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Congenital Malaria (CM) is an underestimated and under-researched problem in Colombia, despite its severe clinical, epidemiological, economic, and public health consequences. The objective was to determine the general frequency of CM, the specific frequency of CM by diagnostic test and plasmodial species, and identify its associated factors. A retrospective study was carried out using the records of 567 newborns. qPCR and Thick Blood Smear (TBS) were performed. The frequency of infection was determined with a 95% confidence interval. Associated factors were identified by non-parametric tests and odds ratios; the confusion was controlled with a logistic regression model. All cases corresponded to submicroscopic CM (negative with TBS and positive with PCR), and the frequency was 12.2% (95%CI = 9.4-14.9). The detection was statistically higher in the umbilical cord with 16,2% (95%CI = 12.4-19.9) versus peripheral blood of the newborn with 2.2% (95%CI = 0.7-4.9). CM was statistically higher in newborn whose mothers had malaria in the last year, gestational and placental malaria. The median birth weight in newborn infected with CM was lower compared to the one of healthy neonates. Because the control program in Colombia is based on TBS, it must be improved with the inclusion of other tests that allow the detection of submicroscopic CM. In addition, the program has other limitations such as do not have specific actions for pregnant women and have a passive surveillance system. These difficulties do not allow to show the magnitude of CM, its consequences on neonatal and infant health, constituting a serious problem of health injustice., Competing Interests: The authors have declared that no competing interests exist.

A sensitive and accurate hydrophilic interaction liquid chromatography - tandem mass spectrometry method (HILIC-MS/MS) was developed and validated for the determination of phenylephrine concentration in Dried Blood Spot (DBS) samples from preterm infants, after ocular administration of an ophthalmic solution with phenylephrine. Sample preparation involved the extraction of the analyte from an 85 μL DBS sample with methanol - acetonitrile (50:50, v/v). Chromatographic separation was achieved on an ACQUITY UPLC BEH AMIDE column, under isocratic conditions within a 5 min run. Detection was achieved with a triple quadrupole MS applying electrospray ionization in positive mode. The method was fully validated and proved precise and accurate with in a linear range of 0.59-3.53 ng/ml in blood. The method was developed to provide insights on the level of exposure of infant population to phenylephrine after ocular administration., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Objective: Alkaline phosphatase (ALP) is a ubiquitous enzyme in humans that can be used for diagnosing childhood diseases. Infants have the highest rapid growth rate and are susceptible to metabolic bone diseases. In infants, ALP activities exhibit significant month-wise variations, and authoritative standards are lacking. The present study aimed to provide a reference for the diagnosis of diseases related to abnormal ALP activities in infants., Methods: This study included 24,618 samples collected from infants aged 0-12 months from three medical centers in Chongqing, China. Samples of infants diagnosed with diseases that may affect ALP activity have been exclude. ALP activity was analyzed using an automatic biochemical analyzer. A percentile curve for ALP activity in male and female infants was constructed using MATLAB, and the skewness-median-coefficient of variation method was employed for curve fitting., Results: ALP activity in male and female infants peaked at 0-4 months; the peak appeared at 1-2 months and declined gradually thereafter. After 4-5 months of age, the ALP activities declined further, with the lowest values observed at 11-12 months of age. A comparison between the data from this study and a those from a published German study indicates that Chinese infants exhibited peak ALP activity later and subsequent decline greater than German infants., Conclusions: A percentile curve was constructed for month-wise ALP activity in male and female infants, which could provide a reference for diagnosing diseases related to abnormal ALP activity in infants., (Copyright © 2021. Published by Elsevier Inc.)

Carboxyhemoglobin (COHb) is an index of endogenous carbon monoxide formation during the hem degradation process and could be used to confirm hemolysis in neonates. The influence of other clinical factors on COHb values in neonates has not been fully investigated. We aimed to evaluate the influence of hemolysis, sepsis, respiratory distress, and postnatal age on COHb values. We retrospectively analyzed COHb measurements determined with a carbon monoxide-oximeter in 4 groups of term neonates: A-sepsis, B-respiratory distress, C-hemolysis, and D-healthy neonates. The mean COHb values were 1.41% (SD: 0.26), 1.32% (SD: 0.27), 2.5% (SD: 0.69), and 1.27% (SD: 0.19) (P<0.001) in groups A (n=8), B (n=37), C (n=16), and D (n=76), respectively. COHb in group C was significantly higher than in the other groups. There was a negative correlation between postnatal age and COHb in healthy neonates. A cut-off level of 1.7% had 93% (95% confidence interval [CI]: 89%-97%) sensitivity and 94% (95% CI: 90%-98%) specificity for diagnosis of hemolysis. COHb values were higher during the first days of life. We found that COHb levels in neonates with hemolysis were significantly higher and that the influence of sepsis and respiratory distress on COHb values was insignificant., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Identifying risk factors for impaired oral rotavirus vaccine (ORV) efficacy in low-income countries may lead to improvements in vaccine design and delivery. In this prospective cohort study, we measure maternal rotavirus antibodies, environmental enteric dysfunction (EED), and bacterial gut microbiota development among infants receiving two doses of Rotarix in India (n = 307), Malawi (n = 119), and the UK (n = 60), using standardised methods across cohorts. We observe ORV shedding and seroconversion rates to be significantly lower in Malawi and India than the UK. Maternal rotavirus-specific antibodies in serum and breastmilk are negatively correlated with ORV response in India and Malawi, mediated partly by a reduction in ORV shedding. In the UK, ORV shedding is not inhibited despite comparable maternal antibody levels to the other cohorts. In both India and Malawi, increased microbiota diversity is negatively correlated with ORV immunogenicity, suggesting that high early-life microbial exposure may contribute to impaired vaccine efficacy., (© 2021. The Author(s).)

Objective: To compare the effect of comorbidities on the phenotype and outcomes of preeclampsia. Methods: A matched retrospective cohort study of women delivering at a tertiary maternity center following a diagnosis of preeclampsia. We collected data on signs and symptoms, biochemical markers, and maternal and perinatal outcomes. Results: We studied 474 women; 158 women with and 316 without comorbidities. Compared to women without comorbidities, women with comorbidities delivered earlier. They suffered fewer maternal but more neonatal complications. Conclusion: Women with comorbidities receive earlier intervention than women without comorbidities, which may lead to fewer maternal complications but worse neonatal outcomes.

Objective: This study examined patterns of care after birth in newborns treated with therapeutic hypothermia to identify remediable causes for the poorer outcomes observed in outborn infants., Study Design: This was a secondary analysis of 150 newborns (68 outborn) prospectively enrolled at our center in the Vermont Oxford Neonatal Encephalopathy Registry from January 2008 to October 2016., Results: The 5-minute Apgar's score and cord pH value did not differ, but cord blood gases were obtained far less frequently in outborns ( p  = 0.002). Outborns needed more chest compressions ( p  = 0.01) and epinephrine ( p  = 0.04), and had more brain injury on neuroimaging ( p  = 0.05). Outborns took longer to reach target hypothermia temperature ( p  < 0.0001)., Conclusion: The lack of cord gas values and longer time to reach target temperature observed in the outborns are two observed differences in care that can be potentially remedied by providing education and resources at delivering hospitals in rapid identification of hypothermia candidates, though further research is needed to define the effects of such measures. Possible solutions are also discussed here., Competing Interests: M.J.A.H. reports grants from The Hartwell Foundation during the conduct of the study., (Thieme. All rights reserved.)

Extracellular vesicles (EVs) are cell-derived membrane-bound particles, extensively investigated across many fields to improve the understanding of pathophysiological processes, as biomarkers of disease and as therapeutic targets for pharmacological intervention. We aim to describe the current knowledge of EVs detected in the body fluids of human neonates, both term and preterm, from birth to 4 weeks of age. To date, EVs have been described in several neonatal body fluids, including cerebrospinal fluid, umbilical cord blood, neonatal blood, tracheal aspirates and urine. These studies demonstrate some important roles of EVs in the neonatal population, particularly in haemostasis. Moreover, some studies have demonstrated the pathophysiological mechanisms and the identification of potential biomarkers of neonatal disease. We must continue to build on this knowledge, evaluating the role of EVs in neonatal pathology, particularly in prematurity and during the perinatal adaption period. Future studies should use larger numbers, robust EV characterisation techniques and always correlate the findings to clinical outcomes. IMPACT: This article summarises the current knowledge of the effect of EVs in neonates. It describes the potential compensatory role of EVs in neonatal haemostasis. It also describes the role of EVs as mediators of pathology and as potential biomarkers of perinatal and neonatal disease., (© 2020. International Pediatric Research Foundation, Inc.)

