Neonatal DNA methylation and childhood low prosocial behavior: An epigenome-wide association meta-analysis.

Low prosocial behavior in childhood has been consistently linked to later psychopathology, with evidence supporting the influence of both genetic and environmental factors on its development. Although neonatal DNA methylation (DNAm) has been found to prospectively associate with a range of psychological traits in childhood, its potential role in prosocial development has yet to be investigated. This study investigated prospective associations between cord blood DNAm at birth and low prosocial behavior within and across four longitudinal birth cohorts from the Pregnancy And Childhood Epigenetics (PACE) Consortium. We examined (a) developmental trajectories of "chronic-low" versus "typical" prosocial behavior across childhood in a case-control design (N = 2,095), and (b) continuous "low prosocial" scores at comparable cross-cohort time-points (N = 2,121). Meta-analyses were performed to examine differentially methylated positions and regions. At the cohort-specific level, three CpGs were found to associate with chronic low prosocial behavior; however, none of these associations was replicated in another cohort. Meta-analysis revealed no epigenome-wide significant CpGs or regions. Overall, we found no evidence for associations between DNAm patterns at birth and low prosocial behavior across childhood. Findings highlight the importance of employing multi-cohort approaches to replicate epigenetic associations and reduce the risk of false positive discoveries.

Urinary Bile Acid Profile of Newborns Born by Cesarean Section Is Characterized by Oxidative Metabolism of Primary Bile Acids: Limited Roles of Fetal-Specific CYP3A7 in Cholate Oxidations.

This work aims to investigate how the bile acid metabolism of newborns differs from that of adults along the axis of primary, secondary, and tertiary bile acids (BAs). The total unconjugated BA profiles were quantitatively determined by enzyme digestion techniques in urine of 21 newborns born by cesarean section, 29 healthy parturient women, 30 healthy males, and 28 healthy nonpregnant females. As expected, because of a lack of developed gut microbiota, newborns exhibited poor metabolism of secondary BAs. Accordingly, the tertiary BAs contributed limitedly to the urinary excretion of BAs in newborns despite their tertiary-to-secondary ratios significantly increasing. As a result, the primary BAs of newborns underwent extensive oxidative metabolism, resulting in elevated urinary levels of some fetal-specific BAs, including 3-dehydroCA, 3ß,7α,12α-trihydroxy-5ß-cholan-24-oic acid, 3α,12-oxo-hydroxy-5ß-cholan-24-oic acid, and nine tetrahydroxy-cholan-24-oic acids (Tetra-BAs). Parturient women had significantly elevated urinary levels of tertiary BAs and fetal-specific BAs compared with female control, indicating that they may be excreted into amniotic fluid for maternal disposition. An in vitro metabolism assay in infant liver microsomes showed that four Tetra-BAs and 3-dehydroCA were hydroxylated metabolites of cholate, glycocholate, and particularly taurocholate. However, the recombinant cytochrome P450 enzyme assay found that the fetal-specific CYP3A7 did not contribute to these oxidation metabolisms as much as expected compared with CYP3A4. In conclusion, newborns show a BA metabolism pattern predominated by primary BA oxidations due to immaturity of secondary BA metabolism. Translational studies following this finding may bring new ideas and strategies for both pediatric pharmacology and diagnosis and treatment of perinatal cholestasis-associated diseases. SIGNIFICANCE STATEMENT: The prenatal BA disposition is different from adults because of a lack of gut microbiota. However, how the BA metabolism of newborns differs from that of adults along the axis of primary, secondary, and tertiary BAs remains poorly defined. This work demonstrated that the urinary BA profiles of newborns born by cesarean section are characterized by oxidative metabolism of primary BAs, in which the fetal-specific CYP3A7 plays a limited role in the downstream oxidation metabolism of cholate.

Neonatal Iron: Factors Influencing its Level and Associated Complications - a Review Article.

