Comparison of Estradiol, Testostosterone, and CYP19 Methylation Levels between Full-Term and Preterm Newborns.

Estradiol (E), testosterone (T), and their ratio are crucial axis in life. Especially during intrauterine growth, they orchestrate the complex development of organs and their interaction, which have lifelong impact on health and an organism's capacity to respond to environmental stressors. The aim of this study was to compare for the first time E, T, and their ratio levels with aromatase (CYP19) gene methylation levels between preterm newborns (PN) and full-term newborns (FN) with respect to their mother's environmental exposure and diet. In this study, 56 FN of 37-42 weeks of gestation age (GA) and 46 PN at GA 27-36 weeks were analysed for E and T levels and CYP19A1 gene pI.3/II promoter region methylation. Results showed there was no difference in E levels between PN and FN, but there were significantly lower levels of T in PN than in FN (2.81 nmol vs. 3.76 nmol, respectively) and consequently a significantly higher E/T ratio in PN than in FN (5278.04 vs. 2891.23, respectively). CYP19A1 methylation was significantly lower in PN than in FN (86.04% vs. 90.04%, respectively). CYP19A1 methylation was significantly reduced in newborns whose mothers reported daily milk consumption. Our study is the first to provide referent values for CYP19A1 methylation levels in FN and PN and shows that PN and FN significantly differ in CYP19A1 methylation levels, T levels, and E/T ratio. Future research should further investigate the mechanisms involved in GA-dependent CYP19A1 methylation levels and mechanisms of sex hormone disturbances which may contribute to preterm birth.

An Evaluation to Establish the Acceptable Serum Triglyceride Levels in Neonates Receiving Intravenous Fat Emulsion Infusion in a Multicenter Retrospective Study.

OBJECTIVE: This study aimed to establish neonatal serum triglyceride (TG) level reference ranges during lipid infusion and correlate peak TG with neonatal outcomes. STUDY DESIGN: This is a retrospective review of 356 neonates with 696 TG measures obtained in four neonatal intensive care units between 2015 and 2017. TG was evaluated collectively to establish a reference range and a threshold limit. To analyze the effects of a higher TG threshold, neonates were categorized by their peak TG: <180 (TG<180), 180 to 400 (TG180-400), and > 400 mg/dL (TG>400). Univariable and multivariable regression models were constructed to compare peak TG to patient characteristic and clinical outcomes. RESULTS: The frequency of TG > 400 mg/dL was 5% and found only in neonates weighing < 1.5 kg. Neonates in the TG180-400 (n = 91) group were significantly lower in birth weight and gestational age, had lower 5-minute APGAR scores, and had increased ventilatory requirement when compared with neonates in the TG<180 (n = 240) group (all p < 0.001). The TG180-400 group had increased risk of severe intraventricular hemorrhage (p = 0.02) and bronchopulmonary dysplasia (p = 0.03). Elevated TG was associated with mortality (odds ratio [OR]: 14.4, p < 0.001) in univariable analysis, but the relationship weakened (OR: 4.4, p = 0.05) after adjusting for comorbidities in multivariable logistic regression. CONCLUSION: It is unclear if the adverse outcomes seen in neonates with higher peak TG were due to elevated TG alone, or whether illness severity predicted the increased TG. More prospective studies are needed to further delineate the relationships.

Evaluation of Plasma Asymmetric Dimethylarginine Levels and Abdominal Aortic Intima-Media Thickness in Infants of Smoker Mothers.

