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Objectives: This case report delves into the intricate management of a newborn with transient neonatal diabetes mellitus (TNDM), shedding light on the complexities and challenges in treatment decisions., Case Presentation: Born prematurely with a low birth weight and a maternal background of gestational diabetes, the infant developed hyperglycaemia necessitating intravenous insulin therapy. Subsequent genetic testing confirmed 6q24-TNDM, due to the uniparental disomy of the whole of chromosome 6. Glibenclamide, a second-generation sulfonylurea, was cautiously introduced but discontinued due to adverse effects. Despite post-meal hyperglycaemia, blood glucose levels stabilised over subsequent weeks. Regular follow-ups demonstrated appropriate growth and development and the resolution of diabetes., Conclusions: This unique case highlights the need for multidisciplinary collaboration, tailored treatment strategies, and vigilant monitoring in managing 6q24-TNDM., (© 2024 Walter de Gruyter GmbH, Berlin/Boston.)

Diuretics are medications that promote the excretion of water and electrolytes. They are primarily used in the management and treatment of states of inappropriate salt and water retention. Diuretics represent one of the most common classes of drugs administered to sick neonates, the more so in very low birth weight infants. Diuretic drugs, especially loop diuretics, are often administered in the neonatal intensive care unit as off-label medications. This is the case for a variety of clinical situations, in which an increase in sodium excretion is not the primary goal of treatment (transitory tachypnoea of the newborn at term, hyaline membrane disease, patent ductus arteriosus of preterm infants). Thiazides and furosemide are widely used to treat preterm infants with oxygen-dependent chronic lung disease, despite a lack of data on beneficial effect of long-term therapy on pulmonary function or clinical outcome. This article reviews the mechanism of action, indications, administration, posology, adverse effects and contraindications of diuretics in newborn infants. Based on the most recent information available in the literature, we will discuss data supporting (or questioning) the use of diuretic in specific neonatal diseases. Research priorities over this issue will be briefly presented.

Background: This study aimed to examine early clinical and laboratory findings in infants born to mothers who had organ transplants and received immunosuppressive treatment., Methods: Between 2016 and 2023, the study examined infants of mothers who underwent organ transplantation and were receiving immunosuppressive treatment, and followed at the Department of Neonatology at Akdeniz University. Demographic, clinical, and laboratory characteristics of mothers and infants were recorded. On the first day of life, complete blood count values were examined, as well as potassium levels on the first, third, and seventh days, and creatinine levels on the third and seventh days. The tacrolimus blood level was calculated by taking the average of the tacrolimus blood values of the mother measured during the pregnancy. The infants were evaluated for any potential morbidities caused by intrauterine immunosuppressive drug exposure., Results: The study included 21 mothers (some with multiple pregnancies) and 27 infants. According to the findings of this study, 74% of these infants were born premature, 67% had low birth weight, and all were delivered via cesarean section. Prematurity was associated with the morbidities found in the infants. In the early period, lymphopenia was detected in 37%, neutropenia in 25.9%, thrombocytopenia in 11.1%, hyperkalemia in 18.5%, and creatinine elevation in 7.4%, all of which returned to normal within a few days. There was no significant relationship between maternal tacrolimus blood levels and infant potassium and creatinine levels., Conclusion: Apart from an increased risk of prematurity, low birth weight, and cesarean delivery, no effects were observed in these infants during the early period. However, long-term follow-up is necessary to monitor for any potential morbidities.

Introduction: We evaluated the relative effects of newer versus older medications for neonatal conditions and trends in margin of superiority across generations., Materials and Methods: We assessed network meta-analyses (NMAs) on neonatal pharmacological interventions identified from MEDLINE, Cochrane, and PROSPERO. Interventions were chronologically arranged based on the earliest study and compared for their effects against placebo or no treatment and their immediate predecessor. We assessed the time trend in effect sizes using the Mann-Kendall test., Results: From 8,048 retrieved records, 10 neonatal NMAs covering 352 trials and 102,653 participants were included. Compared to placebo, 56/61 (91.8%) interventions showed superiority with 23 (37.7%) statistically significant. Compared to previous generation, 47/72 (65.3%) showed superiority with 3 (4.2%) statistically significant. No significant trends in effect sizes were observed across generations for most conditions (p = 0.09-1)., Conclusions: We found no evidence that newer generation medications in neonatal care are consistently more effective than older generation medications., (© 2024 The Author(s). Published by S. Karger AG, Basel.)

Background: Respiratory distress is common in neonates admitted to neonatal intensive care units. Additionally, infectious diseases such as intrauterine infections or vertical transmission are important underlying causes of respiratory failure. However, pathogens often cannot be identified in neonates, and there are many cases in which antibacterial drugs are empirically administered. Next-generation sequencing (NGS) is advantageous in that it can detect trace amounts of bacteria that cannot be detected by culturing or bacteria that are difficult to cultivate. However, there are few reports on the diagnosis of infectious diseases using NGS in the neonatal field, especially those targeting respiratory distress., Objective: The purpose of our study was to investigate the microorganisms associated with neonatal respiratory distress and to determine whether less invasive collection specimens such as plasma and gastric fluid are useful., Methods: Neonates were prospectively recruited between January and August 2020 from Nagoya University Hospital. The inclusion criteria were as follows: 1) admission to the neonatal intensive care unit; 2) respiratory distress presentation within 48 h of birth; and 3) suspected infection, collection of blood culture, and administration of antibiotics. Plasma samples and blood cultures were simultaneously collected. Gastric fluid samples were also collected if the patient was not started on enteral nutrition. Information on the patients and their mothers were collected from the medical records. DNA was extracted from 140 µL of plasma and gastric fluid samples. DNA sequencing libraries were prepared, and their quality was analyzed. DNA libraries were sequenced using high-throughput NGS. The NGS data of plasma and gastric fluid samples were analyzed using the metagenomic pipeline PATHDET, which calculated the number of reads assigned to microorganisms and their relative abundance. Putative pathogens were listed., Results: Overall, 30 plasma samples and 25 gastric fluid samples from 30 neonates were analyzed. Microorganism-derived reads of gastric fluid samples were significantly higher than those of plasma samples. Transient tachypnea of the newborn was the most common cause of respiratory distress with 13 cases (43%), followed by respiratory distress syndrome with 7 cases (23%). There were 8 cases (29%) of chorioamnionitis and 7 cases (25%) of funisitis pathologically diagnosed. All blood cultures were negative, and only two gastric fluid cultures were positive for group B Streptococcus (Patient 15) and Candida albicans (Patient 24). Putative pathogens that met the positive criteria for PATHET were detected in four gastric fluid samples, one of which was group B Streptococcus from Patient 15. In the gastric fluid sample of Patient 24, Candida albicans were detected by NGS but did not meet the positive criteria for PATHDET. Cluster analysis of the plasma samples divided them into two study groups, and the indicator genera of each cluster ( Phormidium or Toxoplasma ) are shown in Figure 1. Clinical findings did not show any significant differences between the two groups. Cluster analysis of the gastric fluid samples divided them into three study groups, and the indicator genera of each cluster ( Ureaplasma , Nostoc , and Streptococcus ) are shown in Figure 2. The incidence rate of chorioamnionitis was significantly higher in Ureaplasma group than in the other two groups., Conclusion: Gastric fluid may be useful for assessing neonatal patients with respiratory distress. To the best of our knowledge, this was the first study to reveal that the presence of Ureaplasma in the gastric fluid of neonates with respiratory distress was associated with chorioamnionitis. The early diagnosis of intra-amniotic infections using gastric fluid and its treatment may change the treatment strategy for neonatal respiratory distress. Screening for Ureaplasma in neonates with respiratory distress may reduce the need for empirical antibiotic administration. Further research is required to confirm these findings.

Background: Neonatal hypoglycemia (NH) is the most prevalent metabolic disorder in neonates and glucose gel in oral solution is a relatively new treatment option for NH. We aimed to determine whether oral glucose gel can prevent NH., Methods: We conducted an open literature search using PubMed, Embase, Cochrane Library, and Web of Science. We used relative risk as the statistical data, expressed each outcome effect as a 95% confidence interval, and conducted a heterogeneity test. If heterogeneity statistics indicated that I2 was ≥ 50%, the random effects model analysis was used; otherwise, the fixed effects model analysis was conducted, and sensitivity analyses were conducted for all outcomes., Results: In this review, we included a total of 10 studies involving 4801 neonates. Meta-analysis revealed that there were no significant differences between the preventive oral glucose gel group and the control group in terms of blood glucose concentration, glucose concentration 30 minutes after the first breastfeeding, length of stay, Bayley-III composite score, subsequent need for intravenous injection of glucose, 24-hour glucose > 50 mg/dL, separation from mother for treatment of hypoglycemia/admitted to neonatal intensive care unit for hypoglycemia, normoglycemia after 1 to 2 treatments, or normoglycemia after more than 2 treatments, breastfeeding at discharge, delayed feeding, neurosensory impairment, parental satisfaction, developmental delay, and seizure. The subsequent intake was significantly lower in the glucose gel group compared to the control group., Interpretation: The use of oral glucose gel as a preventative measure may not reduce the incidence of NH. In order to assess the efficacy of glucose gel in preventing NH, a more high-quality, large-sample, and rigorously designed randomized controlled trial is required., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2023 the Author(s). Published by Wolters Kluwer Health, Inc.)