BACKGROUND: Iron is an essential micronutrient which plays a significant role, particularly vital for early brain growth and function. Maternal iron condition influences the iron status of neonates since iron transferred from the mother is the only source for fetal iron. A depletion in iron as a result of rapid growth leads to iron deficiency which is common in neonates. Although there are inconsistencies with regard to the normal reference ranges for neonatal iron level, the current review summarized literature to provide compressive information about neonatal iron status and factors that influence its level. METHODS: This is a narrative review on the basis of relevant literatures mainly on neonatal iron from peer-reviewed journals. Electronic databases such as PubMed, PMC, Scopus, Science Direct, Google scholar, Google, and Yahoo were used to retrieve relevant literatures using key terms like "newborn iron, neonatal iron, iron overload, maternal factors, complication, iron level and neonates" separately and in combination. RESULTS: Several factors had been postulated as factors associated with neonatal iron status. The current review figured out that maternal obesity, gestational diabetes mellitus, preterm delivery, placental transferrin receptor, inappropriate iron supplementation, use of iron fortified formula, uses of recombinant erythropoietin therapy, smoking, maternal iron deficiency anemia, umbilical cord clamping, and transfusion are the major factors which can influence neonatal iron level. These factors may have either positive or negative effects on neonatal iron level. Both iron deficiency and iron overload at some stage in the fetal development or at early stage of neonatal development cause abnormal functions of multiple organ system of neonates and subsequently contributed to neonatal and childhood morbidity and mortality. CONCLUSIONS: By one and other means insufficient, late and extra maternal iron supplementation, early and delayed umbilical cord clamping have negative effects on the iron level of neonates. Therefore, careful prenatal and antenatal follow-up need to be strengthened with due emphasis for maternal iron assessment.

Glucose Homeostasis and the Neonatal Brain: A Sweet Relationship.

Glucose is the primary substrate for energy metabolism in the brain and although the brain is dependent on a constant glucose supply for normal function, both local energy stores and the supply of alternate substrates are limited. In utero, the placenta provides a continuous supply of glucose to the fetus while transition to extrauterine life marks an abrupt change in substrate delivery and a major change in glucose metabolism where insufficiencies and disruptions can occur. Hypoglycemia is one of the most common biochemical disturbances in the neonatal period, affecting a wide range of neonates. Prolonged or persistent low plasma glucose concentrations can lead to neonatal brain injury and abnormal neurological outcomes. This article discusses fetal and neonatal metabolic adaptation, the physiology of glucose homeostasis, hypoglycemic brain injury (HBI), and neurodevelopmental long-term outcomes.

Induced pluripotent stem cell modelling of HLHS underlines the contribution of dysfunctional NOTCH signalling to impaired cardiogenesis.

Hypoplastic left heart syndrome (HLHS) is among the most severe forms of congenital heart disease. Although the consensus view is that reduced flow through the left heart during development is a key factor in the development of the condition, the molecular mechanisms leading to hypoplasia of left heart structures are unknown. We have generated induced pluripotent stem cells (iPSC) from five HLHS patients and two unaffected controls, differentiated these to cardiomyocytes and identified reproducible in vitro cellular and functional correlates of the HLHS phenotype. Our data indicate that HLHS-iPSC have a reduced ability to give rise to mesodermal, cardiac progenitors and mature cardiomyocytes and an enhanced ability to differentiate to smooth muscle cells. HLHS-iPSC-derived cardiomyocytes are characterised by a lower beating rate, disorganised sarcomeres and sarcoplasmic reticulum and a blunted response to isoprenaline. Whole exome sequencing of HLHS fibroblasts identified deleterious variants in NOTCH receptors and other genes involved in the NOTCH signalling pathway. Our data indicate that the expression of NOTCH receptors was significantly downregulated in HLHS-iPSC-derived cardiomyocytes alongside NOTCH target genes confirming downregulation of NOTCH signalling activity. Activation of NOTCH signalling via addition of Jagged peptide ligand during the differentiation of HLHS-iPSC restored their cardiomyocyte differentiation capacity and beating rate and suppressed the smooth muscle cell formation. Together, our data provide firm evidence for involvement of NOTCH signalling in HLHS pathogenesis, reveal novel genetic insights important for HLHS pathology and shed new insights into the role of this pathway during human cardiac development.

