The safety of fetal exposure to proton-pump inhibitors during pregnancy.

BACKGROUND: Proton-pump inhibitors (PPIs) are often needed in pregnancy due to the high rates of acid reflux. Previous studies did not include medical pregnancy terminations data, which may cause a bias toward the null hypothesis. We assessed the fetal safety of PPIs following exposure during gestation including data from medical pregnancy terminations. METHODS: A unified computerized database was created by linking a computerized database of medications dispensed from 1998 to 2009 to all women registered in "Clalit" HMO, southern district of Israel, with computerized databases containing maternal and infant hospitalization records from the district hospital. Rates of congenital malformations in PPIs exposed and unexposed pregnancies, as well as other adverse fetal effects were compared. Medical pregnancy termination data were included in the analysis. RESULTS: A total of 114,960 (75%) infants were born during the study period to women registered at "Clalit," 110,783 of them were singleton pregnancies; 1,239 women had medical pregnancy terminations, of which 468 were performed due to fetal malformations. A total of 1,186 infants and abortuses had been exposed to PPIs during the first trimester of pregnancy. Exposure to PPIs was not associated with an increased risk of congenital malformations (adjusted OR 1.06; 95% CI = 0.84-1.33). Similarly, exposure to PPIs during the third trimester of pregnancy was not associated with increased risk of perinatal mortality, premature delivery, low birth weight, or low Apgar scores. CONCLUSIONS: Intrauterine exposure to PPIs was not associated with increased risk for congenital malformations, perinatal mortality, or morbidity. These results are strengthened with the inclusion of data from medical pregnancy terminations.

Beta lactam allergy and resensitization in children with suspected beta lactam allergy.

BACKGROUND: In patients who were clinically diagnosed as having beta lactam allergy and had negative skin tests, the rates of reported resensitization to beta lactams after subsequent exposures, vary significantly. Some allergists advocate skin testing before every exposure to beta lactams. OBJECTIVE: We sought to determine the true rate of beta lactam allergy and of resensitization in children with a positive history for suspected beta lactam allergy. METHODS: The study was conducted from July 1998 to May 2004, with follow-up during 2007. Beta lactam allergy tests with the major determinant and freshly prepared minor determinant mixtures were offered to history positive children. Negative skin tests were followed by oral challenge. The tests were performed again 1-5 months later in order to address the possibility of resensitization. RESULTS: Tests were performed on 166 children: 150 for penicillins alone, 14 for penicillin in combination with cephalosporins, and an additional 2 patients solely for cephalosporins. Only 10 children (6%) were positive in the initial evaluation, four by skin test and six by oral challenge. A second set of tests was performed in 98 children with a negative initial evaluation; only two children (2%) were resensitized. On a follow-up survey of 71 of the 96 patients, 59 (83%) had received beta lactams; only one had developed a minor rash after subsequent exposure to amoxicillin. CONCLUSIONS: Most children with suspected beta lactam allergy were not allergic to beta lactams. Resensitization to beta lactam antibiotics in children in this study was infrequent. In children with a clinical diagnosis of beta lactam allergy and negative skin tests, repeated skin testing before every exposure is usually unnecessary.

Tissue and erythrocyte distribution of digoxin in infants.

The distribution of digoxin in the myocardium, skeletal muscle, erythrocytes, and plasma (or serum) was studied in 19 infants. There was a linear relationship between myocardium and serum concentrations and no saturation was observed over the serum concentration range of 0.5-8.6 ng/ml. Myocardium uptake of digoxin was nearly twice as great in infants as in adults at any given serum concentration. Erythrocyte: plasma concentration ratios of digoxin were one-third smaller during digitalization than during maintenance digoxin therapy. The latter ratios were also three times greater in infants than found previously in adults. Their findings are consistent with a greater apparent volume of distribution of digoxin in infants and may partly explain the unusually large therapeutic doses needed in infants.

Massive clonidine ingestion with hypertension in a 9-month-old infant.

The antihypertensive drug clonidine has a double and antagonistic effect on arterial blood pressure. As a result of activation of peripheral alpha-adrenergic receptors, it causes a transient increase in blood pressure; by a central action it decreases sympathetic tone which results in sustained bradycardia and hypotension. Both central and peripheral effects are experimentally blocked by tolazoline, an alpha-adrenergic blocking agent. The toxic symptoms seen in clonidine poisoning are usually produced by the central effect. A case of severe clonidine poisoning in a 9-month-old infant is reported. The clinical picture included coma, miosis, apneic spells, bradycardia, and hypertension. Rapid and complete recovery was obtained with supportive treatment that included assisted ventilation. No adrenergic blockers or antihypertensive drugs were given. Use of tolazoline in cases of clonidine overdose in children remains controversial. Supportive measures alone may be adequate for even the most severe cases.

