Search

BACKGROUND: Neonatal hypoxic-ischemic encephalopathy disproportionately affects low- and middle-income countries, where ≈96% of affected infants reside. The current standard of care, therapeutic hypothermia, is frequently ineffective in this setting, likely because injury may be occurring earlier during labor. Here, we studied the pharmacokinetics, safety, and efficacy of perinatal caffeine administration in near-term lambs following global ischemic injury to support the development of earlier treatment strategies targeting the fetus in utero as well as the infant postnatally. METHODS: Ewes were randomly assigned to receive either 1 g IV caffeine citrate or placebo before delivery and placental transport assessed. Near-term lambs (141-143 days) of both sexes were subjected to severe global hypoxia-ischemia utilizing an acute umbilical cord occlusion model. Lambs that received caffeine in utero also received 20 mg/kg IV caffeine citrate following resuscitation and 10 mg/(kg·d) IV for 2 days. An additional cohort received 60 mg/kg followed by 30 mg/(kg·d) (low dose versus high dose) postnatally. Biochemical, histological, and neurological outcome measures in lambs were assessed over a 6-day period. RESULTS: Perinatal caffeine administration demonstrated excellent placental transport kinetics and was well tolerated with lamb plasma levels comparable to those targeted in neonates with apnea of prematurity. Caffeine administration resulted in a systemic immunomodulatory effect, evidenced by significant reductions in proinflammatory IP-10 levels. Treated lambs demonstrated improved neurodevelopmental outcomes, while histological analysis revealed that caffeine reduced gray matter injury and attenuated inflammation in the cingulate and parasagittal cortex. This neuroprotective effect was greater and via a different mode of action than we previously reported for azithromycin. A higher caffeine dosing regimen demonstrated significant toxicity. CONCLUSIONS: Perinatal caffeine administration is well tolerated, attenuates systemic and brain inflammation, and contributes to improvements in histological and neurological outcomes in an ovine model of neonatal hypoxic-ischemic encephalopathy.

OBJECTIVES: Up to a quarter of pregnant individuals with SLE have small for gestational age (SGA) infants. We aimed to characterize placental pathology associated with SGA infants in SLE. METHODS: We retrospectively analysed SLE deliveries with placental analysis at UCSD from November 2018 to October 2023, comparing SLE pregnancies resulting in SGA to those that did not, and additionally, to matched pregnancies with SGA but without SLE. RESULTS: Placental analysis was available only for 28/70 (40%) SLE deliveries, which had high rates of adverse outcomes (75%). All exhibited at least one histopathologic abnormality. Key findings distinguishing 12 SLE placentas resulting in SGA infants (vs.16 without) included small placental disc for gestational age (100% vs 56%, P = 0.01), placental disc infarct (50% vs 6%, P = 0.02) and increased perivillous fibrin deposition (PVFD, 58% vs 0%, P = 0.001). All seven SLE placentas with increased PVFD resulted in SGA infants. Compared with matched non-SLE pregnancies with SGA (n = 36), the only distinguishing placental lesion was a higher prevalence of increased PVFD in SLE-associated SGA (58% vs 22%, P = 0.03). CONCLUSION: The higher prevalence of increased PVFD in placentas of SLE-associated SGA may indicate a specific mechanism of placental injury leading to SGA in this context. Thus, its presence, particularly in context of SGA, should prompt providers to screen for an underlying autoimmune disease, including SLE. Systematic placental examination in context of SLE and associated autoimmune diseases could help evaluate responses to existing therapies, comparative studies of novel therapies and correlation to adverse outcomes.

BACKGROUND: In 2022-2023, 15- and 20-valent pneumococcal conjugate vaccines (PCV15/PCV20) were recommended for infants. We aimed to estimate the incidence of outpatient visits and antibiotic prescriptions in US children (≤17 years) from 2016-2019 for acute otitis media, pneumonia, and sinusitis associated with PCV15- and PCV20-additional (non-PCV13) serotypes to quantify PCV15/20 potential impacts. METHODS: We estimated the incidence of PCV15/20-additional serotype-attributable visits and antibiotic prescriptions as the product of all-cause incidence rates, derived from national health care surveys and MarketScan databases, and PCV15/20-additional serotype-attributable fractions. We estimated serotype-specific attributable fractions using modified vaccine-probe approaches incorporating incidence changes post-PCV13 and ratios of PCV13 versus PCV15/20 serotype frequencies, estimated through meta-analyses. RESULTS: Per 1000 children annually, PCV15-additional serotypes accounted for an estimated 2.7 (95% confidence interval, 1.8-3.9) visits and 2.4 (95% CI, 1.6-3.4) antibiotic prescriptions. PCV20-additional serotypes resulted in 15.0 (95% CI, 11.2-20.4) visits and 13.2 (95% CI, 9.9-18.0) antibiotic prescriptions annually per 1000 children. PCV15/20-additional serotypes account for 0.4% (95% CI, 0.2%-0.6%) and 2.1% (95% CI, 1.5%-3.0%) of pediatric outpatient antibiotic use. CONCLUSIONS: Compared with PCV15-additional serotypes, PCV20-additional serotypes account for > 5 times the burden of visits and antibiotic prescriptions. Higher-valency PCVs, especially PCV20, may contribute to preventing pediatric pneumococcal respiratory infections and antibiotic use.

Seasonal influenza epidemics result in high levels of healthcare utilization. Vaccination is an effective strategy to reduce the influenza-related burden of disease. However, reporting vaccine effectiveness does not convey the population impacts of influenza vaccination. We aimed to calculate the burden of influenza-related hospitalizations and emergency department (ED) attendance averted by influenza vaccination in Victoria, Australia, from 2017 to 2019, and associated economic savings. We applied a compartmental model to hospitalizations and ED attendances with influenza-specific, and pneumonia and influenza (P&I) with the International Classification of Diseases, 10th Revision, Australian Modification (ICD-10-AM) diagnostic codes of J09-J11 and J09-J18, respectively. We estimated an annual average of 7657 (120 per 100000 population) hospitalizations and 20560 (322 per 100000 population) ED attendances over the study period, associated with A$85 million hospital expenditure. We estimated that influenza vaccination averted an annual average of 1182 [range: 556 - 2277] hospitalizations and 3286 [range: 1554 - 6257] ED attendances and reduced the demand for healthcare services at the influenza season peak. This equated to approximately A13 [range: A6 - A25] million of savings over the study period. Calculating the burden averted is feasible in Australia and auseful approach to demonstrate the health and economic benefits of influenza vaccination.

BACKGROUND: Women who reach menarche and menopause at earlier ages have been shown to be at increased risk for numerous conditions including cardiovascular disease, cancer, depression, and obesity; however, risk factors for earlier ages of menarche and menopause are not fully understood. Therefore, we aimed to perform a retrospective investigation of the associations between a personal birthweight and/or being born preterm and the age of and menarche and menopause and related events in the Womens Health Initiative, a large, racially and ethnically diverse cohort of postmenopausal women. METHODS: At study entry, women reported their birthweight by category (

BACKGROUND: Undernutrition during pregnancy increases the risk of giving birth to a small vulnerable newborn. Small-quantity lipid-based nutrient supplements (SQ-LNSs) contain both macro- and micronutrients and can help prevent multiple nutritional deficiencies. OBJECTIVES: We examined the effects of SQ-LNSs provided during pregnancy compared with 1) iron and folic acid or standard of care (IFA/SOC) or 2) multiple micronutrient supplements (MMSs) and identified characteristics that modified the estimates of effects of SQ-LNSs on birth outcomes. METHODS: We conducted a 2-stage meta-analysis of individual participant data from 4 randomized controlled trials of SQ-LNSs provided during pregnancy (n = 5273). We generated study-specific and subgroup estimates of SQ-LNS compared with IFA/SOC or MMS and pooled the estimates. In sensitivity analyses, we examined whether the results differed depending on methods for gestational age dating, birth anthropometry, or study design. RESULTS: SQ-LNSs (compared with IFA/SOC) increased birth weight [mean difference: +49 g; 95% confidence interval (CI): 26, 71 g] and all birth anthropometric z-scores (+0.10-0.13 standard deviation); they reduced risk of low birth weight by 11%, newborn stunting by 17%, newborn wasting by 11%, and small head size by 15%. Only 2 trials compared SQ-LNSs and MMSs; P values for birth outcomes were >0.10 except for head circumference (e.g., z-score for gestational age: +0.11; 95% CI: -0.01, 0.23). Effect estimates for SQ-LNSs compared with IFA/SOC were greater among female infants and, for certain outcomes, among mothers with body mass index

Climate change, wildfires, and environmental justice concerns have drawn increased attention to the impact of air pollution on children's health and development. Children are especially vulnerable to air pollution exposure, as their brains and bodies are still developing. The objective of this systematic review was to synthesize available empirical evidence on the associations between air pollution exposure and brain outcomes in developmental samples (ages 0-18 years old). Studies were identified by searching the PubMed and Web of Science Core Collection databases and underwent a two-phase screening process before inclusion. 40 studies were included in the review, which included measures of air pollution and brain outcomes at various points in development. Results linked air pollution to varied brain outcomes, including structural volumetric and cortical thickness differences, alterations in white matter microstructure, functional network changes, metabolic and molecular effects, as well as tumor incidence. Few studies included longitudinal changes in brain outcomes. This review also suggests methodologies for incorporating air pollution measures in developmental cognitive neuroscience studies and provides specific policy recommendations to reduce air pollution exposure and promote healthy brain development by improving access to clean air.

