National Rapid Genome Sequencing in Neonatal Intensive Care.

Importance: National implementation of rapid trio genome sequencing (rtGS) in a clinical acute setting is essential to ensure advanced and equitable care for ill neonates. Objective: To evaluate the feasibility, diagnostic efficacy, and clinical utility of rtGS in neonatal intensive care units (NICUs) throughout Israel. Design, Setting, and Participants: This prospective, public health care-based, multicenter cohort study was conducted from October 2021 to December 2022 with the Community Genetics Department of the Israeli Ministry of Health and all Israeli medical genetics institutes (n = 18) and NICUs (n = 25). Critically ill neonates suspected of having a genetic etiology were offered rtGS. All sequencing, analysis, and interpretation of data were performed in a central genomics center at Tel-Aviv Sourasky Medical Center. Rapid results were expected within 10 days. A secondary analysis report, issued within 60 days, focused mainly on cases with negative rapid results and actionable secondary findings. Pathogenic, likely pathogenic, and highly suspected variants of unknown significance (VUS) were reported. Main Outcomes and Measures: Diagnostic rate, including highly suspected disease-causing VUS, and turnaround time for rapid results. Clinical utility was assessed via questionnaires circulated to treating neonatologists. Results: A total of 130 neonates across Israel (70 [54%] male; 60 [46%] female) met inclusion criteria and were recruited. Mean (SD) age at enrollment was 12 (13) days. Mean (SD) turnaround time for rapid report was 7 (3) days. Diagnostic efficacy was 50% (65 of 130) for disease-causing variants, 11% (14 of 130) for VUS suspected to be causative, and 1 novel gene candidate (1%). Disease-causing variants included 12 chromosomal and 52 monogenic disorders as well as 1 neonate with uniparental disomy. Overall, the response rate for clinical utility questionnaires was 82% (107 of 130). Among respondents, genomic testing led to a change in medical management for 24 neonates (22%). Results led to immediate precision medicine for 6 of 65 diagnosed infants (9%), an additional 2 (3%) received palliative care, and 2 (3%) were transferred to nursing homes. Conclusions and Relevance: In this national cohort study, rtGS in critically ill neonates was feasible and diagnostically beneficial in a public health care setting. This study is a prerequisite for implementation of rtGS for ill neonates into routine care and may aid in design of similar studies in other public health care systems.

Can Mild-to-Moderate Iodine Deficiency during Pregnancy Alter Thyroid Function? Lessons from a Mother-Newborn Cohort.

Severe iodine deficiency during pregnancy has substantial hormonal consequences, such as fetal brain damage. Data on the potential effects of mild-to-moderate iodine deficiency on the thyroid function of pregnant women and their newborns are scarce and divergent. We investigated the association between iodine intake in pregnancy and maternal and neonatal thyroid function in a region with mild-to-moderate iodine deficiency. Pregnant women's iodine status was evaluated using an iodine food frequency questionnaire, serum thyroglobulin (Tg), and urinary iodine concentration (UIC). Neonatal thyrotropin (nTSH) values were measured after birth. Obstetrics and anthropometric data were also collected. Among the 178 women (median age 31 years) included in the study, median (interquartile range) estimated dietary iodine intake, Tg and UIC were 179 (94−268) µg/day, 18 (11−33) µg/L, and 60 (41−95) µg/L, respectively. There was a significant inverse association of iodine intake with Tg values among the study population (ß = −0.2, F = 7.5, p < 0.01). Women with high free triiodothyronine (FT3) values were more likely to exhibit an estimated iodine intake below the estimated average requirement (160 µg/day, odds ratio [OR] = 2.6; 95% confidence interval [CI], 1.1−6.4; p = 0.04) and less likely to consume iodine-containing supplements (OR = 0.3, 95% CI, 0.1−0.8; p = 0.01). It is possible that thyroid function may be affected by iodine insufficiency during pregnancy in regions with mild-to-moderate iodine deficiency. The relatively small sample size of the studied population warrants further investigation.

