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Dichotomy in the Impact of Elevated Maternal Glucose Levels on Neonatal Epigenome.
Lim, IY, Lin, X, Teh, AL, Wu, Y, Chen, L, He, M, Chan, SY, MacIsaac, JL, Chan, JKY, Tan, KH, et al
The Journal of clinical endocrinology and metabolism. 2022;(3):e1277-e1292
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CONTEXT Antenatal hyperglycemia is associated with increased risk of future adverse health outcomes in both mother and child. Variations in offspring's epigenome can reflect the impact and response to in utero glycemic exposure, and may have different consequences for the child. OBJECTIVE We examined possible differences in associations of basal glucose status and glucose handling during pregnancy with both clinical covariates and offspring cord tissue DNA methylation. RESEARCH DESIGN AND METHODS This study included 830 mother-offspring dyads from the Growing Up in Singapore Towards Healthy Outcomes cohort. The fetal epigenome of umbilical cord tissue was profiled using Illumina HumanMethylation450 arrays. Associations of maternal mid-pregnancy fasting (fasting plasma glucose [FPG]) and 2-hour plasma glucose (2hPG) after a 75-g oral glucose challenge with both maternal clinical phenotypes and offspring epigenome at delivery were investigated separately. RESULTS Maternal age, prepregnancy body mass index, and blood pressure measures were associated with both FPG and 2hPG, whereas Chinese ethnicity (P = 1.9 × 10-4), maternal height (P = 1.1 × 10-4), pregnancy weight gain (P = 2.2 × 10-3), prepregnancy alcohol consumption (P = 4.6 × 10-4), and tobacco exposure (P = 1.9 × 10-3) showed significantly opposite associations between the 2 glucose measures. Most importantly, we observed a dichotomy in the effects of these glycemic indices on the offspring epigenome. Offspring born to mothers with elevated 2hPG showed global hypomethylation. CpGs most associated with the 2 measures also reflected differences in gene ontologies and had different associations with offspring birthweight. CONCLUSIONS Our findings suggest that 2 traditionally used glycemic indices for diagnosing gestational diabetes may reflect distinctive pathophysiologies in pregnancy, and have differential impacts on the offspring's DNA methylome.
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Sertraline concentrations in pregnant women are steady and the drug transfer to their infants is low.
Heinonen, E, Blennow, M, Blomdahl-Wetterholm, M, Hovstadius, M, Nasiell, J, Pohanka, A, Gustafsson, LL, Wide, K
European journal of clinical pharmacology. 2021;(9):1323-1331
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PURPOSE Sertraline, a selective serotonin reuptake inhibitor (SSRI), is one of the most commonly used antidepressant during pregnancy. Plasma sertraline concentrations vary markedly between individuals, partly explained by variability in hepatic drug metabolizing cytochrome P450-enzyme activity. Our purpose was to study the variability in the plasma concentrations in pregnant women and the passage to their infants. METHOD Pregnant women with moderate untreated depression were recruited in 2016-2019 in Stockholm Region and randomized to treatment with sertraline or placebo. All received Internet-based cognitive behavior therapy as non-medical treatment. Sertraline plasma concentrations were measured around pregnancy weeks 21 and 30, at delivery, 1-month postpartum, in cord blood and at 48 h of age in the infant. The clinical course of the infants was followed. RESULTS Nine mothers and 7 infants were included in the analysis. Median dose-adjusted sertraline concentration in second trimester was 0.15(ng/mL) /(mg/day), in third trimester and at delivery 0.19 and 1-month postpartum 0.25, with a 67% relative difference between second trimester and postpartum. The interindividual variation was 10-fold. Median concentrations in the infants were 33% and 25% of their mothers', measured in cord blood, and infant plasma, respectively. Only mild and transient adverse effects were seen on the infants. CONCLUSION Placental passage of sertraline to the infant is low. However, the interindividual variation in maternal concentrations during pregnancy is huge, why therapeutic drug monitoring might assist in finding the poor metabolizers at risk for adversity and increase the safety of the treatment. TRIAL REGISTRATION The trial was registered at clinicaltrials.gov July 9, 2014 with TRN: NCT02185547.
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Neurological development of children who are HIV-exposed and uninfected.