Background/Objectives: Human milk is the optimal source of nutrition and protection against infection for infants. If breastfeeding is not possible, standard and hydrolyzed infant formulas (IF) are an alternative. Extensively hydrolyzed IFs (eHFs) contain bioactive peptides, but their activities have rarely been evaluated. The aim of this study was to characterize and compare the bioactive peptide profiles of different eHFs and standard IFs before and after in vitro digestion. Methods: Two forms, liquid and powder, of intact protein formula (iPF) and eHF were subjected to in vitro gastrointestinal digestion, mimicking a young infants gut (age 0-4 months) and an older infants gut (>6 months). Bioactive peptides of in vitro digested and undigested formulas were analysed with Liquid Chromatography-Mass Spectrometry (LC-MS). Results: In all samples, a variety of peptides with potential bioactive properties were found. Immuno-regulatory peptides, followed by antimicrobial and antioxidative peptides were most frequent, as were peptides promoting wound healing, increasing mucin secretion, regulating cholesterol metabolism, and preventing bacterial infection. Peptides typically found in yoghurt and colostrum were identified in some formula samples. Conclusions: The high amounts of bioactive peptides with various properties in eHFs and iPFs indicate a possible contribution to infection protection, healthy gut microbiomes, and immunological development of infants. eHFs showed similar compositions of bioactive peptides to iPFs, with intermittently increased peptide variety and quantity.

Pregnancies ending before 26 weeks contribute 1% of births but 40% of infant deaths in the United States. The rate of these periviable births to non-Hispanic (NH) Black women exceeds four times that for NH whites. Small male periviable infants remain most likely to die. NH white periviable males weigh more than their NH Black counterparts. We argue that male infants born from twin gestations, in which one fetus died in utero (i.e., the vanishing twin syndrome), contribute to the disparity. We cannot directly test our argument because vanishing typically occurs before clinical recognition of pregnancy. We, however, describe and find associations that would emerge in vital statistics were our argument correct. Among male periviable singleton births from 288 monthly conception cohorts (January 1995 through December 2018), we found an average NH white advantage of 30 grams (759 grams versus 729 grams). Consistent with our argument, however, cohorts signaling relatively few survivors of the vanishing twin syndrome showed no disparity.

Single-dose azithromycin is being considered by the WHO as an intervention for prevention of child mortality. However, concerns have emerged related to longer term unintended consequences of early life antibiotic use, particularly among infants. We conducted a long-term follow-up in a random sample of children who had been enrolled in a trial of neonatal azithromycin versus placebo for prevention of mortality to assess whether neonatal azithromycin exposure led to differences in child growth up to 4 years of age. We found no evidence of a difference in any anthropometric outcome among children who had received a single oral dose of azithromycin compared with placebo during the neonatal period. These results do not support long-term growth-promoting or deleterious effects of early life azithromycin exposure.

Our objective was to interrogate mesenchymal stem cell (MSC) lipid metabolism and gestational exposures beyond maternal body mass that may contribute to child obesity risk. MSCs were cultured from term infants of mothers with obesity (n = 16) or normal weight (n = 15). In MSCs undergoing myogenesis in vitro, we used lipidomics to distinguish phenotypes by unbiased cluster analysis and lipid challenge (24-hour excess fatty acid [24hFA]). We measured MSC AMP-activated protein kinase (AMPK) activity and fatty acid oxidation (FAO), and a composite index of maternal glucose, insulin, triglycerides, free fatty acids, TNF-α, and high-density lipoprotein and total cholesterol in fasting blood from mid and late gestation (~17 and ~27 weeks, respectively). We measured child adiposity at birth (n = 29), 4-6 months (n = 29), and 4-6 years (n = 13). Three MSC clusters were distinguished by triacylglycerol (TAG) stores, with greatest TAGs in Cluster 2. All clusters increased acylcarnitines and TAGs with 24hFA, although Cluster 2 was more pronounced and corresponded to AMPK activation and FAO. Maternal metabolic markers predicted MSC clusters and child adiposity at 4-6 years (both highest in Cluster 3). Our data support the notion that MSC phenotypes are predicted by comprehensive maternal metabolic milieu exposures, independent of maternal BMI, and suggest utility as an at-birth predictor for child adiposity, although validation with larger longitudinal samples is warranted.

Improvement of water and sanitation conditions may reduce infant mortality, particularly in countries like India where open defecation is highly prevalent. We conducted a quasi-experimental study to investigate the association between the Swachh Bharat Mission (SBM)-a national sanitation program initiated in 2014-and infant (IMR) and under five mortality rates (U5MR) in India. We analyzed data from thirty-five Indian states and 640 districts spanning 10 years (2011-2020), with IMR and U5MR per thousand live births as the outcomes. Our main exposure was the district-level annual percentage of households that received a constructed toilet under SBM. We mapped changes in IMR and U5MR and toilet access at the district level over time. We fit two-way fixed effects regression models controlling for sociodemographic, wealth, and healthcare-related confounders at the district-level to estimate the association between toilets constructed and child mortality. Toilet access and child mortality have a historically robust inverse association in India. Toilets constructed increased dramatically across India following the implementation of SBM in 2014. Results from panel data regression models show that districts with > 30% toilets constructed under SBM corresponds with 5.3 lower IMR (p

BACKGROUND: Preterm white matter injury (PWMI) is the most common cause of brain injury in premature neonates. PWMI involves a differentiation arrest of oligodendrocytes, the myelinating cells of the central nervous system. Clemastine was previously shown to induce oligodendrocyte differentiation and myelination in mouse models of PWMI at a dose of 10 mg/kg/day. The minimum effective dose (MED) of clemastine is unknown. Identification of the MED is essential for maximizing safety and efficacy in neonatal clinical trials. We hypothesized that the MED in neonatal mice is lower than 10 mg/kg/day. METHODS: Mouse pups were exposed to normoxia or hypoxia (10% FiO2) from postnatal day 3 (P3) through P10. Vehicle or clemastine at one of four doses (0.5, 2, 7.5 or 10 mg/kg/day) was given to hypoxia-exposed pups. Myelination was assessed at age P14 and 10 weeks to determine the MED. Clemastine pharmacokinetics were evaluated at steady-state on day 8 of treatment. RESULTS: Clemastine rescued hypoxia-induced hypomyelination with a MED of 7.5 mg/kg/day. Pharmacokinetic analysis of the MED revealed Cmax 44.0 ng/mL, t1/2 4.6 h, and AUC24 280.1 ng*hr/mL. CONCLUSIONS: Based on these results, myelination-promoting exposures should be achievable with oral doses of clemastine in neonates with PWMI. IMPACT: Preterm white matter injury (PWMI) is the most common cause of brain injury and cerebral palsy in premature neonates. Clemastine, an FDA-approved antihistamine, was recently identified to strongly promote myelination in a mouse model of PWMI and is a possible treatment. The minimum effective dose in neonatal rodents is unknown and is critical for guiding dose selection and balancing efficacy with toxicity in future clinical trials. We identified the minimum effective dose of clemastine and the associated pharmacokinetics in a murine chronic hypoxia model of PWMI, paving the way for a future clinical trial in human neonates.

ObjectiveTo test the effect of proactive home visits by trained community health workers (CHWs) on child survival.MethodsWe conducted a two arm, parallel, unmasked cluster-randomized trial in 137 village-clusters in rural Mali. From February 2017 to January 2020, 31 761 children enrolled at the trial start or at birth. Village-clusters received either primary care services by CHWs providing regular home visits (intervention) or by CHWs providing care at a fixed site (control). In both arms, user fees were removed and primary health centres received staffing and infrastructure improvements before trial start. Using lifetime birth histories from women aged 15-49 years surveyed annually, we estimated incidence rate ratios (IRR) for intention-to-treat and per-protocol effects on under-five mortality using Poisson regression models.FindingsOver three years, we observed 52 970 person-years (27 332 in intervention arm; 25 638 in control arm). During the trial, 909 children in the intervention arm and 827 children in the control arm died. The under-five mortality rate declined from 142.8 (95% CI: 133.3-152.9) to 56.7 (95% CI: 48.5-66.4) deaths per 1000 live births in the intervention arm; and from 154.3 (95% CI: 144.3-164.9) to 54.9 (95% CI: 45.2-64.5) deaths per 1000 live births in the control arm. Intention-to-treat (IRR: 1.02; 95% CI: 0.88-1.19) and per-protocol estimates (IRR: 1.01; 95% CI: 0.87-1.18) showed no difference between study arms.ConclusionThough proactive home visits did not reduce under-five mortality, system-strengthening measures may have contributed to the decline in under-five mortality in both arms.

