Postnatal Age Research Articles

Pediatric AIDS-Therapeutic Successes Built on a Foundation of Pediatric Clinical Pharmacology with Pharmacokinetic-Pharmacodynamic Modeling.

Pediatric AIDS-Therapeutic Successes Built on a Foundation of Pediatric Clinical Pharmacology with Pharmacokinetic-Pharmacodynamic Modeling.

Maturation of GFR in Term-Born Neonates: An Individual Participant Data Meta-Analysis.

The evidence from individual studies to support the maturational pattern of GFR in healthy, term-born neonates is inconclusive. We performed an individual participant data (IPD) meta-analysis of reported measured GFR (mGFR) data, aiming to establish neonatal GFR reference values. Furthermore, we aimed to optimize neonatal creatinine-based GFR estimations. We identified studies reporting mGFR measured by exogenous markers or creatinine clearance (CrCL) in healthy, term-born neonates. The relationship between postnatal age and clearance was investigated using cubic splines with generalized additive linear mixed models. From our reference values, we estimated an updated coefficient for the Schwartz equation (eGFR [ml/min per 1.73 m2]=(k×height [cm])/serum creatinine [mg/dl]). Forty-eight out of 1521 screened articles reported mGFR in healthy, term-born neonates, and 978 mGFR values from 881 neonates were analyzed. IPD were available for 367 neonates, and the other 514 neonates were represented by 41 aggregated data points as means/medians per group. GFR doubled in the first 5 days after birth, from 19.6 (95% CI, 14.7 to 24.6) to 40.6 (95% CI, 36.7 to 44.5) ml/min per 1.73 m2, and then increased more gradually to 59.4 (95% CI, 45.9 to 72.9) ml/min per 1.73 m2 by 4 weeks of age. A coefficient of 0.31 to estimate GFR best fitted the data. These reference values for healthy, term-born neonates show a biphasic increase in GFR, with the largest increase between days 1 and 5. Together with the re-examined Schwartz equation, this can help identify altered GFR in term-born neonates. To enable widespread implementation of our proposed eGFR equation, validation in a large cohort of neonates is required.

Oral Ibuprofen Versus Oral Paracetamol in Pain Management During Screening for Retinopathy of Prematurity

Screening examinations for retinopathy of prematurity (ROP) are critical to reduce ROP-related vision loss; however, the procedure is painful and uncomfortable, and topical anesthetics do not completely suppress the pain responses. The number of safe and effective pharmacological options to reduce pain during eye examinations for ROP screening in preterm infants is limited. This study compared the efficacy of oral ibuprofen and oral paracetamol in reducing pain during screening for ROP in preterm infants. This prospective observational study was conducted at a tertiary-care neonatal intensive care unit. Forty-four preterm infants with gestational age of 32 weeks and less undergoing ROP screening were included. Each enrolled infant received either oral ibuprofen 10 mg/kg (n = 22) or oral paracetamol 10 mg/kg (n = 22) 1 hour before eye examination. The primary outcome measure was pain assessed by the Neonatal Pain, Agitation, and Sedation Scale (N-PASS). Secondary outcome measures were tachycardia, bradycardia, desaturations, and crying time. The groups were similar for gestational age, birth weight, and postnatal age at examination (P > .05). The mean N-PASS scores were not significantly different between the oral ibuprofen and oral paracetamol groups (8.64 ± 1.57 vs 8.50 ± 1.71, respectively, P = .605). Moreover, no significant intergroup differences were observed in the crying time and the incidence of tachycardia/bradycardia and desaturation (P > .05). Ibuprofen or paracetamol administered orally before ROP screening in preterm infants had similar analgesic effects and did not significantly alleviate pain during eye examination.