Totally vegetarian diets and infant nutrition.

Observations on the deleterious effects of a totally vegetarian diet in infancy are reported and the difficulties encountered in the prevention of nutritional deficiencies in a vegan religious community are discussed. Twenty-five infants of this community who were seen at the hospital showed evidence of protein-calorie malnutrition, iron- and vitamin B12-deficient anemia, rickets, zinc deficiency, and multiple recurrent infections. Evidence of growth retardation was also found in 47 infants seen at the local mother-child health (well-baby) clinic. Samples of breast milk showed low levels of carbohydrate (1.6 to 3.5 gm/100 ml), protein (0.8 to 1.4 gm/100 ml), and fat (2.4 to 4.1 gm/100 ml). The main constituent of the infants' diet after the age of 3 months (a "soya milk" prepared at the community's central kitchen) was extremely dilute with a very low calorific value (13.7 kcal/100 ml). Persistent attempts to find dietary modifications that would satisfy both the vegan philosophy and also the recommended dietary allowances failed. This problem represents a scientific and medicosocial challenge to pediatricians and nutritionists.

Tracheobronchial foreign bodies: the impact of a postgraduate educational program on diagnosis, morbidity, and treatment.

Aspirated foreign bodies (FBs) may remain undetected and cause serious complications. As part of a postgraduate educational program, results of a local survey were presented to the local medical staff in order to increase its awareness of this diagnostic possibility. The present study was carried out in order to evaluate the management of children with tracheobronchial FBs during two 2-year periods, before and after teaching sessions held in December 1976. In comparison with the previous two years during the 1977-1978 period, the percentage of cases in which a positive history of aspiration was obtained increased from 47.6% to 84.0%; the mean number of hospitalizations due to tracheobronchial FBs decreased from 1.9 to 1.04 per infant, and the mean number of hospital days required for final diagnosis decreased from 17.6 to 5.3. The postgraduate educational program had a positive effect on physician performance and patient care.

Monitoring theophylline therapy using citric acid-stimulated saliva in infants and children with asthma.

Saliva stimulation is required for measurement of drugs in saliva. Chewing on a piece of paraffin, which is the method usually used for saliva stimulation, requires cooperation of the patient and, thus, is inapplicable in infants and young children. To assess the value of determining theophylline concentrations from noninvasively obtained saliva in this age group, we studied the theophylline plasma to saliva concentration ratio in citric acid-stimulated saliva. Theophylline concentration was measured in 137 simultaneously obtained paired specimens of plasma and saliva from 68 patients 2 1/2 months to 14 years of age treated with theophylline for asthma (dosage 20.8 +/- 5.2 mg/kg/d, mean +/- SD). Saliva secretion was stimulated by placing citric acid crystals on the tongue. A strong and highly significant correlation was observed between both determinations (r = .96; P less than .01). The plasma to saliva ratio was 1.78 +/- 0.22 (mean +/- SD), with theophylline concentrations between 3.1 and 32.1 micrograms/mL of plasma. The ratio of estimated to actual plasma theophylline concentrations was 1.02 +/- 0.12 (mean +/- SD). Interindividual coefficient of variation of plasma to saliva theophylline concentrations ratios was 12.4%; mean intraindividual coefficient of variation was 5.3%. The use of citric acid for saliva stimulation is easily applicable to infants and young children. Compared with blood drawing, stimulation of saliva secretion by citric acid is painless and noninvasive, is more readily accepted to patients, is at least as clinically relevant for theophylline determination, and allows frequent measurements of drug levels for individualization of the dosage with samples taken at home.(ABSTRACT TRUNCATED AT 250 WORDS)

Dexamethasone and salbutamol in the treatment of acute wheezing in infants.

