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Objective: General anesthesia may be required for placenta accreta cesarean delivery. Intrauterine fetal anesthetic exposure should be minimized to avoid neonatal respiratory depression; opioids are often delayed until post-delivery.Methods: In this observational study, we compared neonatal outcome using pre-delivery remifentanil versus post-delivery (deferred) opioids for placenta accreta cesarean delivery. Choice of anesthesia was discretionary. The primary outcome was Apgar score at 5 min comparing women who received pre-delivery remifentanil versus deferred opioid administration. We recorded maternal/obstetric characteristics, surgical characteristics, maternal hemodynamic data, neonatal outcomes: Apgar scores, umbilical vein pH and respiratory interventions at birth.Results: Between February 2007 and April 2014 we identified 40 general anesthesia placenta accreta cesarean deliveries. The remifentanil dose rate ranged from 0.06 to 0.46 mcg kg(-1 )min(-1). Obstetric and maternal characteristics were similar. Neonatal Apgar, umbilical pH and respiratory intervention outcomes were similar in both groups; Apgar scores median (interquartile range IQR [range]) at 5 min were 9 (8-10) for pre-delivery remifentanil versus 9 (9-10) for deferred opioid administration, p = 0.18.Conclusions: We did not observe a significant effect on neonatal Apgar scores at 1 and 5 min, or respiratory interventions at birth when remifentanil infusion was administered pre-delivery. [ABSTRACT FROM AUTHOR]

Objective: Defining an optimal costimulatory blockade-based immune suppression protocol enabling engraftment and functional development of E42 pig embryonic pancreatic tissue in mice.Research Design and Methods: Considering that anti-CD40L was found to be thrombotic in humans, we sought to test alternative costimulatory blockade agents already in clinical use, including CTLA4-Ig, anti-LFA1, and anti-CD48. These agents were tested in conjunction with T-cell debulking by anti-CD4 and anti-CD8 antibodies or with conventional immunosuppressive drugs. Engraftment and functional development of E42 pig pancreatic tissue was monitored by immunohistology and by measuring pig insulin blood levels.Results: Fetal pig pancreatic tissue harvested at E42, or even as early as at E28, was fiercely rejected in C57BL/6 mice and in Lewis rats. A novel immune suppression comprising anti-LFA1, anti-CD48, and FTY720 afforded optimal growth and functional development. Cessation of treatment with anti-LFA1 and anti-CD48 at 3 months posttransplant did not lead to graft rejection, and graft maintenance could be achieved for >8 months with twice-weekly low-dose FTY720 treatment. These grafts exhibited normal morphology and were functional, as revealed by the high pig insulin blood levels in the transplanted mice and by the ability of the recipients to resist alloxan induced diabetes.Conclusions: This novel protocol, comprising agents that simulate those approved for clinical use, offer an attractive approach for embryonic xenogeneic transplantation. Further studies in nonhuman primates are warranted. [ABSTRACT FROM AUTHOR]

Aim: To compare volume-driven and cue-based feeding of low birth weight preterm infants, regarding short-term outcomes, including transition to oral feeds, weight gain, and length of stay., Methods: This was a retrospective cohort study. Feeding and weight gain outcomes were compared between infants fed by volume-driven and cue-based feeds. The groups were subdivided by birth weight categories., Results: The study group included 240 low birth weight preterm infants born before 34 weeks of gestation, 120 infants fed by volume-driven feeding were compared to 120 infants fed by cue-based feeding. The groups were sub-analyzed by birth weight categories: <1,500 g and 1,500-2,500 g. Study groups were comparable regarding baseline characteristics and neonatal morbidities. Infants fed by cue-based feeding were more likely to achieve full oral feeding faster and at an earlier gestational age. Infants with a birth weight <1,500 g were less likely to experience adverse respiratory episodes during cue-based feeding. Although the rate of weight gain was reduced in cue-based feeding in the heavier infant group, discharge weight, breastfeeding rates, and length of stay were comparable between the groups., Conclusions: Cue-based feeding results in faster transition to full oral feeding in very low birth weight preterm infants and at an earlier gestational age., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2024 Ofek Shlomai, Mordechai, Morag, Bdolach Abram and Eventov Friedman.)

Objective: Coagulase-negative Staphylococcus (CoNS) is the most frequent pathogen causing late-onset sepsis (LOS) in neonatal intensive care units (NICUs). Technical difficulties hinder blood culture (BC) collection and obtaining only one culture before initiating antibiotic therapy is a common practice. We sought to assess specific clinical information and CoNS cultures for the diagnosis of true bacteremia in the NICU., Study Design: This historical cohort study was conducted in NICUs at the Hadassah-Hebrew University Medical Center of Jerusalem in Israel. Clinical and laboratory data in every CoNS bacteremia were collected and compared between bacteremia groups as follows: true positive, two positive BCs; contaminant, one positive BC out of two; undefined, one BC obtained and found positive., Results: For 3.5 years, CoNS was isolated in 139 episodes. True positive was identified in 44 of 139 (31.7%), contaminant in 42 of 139 (30.2%), and the event was undefined in 53 of 139 (38.1%). Vancomycin treatment was more frequent in the true positive and undefined groups than the contaminant group (100, 90.6, and 73.8% respectively, p  = 0.001); treatment was also prolonged in these two groups ( p  < 0.001). No clinical variables were associated with true bacteremia on multivariable analysis., Conclusion: Diagnosis should definitely be based on at least two positive BCs, despite objective difficulties in obtaining BCs in neonates., Key Points: · CoNS is a frequent pathogen causing LOS in neonates.. · Due to technical difficulties, often only one culture is collected prior to antibiotic therapy.. · No clinical/laboratory variables were associated with the diagnosis of true CoNS bacteremia.., Competing Interests: None declared., (Thieme. All rights reserved.)