Longitudinal Measurements of Resting Energy Expenditure by Indirect Calorimetry in Healthy Term Infants during the First 2 Months of Life.

OBJECTIVE: To determine longitudinal measurements of resting energy expenditure (REE) by indirect calorimetry (IC) in healthy term infants during the first 2 months of life. STUDY DESIGN: An outpatient prospective pilot study was performed in healthy term infants to estimate REE by measuring expired gas fractions of oxygen (O2) and carbon dioxide (CO2) with IC in a respiratory and metabolic steady state. RESULTS: A total of 30 measurements were performed. Fourteen subjects completed measurements at both 1 and 2 months of life, and two subjects had only measurements made at 1 month of life. Mean REE values were 64.1 ± 12.7 and 58.4 ± 14.3 kcal/kg/d at 1 and 2 months of age, respectively. Mean O2 consumption and CO2 production measurements were 9.3 ± 2.0 and 7.7 ± 1.2 mL/kg/min and 8.1 ± 2.2 and 6.4 ± 1.1 mL/kg/min at 1 and 2 months of age, respectively. CONCLUSION: This pilot study demonstrates longitudinal measurements of REE by IC in healthy term infants during the first 2 months of life. We also demonstrate that, overall, there is consistency in REE values in this population, with a likely decrease in individual longitudinal measurements over the first 2 months of life.

[Which medications are safe while breastfeeding? : A synopsis for the anesthetist, obstetrician and pediatrician]. / Welche Medikamente sind in der Stillzeit erlaubt? : Eine Übersicht für den Anästhesisten, Geburtshelfer und Kinderarzt.

Pharmacokinetic data on drug administration during lactation are often inconsistent or missing. For legal reasons medicinal drug product information generally advises to interrupt breastfeeding for 24 h after medication intake. However this is not standard of care in clinical practice as the mother should be instructed to initiate breastfeeding as soon as possible after giving birth. At the same time the medication exposure over the breast milk for the newborn should be minimized. Aim of this article is to summarize pharmacokinetic data and to give important clinical information on medications frequently administered during the lactation period. As a general rule a mother can start breastfeeding following anesthesia as soon as she is able to get her baby latched on her breast.

Anthropometry and Body Composition of Preterm Neonates in the Light of Metabolic Programming.

The improved survival of preterm infants has led to increased interest regarding their health as adults. In the context of metabolic programming, the connection between perinatal and early postnatal nutrition and growth with health in later life has brought to the fore the role of catch-up growth during the first months of preterm infants' lives and its association with body fat and obesity in childhood or puberty. A state-of-the art review was conducted in order to assess the way catch-up is evaluated, in terms of timing and rate. Adequate growth is of major importance for neurodevelopment; however, it may compete with adiposity or metabolic health. Studies based on body composition assessment have given conflicting results as regards the effect of early versus late and rapid versus slow catch-up growth on later health, mainly attributed to the lack of established criteria and definitions. Given that adequate early nutrition is crucial for the neurodevelopment of preterm infants, further studies are needed on the role of catch-up growth in long-term outcome, using generally accepted qualitative and quantitative criteria.

The relationship between early pregnancy dietary intakes and subsequent birthweight and neonatal adiposity.

Background: Maternal nutrition intakes may influence neonatal birthweight and adiposity; however, inconsistencies within the literature exist. The relationships between maternal dietary intakes in early pregnancy and both birthweight and neonatal adiposity requires elucidation. This study examined the relationship between early pregnancy dietary intakes and subsequent birthweight and neonatal adiposity. Methods: Women were recruited at their convenience after sonographic confirmation of a singleton pregnancy. Women completed a Willet food frequency questionnaire evaluating habitual food and nutrient intakes at their first antenatal visit. Neonatal body composition was measured using air-displacement plethysmography. Results: Of the 385 mother-neonate dyads, mean maternal age was 30.8 ± 5.3 years, mean Body Mass Index (BMI) was 24.5 ± 4.8 kg/m2 and 41.8% (n = 161) were nulliparous. There were no relationships between maternal food intakes and birthweight (P > 0.05) (n = 385). On multivariable analysis there was a positive relationship between polyunsaturated fat and neonatal fat mass index (FMI) (beta = 0.015, 95% CI = 0.002-0.028, P = 0.04) (n = 80). Conclusion: Dietary intakes of polyunsaturated fat in early pregnancy are positively associated with neonatal FMI at birth on multivariable analysis. Further longitudinal studies need to explore this association and the long-term implications for the neonate.