OBJECTIVE: Smoking during pregnancy has harmful effects on the fetus and infant. Although some studies suggest that exposure to fetal-maternal smoking adversely affects both fetal growth and cardiovascular development, the mechanisms and biochemical consequences of smoking in pregnancy and newborns are not yet fully understood. We aimed to investigate whether maternal smoking during pregnancy causes fetal cardiovascular effect by measuring serum asymmetric dimethylarginine (ADMA) level and abdominal aortic intima-media thickness (aIMT). STUDY DESIGN: This prospective study was conducted in newborns of smoking mothers and never-smoker control mothers during their pregnancies. The babies were evaluated echocardiographically on the first day following birth. In two-dimensional mode, abdominal aIMT measurements were performed. ADMA was measured in umbilical cord blood at birth. RESULTS: There were 25 mothers in the study group and 25 mothers in the control group. Serum ADMA levels were 0.459 ± 0.119 µmol/L in the study group and 0.374 ± 0.1127 µmol/L in the control group (p = 0.034). The aIMT value in the study group was 0.84 ± 0.026 mm and the aIMT value in the control group was 0.63 ± 0.011 mm (p = 0.005). CONCLUSION: We found that both the serum ADMA and the aIMT significantly increased in the group with newborns of smoker mothers compared with the group of the newborns of never-smoker mothers. It may also be suggested that exposure to fetal-maternal smoking adversely affects cardiovascular development. KEY POINTS: · It is a known fact that smoking during pregnancy has harmful effects on the development of the fetus and infant.. · We found that both the serum ADMA and aIMT were significantly higher in the group of infants of smoker mothers..

Therapeutic Drug Monitoring Is a Feasible Tool to Personalize Drug Administration in Neonates Using New Techniques: An Overview on the Pharmacokinetics and Pharmacodynamics in Neonatal Age.

Therapeutic drug monitoring (TDM) should be adopted in all neonatal intensive care units (NICUs), where the most preterm and fragile babies are hospitalized and treated with many drugs, considering that organs and metabolic pathways undergo deep and progressive maturation processes after birth. Different developmental changes are involved in interindividual variability in response to drugs. A crucial point of TDM is the choice of the bioanalytical method and of the sample to use. TDM in neonates is primarily used for antibiotics, antifungals, and antiepileptic drugs in clinical practice. TDM appears to be particularly promising in specific populations: neonates who undergo therapeutic hypothermia or extracorporeal life support, preterm infants, infants who need a tailored dose of anticancer drugs. This review provides an overview of the latest advances in this field, showing options for a personalized therapy in newborns and infants.

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.

Association between Maternal Serum Hormones along the Maternal-Fetal Hypothalamic-Pituitary-Adrenal Axis and Successful Vaginal Delivery Measured Prior to Labor Induction.

OBJECTIVE: This study aimed to evaluate if maternal serum hormones along the maternal-fetal hypothalamic-pituitary-adrenal (HPA) axis, when drawn prior to labor induction, differed between women who delivered vaginally and those who underwent cesarean. STUDY DESIGN: This was a prospective observational study at a single perinatal center performed from August 2017 to May 2018. Nulliparous women with uncomplicated singleton pregnancies ≥39 weeks had maternal serum collected prior to induction. Corticotrophin-releasing hormone (CRH) was measured by ELISA; dehydroepiandrosterone sulfate (DHEA-S), cortisol, estriol (E3) estradiol (E2), and progesterone (P4) were measured by chemiluminescent reaction. Mean analyte concentrations as well as three ratios (E2/P4, E3/P4, and E2/E3) were compared between women who had a vaginal versus cesarean delivery. Logistic regression was used to model the relationship between CRH and the odds of vaginal birth. We estimated that a sample size of 66 would have 90% power to detect a 25% difference in mean CRH levels assuming a vaginal:cesarean ratio of 2:1 with a baseline CRH concentration of 140 (standard deviation = 36) pg/mL. RESULTS: Of the 88 women who had their serum analyzed, 27 (31%) underwent cesarean. Mean maternal serum CRH levels were similar between the vaginal delivery and cesarean groups (122.6 ± 95.2 vs. 112.3 ± 142.4, p = 0.73). Similarly, there were no significant differences in any other maternal serum analytes or ratios. Logistic regression showed a nonsignificant odds ratio for successful vaginal birth (p = 0.69) even when evaluating only the 16 women who had a cesarean for an arrest disorder (p = 0.08). CONCLUSION: In low-risk nulliparous women undergoing full-term labor induction, there were no differences noted in a broad array of other maternal-fetal HPA-axis hormones between women who had a vaginal or cesarean delivery.

