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Aims In breastfeeding women, anti-epileptic therapy can lead to infant toxicities, even with newer anti-epileptic drugs such as levetiracetam. This study assessed levetiracetam breastmilk excretion and its correlation with the maternal oral dose and serum concentrations. Methods Women with epilepsy treated with levetiracetam were recruited to this study and completed a questionnaire. Levetiracetam concentrations were determined in serial breastmilk samples (pre-dose to 12 h post-dose period) and in a single pre-dose maternal serum sample. Results Twenty breastfeeding women and 21 infants (one woman with twins; 16 fully and five partially breastfed infants) participated in this study. The trough breastmilk/serum ratio of levetiracetam was 0.98 ± 0.20. The infant levetiracetam daily dose was 5.39 ± 1.96 and 2.70 ± 0.98 mg. kg-1. d-1 , and the relative infant dose (RID) was 13.8 ± 3.1% and 6.9 ± 1.6% in the fully and partially breastfed infants, respectively. Substantial correlations between the levetiracetam dose, maternal serum and breastmilk trough concentrations, and breastmilk AUC values were found. Three women reported somnolence in their fully breastfed infants, which resolved shortly after switching to partial breastfeeding. All the infants gained weight according to their age. Conclusions Infant levetiracetam exposure via the breastmilk was close to the safety thresholds (trough breastmilk/serum ratio slightly below 1, RID > 10% in fully breastfed infants), and infant somnolescence reports could be related to exposure of the infants to levetiracetam via breastmilk. Further studies are warranted to reveal the short- and long-term safety of levetiracetam in breastfeeding.

Pathophysiology of type 1 diabetes (T1D) involves immune responses that may be associated with early exposure to environmental factors among preterm newborns. The aim of this work was to evaluate for association between T1D and maternal, nutritional, and medical exposures during the neonatal period among premature newborns.This is a multicenter, matched case-control study. Preterm newborns, who developed T1D before 18 years, were matched by sex, gestational age (GA), birth date, and medical center of birth with newborns who did not develop TID. Data included maternal medical history, birth weight (BW), length of hospitalization, enteral and parenteral medications, fluid administration, and feeding modalities during hospitalization.Fifty-two patients with T1D, 26 males, median age at T1D diagnosis 8.17 years (5.92-9.77), median GA 34 weeks (33-m36), and 132 matched controls, were included. Multivariate-conditional-regression demonstrated a significant association between T1D and any maternal illness (23.1% vs. 9.1%, OR = 4.99 (1.69-14.72), p = 0.004), higher BW-SDS (0.07 ± 0.95 vs. -0.27 ± 0.97, OR = 2.03 (1.19-3.49), p = 0.01), longer duration of glucose infusion (3 (1-5) days vs. 2 (0-4), OR = 1.23 (1.03-1.46), p = 0.02), and antibiotic therapy beyond the first week of life (19.2% vs. 6.9%, OR = 5.22 (1.32-20.70), p = 0.019). Antibiotic treatment during the first week of life was negatively associated with T1D (51.9% vs. 67.2%, OR 0.31 (0.11-0.88), p = 0.027).A novel association was demonstrated between the development of T1D and early interventions and exposures among preterm newborns.Type 1 diabetes mellitus during childhood may be associated with early exposures during the neonatal period, in addition to known maternal and neonatal metabolic parameters. Early exposure to intravenous antibiotics, differing between the first week of life and later, and longer parenteral glucose administration to preterm newborns were associated with childhood type 1 diabetes. This is in addition to familiar maternal risk factors. Future prospective studies should examine the microbial changes and immune system characteristics of preterm and term neonates exposed to parenteral antibiotics and glucose treatment, in order to validate our exploratory findings.