Population Pharmacokinetics of Levetiracetam: A Systematic Review

The use of levetiracetam (LEV) has been increasing given its favorable pharmacokinetic profile. Numerous population pharmacokinetic studies for LEV have been conducted. However, there are some discrepancies regarding factors affecting its pharmacokinetic variability. Therefore, this systematic review aimed to summarize significant predictors for LEV pharmacokinetics as well as the need for dosage adjustments. We performed a systematic search for population pharmacokinetic studies of LEV conducted using a nonlinear-mixed effect approach from PubMed, Scopus, CINAHL Complete, and Science Direct databases from their inception to March 2020. Information on study design, model methodologies, significant covariate-parameter relationships, and model evaluation was extracted. The quality of the reported studies was also assessed. A total of 16 studies were included in this review. Only two studies were conducted with a two-compartment model, while the rest were performed with a one-compartment structure. Bodyweight and creatinine clearance were the two most frequently identified covariates on LEV clearance (CLLEV). Additionally, postmenstrual age (PMA) or postnatal age (PNA) were significant predictors for CLLEV in neonates. Only three studies externally validated the models. Two studies conducted pharmacodynamic models for LEV with relatively small sample size. Significant predictors for LEV pharmacokinetics are highlighted in this review. For future research, a population pharmacokinetic-pharmacodynamic model using a larger sample size should be conducted. From a clinical perspective, the published models should be externally evaluated before clinical implementation.

Growth pattern of the middle ear in the gray short-tailed opossum, Monodelphis domestica

We studied the mass growth trajectories of middle ear ossicles and tympanic membrane and oval window area in 19 specimens of postnatal ages 30–180 days of the gray short-tailed opossum Monodelphis domestica. We weighed the skull mass and the mass of the three middle ear ossicles with appropriate balances. Using a binocular microscope provided with a grid, we measured the length of malleus and incus, as well as the longest axis and the one perpendicular to it on both the tympanic membrane and the stapes footplate. The size variation was studied with least squares regression analyses between various measurements. The incus and stapes change little in mass after 40 days of postnatal life, while the malleus does, reaching maximum mass at around 100 PND (postnatal days). This modularity in growth trajectory is in contrast with the shared evolutionary origin of malleus and incus from branchial arch 1. The maturation of the middle – and as indicated by previous work, that of the inner ear – is coupled with the improvement of hearing sensitivity at low and high frequencies after the initial onset of hearing at 29 PND.

Urinary protein to creatinine ratio during the first month of life in very preterm infants-a prospective cohort study (PROTIPREMA).

Preterm infants have physiological proteinuria and values of urine protein to creatinine ratio (UPr/Cr) are higher compared to full-term infants during the first week of life. Few investigations explored the changes of proteinuria in very preterm infants (VPI, ≤ 31weeks of gestation) older than a week, and it is unclear whether high and persistent proteinuria is associated with kidney injury in this population. This study aimed to (1) observe the changes of UPr/Cr during the first month of life in VPI and (2) describe clinical and biological variables associated with the changes of UPr/Cr. Spot urine samples for UPr/Cr were collected on the first day of life (DOL1) and then on DOL2-3, DOL5-6, second week of life (WOL2), WOL3, and WOL4 in VPI cared for in a third-level NICU. We tested the relationship of UPr/Cr with perinatal variables and diseases. A total of 1140 urine samples were obtained for 190 infants. UPr/Cr values (mg/mmol) (median with interquartile) at DOL1, DOL2, DOL3, WOL2, WOL3, and WOL4 were, respectively, 191 (114-399), 226 (152-319), 225 (156-350), 282 (200-488), 308 (188-576), and 325 (175-664). At the multivariate analysis, lower gestational age (GA) and increasing postnatal age were the only variables significantly associated with higher UPr/Cr values (p < 0.001). There was wide intra- and interindividual variability in UPr/Cr, especially in infants with higher GA and clinical stability. In VPI, UPr/Cr is higher at lower GA and increases with advancing postnatal age. High persistent proteinuria is not associated with clinical and biological variables reflecting kidney injury during the first month of life. A higher resolution version of the Graphical abstract is available as Supplementary information.

Pharmacokinetics of Gentamicin Components C1, C1a, and C2/C2a/C2b and Subsequent Decline in Glomerular Filtration Rate in Neonates.

