days of age, while sulfokinase activity was greatest at 28 days of age. The similarity of the results for both enzymatic functions suggests a common regulatory factor.

Advanced salicylate intoxication in young children may produce severe acidosis due not only to the production and accumulation of organic acids in tissues, but also to the diminished content of buffer cation which is secondary to the loss of buffer cation during the excretion of organic acids. The excretion of an intensely acid urine all but prevents the excretion of free salicylate and thereby perpetuates the toxic effects of this ion. Despite severe deficit of buffer cation, the kidney responds to administration of a carbonic anhydrase inhibitor with excretion of alkaline urine. The magnitude of the loss of buffer cation is unpredictable both before and after enzyme inhibition. However, the systemic acidosis may be controlled by infusion of solutions of sodium bicarbonate, but frequent determinations of pH and content of carbon dioxide in the serum are mandatory. While the alterations in acid-base disturbance may be controlled during administration of acetazolamide, the occurrence of neurologic complications late in the course must be accepted as a serious additional hazard which may preclude the successful therapeutic value of this agent.

Neonatal deaths from tracheal obstruction caused by congenital goiters have been reported from such widely scattered locales as Buffalo, New York, New York City, Philadelphia, Washington, D.C., Seattle, Tokyo, Japan, and Glasgow, Scotland. The mothers of these infants had asthma and were receiving conventional doses of iodides, either as potassium iodide or as mixtures of bronchodilators and iodides. Because of these deaths, the Committee on Drugs of the American Academy of Pediatrics has reviewed the use of iodides in the therapy of asthma and other chronic pulmonary diseases. Five current textbooks advocate the use of iodides in chronic asthma.1-5 "Iodide compounds have a stimulating effect on bronchial secretions and represent expectorants of major importance in treating asthma and particularly status asthmaticus."2 The AMA Drug Evaluations6 recommends the use of iodides only for short-term medication. Current Pediatric Therapy7 emphasizes careful patient selection because only an occasional patient may benefit. Dosage recommendations usually are 300 mg of potassium iodide every two hours in adults1 and 60 mg per year of age four times daily in children.4 These dosage recommendations are many times greater than the 65 mg of organic iodine (T4 and T3) which the average human thyroid gland delivers to the circulation per day, or the estimated daily adult iodide requirement of 200 mg of iodide.8 As a matter of fact, these recommended dosages for iodides represent 10 to 30 times the total body content of iodide! Many preparations–some of which are available on an over-the-counter (nonprescription) basis–contain iodides, including antiasthmatic preparations, expectorants, and preparations whose trade names may not suggest the presence of iodides.

Consent must be obtained prior to the institution of medical or surgical treatment. Pediatricians should keep informed concerning court decisions and statutes relative to consent and minors.

During the last several years there has been continued pressure from consumers, legislators, and health administrators to mandate generic prescribing. It has been proposed that requiring physicians to prescribe by generic rather than brand name and allowing pharmacists to substitute generically equivalent drug products would save consumers millions of dollars. These assumptions and the following events have stimulated the American Academy of Pediatrics to bring this issue to the attention of its membership. (1) The report of the Office of Technology Assessment, Drug Bioequivalence Study Panel, entitled "Drug Bioequivalence," concluded that current standards and regulatory practices do not ensure bioequivalence for drug products, although most of the analytical methodology and experimental procedures for the conduct of bioavailability studies in man are available.1 Additional work may be required to develop the means of applying them to certain drugs and to special situations of drug use. (2) The Drug Research Board of the National Academy of Sciences (October 25, 1974) recommended that the physician "should be required to delegate to the pharmacist, or explicitly to retain to himself, selection of the particular drug product to be dispensed."2 (3) The Maximum Allowable Cost Proposal published in the Federal Register (November 15, 1974)3 would establish a system to fix a "maximum allowable cost" for reimbursement for drugs dispensed under health financing and service programs of the Department of Health, Education, and Welfare which have multiple sources and are deemed bioequivalent. Other provisions of this proposal call for a fixed dispensing fee and supplying comparative price information to physicians and pharmacists.

The common problem of short stature in children who are growing at a normal rate is best managed by clarification of, and attention to, the psychological issues. This may require referral for expert psychological counseling. In a few instances, the physician, parents, and patient may agree that carefully supervised use of one of the synthetic will be made on a short-term basis in an attempt to accelerate growth rate.