Negligible impact of birth on renal function and drug metabolism.

BACKGROUND: Transition from the intrauterine to the extrauterine environment in neonates is associated with major changes in blood flow and oxygenation with consequent increases in metabolic functions. The additional impact of birth on renal function and drug metabolism above that predicted by postmenstrual age and allometry is uncertain. Increased clearance at birth could reduce analgesic effect attributable to a lowering of plasma concentration. These elimination processes can be described using the clearance concept. METHODS: Data from four publications that investigated the time course of glomerular filtration rate and clearance of paracetamol, morphine and tramadol were reanalyzed. The effect of birth, based on postnatal age, was used in conjunction with a theory-based allometric size scaling and maturation based on postmenstrual age. RESULTS: Postnatal age had a short-term effect on the time course of clearance distinguishable from the well-known slower maturation based on postmenstrual age. While elimination might be relatively reduced by 15%-45% at birth, there is a rapid increase in elimination for 1-3 weeks after birth to be 15% greater than that predicted by postmenstrual age alone. CONCLUSION: Birth is associated with a small increase in clearance in addition to that described by postmenstrual age for common analgesic drugs cleared by glucuronide conjugation (morphine, paracetamol) or by the P450 cytochrome oxidase (tramadol) and renal systems. While the increase is of biological interest, it would not be expected to have any clinically relevant impact on renal function or drug dosing. The processes of maturation described by these models are potentially applicable to any drug elimination process.

Correlations of Enzyme Levels at Birth in Stressed Neonates with Short-Term Outcomes.

INTRODUCTION: Multi-organ injury causes leakage of several intracellular enzymes into the circulation. We evaluated the correlation between the serum-leaked intracellular enzyme levels at the beginning of treatment and the outcome in perinatally stressed neonates. MATERIALS AND METHODS: We retrospectively studied neonates whose 1 minute Apgar score was < 7. We collected initial venous blood sample data, including aspartate transaminase (AST), alanine transaminase (ALT), lactate dehydrogenase (LDH), and creatine kinase (CK) levels, and correlated these with patient short-term outcomes. RESULTS: Of 60 neonates, nine patients were treated with therapeutic hypothermia, and 32 needed mechanical ventilation. The therapeutic hypothermia group showed significantly larger base deficit, and higher lactate, AST, ALT, LDH, and CK (all p < 0.01). The duration of mechanical ventilation significantly correlated with AST, ALT, LDH, and CK levels (all p < 0.01). CONCLUSION: Initial enzyme levels are useful for predicting the duration of mechanical ventilation in stressed neonates.

Tissue oxygen saturation levels from fetus to neonate.

AIM: Oxygen saturation during the term of delivery to the first cry, when fetal circulation dynamically changes, has not yet been examined. The aim of this study was therefore to determine whether the continuous measurement of regional tissue oxygen saturation (rSO2 ) from crowning until 5 min after delivery is possible using fetal tissue oximetry with a sensor attached to the examiner's finger. METHODS: Oxygen saturation levels in fetal cranial tissue between the second stage of delivery to crowning and up to 5 min after delivery were measured using fetal tissue oximetry with a sensor attached to the examiner's finger. Thirty-five deliveries were examined, and oxygen saturation was measured in seven infants from delivery of the head until 5 min after birth. Umbilical cord blood gas was measured in all cases. This clinical test was performed under the permission of the Ethics Committee of Hamamatsu University School of Medicine. RESULTS: Average tissue oxygen saturation in the second stage of delivery and at 5 min after delivery were 50.3 ± 16.3% and 56.8 ± 8.46%, respectively. In cases of continuous measurement, average rSO2 for crowning, immediately after delivery, and the first cry was 32.7 ± 9.5%, 30.0 ± 6.6%, and 31.6 ± 5.5%, respectively. CONCLUSION: We herein successfully measured oxygen saturation levels in fetal cranial tissue during crowning, delivery of the head, the first cry, and 5 min after delivery using fetal tissue oximetry with a sensor attached to the examiner's finger.