Congenital cytomegalovirus (cCMV) is the most common intrauterine infection, leading to neurodevelopmental disabilities. Universal newborn infant screening of cCMV has been increasingly advocated. In the absence of a high-throughput screening test, which can identify all infected newborn infants, the development of an accurate and efficient testing strategy has remained an ongoing challenge. Here we assessed the implementation of pooled saliva polymerase chain reaction (PCR) tests for universal screening of cCMV, in two hospitals of Jerusalem from April 2022 through April 2023. During the 13-month study period, 15,805 infants (93.6% of all live newborn infants) were screened for cCMV using the pooled approach that has since become our routine screening method. The empirical efficiency of the pooling was six (number of tested newborn infants per test), thereby sparing 83% of the saliva tests. Only a minor 3.05 PCR cycle loss of sensitivity was observed for the pooled testing, in accordance with the theoretical prediction for an eight-sample pool. cCMV was identified in 54 newborn infants, with a birth prevalence of 3.4 per 1,000; 55.6% of infants identified with cCMV were asymptomatic at birth and would not have been otherwise targeted for screening. The study demonstrates the wide feasibility and benefits of pooled saliva testing as an efficient, cost-sparing and sensitive approach for universal screening of cCMV., (© 2024. The Author(s).)

Background: 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., Methods: 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., Results: 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)., Conclusions: A novel association was demonstrated between the development of T1D and early interventions and exposures among preterm newborns., Impact: 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., (© 2022. The Author(s), under exclusive licence to the International Pediatric Research Foundation, Inc.)

Objective: This study aimed to assess the association between treatment characteristics of prostaglandin E1 including initiation time and duration, maximal and cumulative doses, and adverse effects., Design: A retrospective cohort study in which medical records of neonates with duct-dependent lesions were studied for treatment parameters and adverse effects. Multivariable logistic regression model was applied for testing the effect PGE1 variables on outcomes., Main Outcome Measures: The primary outcomes of this study were association of adverse effects of PGE1 treatment with maximal dose, cumulative dose, and treatment duration. The secondary outcomes included safety of feeding in infants treated with PGE1., Results: Eighty-two infants with duct-dependent lesions receiving PGE1 were included. Several infants who received early PGE1 treatment required ventilation support. Feeds were ceased more often as the cumulative dose and duration of PGE1 treatment increased. Gastrointestinal adverse effects were significantly associated with the cumulative dose of PGE1 and treatment duration. Apneas, hyperthermia, and tachycardia were associated with maximal dose. Our data did not demonstrate a difference in the incidence of NEC associated with characteristics of PGE1 treatment., Conclusion: Cumulative PGE1 dose is associated with gastrointestinal adverse effects in neonates. Lower doses should be considered in neonates expecting prolonged PGE1 treatment.

Background: Less invasive forms of ventilation have evolved aiming to decrease bronchopulmonary dysplasia (BPD) morbidity. It is unclear whether changes in ventilation practices have been associated with improvements in respiratory outcomes., Objective: To examine the changes in ventilation modes in preterm neonates between two periods during the last decade and their impact on BPD prevalence., Methods: A retrospective chart review of very low birth weight infants and those born at less than 32 weeks gestation hospitalized during two periods: the years 2012-2013 and 2018-2019. The primary outcome was the prevalence of BPD. Study variables included the mode and duration of ventilation, duration of oxygen need, and perinatal clinical parameters., Results: Four hundred eighty-one infants were enrolled. Between the two study periods, a significant increase was observed in invasive (33%-47%, p = 0.002), and noninvasive ventilation rates (44%-72%, p < 0.001). The average duration of noninvasive ventilation increased significantly (from 9.24 to 14.08 days, p = 0.016). The total duration of respiratory support remained unchanged. The overall prevalence of moderate and severe BPD at 36 weeks corrected age remained approximately 40% in preterm infants born at less than 28 weeks gestation., Conclusion: The increasing use of non-invasive ventilation was not accompanied by a reduction in the use of invasive ventilation, nor by a reduced prevalence of BPD. The high prevalence of BPD remains a significant problem in extreme prematurity. Other interventions, in addition to less aggressive ventilation, need to be explored., (© 2023 Wiley Periodicals LLC.)

Adjusting the chronological age of preterm infants according to their gestational age is a widely accepted practice in the field of neurodevelopment. It has been suggested for the assessment of preterm infants with suspected infection, but has been poorly validated. Correcting for chronological age is especially critical in infants with a chronological age above 3 months, but a corrected age below 3 months due to the differences in assessment protocols. This study assessed the difference in incidence of serious bacterial infection (SBI) according to chronological and corrected age in preterm infants. A retrospective analysis of pediatric emergency department (PED) presentations was conducted for all 448 preterm infants born in between January 2010 and August 2019. Of the 448 preterm infants, 204 (46%) presented at one of 3 PEDs in Jerusalem, Israel, during their first year of life. Overall, 141 (31.4%) presented with fever and were included in the study. The infants were divided into 3 age groups: 1-corrected age >3 months; 2-chronological age >3 months, but corrected age <3 months; 3-chronological and corrected age <3 months. SBI was diagnosed in 2.6%, 16.7%, and 33.3% of the infants in groups 1, 2 and 3, respectively; ( p < 0.01, p = 0.17, p < 0.001). The incidence of SBI in the control group of 300 term infants <3 months presenting to the PED due to fever was 15.3%. Preterm infants with a corrected age <3 months are at increased risk for SBI, similarly to term infants <3 months of age. Age correction should thus be considered for preterm infants presenting with fever.