Thirty-two infants, aged 1 to 12 months, hospitalized with acute wheezing, were studied. They were randomly divided into four treatment groups of eight patients each. The treatments were intramuscular dexamethasone or placebo (double-blind), and salbutamol (oral and inhaled), or none (open), in all four possible combinations. The study was carried out as a randomized block design with eight blocks of four infants each, matched by age and clinical score. Average daily improvements, as reflected by changes in the clinical score and length of hospital stay, was essentially the same for infants treated with placebo, salbutamol alone, and dexamethasone alone. However, combined salbutamol-dexamethasone treatment resulted in more than twice the rate of improvement of the other treatments. The difference was statistically highly significant (P less than .01). Furthermore, the response of this combined treatment was observed within 24 hours; none of the ten infants in whom there was no significant improvement within 48 hours and neither of the two patients who developed respiratory failure received the combined salbutamol-dexamethasone treatment. A potentiating effect of corticosteroids on the beta-adrenergic responsiveness is a possible explanation for the advantage of this combined treatment in the management of acute wheezing in infancy.

Changes in theophylline metabolism during postnatal development in rat liver slices.

The metabolism of theophylline was studied in liver slices of young and adult rats. Theophylline and six metabolite fractions were recognized in adult liver by thin-layer radiochromatography and high performance liquid chromatography: 1-methyluric acid; 1-methylxanthine; 1,3-dimethyluric acid and/or 3-methylxanthine; caffeine; a uracil derivative and two unknown polar compounds. Preincubation with caffeine or theobromine inhibited theophylline metabolism. Allopurinol decreased the formation of three metabolite fractions but markedly increased the production of 1-methylxanthine. SKF 525-A inhibited the overall metabolism of theophylline. The specific activity of the enzyme system was 3.2 +/- 0.4 nmoles X (g liver)-1 X hr-1 in the 4- to 5-day-old rat and increased to a peak of 25.7 +/- 1.7 in the 28-day-old; values for Km and Vmax in the 7- and 28-day-olds were 132.1 and 67.5 microM, and 23.9 and 52.1 nmoles X (g liver)-1 X hr-1 respectively. Theophylline and the same six metabolites were identified in young and adult rats, but the development pattern was not uniform. Peak age-related activity and involvement of mixed-function oxidase system are features which are common to theophylline and caffeine metabolism. Xanthine oxidase played a role in theophylline metabolism. Formation of caffeine from theophylline was not dependent on a lack of activity of other pathways.

Thyroid-stimulating hormone levels in children from Chernobyl.

This study assesses parameters of thyroid function in persons who resided in Ukraine, Belarus, and southern Russia and exposed at 0 to 16 years of age to radioiodine contamination from the Chernobyl accident. Six to eight years after the accident a group of 300 young people who had immigrated to Israel were interviewed, underwent physical and ultrasound thyroid examination, and had their serum tested for thyroid-stimulating hormones (TSH), thyroid hormones, thyroglobulin, and antithyroid antibodies. Comparative groups came from areas with high (>1 Ci/km2) or low (< 1 Ci/km2) 137Cs ground contamination. Girls from high contamination areas, when compared to girls from areas with low ground contamination, showed significant upward shifts in levels of serum TSH (p = 0.023) although remaining within normal limits. Boys showed no significant differences. There was no evidence for differences in thyroid size or nodularity between the two groups of girls. A working hypothesis is proposed by which the shift in TSH levels in girls from high radiocontamination areas was associated with subclinical radiation damage from environmental radioiodine at the time of the accident.

Health effects in a casual sample of immigrants to Israel from areas contaminated by the Chernobyl explosion.

We analyzed questionnaire and physician examination data for 1560 new immigrants from the former USSR divided into three groups by potential exposure to Chernobyl radiation. Two groups were chosen according to soil contamination by cesium-137 at former residences, as confirmed by our findings in a 137Cs body burden study. The third group consisted of "liquidators," persons who worked at the Chernobyl site after the disaster. Liquidators had greater self-reported incidences of symptoms commonly accepted as acute effects of radiation exposure, increases in prevalence of hypertension, and more health complaints. Excesses of bronchial asthma and health complaints were reported in children from the more exposed communities. Asthma prevalence in children potentially exposed in utero appears to be increased eightfold. Older adults from more exposed areas had more hypertension as assessed by history and measurements. These findings suggest the possible association of radiation exposure with several nonmalignant effects.

The use of prophylactic furazolidone to control a nosocomial epidemic of multiply resistant Salmonella typhimurium in pediatric wards.