Pre- and Post-ductal oxygen saturation among apparently healthy low birth weight neonates.

INTRODUCTION: Reference values of oxygen saturation (SpO2) to guide care of low birth weight neonates have been obtained mainly from Caucasians. Data from African newborns are lacking. To determine the pre- and post-ductal SpO2values of low birth weight neonates within the first 72 h of life, compare SpO2values of moderate-late preterm and term low birth weight neonates and determine how mode of delivery affected SpO2in the first 24 h of life. METHODOLOGY: An observational descriptive study was carried out on apparently healthy low birth weight newborns weighing 1500 to ≤2499 g. Pre and post ductal SpO2values were recorded at the following hours of life: 10-24 h, >24-48 h and >48-72 h using a NONIN® pulse oximeter. RESULTS: The ranges of pre- and post-ductal SpO2in the study were similar for both preterm and term neonates in the study (89%-100%). The mean (standard deviation [SD]) pre-ductal SpO2was 95.9% (2.3) and the mean (SD) post-ductal SpO2was 95.9% (2.1). There was a significant increase in pre-ductal SpO2from 10 to 24 h through >48-72 h of life (P = 0.027). The mode of delivery did not affect SpO2values within 10-24 h of life. CONCLUSION: The present study documented daily single pre- and post-ductal SpO2 values for preterm and term low birth weight neonates weighing 1500 g to <2500 g during the first 72 h of life. The overall range and mean pre- and post-ductal SpO2 were similar for both categories of stable low birth weight neonates in the study. There was no significant difference between SpO2ranges for late preterm compared to term low birth weight neonates. The results obtained could serve as guide in assessing SpO2of low birth weight neonates weighing between 1500 and 2499 g in the first 72 h of life.

Evaluation of changes in oral drug absorption in preterm and term neonates for Biopharmaceutics Classification System (BCS) class I and II compounds.

AIMS: Evidence suggests that the rate of oral drug absorption changes during early childhood. Yet, respective clinical implications are currently unclear, particularly for preterm neonates. The objective of this study was to evaluate changes in oral drug absorption after birth for different Biopharmaceutics Classification System (BCS) class I and II compounds to better understand respective implications for paediatric pharmacotherapy. METHODS: Two paradigm compounds were selected for BCS class I (paracetamol (acetaminophen) and theophylline) and II (indomethacin and ibuprofen), respectively, based on the availability of clinical literature data following intravenous and oral dosing. A comparative population pharmacokinetic analysis was performed in a step-wise manner in NONMEM® 7.2 to characterize and predict changes in oral drug absorption after birth for paracetamol, theophylline and indomethacin. RESULTS: A one compartment model with an age-dependent maturation function for oral drug absorption was found appropriate to characterize the pharmacokinetics of paracetamol. Our findings indicate that the rate at which a drug is absorbed from the GI tract reaches adult levels within about 1 week after birth. The maturation function for paracetamol was found applicable to theophylline and indomethacin once solubility limitations were overcome via drug formulation. The influence of excipients on solubility and, hence, oral bioavailability was confirmed for ibuprofen, a second BCS class II compound. CONCLUSIONS: The findings of our study suggest that the processes underlying changes in oral drug absorption after birth are drug-independent and that the maturation function identified for paracetamol may be generally applicable to other BCS class I and II compounds for characterizing drug absorption in preterm as well as term neonates.

Cholesterol acceptor capacity is preserved by different mechanisms in preterm and term fetuses.