The testillg of drugs for use ill cilildren is difficult to accomplish, and it is even difficult to write about. Anything that smacks of "experimentation" on a child or even the use of a placebo given to a sick child is an emotionally charged subject. To carry out procedures that cannot be considered as essential to therapy, especially when they are painful or tiresome, seems abhorrent. However, it is recognized that the effects of many drugs on children may vary considerably from the effects on adults even when careful calculation is made to arrive at a dosage proportional to the body weight or estimated body surface area. Pharmacologically, children cannot be regarded as little adults. Intensified, or toxic effects of drugs administered to children, especially infants, may reflect immaturity in enzymatic mechanisms for drug metabolism, as well as other detoxification and excretory functions. In view of these circumstances, there is need for special caution in prescribing medication in the treatment of childhood disorders, particularly when the medication is used for an extended period of time or when a newly marketed drug is employed. Even greater caution is needed with the use of a new drug under investigation, in advance of approval for marketing. Known serious adverse effects of drugs in children include the effects of sex hormones on growth, steroids on genital development, and antibiotics on tooth enamel. According to the regulations of the Food and Drug Administration, a drug which has not been subjected to investigation in children may not be labeled for use in pediatric therapy.

Since their introduction into clinical use, corticosteroids have been employed as therapeutic agents in virtually every known disease state, ranging from minor dermatologic disorders to major and serious diseases. These agents have undoubtedly altered the clinical picture and prognosis of certain diseases. However, the use of corticosteroids is always potentially associated with a variety of untoward effects, some of which may be life threatening, i.e., decreased resistance to infection, growth retardation, neurological reactions, hypertension, peptic ulcerations, and many others.1 The time honored principle—first do no harm—should always be the guideline of therapy, especially when a definite indication for a particular therapeutic agent has not been established. In recent years corticosteroids have been employed in the treatment of bronchiolitis on the hypothesis that their anti-inflammatory action would decrease swelling, inflammation, and the consequent respiratory obstruction. The opinions of different investigators on the efficacy of corticosteroids in this disorder have varied greatly; some have regarded their use as ineffective and others as lifesaving. It is the purpose of this report to review the findings from various studies and to outline the current status the use of corticosteroids in this common disorder of infants and children. Bronchiolitis is a common, acute respiratory syndrome characterized by infection of the bronchioles and respiratory distress of varying degrees due to obstructive emphysema. It is common in the first year of life and is rare in the child over 2 years of age. It frequently occurs in outbreaks. The great majority of cases are due to viruses, especially the respiratory syncitial, influenza B, and parainfluenza viruses, but it may be due to bacteria and other respiratory pathogens.

The frequent use of marijuana by American youth has compelled the Committee on Drugs to explore the present methods of and recommendations for controlling marijuana. On October 15, 1970, the Executive Board of the American Academy of Pediatrics endorsed in principle a statement on marijuana which was prepared by the Massachusetts Chapter of the Academy and published in the Academy's Newsletter.1 This statement called for considering possession of marijuana as a misdemeanor rather than a felony, but it was against legalizing use of marijuana at the present time. On October 27, 1970, President Nixon signed into law the Comprehensive Drug Abuse, Prevention and Control Act of 1970 (P.L. 91-513). This law became effective May 1, 1971; it is the Federal Government's attempt to control drug abuse by scientific and medical measures (under control of the Department of Health, Education, and Welfare) and by law enforcement activities (Department of Justice). The new Federal law has stopped short of legalizing marijuana, but it does allow a judge the discrelion to withhold criminal charges for the first offense of possession. The Massachusetts Chapter notes2 that marijuana is not a narcotic and does not produce addiction. Short-term physical effects are innocuous. However, impaired performance on simple intellectual and psychomotor tests is seen after individuals have smoked marijuana for the first time; but, such effects are not seen in regular users. There is no evidence to substantiate the common misconceptions that use of marijuana leads to crime or addiction to opiates. But, so little scientific information is available on the long-term use of marijuana that it should be considered a potentially harmful drug.

When broad-spectrum antibiotics were first introduced two decades ago for the treatment of acne, justification for such therapy seemed reasonably straightforward, e.g., the suppression of the suppurative inflammatory lesions commonly encountered in acne. As time went on, however, certain observations raised questions concerning the rationale for this form of treatment. First, it became apparent with cumulative clinical experience that the disease could ordinarily be controlled by doses of antibiotics lower than those required to treat bacterial infections. Second, bacteriologic studies disclosed that the only bacteria regularly recoverable from acne lesions were the anaerobic diphtheroid Corynebacterium acnes and aerobic coagulase-negative cocci, predominantly staphylococcus type II; both of these bacteria are known to be normal resident skin organisms.1 Thus, as no reports of controlled studies were then available for assessing the true efficacy of antibiotics used in the treatment of acne, the uneasy suspicion arose that such therapy might be inducing a primarily placebo response. In 1965, Freinkel and her collaborators2 demonstrated that the oral administration of tetracycline, even in doses as small as 250 mg daily, resulted in a significant reduction of the free fatty acid concentration of the lipid (sebum) secreted to the skin surface by the sebaceous glands. This effect could be observed in normal subjects as well as in patients with acne and was entirely reversible on discontinuance of drug. The inflammatory lesions of acne are known to result from disorganization of the follicular epithelium, with consequent liberation of the intrafollicular contents, containing sebum, into the dermis.3