Necrotizing enterocolitis (NEC) and focal intestinal perforation (FIP) are two of the most common emergencies of the gastrointestinal tract in preterm infants with very low birth weight (VLBW, birth weight < 1500 g). Identification of risk factors among these children is crucial for earlier diagnosis and prompt intervention. In this study, we investigated a relationship between ABO blood groups and the risk for surgical NEC/FIP. We genotyped the ABO locus (rs8176746 and rs8176719) in VLBW infants enrolled in a prospective, population-based cohort study of the German Neonatal Network (GNN). Of the 10,257 VLBW infants, 441 (4.3%) had surgical NEC/FIP. In univariate analyses, the blood group AB was more prevalent in VLBW infants with surgical NEC/FIP compared to non-AB blood groups (OR 1.51, 95% CI 1.07-2.13, p = 0.017; absolute risk difference 2.01%, 95% CI 0.06-3.96%). The association between blood group AB and surgical NEC/FIP was observed in a multivariable logistic regression model (OR of 1.58, 95% CI 1.10-2.26, p = 0.013) as well. In summary, our study suggests that the risk of surgical NEC and FIP is higher in patients with blood group AB and lower in those having non-AB blood groups.

Background: Early-onset sepsis (EOS) remains a substantial cause of morbidity and mortality among neonates. Yet, currently available biological parameters have not proven to be accurate enough to predict EOS reliably. This study aimed to determine serum concentrations of 13 cytokines in umbilical cord blood and evaluate their diagnostic value for EOS., Methods: A prospective single-center study that included analysis of umbilical cord blood of term and preterm neonates who were born from March 2017 to November 2017. Using ELISA analysis, 13 cytokines were simultaneously quantified and correlated with the development of EOS., Results: Four hundred and seventy-four neonates were included, of which seven met the criteria for culture-positive EOS. Interleukin (IL)-6 (p < 0.001), IL-9 (p = 0.003), and IL-21 (p < 0.001) were significantly increased in neonates with EOS compared to controls. Sensitivity and specificity for IL-6, IL-9, and IL-21 at the defined cut-off points were 85.7 and 77.3%, 71.4 and 62.5%, and 71.4 and 52.0%, respectively., Conclusions: In neonates with EOS, IL-9 and IL-21 are significantly elevated and may be employed in the diagnostic of EOS. However, diagnostic accuracy remains lower than with IL-6. Values of 13 T cell cytokines may be used as reference values for future studies in neonates., Impact: Interleukin-9 (IL-9) and interleukin-21 (IL-21) are significantly elevated in neonates with early-onset sepsis. IL-9 and IL-21 have been shown to play a specific role in neonatal sepsis. Neonatal reference values were generated for several cytokines. IL-9 and IL-21 might be attractive biomarkers for neonatal sepsis in future. This study is likely to promote further research in this area. Values of several T cell cytokines may be used as reference values for future studies in neonates., (© 2020. International Pediatric Research Foundation, Inc.)

Purpose: The role of hypoalbuminemia and raised C-reactive protein (CRP) levels in predicting critical prognosis has been described extensively in adult literature. However, there are limited studies in pediatrics, particularly neonates. The CRP/albumin (CRP/ALB) ratio is often associated with higher mortality, organ failure and prolonged hospital stay. We hypothesized that the serum CRP/ALB ratio has a prognostic value in predicting surgery and mortality in neonates with necrotizing enterocolitis (NEC)., Methods: Retrospective review of all neonates with clinical and radiological evidence of non-perforated NEC that were treated in a tertiary-level referral hospital between 2009 and 2018. General patient demographics, laboratory parameters and outcomes were recorded. Receiver operating characteristics analysis was performed to evaluated optimal cut-offs and area under the curve (AUC) with 95% confidence intervals (CI)., Results: A total of 191 neonates were identified. Of these, 103 (53.9%) were born at ≤ 28 weeks of gestation and 101 (52.9%) had a birth weight of ≤ 1000 g. Eighty-four (44.0%) patients underwent surgical intervention for NEC. The overall survival rate was 161/191 (84.3%). A CRP/ALB ratio of ≥ 3 on day 2 of NEC diagnosis was associated with a statistically significant higher likelihood for surgery [AUC 0.71 (95% CI 0.63-0.79); p < 0.0001] and mortality [AUC 0.66 (95% CI 0.54-0.77); p = 0.0150], respectively., Conclusions: A CRP/ALB ratio of ≥ 3 on day 2 is indicative of a critical pathway in neonates with radiologically confirmed, non-perforated NEC. This could be used as an additional criterion to guide parental counselling in NEC for surgical intervention and mortality.

Introduction: As the clinical manifestation of neonatal infection is nonspecific and characterised by varied clinical features, it is highly problematic to establish an early diagnosis. Recently, hopes have been raised by the new acute-phase protein-pentraxin 3 (PTX3). PTX3 belongs to the family of long pentraxins, which is synthesized in numerous cells like endothelial cells, macrophages, and monocytes infiltrating sites of inflammation. Material and Methods . In our research, we have enrolled 29 newborns with infection as the study group and 47 healthy ones as the control group, as well as their mothers. The C-reactive protein (CRP), procalcitonin (PCT), and PTX3 levels were determined in venous blood samples from all investigated neonates and their mothers. Moreover, PTX3 concentrations were assessed in the umbilical cord., Results: There were statistically significant differences in PTX3 levels between healthy and sick newborns both in the umbilical cord ( p = 0.02) and venous blood ( p = 0.01). The highest PTX3 concentrations were observed in children with infection in the presence of premature rupture of membranes (PROM). PTX3 concentrations in this group were significantly higher compared to those in healthy children without PROM. We observed elevated PCT levels in newborns with infection. No differences in CRP levels in 12 hours of life were noticed between the investigated groups. A comparison of ROC curves for PTX3 and PCT concentrations revealed similar sensitivity and specificity in the prediction of infection in neonates., Conclusions: Serum PTX3 is an important and specific biomarker of early infection. It is already elevated in the umbilical cord, so measuring PTX3 concentration might be useful in the early prediction of infection in newborns., Competing Interests: The authors declare that there is no conflict of interest regarding the publication of this paper., (Copyright © 2021 Małgorzata Baumert et al.)

The detection of epigenetic changes associated with neonatal hypoglycaemia may reveal the pathophysiology and predict the onset of future diseases in offspring. We hypothesized that neonatal hypoglycaemia reflects the in utero environment associated with maternal gestational diabetes mellitus. The aim of this study was to identify epigenetic changes associated with neonatal hypoglycaemia. The association between DNA methylation using Infinium HumanMethylation EPIC BeadChip and neonatal plasma glucose (PG) level at 1 h after birth in 128 offspring born at term to mothers with well-controlled gestational diabetes mellitus was investigated by robust linear regression analysis. Cord blood DNA methylation at 12 CpG sites was significantly associated with PG at 1 h after birth after adding infant sex, delivery method, gestational day, and blood cell compositions as covariates to the regression model. DNA methylation at two CpG sites near an alternative transcription start site of ZNF696 was significantly associated with the PG level at 1 h following birth (false discovery rate-adjusted P < 0.05). Methylation levels at these sites increased as neonatal PG levels at 1 h after birth decreased. In conclusion, gestational diabetes mellitus is associated with DNA methylation changes at the alternative transcription start site of ZNF696 in cord blood cells. This is the first report of DNA methylation changes associated with neonatal PG at 1 h after birth., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Kasuga, Kawai, Miyakoshi, Saisho, Tamagawa, Hasegawa, Ikenoue, Ochiai, Hida, Tanaka and Hata.)

