Congenital diaphragmatic hernia: quality improvement using a maximal lung protection strategy and early surgery-improved survival.

To evaluate the effectiveness of a novel protocol, adopted in our institution, as a quality improvement project for congenital diaphragmatic hernia (CDH). A maximal lung protection (MLP) protocol was implemented in 2019. This strategy included immediate use of high-frequency oscillatory ventilation (HFOV) after birth, during the stay at the Neonatal Intensive Care Unit (NICU), and during surgical repair. HFOV strategy included low distending pressures and higher frequencies (15 Hz) with subsequent lower tidal volumes. Surgical repair was performed early, within 24 h of birth, if possible. A retrospective study of all inborn neonates prenatally diagnosed with CDH and without major associated anomalies was performed at the NICU of Schneider Children's Medical Center of Israel between 2009 and 2022. Survival rates and pulmonary outcomes of neonates managed with MLP were compared to the historical standard care cohort. Thirty-three neonates were managed with the MLP protocol vs. 39 neonates that were not. Major adverse outcomes decreased including death rate from 46 to 18% (p = 0.012), extracorporeal membrane oxygenation from 39 to 0% (p < 0.001), and pneumothorax from 18 to 0% (p = 0.013). CONCLUSION:  MLP with early surgery significantly improved survival and additional adverse outcomes of neonates with CDH. Prospective randomized studies are necessary to confirm the findings of the current study. WHAT IS KNOWN: • Ventilator-induced lung injury was reported as the main cause of mortality in neonates with congenital diaphragmatic hernia (CDH). • Conventional ventilation is recommended by the European CDH consortium as the first-line ventilation modality; timing of surgery is controversial. WHAT IS NEW: • A maximal lung protection strategy based on 15-Hz high-frequency oscillatory ventilation with low distending pressures as initial modality and early surgery significantly reduced mortality and other outcomes.

Long-term follow-up of premature infants with urinary tract infection.

Urinary tract infection (UTI) is common in preterm infants and may have long-term sequela, such as recurrent infections and renal scarring in older children. We assessed long-term outcomes of preterm infants with UTI, born during 1996-2008 in Schneider Children's Medical Center's neonatal intensive care unit (NICU), and incidence of UTI recurrence. Of 89 preterm infants, seven were excluded due to prenatal diagnosis of congenital anomalies of the kidney and urinary tract (CAKUT), 41 interviewed by phone, 18 presented for follow-up evaluation in the nephrology clinic, and 23 lost to follow-up. No patient who completed follow-up reported additional UTI episodes or issues related to kidney and urinary tract. Clinically evaluated participants were 17.1 ± 3.6 years, born prematurely at 29.4 ± 4 weeks. All had a normal estimated glomerular filtration rate of >90 ml/min/1.73m2; four (22%) had systolic blood pressure >90th percentile; none had proteinuria (mean protein/creatinine ratio 0.09 ± 0.04 mg/mg) or albuminuria (mean albumin/creatinine ratio 10.2 ± 6.3 mcg/mg). Renal ultrasonography done in the first years of life in 12 (66%) patients demonstrated normal kidney size and structure.Conclusion: In this pilot study, a single episode of UTI in premature infants without CAKUT did not constitute a risk factor for recurrence of infections or kidney injury in their first two decades of life. Thus, normal ultrasound in NICU excluding CAKUT may be sufficient for premature patients with UTI, with no need of further imaging or long-term nephrology follow-up. What is Known: • Urinary tract infection (UTI) is one of the most common bacterial infections in neonates and premature infants. Risk factors for UTI recurrence in children are congenital anomalies of the kidney and urinary tract (CAKUT) and bladder and bowel dysfunction. • The recurrence rate and long-term renal sequela of UTI in preterm infants have not been studied. Guidelines regarding management and long-term follow-up for infants less than 2 months old are lacking. What is New: • A single episode of UTI in premature infants without CAKUT probably does not constitute a risk factor for UTI recurrence, and it is unlikely to cause renal injury in the first two decades of life. • For premature infants with UTI without sonographic diagnosis of CAKUT in NICU, prophylactic antibiotic treatment, further imaging, or long-term nephrology follow-up may be unnecessary.