AimTo assess, from a United States (US) payer's perspective, the cost-effectiveness of gels designed to separate the endometrial surfaces (intrauterine spacers) placed following intrauterine surgery.Materials and methodsA decision tree model was developed to estimate the cost-effectiveness of intrauterine spacers used to facilitate endometrial repair and prevent the formation (primary prevention) and reformation (secondary prevention) of intrauterine adhesions (IUAs) and associated pregnancy- and birth-related adverse outcomes. Event rates and costs were extrapolated from data available in the existing literature. Sensitivity analyses were conducted to corroborate the base case results.ResultsIn this model, using intrauterine spacers for adhesion prevention led to net cost savings for US payers of $2,905 per patient over a 3.5-year time horizon. These savings were driven by the direct benefit of preventing procedures associated with IUA formation ($2,162 net savings) and the indirect benefit of preventing pregnancy-related complications often associated with IUA formation ($3,002). These factors offset the incremental cost of intrauterine spacer use of $1,539 based on an assumed price of $1,800 and the related increase in normal deliveries of $931. Model outcomes were sensitive to the probability of preterm and normal deliveries. Budget impact analyses show overall cost savings of $19.96 per initial member within a US healthcare plan, translating to $20 million over a 5-year time horizon for a one-million-member plan.LimitationsThere are no available data on the effects of intrauterine spacers or IUAs on patients' quality of life. Resultingly, the model could not evaluate patients' utility related to treatment with or without intrauterine spacers and instead focused on costs and events avoided.ConclusionThis analysis robustly demonstrated that intrauterine spacers would be cost-saving to healthcare payers, including both per-patient and per-plan member, through a reduction in IUAs and improvements to patients' pregnancy-related outcomes.

Exposure to social adversity has been associated with cortisol dysregulation during pregnancy and in later childhood; less is known about how prenatal exposure to social stressors affects postnatal cortisol of infants. In a secondary analysis of data from a longitudinal study, we tested whether a pregnant woman's reports of social adversity during the third trimester were associated with their infant's resting cortisol at 1, 6, and 12 months postnatal. Our hypothesis was that prenatal exposure to social adversity would be associated with elevation of infants' cortisol. Measures included prenatal survey reports of social stressors and economic hardship, and resting cortisol levels determined from infant saliva samples acquired at each postnatal timepoint. Data were analyzed using linear mixed effects models. The final sample included 189 women and their infants (46.56% assigned female sex at birth). Prenatal economic hardship was significantly associated with infant cortisol at 6 months postnatal; reports of social stressors were not significantly associated with cortisol at any time point. Factors associated with hardship, such as psychological distress or nutritional deficiencies, may alter fetal HPA axis development, resulting in elevated infant cortisol levels. Developmental changes unique to 6 months of age may explain effects at this timepoint. More work is needed to better comprehend the complex pre- and post-natal physiologic and behavioral factors that affect infant HPA axis development and function, and the modifying role of environmental exposures.

Autism spectrum disorders (ASD) can be caused by environmental factors. These factors act early in the development of the nervous system and induce stereotyped repetitive behaviors and diminished social interactions, among other outcomes. Little is known about how these behaviors are produced. In pregnant women, delivery of valproic acid (VPA) (to control seizure activity or stabilize mood) or immune activation by a virus increases the incidence of ASD in offspring. We found that either VPA or Poly Inosine:Cytosine (which mimics a viral infection), administered at mouse embryonic day 12.5, induced a neurotransmitter switch from GABA to glutamate in PV- and CCK-expressing interneurons in the medial prefrontal cortex by postnatal day 10. The switch was present for only a brief period during early postnatal development, observed in male and female mice at postnatal day 21 and reversed in both males and females by postnatal day 30. At postnatal day 90, male mice exhibited stereotyped repetitive behaviors and diminished social interaction while female mice exhibited only stereotyped repetitive behavior. Transfecting GAD1 in PV- and CCK-expressing interneurons at postnatal day 10, to reintroduce GABA expression, overrode the switch and prevented expression of autistic-like behavior. These findings point to an important role of neurotransmitter switching in mediating the environmental causes of autism.

Preterm birth (PTB) remains a global health concern, impacting neonatal mortality and lifelong health consequences. Traditional methods for estimating PTB rely on electronic health records or biomedical signals, limited to short-term assessments in clinical settings. Recent studies have leveraged wearable technologies for in-home maternal health monitoring, offering continuous assessment of maternal autonomic nervous system (ANS) activity and facilitating the exploration of PTB risk. In this paper, we conduct a longitudinal study to assess the risk of PTB by examining maternal ANS activity through heart rate (HR) and heart rate variability (HRV). To achieve this, we collect long-term raw photoplethysmogram (PPG) signals from 58 pregnant women (including seven preterm cases) from gestational weeks 12-15 to three months post-delivery using smartwatches in daily life settings. We employ a PPG processing pipeline to accurately extract HR and HRV, and an autoencoder machine learning model with SHAP analysis to generate explainable abnormality scores indicative of PTB risk. Our results reveal distinctive patterns in PTB abnormality scores during the second pregnancy trimester, indicating the potential for early PTB risk estimation. Moreover, we find that HR, average of interbeat intervals (AVNN), SD1SD2 ratio, and standard deviation of interbeat intervals (SDNN) emerge as significant PTB indicators.

INTRODUCTION: Children who are deaf or hard-of-hearing (DHH) are at risk for speech and language delay. Language outcomes are worse in DHH children from lower socioeconomic backgrounds, due in part to disparities in access to specialised speech-language therapy. Teletherapy may help improve access to this specialised care and close this language gap. Inclusion of diverse DHH children in prospective randomised clinical trials has been challenging but is necessary to address disparities and pursue hearing health equity. Stakeholder input regarding decisions on study design elements, including comparator groups, masking, assessments and compensation, is necessary to design inclusive studies. We have designed an inclusive, equitable comparativeness effectiveness trial to address disparities in paediatric hearing health. The specific aims of the study are to determine the effect of access to and utilisation of speech-language teletherapy in addressing language disparities in low-income children who are DHH. METHODS AND ANALYSIS: After stakeholder input and pilot data collection, we designed a randomised clinical trial and concurrent longitudinal cohort trial to be conducted at four tertiary childrens hospitals in the USA. Participants will include 210 DHH children aged 0-27 months. 140 of these children will be from lower income households, who will be randomised 1:1 to receive usual care versus usual care plus access to supplemental speech-language teletherapy. 70 children from higher income households will be simultaneously recruited as a comparison cohort. Primary outcome measure will be the Preschool Language Scales Auditory Comprehension subscale standard score, with additional speech, language, hearing and quality of life validated measures as secondary outcomes. ETHICS AND DISSEMINATION: This study was approved by the Institutional Review Boards of the participating sites: the University of California, San Francisco (19-28356), Rady Childrens Hospital (804651) and Seattle Childrens Hospital (STUDY00003750). Parents of enrolled children will provide written informed consent for their childs participation. Professional and parent stakeholder groups that have been involved throughout the study design will facilitate dissemination and implementation of study findings via publication and through national and regional organisations. TRIAL REGISTRATION NUMBER: NCT04928209.

BACKGROUND AND OBJECTIVE: Congenital heart defects are known to be associated with increased odds of severe COVID-19. Congenital anomalies affecting other body systems may also be associated with poor outcomes. This study is an exhaustive assessment of congenital anomalies and odds of severe COVID-19 in pediatric patients. METHODS: Data were retrieved from the COVID-19 dataset of Cerner® Real-World Data for encounters from March 2020 to February 2022. Prior to matching, the data consisted of 664,523 patients less than 18 years old and 927,805 corresponding encounters with COVID-19 from 117 health systems across the United States. One-to-one propensity score matching was performed, and a cumulative link mixed-effects model with random intercepts for health system and patients was built to assess corresponding associations. RESULTS: All congenital anomalies were associated with worse COVID-19 outcomes, with the strongest association observed for cardiovascular anomalies (odds ratio [OR], 3.84; 95% CI, 3.63-4.06) and the weakest association observed for anomalies affecting the eye/ear/face/neck (OR, 1.16; 95% CI, 1.03-1.31). CONCLUSIONS AND RELEVANCE: Congenital anomalies are associated with greater odds of experiencing severe symptoms of COVID-19. In addition to congenital heart defects, all other birth defects may increase the odds for more severe COVID-19. IMPACT: All congenital anomalies are associated with increased odds of severe COVID-19. This study is the largest and among the first to investigate birth defects across all body systems. The multicenter large data and analysis demonstrate the increased odds of severe COVID19 in pediatric patients with congenital anomalies affecting any body system. These data demonstrate that all children with birth defects are at increased odds of more severe COVID-19, not only those with heart defects. This should be taken into consideration when optimizing prevention and intervention resources within a hospital.