Neonatal alloimmune thrombocytopenia (NAIT) arises from fetomaternal platelet incompatibility that results in transplacental passage of maternal antibodies mostly against fetal human platelet antigens (HPA), whereas NAIT due to anti-human leukocyte antigen (HLA) antibodies is extremely rare. Here, we report a case of Down syndrome (DS) with NAIT that was attributed to HLA antibodies. A boy with DS was delivered at 36 weeks' gestation. His platelet count declined to 13.0 × 10 9 /L, suggestive of NAIT rather than other conditions, including transient abnormal myelopoiesis. Random platelet concentrates and intravenous immunoglobulin administration resolved the thrombocytopenia without clinical complications. Immunoserological investigations detected anti-HLA, but no anti-HPA antibodies in samples from the patient and the mother. HLA typing and cross-matching indicated that anti-HLA antibodies to paternal HLA A31 and B61, which had probably been induced during a prior pregnancy, led to NAIT in this case. Although it is a rare condition, healthcare providers should consider NAIT due to HLA antibodies and be vigilant for subsequent cases in DS.

Background: Congenital cytomegalovirus disease (cCMV) is common and can be fatal or cause severe sequelae. Circulating strains of cytomegalovirus carry a high number of variable or disrupted genes. One of these is UL146, a highly diverse gene with 14 distinct genotypes encoding a CXC-chemokine involved in viral dissemination. UL146 genotypes 5 and 6 lack the conserved ELR motif, potentially affecting strain virulence. Here, we investigate whether UL146 genotypes 5 and 6 were associated with congenital CMV infection., Methods: Viral DNA was extracted and UL146 sequenced from 116 neonatal dried blood spots (DBS) stored in the Danish National Biobank since 1982 and linked to registered cCMV cases through a personal identifier. These sequences were compared to UL146 control sequences obtained from CMV DNA extracted from 83 urine samples from children with suspected bacterial urinary tract infections., Results: Three non-ELR UL146 genotypes (5 and 6) were observed among the cases (2.6%) and two were observed among the controls (2.4%; P > 0.99). Additionally, no significant association with cCMV was found for the other 12 genotypes in a post-hoc analysis, although genotype 8 showed a tendency to be more frequent among cases with 12 observations against three (P = 0.10). All fourteen genotypes were found to have little intra-genotype variation. Viral load, gender, and sample age were not found to be associated with any particular UL146 genotype., Conclusions: No particular UL146 genotype was associated with cCMV in this nationwide retrospective case-control study. Associations between CMV disease and disrupted or polymorph CMV genes among immunosuppressed people living with HIV/AIDS and transplant recipients should be investigated in future studies.

Vertical transmission of Trypanosomacruzi is the cause of congenital Chagas disease, a re-emerging infectious disease that affects endemic and nonendemic regions alike. An early diagnosis is crucial because prompt treatment achieves a high cure rate, precluding evolution to symptomatic chronic Chagas disease. However, early diagnosis involves low-sensitive parasitologic assays, making necessary serologic confirmation after 9 months of life. With the aim of implementing early diagnostic strategies suitable for minimally equipped laboratories, a T. cruzi-loop-mediated isothermal amplification (LAMP) prototype was coupled with an automated DNA-extraction device repurposed from a three-dimensional printer (PrintrLab). The whole process takes <3 hours to yield a result, with an analytical sensitivity of 0.1 to 2 parasite equivalents per milliliter, depending on the T. cruzi strain. Twenty-five blood samples from neonates born to seropositive mothers were tested blindly. In comparison to quantitative real-time PCR, the PrintrLab-LAMP dual strategy showed high agreement, while both molecular-based methodologies yielded optimal sensitivity and specificity with respect to microscopy-based diagnosis of congenital Chagas disease. PrintrLab-LAMP detected all 10 congenitally transmitted T. cruzi infections, showing promise for point-of-care early diagnosis of congenital Chagas disease., (Copyright © 2021 Association for Molecular Pathology and American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Necrotizing enterocolitis (NEC) is an inflammatory bowel necrosis of premature infants and is a leading cause of morbidity and mortality in infants born between 23 and 28 weeks of gestation. Fifty to 95% of all infants with NEC develop thrombocytopenia (platelet counts <150 × 10 9 /L) within 24-72 h of receiving this diagnosis. In many patients, thrombocytopenia is severe and is treated with one or more platelet transfusions. However, the underlying mechanism(s) and biological implications of NEC-related thrombocytopenia remain unclear. This review presents current evidence from human and animal studies on the clinical features and mechanisms of platelet depletion in NEC. Anecdotal clinical experience is combined with evidence from laboratory studies and from an extensive literature search in databases PubMed, EMBASE, and Scopus and the electronic archives of abstracts presented at the annual meetings of the Pediatric Academic Societies. To avoid bias in identification of existing studies, key words were short-listed prior to the actual search both from anecdotal experience and from PubMed's Medical Subject Heading (MeSH) thesaurus. IMPACT: Fifty to 95% of infants with necrotizing enterocolitis (NEC) develop idiopathic thrombocytopenia (platelet counts <150 × 10 9 /L) within 24-72 h of disease onset. Early clinical trials suggest that moderate thrombocytopenia may be protective in human NEC, although further work is needed to fully understand this relationship. We have developed a neonatal murine model of NEC-related thrombocytopenia, where enteral administration of an immunological stimulant, trinitrobenzene sulfonate, on postnatal day 10 induces an acute necrotizing ileocolitis resembling human NEC. In this murine model, thrombocytopenia is seen at 15-18 h due to platelet consumption and mild-moderate thrombocytopenia is protective.

Objective: Evaluate the effectiveness and safety of application of oral glucose to neonates with an increased risk of neonatal hypoglycaemia., Background: Neonatal hypoglycaemia is a common problem in neonates with potential permanent neurological damage. Recent studies show that the use of oral glucose to prevent and treat neonatal hypoglycaemia leads to a decrease in intravenous glucose administration and fewer clinical admissions. However, oral glucose administration is still rarely used. In 2019 Isala hospital implemented the use of oral glucose in neonates with an increased risk of neonatal hypoglycaemia., Method: Retrospective evaluation study in Isala hospital between November 1, 2018 and December 31. Neonates with one of the following risk factors for neonatal hypoglycaemia: prematurity (gestational age between 34+0-37+0), maternal diabetes requiring medication, asphyxia with an Apgar score <7 at five minutes and/or a birthweight <2500 grams. The frequency of glucose infusions, the lowest glucose value and the type of food were compared between neonates treated before and after the use of oral glucose., Results: The number of glucose infusions decreased after introduction of oral glucose (14.0% versus 5.9%, -8.1% [-14.1, -2.1]). The lowest measured glucose value (2.2 mmol/l versus 2.5 mmol/l, 0.3 mmol/l [0.15, 0.47]) was significantly higher after introduction of oral glucose. Mild complications (vomiting and food refusal) occurred in 3.8% of neonates receiving oral glucose, all without clinical consequence., Conclusion: The use of oral glucose administration in neonates with an increased risk of hypoglycaemia reduces the number of intravenous glucose by half and is safe to use.