Maternal iodine deficiency: a newborns' overweight risk factor? A prospective study.

OBJECTIVES: Childhood obesity and iodine deficiency are global public health concerns. Whether maternal iodine status mediates overweight in infancy has yet to be explored. We aimed to assess the relationship between maternal iodine status and infant birth weight, including small and large for gestational age (SGA and LGA, respectively). METHODS: A prospective study was carried out among 134 mother-infant pairs from Israel. Maternal iodine intake and status were estimated via questionnaire and serum thyroglobulin (Tg), respectively. Estimated iodine intake below the Recommended Daily Allowance for iodine sufficiency in pregnancy (220 µg/d) considered Inadequate. Maternal and neonatal thyroid function and anthropometric measurements, as well as maternal thyroid antibodies were also tested. RESULTS: After screening, 118 participants met the inclusion criteria (distributed trimesters I, II and III: n = 3, n = 21, and n = 94, respectively). There was a negative association of iodine intake with Tg values among the study population. Maternal median Tg value was higher than the sufficiency cutoff (16.5 vs 13 µg/L), indicating insufficient iodine status. No SGA cases were found. Inadequate iodine intake was associated with maternal isolated hypothyroxinemia (OR = 3.4; 95% CI 1.2, 9.9) and higher birthweight (including macrosomia and LGA) rates. A suggestive association of elevated Tg with a greater risk of LGA was observed. Offsprings' birth weight percentiles were associated with Tg values in pregnant women with suggestive sufficient iodine status (n = 62, R2 = 0.11, p < 0.05). CONCLUSIONS: Iodine status during pregnancy can be associated with newborn anthropometric index. Maternal inadequate iodine intake may alter fetal growth and might increase the risk of LGA among newborns. These initial findings support the need to further study the impact of iodine deficiency on newborns overweight in Israel and elsewhere.

[COMPETENCY-BASED TRAINING AS A WAY TO CREATE ORGANIZATIONAL CHANGE AND IMPROVE PROFESSIONALISM: A REVIEW OF THE PROCESS OF IMPLEMENTING A COMPETENCY-BASED MEDICAL EDUCATION (CBME) TRAINING PROGRAM IN NEONATOLOGY FELLOWSHIP IN ISRAEL].

INTRODUCTION: Competency-based medical education (CBME) is a model aimed to address certain challenges and shortcomings attributed to the contemporary models of medical education and the medical profession in general. The CBME model has been used mainly in the education of undergraduate medical students with no continuation to residency, fellowship, or independent practice. In this review, we present a program based on the CBME model for the design and implementation of a new fellowship program in neonatology in Israel. As part of the program, we propose a mentorship program as a means to facilitate the implementation and acceptance of the program in the different wards. We designed assessment tools that can help the mentor track the fellow's development over time as well as to examine the impact of the proposed program on performance and on all stakeholders' satisfaction over time. We aim to evaluate the benefits and effectiveness of this CBME training not only on the fellows' abilities and performance outcomes, but also on the accompanying general organizational changes that can lead to general improvement in the neonatal profession in Israel.

Inhaled corticosteroids in transient tachypnea of the newborn: A randomized, placebo-controlled study.