Elizabethkingia anophelis is a Gram-negative bacillus that can exhibit highly resistant phenotypes against most antibiotics with evidence of efficacy and safety in the neonatal population. Given the limited antimicrobial options, clinicians may be forced into challenging treatment scenarios when faced with central nervous system infections in premature neonates caused by E. anophelis . We report a case of successful treatment of hospital-acquired meningitis and bacteremia caused by E. anophelis at 11 days of life in a male infant born at 29 weeks, 1 day gestation and birth weight of 1.41 kg. Therapy consisted of vancomycin, dose adjusted to maintain goal troughs of 15-20 mg/L, and rifampin 10 mg/kg/dose every 12 hours, with ciprofloxacin 15 mg/kg/dose every 12 hours and trimethoprim/sulfamethoxazole 5 mg/kg/dose every 12 hours added due to antimicrobial susceptibilities and unsatisfactory response, for a total of 21 days. Following initiation of this multidrug regimen, repeat cultures were negative, laboratory parameters improved [with exception of elevated cerebrospinal fluid (CSF) white blood cell count], the patient remained otherwise stable, and there were no adverse effects noted from therapy. Complications after treatment included the requirement of bilateral hearing aids and the development of hydrocephalus necessitating ventriculoperitoneal shunt placement. To our knowledge, we report the first case of meningitis in a premature neonate initially identified as E. anophelis in the United States treated with this regimen which led to successful microbiologic eradication with no antimicrobial safety concerns., Competing Interests: T.M. has received grant support from Stellus Rx and has participated in scientific advisory boards for AbbVie Inc. and Basilea Pharmaceutica. The other authors have no conflicts of interest to disclose., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Introduction/objective: Magnesium sulfate (MgSO 4 ) treatment is widely used for fetal neuroprotection despite the controversy concerning the side effects. There is limited data regarding the impact of various cumulative maternal doses and neonatal serum magnesium (Mg) levels on short-term neonatal morbidity and mortality. We opted to carry out a study to determine the impact of neonatal serum Mg levels on neonatal outcomes., Method: We conducted this prospective observational study between 2017 and 2021. Antenatal MgSO 4 was used for neuroprotective purpose only during the study period. Inborn preterm infants delivered between 23 and 31 6/7 weeks of gestation were enrolled consecutively. Babies who underwent advanced resuscitation in the delivery room, inotropic treatment due to hemodynamic instability in the first 7 days of life, >12 hours since the discontinuation of maternal MgSO 4 treatment, severe anemia, and major congenital/chromosomal anomalies were excluded from the study. The subgroup of babies with serum Mg level at the 6th hour of life underwent an analysis. A neonatal Mg concentration of 2.5 mg/dL was used to classify MgSO 4 -exposed patients into 2 groups (<2.5 mg/dL and ≥2.5 mg/dL). Another analysis was performed between babies whose mothers were exposed to MgSO 4 and those not exposed. Finally, the groups' neonatal outcomes were compared., Results: Of the 584 babies, 310 received antenatal MgSO 4 . The birth weights were significantly lower in the MgSO 4 exposed group (1113 ± 361 g vs 1202 ± 388 g, P = 0.005). Antenatal corticosteroid usage and intrauterine growth restriction were also noted to be higher. The MgSO 4 group was more likely to have bronchopulmonary dysplasia, prolonged invasive ventilation, necrotizing enterocolitis, delayed enteral nutrition, and feeding intolerance ( P < 0.05). MgSO 4 treatment was shown as an independent risk factor for feeding intolerance when corrected for confounders (odds ratio 2.13, 95% confidence interval: 1.4-3.1, P = 0.001). Furthermore, serum Mg level significantly correlated with feeding intolerance ( r = 0.21, P = 0.002)., Conclusion: This study highlighted the effect of MgSO 4 treatment and the potential superiority of serum Mg level as a predictor of immediate neonatal outcomes, particularly delayed enteral nutrition and feeding intolerance. Further studies are warranted to ascertain the optimal serum Mg concentration of preterm infants in early life to provide maximum benefit with minimal side effects., Competing Interests: The authors report no conflicts of interest., (Copyright © 2023 by European Society for European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition.)

Necrotizing enterocolitis (NEC) is a devastating neonatal disease that affects neonates worldwide and often leads to high morbidity and mortality rates. Despite extensive research, the cause of NEC remains unclear, and current treatment options are limited. An important novel finding is the potential role of intestinal Alkaline Phosphatase (IAP) in both pathogenesis and treatment of NEC. IAP can play a vital role in detoxifying liposaccharides (LPS), a key mediator of many pathological processes, thereby reducing the inflammatory response associated with NEC. Furthermore, IAP can help prevent dysbiosis, improve intestinal perfusion, and promote autophagy. In this comprehensive review, we present evidence of the possible connection between IAP and the LPS/Toll-like receptor 4 (TLR4) pathway, impaired gut immunity, and dysbiosis in the preterm gut. Based on these findings, the administration of exogenous IAP might provide promising preventive and therapeutic avenues for the management of NEC., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: Methicillin-susceptible Staphylococcus aureus (MSSA) occurs more frequently in the neonatal intensive care unit (NICU) than methicillin-resistant S. aureus (MRSA) and can result in comparable morbidity and mortality in the neonatal population. MSSA infection may present as pustulosis or cellulitis and evolve into bacteremia, pneumonia, endocarditis, brain abscesses, and osteomyelitis. There is a paucity of literature regarding the treatment and long-term outcomes in the premature infant., Clinical Findings: A 32-week twin developed MSSA sepsis with presentation of pain, decreased movement of upper extremities, and global hypotonia. Blood cultures remained positive despite antibiotic coverage., Primary Diagnosis: The infant was admitted to the level IV NICU with the diagnosis of MSSA bacteremia, with concern for dissemination and osteomyelitis., Interventions: Diagnostic studies included laboratory testing for sepsis evaluation, radiologic studies to evaluate for dissemination, immunologic testing to rule out complement deficiency, and hematology testing to rule out hypercoagulable conditions., Outcomes: Diagnostic testing showed extensive cellulitis, osteomyelitis, multiple liver abscesses, and epidural abscesses suggestive of spinal epidural abscess (SEA). Abscess debridement and irrigation on the left distal femur, left elbow, and right tibia were performed. The infant completed 8 weeks of IV antibiotic therapy. Immunologic and hematology testing was within normal limits., Practice Recommendations: Prompt recognition and follow-up for clinical signs of sepsis are vital when caring for premature infants. Inclusion of pediatric subspecialist recommendations to assure all diagnostic studies and treatments are completed can significantly impact the patient's outcome. Long-term follow-up is needed for premature infants with the diagnosis of SEA., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2023 by The National Association of Neonatal Nurses.)

Introduction: A substantial proportion of SGA patients present with a syndrome underlying their growth restriction. Most SGA cohorts comprise both syndromic and non-syndromic patients impeding delineation of the recombinant human growth hormone (rhGH) response. We present a detailed characterization of a SGA cohort and analyze rhGH response based on adult height (AH)., Methods: Clinical and auxological data of SGA patients treated with rhGH, who had reached AH, were retrieved from BELGROW, a national database of all rhGH treated patients held by BESPEED (BElgian Society for PEdiatric Endocrinology and Diabetology). SGA patients were categorized in syndromic or non-syndromic patients., Results: 272 patients were included, 42 classified as syndromic (most frequent diagnosis (n=6): fetal alcohol syndrome and Silver-Russell syndrome). Compared with non-syndromic patients, syndromic were younger [years (median (P10/P90)] 7.43 (4.3/12.37) vs 10.21 (5.43/14.03), p=0.0005), shorter (height SDS -3.39 (-5.6/-2.62) vs -3.07 (-3.74/-2.62), p=0.0253) and thinner (BMI -1.70 (-3.67/0.04) vs -1.14 (-2.47/0.27) SDS, p=0.0054) at start of rhGH treatment. First year rhGH response was comparable (delta height SDS +0.54 (0.24/0.94) vs +0.56 (0.26/0.92), p=0.94). Growth pattern differed with syndromic patients having a higher prepubertal (SDS +1.26 vs +0.83, p=0.0048), but a lower pubertal height gain compared to the non-syndromic group (SDS -0.28 vs 0.44, p=0.0001). Mean rhGH dose was higher in syndromic SGA patients (mg/kg body weight/day 0.047 (0.039/0.064) vs 0.043 (0.035/0.056), p=0.0042). AH SDS was lower in syndromic SGA patients (-2.59 (-4.99/-1.57) vs -2.32 (-3.3/-1.2), p=0.0107). The majority in both groups remained short (<-2 SDS: syndromic 71%, non-syndromic 63%). Total height gain was comparable in both groups (delta height SDS +0.76 (-0.70/1.48) vs +0.86 (-0.12/1.86), p=0.41)., Conclusions: Compared to non-syndromic SGA patients, syndromic SGA patients were shorter when starting rhGH therapy, started rhGH therapy earlier, and received a higher dose of rhGH. At AH, syndromic SGA patients were shorter than non-syndromic ones, but their height gain under rhGH therapy was comparable., Competing Interests: MB has received a travel grant form Pfizer and participated in advisory boards of Novonordisk and Pfizer. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be constructed as a potential conflict of interest., (Copyright © 2023 Becker, Thomas, Brachet, Heinrichs, Dotremont, De Schepper, Lysy, Beckers and the BESPEED group.)