Objective: This study is to investigate the role of microRNA (miR)-30b in the pathogenesis of hypoxic-ischemic encephalopathy (HIE) in neonates., Methods: Totally 26 cases of neonatal HIE were included in this study. The protein expression levels of CD26P and PAI-1 were detected with ELISA. Serum levels of miR-30b and PAI-1 mRNA was measured by quantitative real-time PCR. Human brain microvascular endothelial cells (HBMECs) were cultured under hypoxic condition, and the intracellular expression levels of miR-30b and PAI-1 were evaluated. Dual-luciferase reporter assay was performed to confirm the interaction between miR-30b and PAI-1., Results: Compared with the control group, both the mRNA and protein expression levels of PAI-1 in the serum were up-regulated in the neonates with HIE, together with up-regulated serum CD26P levels. However, the serum expression level of miR-30b was down-regulated in neonatal HIE. In hypoxia-induced HBMECs, the mRNA and protein expression levels of PAI-1 were significantly up-regulated, while the miR-30b expression level was significantly down-regulated. Dual-luciferase reporter assay showed that PAI-1 was the direct target of miR-30b., Conclusion: Neonatal HIE is accompanied with abnormal platelet activation, significantly up-regulated serum PAI-1 expression levels, and down-regulated miR-30b expression. MiR-30b might regulate the disease pathogenesis and immune responses via modulating PAI-1., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Neonatal alloimmune neutropenia (NAIN) is caused by maternal alloimmunisation to fetal human neutrophil antigens (HNAs). This study investigated maternal HNA/HLA alloantibodies involved with NAIN and identified the frequency of NAIN in Brazilian neonates. Neonatal neutropenia (neutrophil count < 1.5 × 10 9 /L) was investigated in samples from 10,000 unselected neonates, resulting in 88 neutropenic newborns (NBs) and their 83 mothers. Genotyping was performed by PCR-SSP (HNA-1/-4) and PCR-RFLP (HNA-3/-5). Serologic studies were performed by GAT (granulocyte agglutination test), Flow-WIFT (white blood cells immunofluorescence test) and LABScreen-Multi-HNA-Kit (OneLambda®) (LSM). Neonatal neutropenia was identified in 88/10,000 (0·9%) NBs. Genotyping revealed 60·2% maternal-fetal HNA incompatibilities (31·8% for HNA-1; 14·8% for HNA-3; 15·9% for HNA-4; 21·6% for HNA-5). Serologic studies revealed 37·3% of mothers with positive results with at least one technique. The detected anti-HNA specificities were confirmed in eight positive cases related to HNA-1/-3 systems. In cases with maternal-fetal HNA-4/-5 incompatibility, no specific neutrophil alloantibodies were found but anti-HLA I/II were present. Anti-HNA-2 was not identified. This is a large Brazilian study which involved the investigation of antibodies against all five HNA systems in neutropenia cases and showed a frequency of NAIN in 8/10,000 neonates. Among the HNA antibodies identified, we highlight the anti-HNA-1d and anti-HNA-3b, antibodies unusual in alloimmunised women, and rarely related to NAIN cases., (© 2021 British Society for Haematology and John Wiley & Sons Ltd.)

Objective: To investigate the clinical efficacy of combination of mouse nerve growth factor (NGF) and nimodipine in the treatment of neonatal intracranial hemorrhage (NICH) and its effect on plasma platelet-activating factor (PAF), C-type natriuretic peptide (CNP), matrix metalloproteinase-2 (MMP-2), and neurological function., Patients and Methods: A total of 90 infants with severe ICH admitted to our hospital from December 2016 to December 2018 were enrolled for retrospective study. According to different treatment schemes, they were assigned into 2 groups: group A (n=40) treated with mouse NGF plus nimodipine; group B (n=50) treated with nimodipine. The recovery time, serum indexes (PAF, MMP-2, CNP), neurological function (neonatal behavioral neurological assessment (NBNA) score), complications, and total effective rate of patients were recorded, and the satisfaction degree of family members was statistically analyzed., Results: Patients in group A showed shorter recovery time, down-regulated PAF and MMP-2, evidently up-regulated CNP, and significantly increased NBNA score after one/two weeks of treatment, as well as fewer complications, higher total effective rate and higher satisfaction of family members., Conclusions: To sum up, the combination of mouse NGF and nimodipine achieves good clinical efficacy in NICH, which down-regulates plasma PAF and MMP-2, up-regulates CNP, and improves neurological function. Therefore, it is suitable for clinical promotion.

The influence of the blood group on the occurrence and severity of diseases has aroused the curiosity of scientists for many years. The AB0 group system is the best known and described blood group system. It is also the only system whose antibodies are constantly present in the blood serum. The most common blood type in Poland, according to data provided by Honorary blood donation and blood therapy, is group A Rh+ (plus), while the least common is group AB Rh- (minus). In studies of pregnant women scientists discovered the influence of blood type in the development of preeclampsia, gestational diabetes, the risk of preterm labor, and even COVID-19 infection. The impact of the mothers' blood group also affects the birth weight of newborns, as well as the development of hemolytic disease of the newborn due to the heterospecificity of AB0. The influence of the blood group on the increased risk of developing certain diseases and complications of the neonatal period has also been proven. Therefore, it seems important to study blood groups of pregnant women and newborns of different nationalities, correlate the results with available reports and use this knowledge in everyday clinical practice. This will help to increase the speed of detection of diseases in pregnancy and neonatal period. It will also facilitate the management of the patient depending on their blood group.

Background: Nucleated red blood cells (nRBCs) are associated with adverse outcomes for pediatric and adult intensive care patients., Methods: The association between nRBC count and mortality was examined in an observational cohort of patients admitted to the neonatal intensive care unit from December 2015-December 2018., Results: Among the 1059 patients with at least one nRBC count obtained, 45 infants (4.2%) experienced in-hospital mortality prior to NICU discharge, the primary outcome measured in this study. Infants with any nRBC count >0 had a significantly higher risk of mortality (5.3% [45/849] vs. 0% [0/351], p < 0.001 by Fisher exact), and time to mortality decreased with higher nRBC counts (Spearman correlation -0.59, p < 0.001). The association between nRBC count and mortality remained significant even when restricting only to infants who were older than 7 days at time of nRBC count., Conclusion: Among neonatal intensive care unit patients, including those >7 days old, nRBCs are associated with significantly elevated mortality risk. A prospective study to better characterize clinical co-variants is necessary to better establish the use of nRBCs as a predictor of mortality., Competing Interests: Declaration of Competing Interest There was no financial support for this work. The authors have no disclosures., (Copyright © 2020. Published by Elsevier B.V.)

Background: Group B Streptococcus (GBS) infections caused by Streptococcus agalactiae is a leading cause of meningitis and sepsis in neonates, with early-onset GBS symptoms emerging during the first week of life and late-onset occurring thereafter. Perinatal transmission of GBS to the neonate through the birth canal is the main factor associated with early-onset neonate infections, while less is understood about the source of late-onset infections., Methods: In this report we describe a case of twin ex-premature infants who presented one month after birth with GBS septicemia. The mother had been appropriately screened at gestational age 35-37 weeks and laboratory methods failed to detect GBS colonization by culture or clinical molecular methods. In attempts to identify and isolate the source of GBS infection, additional surveillance swabs were collected from the mother at the time of neonate admission. Culture and a commercially available, FDA-cleared molecular PCR assay were performed., Results: No GBS was detected from swabs collected from the perianal, thigh/groin or axillary areas. However, expressed breast milk and swabs from the breastmilk pump were positive by both methods. Since simultaneous culture and molecular methods which used breastmilk as a source were performed, investigators ascertained the limit of detection for GBS in breastmilk. The limit of detection was determined to be tenfold lower than that of LIM-broth enriched cultures-the FDA-approved source. Subsequent whole genome sequencing (WGS) analysis of isolates recovered from breastmilk and blood cultures from the infants demonstrated all strains were related and characterized as ST-452. Both infants responded very well to treatment and continued to have no related events or concerns at the two-year follow up appointment., Conclusions: Strain type 452 (capsular type IV) has recently emerged as a hypervirulent strain and has previously been documented as causing GBS infections in elderly populations. Antibiotic therapy resolved both mother and infant infections. Subsequent testing for the presence of GBS in breastmilk samples also showed an absence of bacteria. This is the first report of infant twins late-onset GBS infections caused by the hypervirulent S. agalactiae ST-452 with breastmilk as the source.

Activity of Graves' disease (GD) is known to improve during gestation, as values of thyrotropin (TSH) receptor antibody (TRAb) also improve. However, the risk of neonatal hyperthyroidism increases when maternal TRAb values are high in the second to third trimester. A 29-year-old woman who had undergone radioactive iodine (RAI) therapy for GD 10 years earlier visited our hospital at 17 weeks of gestation, showing subclinical hypothyroidism and a positive TRAb value of 2.6 IU/L (reference range, <2.0 IU/L). Thyroid hormone replacement therapy was commenced and thyroid function normalized within 4 weeks, although TRAb was elevated at the time (3.8 IU/L). Prenatal check-up showed normal growth development and no irregularities. At 29 weeks of gestation, serum TRAb was extremely elevated, up to 16.8 IU/L. Since the risk of neonatal hyperthyroidism was of great concern, delivery was planned at an advanced-care medical center. At 38 weeks 5 days of gestation, she delivered a female neonate without any complications, although blood testing of the neonate showed subclinical hyperthyroidism with positive TRAb and TSH receptor stimulating antibody (TSAb). According to the American Thyroid Association guidelines, the TRAb value should be checked in the third trimester if mothers show a TRAb elevation between the initial visit after pregnancy and 18-22 weeks of gestation. However, if the mother has a history of RAI therapy for GD, regardless of thyroid function during gestation, the possibility of TRAb values elevating over time even years after the definitive therapy must be considered.