Antepartum Hemorrhage and Outcome of Very Low Birth Weight, Very Preterm Infants: A Population-Based Study.

OBJECTIVE: We aimed to determine the independent effect of maternal antepartum hemorrhage (APH) on mortality and major neonatal morbidities among very low birth weight (VLBW), very preterm infants. STUDY DESIGN: A population-based cohort study of VLBW singleton infants born at 24 to 31 weeks of gestation between 1995 and 2016 was performed. Infants born with the following pregnancy associated complications were excluded: maternal hypertensive disorders, prolonged rupture of membranes, amnionitis, maternal diabetes, and small for gestational age. APH included hemorrhage due to either placenta previa or placental abruption. Univariate and multivariable logistic regression analyses were performed to assess the effect of maternal APH on mortality and major neonatal morbidities. RESULTS: The initial cohort included 33,627 VLBW infants. Following exclusions, the final study population comprised 6,235 infants of whom 2,006 (32.2%) were born following APH and 4,229 (67.8%) without APH. In the APH versus no APH group, there were higher rates of extreme prematurity (24-27 weeks of gestation; 51.6% vs. 45.3%, p < 0.0001), mortality (20.2 vs. 18.5%, p = 0.011), bronchopulmonary dysplasia (BPD, 16.1 vs. 13.0%, p = 0.004) and death or adverse neurologic outcome (37.4 vs. 34.5%, p = 0.03). In the multivariable analyses, APH was associated with significantly increased odds ratio (OR) for BPD in the extremely preterm infants (OR: 1.31, 95% confidence interval: 1.05-1.65). The OR's for mortality, adverse neurological outcomes, and death or adverse neurological outcome were not significantly increased in the APH group. CONCLUSION: Among singleton, very preterm VLBW infants, maternal APH was associated with increased odds for BPD only in extremely premature infants, but was not associated with excess mortality or adverse neonatal neurological outcomes. KEY POINTS: · Outcome of very low birth weight infants born after antepartum hemorrhage (APH) was assessed.. · APH was not associated with higher infant mortality.. · APH was not associated with adverse neurological outcome.. · APH was associated with increased bronchopulmonary dysplasia in extremely preterm infants..

Changing epidemiology and resistance patterns of pathogens causing neonatal bacteremia.

To conduct a survey of the local prevalent bacteria and antibiotic resistance in a referral tertiary neonatal intensive care unit (NICU), in order to assess the efficacy of local antibiotic policies. We reviewed all positive blood and cerebrospinal fluid cultures obtained between January 2007 and December 2017 in the NICU of Schneider Children's Medical Center of Israel. Early and late-onset bacteremia were defined as episodes occurring within or after the first 3 calendar days of life respectively. Empiric treatment included ampicillin and gentamicin or piperacillin-tazobactam and amikacin for early or late-onset bacteremia respectively. The prevalence and antibiotic resistance of the bacteria were described and compared over time. Eight hundred and twenty nine of 15,947 (5.2%) newborns had at least one episode of bacteremia; 81 had multiple episodes. The most common bacteria were Escherichia coli (32.35%) and group B Streptococcus (19.11%) or coagulase negative Staphylococcus (CoNS) (60.5%) and Klebsiella sp. (12.4%) in early or late-onset bacteremia respectively. Overall, all Gram-positive bacteria were susceptible to vancomycin and most non-CoNS to ampicillin. Nosocomial vs. vertical bacteremia had increased resistance to ampicillin and cephalosporins. Resistance of nosocomial bacteria to piperacillin-tazobactam was 22.4%, to amikacin 3.3%, and to meropenem 1.8%. Changes over time: Gram-negative bacteria had a significant increase in resistance to cotrimoxazole and piperacillin. The resistance to gentamicin doubled. Our empiric antibiotic regimen covers the most frequent isolates. Amikacin may replace gentamicin for selected sick patients in early-onset bacteremia. Piperacillin-tazobactam should be combined with amikacin until susceptibility is available.