Toledo, G, Côté, HCF, Adler, C, Thorne, C, Goetghebuer, T
Developmental medicine and child neurology. 2021;(10):1161-1170
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Widespread use of antiretroviral drugs for pregnant/breastfeeding females with human immunodeficiency virus (HIV) has led to declining vertical transmission. Despite being HIV-uninfected, the increasing number of children who are HIV-exposed and uninfected (CHEU) often present with developmental alterations. We review seminal and recent evidence on the neurological development of CHEU and associations with early life HIV/antiretroviral exposure. Our conceptual model highlights the numerous exposures and universal risk factors for CHEU developmental disorders. Early studies suggest a significant association between HIV exposure and neurological abnormalities, varying according to the burden of HIV-specific exposures and other risk factors. More recent observations from the modern era are inconsistent, although some studies suggest specific antiretrovirals may adversely affect neurological development of CHEU. As the CHEU population continues to grow, alongside simultaneous increases in types and combinations of antiretrovirals used in pregnancy, long-term monitoring of CHEU is necessary for understanding the effects of HIV/antiretroviral exposure on CHEU developmental outcomes. What this paper adds Evidence on the neurological development of children who are human immunodeficiency virus (HIV)-exposed and uninfected (CHEU) is synthesized. Comparisons are made to children who are HIV-unexposed, across treatment eras and settings, and by antiretroviral drug regimens and drug classes. CHEU exposures are complex and include HIV-specific and universal risk factors which may affect development during the early years of life.
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Environmental and Genetic Risk Factors of Congenital Anomalies: an Umbrella Review of Systematic Reviews and Meta-Analyses.
Lee, KS, Choi, YJ, Cho, J, Lee, H, Lee, H, Park, SJ, Park, JS, Hong, YC
Journal of Korean medical science. 2021;(28):e183
Abstract
BACKGROUND The prevalence of congenital anomalies in newborns in South Korea was 272.9 per 100,000 in 2005, and 314.7 per 100,000 in 2006. In other studies, the prevalence of congenital anomalies in South Korea was equivalent to 286.9 per 10,000 livebirths in 2006, while it was estimated 446.3 per 10,000 births during the period from 2008 to 2014. Several systematic reviews and meta-analyses analyzing the factors contributing to congenital anomalies have been reported, but comprehensive umbrella reviews are lacking. METHODS We searched PubMed, Google Scholar, Cochrane, and EMBASE databases up to July 1, 2019, for systematic reviews and meta-analyses that investigated the effects of environmental and genetic factors on any type of congenital anomalies. We categorized 8 subgroups of congenital anomalies classified according to the 10th revision of the International Statistical Classification of Diseases (ICD-10). Two researchers independently searched the literature, retrieved the data, and evaluated the quality of each study. RESULTS We reviewed 66 systematic reviews and meta-analyses that investigated the association between non-genetic or genetic risk factors and congenital anomalies. Overall, 269 associations and 128 associations were considered for environmental and genetic risk factors, respectively. Congenital anomalies based on congenital heart diseases, cleft lip and palate, and others were associated with environmental risk factors based on maternal exposure to environmental exposures (air pollution, toxic chemicals), parental smoking, maternal history (infectious diseases during pregnancy, pregestational and gestational diabetes mellitus, and gestational diabetes mellitus), maternal obesity, maternal drug intake, pregnancy through artificial reproductive technologies, and socioeconomic factors. The association of maternal alcohol or coffee consumption with congenital anomalies was not significant, and maternal folic acid supplementation had a preventive effect on congenital heart defects. Genes or genetic loci associated with congenital anomalies included MTHFR, MTRR and MTR, GATA4, NKX2-5, SRD5A2, CFTR, and 1p22 and 20q12 anomalies. CONCLUSION This study provides a wide perspective on the distribution of environmental and genetic risk factors of congenital anomalies, thus suggesting future studies and providing health policy implications.
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Maternal and Perinatal Factors Associated With Kawasaki Disease Among Offspring in Taiwan.
Chang, CL, Lin, MC, Lin, CH, Ko, TM
JAMA network open. 2021;(3):e213233
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This case-control study investigates the association of perinatal factors and maternal autoimmune diseases with the development of Kawasaki disease using the Taiwan Maternal and Child Health Database.