Background and Objectives: Very low birth weight (VLBW) infants are at high risk of developing acute kidney injury (AKI), presumably secondary to low kidney reserves, stressful postnatal events, and drug exposures. Our study aimed to identify the prevalence, risk factors, and outcomes associated with AKI in VLBW infants., Study Design: Records of all VLBW infants admitted to two medical campuses between January 2019 and June 2020 were retrospectively reviewed. AKI was classified using the modified KDIGO definition to include only serum creatinine. Risk factors and composite outcomes were compared between infants with and without AKI. We evaluated the main predictors of AKI and death with forward stepwise regression analysis., Results: 152 VLBW infants were enrolled. 21% of them developed AKI. Based on the multivariable analysis, the most significant predictors of AKI were the use of vasopressors, patent ductus arteriosus, and bloodstream infection. AKI had a strong and independent association with neonatal mortality., Conclusions: AKI is common in VLBW infants and is a significant risk factor for mortality. Efforts to prevent AKI are necessary to prevent its harmful effects.

Introduction: To investigate manifestations of developmental defects of enamel (DDE) in children born preterm (PT), and to explore possible neonatal morbidities related to DDE manifestation and severity., Methods: A cohort study of 52 children born before gestational week 32 and treated in the neonatal intensive care unit; and 55 children born at full term (FT) as a control group. All the children had a dental examination at age 1-4 years by a professional pediatric dentist. DDE was defined as an alteration in the enamel surface., Results: DDE were observed in 23 (44%) and 6 (11%) children, in the PT and FT groups, respectively, odds ratio (OR) = 6.47. The OR for damaged anterior teeth was 12.87 times higher in the PT group. DDE of molars was diagnosed in 19% and 11% of the respective groups. In the PT group, the OR of DDE was 4.1 higher among those with than without respiratory distress. The risk for DDE was 5.7 higher in those who received surfactant than in those who did not. Ventilation length, both invasive and non-invasive, was significantly related to DEE., Conclusions: DDE was higher in children born PT than FT. The DDE rate was lower than expected based on current literature, and considering the overall increase in survival; this suggests improvement in treatments affecting DEE. Respiratory distress syndrome, surfactant administration reflecting the need for intubation, longer ventilation and local oral trauma were risk factors for DDE. We recommend routine dental examinations in follow up of children born PT, particularly those exposed to assisted ventilation., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2022 Halperson, Shafir, Fux-Noy, Ram and Eventov-Friedman.)

Aim: About 50% of premature neonates (PN) are treated with transfusion of packed red blood cells (PRBC) collected from adult donors, which has been suggested to potentially provoke PN pathologies, characterized as blood circulation disorders. RBC have properties that are key determinants of blood circulation, primarily the cell deformability. In previous studies we have shown that transfusion of RBC with reduced deformability impaired the transfusion outcome. Although RBC of PN (PN-RBC) are larger, and their microvessels are narrower than those of adults, their blood circulation is very efficient, pointing to the possibility that the deformability of adults' PRBC is inferior to that of PN-RBC, and that treating PN with PRBC transfusion might, therefore, introduce a risk to the recipients. This would infer that PN should be given RBC with high deformability. However, since using PN-RBC is not feasible, the use of cord blood RBC (CB-RBC) is a sound alternative, assuming that the deformability of CB-RBC is comparable to that of PN-RBC.The present study is aimed at testing this hypothesis., Methods: We compared the deformability of (1) RBC of PN vs. the PRBC they received, and (2) PN-RBC vs. their autologous CB-RBC., Results: 1. The deformability of the transfused PRBC is indeed inferior to that of PN-RBC. 2. The deformability of CB-RBC is equivalent to that of PN-RBC., Conclusion: This study supports the notion that treating PN with transfusion of adults' PRBC has the potential to introduce a circulatory risk to the recipients, while CB-RBC, with their superior deformability, provides a safer and more effective PN-specific transfusion therapy.

Aim: To assess postnatal growth in infants with and without major neonatal morbidities., Methods: This study is based on analysis of data collected by the Israel Neonatal Network on VLBW infants (≤1500 g) born in Israel from 2009 to 2018. Postnatal growth was assessed in two 5 years epochs: 2009-2013 (n = 4583) and 2014-2018 (n = 4558). Outcome was considered as severe, mild and no postnatal growth failure (PNGF). Morbidities included respiratory distress syndrome, bronchopulmonary dysplasia, necrotising enterocolitis, patent ductus arteriosus and grades 3-4 intraventricular haemorrhage. Multinomial logistic regression analyses with the generalised estimating equation approach were applied., Results: The study population composed 9141 infants. Of them, 2089 had at least one major morbidity and 7052 infants had none. In infants with no morbidities, 2.1% had severe PNGF, 23.7% mild PNGF and 74.2% had no PNGF, as compared to 13.6%, 43.9% and 42.5%, respectively, in infants with any major neonatal morbidity (p < 0.0001)., Conclusion: Despite enormous advances in neonatal care, postnatal growth remains a challenge in VLBW infants, particularly in infants with major neonatal morbidities. Along with efforts to decrease morbidity, a more personalised plan and follow-up may be required in infants with major morbidities, given their high risk for diminished growth and potentially, adverse neurodevelopmental outcomes., (© 2022 Foundation Acta Paediatrica. Published by John Wiley & Sons Ltd.)