Urea cycle disorders (UCDs), including OTC deficiency (OTCD), are life-threatening diseases with a broad clinical spectrum. Early diagnosis and initiation of treatment based on a newborn screening (NBS) test for OTCD with high specificity and sensitivity may contribute to reduction of the significant complications and high mortality. The efficacy of incorporating orotic acid determination into routine NBS was evaluated. Combined measurement of orotic acid and citrulline in archived dried blood spots from newborns with urea cycle disorders and normal controls was used to develop an algorithm for routine NBS for OTCD in Israel. Clinical information and genetic confirmation results were obtained from the follow-up care providers. About 1147986 newborns underwent routine NBS including orotic acid determination, 25 of whom were ultimately diagnosed with a UCD. Of 11 newborns with OTCD, orotate was elevated in seven but normal in two males with early-onset and two males with late-onset disease. Orotate was also elevated in archived dried blood spots of all seven retrospectively tested historical OTCD patients, only three of whom had originally been identified by NBS with low citrulline and elevated glutamine. Among the other UCDs emerge, three CPS1D cases and additional three retrospective CPS1D cases otherwise reported as a very rare condition. Combined levels of orotic acid and citrulline in routine NBS can enhance the detection of UCD, especially increasing the screening sensitivity for OTCD and differentiate it from CPS1D. Our data and the negligible extra cost for orotic acid determination might contribute to the discussion on screening for proximal UCDs in routine NBS.

Polychlorinated Biphenyls (PCBs) are widespread environmental contaminants. PCBs have endocrine disrupting properties which raises concerns regarding their effect on the developing fetus. This study aimed to examine the association between prenatal exposure to PCBs and anogenital distance (AGD) in newborns. Serum concentrations of PCB congeners -118, -138, -153 and -180 were measured in 175 pregnant women presenting to the delivery room. AGD was measured in their newborns. Regression models were used to estimate associations between maternal PCB exposure and infant anogenital measurements, controlling for possible confounding variables. Mean maternal serum concentrations were 2.95 ± 2.18 ng/g, 4.62 ± 3.54 ng/g, 7.67 ± 6.42 ng/g and 5.10 ± 3.91 ng/g for congeners -118, -138, -153 and -180, respectively. Higher maternal concentrations of PCBs were associated with reduced AGD measures in male infants. Higher maternal concentrations of PCB-138 and PCB-153 were associated with reduced ano-scrotal distances and higher maternal concentrations of all four PCB congeners were associated with reduced ano-penile distances. No significant associations were found between any PCB congener and any AGD measure in female newborns. This study demonstrates that intrauterine exposure to PCBs may be associated with reduced AGD in male newborns. More research is needed to reveal the implications for adult reproductive health.

Small for gestational age (SGA) and large for gestational age (LGA) newborns are at increased risk for developmental, metabolic and cardiovascular morbidities.To compare the metabolic biomarkers of SGA and LGA infants with those of appropriate for gestational age (AGA) newborns in order to shed more light on a possible pathogenesis of those morbidities.An observational retrospective study.70,809 term newborns divided into AGA, SGA, LGA, and severe subcategories (3rd percentile or ≥97th percentile).18 metabolites were measured by dried blood tandem mass spectrometry and compared in between groups in univariate and multivariate logistic regression.SGA newborns had a significant likelihood for elevated methionine, proline, free carnitine, and reduced valine levels compared to AGA newborns (P .0001). Severe SGA showed more apparent trends including elevated leucine. LGA newborns had a significant likelihood for low citrulline, glutamine, proline, tyrosine, and elevated leucine levels (P ≤ .0033). Severe LGA newborns showed the same trends, with the exception of citrulline and glutamine.SGA and LGA newborns demonstrate distinct metabolic biomarkers in newborn screening. Most of the altered metabolites in the SGA group were elevated while those in the LGA group were decreased in comparison to AGA newborns. These trends were more apparent in the severe SGA subgroup while they mostly remained the same in the severe LGA subgroup. Whether these metabolic changes are involved with or can predict long-term outcome awaits further trials.

Background: The reporting rate of adverse drug reactions (ADRs) by healthcare professionals is low. ADR interventional programs may improve the reporting rate by the medical team. Our literature search revealed that only a few interventional studies among the pediatric population have been published. Objective: We aimed to create an interventional program in order to improve the reporting rate of ADRs during the interventional period compared to the control period, detect which drugs frequently lead to ADRs and determine the most serious ADRs. Design: A 3-month prospective intervention study compared with one year prior to the intervention (control period). ADR data was also collected for the year following the study period. Healthcare professionals were encouraged to report ADRs and an ADR reporting system was created for them. Setting: Pediatric Division at Shamir Medical Center (Assaf Harofeh), a tertiary care medical center. Results: The study population included 3,753 admitted patients with 1,323 prescriptions during the study period. During the period before the intervention was started, the ADR reporting rate was null. During the study period, 46 reports were collected: 46% from the general pediatric department, 26% from the pediatric neurology department, and 22% and 6% from the pediatric and neonatal intensive care units, respectively. Antiepileptic medications, IVIG, steroids and antibiotics were frequently reported to induce ADRs. Serious ADRs were also reported in 5 cases. One year of follow up after the intervention revealed a significant decline in the reporting rate. Conclusion: It is important to periodically encourage healthcare professionals to report any ADRs in order to increase knowledge about medication safety and prevent fatal harm.