The aim of this study was to determine the association between glucose control indices of parturient with type 1 diabetes (T1DM), treated with an insulin pump and utilizing continuous glucose monitoring (CGM), and clinically significant neonatal hypoglycemia. This was a retrospective cohort study which included 37 pregnant women with T1DM. All women were followed at a single tertiary center and had available CGM data. The association between maternal glucose indices before delivery and the risk for neonatal hypoglycemia requiring IV glucose (clinically significant hypoglycemia) was assessed using logistic regression. Mothers to neonates that experienced clinically significant hypoglycemia had a higher glucose standard deviation (SD) before delivery than did mothers to neonates who did not (25.5 ± 13 mg/dL vs. 14.7 ± 6.7 mg/dl respectively; p  = .008). This association persisted after adjustment for maternal age, maternal pregestational body mass index (BMI), gestational age at delivery, neonatal birth weight, large for gestational age (LGA) and gender. This study demonstrates an association between high maternal glucose standard deviation before delivery and the risk for clinically significant neonatal hypoglycemia. Larger studies are needed to confirm these results and further explore the role of intrapartum glucose variability in the prediction and prevention of significant neonatal hypoglycemia.

Objective: To investigate the placental morphology alterations and identify the clinical characteristics of women with polycystic ovary syndrome (PCOS) and their newborns. Pregnant women with PCOS (n = 12) and pregnant women without PCOS (n = 11) were recruited. Then, the placenta, maternal blood and cord blood were collected after delivery., Design: Clinical observational study., Setting: Not applicable., Patient(s): In the present study, pregnant women with PCOS and healthy pregnant women were recruited from the clinic of the Department of Obstetrics and Gynecology, First Affiliated Hospital, Heilongjiang University of Chinese Medicine, China, between February 2015 and October 2015., Intervention(s): None., Main Outcome Measure(s): A proteomic analysis was performed on the placenta in women with PCOS and healthy women., Result(s): The maternal testosterone, androstenedione, dehydroepiandrosterone sulfate, free androgen index, cholesterol, apolipoprotein B, and apolipoprotein B/apolipoprotein A-I levels were significantly higher in the PCOS group than in the control group, and the offspring in the PCOS group had higher dehydroepiandrosterone sulfate, high-density lipoprotein, and cholesterol levels, when compared with the control group. The placenta in the PCOS group demonstrated infarction, calcification, and a greater intervillous space, when compared with the control group. A higher level of estrogen receptor-β protein was observed in the placenta of women with PCOS, when compared with women without PCOS. A total of 258 proteins in the placenta were identified to be significantly different, when the PCOS and control groups were compared, and fibronectin 1 exhibited the closest relationship with other differential proteins., Conclusion(s): The overexposure to hyperandrogenism and hyperlipidemia affects the functions of the placenta, which are associated with the development of metabolic disorders in newborns., (Copyright © 2020. Published by Elsevier Inc.)

Background: Phlebotomy is among the main determinants of anemia of prematurity. Blood sparing policies endorsed umbilical cord blood (here called placental) as an alternative source for laboratory testing. Little is known on the suitability of placental blood to evaluate neonatal hemostasis of newborn infants. We aimed to compare the hemostatic profile of paired placental and infant venous blood, by means of prothrombin time (PT), activated partial thromboplastin time (APTT), fibrinogen, antithrombin, protein C, thromboelastography (TEG) and thrombin generation assay (TGA)., Study Design: This was an observational single-center study., Methods: We collected at birth venous citrated blood from both placental and infant venous source and performed PT, APTT, fibrinogen, antithrombin, protein C, TEG (reaction time-R; kinetics-K alpha angle-α, maximum amplitude-MA and lysis at 30 minutes-LY30), and TGA (endogenous thrombin potential-ETP)., Results: We enrolled 60 neonates with a median gestational age (range) of 37 weeks (28 +1 -41) and birth-weight 2417 g (950-4170). Based on TEG and TGA, placental blood showed a procoagulant imbalance as indicated by lower median R (4.0 vs. 6.1 min; p < 0.001) and K (1.3 vs. 2.2 min; p < 0.001); higher α-angle (69.7 vs. 57.4°; p < 0.001) and ETP (1260 vs. 1078; p = 0.002) than those observed for infant venous blood. PT and APTT did not differ significantly between the two groups., Conclusions: While placental and neonatal blood samples are equally suitable to measure the standard coagulation tests PT and APTT, placental blood leads to a procoagulant imbalance when testing is performed with TEG or TGA. These effects should be considered when interpreting results stemming from investigation of neonatal hemostasis., (© 2020 AABB.)

Introduction: Optimal glucose metabolism is important in neonatal survival especially in the first days of life. Insulin play a significant role in maintaining blood glucose homeostasis. This study set out to determine the serum insulin levels of ill neonates as related to their point-of-admission blood glucose estimation at the Wesley Guild Hospital, Ilesa, Nigeria., Methods: Three hundred babies took part in the study. Blood glucose and serum insulin levels were assayed at admission using Accu-Chek Active glucometer (R) and Accu-Ɔ-Bind ELISA Microwells (R) respectively. Hyperglycaemia was defined as blood glucose ≥7mmol/L and hypoglycaemia as blood glucose <2.2mmol/L., Results: The median (IQR) age of the babies was 10.0 (0.5 - 70.0) hours with male to female ratio of 1.5:1. Seventy-four (24.7%) were preterms and 35 (11.7%) were small-for-gestational age. The mean (SD) blood glucose level of the babies was 4.1(2.1) mmol/L with a range of 0.6-13.4mmol/L. Hyperglycaemia and hypoglycaemia were observed in 18(6.0%) and 40(13.3%) babies respectively. The median (IQR) serum insulin level was 9.8(3.0-35.3) μIU/ml. There was weak positive correlation between serum insulin and blood glucose levels of the babies (r = 0.197, p = 0.001). Birth asphyxia was associated with lower serum insulin, while probable sepsis with relatively higher levels., Conclusion: Serum insulin level increases with increasing blood glucose in ill Nigerian babies at presentation to the hospital. Babies with asphyxia and sepsis particularly tend to have abnormal serum insulin at admission. Hyperinsulinaemia in ill babies may connote a compensatory mechanism to normalise abnormal blood glucose rather than playing significant role in its aetio-pathogenesis., Competing Interests: The authors declare no competing interests., (© Emmanuel Oluwatosin Adeniji et al.)