Background: Women with congenital heart disease (CHD) are at risk for peripartum cardiac deterioration. Previous studies focused on women after one or two pregnancies. We investigated effects of multiple births on maternal cardiac status by comparing women with CHD and ≥3 live births to women with <3 live births., Methods: Participants were identified from the Adult CHD clinic (2010-2018). Women with CHD and ≥3 live births were matched with women with <3 live births and similar CHD and age (±5 years). New York Heart Association class (NYHA), and cardiac impairment on echocardiography, scored by a cardiologist blinded to parity, medication, and arrhythmia were compared., Results: For 58 women in 29 matched pairs mean age was 42.4 (SD 14.2). Pregnancy modified WHO risk score was mild (I,II) in 71% and moderate-severe (II-III-IV) in 29%. Mean number of births was 1.2 (SD 0.8) for <3 live births group, 5 (SD 2.3) for ≥3 live births group. Mean difference in live births between pairs was 3.8 (SD 2.5). Seventeen (58.6%) pairs had concordant NYHA for women with ≥3 live births and those with <3 live births. Echocardiography score was concordant in 19 (65.5%) pairs. Women with ≥3 live births had lower NYHA in 8 (27.6%) pairs and lower echocardiography scores in 6 (20.6%) pairs. Differences were not significant (p = 0.129, p = 0.801). No difference was found in medication use or arrhythmia., Conclusions: Cardiac status was not different for women with mainly mild-moderate CHD when comparing women with ≥3 live births to those with <3 live births., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2022 The Authors.)

Background: Growth hormone therapy is indicated for children who are both born 'small for gestational age' (SGA) and do not achieve adequate catch-up growth (ACUG)., Objective: To evaluate the actual incidence of infants born SGA and their actual ACUG., Methods: Birth weight data from the newborn registry at two hospitals were analysed during four consecutive years. SGA was defined according to WHO parameters and the corresponding Israeli criteria. Follow-up measurements of height and weight were abstracted from either the Ministry of Health-child growth follow-up centres, or their paediatrician clinic. ACUG was declared when the height reached was above -2.5 or -2 standard deviations (SDS) from the mean for age and gender., Results: Out of 43 307, only 524 babies in the cohort (1.2%) were SGA (52% of expected). This finding was consistent annually. Out of the 446 SGA born children with available growth data (85%) during 4-8 years, 405 children (90.8%) reached a height greater than -2SDS and 428 (96%!) reached a height greater than -2.5 SDS. Term children had higher rate of ACUG achievement as compared to preterm 97.2% vs 86.8% (P < .001). Birth week and birth weight were also related to achievement of ACUG (P < .001)., Conclusion: This large representative, heterogeneous and Western Caucasian cohort indicates that the actual number of SGA newborns is nearly half of the expected and that the actual prevalence of ACUG is also significantly higher than previously reported. These findings may have an impact on morbidity, health cost planning and growth hormone requirements in SGA babies., (© 2021 John Wiley & Sons Ltd.)

Objectives: To assess infection rates predischarge and postdischarge in breast milk-fed newborns with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-positive mothers who were separated postdelivery from their mothers and discharged from the hospital. Also, we aim to evaluate breastfeeding rates predischarge and postdischarge., Methods: Nasopharyngeal swabs for SARS-CoV-2 were obtained from symptomatic and high-risk women in the delivery room. Mothers with positive SARS-CoV-2 test results were separated from the newborns. Newborns were screened within 48 hours of delivery, and anti-infectious guidelines were imparted to the mothers before discharge. Rescreening took place ≥14 days postdischarge. Data regarding SARS-CoV-2-positive household members and breastfeeding were obtained by follow-up phone calls., Results: A total of 73 newborns of SARS-CoV-2-positive mothers were born in Israel during the ∼3-month period under study. Overall, 55 participated in this study. All neonates tested negative for the virus postdelivery. A total 74.5% of the neonates were fed unpasteurized expressed breast milk during the postpartum separation until discharge. Eighty-nine percent of the neonates were discharged from the hospital after their mothers were instructed in anti-infection measures. In 40% of the households, there were additional SARS-CoV-2-positive residents. A total of 85% of the newborns were breastfed postdischarge. Results for all 60% of the newborns retested for SARS-CoV-2 postdischarge were negative., Conclusions: No viral infection was identified in neonates born to and separated from their SARS-CoV-2-positive mothers at birth and subsequently fed unpasteurized breast milk. All infants breastfed at home remained SARS-CoV-2 negative. These findings may provide insights regarding the redundancy of postpartum mother-newborn separation in SARS-CoV-2-positive women and, assuming precautions are adhered to, support the safety of breast milk., Competing Interests: POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose., (Copyright © 2021 by the American Academy of Pediatrics.)

AMOTL1 belongs to the Motin family of proteins that are involved in organogenesis and tumorigenesis through regulation of cellular migration, tube formation, and angiogenesis. While involvement of all AMOTs in development or suppression of cancers is relatively well described, little is known about the congenital phenotype of pathogenic variants in these genes in humans. Recently, a heterozygous variant in AMOTL1 was published in association with orofacial clefts and cardiac abnormalities in an affected father and his daughter. However, studies in mice did not recapitulate the human phenotype and the case was summarized as inconclusive. We present a female infant with cleft lip and palate, imperforate anus and dysmorphic features, in whom trio exome sequencing revealed a de novo variant in AMOTL1 affecting a highly conserved amino acid (c.479C>T; p.[Pro160Leu]). Bioinformatic predictions and in silico modeling supported pathogenicity. This case reinforces the conjecture regarding the disruptive effect of pathogenic variants in AMOTL1 on organ formation in humans. Studies of additional families will reveal the full phenotypic spectrum associated with this multiple malformation syndrome., (© 2020 Wiley Periodicals LLC.)