Background: The incidence of both the survival of premature infants and type 1 diabetes (T1D) is rising worldwide. The pathophysiology of T1D depends on the differentiation of cellular and humoral immune systems recognition of the self, which occurs during the neonatal period and is influenced by environmental exposures. Aim: To assess the association between nutritional, antibiotic and parenteral exposures during the neonatal period and the development of pediatric T1D. Methods: a multicenter, paired case-control study. Preterm subjects who were born between 1990-2013, and developed T1D before the age of 18 years (T1D group), were paired with subjects who didn't develop TID (Control group) at a ratio of 1:3 by: gender, gestational age (GA), month of birth and birth medical center . This preterm population is a model of a neonatal population with strictly meticulous follow up data available in all medical centers in Israel. Data retrieved from charts included maternal history, delivery method, ethnic origin, weight for GA, NICU length of hospitalization, medications, parenteral fluid types, feeding modes and their timing. Univariate and multivariate analysis via Generalized Estimating Equations (GEE) using a binary logistic regression model were performed to evaluate the association between T1D and the assessed exposures. Results: T1D group included 52 subjects, 26 males, median GA 35 (26-36), mean BW 2307.6±534.5. Control group included 133 subjects, 69 males. median GA 35 (27-36), mean BW 2094.5±484.1. In univariate analysis, the odds ratio (OR) for T1D increased with each extra 100 grams in BW (OR 1.13, 95%CI 1.057-1.206, p < 0.001), later day of parenteral glucose initiation (OR 1.61, 95%CI 1.05-2.48, p 0.03), and parenteral cephalosporines initiated beyond the first week of life (OR 3.25, 95%CI 1.504-7.04, p 0.003). Treatment with narrow spectrum beta-lactam antibiotics during the first week of life was associated with lower risk for T1D development (OR 0.23, 95%CI 0.12-0.47, p < 0.001). Multivariate analysis revealed significant association between both treatment with cephalosporins beyond the first week of life and later day of parenteral glucose initiation and the development of pediatric T1D (OR 6.49, 95%CI 1.54-27.44, p 0.011 and OR 1.61, 95%CI 1.05-2.48, p 0.002, respectively). No association with feeding modality (oral/nasogastric), timing and type of feeding (breast or bottle) was found. Conclusions: This is the first report indicating a significant association between parenteral exposure and timing of variable antibiotic treatments and glucose solution administration during the neonatal period with development of T1D. This report indicates the need for a larger study to conclude clinical implications of management and exposure to these substances during the neonatal period and its relevance to the neonatal microbiome.

Context Delayed thyrotropin (TSH) elevation (dTSH) is defined as elevated TSH at the second neonatal screening (after normal TSH levels at the initial screening) in premature, low-birth-weight, and ill newborns, mostly in the neonatal intensive care unit (NICU) setting. The pathogenesis of dTSH is elusive. Objective To identify the risk factors for dTSH development among newborns in the NICU. Design, Setting, and Patients A retrospective medical record review of neonates with dTSH was conducted in eight university-affiliated NICUs. Two controls were selected for each patient, matched for sex and birth weight. The risk factors for dTSH were identified by univariate analysis, followed by multivariate analysis. Main Outcome Measures Maternal variables, types of NICU treatments and procedures, syndromes, and various medical conditions were compared between dTSH patients and their matched controls. Results We enrolled 100 dTSH patients and 200 matched controls and 46 variables were compared between the two groups. Twelve risk factors for dTSH were identified on univariate analysis: cesarean section, mechanical ventilation, patent ductus arteriosus (PDA), pneumothorax, and administration of cefotaxime, vancomycin, fluconazole, dopamine, ibuprofen, furosemide, insulin, and packed red blood cells. On multivariate analysis, four risk factors were identified: PDA and vancomycin, insulin, and furosemide administration. In 26 twin pairs, in which one twin had dTSH, all variables presented similarly in both twins. Conclusions Although some variables had direct effects on pituitary–thyroid axis dysfunction, these variables, altogether, reflect the severity of the clinical conditions in the NICU, which is the common basis for dTSH.