Context: Gestational diabetes mellitus (GDM) diagnosed in early pregnancy is a health care challenge because it increases the risk of adverse outcomes. Plasma-glycated CD59 (pGCD59) is an emerging biomarker for diabetes and GDM. The aim of this study was to assess the performance of pGCD59 as a biomarker of early GDM and its association with delivering a large for gestational age (LGA) infant., Objectives: To assess the performance of pGCD59 to identify women with GDM in early pregnancy (GDM < 20) and assess the association of pGCD59 with LGA and potentially others adverse neonatal outcomes linked to GDM., Methods: Blood levels of pGCD59 were measured in samples from 693 obese women (body mass index > 29) undergoing a 75-g, 2-hour oral glucose tolerance test (OGTT) at <20 weeks' gestation in the Vitamin D and Lifestyle Intervention study: the main analyses included 486 subjects who had normal glucose tolerance throughout the pregnancy, 207 who met criteria for GDM at <20 weeks, and 77 diagnosed with GDM at pregnancy weeks 24 through 28. Reference tests were 75-g, 2-hour OGTT adjudicated based on International Association of Diabetes and Pregnancy Study Group criteria. The index test was a pGCD59 ELISA., Results: Mean pGCD59 levels were significantly higher (P < 0.001) in women with GDM < 20 (3.9 ± 1.1 standard peptide units [SPU]) than in those without (2.7 ± 0.7 SPU). pGCD59 accurately identified GDM in early pregnancy with an area under the curve receiver operating characteristic curves of 0.86 (95% confidence interval [CI], 0.83-0.90). One-unit increase in maternal pGCD59 level was associated with 36% increased odds of delivering an LGA infant (odds ratio for LGA vs non-LGA infant: 1.4; 95% CI, 1.1-1.8; P = 0.016)., Conclusion: Our results indicate that pGCD59 is a simple and accurate biomarker for detection of GDM in early pregnancy and risk assessment of LGA., (© Endocrine Society 2020. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Context: Neonatal severe hyperparathyroidism (NSHPT) is rare and potentially lethal. It is usually from homozygous or heterozygous germline-inactivating CASR variant(s). NSHPT shows a puzzling range of serum calcium and parathyroid hormone (PTH) levels. Optimal therapy is unclear., Evidence Acquisition: We categorized genotype/phenotype pairings related to CASRs. For the 2 pairings in NSHPT, each of 57 cases of neonatal severe hyperparathyroidism required calcium, PTH, upper normal PTH, and dosage of a germline pathogenic CASR variant., Evidence Synthesis: Homozygous and heterozygous NSHPT are 2 among a spectrum of 9 genotype/phenotype pairings relating to CASRs and NSHPT. For the 2 NSHPT pairings, expressions differ in CASR allelic dosage, CASR variant severity, and sufficiency of maternofetal calcium fluxes. Homozygous dosage of CASR variants was generally more aggressive than heterozygous. Among heterozygotes, high-grade CASR variants in vitro were more pathogenic in vivo than low-grade variants. Fetal calcium insufficiency as from maternal hypoparathyroidism caused fetal secondary hyperparathyroidism, which persisted and was reversible in neonates. Among NSHPT pairings, calcium and PTH were higher in CASR homozygotes than in heterozygotes. Extreme hypercalcemia (above 4.5 mM; normal 2.2-2.6 mM) is a robust biomarker, occurring only in homozygotes (83% of that pairing). It could occur during the first week., Conclusions: In NSHPT pairings, the homozygotes for pathogenic CASR variants show higher calcium and PTH levels than heterozygotes. Calcium levels above 4.5 mM among NSHPT are frequent and unique only to most homozygotes. This cutoff supports early and robust diagnosis of CASR dosage. Thereby, it promotes definitive total parathyroidectomy in most homozygotes., (© Published by Oxford University Press on behalf of the Endocrine Society 2019.)

Absence of adequate maternal vitamin D supplementation and decreased maternal ultraviolet exposure during pregnancy are key determinants for the manifestation of neonatal hypovitaminosis D at birth. These parameters may vary, according to country-specific dietary patterns, health policies and sunshine exposure. We aimed to investigate differences in calcium metabolism and anthropometric profiles according to neonatal vitamin D status at birth, in a sunny region of Northern Greece. A secondary aim was to identify maternal parameters as risk factors for developing neonatal vitamin D deficiency at birth. A total of 129 mother-neonate pairs were included in the study and classified into three groups, according to neonatal 25-hydroxy-D [25(OH)D)] concentrations at birth [deficiency (<30 nmol/l), insufficiency (30-50 nmol/l) and sufficiency (>50 nmol/l)]. Neonatal biochemical and anthropometric profiles and maternal demographic, social, dietary and biochemical profiles were comparatively evaluated between the three groups. Univariate and multivariate logistic regression was performed to identify independent associations of maternal factors with neonatal vitamin D status. Vitamin D deficient-neonates manifested higher parathyroid hormone (7.20 ± 2.60 vs 5.50 ± 1.50 pg/ml, p = 0.01) and lower corrected calcium (10.70 ± 0.70 vs 11.30 ± 1.30 mg/dl, p = 0.02) concentrations compared with vitamin d-insufficient neonates. Mothers of vitamin D deficient and insufficient neonates had a lower total of 25(OH)D (31.7 ± 19.2 and 36.5 ± 22.3 vs 53.3 ± 39.0 nmol/l, p < 0.01) and 25(OH)D 3 (27.4 ± 17.5 and 33.3 ± 19.9 vs 47.3 ± 36.7 nmol/l, p < 0.01 and p = 0.04, respectively) concentrations respectively, compared with those of vitamin D-sufficient neonates. Maternal use of alcohol during pregnancy was associated with a 5.57-fold higher risk for neonatal vitamin D deficiency at birth (OR 5.57, 95 % CI1.17-26.56, p = 0.03). Newborns with vitamin D deficiency presented a 6.89-fold higher risk of having been given birth by vitamin D deficient mothers (OR 6.89, 95 % CI 3.09-15.38, p < 0.01). In conclusion, neonatal vitamin D deficiency is associated with maternal 25(OH)D concentrations at birth and maternal alcohol use. Further studies are required to replicate these findings in other regions and populations., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Aims: This retrospective audit aimed to analyze whether routine frequent monitoring for hypoglycemia is required in asymptomatic infant of diabetic mother born in tertiary care hospital., Methods: The study analyzed the blood sugar level of 196 infants of diabetic mothers., Results: The overall incidence of hypoglycemia from 196 study participants was 9.18% (N = 18). The incidence of hypoglycemia at 2 h of life was maximum (83.33%) and it was significant when compared to 3, 6, 9 and 12 h (p < 0.0001). Blood glucose levels were significantly more at 6 (p = 0.0002)), 9 (p = 0.0001) and 12 h (p = 0.0001) when compared to glucose level at 2 h except at 3 h of life (p = 0.062). Similarly blood glucose at 9 (p = 0.0001) and 12 h of life (p = 0.0002) were significantly more than at 3 h of life. Blood glucose at 9 h was significantly more than at 6 h of life (0.032) and at 12 hours of life (p = 0.0237) was significantly higher than at 6 h of life., Conclusion: The frequent blood glucose monitoring for hypoglycemia in infant of diabetic mother as per American Academy of Pediatrics may be reduced as per the findings in our study. However, this needs to be confirmed by a properly designed observational study/adequately powered randomized controlled trial., (© The Author(s) [2019]. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Vitamin K is essential for the synthesis of few coagulation factors. Infants can easily develop vitamin K deficiency owing to poor placental transfer, low vitamin K content in breast milk, and poor intestinal absorption due to immature gut flora and malabsorption. Vitamin K deficiency bleeding (VKDB) in infancy is classified according to the time of presentation: early (within 24 h), classic (within 1 week after birth), and late (between 2 week and 6 months of age). VKDB in infancy, particularly late-onset VKDB, can be life-threatening. Therefore, all infants, including newborn infants, should receive vitamin K prophylaxis. Exclusive breastfeeding and cholestasis are closely associated with this deficiency and result in late-onset VKDB. Intramuscular prophylactic injections reduce the incidence of early-onset, classic, and late-onset VKDB. However, the prophylaxis strategy has recently been inclined toward oral administration because it is easier, safer, and cheaper to administer than intramuscular injection. Several epidemiological studies have shown that vitamin K oral administration is effective in the prevention of VKDB in infancy; however, the success of oral prophylaxis depends on the protocol regimen and parent compliance. Further national surveillance and studies are warranted to reveal the optimal prophylaxis regimen in term and preterm infants.

Competing Interests: Financial disclosure This research was supported by the Scientific Research Unit of the Hitit University, Corum, Turkey. Declaration of competing interest The authors declare that they have no conflict of interest.

Neonatal infections are a major risk factor for neonatal mortality. A reliable diagnosis of early-onset sepsis (EOS) is hampered by the variable clinical presentations of the children. We hypothesized that changes in the Se or Cu status, or the biomarkers selenoprotein P (SELENOP) or ceruloplasmin (CP) alone or in combination may be informative of EOS. We generated a new human CP-specific non-competitive immunoassay (ELISA) suitable of analysing small sample volumes and validated the method with a commercial CP source. Using this novel CP assay, we analysed a case-control study of EOS (n = 19 control newborns, n = 18 suspected cases). Concentrations of Se, Cu, SELENOP, CP, interleukin-6 (IL-6), and C-reactive protein (CRP) along with the Cu/Se and CP/SELENOP ratios were evaluated by correlation analyses as biomarkers for EOS. Diagnostic value was estimated by receiver operating characteristic (ROC) curve analyses. The new CP-ELISA displayed a wide working range (0.10-6.78 mg CP/L) and low sample requirement (2 μL of serum, EDTA-, heparin- or citrate-plasma). Plasma CP correlated positively with Cu concentrations in the set of all samples (Pearson r = 0.8355, p < 0.0001). Three of the infected neonates displayed particularly high ratios of Cu/Se and CP/SELENOP, i.e., 3.8- to 6.9-fold higher than controls. Both the Cu/Se and the CP/SELENOP ratios correlated poorly with the early infection marker IL-6, but strongly and positively with the acute-phase protein CRP (Cu/Se-CRP: Spearman ϱ = 0.583, p = 0.011; CP/SELENOP-CRP: ϱ = 0.571, p = 0.013). The ROC curve analyses indicate that a combination of biomarkers for the Se and Cu status do not improve the early identification of EOS considerably. This study established a robust, highly precise, partly validated and scalable novel CP sandwich ELISA suitable for basic and clinical research, requiring minute amounts of sample. The ratio of circulating CP/SELENOP constitutes a promising new composite biomarker for detection of EOS, at least in a subset of severely diseased children., Competing Interests: Declaration of Competing Interest LS holds shares in selenOmed GmbH, a company involved in selenium status assessment and supplementation. JH, MW, LG-W, MW, MC, and CB have nothing to declare., (Copyright © 2019. Published by Elsevier GmbH.)