Effect of Delayed Cord Clamping on Umbilical Blood Gas Values in Term Newborns: A Systematic Review.

OBJECTIVE: To compare the effect of delayed cord clamping on cord blood gas values in vaginally delivered, healthy, term singletons. DATA SOURCE: We used MEDLINE, CINAHL, CENTRAL, EMBASE, and ClinicalTrials.gov databases. METHODS OF STUDY SELECTION: Eligible studies included randomized controlled trials (RCTs) comparing cord blood gas values obtained from early compared with delayed cord clamping groups and observational studies using serial cord blood gas from the same umbilical cord. We described the difference in means of cord blood gas parameters and comparative descriptive statistics when a difference in means was not available. We used a domain-based risk bias tool to extract methodologic details and assess potential risk of bias. TABULATION, INTEGRATION, AND RESULTS: This review included two RCTs and three observational studies. These studies included a total of 234 newborns with early cord clamping and 218 newborns with delayed cord clamping. The observational studies showed that 45-90 seconds delayed cord clamping was associated with mean decreases in umbilical arterial pH (0.02-0.03), HCO3 (0.3-0.8 mmol/L) and increases in base deficit (0.3-1.3 mmol/L) compared with early cord clamping. One observational study showed that delayed cord clamping was associated with decreases in umbilical venous pH (0.01) and HCO3 (0.2 mmol/L) and increase in venous base deficit (0.1-0.3 mmol/L) compared with early cord clamping. These changes were not observed in the two RCTs. CONCLUSION: Delayed cord clamping up to 120 seconds has either no effect or only a small effect on cord blood acid-base balance; overall, the magnitude of these changes is not clinically significant in vaginally delivered, healthy, term singletons. SYSTEMATIC REVIEW REGISTRATION: PROSPERO, CRD42019135779.

Epigenome wide comparison of DNA methylation profile between paired umbilical cord blood and neonatal blood on Guthrie cards.

DNA methylation (DNAm) in blood (umbilical cord blood and capillary blood collected after birth on Guthrie cards) during the perinatal period is being increasingly studied with the aim of identifying epigenetic markers of in utero environmental exposures or later disease development. However, the comparability in DNAm between these two sources is unknown. To this end, DNAm from the cord blood and capillary blood of 34 subjects in the Isle of Wight 3rd Generation Birth Cohort (68 samples) were included to assess the comparability. Differences in average DNAm (overall agreement), correlations in DNAm, and intra-class correlation coefficients (ICC) in DNAm between the two sources, at each of the 430,742 CpG sites, were evaluated. The results showed that a high proportion (70.1%) of the CpGs DNAm agreed between cord blood and neonatal blood on Guthrie cards. A small portion of CpGs showed high correlation (correlation ≥0.5) or high ICC (ICC ≥0.5) in DNAm of the whole genome. This proportion increased dramatically in differentially methylated regions (DMRs) that are associated with exposure to maternal smoking, between the two sources.

Exposure to Persistent Organic Pollutants and Birth Characteristics: The Upstate KIDS Study.

BACKGROUND: Prenatal exposure to persistent organic pollutants (POPs) may be associated with obesogenic effects in offspring. Our study is the first to investigate associations between concentrations of POPs from newborn dried blood spots (DBS) and birth characteristics. METHODS: Concentrations of 10 polychlorinated biphenyl congeners (PCBs), polybrominated diphenyl ether-47 (PBDE-47), and p,p'-dichlorodiphenyldichloroethylene (p,p'-DDE) were measured from DBSs collected at birth from 2,065 singleton infants. DBS samples were pooled in groups of five and assayed together to reach limits of detection. Differences in risk of large for gestational age (LGA, defined as >90th percentile of birth weight for sex and gestational age), small for gestational age (SGA, <10th), and preterm birth (gestational age <37 weeks) were estimated using logistic regression per unit (ng/ml) increase in concentration of each chemical, adjusting for individual-level covariates, including maternal age, race/ethnicity, prepregnancy BMI, education, parity, smoking, and infant sex while assuming a gamma distribution and using multiple imputation to account for pools. RESULTS: There were 215 (11.3%) singletons born LGA, 158 (7.5%) born SGA, and 157 (7.6%) born preterm. Higher concentrations of POPs were positively associated with slightly higher risk of LGA and higher birth weight. CONCLUSIONS: Relationships between POPs measured in newborn DBS and birth size were mixed. Pooled analysis methods using DBS could address challenges in limits of detection and costs for population-based research.

Constitutive TNF-α signaling in neonates is essential for the development of tissue-resident leukocyte profiles at barrier sites.

Newborn infants have a high disposition to develop systemic inflammatory response syndromes (SIRSs) upon inflammatory or infectious challenges. Moreover, there is a considerable trafficking of hematopoietic cells to tissues already under noninflammatory conditions. These age-specific characteristics suggest a hitherto unappreciated crucial role of the vascular endothelium during the neonatal period. Here, we demonstrate that healthy neonates showed already strong endothelial baseline activation, which was mediated by a constitutively increased production of TNF-α. In mice, pharmacological inhibition of TNF-α directly after birth prevented subsequent fatal SIRS but completely abrogated the recruitment of leukocytes to sites of infection. Importantly, in healthy neonates, blocking TNF-α at birth disrupted the physiologic leukocyte trafficking, which resulted in persistently altered leukocyte profiles at barrier sites. Collectively, these data suggest that constitutive TNF-α-mediated sterile endothelial activation in newborn infants contributes to the increased risk of developing SIRS but is needed to ensure the postnatal recruitment of leukocytes to organs and interfaces.-Bickes, M. S., Pirr, S., Heinemann, A. S., Fehlhaber, B., Halle, S., Völlger, L., Willers, M., Richter, M., Böhne, C., Albrecht, M., Langer, M., Pfeifer, S., Jonigk, D., Vieten, G., Ure, B., von Kaisenberg, C., Förster, R., von Köckritz-Blickwede, M., Hansen, G., Viemann, D. Constitutive TNF-α signaling in neonates is essential for the development of tissue-resident leukocyte profiles at barrier sites.

Osteoprotegerin and RANKL serum concentrations in neonates of mothers with early-onset pre-eclampsia: comparison with neonates of normotensive mothers.

BACKGROUND: Pre-eclampsia is a known risk factor for long-term cardiovascular complications. Osteoprotegerin (OPG) and the receptor activator of nuclear factor κB ligand (RANKL) have been implicated in the pathogenesis of cardiovascular disease. The OPG-RANKL axis function is also altered in pregnant women with pre-eclampsia, but there is lack of data regarding OPG and RANKL concentrations in their neonates. AIMS: To examine the effects of early-onset pre-eclampsia on OPG and RANKL serum concentrations at birth, taking into account the influence of various perinatal factors. STUDY DESIGN: OPG and RANKL serum concentrations were measured in 28 premature newborns of mothers with early onset pre-eclampsia, and in 28 preterm and 28 full-term neonates of normotensive mothers (control groups). RESULTS: Neonates of pre-eclamptic mothers had higher OPG and lower RANKL levels compared to both control groups (Kruskal-Wallis P < 0.0001 and P = 0.014, respectively). Regression analysis showed that pre-eclampsia (P < 0.0001), birth weight z-score (P = 0.048) and antenatal steroid administration (P = 0.034) were significant determinants of OPG levels. Multivariable regression analysis also showed that pre-eclampsia was an independent predictor of increased diastolic and mean blood pressure in these neonates. CONCLUSIONS: Early-onset pre-eclampsia affects OPG concentrations at birth and is an independent predictor of increased blood pressure in the offspring. Our findings suggest that altered OPG-RANKL axis function may be one of the mechanisms of cardiovascular 'programming' in fetuses exposed to pre-eclampsia.

Improving preoperative identification of infants at risk for severe retinopathy of prematurity.

OBJECTIVE: To increase preoperative identification of at-risk infants for severe Retinopathy of prematurity (ROP) to >95% by August 2016, with a secondary aim of reducing the number of infants with 100% intraoperative peripheral oxygen saturation (SpO2) during the same time. STUDY DESIGN: Prospective quality improvement project centered on preterm surgical infants admitted to Primary Children's Hospital (n = 41). Preoperative ROP risk identification rates were analyzed using an annotated run chart, intraoperative SpO2 and laser intervention were compared using un-paired t test. RESULTS: Preoperative identification of ROP risk increased from 60 to 100% and no infant was exposed to 100% SpO2 intraoperatively during the study period. The incidence of laser intervention in this population decreased by 45% from 22 to 12% (p = 0.21). CONCLUSION: Simplifying our preoperative handoff increased our rates of correct identification and communication ROP risk in preterm infants while decreasing exposure to 100% SpO2.

Procalcitonin versus C-reactive protein: review of kinetics and performance for diagnosis of neonatal sepsis.

Procalcitonin (PCT) and C-reactive protein (CRP) are commonly used biomarkers, but their diagnostic advantage for neonatal early-onset (EOS) or late-onset (LOS) sepsis is controversial. In a comprehensive literature review we found significant heterogeneity between studies in sample timing, cut-off values, consideration of blood culture results for sepsis classification, and definition of EOS versus LOS. We identified 39 studies directly comparing PCT with CRP, but only four in very low birth weight (VLBW) neonates. The mean sensitivity for EOS, LOS, and EOS + LOS was 73.6%, 88.9%, and 76.5% for PCT, compared to 65.6%, 77.4%, and 66.4% for CRP, respectively. Mean specificity of PCT and CRP was 82.8% versus 82.7% for EOS, 75.6% versus 81.7% for LOS, and 80.4% versus 91.3% for EOS + LOS. More studies directly comparing both biomarkers for EOS and LOS, especially in extremely and very-low-birth-weight infants, are needed to determine their clinical value for guidance of antibiotic therapy in neonatal sepsis.

Maternal risk factors and newborn infant vitamin D status: a scoping literature review.

Low vitamin D (VitD) status is common among newborn infants, more so in temperate latitudes with evidence that maternal VitD deficiency is a major risk factor given that the neonate relies solely on maternal-fetal transfer of VitD. This scoping review was conducted to provide an overview of the latest evidence from studies regarding the impact of maternal risk factors on infant 25-hydryoxyvitamin D [25(OH)D] concentrations with a focus on studies in Canada and the United States. Several maternal risk factors that contribute to low maternal-fetal 25(OH)D concentrations have been reported over many decades, but no clear pattern has been established for multiethnic populations. For example, darker skin pigmentation and ethnicity are common risk factors for low VitD status. Studies in predominantly white women showed that supplementation of VitD during pregnancy causes significant increases in maternal serum 25(OH)D which often improves cord serum 25(OH)D values. In addition, VitD recommendations by health care professionals and adherence to supplementation by pregnant women appear to positively influence maternal and infant 25(OH)D concentrations. Conversely, winter season, obesity, lower socioeconomic status including lifestyle factors (smoking), and use of medication pose risk for lower maternal-fetal transfer of VitD. However, there is still a dearth of pertinent data on the relationship between some of the maternal risk factors and newborn 25(OH)D concentrations, for instance, relationships between gestational diabetes and neonatal VitD status. Additional research is required to determine if the same target for 25(OH)D concentrations applies for pregnant women, neonates, and infants.

Associations between Maternal AFP and ß-HCG and Preterm Birth.

OBJECTIVE: Preterm birth (PTB) is a significant public health problem. We aimed to explore whether alpha fetal protein (AFP) or ß-human gonadotropin (ß-HCG) levels during pregnancy were associated with PTB in Chinese population. STUDY DESIGN: The clinical data collected Nanjing Medical University Affiliated Suzhou Hospital and Wuxi Maternity and Child Health Care Hospital between January 2006 and December 2011 were analyzed retrospectively. A total of 64,999 pregnant women were registered. In addition, 13,828 pregnant women were collected serum from the second trimester. The maternal serum AFP and ß-HCG were measured by enzyme immunoassay. RESULTS: In our study, the rate of PTB is 6.23%. With each unit increase of maternal AFP concentration, the adjusted odds of PTB was increased by 69.3% (odds ratio = 1.693, 95% confidence interval: 1.434-1.999, p = 0.00). We set AFP concentrations as high, medium, and low levels. When comparing with low concentration of AFP, high concentration of AFP (≥1.179 M) was positively associated with PTB with adjustment for potential confounders (p < 0.05). Nevertheless, no statistically significant associations were observed between maternal ß-HCG and PTB. CONCLUSION: In this study, maternal AFP concentration was associated with increased risk of PTB.

Inhaled Epoprostenol for Pulmonary Hypertension Treatment in Neonates: A 12-Year Experience.

BACKGROUND: Persistent pulmonary hypertension of the newborn (PPHN) occurs in 10% of neonatal respiratory insufficiency. To selectively reduce pulmonary vascular resistance, several treatments have been tried. Inhaled epoprostenol (iPGI2) has been used for 12 years in our institution for the management of refractory PPHN despite the gaps in the literature to support this use. OBJECTIVES: The primary objective was to evaluate the efficacy of iPGI2 for PPHN. The secondary objectives were to describe its use in neonates and assess side effects. STUDY DESIGN: This retrospective cohort study included infants < 28 days with PPHN treated with iPGI2 in the neonatal or pediatric intensive care units of our institution between 2004 and 2016. RESULTS: We reviewed 43 patient' care episodes (mean gestational age of 36 weeks). This was an extremely ill population with 54% mortality rate. Oxygenation index improved significantly after 12-hour treatment (p = 0.047), with a rebound effect when discontinuing nebulization. By the end of the therapy, the fraction of inspired oxygen had significantly dropped (p = 0.0018). Echocardiographic markers tended to normalize during treatment. No potential side effects were reported. CONCLUSION: In these sick newborns, we observed an improvement in PPHN under iPGI2 without significant adverse effects. To our knowledge, this is the largest neonatal cohort reported to have received iPGI2 for PPHN.

The Role of Umbilical Cord Blood Concentration of IGF-I, IGF-II, Leptin, Adiponectin, Ghrelin, Resistin, and Visfatin in Fetal Growth.

OBJECTIVE: Herein, we measured the concentration of insulinlike growth factor I (IGF-I), IGF-II, leptin, adiponectin, ghrelin, resistin, and visfatin in the umbilical cord blood of newborns categorized as "small for gestational age" (SGA), "appropriate for gestational age" (AGA), and "large for gestational age" (LGA). Our aim was to elucidate the link between the levels of these proteins and fetal growth. STUDY DESIGN: A total of 96 term infants were included and categorized into three weight categories. Their venous cord blood samples were collected to measure the levels of IGF-I, IGF-II, leptin, adiponectin, ghrelin, resistin, and visfatin. RESULTS: IGF-I, visfatin, and leptin levels showed significant differences among the groups. Pairwise comparisons showed that adiponectin (p = 0.023), resistin (p = 0.025), and ghrelin (p = 0.005) levels were significantly lower in the SGA group than in the LGA group. Correlation analyses showed a strong association of IGF-1, IGF-II, and leptin levels with birth weight (r = 0.644, p < 0.001; r = 0.441, p < 0.001; and r = 0.404, p < 0.001, respectively). CONCLUSION: SGA newborns showed a significantly higher visfatin concentration and lower ghrelin, leptin, resistin, and adiponectin levels than the AGA and LGA newborns did.