One of the most important concepts in pediatric pharmacology is that exposure to drugs or chemicals may have latent, unforeseen effects on the child later in life. Some of the most dramatic occurrences, other than teratogenesis, are those in which hormonal exposure during the fetal or newborn period alters adult sexual development. However, none of these episodes is more impressive and ominous than that reported by Herbst et al.1 Herbst, an obstetrician at the Massachusetts General Hospital, was intrigued by the presentation of seven patients with adenocarcinoma of the vagina, an extremely rare tumor not previously seen at the hospital. The patients ranged in age from 14 to 22 years and sought medical advice because of vaginal bleeding. Several had benign adenosis, suggesting that the malignant change seen in all was based on a fundamental alteration in the biology of the vaginal epithelium. Six of the patients were treated with radical surgery, and one was treated with wide, local excision. One of the patients died after surgery. In what could serve as a model of a scientifically conducted, epidemiologic study, each of the seven patients, plus an additional patient from another hospital, was matched with four controls born in the same hospital within four days. Thus, the "control" group was chosen in a manner to eliminate many biases of artificially contrived control populations. A wide variety of possible influences in both mothers and offspring were considered, e.g., maternal age, smoking habits, exposure to X-rays, breast-feeding, birth weight, age at menarche, medications during pregnancy, and so forth.

Antihistamines were introduced in France by Halpern in 1942 and in the United States at the end of World War II; they had been investigated extensively during the war for therapy of motion sickness. By the late 1940s, a mass of information on the structure activity relationship had accumulated and most major drug manufacturens had introduced antihistamines into the market for oral, parenteral, and topical administration. Topical use was efficacious in acute dermatitis because the local anesthetic activity of the drugs diminished pruritus. The first reports of sensitization to the topical antihistamines, which began to appear in 1947, incriminated tnipelennamine (Pyribenzamine), diphenhydramine (Benadryl), antazoline (Antistine), and pheniramine (Trimeton).1-4 In the ensuing 25 years, though thousands of instances of antihistamine contact dermatitis have occurred, many topical antihistamines remain on the market. The Committee is concerned about the use of topical antihistamines which are sold over the counter for use in such conditions as chickenpox and poison ivy. Table I lists most of the preparations currently available for topical use. CLASSES OF ANTIHISTAMINES The antihistamines are classified according to their chemical structure into five primary groups as shown in Table II. Each drug carries its own index of sensitization and other adverse effects when employed topically. The ethylenediamine derivatives include the following: antazoline phosphate (Antistine), promethazine hydrochloride (Phenergan*), and tripelennamine (Pyribenzamine). They are particularly active in inducing contact dermatitis and were responsible for the cases first reported.5,6 Ethylenediamine, because of its dibasic structure, is widely used in various organic syntheses for the preparation of dyes, inhibitors, rubber accelerators, fungicides, synthetic waxes, resins, insecticides, and asphalt-wetting agents.

Studies indicate that certain drugs have a promising effect in the treatment of children with learning impediments. The valid assessment of the true pharmacologic effect necessitates an accumulation of comparable, long-term, properly controlled studies and a careful evaluation of these data compared alone and with adjunctive therapy.

The absorption and excretion of riboflavin, a vitamin which is absorbed in adults by a saturable transport process in the proximal small intestine, was investigated in healthy, 5-day-old infants. After oral administration of a saturation dose of the vitamin (150 mg/sq m), the urinary recoveries of riboflavin in the neonates were similar (about 7% of the dose) to those obtained previously in 3-to 6-month-old infants. However, the maximum excretion rate (per unit of body surface area) of riboflavin was much lower and the duration of maximum excretion rates was much longer in the neonates than in older infants. Data obtained after parenteral administration of riboflavin show that the low maximum excretion rate was not due to limited renal capacity and that the longer duration of excretion was due to prolonged absorption of the vitamin from the intestinal tract.