ABSTRACT
CONTEXT/OBJECTIVE: Fetuin-B is a hepatokine/adipokine implicated in glucose homeostasis and lipid metabolism. We sought to assess whether cord blood fetuin-B levels are altered in gestational diabetes mellitus (GDM) and the association with fetal growth factors and lipids. STUDY DESIGN, POPULATION, AND OUTCOMES: In a nested case-control study of 153 pairs of neonates of mothers with GDM and euglycemic pregnancies in the Shanghai Birth Cohort, we assessed cord blood fetuin-B in relation to fetal growth factors and lipids [high-density lipoprotein (HDL), low-density lipoprotein (LDL), total cholesterols (TC) and triglycerides (TG)]. RESULTS: Cord blood fetuin-B concentrations were higher in the newborns of GDM vs. euglycemic mothers (mean ± SD: 2.35±0.96 vs 2.05±0.73 mg/L, P=0.012), and were positively correlated with LDL (r=0.239, P<0.0001), TC (r=0.230, P=0.0001), insulin-like growth factor-â [IGF-â (r=0.137, P=0.023)] and IGF-â ¡ (r=0.148, P=0.014) concentrations. Similar associations were observed adjusting for maternal and neonatal characteristics. CONCLUSIONS: The study is the first to demonstrate that fetuin-B levels are elevated in fetal life in GDM, and that fetuin-B affects lipid metabolic health during fetal life in humans. The secretion of fetuin-B appears to be related to the secretion of insulin-like growth factors (IGF-â and IGF-â ¡).
ABSTRACT
Maternal blood glucose regulation adaptation to pregnancy aims to support fetal growth but may also lead to the development of gestational diabetes mellitus, the most common pregnancy complication. MiRNAs are small RNA molecules secreted and stable in the blood, where they could have paracrine hormone-like functions (ribo-hormone) and regulate metabolic processes including fetal growth and glucose metabolism. The objective of this study was to identify plasmatic microRNA (miRNAs) measured during the first trimester of pregnancy that were associated with glucose levels during a 75 g oral glucose tolerance test (OGTT) at ~26 weeks of pregnancy. miRNAs were quantified using next-generation sequencing in 444 pregnant women and replicated in an independent cohort of 106 pregnant women. MiRNAs associated with glucose levels were identified with the DESeq2 package. We identified 24 miRNAs associated with fasting glycemia, of which 18 were common to both cohorts (q-value < 0.1). However, no association was found between miRNAs and 1 h or 2 h post OGTT glycemia. To conclude, we identified 18 miRNAs early in pregnancy that were associated with fasting blood glucose measured 3 months later. Our findings offer new insights into the mechanisms involved in fasting glucose homeostasis regulation in pregnancy, which is critical to understanding how gestational diabetes develops.
ABSTRACT
Children's exposures to environmental antibiotics are a major public health concern. However, limited data are available on the effects of environmental antibiotic exposures on childhood obesity. Our study aimed to explore this relationship. We conducted a cross-sectional case-control study nested in a population-based survey of primary school students, including 1855 obese and 1875 random selected control children. A total of 10 antibiotics in urine samples were measured by liquid chromatography-tandem mass spectrometry. Multivariable survey logistic regression was used to assess the associations between environmental antibiotics exposures and childhood obesity. After adjusting for potential confounders, increased odds of obesity were observed in children exposed to tetracycline (OR = 1.31, 95% CI: 1.09-1.57) and sulfamonomethoxine (OR = 1.43, 95% CI: 1-2.05). Comparing none (Subject(s)
Anti-Bacterial Agents
, Environmental Exposure
, Pediatric Obesity
, Humans
, Case-Control Studies
, Anti-Bacterial Agents/adverse effects
, Male
, Child
, Cross-Sectional Studies
, Female
, Environmental Exposure/statistics & numerical data
, Pediatric Obesity/epidemiology
, Pediatric Obesity/chemically induced
, Environmental Pollutants/urine
, Logistic Models
ABSTRACT
BACKGROUND: Large-for-gestational age (LGA), a marker of fetal overgrowth, has been linked to obesity in adulthood. Little is known about how infancy growth trajectories affect adiposity in early childhood in LGA. METHODS: In the Shanghai Birth Cohort, we followed up 259 LGA (birth weight >90th percentile) and 1673 appropriate-for-gestational age (AGA, 10th-90th percentiles) children on body composition (by InBody 770) at age 4 years. Adiposity outcomes include body fat mass (BFM), percent body fat (PBF), body mass index (BMI), overweight/obesity, and high adiposity (PBF >85th percentile). RESULTS: Three weight growth trajectories (low, mid, and high) during infancy (0-2 years) were identified in AGA and LGA subjects separately. BFM, PBF and BMI were progressively higher from low- to mid-to high-growth trajectories in both AGA and LGA children. Compared to the mid-growth trajectory, the high-growth trajectory was associated with greater increases in BFM and the odds of overweight/obesity or high adiposity in LGA than in AGA children (tests for interactions, all P < 0.05). CONCLUSIONS: Weight trajectories during infancy affect adiposity in early childhood regardless of LGA or not. The study is the first to demonstrate that high-growth weight trajectory during infancy has a greater impact on adiposity in early childhood in LGA than in AGA subjects. IMPACT: Large-for-gestational age (LGA), a marker of fetal overgrowth, has been linked to obesity in adulthood, but little is known about how weight trajectories during infancy affect adiposity during early childhood in LGA subjects. The study is the first to demonstrate a greater impact of high-growth weight trajectory during infancy (0-2 years) on adiposity in early childhood (at age 4 years) in subjects with fetal overgrowth (LGA) than in those with normal birth size (appropriate-for-gestational age). Weight trajectory monitoring may be a valuable tool in identifying high-risk LGA children for close follow-ups and interventions to decrease the risk of obesity.