OBJECTIVE: Prenatal corticosteroids were shown to reduce the respiratory complication in late preterm infants. Our objective was to determine if early inhaled corticosteroids could alleviate the respiratory distress and morbidity in late preterm and term neonates with transient tachypnea of the newborn (TTN). STUDY DESIGN: Double-blind, randomized placebo-controlled, multicenter pilot study. Infants born at >34 weeks gestational age with TTN at 4 h of age were randomized to two doses, 12 h apart, of inhaled Budesonide 1000 µg/dose or placebo within 6 h from delivery. Analysis was done by intention to treat. RESULTS: The study (n = 24) and control (n = 25) groups were comparable in birth characteristics (gestational age: 36.8 ± 1.9 vs 36.4 ± 1.8 weeks) and clinical condition at the time of recruitment (vital signs, clinical score, ventilation support, and blood gases). There was no difference between the study and control groups in clinical score (based on grunting, retractions, ala nasi, and respiratory rate) at recruitment and at 12, 24, and 48 h after the first inhalation (4.3 ± 1.6 vs 4.1 ± 2.1; 1.9 ± 1.8 vs 1.5 ± 1.7; 1.1 ± 1.4 vs 1.3 ± 1.6; 0.5 ± 0.8 vs 0.6 ± 1.0; respectively). Respiratory support at each time point, time to spontaneous unsupported breathing (67.4 ± 74.1 vs 75.2 ± 95.2 h), time to full feeds (86.7 ± 68.7 vs 84.3 ± 66.6 h) and length of stay (9.9 ± 5.5 vs 12.4 ± 8.0 days) did not differ between the groups. We did not detect any side effects. CONCLUSIONS: Our pilot study was unable to detect a beneficial effect of early administration of inhaled steroids on the clinical course of TTN in late preterm and term infants.

[DIVERSITY IN PRODUCT SELECTION AND THRESHOLDS FOR PLATELETS TRANSFUSION IN NEONATES AND PREMATURE INFANTS].

INTRODUCTION: Many premature and full-term newborns receive prophylactic platelet transfusions to prevent bleeding, particularly the most prevalent one, i.e, intracranial hemorrhages. However, the platelet count threshold above which bleeding is prevented and the efficacy of platelet transfusion in thrombocytopenic neonates, have yet to be established. Therefore, inter-Neonatal Intensive Care Units (NICU) variations in treatment indications and practices are expected. Considerable inter-NICU variations will emphasize the need for guidelines on platelet transfusions to neonates and premature infants. AIMS: To examine platelet products selection and indications for transfusion among neonatologists in Israel. Research and Methods: Electronic questionnaires addressing the choice of platelet products and the platelet count threshold for transfusion in various clinical settings were sent to 25 neonatal units. RESULTS: All 25 neonatal units responded (100% response rate). There was considerable variation in product selection among the different neonatal units. Up to 24% of the participating units reported selecting nontraditional products. Variation was also found in thresholds for platelet transfusion - several units used high thresholds while others used low ones. Traditional guidelines were followed in up to 64% of cases in selected clinical scenarios. CONCLUSIONS: There is considerable variation in both platelet product selection and platelet count thresholds for transfusion among the different neonatal units. DISCUSSION: A low threshold for platelet transfusion increases the risk for bleeding, whereas a high threshold increases the prevalence of complications from transfusion of blood products. Adherence to guidelines may prevent both such sequelae. Summary: Such variation in platelet transfusion among neonatologists emphasizes the need for an accepted policy. We recommend setting up a committee of neonatologists, pediatric hematologists and blood service experts which aims to establish an appropriate policy regarding the prevention of platelet transfusion sequelae in newborns.

Factors associated with iatrogenesis in neonatal intensive care units: an observational multicenter study.

The objective of our study was to assess factors associated with iatrogenic events in Neonatal Intensive Care Units (NICUs). This was a retrospective analysis based on a cohort of patients who participated in our previous prospective study (Pediatrics 122:550-555, 2008), conducted in four tertiary university-affiliated NICUs in Israel, that included all consecutive infants (n = 615) hospitalized during the study period. Ongoing monitoring of iatrogenic events was performed by designated "iatrogenesis advocates." The main outcome measures were the association of individual infant characteristics and NICUs' environmental characteristics with iatrogenic events assessed by univariate and multiple logistic regression analysis. We found that four infant characteristics were significantly (p < 0.001) associated with iatrogenic events in a univariate analysis: gestational age, birth weight, severity of initial illness as assessed by the Score for Neonatal Acute Physiology and Perinatal Extension (SNAPPE II), and length of stay (LOS). All four factors demonstrated a significant (p < 0.001) dose-response relationship with iatrogenic events. Univariate analysis for environmental characteristics showed that type of shift, but not nursing workload, was significantly associated with iatrogenic events (p < 0.001). In a multiple logistic regression analysis, only LOS (adjusted OR 1.02 [95 % CI, 1.01-1.03]) and type of shift, morning vs. evening (adjusted OR 3.44 [95 % CI, 2.33-5.08]) and morning vs. night (adjusted OR 6.07 [95 % CI, 3.86-9.56]), remained independently associated with iatrogenic events (p < 0.001). Prolonged LOS and morning shifts were found to be significantly associated with iatrogenic events. Further prospective research is warranted to identify the specific causes for iatrogenic events in order to target active interventions to prevent them.