Perinatal risk factors for bronchopulmonary dysplasia in a national cohort of very-low-birthweight infants.

OBJECTIVE: We sought to assess the independent effect of perinatal factors on the risk for bronchopulmonary dysplasia (BPD) in very-low-birthweight infants. STUDY DESIGN: This was a population-based observational study. Data were prospectively collected by the Israel Neonatal Network. Multivariable analyses identified independent risk factors for BPD. RESULTS: Of 12,139 infants surviving to a postmenstrual age of 36 weeks, 1663 (13.7%) developed BPD. BPD was independently associated with young maternal age (odds ratio [OR], 1.53), maternal hypertensive disorders (OR, 1.28), antepartum hemorrhage (OR, 1.26), male gender (OR, 1.41), non-Jewish ethnicity (OR, 1.23), birth defects (OR, 1.94), small for gestational age (GA) (OR, 2.65), and delivery room resuscitation (OR, 1.86). Stratified analysis by GA groups showed that postdelivery resuscitation had a more pronounced effect with increasing maturity. CONCLUSION: Perinatal factors and pregnancy complications were independently associated with development of BPD in very-low-birthweight infants. Most risk factors identified were consistent within GA groups.

Late-Onset Sepsis in Very Low Birth Weight Infants.

BACKGROUND AND OBJECTIVES: Late-onset sepsis is associated with significant morbidity and mortality among very low birth weight (VLBW) infants. Our objective was to determine risk factors associated with late-onset sepsis and to present temporal trends in overall and pathogen-specific rates. METHODS: Population-based study by the Israel Neonatal Network on VLBW infants (≤1500 g) born between 1995 and 2019. Late-onset sepsis required clinical symptoms and microbiologic confirmation. Bivariate and multivariable analyses were performed to identify risk factors. The study period was divided into 4 epochs. Overall and pathogen-specific late-onset sepsis rates for each epoch were compared. RESULTS: The study population comprised 31 612 VLBW infants, of whom 7423 (23.5%) had late-onset sepsis. An increased adjusted risk of late-onset sepsis was associated with gestational age <27 w (odds ratio [OR] 8.90, 95% confidence interval [CI] 7.85-10.09) and delivery room resuscitation (OR 1.43, 95% CI 1.34-1.52) and a decreased adjusted risk among infants born between 2013 and 2019 (OR 0.32, 95% CI 0.29-0.35). Late-onset sepsis rates declined from 29.5% in 1995 to 2000 to 13.0% in 2013 to 2019. Gram-negative and fungal rates decreased in all epochs, whereas gram-positive rates decreased only in the last epoch. The adjusted hazard ratios (95% CI) decreased in the 2013 to 2019 versus 1995 to 2000 epochs and were: all late-onset sepsis, 0.40 (0.37-0.43); gram-positive, 0.47 (0.37-0.59); gram- negative, 0.54 (0.48-0.61); fungal, 0.17 (0.12-0.22). CONCLUSIONS: The strongest risk factor for late-onset sepsis was gestational age <27 w. Over a 25-year period, the pathogen-specific rates of late-onset sepsis among VLBW infants decreased approximately twofold for gram-positive and gram-negative bacterial infections and sixfold for fungal infections.

Antibiotic Discontinuation 24 h After Neonatal Late-Onset Sepsis Work-Up-A Validated Decision Tree Model.