Worldwide trends to delay childbearing have increased parental ages at birth. Older parental age may harm offspring health, but mechanisms remain unclear. Alterations in offspring DNA methylation (DNAm) patterns could play a role as aging has been associated with methylation changes in gametes of older individuals. We meta-analyzed epigenome-wide associations of parental age with offspring blood DNAm of over 9500 newborns and 2000 children (5-10 years old) from the Pregnancy and Childhood Epigenetics consortium. In newborns, we identified 33 CpG sites in 13 loci with DNAm associated with maternal age (PFDR

BackgroundHepatitis-E virus (HEV), an etiologic agent of acute inflammatory liver disease, is a significant cause of morbidity and mortality in South Asia. HEV is considered endemic in Nepal; but data on population-level infection transmission is sparse.MethodsWe conducted a longitudinal serosurvey in central Nepal to assess HEV exposure. At each visit, capillary blood samples were collected and analyzed for the presence of anti-HEV IgG antibodies. The study took place between February 2019 and April 2021, with up to 4 visits per participant approximately 6 months apart.ResultsWe collected 2513 samples from 923 participants aged 0-25 years, finding a seroprevalence of 4.8% and a seroincidence rate of 10.9 per 1000 person-years. Young adults and individuals consuming surface water faced the highest incidence of infection. Geospatial analysis identified potential HEV clusters, suggesting a need for targeted interventions.SignificanceOur findings demonstrate that HEV is endemic in Nepal and that the risk of infection increases with age.

Cerebellar injury in preterm infants with central nervous system (CNS) hemorrhage results in lasting neurological deficits and an increased risk of autism. The impact of blood-induced pathways on cerebellar development remains largely unknown, so no specific treatments have been developed to counteract the harmful effects of blood after neurovascular damage in preterm infants. Here, we show that fibrinogen, a blood-clotting protein, plays a central role in impairing neonatal cerebellar development. Longitudinal MRI of preterm infants revealed that cerebellar bleeds were the most critical factor associated with poor cerebellar growth. Using inflammatory and hemorrhagic mouse models of neonatal cerebellar injury, we found that fibrinogen increased innate immune activation and impeded neurogenesis in the developing cerebellum. Fibrinogen inhibited sonic hedgehog (SHH) signaling, the main mitogenic pathway in cerebellar granule neuron progenitors (CGNPs), and was sufficient to disrupt cerebellar growth. Genetic fibrinogen depletion attenuated neuroinflammation, promoted CGNP proliferation, and preserved normal cerebellar development after neurovascular damage. Our findings suggest that fibrinogen alters the balance of SHH signaling in the neurovascular niche and may serve as a therapeutic target to mitigate developmental brain injury after CNS hemorrhage.

INTRODUCTION: Brace treatment is common to address radiological dysplasia in infants with developmental dysplasia of the hip (DDH); however, it is unclear whether bracing provides significant benefit above careful observation by ultrasound. If observation alone is non-inferior to bracing for radiological dysplasia, unnecessary treatment may be avoided. Therefore, the purpose of this study is to determine whether observation is non-inferior to bracing for infants with radiological dysplasia. METHODS AND ANALYSIS: This will be a multicentre, global, randomised, non-inferiority trial performed under the auspices of a global prospective registry for infants and children diagnosed with DDH. Patients will be included if they present with radiological dysplasia (centred hip, alpha angle 43-60°, percent femoral head coverage greater than 35% measured on ultrasound) of a clinically stable hip under 3 months old. Patients will be excluded if they present with clinical hip instability, have received prior treatment or have known/suspected neuromuscular, collagen, chromosomal or lower-extremity congenital abnormalities or syndromic-associated hip abnormalities. Patients will be enrolled and randomised to undergo observation alone or brace treatment with a Pavlik harness for a minimum of 6 weeks. Follow-up visits will occur at 6 weeks, 1 year and 2 years post-enrolment. The primary outcome will be the norm-referenced acetabular index measured on the 2-year radiograph with a 3° non-inferiority margin. A total of 514 patients will be included.The study is anticipated to start in April 2024 and end in September 2028.The primary outcome will be compared between arms with a mixed-effects model with a random intercept for study centre, and a single covariate for the treatment group. If the lower bound of the 95% CI lies within 3° of the mean, we will treat this as evidence for non-inferiority. ETHICS AND DISSEMINATION: Ethics approval has been obtained from the lead sites ethics board (University of British Columbia, Childrens and Womens Research Ethics Board). Ethics approval will be obtained from the local ethics committees or institutional review boards at each institution prior to patient enrolment. It is intended that the results of this study shall be published in peer-reviewed journals and presented at suitable conferences. TRIAL REGISTRATION NUMBER: NCT05869851.

Machine learning (ML)-driven diagnosis systems are particularly relevant in pediatrics given the well-documented impact of early-life health conditions on later-life outcomes. Yet, early identification of diseases and their subsequent impact on length of hospital stay for this age group has so far remained uncharacterized, likely because access to relevant health data is severely limited. Thanks to a confidential data use agreement with the California Department of Health Care Access and Information, we introduce Ped-BERT: a state-of-the-art deep learning model that accurately predicts the likelihood of 100+ conditions and the length of stay in a pediatric patients next medical visit. We link mother-specific pre- and postnatal period health information to pediatric patient hospital discharge and emergency room visits. Our data set comprises 513.9K mother-baby pairs and contains medical diagnosis codes, length of stay, as well as temporal and spatial pediatric patient characteristics, such as age and residency zip code at the time of visit. Following the popular bidirectional encoder representations from the transformers (BERT) approach, we pre-train Ped-BERT via the masked language modeling objective to learn embedding features for the diagnosis codes contained in our data. We then continue to fine-tune our model to accurately predict primary diagnosis outcomes and length of stay for a pediatric patients next visit, given the history of previous visits and, optionally, the mothers pre- and postnatal health information. We find that Ped-BERT generally outperforms contemporary and state-of-the-art classifiers when trained with minimum features. We also find that incorporating mother health attributes leads to significant improvements in model performance overall and across all patient subgroups in our data. Our most successful Ped-BERT model configuration achieves an area under the receiver operator curve (ROC AUC) of 0.927 and an average precision score (APS) of 0.408 for the diagnosis prediction task, and a ROC AUC of 0.855 and APS of 0.815 for the length of hospital stay task. Further, we examine Ped-BERTs fairness by determining whether prediction errors are evenly distributed across various subgroups of mother-baby demographics and health characteristics, or if certain subgroups exhibit a higher susceptibility to prediction errors.

ImpactFindings from this study provide further reassuring evidence that infant exposure through human milk received from lactating individuals who require treatment with remdesivir is negligible.

Congenital diarrheas and enteropathies (CODE) are a group of rare, heterogenous, monogenic disorders that lead to chronic diarrhea in infancy. Definitive treatment is rarely available, and supportive treatment is the mainstay. Nutritional management in the form of either specialized formulas, restrictive diet, or parenteral nutrition support in CODE with poor enteral tolerance is the cornerstone of CODE treatment and long-term growth. The evidence to support the use of specific diet regimens and nutritional approaches in most CODE disorders is limited due to the rarity of these diseases and the scant published clinical experience. The goal of this review was to create a comprehensive guide for nutritional management in CODE, based on the currently available literature, disease mechanism, and the PediCODE group experience. Enteral diet management in CODE can be divided into 3 distinct conceptual frameworks: nutrient elimination, nutrient supplementation, and generalized nutrient restriction. Response to nutrient elimination or supplementation can lead to resolution or significant improvement in the chronic diarrhea of CODE and resumption of normal growth. This pattern can be seen in CODE due to carbohydrate malabsorption, defects in fat absorption, and occasionally in electrolyte transport defects. In contrast, general diet restriction is mainly supportive. However, occasionally it allows parenteral nutrition weaning or reduction over time, mainly in enteroendocrine defects and rarely in epithelial trafficking and polarity defects. Further research is required to better elucidate the role of diet in the treatment of CODE and the appropriate diet management for each disease.

