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.

Renal pathology and retinol status in multiple myeloma patients.

Renal dysfunction is a common and serious complication in multiple myeloma (MM) patients. Renal proximal tubule injury is characteristic in MM, and may result in disturbed renal handling of various vitamins. The abnormal excretion of vitamins in urine may result in their low serum levels. The goal of this study was to investigate the urinary excretion of retinol in MM and its relationship with serum retinol concentration. For this purpose, 24 MM patients and 10 healthy individuals were studied. Serum and urinary retinol and retinol-binding protein (RBP) were measured by the high-performance liquid chromatography method and enzyme-linked immunosorbent assay, respectively. The study showed that 58% of MM patients excreted retinol in urine, while only 29% had elevated serum creatinine (P<0.05). There was a strong and highly significant correlation between urinary retinol and RBP (r=0.973, P<0.006). Patients with normal and mildly elevated serum creatinine who excreted retinol in urine had a marked decrease in serum retinol (P<0.007). On the other hand, serum retinol was not decreased in patients with moderate or severe renal failure, despite its urinary loss. Our data indicate that (i) urinary retinol is a more frequent marker of renal dysfunction than elevated serum creatinine in MM patients, (ii) serum retinol is decreased in MM with normal or mildly elevated serum creatinine, but not in patients with moderate/severe renal failure, and (iii) urinary retinol may serve as a diagnostic marker of renal proximal tubule dysfunction in MM patients.

Off label and unlicensed drugs use in paediatric cardiology.

OBJECTIVES: The use of drugs in an off label or unlicensed manner to treat children is a widespread phenomenon in Europe and the United States. The incidence of unlicensed and off label prescribing in paediatric cardiology practice has not been studied to date. This study was designed to assess the extent and nature of off label and unlicensed drug use in paediatric cardiology inpatients. METHODS: In a prospective study, drug prescriptions in a paediatric cardiology ward were reviewed during a 2-year period. Data were collected and analyzed by special software created for this purpose. RESULTS: The children (n = 544) studied varied in age from 4 h to 18 years. One or more off label and unlicensed prescriptions were given to 414 (76%) patients. Of the 2,130 prescriptions given during the 2-year period, more than one-half were unlicensed (11%) or off label (47%). While children aged 2-11 years received most of the unlicensed drug prescriptions (17%), neonates, who did not receive unlicensed drugs, led (64%) in the use of off label drugs. CONCLUSIONS. This study showed that the problem of off label and unlicensed drug use also exists in paediatric cardiology. The findings imply that the phenomenon of off label and unlicensed use of drugs in children can be correlated with the deficiency of paediatric drug formulations on the global market and insufficient data from clinical studies which must be performed to confirm the efficacy and safety of drugs in the paediatric population. Therefore, efforts to improve paediatric labelling are important and need the full support of all involved.

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).

Off-label and unlicensed use of antidotes in paediatric patients.

OBJECTIVE: To determine the extent of unlicensed and off-label antidotes among medicines recommended by the International Programme on Chemical Safety (IPCS) for children. MATERIALS AND METHODS: We considered 77 antidotes from the "IPCS List of antidotes and other useful agents in the treatment of human poisoning" (1996 version). Primary reference sources used were the Physicians' Desk Reference (PDR) and package inserts. Antidotes were assessed for off-label (outside of the term of product license) and unlicensed use in children. RESULTS: Our data show that only 31 (40.3%) of 77 recommended antidotes correspond to the demands of licensing systems for use in children. The rest (46 or 59.7%) are either off-label (32 or 41.5%) or unlicensed (14 or 18.2%). Five antidotes are off-label for two reasons; thus the total number of off-label use (37) is greater than the number of such drugs (32). Inappropriate age is the main reason for use outside the stipulations of the product license (24 of 77 antidotes or 31.2%), whereas different indication and route occur in 11 (14.3%) and 2 (2.6%) antidotes, respectively. The 14 unlicensed antidotes have been used only in animal experiments or in a small number of patients in certain poison centres. CONCLUSIONS: Sixty percent of antidotes and other useful agents in the poison treatment of children do not correspond to the demands of licensing systems. Drugs used in the treatment of poisoned children, as well as adults, must be evaluated scientifically.

[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.

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.

Prenatal diagnosis of hypoparathyroidism retardation and dysmorphism (HRD) syndrome.

We used linkage analysis for prenatal diagnosis of the recently reported hypoparathyroidism, retardation, and dysmorphism (HRD) syndrome. Five cases from four families were evaluated. Three fetuses were carriers and were born healthy. Two fetuses were affected but the parents decided not to terminate the pregnancies. The diagnosis of HRD syndrome was confirmed in these newborns. This is the first report about prenatal diagnosis of HRD syndrome.

[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.

[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.

Homozygosity and linkage-disequilibrium mapping of the syndrome of congenital hypoparathyroidism, growth and mental retardation, and dysmorphism to a 1-cM interval on chromosome 1q42-43.

The syndrome of hypoparathyroidism associated with growth retardation, developmental delay, and dysmorphism (HRD) is a newly described, autosomal recessive, congenital disorder with severe, often fatal consequences. Since the syndrome is very rare, with all parents of affected individuals being consanguineous, it is presumed to be caused by homozygous inheritance of a single recessive mutation from a common ancestor. To localize the HRD gene, we performed a genomewide screen using DNA pooling and homozygosity mapping for apparently unlinked kindreds. Analysis of a panel of 359 highly polymorphic markers revealed linkage to D1S235. The maximum LOD score obtained was 4.11 at a recombination fraction of 0. Analysis of three additional markers-GGAA6F06, D1S2678, and D1S179-in a 2-cM interval around D1S235 resulted in LOD scores >3. Analysis of additional chromosome 1 markers revealed evidence of genetic linkage disequilibrium and place the HRD locus within an approximately 1-cM interval defined by D1S1540 and D1S2678 on chromosome 1q42-43.

Is saliva suitable for therapeutic monitoring of anticonvulsants in children: an evaluation in the routine clinical setting.

Studies performed in the research setting suggested that saliva instead of blood may be used for therapeutic drug monitoring (TDM) of anticonvulsants in children. This is an attractive alternative because its collection is painless, and simpler and cheaper than blood drawing. Citric acid stimulation of saliva secretion facilitates sampling in the youngest patients. The aim of the study was to evaluate the suitability of saliva in routine TDM of anticonvulsants in infants and children with epilepsy. Blood and saliva samples were obtained simultaneously during routine TDM in 170 patients on chronic anticonvulsant drug therapy attending a neurology clinic. Saliva, plasma total, and plasma free concentrations of anticonvulsants were measured by high-performance liquid chromatography and enzyme multiplied immunoassay technique. Strong and highly significant correlations between saliva and plasma concentrations were found over a wide range of concentrations for carbamazepine, phenytoin, clobazam, and desmethylclobazam, and for phenobarbital in children > or = 8 years of age (r = 0.90 to 0.97; p < 0.001). Correlations between saliva and plasma concentrations were poor for phenobarbital in children < 8 years of age and for valproate. Correlations between saliva and plasma-free anticonvulsant concentrations were equal or only slightly better than between saliva and plasma total concentrations. Citric acid-stimulated saliva constitutes a convenient alternative for TDM of carbamazepine and phenytoin therapy in pediatric patients and of phenobarbital in children > or = 8 years of age.

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.