Background: Worldwide, many newborns who are preterm, small or large for gestational age, or born to mothers with diabetes are screened for hypoglycemia, with a goal of preventing brain injury. However, there is no consensus on a treatment threshold that is safe but also avoids overtreatment., Methods: In a multicenter, randomized, noninferiority trial involving 689 otherwise healthy newborns born at 35 weeks of gestation or later and identified as being at risk for hypoglycemia, we compared two threshold values for treatment of asymptomatic moderate hypoglycemia. We sought to determine whether a management strategy that used a lower threshold (treatment administered at a glucose concentration of <36 mg per deciliter [2.0 mmol per liter]) would be noninferior to a traditional threshold (treatment at a glucose concentration of <47 mg per deciliter [2.6 mmol per liter]) with respect to psychomotor development at 18 months, assessed with the Bayley Scales of Infant and Toddler Development, third edition, Dutch version (Bayley-III-NL; scores range from 50 to 150 [mean {±SD}, 100±15]), with higher scores indicating more advanced development and 7.5 points (one half the SD) representing a clinically important difference). The lower threshold would be considered noninferior if scores were less than 7.5 points lower than scores in the traditional-threshold group., Results: Bayley-III-NL scores were assessed in 287 of the 348 children (82.5%) in the lower-threshold group and in 295 of the 341 children (86.5%) in the traditional-threshold group. Cognitive and motor outcome scores were similar in the two groups (mean scores [±SE], 102.9±0.7 [cognitive] and 104.6±0.7 [motor] in the lower-threshold group and 102.2±0.7 [cognitive] and 104.9±0.7 [motor] in the traditional-threshold group). The prespecified inferiority limit was not crossed. The mean glucose concentration was 57±0.4 mg per deciliter (3.2±0.02 mmol per liter) in the lower-threshold group and 61±0.5 mg per deciliter (3.4±0.03 mmol per liter) in the traditional-threshold group. Fewer and less severe hypoglycemic episodes occurred in the traditional-threshold group, but that group had more invasive diagnostic and treatment interventions. Serious adverse events in the lower-threshold group included convulsions (during normoglycemia) in one newborn and one death., Conclusions: In otherwise healthy newborns with asymptomatic moderate hypoglycemia, a lower glucose treatment threshold (36 mg per deciliter) was noninferior to a traditional threshold (47 mg per deciliter) with regard to psychomotor development at 18 months. (Funded by the Netherlands Organization for Health Research and Development; HypoEXIT Current Controlled Trials number, ISRCTN79705768.)., (Copyright © 2020 Massachusetts Medical Society.)

Background: Neonatal antibiotics disturb the developing gut microbiome and are therefore thought to influence the developing immune system, but exact mechanisms and health consequences in later life still need to be elucidated. Therefore, we investigated whether neonatal antibiotics influence inflammatory markers at 1 year of age. In addition, we determined whether health problems during the first year of life, e.g., allergic disorders (eczema and wheezing) or infantile colics, were associated with changes in the circulating immune marker profile at 1 year of age. Methods: In a subgroup ( N = 149) of the INCA-study, a prospective birth-cohort study, a blood sample was drawn from term born infants at 1 year of age and analyzed for 84 immune related markers using Luminex. Associations of antibiotic treatment, eczema, wheezing, and infantile colics with immune marker concentrations were investigated using a linear regression model. The trial is registered as NCT02536560. Results: The use of broad-spectrum antibiotics in the first week of life, was significantly associated with different levels of inflammatory markers including sVCAM-1, sCD14, sCD19, sCD27, IL-1RII, sVEGF-R1, and HSP70 at 1 year of age. Eczema was associated with decreased concentrations of IFNα, IFNγ, TSLP, CXCL9, and CXCL13, but increased concentrations of CCL18 and Galectin-3. Wheezing, independent of antibiotic treatment, was positively associated to TNF-R2 and resistin. Infantile colics were positively associated to IL-31, LIGHT, YKL-40, CXCL13, sPD1, IL1RI, sIL-7Ra, Gal-1, Gal-9, and S100A8 at 1 year of age, independent of early life antibiotic treatment. Conclusion: In this explorative study, we identified that neonatal antibiotics are associated with immunological alterations at 1 year of age and that, independent of the antibiotic treatment, infantile colics were associated with alterations within gut associated markers. These findings support the importance of the first host microbe interaction in early life immune development., (Copyright © 2020 Oosterloo, van't Land, de Jager, Rutten, Klöpping, Garssen, Vlieger and van Elburg.)

The majority of congenital cytomegalovirus (cCMV) infections are asymptomatic at birth and therefore not diagnosed. Approximately 10-15% of these infants develop late-onset hearing loss and other developmental disorders. Implementation of a universal screening approach at birth may allow early initiation of symptomatic interventions due to a closer follow-up of infants at risk and offers the opportunity to consider treatment of late-onset disease. Real-time PCR assays for the detection of CMV DNA in buccal swab samples demonstrated feasibility and good clinical sensitivity in comparison to a rapid culture screening assay. Because most cCMV infections remain asymptomatic, a universal screening assay that stratifies CMV infected infants according to low and high risk of late-onset cCMV disease could limit the parental anxiety and reduce follow-up costs. We therefore developed and characterized a screening algorithm based on a highly-sensitive quantitative real-time PCR assay that is compatible with centralized testing of samples from universal screening and allows to determine CMV DNA load of saliva samples either as International Units (IU)/ml saliva or IU/105 cell equivalents. 18 of 34 saliva samples of newborns that tested positively by the screening algorithm were confirmed by detection of CMV DNA in blood and/or urine samples obtained during the first weeks of life. All screening samples that could not be confirmed had viral loads of <2.3x105 IU/ml saliva (median: 6.8x103) or 1.3x105 IU/105 cell equivalents (median: 4.0x102). The viral load of screening samples with confirmed cCMV infection ranged from 7.5x102 to 8.2x109 IU/ml saliva (median: 9.3x107) or 1.5x102 to 5.6x1010 IU/105 cell equivalents (median: 3.5x106). Clinical follow-up of these newborns with confirmed cCMV infection should reveal whether the risk of late-onset cCMV disease correlates with CMV DNA load in early life saliva samples and whether a cut-off can be defined identifying cCMV infected infants with or without risk for late-onset cCMV disease., Competing Interests: The authors have declared that no competing interests exist.

Congenital hypothyroidism (CH) is one of the most common preventable causes of intellectual disability. Thyroid hormone is required for normal brain development, but neonates with CH typically appear healthy at birth, which leads to delays in diagnosis and treatment. In developed countries, newborn screening programs have led to earlier diagnosis and treatment of CH, resulting in improved neurodevelopmental outcomes. Neonates with an abnormal newborn screen require prompt confirmatory serum thyroid function tests and treatment with thyroid hormone. Further evaluation for the etiology of CH should not delay treatment decisions., (Copyright © 2020 by the American Academy of Pediatrics.)