Gentamicin is a commonly used antibiotic in neonates. Its components C1, C1a, C2, C2a, and C2b may have different nephrotoxic potential. We aimed to describe pharmacokinetics and nephrotoxic potential of gentamicin components in a joint model in neonates. Neonates with gestational age ≥ 32weeks treated with gentamicin blood samples were collected at a steady state. Pharmacokinetics of C1, C1a, and C2/C2a/C2b were modelled in NONMEM and included competitive uptake into kidney proximal tubular cells and decrease in glomerular filtration rate. The nephrotoxic potential of total gentamicin, C1, C1a, and C2/C2a/C2b was evaluated by simulations. A total of 30 neonates (median (range) gestational age 36.4 (32-42) weeks, postnatal age 3 (1-5) days, creatinine value 47.5 (17-78) µmol/L) were included. Pharmacokinetics of all components was best described by a two-compartment model. Clearance of C1 was smaller than clearances of C1a and C2/C2a/C2b, and other parameters were similar. The model with different Km (concentration for which half-maximal uptake into kidney proximal tubular cells is achieved) for C1, C1a, and C2/C2a/C2b (37.5, 18, 15mg/L) provided a better fit than the model with equal Km (15mg/L). According to simulations, decrease in glomerular filtration rate in the case of once-daily dosing of 4mg/kg/day was the largest for C2/C2a/C2b (median (5th and 95th percentile) 0.22% (0.00-8.12%)), followed by total gentamicin (0.20% (0.00-4.10%)), C1a (0.11% (0.00-7.57%)), and C1 (0.04% (0.00-1.55%)). Different gentamicin components C1, C1a, and C2/C2a/C2b exhibited different pharmacokinetic profiles. Once-daily dosing of 4mg/kg/day results in low nephrotoxicity in neonates, in line with previous studies.

Rescue Paracetamol in Postoperative Pain Management in Extremely Low Birth Weight Neonates Following Abdominal Surgery: A Single Unit Retrospective Study.

BackgroundIntravenous paracetamol added to morphine reduces postoperative morphine consumption in (near)term neonates. However, there are only sparse data on intravenous paracetamol as multimodal strategy in extremely low birth weight (ELBW) neonates.ObjectivesThis study aims to assess the effects of rescue intravenous paracetamol on postoperative pain management (≤48 h postoperatively) in relation to both analgesic efficacy (validated pain assessment, drug consumption, adequate rescue medication) and safety (hypotension and bradycardia). This rescue practice was part of a standardized pain management approach in a single neonatal intensive care unit (NICU).MethodsA single-center retrospective observational study included 20 ELBW neonates, who underwent major abdominal surgery. The primary endpoints of the postoperative study period were pain intensity, over-sedation, time to first rescue analgesic dose, and the effect of paracetamol on opiate consumption. Secondary endpoints were safety parameters (hypotension, bradycardia). And as tertiary endpoints, the determinants of long-term outcome were evaluated (i.e., duration of mechanical ventilation, intraventricular hemorrhage - IVH, periventricular leukomalacia - PVL, postnatal growth restriction, stage of chronic lung disease – CLD or neurodevelopmental outcome according to Bayley-II Scales of Infant Development at 18–24 months).ResultsAll neonates received continuous opioids (sufentanil or morphine) and 13/20 also intravenous paracetamol as rescue pain medication during a 48-h postoperative period. Although opioid consumption was equal in the non-paracetamol and the paracetamol group over 48 h, the non-paracetamol group was characterized by oversedation (COMFORTneo < 9), a higher incidence of severe hypotension, and younger postnatal age (p < 0.05). All long-term outcome findings were similar between both groups.ConclusionsOur study focused on postoperative pain management in ELBW neonates, and showed that intravenous paracetamol seems to be safe. Prospective validation of dosage regimens of analgesic drugs is needed to achieve efficacy goals.

The D-dimer reference intervals in healty term newborns

ObjectiveTo determine the D-dimer reference intervals in the neonatal period. Materials and methodsThe research had been carried out in the obstetrics and gynecology clinic and neonatal outpatient clinic of a third level hospital. Healthy term newborns aged between 1 and 28 days were enrolled in the study. Venous blood samples were collected from peripheral veins in all babies and D-dimer, prothrombin time, activated partial thromboplastin time and platelet counts were measured. Reference intervals for D-dimer in the neonatal period were determined using 2.5th and 97.5th percentile values. ResultsA hundred and thirty four newborns (71 boys, 63 girls) were enrolled in the study. Mean D-dimer levels of infants aged 1–28 days was 1.74 ± 1.88 mg/L (reference range; 0.25–2.81 mg/L). D-dimer levels were between 2.44 and 2.45 mg/L, 1.71–1.76 mg/L, 1.26–0.89 mg/L and 0.88–0.66 mg/L in the first, second, thirth and fourth week of life,respectively. D-dimer values inversely correlated with postnatal age (r:−0.3, p < 0.001). However, it remained above adult levels even in the last week. There was no statistically significant difference between the D-dimer levels of girls (1.93 ± 2.06 mg/L) and of boys (1.57 ± 1.71 mg/L). DiscussionIn this study, D-dimer levels in the neonatal period were found to be higher than adult levels stated in the literature. D-dimer levels gradually decreased overtime in the first month. It would be appropriate to use age-specific reference values in the evaluation of D dimer levels in the neonatal period.