Fatal kernicterus in a girl deficient in glucose-6-phosphate dehydrogenase: a paradigm of synergistic heterozygosity.

A 6-day-old female newborn, readmitted for extreme hyperbilirubinemia with bilirubin encephalopathy, died despite 2 double-volume exchange transfusions. On autopsy examination the basal ganglia and hippocampus were selectively stained deep yellow. The infant was heterozygous for both the glucose-6-phosphate dehydrogenase Mediterranean mutation and for the (TA)(6)/(TA)(7) promoter polymorphism for the gene encoding the bilirubin conjugating enzyme uridine diphosphate-glucuronosyltransferase 1A1 (UGT1A1*28, associated with Gilbert syndrome). No additional mutations of the UGT1A1 were detected. Seemingly innocuous, heterozygotic mutations may interact synergistically to result in serious and even fatal outcomes.

Iatrogenesis in neonatal intensive care units: observational and interventional, prospective, multicenter study.

OBJECTIVES: The goals were to determine the incidence of iatrogenic events in NICUs and to determine whether awareness of iatrogenic events could influence their occurrence. METHODS: We performed a prospective, observational, interventional, multicenter study including all consecutive infants hospitalized in 4 NICUs. In the first 3 months (observation period), the medical teams were unaware of the study; in the next 3 months (intervention period), they were made aware of daily ongoing monitoring of iatrogenic events by a designated "Iatrogenesis Advocate." RESULTS: The numbers of infants admitted to the NICUs were comparable during the observation and intervention periods (328 and 369 infants, respectively). There was no difference between the 2 periods with respect to the number of infants of <1500 g, hospitalization days, or mean daily occupancy of the NICUs. Although the prevalence rates of iatrogenic events were comparable in the observation and intervention periods (18.0 and 18.2 infants with iatrogenic events per 100 hospitalized infants, respectively), the incidence rate decreased significantly during the intervention period (3.2 and 2.4 iatrogenic events per 100 hospitalization days of new admissions, respectively). Of all iatrogenic events, 7.9% were classified as life-threatening and 45.1% as harmful. There was no death related to an iatrogenic event. Eighty-three percent of iatrogenic events were considered preventable, of which 26.9% resulted from medical errors in ordering or delivery of medical care. Only 1.6% of all iatrogenic events were intercepted before reaching the infants, and only 47.0% of iatrogenic events were corrected. For younger and smaller infants, the rate of iatrogenic events was higher (57% at gestational ages of 24 to 27 weeks, compared with 3% at term) and the iatrogenic events were more severe and harmful. Increased length of stay was associated independently with more iatrogenic events. CONCLUSIONS: Neonatal medical teams and parents should be aware of the burden of iatrogenesis, which occurs at a significant rate.

Langerhans cell histiocytosis in a premature baby presenting with skin-isolated disease: case report and literature review.

UNLABELLED: Langerhans cell histiocytosis (LCH) in premature babies is extremely rare as is a vesicular skin rash, while gastrointestinal involvement is associated with a poor outcome. We report a case of LCH in a premature baby presented with isolated vesiculo-papulo-macular skin lesions and insidiously developed gastrointestinal symptoms, haematological and severe pulmonary involvement. We also reviewed a few cases of LCH in premature babies in the English language medical literature. LCH in preterm babies appears to be a severe systemic disease, usually lethal in-utero or post delivery. CONCLUSION: Careful observation should be applied to newborns with skin-only Langerhans cell histiocytosis in order to identify in time progression to potentially fatal systemic disease.