ABSTRACT
OBJECTIVES: Diabetes in pregnancy, whether pre-gestational (chronic) or gestational (de novo hyperglycaemia), increases the risk of adverse birth outcomes. It is unclear whether gestational diabetes increases the risk of postnatal morbidity in infants. Cree First Nations in Quebec are at high risk for diabetes in pregnancy. We assessed whether pre-gestational or gestational diabetes may increase infant hospitalisation (an infant morbidity indicator) incidence, and whether this may be related to more frequent infant hospitalisations in Cree and other First Nations in Quebec. DESIGN: Population-based birth cohort study through administrative health data linkage. SETTING AND PARTICIPANTS: Singleton infants (≤1 year) born to mothers in Cree (n=5070), other First Nations (9910) and non-Indigenous (48 200) communities in rural Quebec. RESULTS: Both diabetes in pregnancy and infant hospitalisation rates were much higher comparing Cree (23.7% and 29.0%) and other First Nations (12.4% and 34.1%) to non-Indigenous (5.9% and 15.5%) communities. Compared with non-diabetes, pre-gestational diabetes was associated with an increased risk of any infant hospitalisation to a greater extent in Cree and other First Nations (relative risk (RR) 1.56 (95% CI 1.28 to 1.91)) than non-Indigenous (RR 1.26 (1.15 to 1.39)) communities. Pre-gestational diabetes was associated with increased risks of infant hospitalisation due to diseases of multiple systems in all communities. There were no significant associations between gestational diabetes and risks of infant hospitalisation in all communities. The population attributable risk fraction of infant hospitalisations (overall) for pre-gestational diabetes was 6.2% in Cree, 1.6% in other First Nations and 0.3% in non-Indigenous communities. CONCLUSIONS: The study is the first to demonstrate that pre-gestational diabetes increases the risk of infant hospitalisation overall and due to diseases of multiple systems, but gestational diabetes does not. High prevalence of pre-gestational diabetes may partly account for the excess infant hospitalisations in Cree and other First Nations communities in Quebec.
Subject(s)
Diabetes, Gestational , Hospitalization , Indigenous Canadians , Female , Humans , Infant , Pregnancy , Cohort Studies , Diabetes, Gestational/epidemiology , Infant Mortality , Pregnancy Outcome , Quebec/epidemiologyABSTRACT
Intrauterine exposure to heavy metals may adversely affect the developing fetus and health later in life, while certain trace elements may be protective. There is limited data on their dynamic fluctuation in circulating concentration of women from preconception to pregnancy and the degree of transplacental passage to fetus. Such information is critically needed for an optimal design of research studies and intervention strategies. In the present study, we profiled the longitudinal patterns and trajectories of metal(loid)s and trace elements from preconception to late pregnancy and in newborns. We measured whole blood metal(loid)s in women at preconception, 16, 24 and 32 weeks of gestation and in cord blood in 100 mother-newborn pairs. Our data showed that the mean concentrations of mercury (Hg), lead (Pb), rubidium (Rb), manganese (Mn), and iron (Fe) were lower during early-, mid-, and late-pregnancy than at preconception. Copper (Cu), and calcium (Ca) concentrations increased after pregnancy (Cu 798 versus 1353, 1488, and 1464 µg/L). Concentrations at preconception were correlated with those during pregnancy for all examined metal(loid)s. Maternal Hg, Pb, and Se concentrations at late-pregnancy were correlated with those in newborn cord blood in various degrees (correlation coefficients: Hg 0.66, Pb 0.29, Se 0.39). The estimated placental transfer ratio for toxic metal(loid)s ranging from 1.68 (Hg) to 0.18 (Cd). Two trajectory groups were identified for Hg, Pb, Cd, Se concentrations. Hg concentrations may be correlated with maternal education levels. The study is the first to present longitudinal circulating concentration trajectories of toxic metal(loid)s and trace elements from preconception to pregnancy stages. A high degree of transplacental passage was observed in toxic metals Pb and Hg which may pose hazards to the developing fetus.