Introduction: Apnea of prematurity affects the majority of infants born before 34 weeks of complete gestation. Significant recurrent apnea of prematurity is associated with both short and long term complications and is a risk factor for increased mortality and neurodevelopmental disability. The current review discusses the recent advances in the understanding of the pathophysiology of apnea of prematurity, as well as the clinical questions relevant to physicians and staff treating infants with apnea of prematurity. Finally, we discuss monitoring and discharge decisions, and present recommendations following discharge from the neonatal intensive care unit.

Background : Women may be unaware of the potential impact on subsequent deliveries of the decision to undergo primary breech cesarean (PBC) delivery rather than attempt external cephalic version (ECV). We investigated cesarean delivery rates and adverse maternal outcomes in the subsequent delivery following management of breech presentation by ECV versus PBC. Methods: This retrospective study identified women who delivered subsequent to breech presentation managed by attempted ECV or PBC. We assessed cesarean delivery rates and adverse maternal outcomes including hemorrhage, placental complications, infection, and obstetric complications in the subsequent delivery following attempted ECV versus PBC. Results: We identified 307 women who had attempted ECV and 508 with PBC in the index breech pregnancy. Following attempted ECV, 47 (15.3%) women had cesarean delivery in the subsequent pregnancy versus 246 (48.4%) following PBC, adjusted OR 0.24, 95% CI 0.16-0.35 for subsequent cesarean delivery after attempted ECV in the index pregnancy. The frequency of composite adverse outcomes related to cesarean delivery was 30 (9.8%) following attempted ECV versus 104 (20.5%) after PBC, p  < .0001. The frequency of composite severe adverse maternal outcome was similar following attempted ECV 25 (8.8%) versus PBC 59 (11.9%). Conclusions: The current study suggests that attempted external cephalic version was associated with a five-fold decrease risk to undergo cesarean in the subsequent delivery and a significantly decreased frequency of composite adverse outcomes related to cesarean delivery in the subsequent delivery.

Objective: To evaluate factors associated with subgaleal hemorrhage (SGH) severity following attempted vacuum-assisted delivery (VAD)., Study Design: This retrospective cohort study was conducted in a tertiary medical center. The population comprised parturients who delivered at our medical center during 2009-2018, and who underwent attempted VAD with singleton pregnancies that resulted in neonatal SGH formation. SGH severity was classified as mild and non-mild (moderate or severe). The main outcome measures were determinants associated with SGH severity., Results: Among 350 neonates with SGH, the degree of severity was non-mild for 48 (13.7%). Compared to the mild group, in the non-mild group, small for gestational age was more common (8.2% vs. 2.6%, p = 0.04). Compared to the mothers in the mild group, in the non-mild group, the proportion with two or more deliveries was lower (0% vs. 7.3%, p = 0.05), gestational diabetes was more common (12.5% vs. 4.6%, p = 0.02), the rate of cervical ripening was higher (27.1% vs. 12.9%, p = 0.02), the duration of the second stage of delivery was longer (mean 177 vs. 152 min, p = 0.04), and the rate of two dislodgments was higher (31.2% vs. 15.2%, p = 0.006). On multivariate analysis, only cervical ripening (adjusted odds ratio [OR]: 2.50; 95% confidence interval [CI]: 1.20-5.26; P = 0.01 and second stage duration (adjusted OR: 1.13; 95% [CI]: 1.00-1.29; P = 0.05) were independently associated with more severe SGH., Conclusions: The duration of second stage and ripening of the cervix during induction of labor are independently associated with SGH severity following attempted VAD., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: The current study aims to evaluate the association between preterm birth and the quality of mother-child interaction of very preterm-, moderate preterm-, and full-term-born children at 18 and 36 months and to determine whether developmental and behavioral characteristics mediate the association between preterm birth and the quality of mother-child interaction., Method: Participants included 110 preterm-born children and 39 full-term-born children assessed at ages 18 and 36 months. Mother-child free play interactions, the Mullen Scales of Early Learning, the Infant Behavior Questionnaire, and the Early Childhood Behavior Questionnaire were administered., Results: Significant associations between preterm birth and the quality of mother-child interaction were found at 18 and 36 months. The mother-child interaction quality was less optimal for the preterm-born children compared with the full-term-born children, mainly so for the very preterm-born children. Unlike behavioral characteristics, cognitive development was found to mediate the association between the gestational age-based group and the quality of mother-child interaction., Conclusions: Intervention programs for preterm-born children and their families, should consider maternal and children's behaviors during mother-child interactions, in addition to cognitive, language, motor and emotional regulation abilities, and particularly so with very preterm-born children, who exhibit slower cognitive development., Competing Interests: Declaration of Competing Interest The authors have no conflicts of interest to disclose., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Purpose: The purpose of the study was to evaluate the occurrence of subgaleal hemorrhage (SGH) following non-assisted vaginal delivery (normal vaginal delivery or cesarean delivery), and to characterize associated factors, clinical course, and outcomes, compared to attempted assisted vaginal delivery (AVD)-associated SGH METHODS: A retrospective cohort study was conducted. All cases of SGH encountered following delivery of a singleton neonate at Hadassah, Hebrew University Medical Center during 2011-2018 were included. Maternal, fetal, intrapartum, and neonatal characteristics and outcomes were compared between AVD-related and non-AVD-related SGH groups., Results: The overall incidence of SGH was 4.5/1000 (369/82,256) singleton deliveries. The incidences of AVD- and non-AVD-related SGH were 44.6/1000 (350/7852) and 0.3/1000 (19/74,404) singleton deliveries, respectively. Ten (53%) of the 19 non-AVD-related SGH were diagnosed after vaginal delivery and 9 (47%) after an urgent cesarean section. SGH severity was mild, moderate, and severe in 68%, 16%, and 16% of the cases, respectively. SGH severity did not differ between the attempted AVD group and the non-AVD-related SGH group. A higher proportion of neonates with non-AVD SGH required phototherapy treatment than did those diagnosed with AVD-related SGH (56% vs. 24%, P = 0.003). Other neonatal outcomes, including Apgar scores, maximal bilirubin level, length of stay, and the rate of composite adverse outcomes, did not differ between the groups., Conclusions: SGH, although rare, may be diagnosed after unassisted vaginal or cesarean delivery in the absence of an AVD attempt. We advocate continuing education for all medical staff who participate in peripartum and neonatal care, regarding the possible occurrence of non-AVD-related SGH.