BACKGROUND: Promotion of facial cleanliness is recommended for the elimination of blinding trachoma, largely because of observational studies that have found an association between various measures of facial uncleanliness and trachoma. However, when a field grader assesses both facial cleanliness and trachoma, associations may be biased. Assessment of photographs of the face and conjunctiva by masked graders may provide a less biased estimate of the relationship between facial cleanliness and trachoma. METHODS: Face photographs, conjunctival photographs, and conjunctival swabs were obtained on a random sample of 0-9-year-old children from each of 40 communities in Amhara region, Ethiopia. Face photographs were assessed for the presence of seven measures of an unclean face (i.e., wet nasal discharge, dry nasal discharge, wet ocular discharge, dry ocular discharge, food, dust/dirt, and flies) by three independent masked photo-graders. Conjunctival photographs were similarly graded in a masked fashion for signs of clinically active trachoma. Conjunctival swabs were processed for Chlamydia trachomatis DNA. RESULTS: Of 2073 children with complete data, 808 (39%) had evidence of clinically active trachoma, 150 (7%) had evidence of ocular chlamydia infection, and 2524 (91%) had at least one measure of an unclean face. Dry ocular discharge had the strongest association with clinically active trachoma (age- and sex-adjusted prevalence ratio [PR] 1.4, 95% CI 1.2-1.6) and ocular chlamydia infection (PR 1.9, 95%CI 1.3-2.9), although significant associations were observed between each of the measures of facial uncleanliness and trachoma. CONCLUSIONS: Masked assessment of face and conjunctival photographs confirmed prior observational studies that have noted associations between various measures of facial uncleanliness and trachoma. The causal relationship between facial uncleanliness and trachoma is unclear since many features used to measure facial cleanliness (e.g., ocular discharge, nasal discharge, and flies) could be consequences of antecedent ocular chlamydia infection. TRIAL REGISTRATION: NCT02754583, clinicaltrials.gov.

During postnatal cardiac hypertrophy, cardiomyocytes undergo mitotic exit, relying on DNA replication-independent mechanisms of histone turnover to maintain chromatin organization and gene transcription. In other tissues, circadian oscillations in nucleosome occupancy influence clock-controlled gene expression, suggesting a role for the circadian clock in temporal control of histone turnover and coordinated cardiomyocyte gene expression. We sought to elucidate roles for the master circadian transcription factor, Bmal1, in histone turnover, chromatin organization, and myocyte-specific gene expression and cell growth in the neonatal period. Bmal1 knockdown in neonatal rat ventricular myocytes decreased myocyte size, total cellular protein synthesis, and transcription of the fetal hypertrophic gene Nppb after treatment with serum or the α-adrenergic agonist phenylephrine. Depletion of Bmal1 decreased the expression of clock-controlled genes Per2 and Tcap, as well as Sik1, a Bmal1 target upregulated in adult versus embryonic hearts. Bmal1 knockdown impaired Per2 and Sik1 promoter accessibility as measured by micrococcal nuclease-quantitative PCR and impaired histone turnover as measured by metabolic labeling of acid-soluble chromatin fractions. Sik1 knockdown in turn decreased myocyte size, while simultaneously inhibiting natriuretic peptide B transcription and activating Per2 transcription. Linking these changes to chromatin remodeling, depletion of the replication-independent histone variant H3.3a inhibited myocyte hypertrophy and prevented phenylephrine-induced changes in clock-controlled gene transcription. Bmal1 is required for neonatal myocyte growth, replication-independent histone turnover, and chromatin organization at the Sik1 promoter. Sik1 represents a novel clock-controlled gene that coordinates myocyte growth with hypertrophic and clock-controlled gene transcription. Replication-independent histone turnover is required for transcriptional remodeling of clock-controlled genes in cardiac myocytes in response to growth stimuli.

ObjectiveDespite an increase in twin pregnancies in recent decades, the Institute of Medicine twin weight gain recommendations remain provisional and provide no guidance for the pattern or timing of weight change. We sought to characterize gestational weight change trajectory patterns and examine associations with birth outcomes in a cohort of twin pregnancies.Study designPrenatal and delivery records were examined for 320 twin pregnancies from a maternal-fetal medicine practice in Austin, TX 2011-2019. Prenatal weights for those with >1 measured weight in the first trimester and ≥3 prenatal weights were included in analyses. Trajectories were estimated to 32 weeks (mean delivery: 33.7 ± 3.3 weeks) using flexible latent class mixed models with low-rank thin-plate splines. Associations between trajectory classes and infant outcomes were analyzed using multivariable Poisson or linear regression.ResultsWeight change from prepregnancy to delivery was 15.4 ± 6.3 kg for people with an underweight body mass index, 15.4 ± 5.8 kg for healthy weight, 14.7 ± 6.9 kg for overweight, and 12.5 ± 6.4 kg for obesity. Three trajectory classes were identified: low (Class 1), moderate (Class 2), or high gain (Class 3). Class 1 (24.7%) maintained weight for 15 weeks and then gained an estimated 6.6 kg at 32 weeks. Class 2 (60.9%) exhibited steady gain with 13.5 kg predicted total gain, and Class 3 (14.4%) showed rapid gain across pregnancy with 21.3 kg predicted gain. Compared to Class 1, Class 3 was associated with higher birth weight z-score (β = 0.63, 95% confidence interval [CI]: 0.31,0.96), increased risk for large for gestational age (IRR = 5.60, 95% CI: 1.59, 19.67), and birth

OBJECTIVE: There is widespread overuse of antibiotics in neonatal intensive care units (NICUs). The objective of this study was to safely reduce antibiotic use in participating NICUs by targeting early-onset sepsis (EOS) management. STUDY DESIGN: Twenty-eight NICUs participated in this statewide multicenter antibiotic stewardship quality improvement collaborative. The primary aim was to reduce the total monthly mean antibiotic utilization rate (AUR) by 25% in participant NICUs. RESULT: Aggregate AUR was reduced by 15.3% (p

OBJECTIVE: Despite limited safety and efficacy data, inhaled corticosteroids (ICS) are prescribed to premature infants in the neonatal intensive care unit (NICU). We examined contemporary use and risk factors for ICS use in the NICU. STUDY DESIGN: Infants

BACKGROUND: High ambient temperature is increasingly common due to climate change and is associated with risk of adverse pregnancy outcomes. Acute lymphoblastic leukaemia is the most common malignancy in children, the incidence is increasing, and in the USA disproportionately affects Latino children. We aimed to investigate the potential association between high ambient temperature in pregnancy and risk of childhood acute lymphoblastic leukaemia. METHODS: We used data from California birth records (children born from Jan 1, 1982, to Dec 31, 2015) and California Cancer Registry (those diagnosed with childhood cancer in California from Jan 1, 1988, to Dec 31, 2015) to identify acute lymphoblastic leukaemia cases diagnosed in infants and children aged 14 years and younger and controls matched by sex, race, ethnicity, and date of last menstrual period. Ambient temperatures were estimated on a 1-km grid. The association between ambient temperature and acute lymphoblastic leukaemia was evaluated per gestational week, restricted to May-September, adjusting for confounders. Bayesian meta-regression was applied to identify critical exposure windows. For sensitivity analyses, we evaluated a 90-day pre-pregnancy period (assuming no direct effect before pregnancy), adjusted for relative humidity and particulate matter less than 2·5 microns in aerodynamic diameter, and constructed an alternatively matched dataset for exposure contrast by seasonality. FINDINGS: 6849 cases of childhood acute lymphoblastic leukaemia were identified and, of these, 6258 had sufficient data for study inclusion. We also included 307 579 matched controls. Most of the study population were male (174 693 [55·7%] of the 313 837 included in the study) and of Latino ethnicity (174 906 [55·7%]). The peak association between ambient temperature and risk of acute lymphoblastic leukaemia was observed in gestational week 8, where a 5°C increase was associated with an odds ratio of 1·07 (95% CI 1·04-1·11). A slightly larger effect was seen among Latino children (OR 1·09 [95% CI 1·04-1·14]) than non-Latino White children (OR 1·05 [1·00-1·11]). The sensitivity analyses supported the results of the main analysis. INTERPRETATION: Our findings suggest an association between high ambient temperature in early pregnancy and risk of childhood acute lymphoblastic leukaemia. Further replication and investigation of mechanistic pathways might inform mitigation strategies. FUNDING: Yale Center on Climate Change and Health, The National Center for Advancing Translational Science, National Institutes of Health.