The nosocomial spread of enteric pathogens is often difficult to control in overcrowded pediatric wards. During 1983 and 1984, despite cohorting of patients and enforced hand washing, more than 200 cases of nosocomial multiply resistant Salmonella typhimurium phage type R-9 were observed on two adjacent pediatric wards. Most cases occurred during the summer months. After 19 new cases were detected early in the summer of 1985, oral administration of furazolidone throughout their entire hospital stay (2.5 mg/kg twice daily) was recommended for all subsequently hospitalized infants. Among the 114 (65%) infants who were appropriately treated, only one additional case (1%) was detected. In contrast 11 (19%) cases occurred among the 59 infants who were inappropriately treated: 5 of 35 (14%) of those who were not treated and 6 of 24 (25%) in whom treatment with furazolidone was delayed greater than 24 hours (P less than 0.001 between the appropriately and inappropriately treated groups). In pediatric wards where infection control measures cannot be optimally applied, prophylactic furazolidone administration may be helpful in preventing the spread of enteric pathogens.

Subclinical vitamin A deficiency in Israeli-Bedouin toddlers.

OBJECTIVE: This study was designed to estimate the prevalence of and evaluate risk factors for subclinical vitamin A deficiency in Arab-Bedouin children at age 18 months, followed from birth. DESIGN: Community-based, prospective, cohort study conducted in Rahat, a large Arab-Bedouin township, located near the city of Beer Sheva in the Negev region of southern Israel. SUBJECTS: Healthy Bedouin infants (n=117) from the township, born at Soroka University Medical Center (SUMC) in Beer Sheva, were randomly recruited at birth. Enrollment was restricted to well infants born weighing >2500 g at birth. RESULTS: More than 15% of the children had serum retinol concentrations below 0.7 micromol/l. Male sex (odds ratio (OR) 4.17 [1.14-15.32], P=0.031), stunting at age 12 months (OR 10.09 [2.00-50.97], P=0.05) and warm season at age 18 months (OR 6.20 [1.36-28.28], P=0.018) were associated with vitamin A deficiency. Maternal education decreased the risk of vitamin A deficiency (OR 0.81 [0.68-0.95], P=0.011). CONCLUSIONS: Study results indicate a significant vitamin A deficiency problem among Bedouin children. Deficiency may be prevented by increasing dietary intake of vitamin A, especially during the warm season. Other interventions include preventing and controlling diarrheal diseases in order to avert nutritional stunting, and providing nutritional education to women of childbearing age. SPONSORSHIP: This study received financial support from the National Institute of Allergy and Infectious Diseases (AI-26497), the US-Israel Bi-national Science Foundation (BSF 90-00257), and the National Academy of Sciences/Institute of Medicine (AID/ANE 0158-G-SS-9035-00).

Differences in cord serum retinol concentrations by ethnic origin in the Negev (southern Israel).

Subclinical vitamin A deficiency is related to increased morbidity and mortality in infants and children. Previous studies indicate that the traditional diet of Moslem Bedouins, an important ethnic group in Southern Israel, is low in vitamin A content. Cord serum retinol (vitamin A) concentration was measured by HPLC in samples from 251 apparently healthy (birth weight > 2500 g, gestational age > 37 weeks) neonates with no abnormal perinatal events, 138 Jews and 113 Bedouins. Retinol < 15 micrograms/dl was measured in a total of 14% of infants: in 7% of Jewish and 26% of Bedouin newborns (P < 0.001). However, mean cord serum retinol was only slightly lower in Bedouins than in Jews (30 +/- 26 vs. 37 +/- 27 micrograms/dl mean +/- S.D., n.s.). Cord serum retinol was not related to socioeconomic indices. Cord serum retinol < 15 micrograms/dl was measured in 25% and in 12% of infants with birth weight less than and equal or greater than 3000 g, respectively (P = 0.01), and in 28% and 13% of infants with gestational age 37-38 weeks and 39-41 weeks, respectively (P = 0.03). Low cord serum retinol was found to be prevalent in Southern Israel, particularly in Bedouin infants. In the population of healthy neonates studied, very low cord serum retinol concentrations were found more frequently in infants born with a lower weight and/or after a shorter gestation.

Unlicensed and off-label medication use in a general pediatrics ambulatory hospital unit in Israel.