Cases with multiple molecular diagnoses are challenging to diagnose clinically, yet may be resolved by unbiased exome sequencing analysis. We report an infant with developmental delay, severe growth delay, dysmorphic features, and multiple congenital anomalies including retinal coloboma, congenital pyloric stenosis, and circumferential skin creases. Exome sequencing identified a homozygous missense variant in MAPRE2 and a homozygous stopgain (nonsense) variant in CDON. Variants in MAPRE2, encoding a regulator of microtubule dynamics, lead to congenital symmetric circumferential skin creases type 2, with associated dysmorphism, small growth parameters, and congenital cardiac and genital anomalies. Monoallelic variants in CDON, encoding a coreceptor for sonic hedgehog, have been associated with autosomal dominant pituitary stalk interruption syndrome and holoprosencephaly. Cdon-/- mice have multiple eye defects including coloboma, consistent with the observed human phenotype. Thus, the complex phenotypic presentation of the infant may potentially be attributed to a dual molecular diagnosis. Furthermore, we present CDON as a candidate gene for coloboma formation in addition to the known holoprosencephaly phenotype, and propose to expand the allelic spectrum of CDON to variants associated with autosomal recessive inheritance in addition to dominant inheritance., (© 2019 Wiley Periodicals, Inc.)

Introduction: Subgaleal hemorrhage (SGH) is a life-threatening neonatal condition that is strongly associated with vacuum assisted delivery (VAD). The factors associated with the development of SGH following VAD are not well-established. We aimed to evaluate the factors associated with the development of SGH following attempted VAD., Material and Methods: A retrospective case-control study of women who delivered at a tertiary university-affiliated medical center in Jerusalem, Israel, during 2009-2018. Cases comprised all parturients with singleton pregnancies for whom attempted VAD resulted in neonatal SGH. A control group of VAD attempts was established by matching one-to-one according to gestational age at delivery, parity and year of delivery. Fetal, intrapartum and vacuum procedure characteristics were compared between the groups., Results: In all, 313 (89.5%) of the 350 attempted VAD were nulliparous. Baseline maternal and fetal characteristics were similar between the groups except for higher neonatal birthweight in the SGH group. In multivariate logistic regression analysis, only six independent risk factors were significantly associated with the development of SGH: second-stage duration (for each 30-minute increase, adjusted odds ratio [OR] 1.13; 95% confidence intervals [CI] 1.04-1.25; P = .006), presence of meconium-stained amniotic fluid (adjusted OR 2.61; 95% CI 1.52-4.48; P = .001), presence of caput succedaneum (adjusted OR 1.79; 95% CI 1.11-2.88; P = .01), duration of VAD (for each 3-minute increase, adjusted OR 2.04; 95% CI 1.72, 2.38; P < .001), number of dislodgments (adjusted OR 2.38; 95% CI 1.66-3.44; P < .001), and fetal head station (adjusted OR 3.57; 95% CI 1.42-8.33; P = .006). Receiver operating characteristic curves showed that VAD duration of ≥15 minutes had a 96.7% sensitivity and 75.0% specificity in predicting SGH formation, with an area under the curve equal to .849., Conclusions: Vacuum duration, the number of dislodgments, the duration of second stage of delivery, fetal head station, the presence of caput succedaneum and the presence of meconium were found to be independently associated with SGH formation., (© 2019 Nordic Federation of Societies of Obstetrics and Gynecology.)

Background: Saliva real-time polymerase chain reaction (PCR) was shown to be sensitive and specific for the detection of congenital cytomegalovirus (cCMV) in universal screening studies. In the current study, we assessed the performance of saliva real-time PCR in newborns undergoing targeted cCMV screening., Methods: Saliva real-time PCR results were prospectively correlated with reference-standard urine detection in newborns undergoing targeted cCMV screening over a 3-year period, in successive validation (concurrent testing of all saliva and urine specimens) and routine-screening (confirmatory urine testing of positive saliva results) implementation phases., Results: The sensitivity, specificity, and positive and negative predictive values of saliva real-time PCR were 98.3% (95% confidence interval, 90.8%-99.9%), 91.5% (89.3%-93.3%), 45.6% (36.7%-54.7%), and 99.9% (99.2%-99.9%), respectively, in 856 concurrently tested newborns. True-positive saliva real-time PCR detection (defined in relation to urine detection) was associated with earlier saliva sampling (P = .002) and a higher saliva viral load (P < .001). We further identified a saliva viral load cutoff value that reliably distinguished between true-positive and false-positive saliva results., Conclusions: In newborns undergoing targeted screening for cCMV, saliva real-time PCR is highly sensitive yet has a low positive predictive value, necessitating confirmatory testing. Early sampling and application of a validated viral load cutoff could improve the assay performance and support its large-scale implementation in this growing clinical setting., (© The Author(s) 2019. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Gestational age determination by traditional tools (last menstrual period, ultrasonography measurements and Ballard Maturational Assessment in newborns) has major limitations and therefore there is a need to find different approaches. In this study, we looked for a molecular marker that can be used to determine the accurate gestational age of the newborn. To this end, we performed reduced representation bisulfite sequencing (RRBS) on 41 cord blood and matching placenta samples from women between 25 and 40 weeks of gestation and generated an epigenetic clock based on the methylation level at different loci in the genome. We identified a set of 332 differentially methylated regions (DMRs) that undergo demethylation in late gestational age in cord blood cells and can predict the gestational age (r = -.7, P = 2E-05). Once the set of 411 DMRs that undergo de novo methylation in late gestational age was used in combination with the first set, it generated a more accurate clock (R = .77, P = 1.87E-05). We have compared gestational age determined by Ballard score assessment with our epigenetic clock and found high concordance. Taken together, this study demonstrates that DNA methylation can accurately predict gestational age and thus may serve as a good clinical predictor., (© 2019 John Wiley & Sons, Ltd.)