PRENATAL AND POSTNATAL DEVELOPMENT AND COMPARATIVE ANATOMY OF THE MANDIBLE OF THREE BREEDS OF SHEEP: A GROSS STUDY

This study aims to evaluate and compare the development of the mandible and gross anatomy in three breeds of sheep. A total of 180 and 720 prenatal and postnatal samples were used respectively, their skulls were macerated and mandibles detached. In prenatal life, the mental and mandibular foramina were rudimentary in the late 1st trimester and 2nd trimester and developed in the 3rd trimester. The alveolus and mandibular canal differentiated in the 3rd trimesters respectively. In the postnatal life, the ventral border was convexed in Uda but flat in Balami and Yankasa breeds. The angular part of the ramus was thin in Uda and thick in Balami and Yankasa. The mandibular tuberosity was absent in Balami and Yankasa but present in Uda. There was a small accessory foramen caudal to the mental foramen just below the first premolar teeth in the Uda and Yankasa. The labial surface was wide and rough in Balami and Uda but smooth in Yankasa. The medial surface was flat in the young postnatal and convexed in the adult postnatal. It was brought to a conclusion that the mandible in the Nigerian breeds undergoes various morphological changes from prenatal and postnatal ages with peculiar differentiating features.

Exposure-safety relationship for acyclovir in the treatment of neonatal herpes simplex virus disease

BackgroundNeonatal herpes simplex virus (HSV) disease has been treated with high-dose (20 mg/kg/dose) acyclovir since 1991. AimsDetermine the safety of acyclovir in infants with neonatal HSV treated with high-dose acyclovir; examine the association between acyclovir dose and exposure with adverse events (AEs). Study designWe obtained demographic information and acyclovir dosing via medical records. Acyclovir exposure was calculated using an established pharmacokinetic model. SubjectsInfants <120 days of age with neonatal HSV discharged from four academic children's hospitals. Outcome measuresWe identified clinical and laboratory adverse events (AEs). Results and conclusionsWe identified 49 infants with neonatal HSV treated with acyclovir; 42 infants had complete 21-day dosing information. Median mean daily dose was 59 mg/kg/day. Clinical AEs were common among all gestational and postnatal age groups. Rash was the most common clinical AE (37 %). Mild laboratory AEs occurred in 2–37 % of infants. The median maximum doses (mg/kg/day) were higher among infants with hypokalemia, elevated blood urea nitrogen, and thrombocytosis. For all other laboratory AEs, the median maximum doses for infants without events were higher or equal to the median maximum dose of infants with the AE. The odds of experiencing any clinical or laboratory AE did not differ by predicted acyclovir exposure for either area under the curve (AUC) or maximum concentration (Cmax) (odds ratio [OR] = 1.00 [0.98, 1.03] and OR = 1.01 [0.93, 1.12], respectively). Although AEs were common with high-dose acyclovir exposure, severe AEs were rare. Acyclovir exposure was not associated with AEs.

800IU versus 400IU per day of vitamin D3 in term breastfed infants: a randomized controlled trial from an LMIC.