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Prenatal exposure to a mixture of organophosphate esters and intelligence among 8-year-old children of the HOME Study.
Percy, Z, Vuong, AM, Xu, Y, Xie, C, Ospina, M, Calafat, AM, Lanphear, BP, Braun, JM, Cecil, KM, Dietrich, KN, et al
Neurotoxicology. 2021;:149-155
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Many environmental chemicals are being identified as suspected neurotoxicants based on the findings of both experimental and epidemiological studies. Organophosphate esters (OPEs), which are among the chemicals that have replaced neurotoxic polybrominated diphenyl ethers (PBDEs) after 2004, have also become an important public health topic as evidence regarding their potential for early-life neurotoxicity is growing. In 233 mother child pairs from Cincinnati, OH, we measured concentrations of the OPE metabolites bis(1,3-dichloro-2-propyl) phosphate (BDCIPP), bis-2-chloroethyl phosphate (BCEP), diphenyl phosphate (DPHP), and di-n-butyl phosphate (DNBP) in the urine of pregnant women at 16 and 26 weeks gestation and at delivery. At age 8 years, we assessed children's cognition using the Wechsler Intelligence Scale for Children-IV. In models adjusted for maternal race, income, body mass index, and IQ, maternal urinary BCEP was associated with a modest increase in child full-scale IQ (ß: 0.81 per a ln-unit BCEP increase; 95 % CI: 0.00, 1.61) while other OPEs were not associated with changes in full-scale IQ or any IQ subscales. Maternal serum PBDE concentrations did not confound the relationships between urinary OPE metabolites and child IQ. Using Bayesian kernel machine regression, we did not find that concentrations of a mixture of OPE metabolites during gestation was associated with any child cognition measures. The results of this study are not consistent with other published work, and a larger sample size would be beneficial to explore potential associations more fully. Therefore, additional studies are necessary to continue studying prenatal OPE exposure and child neurodevelopment and behavior.
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Prenatal Immunity and Influences on Necrotizing Enterocolitis and Associated Neonatal Disorders.
Sampah, MES, Hackam, DJ
Frontiers in immunology. 2021;:650709
Abstract
Prior to birth, the neonate has limited exposure to pathogens. The transition from the intra-uterine to the postnatal environment initiates a series of complex interactions between the newborn host and a variety of potential pathogens that persist over the first few weeks of life. This transition is particularly complex in the case of the premature and very low birth weight infant, who may be susceptible to many disorders as a result of an immature and underdeveloped immune system. Chief amongst these disorders is necrotizing enterocolitis (NEC), an acute inflammatory disorder that leads to necrosis of the intestine, and which can affect multiple systems and have the potential to result in long term effects if the infant is to survive. Here, we examine what is known about the interplay of the immune system with the maternal uterine environment, microbes, nutritional and other factors in the pathogenesis of neonatal pathologies such as NEC, while also taking into consideration the effects on the long-term health of affected children.
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Association of Maternal DNA Methylation and Offspring Birthweight.
Kheirkhah Rahimabad, P, Arshad, SH, Holloway, JW, Mukherjee, N, Hedman, A, Gruzieva, O, Andolf, E, Kere, J, Pershagen, G, Almqvist, C, et al
Reproductive sciences (Thousand Oaks, Calif.). 2021;(1):218-227
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This study aims to evaluate the association of maternal DNA methylation (DNAm) during pregnancy and offspring birthweight. One hundred twenty-two newborn-mother dyads from the Isle of Wight (IOW) cohort were studied to identify differentially methylated cytosine-phosphate-guanine sites (CpGs) in maternal blood associated with offspring birthweight. Peripheral blood samples were drawn from mothers at 22-38 weeks of pregnancy for epigenome-wide DNAm assessment using the Illumina Infinium HumanMethylation450K array. Candidate CpGs were identified using a course of 100 repetitions of a training and testing process with robust regressions. CpGs were considered informative if they showed statistical significance in at least 80% of training and testing samples. Linear mixed models adjusting for covariates were applied to further assess the selected CpGs. The Swedish Born Into Life cohort was used to replicate our findings (n = 33). Eight candidate CpGs corresponding to the genes LMF1, KIF9, KLHL18, DAB1, VAX2, CD207, SCT, SCYL2, DEPDC4, NECAP1, and SFRS3 in mothers were identified as statistically significantly associated with their children's birthweight in the IOW cohort and confirmed by linear mixed models after adjusting for covariates. Of these, in the replication cohort, three CpGs (cg01816814, cg23153661, and cg17722033 with p values = 0.06, 0.175, and 0.166, respectively) associated with four genes (LMF1, VAX2, CD207, and NECAP1) were marginally significant. Biological pathway analyses of three of the genes revealed cellular processes such as endocytosis (possibly sustaining an adequate maternal-fetal interface) and metabolic processes such as regulation of lipoprotein lipase activity (involved in providing substrates for the developing fetus). Our results contribute to an epigenetic understanding of maternal involvement in offspring birthweight. Measuring DNAm levels of maternal CpGs may in the future serve as a diagnostic tool recognizing mothers at risk for pregnancies ending with altered birthweights.