Background: Early-term cesarean delivery (CD) increases neonatal respiratory morbidity; however, planned late-term cesarean delivery (CD) may generate urgent CD related to spontaneous onset of labor., Aims: We investigated maternal and neonatal morbidity for planned early (37/38 week) versus late-term (39/40 weeks) CD. Our primary study aim was to investigate severe maternal morbidity and general anesthesia rates according to early versus late-term CD. Our secondary study aims were to investigate the rate of urgent surgery and other measures of maternal morbidity, and neonatal morbidity, according to early versus late-term CD and according to urgent versus elective planned CD., Methods: In our retrospective, ethically approved study of planned CD we compared maternal morbidity and neonatal respiratory morbidity, for early versus late-term CD., Results: Among 370 early versus 300 late-term CD, women who delivered at late-term CD had significantly higher rates of urgent surgery 101 (33.7%) versus 85 (23.0%) at early-term, p = .002; spontaneous onset of labor 85 (28.3%) versus 67 (18.1%), p = .0002 and out-of-hours surgery 101 (33.7%) versus 64 (17.3%), p < .0001. The frequency of neonatal respiratory morbidity composite was 10 (2.7%) for early versus 1 (0.3%) for late-term CD, p = .03., Conclusions: Late-term CD was not associated with increased maternal morbidity or use of general anesthesia in our tertiary institution. Prior reports of increased neonatal respiratory morbidity at early term CD were confirmed. Of concern, late-term CD was associated with urgent and out-of-hours CD.

Objective: To examine breastfeeding exclusivity and intensity of early term (ET) infants, born at 37-38 weeks, and term infants, born at 39-41 weeks, during the postpartum hospitalization and the first month of life. Materials and Methods: This was a prospective cohort study of 358 mothers of ET and term infants during the first 72 hours after birth and at 1 month of age. Logistic analysis was used to calculate unadjusted and adjusted odds ratios (aORs) and control for confounding variables. Results: ET infants had significantly lower breastfeeding in the first hour (aOR = 0.43, 95% confidence interval [CI] = 0.21-0.87), lower exclusive breastfeeding in the hospital and at 1 month (aOR = 0.46, 95% CI = 0.27-0.71 and aOR = 0.40, 95% CI = 0.22-0.71), and lower rates of high breastfeeding intensity in the hospital and at 1 month (aOR = 0.39, 95% CI = 0.22-0.71 and aOR = 0.33, 95% CI = 0.15-0.72), after controlling for confounding variables. ET infants had more emergency room (ER) visits in the first month (OR = 7.6, 95% CI = 1.01-60.6), and all ET infants who had ER visits were exclusively breastfed. Conclusions: ET infants had lower breastfeeding in the hospital and at 1 month. They should be regarded as a group at risk for breastfeeding challenges and infant morbidity.

Aim: We surveyed whether clinicians used the WhatsApp messaging application to view neonatal chest radiographs and asked a sub-sample to compare them with computer screen viewings., Methods: The study was conducted at three university-affiliated medical centres in Israel from June-December 2016. Questionnaires on using smartphones for professional purposes were completed by 68/71 paediatric residents and 20/28 neonatologists. In addition, 11 neonatologists viewed 20 chest radiographs on a computer screen followed by a smartphone and 10 viewed the same radiographs in the opposite order, separated by a washout period of 2 months. After another 2 months, five from each group viewed the same radiographs on a computer screen. Different interpretations between viewing modes were assessed., Results: Most respondents used WhatsApp to send chest radiographs for consultation: 82% of the paediatric residents and 80% of the neonatologists. The mean number of inconsistencies in diagnosis was 3.7/20 between two computer views and 2.9/20 between computer and smartphone views (p = 0.88) and the disease severity means were 3.7/20 and 2.85/20, respectively (p = 0.94). Neonatologists using WhatsApp only determined umbilical line placement in 80% of cases., Conclusion: WhatsApp was reliable for preliminary interpretation of neonatal chest radiographs, but caution was needed when assessing umbilical lines., (©2018 Foundation Acta Paediatrica. Published by John Wiley & Sons Ltd.)