Omphalitis is a mild medical condition that can turn severe in exceptional situations leading to necrotising fasciitis. The most common cause of omphalitis is umbilical vein catheterisation (UVC) where the cleanliness measures can be compromised. The treatment options for omphalitis include antibiotics, debridement and supportive care. Sadly, the fatality rate in such cases is high. This report is about a premature female baby who was admitted to a neonatal intensive care unit after her birth at 34 weeks of gestation. UVC was performed on her which led to abnormal changes in the skin around her umbilicus. Further tests revealed that she had omphalitis and was treated with antibiotics and supportive care. Unfortunately, her condition quickly worsened and she was diagnosed with necrotising fasciitis which ultimately resulted in her death. This report provides details about the patient's symptoms, course of illness and treatment for necrotising fasciitis., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Antenatal corticosteroids reduce mortality and respiratory distress syndrome (RDS) in preterm newborns. These benefits decrease after a week of administration, recommending a rescue therapy if there is a new threat of premature delivery. Repeated administration of antenatal corticosteroids may have deleterious effects and their benefits are controversial in intrauterine growth restriction (IUGR)., Objective: to verify the effects in the IUGR population of antenatal betamethasone rescue therapy on neonatal morbidity and mortality, RDS, and neurodevelopment at 2 years., Patients and Method: Retrospective study including ≤ 34 weeks and ≤ 1,500g preterm newborns divided according to antenatal betamethasone exposure: Single-cycle (2 doses) vs Rescue therapy (3 doses). Subgroups were created for those ≥ 30 weeks. Both cohorts were followed up to 24 months of corrected age. The Ages & Stages Questionnaires (ASQ)® was administered to assess neurodevelopment., Results: 62 preterm infants with a diagnosis of IUGR were included. The rescue therapy group compared with the single-dose group showed no differences in morbidity and mortality and less intubation rate at birth (p = 0.02), with no differences in respiratory support at 7 days of life. Preterm newborns ≥ 30 weeks exposed to rescue therapy showed higher morbidity and mortality (p = 0.03) and bronchopulmonary dysplasia (BPD) (p = 0.02), showing no differences in RDS. The rescue therapy group showed worse mean scores on the ASQ-3 scale, with no significant differences in cerebral palsy or sensory deficits., Conclusions: Rescue therapy reduces intubation at birth but does not reduce morbidity and mortality. However, at > 30 weeks, this benefit is not observed and the IUGR population exposed to rescue therapy presented more BPD and lower scores on the ASQ-3 scale at 2 years. Future studies should be aimed at the individualization of antenatal corticosteroid therapy.

Objective: Necrotizing enterocolitis (NEC) is an inflammatory disease of the gastrointestinal tract characterized by ischemic necrosis of the intestinal mucosa, mostly affecting premature neonates. Management of NEC includes medical care and surgical approaches, with supportive care and empirical antibiotic therapy recommended to avoid any disease progression. However, there is still no clear evidence-based consensus on empiric antibiotic strategies or surgical timing. This study was aimed to review the available evidence on the effectiveness and safety of different antibiotic regimens for NEC., Study Design: MEDLINE, EMBASE, Cochrane CENTRAL, and CINAHL databases were systematically searched through May 31, 2020. Randomized controlled trials (RCTs) and nonrandomized interventions reporting data on predefined outcomes related to NEC treatments were included. Clinical trials were assessed using the criteria and standard methods of the Cochrane risk of bias tool for randomized trials, while the risk of bias in nonrandomized studies of interventions was evaluated using the ROBINS-I tool. The certainty in evidence of each outcome's effects was assessed using the Grading of Recommendations Assessment, Development, and Evaluation approach., Results: Five studies were included in this review, two RCTs and three observational studies, for a total amount of 3,161 patients. One RCT compared the outcomes of parenteral (ampicillin plus gentamicin) and oral (gentamicin) treatment with parenteral only. Three studies (one RCT and two observational) evaluated adding anaerobic coverage to different parenteral regimens. The last observational study compared two different parenteral antibiotic combinations (ampicillin and gentamicin vs. cefotaxime and vancomycin)., Conclusion: No antimicrobial regimen has been shown to be superior to ampicillin and gentamicin in decreasing mortality and preventing clinical deterioration in NEC. The use of additional antibiotics providing anaerobic coverage, typically metronidazole, or use of other broad-spectrum regimens as first-line empiric therapy is not supported by the very limited current evidence. Well-conducted, appropriately sized comparative trials are needed to make evidence-based recommendations., Key Points: · Ampicillin and gentamicin are effective in decreasing mortality and preventing clinical deterioration in NEC.. · Metronidazole could be added in patients with surgical NEC.. · No study with high-quality evidence was found.., Competing Interests: None declared., (Thieme. All rights reserved.)

Background: Cyclooxygenase inhibitors are commonly used in infants with patent ductus arteriosus (PDA), but the benefit of these drugs is uncertain., Methods: In this multicenter, noninferiority trial, we randomly assigned infants with echocardiographically confirmed PDA (diameter, >1.5 mm, with left-to-right shunting) who were extremely preterm (<28 weeks' gestational age) to receive either expectant management or early ibuprofen treatment. The composite primary outcome included necrotizing enterocolitis (Bell's stage IIa or higher), moderate to severe bronchopulmonary dysplasia, or death at 36 weeks' postmenstrual age. The noninferiority of expectant management as compared with early ibuprofen treatment was defined as an absolute risk difference with an upper boundary of the one-sided 95% confidence interval of less than 10 percentage points., Results: A total of 273 infants underwent randomization. The median gestational age was 26 weeks, and the median birth weight was 845 g. A primary-outcome event occurred in 63 of 136 infants (46.3%) in the expectant-management group and in 87 of 137 (63.5%) in the early-ibuprofen group (absolute risk difference, -17.2 percentage points; upper boundary of the one-sided 95% confidence interval [CI], -7.4; P<0.001 for noninferiority). Necrotizing enterocolitis occurred in 24 of 136 infants (17.6%) in the expectant-management group and in 21 of 137 (15.3%) in the early-ibuprofen group (absolute risk difference, 2.3 percentage points; two-sided 95% CI, -6.5 to 11.1); bronchopulmonary dysplasia occurred in 39 of 117 infants (33.3%) and in 57 of 112 (50.9%), respectively (absolute risk difference, -17.6 percentage points; two-sided 95% CI, -30.2 to -5.0). Death occurred in 19 of 136 infants (14.0%) and in 25 of 137 (18.2%), respectively (absolute risk difference, -4.3 percentage points; two-sided 95% CI, -13.0 to 4.4). Rates of other adverse outcomes were similar in the two groups., Conclusions: Expectant management for PDA in extremely premature infants was noninferior to early ibuprofen treatment with respect to necrotizing enterocolitis, bronchopulmonary dysplasia, or death at 36 weeks' postmenstrual age. (Funded by the Netherlands Organization for Health Research and Development and the Belgian Health Care Knowledge Center; BeNeDuctus ClinicalTrials.gov number, NCT02884219; EudraCT number, 2017-001376-28.)., (Copyright © 2022 Massachusetts Medical Society.)