Objective: Both preeclampsia and neuraxial anesthesia can alter placental perfusion, potentially affecting the neonatal status. The objective of our study is to quantify the association between type of neuraxial anesthetic and short-term neonatal morbidity among preeclamptic patients undergoing cesarean delivery., Methods: We performed a secondary analysis of a prospective observational cohort study. Women with singleton gestations and a diagnosis of preeclampsia who underwent cesarean delivery with neuraxial anesthesia were included in the analysis. Short-term neonatal morbidities, defined as neonatal intensive care unit (NICU) admission, arterial cord gas pH ≤7.2 and 5-minute Apgar <7, were compared based on type of neuraxial anesthetic., Results: A total of 4100 patients were included in the analysis, 1696 (41.4%) received spinal anesthesia 1848 (45.1%) received epidural anesthesia and 556 (13.5%) received a combined spinal-epidural (CSE). Antepartum and intrapartum characteristics significantly differed between the groups (p≤0.02). After adjusted analysis, spinal anesthesia was associated with reduced odds of NICU admission, compared with epidural or CSE (OR; 95% CI: 0.79; 0.63-0.98, 0.71; 0.53-0.94, respectively). Spinal anesthesia was also associated with lower odds of a 5-minute Apgar <7 compared with epidural anesthesia (OR 0.59; 95% CI; 0.43-0.83). We found no association between type of anesthesia and arterial cord pH ≤7.2. In stratiifed analysis by gestational age, no association between the type of neuraxial anesthesia and neonatal outcomes was noted among term infants, but associations persisted in preterm infants., Conclusions: Among women with preeclampsia undergoing cesarean delivery, spinal anesthesia may be associated with reduced short-term neonatal morbidity in preterm infants, compared with epidural or CSE.

Physiologic adaptations in the postnatal period, along with gradual establishment of enteral feeding, help maintain plasma glucose concentrations in the neonatal period. The definition of normal plasma glucose in the neonatal period has been a subject of debate because of a lack of evidence linking a set plasma or blood glucose concentration to clinical symptoms or predictors of short- and long-term outcomes. However, there is consensus that maintaining plasma glucose in the normal range for age is important to prevent immediate and long-term neurodevelopmental consequences of hypoglycemia or hyperglycemia. The specific management strategy for abnormal glucose levels in neonates depends on the underlying etiology, and interventions could include nutritional changes, medications, hormone therapy, or even surgery. Here, we will review the physiological processes that help maintain plasma glucose in newborns and discuss the approach to a newborn with disordered glucose homeostasis, with an emphasis on the endocrine basis of abnormal glucose homeostasis., (Copyright © 2020 by the American Academy of Pediatrics.)

Objective: To evaluate variation in trends in bloodstream infection (BSI) rates in neonatal units (NNUs) in England according to the data sources and linkage methods used., Methods: We used deterministic and probabilistic methods to link clinical records from 112 NNUs in the National Neonatal Research Database (NNRD) to national laboratory infection surveillance data from Public Health England. We calculated the proportion of babies in NNRD (aged <1 year and admitted between 2010-2017) with a BSI caused by clearly pathogenic organisms between two days after admission and two days after discharge. We used Poisson regression to determine trends in the proportion of babies with BSI based on i) deterministic and probabilistic linkage of NNRD and surveillance data (primary measure), ii) deterministic linkage of NNRD-surveillance data, iii) NNRD records alone, and iv) linked NNRD-surveillance data augmented with clinical records of laboratory-confirmed BSI in NNRD., Results: Using deterministic and probabilistic linkage, 5,629 of 349,740 babies admitted to a NNU in NNRD linked with 6,660 BSI episodes accounting for 38% of 17,388 BSI records aged <1 year in surveillance data. The proportion of babies with BSI due to clearly pathogenic organisms during their NNU admission was 1.0% using deterministic plus probabilistic linkage (primary measure), compared to 1.0% using deterministic linkage alone, 0.6% using NNRD records alone, and 1.2% using linkage augmented with clinical records of BSI in NNRD. Equivalent proportions for babies born before 32 weeks of gestation were 5.0%, 4.8%, 2.9% and 5.9%. The proportion of babies who linked to a BSI decreased by 7.5% each year (95% confidence interval [CI]: -14.3%, -0.1%) using deterministic and probabilistic linkage but was stable using clinical records of BSI or deterministic linkage alone., Conclusion: Linkage that combines BSI records from national laboratory surveillance and clinical NNU data sources, and use of probabilistic methods, substantially improved ascertainment of BSI and estimates of BSI trends over time, compared with single data sources., Competing Interests: The authors have declared that no competing interests exist.

Background: Metabolic bone disease of prematurity (MBD) is a common problem among preterm infants. Our previous study identified cholestasis as an important risk factor for the development of MBD. We conducted this study to determine the vitamin D status in preterm infants with MBD and cholestasis., Methods: We retrospectively reviewed medical record of preterm infants evaluated in NICU at Holtz Children's/Jackson Memorial Hospital between June 2014 and May 2016. Demographic, biochemical data, and vitamin D intake were collected and analyzed., Results: We identified 58 preterm infants (median gestational age 25 weeks) with MBD during this period. Twenty five infants also developed cholestasis. Median serum 25-hydroxyvitamin D level at the time of diagnosis of MBD was similar in cholestasis (C), (29.1 ng/ml, IQR 24.4-33.5), and non-cholestasis (NC), (28.7 ng/ml, IQR 22.7-34.6), group (p = 0.41). At the second measurement, average 6 weeks after the first measurement; median serum 25-hydroxyvitamin D level was lower (p = 0.02) in the C group (31.2 ng/ml, IQR 23.0-38.8) than in the NC group (36.5 ng/ml, IQR 28-45). However, the actual percentage of infants with vitamin D deficiency was similar in both the groups., Conclusion: Most preterm infants with cholestasis and MBD had normal vitamin D status.

Objective: To identify clinical parameters and intrapartum fetal heart rate parameters associated with a risk of umbilical cord acidosis at birth, using an automated analysis method based on empirical mode decomposition., Methods: Our single-center study included 381 cases (arterial cord blood pH at birth pHa ≤7.15) and 1860 controls (pHa ≥7.25) extracted from a database comprising 8,383 full datasets for over-18 mothers after vaginal or caesarean non-twin, non-breech deliveries at term (>37 weeks of amenorrhea). The analysis of a 120-min period of the FHR recording (before maternal pushing or the decision to perform a caesarean section during labor) led to the extraction of morphological, frequency-related, and long- and short-term heart rate variability variables. After univariate analyses, sparse partial least square selection and logistic regression were applied., Results: Several clinical factors were predictive of fetal acidosis in a multivariate analysis: nulliparity (odds ratio (OR) 95% confidence interval (CI)]: 1.769 [1.362-2.300]), a male fetus (1.408 [1.097-1.811]), and the term of the pregnancy (1.333 [1.189-1.497]). The risk of acidosis increased with the time interval between the end of the FHR recording and the delivery (OR [95%CI] for a 1-min increment: 1.022 [1.012-1.031]). The risk factors related to the FHR signal were mainly the difference between the mean baseline and the mean FHR (OR [95%CI]: 1.292 [1.174-1.424]), the baseline range (1.027 [1.014-1.040]), fetal bradycardia (1.038 [1.003-1.075]) and the late deceleration area (1.002 [1.000-1.005]). The area under the curve for the multivariate model was 0.79 [0.76; 0.81]., Conclusion: In addition to clinical predictors, the automated FHR analysis highlighted other significant predictors, such as the baseline range, the instability of the FHR signal and the late deceleration area. This study further extends the routine application of automated FHR analysis during labor and, ultimately, contributes to the development of predictive scores for fetal acidosis., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Hypoglycemia may lead to neurological impairment; therefore, high-risk newborns are screened postnatally. However, hypoglycemia monitoring protocols often do not include cord blood acidosis as a risk factor. The study aimed to find an association between asymptomatic cord blood acidosis and hypoglycemia. All healthy term infants born at McMaster Children Hospital, Hamilton, Canada, between October 2013 and September 2014, who had umbilical cord blood pH <7.0 or base excess <12 mmol/L were studied. Infants with evidence of hypoxic-ischemic encephalopathy, birth weights outside of 10th to 95th percentiles for gestation, mothers with preeclampsia, diabetes or taking a -blockers at the time of the birth were excluded. Hypoglycemia was defined as blood glucose <2.6 mmol/L in the first two hours of life. One hundred sixtysix infants met the cord blood gas criteria, but only 16 had hypoglycemia. Although infants with mild perinatal depression are at risk for hypoglycemia, a significant association could not be proved.