This open-label, block-randomized controlled trial compared the effect of 800IU/day and 400IU/day of oral vitamin D3 supplementation in reducing vitamin D insufficiency (VDI) among healthy-term breastfed infants at 14weeks of postnatal age. All eligible infants were randomized to receive either 800 or 400IU/day of oral vitamin D3 (starting within the first week until 14weeks). The primary outcome was the proportion of infants with VDI (25-OH-D < 20ng/ml) at 14weeks. Secondary outcomes were vitamin D deficiency (VDD, < 12ng/ml), severe VDD (< 5ng/ml), anthropometry, biochemical or clinical rickets, and any adverse events related to vitamin D toxicity (VDT). Among 102 enrolled infants, the distribution of baseline variables (including cord 25-OH-D levels; 13.0 versus 14.2ng/ml) was similar in both groups. On intention-to-treat analysis, the proportions of infants with VDI at 14weeks were significantly lower in the 800IU group compared to those in the 400IU group [24% versus 55%; RR 0.44; 95% CI: 0.25-0.76]. The proportions of infants with elevated parathormone (6% versus 26.5%; p = 0.012) and severe VDD (0% versus 12.2%; p = 0.033) were significantly lower in the 800IU group. Clinical rickets developed in three (6.2%) infants in the 400IU group. No infant developed VDT. Conclusions: Daily oral supplementation with 800IU of vitamin D3 resulted in an almost 50% reduction in the proportion of infants with VDI and prevented the occurrence of severe VDD at 14weeks of age compared to 400IU with no evidence of vitamin D toxicity. Trial Registration: Clinical Trial Registry of India (CTRI/2019/02/017374). What is Known: •Breastfeeding is the ideal source of nutrition for healthy-term breastfed infants; however,vitamin D content of breastmilk is suboptimal. •AAP recommends daily oral supplementation of 400 IU of vitamin D to all healthy-term breastfed infants; however, trials from high-income countries support insufficiency of this dose in maintaining serum 25-OH-D levels >20 ng/ml with no such information from low-middle-income countries. What is New: •800 IU/day of oral vitamin D3 supplementation among term breastfed infants significantly reduces vitamin D insufficiency at 14 weeks' age as compared to the recommended dose of 400 IU/day. •This higher supplemental dose is safe with no evidence of vitamin D toxicity.

Caffeine dosing in premature neonates: impact of birth weight on a pharmacokinetic simulation study.

The optimal caffeine dosing in extremely premature neonates remains elusive. This study aimed to evaluate the impact of birth weight on caffeine pharmacokinetics and various dosing regimens. In this pharmacokinetic simulation study, we generated the body weights (0-49 days of postnatal age [PNA]) of neonates <28 weeks gestational age with different birth weights (550, 750, and 1050 g). Their pharmacokinetic parameters were determined based on published pharmacokinetic models. Then, we simulated and compared the caffeine base concentration-time profiles of standard versus off-label caffeine citrate dose regimens. The half-life decreased and the weight-adjusted clearance increased more significantly in neonates with lower birth weights, resulting in lower caffeine plasma concentrations. The neonate with the lowest birth weight did not achieve a threshold trough concentration of 15 mg/L after receiving the standard dose (5 mg/kg/day), while the higher-birth-weights (≥750 g) had trough concentrations below the threshold around the second week of life. Higher caffeine doses (10 mg/kg/day) resulted in peak concentrations of <36 mg/L by 10-14 days of PNA while maintaining trough concentrations above 15 mg/L throughout the 49 days PNA. Higher-than-standard caffeine dosing may be needed for extremely premature neonates, especially for those with lower birth weights. Extremely premature neonates with a lower birth weight may require a higher weight-based caffeine dosing due to their higher weight-adjusted clearance and shorter half-lives. Not only do these extremely premature neonates have a higher risk of developing bronchopulmonary dysplasia due to their structurally underdeveloped lungs, but the low birth weight-related underdosing may further contribute to the reduced caffeine effectiveness. Higher-than-standard caffeine citrate dosing (e.g., 10 mg/kg/day maintenance dose) may be needed to further prevent bronchopulmonary dysplasia.