Fetal serum cholesterol and lipoprotein concentrations differ between preterm and term born neonates. An imbalance of the flow of cholesterol from the sites of synthesis or efflux from cells of peripheral organs to the liver, the reverse cholesterol transport (RCT), is linked to atherosclerosis and cardiovascular disease (CVD). Preterm delivery is a risk factor for the development of CVD. Thus, we hypothesized that RCT is affected by a diminished cholesterol acceptor capacity in preterm as compared to term fetuses. Cholesterol efflux assays were performed in RAW264.7, HepG2, and HUVEC cell lines. In the presence and absence of ABC transporter overexpression by TO-901317, umbilical cord sera of preterm and term born neonates (n = 28 in both groups) were added. Lipid components including high density lipoprotein (HDL), low density lipoprotein (LDL), apolipoprotein A1, and apolipoprotein E were measured and related to fractional cholesterol efflux values. We found overall, fractional cholesterol efflux to remain constant between the study groups, and over gestational ages at delivery, respectively. However, correlation analysis revealed cholesterol efflux values to be predominantly related to HDL concentration at term, while in preterm neonates, cholesterol efflux was mainly associated with LDL In conclusion cholesterol acceptor capacity during fetal development is kept in a steady state with different mechanisms and lipid fractions involved at distinct stages during the second half of fetal development. However, RCT mechanisms in preterm neonates seem not to be involved in the development of CVD later in life suggesting rather changes in the lipoprotein pattern causative.

Pharmacokinetics in neonatal prescribing: evidence base, paradigms and the future.

Paediatric patients, particularly preterm neonates, present many pharmacological challenges. Due to the difficulty in conducting clinical trials in these populations dosing information is often extrapolated from adult populations. As the processes of absorption, distribution, metabolism and excretion of drugs change throughout growth and development extrapolation presents risk of over or underestimating the doses required. Information about the development these processes, particularly drug metabolism pathways, is still limited with weight based dose adjustment presenting the best method of estimating pharmacokinetic changes due to growth and development. New innovations in pharmacokinetic research, such as population pharmacokinetic modelling, present unique opportunities to conduct clinical trials in these populations improving the safety and effectiveness of the drugs used. More research is required into this area to ensure the best outcomes for our most vulnerable patients.

Determinants of maternal pregnancy one-carbon metabolism and newborn human DNA methylation profiles.

Maternal one-carbon (1-C) metabolism provides methylgroups for fetal development and programing by DNA methylation as one of the underlying epigenetic mechanisms. We aimed to investigate maternal 1-C biomarkers, folic acid supplement use, and MTHFR C677T genotype as determinants of 1-C metabolism in early pregnancy in association with newborn DNA methylation levels of fetal growth and neurodevelopment candidate genes. The participants were 463 mother-child pairs of Dutch national origin from a large population-based birth cohort in Rotterdam, The Netherlands. In early pregnancy (median 13.0 weeks, 90% range 10.4-17.1), we assessed the maternal folate and homocysteine blood concentrations, folic acid supplement use, and the MTHFR C677T genotype in mothers and newborns. In newborns, DNA methylation was measured in umbilical cord blood white blood cells at 11 regions of the seven genes: NR3C1, DRD4, 5-HTT, IGF2DMR, H19, KCNQ1OT1, and MTHFR. The associations between the 1-C determinants and DNA methylation were examined using linear mixed models. An association was observed between maternal folate deficiency and lower newborn DNA methylation, which attenuated after adjustment for potential confounders. The maternal MTHFR TT genotype was significantly associated with lower DNA methylation. However, maternal homocysteine and folate concentrations, folic acid supplement use, and the MTHFR genotype in the newborn were not associated with newborn DNA methylation. The maternal MTHFR C677T genotype, as a determinant of folate status and 1-C metabolism, is associated with variations in the epigenome of a selection of genes in newborns. Research on the implications of these variations in methylation on gene expression and health is recommended.

Bone metabolism in the fetus and neonate.