Objective: Dextrose gel is used to treat neonatal hypoglycaemia, but later effects are unknown., Design and Setting: Follow-up of participants in a randomised trial recruited in a tertiary centre and assessed in a research clinic., Patients: Children who were hypoglycaemic (<2.6 mmol/L) recruited to the Sugar Babies Study ( > 35 weeks, <48 hours old) and randomised to treatment with 40% dextrose or placebo gel., Interventions: Assessment of neurological status, cognitive ability (Weschler Preschool and Primary Scale of Intelligence), executive function (five tasks), motor function (Movement Assessment Battery for Children-2 (MABC-2)), vision, visual processing (Beery-Buktenica Development Test of Visual Motor Integration (Beery VMI) and motion coherence thresholds) and growth at 2 years., Main Outcome Measures: Neurosensory impairment (cerebral palsy; visual impairment; deafness; intelligence quotient <85; Beery VMI <85; MABC-2 score <15th centile; low performance on executive function or motion coherence)., Results: Of 237 babies randomised, 185 (78%) were assessed; 96 randomised to dextrose and 89 to placebo gel. Neurosensory impairment was similar in both groups (dextrose 36/96 (38%) vs placebo 34/87 (39%), relative risk 0.96, 95% CI 0.66 to 1.34, p=0.83). Secondary outcomes were also similar, except children randomised to dextrose had worse visual processing scores (mean (SD) 94.5 (15.9) vs 99.8 (15.9), p=0.02) but no differences in the proportion with visual processing scores <85 or other visual test scores. Children randomised to dextrose gel were taller (z-scores 0.18 (0.97) vs -0.17 (1.01), p=0.001) and heavier (0.57 (1.07) vs 0.29 (0.92), p=0.01)., Conclusions: Treatment of neonatal hypoglycaemia (<2.6 mol/L) with dextrose gel does not alter neurosensory impairment at 4.5 years. However, further assessment of visual processing and growth may be warranted., Trial Registration Number: ACTRN1260800062392., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Preterm birth is a major contributor to neonatal morbidity and mortality. Complications of prematurity such as bronchopulmonary dysplasia (BPD, affecting the lung), pulmonary hypertension associated with BPD (BPD-PH, heart), white matter injury (WMI, brain), retinopathy of prematurity (ROP, eyes), necrotizing enterocolitis (NEC, gut) and sepsis are among the major causes of long-term morbidity in infants born prematurely. Though the origins are multifactorial, inflammation and in particular the imbalance of pro- and anti-inflammatory mediators is now recognized as a key driver of the pathophysiology underlying these illnesses. Here, we review the involvement of the interleukin (IL)-1 family in perinatal inflammation and its clinical implications, with a focus on the potential of these cytokines as therapeutic targets for the development of safe and effective treatments for early life inflammatory diseases.

Competing Interests: Competing interests: None declared.

Herpes simplex virus (HSV) infection in newborn infants is a potentially devastating disease leading to death and disability. Skin, eye and mouth (SEM) infections account for approximately half of the cases in the USA. The appearance of skin findings often guides clinicians towards early diagnosis of HSV infection, prompt interventions and life-saving management; however, less than half of neonates with proven disease present with characteristic vesicular lesions. Furthermore, if SEM infections are not treated promptly, there is significant risk of progression to central nervous system and disseminated disease. We present a case of HSV-2 infection in a neonate with an atypical zosteriform eruption on day 3 of life. This case demonstrates that neonatal HSV can unusually present in a zosteriform rash. By elucidating this unique presentation, we highlight atypical HSV skin presentation and emphasise on the importance of earlier diagnosis and antiviral treatment to prevent the associated morbidity and mortality., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: Dextrose gel is widely used as first-line treatment for neonatal hypoglycaemia given its cost-effectiveness and ease of use. The Sugar Babies randomized trial first showed that 40% dextrose gel was more effective in reversing hypoglycaemia than feeding alone. Follow-up of the Sugar Babies Trial cohort at 2 and 4.5 years of age reported that dextrose gel appeared safe, with similar rates of neurosensory impairment in babies randomized to dextrose or placebo gel. However, some effects of neonatal hypoglycaemia may not become apparent until school age., Methods: Follow-up of the Sugar Babies Trial cohort at 9-10 years of age was reported. The primary outcome was low educational achievement in reading or mathematics. Secondary outcomes included other aspects of educational achievement, executive function, visual-motor function, and psychosocial adaptation., Results: Of 227 eligible children, 184 (81%) were assessed at a mean (SD) age of 9.3 (0.2) years. Low educational achievement was similar in dextrose and placebo groups (36/86 [42%] vs. 42/94 [45%]; RR 1.04, 95% CI 0.76, 1.44; p = 0.79). Children allocated to dextrose gel had lower visual perception standard scores (95.2 vs. 100.6; MD -5.68, 95% CI -9.79, -1.57; p = 0.006) and a greater proportion had low (<85) visual perception scores (20/88 [23%] vs. 10/95 [11%]; RR 2.23, 95% CI 1.13, 4.37; p = 0.02). Other secondary outcomes, including other aspects of visual-motor function, were similar in both groups., Conclusion: Treatment dextrose gel does not appear to result in any clinically significant differences in educational achievement or other neurodevelopmental outcomes at mid-childhood., (© 2022 The Author(s). Published by S. Karger AG, Basel.)

Hypoglycemia is the most frequent metabolic disorder in newborns; the administration of 40% glu cose gel in the oral mucosa could be as effective in its correction as the administration of formula milk, not interfering with breastfeeding., Objective: To evaluate the efficacy of 40% glucose gel com pared with formula milk in the treatment of early asymptomatic hypoglycemia in newborns with risk factors., Patients and Method: Randomized clinical trial, non-inferiority, conducted in a private hos pital. Newborns attended in rooming-in with the following risk factors were included: late preterm, large and small for gestational age at term, and children of diabetic mothers. In the presence of hy poglycemia, one group received 40% glucose gel (A) in the oral mucosa and another group received formula milk (B). Therapeutic failure was considered as persistence or repetition of hypoglycemia in the first 48h of life., Results: 866 NBs with risk factors were registered over 36 month; 278 (32.1 %) presented hypoglycemia; 105 NBs in group A and 115 in group B completed the study. 75 (71 %) NBs in group A and 104 (90,4 %) in group B achieved hypoglycemia correction. After analyzing the trends obtained, it was decided to discontinue the study., Conclusions: The administration of 40% glucose gel was not equivalent to the administration of formula milk in the treatment of early asymptomatic hypoglycemia in newborns with risk factors.

Background: Although phenobarbital (PB) is commonly used as a first-line antiseizure medication (ASM) for neonatal seizures, in 2015 we chose to replace it with levetiracetam (LEV), a third-generation ASM. Here, we compared the safety and efficacy of LEV and PB as first-line ASM, considering the years before and after modifying our treatment protocol., Methods: We conducted a retrospective cohort study of 108 neonates with electroencephalography (EEG)-confirmed seizures treated with first-line LEV or PB in 2012 to 2020., Results: First-line ASM was LEV in 33 (31%) and PB in 75 (69%) neonates. The etiology included acute symptomatic seizures in 69% of cases (30% hypoxic-ischemic encephalopathy, 32% structural vascular, 6% infectious, otherwise metabolic) and neonatal epilepsy in 22% (5% structural due to brain malformation, 17% genetic). Forty-two of 108 (39%) neonates reached seizure freedom following first-line therapy. Treatment response did not vary by first-line ASM among all neonates, those with acute symptomatic seizures, or those with neonatal-onset epilepsy. Treatment response was lowest for neonates with a higher seizure frequency, particularly for those with status epilepticus versus rare seizures (P < 0.001), irrespective of gestational age, etiology, or EEG findings. Adverse events were noted in 22 neonates treated with PB and in only one treated with LEV (P < 0.001)., Conclusions: Our study suggests a potential noninferiority and a more acceptable safety profile for LEV, which may thus be a reasonable option as first-line ASM for neonatal seizures in place of PB. Treatment should be initiated as early as possible since higher seizure frequencies predispose to less favorable responses., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Objective: To compare the performance of cerebrospinal fluid (CSF) polymerase chain reaction (PCR) with bacterial culture for the diagnosis of neonatal bacterial meningitis (NBM)., Method: The CSF analysis of neonate with confirmed bacterial meningitis was performed with PCR and bacterial culture, and results were compared., Result: Among 24 neonates, the pathogens Identified included E. coli K1, GBS, Streptococcus pneumoniae and Listeria. PCR identified 20 (83.3%) pathogens, and culture 4 (16.7%) pathogens. Prior antibiotics were administered to 20 (83.3%) neonates in whom PCR identified 17 (85%) and culture 3 (15%) pathogens., Conclusion: CSF PCR had a higher yield of pathogens than CSF culture in confirmed neonatal bacterial meningitis with a high rate of prior antibiotic therapy.