Transcriptome profile in the skeletal muscle of cattle progeny as a function of maternal protein supplementation during mid-gestation

This study aimed to evaluate the differentially expressed genes (DEG), their biological functions, and the main predictor genes in skeletal muscle of the offspring resulting from dams supplemented or not with protein during mid-gestation. From 100 to 200 days of gestation, 10 Tabapuã cows pregnant of males were assigned to one of two treatments: Control [(CON) - supply of basal diet achieving 5.5% of crude protein (CP); n = 6]; or Supplemented [(SUP) - basal diet plus a supplement with 40% of CP provided at the level of 3.5 g/kg of body weight; n = 4]. Muscle samples were collected from the progeny at 260d of postnatal age to RNA-seq, Gene Ontology (GO) enrichment, and Random Forest (RF) analyses. A total of 310 DEG (q-value < 0.05) were identified for the effect of diet, being 187 and 123 genes down-regulated and up-regulated in the SUP diet, respectively. Within the SUP up-regulated genes, were genes related to insulin receptor signaling pathway (LOC107131843) and apoptosis regulation (KRT18, KRT8 and KRT19). While the enriched GOs terms are implicated in mitochondrial metabolism through the overrepresentation of the GO terms microtubule polymerization or depolymerization (GO:0031109, GO:0046785) and positive regulation of cellular component biogenesis (GO:0044089). Moreover, RF analysis revealed predictor genes related to the skeletal muscle development, including genes that participates in the PI3K/Akt pathways (PITPNA), myoblast proliferation (ALKBH1) and differentiation (CDK5R1 and miR-206). In conclusion, maternal protein supplementation during mid-gestation positively affected the energy metabolism and favored the hypertrophic processes of the skeletal muscle of the offspring.

Clinical presentation of hypoglycemic brain injury suggested by neuroimaging in unanticipated term neonates

Objective- To evaluate the clinical characteristics of hypoglycemic brain injury (HBI) in unanticipated term neonates, confirmed by neuroimaging. Methodology- We reviewed Magnetic resonance imaging (MRI) of brain of term neonatal encephalopathy cases, from January 2018 to November 2020. Neonates with MRI topography suggestive HBI and documented hypoglycemia from case records were enrolled in study. Perinatal data, clinical characteristics and management of cases was recorded. Descriptive statistics was used to analyse the data. Result-Total 13 term neonates had brain MRI suggestive of HBI conducted at median postnatal age of 7 days. The mean birth weight of HBI neonates was 2582 ± 285 gram, mean gestational age 38.15± 0.48 weeks and five (38.4%) babies were low birth weight. Eight (61.5%) babies were delivered by caesarean section, eleven (84.6%) were first born, twelve (92.3%) were male and nine (69.2%) were on exclusive breastfeeding. Out of thirteen neonates twelve (92.3%) were outborn, mean age of symptom noticed was 2.83±0.53 days and mean age of admission was 3.84± 0.82 days. Mean blood glucose at admission was 28.84±3.23 mg/dl and four (30.7%) were diagnosed with hypoglycemia at referral hospital.

Validation of a non-invasive pressure–time index of the inspiratory muscles in spontaneously breathing newborn infants

To validate the pressure–time index of the inspiratory muscles as a non-invasive index of inspiratory muscle function in spontaneously breathing infants by comparing it against the gold-standard pressure–time index of the diaphragm. Prospective observational cohort study of consecutive infants breathing unsupported in room air in a tertiary neonatal intensive care unit, studied prior to discharge from neonatal care. The invasive pressure–time index of the diaphragm was calculated using a transdiaphragmatic dual-pressure catheter that measured transdiaphragmatic pressure by subtraction of the oesophageal from the gastric pressure. The non-invasive pressure–time index of the inspiratory muscles was calculated using pressure measurements at the level of the mouth via a differential pressure transducer connected to a face mask. Both indices were calculated as the product of the ratio of the mean inspiratory pressure divided by the maximum inspiratory pressure and the ratio of the inspiratory time divided by the total time of a respiratory cycle. One hundred and thirty infants (79 male) were included with a mean (SD) gestational age of 35.2 (3.2) weeks, studied at a median (IQR) postnatal age of 9 (6–20) days. The mean (SD) pressure–time index of the diaphragm was 0.063 (0.019) and the mean (SD) pressure–time index of the inspiratory muscles was 0.065 (0.023). The correlation coefficient for the two indices was 0.509 (p < 0.001). The mean (SD) absolute difference between the pressure–time index of the inspiratory muscles and pressure–time index of the diaphragm was 0.002 (0.021). In convalescent infants, the non-invasive pressure–time index of the inspiratory muscles had a moderate degree of correlation with the invasively derived pressure time index of the diaphragm measured with a transdiaphragmatic catheter.

Longitudinal effects of growth restriction on the murine gut microbiome and metabolome.

Undernutrition-induced growth restriction in the early stages of life increases the risk of chronic disease in adulthood. Although metabolic impairments have been observed, few studies have characterized the gut microbiome and gut-liver metabolome profiles of growth-restricted animals during early-to-mid-life development. To induce growth restriction, mouse offspring were either born to gestational undernutrition (GUN) or suckled from postnatal undernutrition (PUN) dams fed a protein-restricted diet (8% protein) or control diet (CON; 20% protein) until weaning at postnatal age of 21 days (PN21). At PN21, all mice were fed the CON diet until adulthood (PN80). Livers were collected at PN21 and PN80, and fecal samples were collected weekly starting at PN21 (postweaning week 1) until PN80 (postweaning week 5) for gut microbiome and metabolome analyses. PUN mice exhibited the most alterations in gut microbiome and gut and liver metabolome compared with CON mice. These mice had altered fecal microbial β-diversity (P = 0.001) and exhibited higher proportions of Bifidobacteriales [linear mixed model (LMM) P = 7.1 × 10-6), Clostridiales (P = 1.459 × 10-5), Erysipelotrichales (P = 0.0003), and lower Bacteroidales (P = 4.1 × 10-5)]. PUN liver and fecal metabolome had a reduced total bile acid pool (P < 0.01), as well as lower abundance of riboflavin (P = 0.003), amino acids [i.e., methionine (P = 0.0018), phenylalanine (P = 0.0015), and tyrosine (P = 0.0041)], and higher excreted total peptides (LMM P = 0.0064) compared with CON. Overall, protein restriction during lactation permanently alters the gut microbiome into adulthood. Although the liver bile acids, amino acids, and acyl-carnitines recovered, the fecal peptides and microbiome remained permanently altered into adulthood, indicating that inadequate protein intake in a specific time frame in early life can have an irreversible impact on the microbiome and fecal metabolome.NEW & NOTEWORTHY Undernutrition-induced early-life growth restriction not only leads to increased disease risk but also permanently alters the gut microbiome and gut-liver metabolome during specific windows of early-life development.

Predischarge Transcutaneous Bilirubin and Total Serum Bilirubin in Predicting Readmission Due to Significant Hyperbilirubinemia in Near-Term and Term Neonates

Background: Prevention of bilirubin encephalopathy in healthy near-term and term neonates is the primary focus of newborn care. This study aims to assess the predictive accuracy of transcutaneous bilirubin (TcB) and total serum bilirubin (TSB) measured before discharge for subsequent readmission because of significant hyperbilirubinemia in near-term and term neonates during the first postnatal week and to analyze the risk factors associated with readmission because of significant hyperbilirubinemia. Methods: TcB with BiliChek device and TSB measurements with bilirubinometer were obtained prior to discharge in all healthy near-term and term neonates delivered and admitted in the postnatal wards during the study period. Postnatal age (in hours) was recorded during bilirubin measurement. Results: The predictive ability of predischarge TcB measurement for the optimum cutoff of 104 µmol/L derived from the area under the receiver operating characteristic curve has a negative predictive value of 99.3% with a negative likelihood ratio (LR) of 0.15 and sensitivity of 91.7%, whereas the predictive ability of predischarge TSB measurement for the optimum cutoff of 109 µmol/L derived from the area under the receiver operating characteristic curve has 100% sensitivity and 100% negative predictive value with a negative LR of 0.0 for no readmission because of significant hyperbilirubinemia. The predischarge TSB level of those readmitted neonates had a very high odds for high-risk zone [OR (95% CI) 358.4 (96.39, 1332.59)] and 7.8 folds higher odds for intermediate-risk zone compared to those neonates who did not require readmission in Bhutani’s predischarge nomogram. Conclusion: The result of our study showed that both TcB obtained by using BiliChek device and TSB measurements obtained by bilirubinometer for the optimum cutoffs of 104 µmol/L and 109 µmol/L, respectively, and with negative LR of 0.15 and 0.0, respectively, can be used as a safe predischarge tool for no readmission because of significant hyperbilirubinemia after 24 h of postnatal age. The existing Bhutani’s predischarge nomogram for predicting significant hyperbilirubinemia should be an additional screening tool to reduce the rate of subsequent readmission because of hyperbilirubinemia.

High Magnitude of Neonatal Anemia Among Sick Newborns Admitted to University of Gondar Comprehensive Specialized Hospital, Northwest Ethiopia.

IntroductionAnemia is a global health problem that affects all ages, particularly children under five years. If not treated early, childhood anemia results in impaired growth, delayed cognitive development, and organ dysfunction. There is a scarcity of studies on the prevalence of anemia among hospitalized sick neonates, especially in developing countries.ObjectiveThis study aimed to determine the magnitude of anemia and associated factors among hospitalized sick newborns at the University of Gondar Comprehensive Specialized Hospital (UOGCSH).MethodsAn institutional-based cross-sectional study was conducted among admitted newborns from June 1 to September 30, 2020. All newborns whose gestational age (GA) ≥28 weeks and postnatal age ≤28 days, admitted to UOGCSH during the study period were included in the study. Data were collected by pediatric residents and a systematic random sampling technique was used to select the study participants. Statistical analysis was performed using SPSS version 20. Binary logistic regression was used to identify associated factors with neonatal anemia. P-value <0.05 was considered statistically significant.ResultsDuring the study period, 272 newborns were enrolled. The mean hemoglobin value was 15.74 ± 4.27 gm/dL. The prevalence of neonatal anemia in the study population was 30.1% (95% CI: 24.6–35.7). Neonatal age >7 days (AOR = 4.41, 95% CI: 1.86–10.5), maternal anemia (AOR = 9.93, 95% CI: 4.36–21.6), antepartum hemorrhage (AOR = 4.05, 95% CI: 1.54–10. 7), being multiple births (AOR = 4.70, 95% CI: 1.73–12.8), subgaleal hemorrhage (AOR = 7.56, 95%: 1.87–30.6), and hyperbilirubinemia (AOR = 3.84, 95% CI: 1.58–9.31) were associated with neonatal anemia.Conclusion and RecommendationThe prevalence of anemia among hospitalized newborns was high. The current study recommends that healthcare providers should screen anemia among sick newborns who had risk factors. Prevention of maternal anemia and early treatment of obstetric complications will reduce the burden of anemia in sick neonates.

248-LB: Nrf2 Is Essential for Expanding Neonatal Pancreatic Beta-Cell Mass

Patients with both major forms of diabetes suffer from insufficient functional β-cell mass. Moreover, the sharp increase in the annual incidence of both type 1 (1.8%) and type 2 (4.8%) diabetes in the pediatric population in the last decades highlights the urgent need for discovering the mechanisms that regulate functional β-cell mass. β-cell proliferation, which reaches its maximal peak during postnatal stages is the major mechanism for increasing β-cell mass in early postnatal ages. We previously found that induction of the antioxidant regulator, Nrf2, is required for adaptive β-cell expansion under hypercaloric conditions via stimulation of β-cell proliferation, increased β-cell survival, and maintenance of β-cell identity in adult mice. Based on these observations, we hypothesize that Nrf2 regulates β-cell proliferation and survival at early stages of life and contribute to maintain normal β-cell mass later in life. Nrf2 expression levels were found to correlate with β-cell proliferation in wild type neonatal mice. Importantly, 28 day-old β-cell specific Nrf2 knockout mice (Ins1Cre-Nrf2lox/lox) exhibited 50% reduction in β-cell mass, 58% reduction in total islet number, 43% decrease in extra-large islets, 46% decrease in large islets and 53% decrease in extra small islets, compared to control mice. No changes in pancreas weight were observed. Additionally, depletion of Nrf2 in β-cells increased β-cell death in 7 (5.8-fold) and 14 (12.5-fold) day-old mice and attenuated β-cell proliferation in 1- and 7-day-old mice. Surprisingly, we also found a marked decrease in islet size in 1- and 7-day-old mice, suggesting that Nrf2 may affect β-cell proliferation, survival and/or development during embryonic stages. We conclude that Nrf2 is required for β-cell mass expansion in postnatal ages by controlling β-cell proliferation and survival. Disclosure S. Baumel-alterzon: None. A. Garcia-ocana: Consultant; Sun Pharmaceutical Industries Ltd. D. Scott: None.