BackgroundChildhood cancers are associated with high mortality and morbidity, and some maternal prescription drug use during pregnancy has been implicated in cancer risk. There are few studies on the effects of hypertension, preeclampsia, and the use of antihypertensives in pregnancy on children's cancer risks.ObjectiveThis population-based cohort study analyzed the relationship between hypertension, preeclampsia, and antihypertensives taken during pregnancy and the risks of childhood cancers in the offspring.MethodsData on all children born in Taiwan between 2004 and 2015 (N = 2,294,292) were obtained from the Maternal and Child Health Database. This registry was linked with the National Health Insurance Database and Cancer Registry to get the records of maternal use of diuretics or other antihypertensives in pregnancy and records of children with cancer diagnosed before 13 years. We used Cox proportional hazard modeling to estimate the influence of maternal health conditions and antihypertensive drug exposure on the risks of developing childhood cancers.ResultsOffspring of mothers with hypertension (chronic or gestational) had a higher risk of acute lymphocytic lymphoma [hazard ratio (HR) = 1.87, 95% Confidence Interval (CI) 1.32 - 2.65] and non-Hodgkin's lymphoma (HR = 1.96, 95% CI 1.34 - 2.86). We estimated only a weak increased cancer risk in children whose mothers used diuretics (HR = 1.16, 95% CI 0.77 - 1.74) or used antihypertensives other than diuretics (HR = 1.15, 95% CI 0.86 - 1.54) before birth.ConclusionsIn this cohort study, children whose mothers had chronic and gestational hypertension had an increased risk of developing childhood cancer.

Exposure to high and low ambient temperatures increases the risk of neonatal mortality, but the contribution of climate change to temperature-related neonatal deaths is unknown. We use Demographic and Health Survey (DHS) data (n = 40,073) from 29 low- and middle-income countries to estimate the temperature-related burden of neonatal deaths between 2001 and 2019 that is attributable to climate change. We find that across all countries, 4.3% of neonatal deaths were associated with non-optimal temperatures. Climate change was responsible for 32% (range: 19-79%) of heat-related neonatal deaths, while reducing the respective cold-related burden by 30% (range: 10-63%). Climate change has impacted temperature-related neonatal deaths in all study countries, with most pronounced climate-induced losses from increased heat and gains from decreased cold observed in countries in sub-Saharan Africa. Future increases in global mean temperatures are expected to exacerbate the heat-related burden, which calls for ambitious mitigation and adaptation measures to safeguard the health of newborns.

BackgroundOxygen saturation (Spo2) screening has not led to earlier detection of critical congenital heart disease (CCHD). Adding pulse oximetry features (ie, perfusion data and radiofemoral pulse delay) may improve CCHD detection, especially coarctation of the aorta (CoA). We developed and tested a machine learning (ML) pulse oximetry algorithm to enhance CCHD detection.Methods and resultsSix sites prospectively enrolled newborns with and without CCHD and recorded simultaneous pre- and postductal pulse oximetry. We focused on models at 1 versus 2 time points and with/without pulse delay for our ML algorithms. The sensitivity, specificity, and area under the receiver operating characteristic curve were compared between the Spo2-alone and ML algorithms. A total of 523 newborns were enrolled (no CHD, 317; CHD, 74; CCHD, 132, of whom 21 had isolated CoA). When applying the Spo2-alone algorithm to all patients, 26.2% of CCHD would be missed. We narrowed the sample to patients with both 2 time point measurements and pulse-delay data (no CHD, 65; CCHD, 14) to compare ML performance. Among these patients, sensitivity for CCHD detection increased with both the addition of pulse delay and a second time point. All ML models had 100% specificity. With a 2-time-points+pulse-delay model, CCHD sensitivity increased to 92.86% (P=0.25) compared with Spo2 alone (71.43%), and CoA increased to 66.67% (P=0.5) from 0. The area under the receiver operating characteristic curve for CCHD and CoA detection significantly improved (0.96 versus 0.83 for CCHD, 0.83 versus 0.48 for CoA; both P=0.03) using the 2-time-points+pulse-delay model compared with Spo2 alone.ConclusionsML pulse oximetry that combines oxygenation, perfusion data, and pulse delay at 2 time points may improve detection of CCHD and CoA within 48 hours after birth.RegistrationURL: https://www.clinicaltrials.gov/study/NCT04056104?term=NCT04056104&rank=1; Unique identifier: NCT04056104.

This study examines the association between antenatal care (ANC) attendance and infant mortality and growth outcomes. The study used data from the Nouveux-nés et Azithromycine: une Innovation dans le Traitement des Enfants (NAITRE) trial conducted in Burkina Faso. This analysis included 21,795 neonates aged 8 to 27 days who were enrolled in the trial and had ANC data available. Infants were followed until 6 months of age. The analysis adjusted for potential confounders including infants sex, maternal age, education, urbanicity, geographic region, season (dry versus rainy), pregnancy type (singleton versus multiple), number of previous pregnancies, if the infant was breastfed, and if the facility had an onsite physician to account for level of care. We used logistic and linear regression models to evaluate the association between ANC visits and all-cause infant mortality and infant growth measurements at 6 months. There was no significant association between ANC visits and 6-month mortality. Higher ANC attendance was associated with improved growth outcomes in infants at 6 months of age. After adjusting for potential confounders, each additional ANC visit was associated with a 0.03 kg increase in mean weight, 0.07 cm increase in mean length, 0.04 SD increase in mean mid-upper-arm circumference, 0.04 SD increase in mean height-for-age, 0.04 SD mean weight-for-age, and 0.02 SD mean weight-for-length Z-scores. These mean differences were statistically significant (except for weight-for-length Z-scores) but may not be clinically meaningful. Further research is warranted to explore the relationship between ANC attendance and longer-term health outcomes among infants.

We previously reported two siblings with inherited PD-1 deficiency who died from autoimmune pneumonitis at 3 and 11 years of age after developing other autoimmune manifestations, including type 1 diabetes (T1D). We report here two siblings, aged 10 and 11 years, with neonatal-onset T1D (diagnosed at the ages of 1 day and 7 wk), who are homozygous for a splice-site variant of CD274 (encoding PD-L1). This variant results in the exclusive expression of an alternative, loss-of-function PD-L1 protein isoform in overexpression experiments and in the patients primary leukocytes. Surprisingly, cytometric immunophenotyping and single-cell RNA sequencing analysis on blood leukocytes showed largely normal development and transcriptional profiles across lymphoid and myeloid subsets in the PD-L1-deficient siblings, contrasting with the extensive dysregulation of both lymphoid and myeloid leukocyte compartments in PD-1 deficiency. Our findings suggest that PD-1 and PD-L1 are essential for preventing early-onset T1D but that, unlike PD-1 deficiency, PD-L1 deficiency does not lead to fatal autoimmunity with extensive leukocytic dysregulation.

In alignment with previous literature, NICU parents reported experiencing racism and NICU staff reported witnessing racism in the NICU. Our study also uniquely describes personal experiences with racism by staff in the NICU. NICU staff reported witnessing and experiencing racism more often than parents reported. Black staff reported witnessing and experiencing more racism than white staff. Differences in reporting is likely influenced by variations in lived experience, social identities, psychological safety, and levels of awareness. Future studies are necessary to prevent and accurately measure racism in the NICU.

Neonatal seizures are common among patients with acute brain injury or critical illness and can be difficult to diagnose and treat. The most common etiology of neonatal seizures is hypoxic-ischemic encephalopathy, with other common causes including ischemic stroke and intracranial hemorrhage. Neonatal clinicians can use a standardized approach to patients with suspected or confirmed neonatal seizures that entails laboratory testing, neuromonitoring, and brain imaging. The primary goals of management of neonatal seizures are to identify the underlying cause, correct it if possible, and prevent further brain injury. This article reviews recent evidence-based guidelines for the treatment of neonatal seizures and discusses the long-term outcomes of patients with neonatal seizures.

BackgroundMaternal solvent exposure has been suspected to increase offspring cancer risk. The study aimed to evaluate the associations between maternal residential exposure to solvents from industrial pollution during pregnancy and childhood cancer.MethodsThe present study included 15,744 cancer cases (aged 0-19 years at diagnosis) identified from California Cancer Registry and 283,141 controls randomly selected from California Birth Registry (20:1 frequency-matched by birth year: 1998-2016). We examined industrial releases of tetrachloroethylene and 1,1,1-trichloroethane within 3 km of the birth address, while we used a 5 km buffer for carbon disulfide. We calculated the total exposure from all linked Toxic Release Inventory sites during each index pregnancy and assigned "ever/never" and "high/low exposed/unexposed" exposure, using median values. We performed quadratic decay models to estimate cancer risks associated with maternal solvent exposure in pregnancy.Results1,1,1-Trichloroethane was associated with rhabdomyosarcoma (adjusted Odds Ratio (aOR): 1.96; 95% Confidence Interval (CI): 1.16, 3.32) in the "ever exposed" group. Ever exposure to carbon disulfide was associated with increased risks of medulloblastoma (OR = 1.85, 95% CI 1.01, 3.40) and ependymoma (OR = 1.63, 95% CI 0.97, 2.74).ConclusionsOverall, our findings suggested maternal residential exposure to solvents from industrial sources might be associated with elevated childhood cancer risks.