Objectives: Neonatal late-onset sepsis work-up is a frequent occurrence in every neonatal department. Blood cultures are the diagnostic gold standard, however, a negative culture prior to 48-72 h is often considered insufficient to exclude sepsis. We aimed to develop a decision tree which would enable exclusion of late-onset sepsis within 24 h using clinical and laboratory variables. Study Design: Infants evaluated for late-onset sepsis during the years 2016-2019, without major malformations, in a tertiary neonatal center were eligible for inclusion. Blood cultures and clinical and laboratory data were extracted at 0 and 24 h after sepsis work-up. Infants with bacteriologically confirmed late-onset sepsis were compared to matched control infants. Univariate logistic regression identified potential risk factors. A decision tree based on Chi-square automatic interaction detection methodology was developed and validated. Results: The study cohort was divided to a development cohort (105 patients) and a validation cohort (60 patients). At 24 h after initial evaluation, the best variables to identify sepsis were C-reactive protein > 0.75 mg/dl, neutrophil-to-lymphocyte ratio > 1.5 and sick-appearance at 24 h. Use of these 3 variables together with blood culture status at 24 h, enabled identification of all infants that eventually developed sepsis through the decision tree model. Our decision tree has an area under the receiver operating characteristic curve of 0.94 (95% CI: 0.90-0.98). Conclusions: In non-sick appearing infants with a negative blood culture at 24 h and normal laboratory values, sepsis is highly unlikely and discontinuing antibiotics after 24 h is a viable option.

New and improved Israeli reference of birth weight, birth length, and head circumference by gestational age: a hospital-based study.

BACKGROUND: Many centers in Israel still use pre-1970 reference data for neonatal weight, length and head circumference. A recently published population-based reference overestimated the weight of premature infants. OBJECTIVE: To develop a national reference for birth weight, birth length and head circumference by gestational age for singleton infants in Israel. METHODS: Data were collected on all singleton live births documented in the neonatal registry of Rabin Medical Center from 1991 to 2005 (n=82,066). Gestational age estimation was based on the last menstrual period until 1977 and early fetal ultrasound thereafter. Neonates with an implausible birth weight for gestational age (identified by the rule of median +/- 5 standard deviations or expert clinical opinion) were excluded. Reference tables for fetal growth by gestational age were created for males and females separately. RESULTS: The growth references developed differed markedly from the Usher curves currently used in our department. Compared to the recently published population-based birth weight reference, our data were free of the problem of differential misclassification of birth weight for gestational age for the premature infants and very similar for the other gestational age groups. This finding reinforced the validity of our measurements of birth weight, as well as of birth length and head circumference. CONCLUSIONS: Use of our new (birth length and head circumference) and improved (birth weight) gender-specific hospital-based reference for fetal growth may help to define normal and abnormal growth in the neonatal population of Israel and thereby improve neonatal care and public health comparisons.

Platelet function and its clinical significance in the myelodysplastic syndromes.

The current study was aimed at investigating platelet function in MDS and its clinical significance. There were 23 patients with untreated MDS at presentation, including refractory anemia (RA), RA with ringed sideroblasts, RA and excess blasts and chronic myelomonocytic leukemia RAEBt. The mean platelet count was 167.9 x 109/L. Patients with a platelet count less than 70 x 109/l were excluded. The mean bleeding time (BT) was 2.7 min. Only four MDS patients had BT longer than the normal 1-4 min range. Platelet aggregation (PA) was studied with epinephrine (Epi), ADP, arachidonic acid (AA), ristocetin and collagen. Overall, 16 (70%) patients had PA abnormality, 65% had impaired Epi-induced PA, 57% demonstrated reduced ADP-induced PA. AA, ristocetin and collagen was decreased PA in 48, 22 and 17%, respectively. Five patients (22%) demonstrated spontaneous PA. Only seven patients (30%) were found to have normal PA with all five inducers. Six (26%) patients had spontaneous mild bleeding and all six bleeding MDS patients demonstrated at least one abnormal platelet function. The only bleeding patient with all five PA tests normal demonstrated prolonged BT. In the present study of 23 newly diagnosed MDS patients, PA abnormalities were relatively common, the BTs were usually normal, and bleedings were relatively uncommon and mild at platelet count between 70 and 397 x 109/l.

Neurologic abnormalities in children presenting with diskitis.