BackgroundAnti-epileptic drug therapy is a great challenge for the practitioners during pregnancy and lactation. Levetiracetam (LEV) is commonly prescribed to pregnant women, however, there are only few publications on its use during lactation with small number of participants.ObjectiveTo monitor LEV levels in breast-milk of epileptic mothers treated with LEV.MethodsBreastfeeding women treated with LEV during pregnancy and after delivery were recruited. Milk sample was collected before administration of the drug and other samples were collected at time points of 1,3,6,9, and 12 hours after drug administration. Breastmilk and blood LEV levels were measured using HPLC.ResultsFourteen breastfeeding women participated in the study: 9 infants were fully breastfed whereas 5 were partially breastfed. Maternal average daily dose of LEV was 2517 mg. Average infant´s age was 8 weeks (3–22w). Average infant´s weight 4368 gr (3300–7000 gr). Milk/Plasma LEV concentration ratio was 0.88 (0.23–1.1). Relative Infant Dose (RID) was 40% in partial breast feeding, and 61% in full breastfeeding. Estimated average daily dose that all infants received through milk was 158 mg/d (83–250 mg). The normalized dose for the average infant weight per day was 36 mg, which is 15% less than the maximal daily dose of LEV in infants (max. daily dose in infants 1–6 months in 42 mg/d). No adverse reactions were observed in the breastfeed infants.ConclusionsAlthough the RID of LEV were found to be high, no adverse reactions were observed in the infants; Nevertheless, further studies are needed to elucidate the high variability of LEV excretion into breastmilk.Disclosure(s)Nothing to disclose

IntroductionPolybrominated Diphenyl Ethers (PBDEs) are non-biodegradable flame retardants, accumulated in biological systems and acting as endocrine disruptors. Breast feeding is a major route of exposure in infancy. Taken together with the critical development of this age and the potential adverse effects of PBDEs, it is important to monitor these contaminants in breastmilk.ObjectiveTo evaluate the exposure of infants to PBDEsMethods343 families were recruited during 2013–2016 in Assaf Harofeh and Ichilov to create the AHI-EHF cohort. Maternal blood and urine, cord blood, breast milk and meconium were collected. Participants filled out questionnaires about socio-demographic status, medical history, exposures and life habits. Colostrum samples were collected from women at the maternity department. PBDEs in colostrum and Infant formulas levels were analyzed using GC-MSResults and discussionOut of 183 serum samples, only 11(6%) detectable levels of PBDEs. PBDEs were found in all colostrum samples. The average concentration of total PBDEs in breastmilk was 714ng/L. PBDEs levels were also measured in three infant formulas. Unlike breastmilk, infant formulas had of only 3 congeners and levels were relatively low. The average concentration of total PBDEs in infant formulas was 153ng/L. PBDEs, were found to be negatively correlated to anno-penile index (API) which serve as a marker for endocrine disruption.ConclusionsPBDEs levels in breast milk are higher than levels in some European countries, but lower than in North America. PBDEs might have negative influence on AGD in boys. Maternal exposure to PBDEs and the significance of it should be further investigated.Disclosure(s)Nothing to disclose

Triploidy (69 chromosomes) is the most common chromosomal anomaly encountered in human gestation, occurring in 1% of all conceptions. Most triploidies abort spontaneously during the 1st trimester. In cases that last, it is usually associated with fetal distress that can Lead to many obstetric complications.To assess the indications for prenatal karyotyping of triploidy during pregnancy in our medical center.This retrospective cohort study involved all singleton pregnancies diagnosed or referred to our institute because of triploidy, during the years 1998-2011.There were 1879 cases of termination of pregnancies (TOPs). During this period 8 cases of triploidy were aborted. The main indications for prenatal karyotyping in our study group were abnormal sonographic findings during anomaly scans. In addition, in all of the triploidy cases, the NT test was normal. Also, the 1st or 2nd trimester serum markers tests for early diagnosis of trisomy 18 predicted all of the triploidy cases that performed the tests.Our findings corresponded with other studies and show that the 1st or 2nd trimester serum markers tests for early diagnosis of trisomy 18, can lead to identification of triploidy pregnancies.The routine screening tests applied in Israel INT, serum markers tests and 2nd trimester anomaly scans) were highly effective in the identification of triploidy pregnancies.