BACKGROUND: Regular, detailed reporting on population health by underlying cause of death is fundamental for public health decision making. Cause-specific estimates of mortality and the subsequent effects on life expectancy worldwide are valuable metrics to gauge progress in reducing mortality rates. These estimates are particularly important following large-scale mortality spikes, such as the COVID-19 pandemic. When systematically analysed, mortality rates and life expectancy allow comparisons of the consequences of causes of death globally and over time, providing a nuanced understanding of the effect of these causes on global populations. METHODS: The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2021 cause-of-death analysis estimated mortality and years of life lost (YLLs) from 288 causes of death by age-sex-location-year in 204 countries and territories and 811 subnational locations for each year from 1990 until 2021. The analysis used 56 604 data sources, including data from vital registration and verbal autopsy as well as surveys, censuses, surveillance systems, and cancer registries, among others. As with previous GBD rounds, cause-specific death rates for most causes were estimated using the Cause of Death Ensemble model-a modelling tool developed for GBD to assess the out-of-sample predictive validity of different statistical models and covariate permutations and combine those results to produce cause-specific mortality estimates-with alternative strategies adapted to model causes with insufficient data, substantial changes in reporting over the study period, or unusual epidemiology. YLLs were computed as the product of the number of deaths for each cause-age-sex-location-year and the standard life expectancy at each age. As part of the modelling process, uncertainty intervals (UIs) were generated using the 2·5th and 97·5th percentiles from a 1000-draw distribution for each metric. We decomposed life expectancy by cause of death, location, and year to show cause-specific effects on life expectancy from 1990 to 2021. We also used the coefficient of variation and the fraction of population affected by 90% of deaths to highlight concentrations of mortality. Findings are reported in counts and age-standardised rates. Methodological improvements for cause-of-death estimates in GBD 2021 include the expansion of under-5-years age group to include four new age groups, enhanced methods to account for stochastic variation of sparse data, and the inclusion of COVID-19 and other pandemic-related mortality-which includes excess mortality associated with the pandemic, excluding COVID-19, lower respiratory infections, measles, malaria, and pertussis. For this analysis, 199 new country-years of vital registration cause-of-death data, 5 country-years of surveillance data, 21 country-years of verbal autopsy data, and 94 country-years of other data types were added to those used in previous GBD rounds. FINDINGS: The leading causes of age-standardised deaths globally were the same in 2019 as they were in 1990; in descending order, these were, ischaemic heart disease, stroke, chronic obstructive pulmonary disease, and lower respiratory infections. In 2021, however, COVID-19 replaced stroke as the second-leading age-standardised cause of death, with 94·0 deaths (95% UI 89·2-100·0) per 100 000 population. The COVID-19 pandemic shifted the rankings of the leading five causes, lowering stroke to the third-leading and chronic obstructive pulmonary disease to the fourth-leading position. In 2021, the highest age-standardised death rates from COVID-19 occurred in sub-Saharan Africa (271·0 deaths [250·1-290·7] per 100 000 population) and Latin America and the Caribbean (195·4 deaths [182·1-211·4] per 100 000 population). The lowest age-standardised death rates from COVID-19 were in the high-income super-region (48·1 deaths [47·4-48·8] per 100 000 population) and southeast Asia, east Asia, and Oceania (23·2 deaths [16·3-37·2] per 100 000 population). Globally, life expectancy steadily improved between 1990 and 2019 for 18 of the 22 investigated causes. Decomposition of global and regional life expectancy showed the positive effect that reductions in deaths from enteric infections, lower respiratory infections, stroke, and neonatal deaths, among others have contributed to improved survival over the study period. However, a net reduction of 1·6 years occurred in global life expectancy between 2019 and 2021, primarily due to increased death rates from COVID-19 and other pandemic-related mortality. Life expectancy was highly variable between super-regions over the study period, with southeast Asia, east Asia, and Oceania gaining 8·3 years (6·7-9·9) overall, while having the smallest reduction in life expectancy due to COVID-19 (0·4 years). The largest reduction in life expectancy due to COVID-19 occurred in Latin America and the Caribbean (3·6 years). Additionally, 53 of the 288 causes of death were highly concentrated in locations with less than 50% of the global population as of 2021, and these causes of death became progressively more concentrated since 1990, when only 44 causes showed this pattern. The concentration phenomenon is discussed heuristically with respect to enteric and lower respiratory infections, malaria, HIV/AIDS, neonatal disorders, tuberculosis, and measles. INTERPRETATION: Long-standing gains in life expectancy and reductions in many of the leading causes of death have been disrupted by the COVID-19 pandemic, the adverse effects of which were spread unevenly among populations. Despite the pandemic, there has been continued progress in combatting several notable causes of death, leading to improved global life expectancy over the study period. Each of the seven GBD super-regions showed an overall improvement from 1990 and 2021, obscuring the negative effect in the years of the pandemic. Additionally, our findings regarding regional variation in causes of death driving increases in life expectancy hold clear policy utility. Analyses of shifting mortality trends reveal that several causes, once widespread globally, are now increasingly concentrated geographically. These changes in mortality concentration, alongside further investigation of changing risks, interventions, and relevant policy, present an important opportunity to deepen our understanding of mortality-reduction strategies. Examining patterns in mortality concentration might reveal areas where successful public health interventions have been implemented. Translating these successes to locations where certain causes of death remain entrenched can inform policies that work to improve life expectancy for people everywhere. FUNDING: Bill & Melinda Gates Foundation.

BACKGROUND: Neonatal Escherichia coli (E coli) meningitis results in significant morbidity and mortality. We present a case of a premature infant with extensive central nervous system (CNS) injury from recurrent E coli infection and the non-traditional methods necessary to identify and clear the infection. CASE PRESENTATION: The infant was transferred to our institutions pediatric intensive care unit (PICU) after recurrence of E coli CNS infection requiring neurosurgical intervention. He had been treated for early onset sepsis (EOS) with ampicillin and gentamicin for 10 days followed by rapid development of ampicillin-resistant E coli septic shock and meningitis after discontinuation of antibiotics. Sterility of the CNS was not confirmed at the end of 21 days of cefepime therapy and was subsequently followed by recurrent ampicillin-resistant E coli septic shock and CNS infection. Despite 6 weeks of appropriate therapy with sterility of CSF by traditional methods, he suffered from intractable seizures with worsening hydrocephalus. Transferred to our institution, he underwent endoscopic 3rd ventriculostomy with cyst fenestration revealing purulent fluid and significant pleocytosis. An additional 3 weeks of systemic and intraventricular antibiotics with cefepime and tobramycin were given but a significant CNS neutrophil-predominant pleocytosis persisted (average of ∼ 21,000 cells/mm3). Repeated gram stains, cultures, polymerase chain reaction (PCR) testing, and metagenomic next generation sequencing (NGS) testing of CSF were negative for pathogens but acridine orange stain (AO) revealed numerous intact rod-shaped bacteria. After the addition of ciprofloxacin, sterility and resolution of CSF pleocytosis was finally achieved. CONCLUSION: Neonatal E coli meningitis is a well-known entity but unlike other bacterial infections, it has not proven amenable to shorter, more narrow-spectrum antibiotic courses or limiting invasive procedures such as lumbar punctures. Further, microbiologic techniques to determine CSF sterility suffer from poorly understood limitations leading to premature discontinuation of antibiotics risking further neurologic damage in vulnerable hosts.

BACKGROUND: Posttraumatic stress (PTS) and anxiety are common mental health problems among parents of babies admitted to a neonatal unit (NNU). This review aimed to identify sociodemographic, pregnancy and birth, and psychological factors associated with PTS and anxiety in this population. METHOD: Studies published up to December 2022 were retrieved by searching Medline, Embase, PsychoINFO, Cumulative Index to Nursing and Allied Health electronic databases. The modified Newcastle-Ottawa Scale for cohort and cross-sectional studies was used to assess the methodological quality of included studies. This review was pre-registered in PROSPERO (CRD42021270526). RESULTS: Forty-nine studies involving 8,447 parents were included; 18 studies examined factors for PTS, 24 for anxiety and 7 for both. Only one study of anxiety factors was deemed to be of good quality. Studies generally included a small sample size and were methodologically heterogeneous. Pooling of data was not feasible. Previous history of mental health problems (four studies) and parental perception of more severe infant illness (five studies) were associated with increased risk of PTS, and had the strongest evidence. Shorter gestational age (≤ 33 weeks) was associated with an increased risk of anxiety (three studies) and very low birth weight (

Millions of doses of azithromycin are distributed each year for trachoma, yet the treatment efficacy of a single dose of azithromycin for ocular Chlamydia infection has not been well characterized. In this study, four villages in Niger received a mass azithromycin distribution for trachoma. All 426 children aged 0-5 years residing in the study villages were offered conjunctival swabbing every 6 months to test for ocular Chlamydia trachomatis. Among the children infected with ocular Chlamydia before treatment, 6% (95% CI: 2-15%) tested positive for ocular Chlamydia infection 6 months later, and 15% (95% CI: 7-28%) tested positive 12 months later. The most important predictor of post-treatment ocular Chlamydia infection was pretreatment ocular Chlamydia infection (relative risk: 3.5, 95% CI: 1.3-9.4). Although the 6-monthly monitoring schedule was suboptimal for testing the treatment efficacy of an antibiotic, these findings are nonetheless consistent with high treatment efficacy of a single dose of azithromycin and suggest that additional interventions might be most effective if targeted to those children infected prior to treatment.