BACKGROUND: Neurologic impairment is not considered a clinical manifestation of diskitis in children and has seldom been associated with it in the medical literature. OBJECTIVE: To describe neurologic findings and their implications in children with diskitis. STUDY DESIGN: Retrospective medical records review of children discharged with a diagnosis of diskitis between January 1992 and December 2000. The study included children in whom the diagnosis was based on the presence of clinical findings, laboratory evidence of an inflammatory process, and findings on imaging studies compatible with diskitis. RESULTS: Neurologic findings of decreased muscle strength or hyporeflexia in the lower extremities were found in 7 (41%) of 17 children who met the diagnostic criteria for diskitis. Five of the 7 underwent magnetic resonance imaging, 2 of whom demonstrated intraspinal inflammatory involvement. CONCLUSIONS: Neurologic impairment does not exclude the diagnosis of diskitis and may be a common manifestation of the disease in children. Nevertheless, when neurologic findings are present, advanced imaging studies are needed to exclude intraspinal involvement.

A novel technique for infant length measurement based on stereoscopic vision.

BACKGROUND: Monitoring infant growth is essential for evaluation of development and is an important indicator of health and illness. Length is an essential indicator of infant growth, however, length measurement methods suffer from limitations which restrict their use. OBJECTIVE: To improve infant length measurement by development of a novel, accurate, precise and practical measurement technique. METHODS: A new system based on stereoscopic vision was developed. The system is comprised of two digital still cameras combined with software that calculates the infant's length from two simultaneously taken pictures. Length measurements of 54 healthy newborns were performed using a standard length board and the stereoscopic system. The two measurement methods were compared. RESULTS: Mean infant length was 473.1 (SD=29.1) mm versus 473.3 (SD=29.3) mm by length board and by the stereoscopic system, respectively. The mean difference between measurements was 0.2 (SD=2.5) mm and the mean of the absolute values of differences was 2.0 (SD=1.4) mm. Bland-Altman analysis showed good agreement between the two measurement methods. Precision of the new technique was demonstrated by a technical error of measurement of 2.57 mm. CONCLUSIONS: The stereoscopic system is accurate, reliable, easy to use, and involves less handling and discomfort to the newborns. It has the potential to measure premature infants or sick neonates through incubators.

Body mass index and weight-for-length ratio references for infants born at 33-42 weeks gestation: a new tool for anthropometric assessment.

BACKGROUND & AIMS: The risk of childhood obesity, an increasingly prevalent problem worldwide, might be predictable by early body mass index measurements. This study sought to develop body mass index and weight-for-length ratio references for infants born at 33-42 weeks gestation and to validate these data against the growth curves of the World Health Organization Multicenter Growth Reference Study. METHODS: Data were collected from the Neonatal Registry of Rabin Medical Center for all healthy singleton babies born live at 33-42 weeks gestation. Crude and smoothed reference tables and graphs for body mass index and weight-for-length ratio by gestational age were created for males and females, separately. RESULTS: Birth weight, length, and body mass index percentiles for full-term neonates were similar to the World Health Organization study, reinforcing the generalizability of our reference charts for infants born at 33-42 weeks. Cutoff values for small for date (<5th, <10th percentile) and large for date (>85th, >95th percentile) infants differed across gestational ages in both pre-term and full-term infants. CONCLUSIONS: As body proportionality indexes provide an assessment of body mass and fatness relative to length, we suggest that BMI and Wt/L ratio percentiles be added to weight and length growth curves as a routine intrauterine growth assessment at birth.

Neonatal recurrent prolonged hypothermia associated with maternal mirtazapine treatment during pregnancy.

We present a case of recurrent hypothermia in concordant monozygotic twins born to a mirtazapine treated mother. The twins were born at 35 weeks gestation at birth weights of 2426 g and 2355 g. Both twins presented with recurrent hypothermia continuing until day 10 of life. Possible etiologies of hypothermia were excluded. The degree of prematurity and the weight of the twins were not consistent with prolonged thermal instability. The twins' mother was treated with mirtazapine during the entire pregnancy. Due to its serotonin and alpha 2 receptors antagonism mirtazapine is known to influence thermoregulation in adult humans and other mammals. We suggest that maternal mirtazapine treatment during pregnancy was associated with recurrent hypothermia in both identical twins.