Subject(s)
Mercury , Metals, Heavy , Trace Elements , Female , Infant, Newborn , Pregnancy , Humans , Cadmium , Lead , Placenta , Metals, Heavy/toxicity , Heavy Metal Poisoning , Fetal BloodABSTRACT
Early growth has long-lasting associations with adult metabolic health. However, the association of adiposity with cardiometabolic risk factors in toddlers remains poorly understood. This study aimed to examine the association of maternal prenatal factors and child adiposity with child cardiometabolic risk factors among boys and girls aged 2 years. This was a birth cohort study of 549 term-born children in Shanghai, China, with follow-up data at the age of 2-years. Child anthropometric and adiposity measurements included weight, length, and skinfold thickness (triceps, subscapular, and abdominal). Child cardiometabolic risk factors included random morning plasma glucose, serum insulin, lipids, and systolic and diastolic blood pressure (SBP, DBP). At 2 years, overweight/obesity (weight-for-length z score, ZWFL > 2) was associated with 12.6 (95%CI 7.7, 17.4) mmHg higher SBP, and 7.9 (4.1, 11.8) mmHg higher DBP in boys, with similar results observed in girls. Maternal hypertensive disorders of pregnancy were associated with 3.0 (0.1, 5.8) higher SBP, 3.17 (0.90, 5.44) mmHg higher DBP, 0.24 (0.01,0.47) mmol/L higher plasma glucose, and 0.26 (0.01,0.51) mmol/L higher serum triglycerides after adjustment for child age, sex, and ZWFL. Maternal hypertensive disorders of pregnancy and child overweight/obesity were associated with higher SBP and DBP at the age of 2 years.
Subject(s)
Hypertension, Pregnancy-Induced , Pediatric Obesity , Pre-Eclampsia , Female , Humans , Male , Pregnancy , Adiposity/physiology , Blood Glucose , Blood Pressure/physiology , Body Mass Index , Cardiometabolic Risk Factors , China/epidemiology , Cohort Studies , East Asian People , Overweight , Pediatric Obesity/complications , Pediatric Obesity/epidemiology , Risk Factors , Child, PreschoolABSTRACT
The impact of maternal exposure to Bisphenol A on child cognitive development as well as its sex dimorphism remains uncertain. This study used data of 215 mothers and their children from a birth cohort in Shanghai. Urinary BPA were measured in spot urine samples of mothers at late pregnancy and children at age 2 years. Cognitive development was evaluated by Ages & Stages Questionnaires, Third Edition (ASQ-3) at age 2 years. Urinary BPA was detectable in 98.9% of mothers (geometric mean, GM: 2.6 µg/g. creatinine) and 99.8% children (GM: 3.4 µg/g. creatinine). Relative to the low and medium BPA tertiles, high tertile of maternal urinary BPA concentrations were associated with 4.8 points lower (95% CI: -8.3, -1.2) in gross motor and 3.7 points lower (95% CI: -7.4, -0.1) in problem-solving domain in girls only, with adjustment for maternal age, maternal education, pre-pregnancy BMI, passive smoking during pregnancy, parity, delivery mode, birth-weight for gestational age, child age at ASQ-3 test. This negative association remained with additional adjustment for child urinary BPA concentrations at age 2 years. No association was observed in boys. These results suggested the sex-dimorphism on the associations of maternal BPA exposure with gross motor and problem-solving domains in children at age 2 years. This study also indicated that optimal early child development should start with a healthy BPA-free "in utero" environment.