During embryonic development most of the skeleton begins as a cartilaginous scaffold that is progressively resorbed and replaced by bone. Such endochondral bone development does not cease until the growth plates fuse during puberty. Growth and mineralization of the skeleton are dependent upon the adequate delivery of mineral. During fetal development, the placenta actively transports calcium, magnesium and phosphorus from the maternal circulation. After birth, the role of mineral transport is assumed by the intestines. The limited data currently available on fetal humans are largely based on cord blood samples from normal fetuses and pathological specimens from fetuses which died in utero or at birth. Consequently, much of our understanding of the regulation of fetal mineral and bone homeostasis comes from the study of animal fetuses that have been manipulated surgically, pharmacologically and genetically. Animal and human data indicate that fetal mineral homeostasis requires parathyroid hormone (PTH) and PTH-related protein-but not vitamin D/calcitriol, calcitonin or sex steroids. In the days to weeks after birth, intestinal calcium absorption becomes an active process, which necessitates that the infant depends upon vitamin D/calcitriol. However, even this postnatal function of calcitriol can be bypassed by increasing the calcium content of the diet or by administering calcium infusions.

Neonatal clinical pharmacology.

Effective and safe drug administration in neonates should be based on integrated knowledge on the evolving physiological characteristics of the infant who will receive the drug and the pharmacokinetics (PK) and pharmacodynamics (PD) of a given drug. Consequently, clinical pharmacology in neonates is as dynamic and diverse as the neonates we admit to our units while covariates explaining the variability are at least as relevant as median estimates. The unique setting of neonatal clinical pharmacology will be highlighted based on the hazards of simple extrapolation of maturational drug clearance when only based on 'adult' metabolism (propofol, paracetamol). Second, maturational trends are not at the same pace for all maturational processes. This will be illustrated based on the differences between hepatic and renal maturation (tramadol, morphine, midazolam). Finally, pharmacogenetics should be tailored to neonates, not just mirror adult concepts. Because of this diversity, clinical research in the field of neonatal clinical pharmacology is urgently needed and facilitated through PK/PD modeling. In addition, irrespective of already available data to guide pharmacotherapy, pharmacovigilance is needed to recognize specific side effects. Consequently, pediatric anesthesiologists should consider to contribute to improved pharmacotherapy through clinical trial design and collaboration, as well as reporting on adverse effects of specific drugs.

Racial variation in vitamin D cord blood concentration in white and black male neonates.

AIM: The aim of this study is to evaluate racial variation in umbilical cord blood concentration of vitamin D and to explore its correlation with markers of the insulin-like growth factor axis (IGFs) and sex steroid hormones in white and black male neonates. METHODS: In 2004-2005, venous umbilical cord blood samples were collected from 75 black and 38 white male neonates, along with maternal and birth characteristics from two hospitals in Maryland, United States. 25-Hydroxyvitamin D [25(OH)D] and 1,25-dihydroxyvitamin D [1,25(OH)(2)D] were measured by radioimmunoassay and testosterone, estradiol, and sex hormone-binding globulin (SHBG) by immunoassay and IGF-1, IGF-2, and IGF-binding protein-3 by ELISA. Crude and multivariable-adjusted geometric mean concentrations were computed. RESULTS: Mean 25(OH)D levels were lower in black than in white neonates (11.44; 95 % CI 10.10-12.95 ng/mL vs. 18.24; 95 % CI 15.32-21.72 ng/mL; p < 0.0001). Black neonates were at higher risk of suboptimal vitamin D levels [25(OH)D < 20 ng/mL] than whites (84 vs. 63 %). 25(OH)D concentrations varied by season in whites but not in blacks and were significantly inversely correlated with mother's parity (number of live births) in blacks but not in whites. Mean concentration of 1,25(OH)(2)D did not differ by race. 25(OH)D and 1,25(OH)(2)D did not correlate with IGFs, sex steroid hormones, and SHBG. CONCLUSIONS: Suboptimal vitamin D levels were prevalent especially in blacks and influenced by mother's parity and by season. The observed vitamin D differences between black and white neonates warrant further evaluation of the etiology of the disparity in chronic diseases in adulthood.