BACKGROUND: Many medications used for children have not undergone evaluation to assure acceptable standards for optimal dose, safety and efficacy. As a result, the majority of children admitted to hospital wards receive medications outside the terms of their license (off-label) or medications that are not specifically licensed for use in children (unlicensed). The extent of unlicensed and off-label medication use in ambulatory children is unknown. OBJECTIVE: To determine the extent of unlicensed and off-label medication use in a general pediatrics ambulatory hospital unit in Israel. PATIENTS AND METHODS: We conducted a retrospective analysis of the medical records of 132 outpatient children treated in the General Pediatrics Ambulatory Unit of the Soroka Medical Center, Beer Sheva, in November-December 1998. RESULTS: The children's ages ranged from 1 month to 18 years (mean +/- SD 50 +/- 58 months). Of the 222 prescriptions given to these children, one-third were unlicensed (8%) or unlabeled (26%). Different dose and age were the most common categories of off-label medication use. All 18 cases of unlicensed use were due to modification of licensed drugs (tablets were crushed to prepare suspensions). Altogether, 42% of children received medicines that were off-label and/or unlicensed. CONCLUSIONS: More off-label than unlicensed medications were used. Further investigations are required to establish the extent of unproved drug use in both hospitalized and ambulatory pediatric patients in Israel. Recommendations recently issued by the Ministry of Health's National Council for Child Health and Pediatrics constitute a first step in the Israeli contribution to the international effort demanding testing of medications for children.

[Use of unlicensed and off-label drugs in hospitalized children].

Many drugs used in children are based on pharmacological data obtained in adults. Therefore, many drugs are either unlicensed for use in children or are prescribed outside the terms of the product license (off-label). This pilot study assessed use of unlicensed or off-label drugs in hospitalized children. Drug orders of patients admitted to a general pediatric ward were reviewed retrospectively in a random sample. Assessment was based on the data of the Physicians' Desk Reference and the Israel Drug Compendium. 80 different drugs and 278 drug orders were written for 92 patients (0.5 months-11 years old, mean 26.9 months) in 97 admissions. Of these 52.9% were either off-label or unlicensed. Patients received 1 or more unlicensed or off-label drugs in 64.9% of admissions. They were more often off-label than unlicensed. The main reasons for use of off-label drugs were unusual doses and inappropriate age. The main reason for unlicensed drugs was modification of a particular formulation of a licensed drug. This pilot study indicates that use of drugs in an off-label or unlicensed manner in children is probably quite frequent in Israel. Our data emphasize the need for licensing a large number of drugs for use in children, based on the same scientific principles as in adults. Further collaborative studies in different pediatric centers in Israel, involving different types of pediatric settings (ambulatory and in-hospital), is required to evaluate comprehensively the magnitude of this preliminary finding.

[Prevention and treatment of procedural pain in pediatric wards: collected guidelines].

Present knowledge and available pharmacological agents allow for adequate prevention and treatment of pain in children. We present guidelines we prepared for the prevention and treatment of procedural pain in children in our general pediatric ward. This followed extensive review of the literature, participation in scientific meetings, discussions with experts and consultation with interested clinicians. Successful implementation of the guidelines requires increased appreciation of the importance of pain prevention, participation of the nursing, as well as medical staff, and ability to evaluate pain in children of various ages.

[Cefaclor and trimethoprim-sulfamethoxazole for recurrent otitis media].

The efficacy of cefaclor and of trimethoprim-sulfamethoxazole (TMP-SMX) in the management of recurrent otitis media was evaluated in a randomized single-blind controlled trial. The median age of the patients was 12 months (range 5-37); there were 37 boys and 19 girls. All had received 1 or more courses of antibacterials for acute otitis media in the previous 2-3 weeks. 27 were treated with oral cefaclor suspension, 40 mg/kg/day in 3 divided doses, and 29 with 1 mg/kg/day of TMP-SMX (trimethoprim 8 mg, sulfamethoxazole 40 mg) in 2 divided doses, each group for 10 days. 70% of the cefaclor group and 90% of the TMP-SMX group were cured after the 10 days of therapy (0.1 greater than p greater than 0.05). Results were not better on the 21st day as compared with the 10th. Our data indicate a mild preference for TMP-SMX (although p was not less than 0.05), since it needs to be given only twice a day and costs less than cefaclor.

[Oral rehydration in acute gastroenteritis in infants and children--advantages of a standardized protocol].

Oral rehydration (OR) for acute gastroenteritis in infants and children has been shown to be as effective as IV therapy, with less discomfort and lower costs. In this retrospective study we compared 2 pediatric wards, in 1 of which only a standardized, simplified, bedside protocol, based on American Academy of Pediatrics guidelines, was used. There were no significant clinical characteristics in the 208 patients. In the ward which used the above protocol, OR utilization was significantly more frequent than in the other ward (48% versus 15%), thus saving equipment costs of nearly $1,000/3 months. There were no significant differences in outcome between the wards. We conclude that introducing a standardized management protocol may increase OR utilization in hospitalized children with acute diarrhea.