Subject(s)
East Asian People , Maternal Exposure , Phenols , Child, Preschool , Female , Humans , Male , Pregnancy , China , Creatinine , Prospective Studies , Phenols/urineABSTRACT
Antibiotic exposure even in low-dose could have potential adverse health effects, especially during early life. There is a lack of data on antibiotic burdens in early infancy. We aim to assess antibiotic exposure in infants from birth to 6 months of age, their related affecting factors and the association between antibiotic exposure and infancy growth. Urine samples were collected at ages of 3 days, 42 days, 3 months and 6 months from 197 term-born Chinese infants. A total of 33 representative antibiotics were measured by high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS). Urinary antibiotics were detectable in 69.4%, 63.2%, 75.0% and 84.3% of infants at ages of 3 days, 42 days, 3 and 6 months, respectively. The dominant antibiotic categories detected were: Preferred as Veterinary Antibiotics (PVAs), Human Antibiotics (HAs), and Veterinary Antibiotics (VAs). The detectable rates were 30.6%, 45.8%, 58.9%, and 81.4% for PVAs, 34.1%, 20.8%, 28.6%, and 45.1% for HAs, and 36.5%, 12.5%, 6.3%, and 5.9% for VAs, at age 3 days, 42 days, 3 and 6 months, respectively. Urinary concentrations of HAs and preferred as human antibiotics (PHAs) in newborns at age 3 days were not associated with maternal intrapartum antibiotic prophylaxis. Similarly, no associations were observed between urinary antibiotics concentration and antibiotics use in infants at age 42 days or 6 months. The numbers and concentrations of urine detectable antibiotics were similar between infants with exclusive breastfeeding and infants fed with formula or mixed-feeding at all ages of 42 days, 3 and 6 months. At age of 42 days, infants in the low tertile of total antibiotics concentration or with one antibiotic detected had higher weight-for-length Z score and greater head circumference, compared to infants with no antibiotics detected. No associations were found between urinary antibiotics and any of the infant anthropometric measures at age 6 months. In conclusion, urinary antibiotics were detectable in most infants during the first 6 months of life, and PVAs, HAs and VAs were the most commonly detected antibiotics. This suggested the possibility of a foods-originated antibiotics exposure in children. No strong nor consistent associations were found between urinary antibiotic concentration and infant growth at the first six months of life. Still, attention is needed on the adverse health effect of early life exposure to antibiotics in future studies.
ABSTRACT
Aim: Adverse (poor or excessive) fetal growth "programs" an elevated risk of type 2 diabetes. Fatty acid binding protein 4 (FABP4) has been implicated in regulating insulin sensitivity and lipid metabolism relevant to fetal growth. We sought to determine whether FABP4 is associated with poor or excessive fetal growth and fetal lipids. Methods: In a nested case-control study in the Shanghai Birth Cohort including 60 trios of small-for-gestational-age (SGA, an indicator of poor fetal growth), large-for-gestational-age (LGA, an indicator of excessive fetal growth) and optimal-for-gestational-age (OGA, control) infants, we measured cord blood concentrations of FABP4 and lipids [high-density lipoprotein (HDL) and low-density lipoprotein (LDL) cholesterols, triglycerides (TG)]. Results: Adjusting for maternal and neonatal characteristics, higher cord blood FABP4 concentrations were associated with a lower odds of SGA [OR = 0.29 (0.11-0.77) per log unit increment in FABP4, P = 0.01], but were not associated with LGA (P = 0.46). Cord blood FABP4 was positively correlated with both LDL (r = 0.29, P = 0.025) and HDL (r = 0.33, P = 0.01) in LGA infants only. Conclusion: FABP4 was inversely associated with the risk of SGA. The study is the first to demonstrate LGA-specific positive correlations of cord blood FABP4 with HDL and LDL cholesterols, suggesting a role of FABP4 in fetal lipid metabolism in subjects with excessive fetal growth.
ABSTRACT
AIM: To assess whether small-for-gestational-age (SGA) - an indicator of poor fetal growth, may affect metabolic health biomarkers in infancy and explore the predictors. METHODS: This was a nested matched (1:2) prospective observational study of 65 SGA (birth weight < 10th percentile) and 130 optimal-for-gestational-age (OGA, birth weight 25th-75th percentiles, control) infants in the 3D birth cohort with subjects recruited in Canada from 1 May 2010 to 31 August 2012. The outcomes included homeostasis model assessment of insulin resistance (HOMA-IR) and beta-cell function (HOMA-ß), circulating leptin and adiponectin concentrations at age 2 years. RESULTS: HOMA-IR, HOMA-ß, leptin and adiponectin concentrations were similar in SGA versus OGA infants. Female sex and accelerated growth in length during mid-infancy (3-12 months) were associated with higher HOMA-IR. Caucasian ethnicity and decelerated growth in weight during late infancy (12-24 months) were associated with lower HOMA-IR. Current BMI was positively associated with circulating adiponectin in SGA infants only (+13.4% [4.0%-23.7%] per BMI z score increment). CONCLUSION: Insulin resistance and secretion, circulating leptin and adiponectin levels were normal in SGA subjects in infancy at age 2 years. The novel observation in SGA-specific positive association between current BMI and circulating adiponectin suggests dysfunctional adiposity-adiponectin negative feedback loop development during infancy in SGA subjects.
Subject(s)
Insulin Resistance , Humans , Infant , Female , Child, Preschool , Insulin Resistance/physiology , Adiponectin , Leptin , Insulin , Birth Weight , Fetal Growth RetardationABSTRACT
Background and objective: Gestational diabetes mellitus (GDM) "programs" an elevated risk of metabolic dysfunctional disorders in the offspring, and has been associated with elevated leptin and decreased adiponectin levels in cord blood. We sought to assess whether docosahexaenoic acid (DHA) supplementation in GDM affects neonatal metabolic health biomarkers especially leptin and adiponectin. