Diabetes Leads to Alterations in Normal Metabolic Transitions of Pregnancy as Revealed by Time-Course Metabolomics.

Women with diabetes during pregnancy are at increased risk of poor maternal and neonatal outcomes. Despite this, the effects of pre-gestational (PGDM) or gestational diabetes (GDM) on metabolism during pregnancy are not well understood. In this study, we utilized metabolomics to identify serum metabolic changes in women with and without diabetes during pregnancy and the cord blood at birth. We observed elevations in tricarboxylic acid (TCA) cycle intermediates, carbohydrates, ketones, and lipids, and a decrease in amino acids across gestation in all individuals. In early gestation, PGDM had elevations in branched-chain amino acids and sugars compared to controls, whereas GDM had increased lipids and decreased amino acids during pregnancy. In both GDM and PGDM, carbohydrate and amino acid pathways were altered, but in PGDM, hemoglobin A1c and isoleucine were significantly increased compared to GDM. Cord blood from GDM and PGDM newborns had similar increases in carbohydrates and choline metabolism compared to controls, and these alterations were not maternal in origin. Our results revealed that PGDM and GDM have distinct metabolic changes during pregnancy. A better understanding of diabetic metabolism during pregnancy can assist in improved management and development of therapeutics and help mitigate poor outcomes in both the mother and newborn.

Global Metabolomics of the Placenta Reveals Distinct Metabolic Profiles between Maternal and Fetal Placental Tissues Following Delivery in Non-Labored Women.

We evaluated the metabolic alterations in maternal and fetal placental tissues from non-labored women undergoing cesarean section using samples collected from 5 min to 24 h following delivery. Using ¹H-NMR, we identified 14 metabolites that significantly differed between maternal and fetal placental tissues (FDR-corrected p-value < 0.05), with 12 metabolites elevated in the maternal tissue, reflecting the flux of these metabolites from mother to fetus. In the maternal tissue, 4 metabolites were significantly altered at 15 min, 10 metabolites at 30 min, and 16 metabolites at 1 h postdelivery, while 11 metabolites remained stable over 24 h. In contrast, in the fetal placenta tissue, 1 metabolite was significantly altered at 15 min, 2 metabolites at 30 min, and 4 metabolites at 1 h postdelivery, while 22 metabolites remained stable over 24 h. Our study provides information on the metabolic profiles of maternal and fetal placental tissues delivered by cesarean section and reveals that there are different metabolic alterations in the maternal and fetal tissues of the placenta following delivery.

Epigenetic markers for newborn congenital heart defect (CHD).

OBJECTIVE: Our objective was to determine whether there were significant differences in genome-wide DNA methylation in newborns with major congenital heart defect (CHD) compared to controls. We also evaluated methylation of cytosines in CpG motifs for the detection of these CHDs. METHODS: Genome-wide DNA methylation analysis was performed on DNA from 60 newborns with various CHDs, including hypoplastic left heart syndrome, ventricular septal deficit, atrial septal defect, pulmonary stenosis, coarctation of the aorta and Tetralogy of Fallot, and 32 controls. RESULTS: Highly significant differences in cytosine methylation were seen in a large number of genes throughout the genome for all CHD categories. Gene ontology analysis of CHD overall indicated over-represented biological processes involving cell development and differentiation, and anatomical structure morphogenesis. Methylation of individual cytosines in CpG motifs had high diagnostic accuracy for the detection of CHD. For example, for coarctation one predictive model based on levels of particular cytosine nucleotides achieved a sensitivity of 100% and specificity of 93.8% (AUC = 0.974, p < 0.00001). CONCLUSION: Profound differences in cytosine methylation were observed in hundreds of genes in newborns with different types of CHD. There appears to be the potential for development of accurate genetic biomarkers for CHD detection in newborns.

Optimal timing for term delivery of twin pregnancies: a population-based study.

OBJECTIVE: The objective of this study was to examine the risk of adverse neonatal outcomes after twin delivery according to gestational age. MATERIALS AND METHODS: The U.S. Natality Database from 2007 to 2010 was reviewed. Inclusion criteria were twin deliveries and gestational age of 37 to 42 weeks. Exclusion criteria were congenital anomalies and missing/incomplete data. Cases were subdivided by gestational age into early term, term, and late term. Singleton pregnancies matched by delivery time and location were selected as controls. Outcome variables included were low Apgar score, assisted ventilation, neonatal intensive care unit admission, surfactant/antibiotic use, seizures, and birth injury. Logistic regression analysis was used to calculate adjusted odds ratios according to gestational age and plurality, using singleton term as reference. RESULTS: A total of 220,169 twin and 270,540 singleton deliveries were identified. The risk of adverse neonatal outcomes for twins was higher than for singletons. For twins, the distribution of the risks of the composite of adverse neonatal outcomes was linear, being the lowest at early term and the highest at late term, whereas the distribution for singletons was u-shaped being lowest at term compared with early and late term. CONCLUSIONS: Twins are at higher risk of suboptimal neonatal outcomes than singletons, but do better when delivered at early term rather than term or late term.

Decreased risk of prematurity after elective repeat cesarean delivery in Hispanics.

BACKGROUND: The current recommendation is to delay elective repeat cesarean deliveries (ERCD) until 39 weeks to decrease prematurity risks. Prior reports suggest accelerated maturity of fetuses according to race (African-Americans and Asians). OBJECTIVE: To analyze the effect of the Hispanic ethnicity on the prematurity risk after ERCD. METHODS: The US Natality Database from 2004 to 2008 was reviewed. Inclusion criteria were singleton delivery, no trial of labor, repeat cesarean. Exclusion criteria were fetal anomalies, history of diabetes/hypertension related disorders. Outcomes analyzed were Apgar score, assisted ventilation, intensive care admission, surfactant/antibiotic use and seizures. Two groups were identified: non-Hispanic Whites (NHW) and Hispanic Whites (HW). Regression analysis was performed to calculate adjusted odds ratios. Deliveries at 36-40 weeks were studied with 40 weeks as the reference group. RESULTS: A total of 930421 ERCDs were identified, 396823 NHW and 236733 HW. For NHW, the risk of prematurity was lower at 39 weeks. For HW, there was no difference in the risks of prematurity at/beyond 38 weeks. CONCLUSION: There appears to be accelerated maturity with no increase in prematurity risk at 38 weeks in HW delivered by ERCD. Ethnicity can be considered for patient counseling and decision making regarding optimal timing of elective interventions.

Maternal race and neonatal outcomes after elective repeat cesarean delivery.

OBJECTIVE: To determine the effect of race in the risks of prematurity-related complications (PRC) after elective repeat cesarean delivery (ERCD). METHODS: The NCHS-CDC Database for the U.S. (2004-2008) was used. ERCD cases were included. Exclusion criteria were multiple gestation, trial of labor, fetal anomalies, history of diabetes and/or hypertension. PRC analyzed were: Apgar score, assisted ventilation, intensive care admission, surfactant use, antibiotic use, seizures. Regression analysis was performed to calculate the odds ratio (OR) of these variables. Deliveries at 36-40 weeks were studied with 40 weeks as reference. RESULTS: Totally, 785,340 ERCDs were performed between 36 and 40 weeks. For the overall population, there was not difference in adverse outcomes between 39 and 40 weeks. The rates of PRC were significantly higher in newborns at 38 compared to 39 weeks, with similar findings in sub-analysis of whites. For African-Americans, the rate of PRC was not significantly different at 38 compared to 39 weeks. CONCLUSIONS: We report increased rates of PRC after ERCD before 39 weeks, similar findings from smaller hospital-based studies. For African-American newborns, there was no further decrease in PRC after 38 weeks suggesting earlier maturation of these fetuses. The study does not propose changing the current 39 weeks threshold for ERCD.

Metabolomic analysis for first-trimester trisomy 18 detection.

OBJECTIVE: The purpose of this study was to determine whether nuclear magnetic resonance-based metabolomic markers in first-trimester maternal serum can detect fetuses with trisomy 18. STUDY DESIGN: This was a study of pregnancies between 11 weeks and 13 weeks 6 days' gestation. We analyzed 30 cases of trisomy 18 and a total of 114 euploid cases. Nuclear magnetic resonance-based metabolomic analysis was performed. A further analysis was performed that compared 30 cases with trisomy 18 and 30 trisomy 21 (T21) cases. RESULTS: Metabolomic markers were sensitive for trisomy 18 detection. A combination of 2-hydroxybutyrate, glycerol and maternal age had a 73.3% sensitivity and 96.6% specificity for trisomy 18 detection, with an area under the receiver operating curve: 0.92 (P < .001). Other metabolite markers, which include trimethylamine, were sensitive for distinguishing trisomy 18 from T21 cases. CONCLUSION: This is the first report of prenatal trisomy 18 detection that has been based on metabolomic analysis. Preliminary results suggest that such markers are sensitive not only for the detection of fetal trisomy 18 but also for distinguishing this aneuploidy from T21.

A rare case of a mosaic unbalanced translocation after chorionic villous sampling.

BACKGROUND: Most of the literature suggests that unbalanced chromosomal translocations may lead to poor obstetrical outcomes. We present a case of an unbalanced translocation resulting in trisomy 1q and partial monosomy 20p identified on chorionic villous sampling (CVS). METHOD: Case report with expert-derived clinical management and guidance. RESULTS: After the abnormal CVS result, a subsequent amniocentesis revealed a normal 46,XX fetal karyotype. Detailed second trimester ultrasound of the fetus revealed no gross structural abnormalities. The CVS karyotype results were attributed to confined placental mosaicism (CPM) of the unbalanced translocation. The infant is 18 months old and has normal phenotype and karyotype. CONCLUSION: We recommend that if CPM with an unbalanced translocation is diagnosed on CVS, parental karyotype and an amniocentesis should be offered in conjunction with genetic counseling. In rare instances, such as this one, an unbalanced translocation may have a favorable outcome.