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Maternal Nutrition and Neurodevelopment: A Scoping Review.
Cortés-Albornoz, MC, García-Guáqueta, DP, Velez-van-Meerbeke, A, Talero-Gutiérrez, C
Nutrients. 2021;(10)
Abstract
In this scoping review, we examined the association between maternal nutrition during pregnancy and neurodevelopment in offspring. We searched the Pubmed and ScienceDirect databases for articles published from 2000 to 2020 on inadequate intake of vitamins (B12, folate, vitamin D, vitamin A, vitamin E, vitamin K), micronutrients (cooper, iron, creatine, choline, zinc, iodine), macronutrients (fatty acids, proteins), high fat diets, ketogenic diets, hypercaloric diets, and maternal undernutrition. Some older relevant articles were included. The search produced a total of 3590 articles, and 84 studies were included in the qualitative synthesis. Data were extracted and analyzed using charts and the frequency of terms used. We concluded that inadequate nutrient intake during pregnancy was associated with brain defects (diminished cerebral volume, spina bifida, alteration of hypothalamic and hippocampal pathways), an increased risk of abnormal behavior, neuropsychiatric disorders (ASD, ADHD, schizophrenia, anxiety, depression), altered cognition, visual impairment, and motor deficits. Future studies should establish and quantify the benefits of maternal nutrition during pregnancy on neurodevelopment and recommend adequate supplementation.
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Does antiretroviral therapy cause congenital malformations? A systematic review and meta-analysis.
Alemu, FM, Yalew, AW
Epidemiology and health. 2021;:e2021008
Abstract
OBJECTIVES This meta-analysis investigated the risk of congenital anomalies among infants of human immunodeficiency virus-infected pregnant women who were exposed to antiretroviral therapy (ART). METHODS Cohort studies, case-control studies, randomized controlled trials, and controlled clinical trials were reviewed by searching MEDLINE/PubMed, Embase, Web of Science, Scopus, AIDSLINE, CINAHL, Cochrane Library, and Google/Google Scholar. Methodological quality was assessed using the GRADE evaluation. A DerSimonian and Laird random-effects model was used. Subgroup analyses and meta-regression were used to investigate heterogeneity. RESULTS The electronic searches yielded 765 items. After quality assessment and grading, 30 studies were suitable for metaanalysis. In total, 1,461 congenital anomalies were found among 53,186 births. Children born to women receiving combined antiretroviral therapy (cART) had an approximately 10% higher risk of developing congenital anomalies (relative risk [RR], 1.09; 95% confidence interval [CI], 1.04 to 1.14). A subgroup analysis found no significant difference in the risk of congenital anomalies between cART and efavirenz users. However, zidovudine and protease inhibitor (RR, 1.09; 95% CI, 1.00 to 1.19) users were found to have a 10% increased risk of congenital anomalies, and integrase inhibitor users had a 60% increase in risk (RR, 1.61; 95% CI, 1.60 to 2.43). The subgroup results should be interpreted cautiously because of the moderate heterogeneity (I2 =58%). CONCLUSIONS The use of protease inhibitors, integrase inhibitors, zidovudine, and newer drugs should be carefully considered in pregnant women. Further studies are needed to address environmental, nutrition, and adherence factors related to ART. Establishing a congenital anomalies surveillance system is recommended.