Objectives: To evaluate variability in antibiotic duration for necrotizing enterocolitis (NEC) and associated clinical outcomes., Study Design: Five-hundred ninety-one infants with NEC (315 medical; 276 surgical) were included from 22 centers participating in Children's Hospitals Neonatal Consortium (CHNC). Multivariable analyses were used to determine predictors of variability in time to full feeds (TFF) and length of stay (LOS)., Results: Median (IQR) antibiotic duration was 12 (9, 17) days for medical and 17 (14, 21) days for surgical NEC. Wide variability in antibiotic use existed both within and among centers. Duration of antibiotic therapy was associated with longer TFF in both medical (OR 1.04, 95% CI [1.01, 1.05], p < 0.001) and surgical NEC (OR 1.02 [1, 1.03] p = 0.046); and with longer LOS in medical (OR 1.03 [1.02, 1.04], p < 0.001) and surgical NEC (OR 1.01 [1.01, 1.02], p = 0.002)., Conclusion: Antibiotic duration for both medical and surgical NEC remains variable within and among high level NICUs., (© 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Introduction: Cefotaxime has been used for the management of neonatal infections since the 1990s for suspected meningitis and to mitigate gentamicin-associated renal injury. Its shortage in 2015 and subsequent removal from the U.S. pharmaceutical market forced providers to consider alternatives. Ceftriaxone, a cephalosporin with an identical antibacterial spectrum of activity to cefotaxime, is contraindicated in neonates due to its risk of biliary pseudolithiasis. Ceftazidime was recommended as an alternative by the American Academy of Pediatrics but is inequivalent., Areas Covered: This article addresses indications for cephalosporin use and considerations when selecting an alternative to cefotaxime. Differences among cefotaxime, ceftriaxone, ceftazidime, and cefepime are discussed and compared to the standard-of-care presumptive regimen, ampicillin, and gentamicin. The authors consider the data behind the neonatal contraindication to ceftriaxone and provide recommendations for their application to practice., Expert Opinion: The data against ceftriaxone use in neonates remain poor, particularly in the context of the cefotaxime shortage and lack of an equivalent alternative. Ceftriaxone could be considered in low-risk neonates without hyperbilirubinemia or exposure to calcium-containing fluids on a case-by-case basis. Ceftazidime monotherapy for presumptive management of neonatal infections is inappropriate; cefepime should be more frequently utilized in neonates who are poor candidates for ceftriaxone.

Objective: Perinatal thrombocytopenia has been shown to affect responsiveness to therapeutic ductal closure with cyclooxygenase (COX) inhibitors. This has not been studied in responsiveness to acetaminophen, which has less effect on platelet function. The objective of this study was to evaluate whether thrombocytopenia affects ductal responsiveness to acetaminophen., Study Design: This study was a retrospective review of preterm neonates <1,500 g. Echocardiograms were performed within the first week of life; if ductal status was found to be hemodynamically significant, infants were treated with acetaminophen., Results: We studied 254 infants. Fifty-seven of these (22%) had a hemodynamically significant patent ductus arteriosus (hsPDA) and were treated with acetaminophen. Forty (70%) of those treated responded with ductal closure after one to two courses of acetaminophen. Seventeen infants were considered nonresponsive, requiring the addition of ibuprofen and/or surgical ligation. Sixty seven of the 254 infants (26%) developed moderate thrombocytopenia (platelets <100,000) within the first 10 days of life, more within the hsPDA group (54 vs. 18% p  < 0.001); however, no differences in platelet-related parameters were observed between those who did and did not respond to acetaminophen treatment when comparing infants with hsPDA. Twenty-six of the 67 thrombocytopenic infants were already thrombocytopenic prior to acetaminophen treatment, and 19 of these 26 (73%) with pretreatment thrombocytopenia responded to acetaminophen treatment-with the overall response rate of 70%., Conclusions: This study is the first to document that, in contrast to the COX inhibitors, there is no association between early neonatal thrombocytopenia and ductal therapeutic responsiveness to acetaminophen., Key Points: · Perinatal thrombocytopenia affects ductal closure with COX inhibitors.. · In contrast to the COX inhibitors, acetaminophen responsiveness is not affected by thrombocytopenia.. · Acetaminophen can be recommended to close hsPDA in the presence of thrombocytopenia.., Competing Interests: None declared., (Thieme. All rights reserved.)

Background: Methylxanthine, including caffeine citrate and aminophylline, is the most common pharmacologic treatment for apnea of prematurity. However, due to the lack of high-quality evidence, there are no clear recommendations or guidelines on how to choose between caffeine and aminophylline., Objective: This meta-analysis aimed to assess the comparative efficacy and safety of caffeine and aminophylline for apnea of prematurity, and provide reliable evidence for clinical medication in the treatment for apnea of prematurity., Methods: PubMed, Scopus, Embase, EBSCO, Web of Science, and Cochrane databases were systematically searched from May 1975 to June 2022., Results: Ten studies including a total of 923 preterm infants were evaluated. Our results showed that there was no significant difference in the effective rate of 1-3days between caffeine and aminophylline (OR 1.05, 95%CI: 0.40-2.74, P = 0.914). However, for side effects such as tachycardia (OR 0.22, 95%CI: 0.13-0.37, P<0.001) and feeding intolerance (OR 0.40, 95%CI: 0.23-0.70, P = 0.001), the incidence rate was lower in the caffeine group compared with the aminophylline group. No significant difference was found in hyperglycemia (OR 0.45, 95%CI: 0.19-1.05, P = 0.064)., Conclusion: This meta-analysis reveals that caffeine citrate and aminophylline have similar therapeutic effectiveness on respiratory function, but caffeine has fewer side effects and should be considered first for treatment., Competing Interests: The authors have declared that no competing interests exist.

Background: Continuous conventional video-electroencephalography (cVEEG), the gold standard, is not routinely available for monitoring neonatal seizures in Australia. Therefore, seizures are monitored with clinical observation and amplitude-integrated electroencephalography (aEEG), which may result in under- or over-treatment with antiseizure medications (ASMs). We aimed to investigate ASM usage and its relation to the "cVEEG-confirmed seizures" (cVEEG seizures) in the at-risk infants admitted to a tertiary referral neonatal intensive care unit (NICU)., Methods: The study was a part of a diagnostic study comparing cVEEG with aEEG for the detection of neonatal seizures. Thirty-six infants ≥35 weeks gestational age and at risk of seizures and admitted to NICU were recruited after informed parental consent. The infants were monitored and treated with ASMs based on clinical observation and aEEG findings. A simultaneous cVEEG, not available for clinical decision making, was recorded for 24-h and interpreted at a later date. Data regarding ASM usage and seizure burden on cVEEG were collected. Spearman's Rho coefficient was used to assess the correlation between the number of doses of ASMs administered and seizure burden on cVEEG., Results: cVEEG recordings of 35 infants were available for analysis. The gestational age of the infants ranged from 36 to 42 weeks, and the most common diagnosis was hypoxic-ischemic encephalopathy. Twelve infants received ASMs during the 24-h study period, of which five (42%) did not have cVEEG seizures. Maximum cVEEG seizure burden was 8.3 h, and maximum number of ASMs used was three. The correlation between the number of doses of ASMs administered in an infant and the seizure burden on cVEEG was low (Spearman's Rho: 0.44; p  = .148)., Conclusion: Treatment of neonatal seizures based on clinical observation and aEEG, without cVEEG, results in unnecessary or inadequate exposure to ASMs for many infants.