Background: The aim of this study was to examine the long-term risk for autism spectrum disorders (ASD) in individuals who are born preterm and full-term using both observational instruments and parental reports. Neonatal risk factors and developmental characteristics associated with ASD risk were also examined., Method: Participants included 110 preterm children (born at a gestational age of ≤ 34 weeks) and 39 full-term children assessed at ages 18, 24, and 36 months. The Autism Diagnostic Observation Schedule, the Modified Checklist for Autism in Toddlers, the Autism Diagnostic Interview-Revised, the Social Communication Questionnaire, and the Mullen Scales of Early Learning were administered., Results and Conclusions: The long-term risk for ASD was higher when parental reports were employed compared to observational instruments. At 18 and 24 months, a higher long-term risk for ASD was found for preterm children compared to full-term children. At 36 months, only one preterm child and one full-term child met the cutoff for ASD based on the ADOS, yet clinical judgment and parental reports supported an ASD diagnosis for the preterm child only. Earlier gestational age and lower general developmental abilities were associated with elevated ASD risk among preterm children.

Background and Objectives: Preterm infants are at risk for neuro-developmental impairments and atypical developmental trajectories. The aims of this study were to delineate early developmental trajectories of preterm and full-term infants., Methods: The cognitive, language, and motor development of 149 infants - 19 extremely preterm (EPT), 34 very preterm (VPT), 57 moderately preterm (MPT), and 39 full-term (FT) - was evaluated using Mullen Scales at 1, 4, 8, 12, and 18 months. Mixed models were applied to examine group differences. Gender, maternal education, and neurobehavior were included as predictors of developmental trajectories., Results: The EPT and VPT infants achieved significantly lower scores than the FT infants in all domains, with a significantly increasing gap over time. The MPT infants' trajectories were more favorable than those of the EPT and VPT infants yet lower than the FT infants on the Visual Reception, Gross, and Fine Motor subscales. Male gender and lower maternal education were associated with lower scores that declined over time. Abnormal neonatal neurobehavior was associated lower Mullen scores and with less stability in scores over time., Conclusions: The EPT and VPT infants were found to have disadvantages across all domains. The MPT infants revealed more favorable developmental trajectories yet displayed vulnerability compared to the FT infants. Gender, maternal education, and neonatal neurobehavior are important in predicting the developmental outcomes of preterm infants., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Background & Aims: Necrotizing Enterocolitis (NEC) is a severe inflammatory disorder of the intestine endangering the health and survival of preterm infants. It is well established that the gut barrier is severely damaged in NEC patients, nonetheless an in depth investigation of modifications at the transcriptional and translational levels of tight junction genes and proteins during NEC are still missing. The aim of this study was to investigate changes in the expression of tight junctions and other associated proteins during NEC and determine their correlation to the disease severity., Methods: We examined intestinal specimens from six NEC patients and compared them with six control specimens from patients that underwent surgeries for reasons other than NEC. The expression of genes was analyzed by real time PCR and protein expression by immunohistochemistry., Results: The tight junction genes ZO-1, occludin, cingulin and claudin-4 were significantly down regulated in NEC. Furthermore TLR4, BAX and SIRT1 genes were found to be significantly down regulated while HIF-1A showed a trend of up regulation in NEC patients. These changes were found to correlate with the severity of the disease. Additionally we demonstrated in an ex-vivo model that hypoxic conditions initiated a destructive process of the epithelial barrier. We also showed that the expression of the tight junction proteins ZO-1 and occludin were significantly down regulated in NEC specimens., Conclusions: The expression of tight junction proteins and their encoding genes are significantly altered in NEC. We surmise that SIRT1 and HIF-1A may play a role in controlling these effects., (Copyright © 2017. Published by Elsevier B.V.)

The aim of this study is to examine the effect of age correction on the developmental assessment scores of preterm infants, using for the first time, the Mullen scales of early learning (MSEL) test. Participants included 110 preterm infants (born at a gestational age of ≤ 34 weeks) at ages 1, 4, 8, 12, 18, 24 and 36 months. The corrected age-based MSEL composite score and each of the five MSEL scale scores were significantly higher than chronological age-based scores at all ages. These corrected scores were significantly higher than the chronological scores regardless of gestational age whether weight was, or adequate or small for gestational age. Larger differences between corrected and chronological age-based scores significantly correlated with earlier gestational age and with lower birth weight between 1 and 24 months but not at 36 months. Using chronological age-based scores yielded significantly more infants identified with developmental delays than using corrected age-based scores. The findings indicate that clinicians and researchers, as well as family members, should be aware of and acknowledge the distinction between corrected and chronological ages when evaluating preterm infants in research and clinical practices., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Very-preterm (VPT), moderately-preterm (MPT), and full-term (FT) infants' emotion-regulation behaviors were assessed via the Still-Face procedure at a corrected age of four months. As a developmental task during the first year of life, emotion regulation is important for social and cognitive development. Although substantial evidence indicates that VPT infants exhibit emotion-regulation difficulties, little is known about MPT infants' emotion regulation capabilities, this group also possibly being at risk. The participants included 135 parent-infant dyads: 46 VPT (gestational age 24-32 weeks), 51 MPT (gestational age 32-34 weeks), and 38 FT (gestational age 37-41 weeks). The infants' affect, gaze-aversion, and self-comforting behaviors were coded. Preterm infants responded to parental still face in similar fashion to FT infants, displaying robust still-face and recovery effects. The preterm infants exhibited less developed emotion-regulation behaviors, however, manifested in less positive affect and more gaze aversion in the face-to-face and reunion episodes compared to FT infants. With respect to self-comforting behaviors, each group displayed a significantly different pattern of behaviors throughout the procedure, suggesting better emotion regulation skills among MPT infants compared to the VPT infants. The findings on gaze aversion and self-comforting behaviors could have implications for strategies to incorporate into intervention programs supporting development of emotion regulation skills., (Copyright © 2018 Elsevier Inc. All rights reserved.)