ObjectiveWe sought to evaluate the impact of the coronavirus disease 2019 (COVID-19) pandemic on perinatal outcomes while accounting for maternal depression or perceived stress and to describe COVID-specific stressors, including changes in prenatal care, across specific time periods of the pandemic.Study designData of dyads from 41 cohorts from the National Institutes of Health Environmental influences on Child Health Outcomes Program (N = 2,983) were used to compare birth outcomes before and during the pandemic (n = 2,355), and a partially overlapping sample (n = 1,490) responded to a COVID-19 questionnaire. Psychosocial stress was defined using prenatal screening for depression and perceived stress. Propensity-score matching and general estimating equations with robust variance estimation were used to estimate the pandemic's effect on birth outcomes.ResultsSymptoms of depression and perceived stress during pregnancy were similar prior to and during the pandemic, with nearly 40% of participants reporting mild to severe stress, and 24% reporting mild depression to severe depression. Gestations were shorter during the pandemic (B =  - 0.33 weeks, p = 0.025), and depression was significantly associated with shortened gestation (B =  - 0.02 weeks, p = 0.015) after adjustment. Birth weights were similar (B =  - 28.14 g, p = 0.568), but infants born during the pandemic had slightly larger birth weights for gestational age at delivery than those born before the pandemic (B = 0.15 z-score units, p = 0.041). More women who gave birth early in the pandemic reported being moderately or extremely distressed about changes to their prenatal care and delivery (45%) compared with those who delivered later in the pandemic. A majority (72%) reported somewhat to extremely negative views of the impact of COVID-19 on their life.ConclusionIn this national cohort, we detected no effect of COVID-19 on prenatal depression or perceived stress. However, experiencing the COVID-19 pandemic in pregnancy was associated with decreases in gestational age at birth, as well as distress about changes in prenatal care early in the pandemic.Key points· COVID-19 was associated with shortened gestations.. · Depression was associated with shortened gestations.. · However, stress during the pandemic remained unchanged.. · Most women reported negative impacts of the pandemic..

BackgroundThere is a lack of research on the relationship between water fluoridation and pregnancy outcomes.ObjectivesWe assessed whether hypothetical interventions to reduce fluoride levels would improve birth outcomes in California.MethodsWe linked California birth records from 2000 to 2018 to annual average fluoride levels by community water system. Fluoride levels were collected from consumer confidence reports using publicly available data and public record requests. We estimated the effects of a hypothetical intervention reducing water fluoride levels to 0.7 ppm (the current level recommended by the US Department of Health and Human Services) and 0.5 ppm (below the current recommendation) on birth weight, birth-weight-for-gestational age z-scores, gestational age, preterm birth, small-for-gestational age, large-for-gestational age, and macrosomia using linear regression with natural cubic splines and G-computation. Inference was calculated using a clustered bootstrap with Wald-type confidence intervals. We evaluated race/ethnicity, health insurance type, fetal sex, and arsenic levels as potential effect modifiers.ResultsFluoride levels ranged from 0 to 2.5 ppm, with a median of 0.51 ppm. There was a small negative association on birth weight with the hypothetical intervention to reduce fluoride levels to 0.7 ppm [-2.2g; 95% confidence interval (CI): -4.4, 0.0] and to 0.5 ppm (-5.8g; 95% CI: -10.0, -1.6). There were small negative associations with birth-weight-for-gestational-age z-scores for both hypothetical interventions (0.7 ppm: -0.004; 95% CI: -0.007, 0.000 and 0.5 ppm: -0.006; 95% CI: -0.013, 0.000). We also observed small negative associations for risk of large-for-gestational age for both the hypothetical interventions to 0.7 ppm [risk difference (RD)=-0.001; 95% CI: -0.002, 0.000 and 0.5 ppm (-0.001; 95% CI: -0.003, 0.000)]. We did not observe any associations with preterm birth or with being small for gestational age for either hypothetical intervention. We did not observe any associations with risk of preterm birth or small-for-gestational age for either hypothetical intervention.ConclusionWe estimated that a reduction in water fluoride levels would modestly decrease birth weight and birth-weight-for-gestational-age z-scores in California. https://doi.org/10.1289/EHP13732.

OBJECTIVE:  The aim of Placental Assessment in Response to Environmental Pollution Study (PARENTs) was to determine whether imaging of the placenta by novel multiparametric magnetic resonance imaging (MRI) techniques in early pregnancy could help predict adverse pregnancy outcomes (APOs) due to ischemic placental disease (IPD). Additionally, we sought to determine maternal characteristics and environmental risk factors that contribute to IPD and secondary APOs. STUDY DESIGN:  Potential patients in their first trimester of pregnancy, who agreed to MRI of the placenta and measures of assessment of environmental pollution, were recruited into PARENTs, a prospective population-based cohort study. Participants were seen at three study visits during pregnancy and again at their delivery from 2015 to 2019. We collected data from interviews, chart abstractions, and imaging. Maternal biospecimens (serum, plasma, and urine) at antepartum study visits and delivery specimens (placenta, cord, and maternal blood) were collected, processed, and stored. The primary outcome was a composite of IPD, which included any of the following: placental abruption, hypertensive disease of pregnancy, fetal growth restriction, or a newborn of small for gestational age. RESULTS:  In this pilot cohort, of the 190 patients who completed pregnancy to viable delivery, 50 (26%) developed IPD. Among demographic characteristics, having a history of prior IPD in multiparous women was associated with the development of IPD. In the multiple novel perfusion measurements taken of the in vivo placenta using MRI, decreased high placental blood flow (mL/100 g/min) in early pregnancy (between 14 and 16 weeks) was found to be significantly associated with the later development of IPD. CONCLUSION:  Successful recruitment of the PARENTs prospective cohort demonstrated the feasibility and acceptability of the use of MRI in human pregnancy to study the placenta in vivo and at the same time collect environmental exposure data. Analysis is ongoing and we hope these methods will assist researchers in the design of prospective imaging studies of pregnancy. KEY POINTS: · MRI was acceptable and feasible for the study of the human placenta in vivo.. · Functional imaging of the placenta by MRI showed a significant decrease in high placental blood flow.. · Measures of environmental exposures are further being analyzed to predict IPD..

OBJECTIVE: To develop a predictive model for thiamine responsive disorders (TRDs) among infants and young children hospitalized with signs or symptoms suggestive of thiamine deficiency disorders (TDDs) based on response to therapeutic thiamine in a high-risk setting. STUDY DESIGN: Children aged 21 days to

OBJECTIVE: There has been little evidence of the impact of preventive services during pregnancy covered under the Affordable Care Act (ACA) on birthing parent and infant outcomes. To address this gap, this study examines the association between Medicaid expansion under the ACA and birthing parent and infant outcomes of low-income pregnant people. METHODS: This study used individual-level data from the 2004-2017 annual waves of the Pregnancy Risk Assessment Monitoring System (PRAMS). PRAMS is a surveillance project of the Centers for Disease Control and Prevention and health departments that annually includes a representative sample of 1,300 to 3,400 births per state, selected from birth certificates. Birthing parents outcomes of interest included timing of prenatal care, gestational diabetes, hypertensive disorders of pregnancy, cigarette smoking during pregnancy, and postpartum care. Infant outcomes included initiation and duration of breastfeeding, preterm birth, and birth weight. The association between ACA Medicaid expansion and the birthing parent and infant outcomes were examined using difference-in-differences estimation. RESULTS: There was no association between Medicaid expansion and the outcomes examined after correcting for multiple testing. This finding was robust to several sensitivity analyses. CONCLUSIONS FOR PRACTICE: Study findings suggest that expanded access to more complete insurance benefits with limited cost-sharing for pregnant people, a group that already had high rates of insurance coverage, did not impact the birthing parents and infant health outcomes examined.