Objective: In monogenic diabetes due to KCNJ11 and ABCC8 mutations that impair KATP- channel function, sulfonylureas improve long-term glycemic control. Although KATP channels are extensively expressed in the brain, the effect of sulfonylureas on neurological function has varied widely. We evaluated published evidence about potential effects of sulfonylureas on neurological features, especially epilepsy, cognition, motor function and muscular tone, visuo-motor integration, and attention deficits in children and adults with KCNJ11 and ABCC8-related neonatal-onset diabetes mellitus., Research Design and Methods: We conducted a systematic review and meta-analyses of the literature (PROSPERO, CRD42021254782), including individual-patient data, according to PRISMA, using RevMan software. We also graded the level of evidence., Results: We selected 34 of 776 publications. The evaluation of global neurological function before and after sulfonylurea (glibenclamide) treatment in 114 patients yielded a risk difference (RD) of 58% (95%CI, 43%-74%; I 2  = 54%) overall and 73% (95%CI, 32%-113%; I 2  = 0%) in the subgroup younger than 4 years; the level of evidence was moderate and high, respectively. EEG studies of epilepsy showed a RD of 56% (95%CI, 23%-89%; I 2  = 34%) in patients with KCNJ11 mutations, with a high quality of evidence. For hypotonia and motor function, the RDs were 90% (95%CI, 69%-111%; I 2  = 0%) and 73% (95%CI, 35%-111%; I 2  = 0%), respectively, with a high level of evidence., Conclusions: Glibenclamide significantly improved neurological abnormalities in patients with neonatal-onset diabetes due to KCNJ11 or ABCC8 mutations. Hypotonia was the symptom that responded best. Earlier treatment initiation was associated with greater benefits., (© 2022 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Objective: The timing of antenatal steroids (ANS) on short- and long-term effects on newborn infants was evaluated., Study Design: This study was conducted at the University of Cincinnati Medical Center Level-III Neonatal Intensive Care Unit by reviewing the medical records of all women with history of ANS exposure from January 2015 to December 2018. We compared outcomes of newborns delivered within the ideal therapeutic window of 24 hours to 7 days (within window [WW]) after administration to those exposed and delivered outside the therapeutic window (outside window primary group [OWP]). Outcomes included anthropometrics, blood sugars, thyroid hormone profile, and neonatal morbidities., Results: A total of 669 patients were identified as having received at least two doses of ANS. Two-thirds of them delivered within the ideal therapeutic window. Significant differences were found in anthroprometrics including lower birth weight, shorter length, and smaller head circumferences in those born within the window compared with those outside the window. Derangements in glucose homeostasis requiring treatment and elevations of thyroid stimulating hormone (TSH) were seen in infants born outside the ideal therapeutic window compared with those born within the therapeutic window. No differences were found in neonatal morbidities including severe intraventricular hemorrhage (sIVH), necrotizing enterocolitis (NEC), need for resuscitation, exogenous surfactant administration, continuous positive airway pressure (CPAP), mechanical ventilation, bronchopulmonary dysplasia (BPD), or periventricular leukomalacia (PVL). After controlling for selected covariates, only birth length was different between the groups., Conclusion: Effects on anthropometrics, glucose homeostasis, and thyroid function support the need to develop new or refine existing risk stratification systems to time the administration of antenatal steroids. Better targeting of women and fetuses may confer the benefits of systemic corticosteroids while mitigating the risks of adverse effects., Key Points: · The timing of antenatal steroids on short and long-term effects on newborn infants was evaluated.. · Differences were found in anthroprometrics, glucoses, and thyroid function.. · No differences were found in neonatal morbidities.., Competing Interests: None declared., (Thieme. All rights reserved.)

Preterm birth is a leading cause of perinatal morbidity and mortality and Preterm premature rupture of the membranes (PPROM) is a major risk factor contributing to approximately one third of preterm deliveries. Vaginal infections are often associated with PPROM and are characterised by loss of lactobacillin normal vaginal flora and overgrowth of other pathogenic microorganisms. Probiotics appear to have an emerging role in prolonging pregnancy after PPROM. This trial compared the efficacy of a vaginal probiotic in combination with standard antibiotic prophylaxis versus only antibiotic in prolongation of latency period and on perinatal outcome in cases of PPROM between 24 and 34 weeks. Although no significant difference was observed in the mean latency period ( p  = 0.937) and mean gestational age at birth ( p  = 0.863) between the two groups, the overall neonatal outcome was better in the study group. There is need of further large-scale clinical trials to demonstrate effectiveness of probiotics.IMPACT STATEMENT What is already known on this subject? PPROM is an important cause of preterm birth. Prematurity leads significant global burden of neonatal morbidity and mortality. Antibiotics in PPROM have a proven benefit to prolong latency period from start of PPROM to birth. Probiotics have a role in improving vaginal flora and reducing infections and have been tried in PPROM. What do the results of this study add? The usefulness of probiotics in prolonging latency period and improving neonatal outcome has been reported in limited trials. In our study it has shown an improvement in neonatal outcome overall but not statistically significant compared to few studies which have reported significant beneficial effects. This might be due to existence of variation in the type of the vaginal microflora in different study population. What are the implications of these findings for clinical practice and/or further research? Preliminary results suggest that use of probiotic may benefit women with PPROM. This also implies need of multicentric larger scales trials with different types of probiotics so as to clarify whether any intervention in vaginal microflora can lead to any benefits in reducing the prematurity and its consequence, both on the neonate and heath care infrastructure.

In his editorial, Kevin Staley criticizes our recent work demonstrating the lack of effect of bumetanide in a novel model of neonatal seizures. The main points in our response are that (1) our work is on an asphyxia model, not one on "hypercarbia only"; (2) clinically relevant parenteral doses of bumetanide applied in vivo lead to concentrations in the brain parenchyma that are at least an order of magnitude lower than what would be sufficient to exert any direct effect-even a transient one-on neuronal functions, including neonatal seizures; and (3) moreover, bumetanide's molecular target in the brain is the Na-K-2Cl cotransporter NKCC1, which has vital functions in neurons, astrocytes, and oligodendrocytes as well as microglia. This would make it impossible even for highly brain-permeant NKCC1 blockers to specifically target depolarizing and excitatory actions of γ-aminobutyric acid in principal neurons of the brain, which is postulated as the rationale of clinical trials on neonatal seizures., (© 2022 The Authors. Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

Background: Globally, although effective prevention strategies and treatment are available, trachoma remains the major cause of infectious loss of sight. Trachoma is a predominant neglected disease in Ethiopia, and there is a 40.4% prevalence of active trachoma in the Goro district, Southeast Ethiopia. World Health Organization (WHO) recommends azithromycin mass treatment of at least 80% coverage to eliminate trachoma, even though the coverage of azithromycin mass treatment has not been studied yet in depth. Thus, this study aimed to assess the coverage and factors influencing azithromycin mass treatment uptake among adults in Goro district, Southeast Ethiopia., Methods: A community-based cross-sectional study was conducted from April 1st to April 30th, 2021 among all adults aged 15 years old and above. The multistage sampling technique was used to select 593 study respondents. A structured interviewer-administered questionnaire was used. Data were entered into Epi-Data version 3.1 and analyzed using SPSS version 23.0 software. Descriptive analysis and binary logistic regression analysis were used to analyze the data. Adjusted odds ratios (AOR) along with a 95% confidence interval (CI) and p-value < 0.05 were used to declare the strength and the significance of association, respectively., Results/principal Findings: Five hundred and seventy eight study participants with a 97% response rate were included. The proportion of azithromycin mass drug administration coverage was found to be 75.80%; 95% CI: (72%-79%) in this study. Having better knowledge about trachoma (AOR = 2.36; 95% CI: 1.19-4.70), having better knowledge about azithromycin mass treatment (AOR = 4.19; 95% CI: 2.19-7.98), being educated (AOR = 7.20; 95% CI: 1.02-51.09), a campaign conducted at the quiet time (off-harvesting/planting season) (AOR = 6.23; 95% CI: 3.23-11.98), heard about the serious adverse effect from others (AOR = 0.25; 95% CI: 0.10-0.59) and being a volunteer to take azithromycin in the next campaign (AOR = 5.46; 95% CI: 2.76-10.79) were significantly associated with azithromycin mass drug administration coverage., Conclusions/significance: The proportion of azithromycin mass treatment coverage of this study was lower than the WHO minimum target coverage. Thus, strengthening awareness, enhancing azithromycin mass trachoma treatment messages, and conducting campaigns off-season outside of harvesting and planting time should be prioritized in the future to meet the 2030 Sustainable Development Goal (SDG) target., Competing Interests: The authors have declared that no competing interests exist.

Purpose: Respiratory distress is known as one of the leading causes of neonatal death. In recent decades, surfactant therapy has revolutionized respiratory failure. Since the implementation of the health system reform plan as well as the allocation of new financial resources for health system in Iran, the rate of irrational prescription has increased and prescription of surfactant for neonates, has raised unexpectedly, which is thought to be due to irrational prescriptions partly. The present study aimed to determine the rate of irrational prescription of surfactant for neonates with respiratory distress., Methods: This research was a cross-sectional descriptive study, which was conducted retrospectively. In the current study, determining the rate of irrational prescription was done in terms of the surfactant prescription guideline. Finally, the medical data of 846 neonates who underwent surfactant therapy in Iran in 2018, were extracted from the information system of the Ministry of Health and the neonatal medical records., Results: The results show that drug selection index, dose index, and time index were irrational for 14.30%, 27.42%, and 1.06% of neonates, respectively. Moreover, the total index of drug prescription, which is a combination of the above-mentioned three components, was found to be irrational for 31.47% of neonates., Conclusions: The results of the present study are considered as a warning to providers and decision makers in the field of neonatal health to reduce irrational prescriptions of surfactant for neonates. This study suggests the use of educational interventions in order to reduce irrational prescriptions due to drug selection as well as the use of computer alert approaches in order to reduce irrational prescriptions due to wrong dose., Competing Interests: The authors have declared that no competing interests exist.

Objective: To compare maternal and infant outcomes with different antihypertensive medications in pregnancy., Design: Retrospective cohort study., Setting: Kaiser Permanente, a large healthcare system in the United States., Population: Women aged 15-49 years with a singleton birth from 2005-2014 treated for hypertension., Methods: We identified medication exposure from automated pharmacy data based on the earliest dispensing after the first prenatal visit. Using logistic regression, we calculated weighted outcome prevalences, adjusted odds ratios (aORs) and 95% confidence intervals, with inverse probability of treatment weighting to address confounding., Main Outcome Measures: Small for gestational age, preterm delivery, neonatal and maternal intensive care unit (ICU) admission, preeclampsia, and stillbirth or termination at > 20 weeks., Results: Among 6346 deliveries, 87% with chronic hypertension, the risk of the infant being small for gestational age (birthweight < 10th percentile) was lower with methyldopa than labetalol (prevalence 13.6% vs. 16.6%; aOR 0.77, 95% CI 0.63 to 0.92). For birthweight < 3rd percentile the aOR was 0.57 (0.39 to 0.80). Compared with labetalol (26.0%), risk of preterm delivery was similar for methyldopa (26.5%; aOR 1.10 [0.95 to 1.27]) and slightly higher for nifedipine (28.5%; aOR 1.25 [1.06 to 1.46]) and other β-blockers (31.2%; aOR 1.58 [1.07 to 2.23]). Neonatal ICU admission was more common with nifedipine than labetalol (25.9% vs. 23.3%, aOR 1.21 [1.02 to 1.43]) but not elevated with methyldopa. Risks of other outcomes did not differ by medication., Conclusions: Risk of most outcomes was similar comparing labetalol, methyldopa and nifedipine. Risk of the infant being small for gestational age was substantially lower for methyldopa, suggesting this medication may warrant further consideration., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: SD received a grant to support this work from the National Institute on Child Health and Human Development. She has also received grant support from GSK for unrelated work. LC received a postdoctoral fellowship from the Group Health Foundation. She is now employed by Genentech (a member of Roche Group). ZBC is now employed by Roche Pharmaceuticals. TRE has consulted for Alnylam Pharmaceuticals, DiabetOmics, and Ferring Pharmaceuticals. SMS has received grant funding through her institutions from Syneos Health for work unrelated to this study. LAA received funding through her institution from Bausch Health Companies and KR from Amgen, Novartis and Merck & Co, all for work unrelated to this study. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Aim: We observed wide variation in the management of babies at risk of hypoglycaemia who participated in the hPOD (hypoglycaemia Prevention with Oral Dextrose gel) multicentre trial of prophylactic dextrose gel. The aim of this study was to identify whether this may be due to variations in the clinical guidelines used by participating hospitals., Methods: Guidelines for management of neonatal hypoglycaemia used by participating hospitals were reviewed. Recommendations regarding definition, risk factors, monitoring and treatment were compared between countries, hospital type (tertiary or secondary) and neonatal intensive care unit size (≤12 cots and >12 cots)., Results: The 18 hospitals used 20 guidelines. The recommended diagnostic threshold for hypoglycaemia ranged from <2.0 mmol/L to <2.6 mmol/L, and glucose oxidase method of testing was recommended in seven (47%) of 15 guidelines. There was broad agreement about which infants should be monitored. Oral dextrose was the recommended first line of treatment in 17 of 20 guidelines, but the glucose threshold at which this should be used varied (≤2.6 mmol/L in New Zealand, 1.5-2.6 mmol/L in Australia). Re-checking blood glucose concentrations after oral dextrose was recommended at 30 min in most (10/11, 91%) New Zealand guidelines but at 60 min in most (4/6, 67%) Australian guidelines. There was greatest variation in recommended thresholds for referral to paediatric services or neonatal intensive care unit, and administration of intravenous dextrose. There were no significant differences between guidelines used by tertiary and secondary hospitals, or large and small hospitals., Conclusion: There is wide variation in guideline recommendations for the management of neonatal hypoglycaemia across New Zealand and Australian neonatal units., (© 2021 Paediatrics and Child Health Division (The Royal Australasian College of Physicians).)

Purpose: Growth hormone (GH) treatment has been used to improve growth in short children who were born small for gestational age (SGA). The aim of this study was to investigate the long-term efficacy of GH treatment in these children., Methods: Data from a multicenter observational clinical trial (ClinicalTrials.gov NCT01604395, LG growth study) were analyzed for growth outcome and prediction model in response to GH treatment. One hundred fifty-two children born SGA were included., Results: The mean age of patients born SGA was 7.13 ± 2.59 years. Height standard deviation score (SDS) in patients born SGA increased from -2.55 ± 0.49 before starting treatment to -1.13 ± 0.76 after 3 years of GH treatment. Of the 152 patients with SGA, 48 who remained prepubertal during treatment used model development. The equation describing the predicted height velocity during 1st year of GH treatment is as follows: the predictive height velocity (cm) = 10.95 + [1.12 x Height SDS at initial treatment (score)] + [0.03 x GH dose (ug/kg/day)] + [0.30 x TH SDS at initial treatment (score)] + [0.05 x age (year)] + [0.15 x Weight SDS at initial treatment (score)] ± 1.51 cm., Conclusions: GH treatment improved growth outcome in short children born SGA. We also developed a prediction model that is potentially useful in determining the optimal growth outcome for each child born SGA., Trial Registration: ClinicalTrials.gov Identifier: NCT01604395., Competing Interests: The authors have read the journal’s policy and have the following competing interests: HSL is a member of the Observational Study Monitoring Board of LG Growth Study (LGS) for LG Chem Corporation. JSH is a member of the LGS Steering Committee for LG Chem Corporation. There are no patents, products in development or marketed products associated with this research to declare. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Necrotizing enterocolitis (NEC) has a 45% mortality in neonatal intensive care units. This paper aimed to evaluate the isolated and combined effects of sildenafil and L-arginine in the prevention of necrotizing enterocolitis. Neonatal rats were fed formula milk and submitted to hypoxia under a 100% N2 atmosphere for 70 s. Then, animals were subjected to hypothermia (4 °C for 10 min), twice a day for 3 days. Forty neonatal rats were divided into five groups: negative control-not submitted to the protocol (n = 5), sildenafil group-NEC protocol (n = 9), L-arginine group-NEC protocol (n = 9), L-arginine and sildenafil group-NEC protocol (n = 9) and positive control-NEC protocol and intraperitoneal saline solution (n = 8). Jejunum and terminal ileus were removed for histopathologic and immunohistochemical Ki-67 analysis. Kruskal-Wallis test was used to analyze mortality, survival, body weight, intestinal injury score and Ki-67 proliferation index. All animals submitted to the protocol developed enterocolitis. Mortality rate was higher in group that received only L-arginine (p = 0.0293). The Ki-67 analysis showed a higher proliferative index in groups that received interventional drugs (p = 0.017). In conclusion, sildenafil and L-arginine were not effective to reduce intestinal injury., (© 2022. The Author(s).)

To truly attain effective and safe pharmacotherapy, the similarities and dissimilarities in physiology between micro-preemies and extreme preterm infants should be explored. The higher incidence of pulmonary hypertension and presence of adrenal insufficiency of prematurity in micro-preemies hereby serve as illustrations. The current limited data on pharmacokinetics, -dynamics and safety reflect the obvious need to collect such data, and to tailor modelling tools to their physiology and needs. Drug utilization hereby mirrors different needs and practices and may serve to guide prioritization decisions. Physiological data, combined with even limited observations on pharmacokinetics and -dynamics can be translated to effective modelling tools to attain effective and safe pharmacotherapy. We therefore discuss how valid research tools in pharmacology like physiology-based pharmacokinetic models can be developed, and how clinicians can contribute to such efforts, with the overarching aim to enable this shift from immature pharmacotherapy to pharmacotherapy for the immature., (Copyright © 2022. Published by Elsevier Ltd.)

High neonatal seizure burden is associated with worsened neurodevelopmental outcomes. We compared the efficacy of initial treatment with levetiracetam vs phenobarbital for maintaining low seizure burden in a retrospective cohort of 25 neonates monitored with video electroencephalography (EEG). Video EEG tracing were reviewed and paired with medication bolus times to determine seizure burden after treatment. Initial cumulative dose of phenobarbital was 20 mg/kg in all but 1 case; initial cumulative dose of levetiracetam ranged from 50 to 100 mg/kg. Eleven of 17 (65%) patients sustained seizure burden <10% following initial treatment with levetiracetam, compared with 5 of 8 (63%) with phenobarbital. Thirteen (76%) patients treated with levetiracetam had sustained seizure burden <20% compared with 6 (75%) treated with phenobarbital. The phenobarbital group showed a larger absolute reduction in average seizure burden in the hour before and after treatment (-24.3  vs -14.2 minutes/h). Six of 17 (35%) patients treated with levetiracetam remained seizure free after initial treatment, compared with 2 of 8 (25%) patients treated with phenobarbital. Initial treatment with levetiracetam was associated with shorter average time to seizure freedom (15 vs 21 hours). None of these results were statistically significant. Cumulative doses of levetiracetam 100 mg/kg were well tolerated and associated with substantial decrease in seizure burden in several cases. Levetiracetam remains a promising first-line treatment for neonatal seizures; additional randomized controlled trials evaluating the effects of high-dose levetiracetam on seizure burden and long-term outcomes are warranted.

Inhaled nitric oxide (iNO) acts as a selective pulmonary vasodilator and it is currently approved by the FDA for the treatment of persistent pulmonary hypertension of the newborn. iNO has been demonstrated to effectively decrease pulmonary artery pressure and improve oxygenation, while decreasing extracorporeal life support use in hypoxic newborns affected by persistent pulmonary hypertension. Also, iNO seems a safe treatment with limited side effects. Despite the promising beneficial effects of NO in the preclinical literature, there is still a lack of high quality evidence for the use of iNO in clinical settings. A variety of clinical applications have been suggested in and out of the critical care environment, aiming to use iNO in respiratory failure and pulmonary hypertension of adults or as a preventative measure of hemolysis-induced vasoconstriction, ischemia/reperfusion injury and as a potential treatment of renal failure associated with cardiopulmonary bypass. In this narrative review we aim to present a comprehensive summary of the potential use of iNO in several clinical conditions with its suggested benefits, including its recent application in the scenario of the COVID-19 pandemic. Randomized controlled trials, meta-analyses, guidelines, observational studies and case-series were reported and the main findings summarized. Furthermore, we will describe the toxicity profile of NO and discuss an innovative proposed strategy to produce iNO. Overall, iNO exhibits a wide range of potential clinical benefits, that certainly warrants further efforts with randomized clinical trials to determine specific therapeutic roles of iNO., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Increased research to improve preclinical models to inform the development of therapeutics for neonatal diseases is an area of great need. This article reviews five common neonatal diseases - bronchopulmonary dysplasia, retinopathy of prematurity, necrotizing enterocolitis, perinatal hypoxic-ischemic encephalopathy and neonatal sepsis - and the available in vivo, in vitro and in silico preclinical models for studying these diseases. Better understanding of the strengths and weaknesses of specialized neonatal disease models will help to improve their utility, may add to the understanding of the mode of action and efficacy of a therapeutic, and/or may improve the understanding of the disease pathology to aid in identification of new therapeutic targets. Although the diseases covered in this article are diverse and require specific approaches, several high-level, overarching key lessons can be learned by evaluating the strengths, weaknesses and gaps in the available models. This Review is intended to help guide current and future researchers toward successful development of therapeutics in these areas of high unmet medical need., Competing Interests: Competing interests The authors declare no competing or financial interests. The information presented in this article is that of the authors and does not necessarily represent that of their employers. The information in these materials is not a formal dissemination of information by the U.S. Food and Drug Administration, the Federal Institute for Drugs and Medicines Devices, or the Federal Agency for Medicines and Health Products and does not represent agency position or policy., (© 2022. Published by The Company of Biologists Ltd.)

Objective: To evaluate the severity of neonatal opioid withdrawal syndrome (NOWS) in infants prenatally exposed to medications for opioid use disorder (MOUD) and serotonin reuptake inhibitors (SRI)., Methods: A prospective cohort included 148 maternal-infant pairs categorized into MOUD (n = 127) and MOUD + SRI (n = 27) groups. NOWS severity was operationalized as the infant's need for pharmacologic treatment with opioids, duration of hospitalization, and duration of treatment. The association between prenatal SRI exposure and the need for pharmacologic treatment (logistic regression), time-to-discharge, and time-to-treatment discontinuation (Cox proportional hazards modeling) was examined after adjusting for the type of maternal MOUD, use of hydroxyzine, other opioids, benzodiazepines/sedatives, alcohol, tobacco, marijuana, gestational age, and breastfeeding., Results: Infants in the MOUD + SRI group were more likely to receive pharmacologic treatment for NOWS (OR = 3.58; 95% CI: 1.31; 9.76) and had a longer hospitalization (median: 11 vs. 6 days; HR = 0.54; 95% CI: 0.33; 0.89) compared to the MOUD group. With respect to time-to-treatment discontinuation, no association was observed in infants who received treatment (HR = 0.59; 95% CI: 0.26, 1.32); however, significant differences were observed in the entire sample (HR = 0.55; 95% CI: 0.34, 0.89)., Conclusions: Use of SRIs among pregnant women on MOUD might be associated with more severe NOWS., Impact: A potential drug-drug interaction between maternal SRIs and opioid medications that inhibit the reuptake of serotonin has been hypothesized but not carefully evaluated in clinical studies. Results of this prospective cohort indicate that the use of SRIs among pregnant women on MOUD is associated with more severe neonatal opioid withdrawal syndrome. This is the first prospective study which carefully examined effect modification between the type of maternal MOUD and SRI use on neonatal outcomes. This report lays the foundation for treatment optimization in pregnant women with co-occurring mental health and substance use disorders., (© 2021. The Author(s), under exclusive licence to the International Pediatric Research Foundation, Inc.)

Perinatal inflammation triggers breathing disturbances early in life and affects the respiratory adaptations to challenging conditions, including the generation of amplitude long-term facilitation (LTF) by acute intermittent hypoxia (AIH). Some of these effects can be avoided by anti-inflammatory treatments like minocycline. Since little is known about the effects of perinatal inflammation on the inspiratory rhythm generator, located in the preBötzinger complex (preBötC), we tested the impact of acute lipopolysaccharide (LPS) systemic administration (sLPS), as well as gestational LPS (gLPS) and gestational chronic IH (gCIH), on respiratory rhythm generation and its long-term response to AIH in a brainstem slice preparation from neonatal mice. We also evaluated whether acute minocycline administration could influence these effects. We found that perinatal inflammation induced by sLPS or gLPS, as well as gCIH, modulate the frequency, signal-to-noise ratio and/or amplitude (and their regularity) of the respiratory rhythm recorded from the preBötC in the brainstem slice. Moreover, all these perinatal conditions inhibited frequency LTF and amplitude long-term depression (LTD); gCIH even induced frequency LTD of the respiratory rhythm after AIH. Some of these alterations were not observed in slices pre-treated in vitro with minocycline, when compared with slices obtained from naïve pups, suggesting that ongoing inflammatory conditions affect respiratory rhythm generation and its plasticity. Thus, it is likely that alterations in the inspiratory rhythm generator and its adaptive responses could contribute to the respiratory disturbances observed in neonates that suffered from perinatal inflammatory challenges., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Progressive loss of pancreatic β-cell functional mass and anti-diabetic drug responsivity are classic findings in diabetes, frequently attributed to compensatory insulin hypersecretion and β-cell exhaustion. However, loss of β-cell mass and identity still occurs in mouse models of human KATP-gain-of-function induced Neonatal Diabetes Mellitus (NDM), in the absence of insulin secretion. Here we studied the temporal progression and mechanisms underlying glucotoxicity-induced loss of functional β-cell mass in NDM mice, and the effects of sodium-glucose transporter 2 inhibitors (SGLT2i) therapy. Upon tamoxifen induction of transgene expression, NDM mice rapidly developed severe diabetes followed by an unexpected loss of insulin content, decreased proinsulin processing and increased proinsulin at 2-weeks of diabetes. These early events were accompanied by a marked increase in β-cell oxidative and ER stress, without changes in islet cell identity. Strikingly, treatment with the SGLT2 inhibitor dapagliflozin restored insulin content, decreased proinsulin:insulin ratio and reduced oxidative and ER stress. However, despite reduction of blood glucose, dapagliflozin therapy was ineffective in restoring β-cell function in NDM mice when it was initiated at >40 days of diabetes, when loss of β-cell mass and identity had already occurred. Our data from mouse models demonstrate that: i) hyperglycemia per se, and not insulin hypersecretion, drives β-cell failure in diabetes, ii) recovery of β-cell function by SGLT2 inhibitors is potentially through reduction of oxidative and ER stress, iii) SGLT2 inhibitors revert/prevent β-cell failure when used in early stages of diabetes, but not when loss of β-cell mass/identity already occurred, iv) common execution pathways may underlie loss and recovery of β-cell function in different forms of diabetes. These results may have important clinical implications for optimal therapeutic interventions in individuals with diabetes, particularly for those with long-standing diabetes., Competing Interests: The authors have declared that no competing interests exist.