RNA-sequencing analysis of umbilical cord plasma microRNAs from healthy newborns.

MicroRNAs are a class of small non-coding RNA that regulate gene expression at a post-transcriptional level. MicroRNAs have been identified in various body fluids under normal conditions and their stability as well as their dysregulation in disease has led to ongoing interest in their diagnostic and prognostic potential. Circulating microRNAs may be valuable predictors of early-life complications such as birth asphyxia or neonatal seizures but there are relatively few data on microRNA content in plasma from healthy babies. Here we performed small RNA-sequencing analysis of plasma processed from umbilical cord blood in a set of healthy newborns. MicroRNA levels in umbilical cord plasma of four male and four female healthy babies, from two different centres were profiled. A total of 1,004 individual microRNAs were identified, which ranged from 426 to 659 per sample, of which 269 microRNAs were common to all eight samples. Many of these microRNAs are highly expressed and consistent with previous studies using other high throughput platforms. While overall microRNA expression did not differ between male and female cord blood plasma, we did detect differentially edited microRNAs in female plasma compared to male. Of note, and consistent with other studies of this type, adenylation and uridylation were the two most prominent forms of editing. Six microRNAs, miR-128-3p, miR-29a-3p, miR-9-5p, miR-218-5p, 204-5p and miR-132-3p were consistently both uridylated and adenylated in female cord blood plasma. These results provide a benchmark for microRNA profiling and biomarker discovery using umbilical cord plasma and can be used as comparative data for future biomarker profiles from complicated births or those with early-life developmental disorders.

Foetal, neonatal and child vitamin D status and enamel hypomineralization.

OBJECTIVES: Recent literature suggested that higher vitamin D concentrations in childhood are associated with a lower prevalence of molar incisor hypomineralization (MIH). As tooth development already starts in utero, we aimed to study whether vitamin D status during foetal, postnatal and childhood periods is associated with the presence of hypomineralized second primary molars (HSPMs) and/or MIH at the age of six. METHODS: Our study was embedded in the Generation R Study, a population-based, prospective cohort from foetal life onwards in Rotterdam, the Netherlands. HSPMs and MIH were scored from intraoral photographs of the children at their age of six. Serum 25(OH)D concentrations were measured at three points in time, which resulted in three different samples; mid-gestational in mothers' blood (n = 4750), in umbilical cord blood (n = 3406) and in children's blood at the age of 6 years (n = 3983). RESULTS: The children had a mean (±SD) age of 6.2 (±0.5) years at the moment of taking the intraoral photographs. After adjustment for confounders, no association was found between foetal 25(OH)D concentrations and the presence of HSPMs (OR 1.02 per 10 nmol/L higher 25(OH)D, 95% CI: 0.98-1.07) or MIH (OR 1.05 per 10 nmol/L increase, 95% CI: 0.98-1.12) in 6-year-olds. A higher 25(OH)D concentration in umbilical cord blood resulted in neither lower odds of having HSPM (OR 1.05, 95% CI: 0.98-1.13) nor lower odds of having MIH (OR 0.95, 95% CI: 0.84-1.07) by the age of six. Finally, we did not find higher 25(OH)D concentrations at the age of six to be associated with a significant change in the odds of having HSPM (OR 0.97, 95% CI: 0.92-1.02) or MIH (OR 1.07, 95% CI: 0.98-1.16). CONCLUSIONS: 25(OH)D concentrations in prenatal, early postnatal and later postnatal life are not associated with the presence of HPSMs or with MIH at the age of six. Future observational research is required to replicate our findings. Furthermore, it is encouraged to focus on identifying other modifiable risk factors, because prevention of hypomineralization is possible only if the causes are known.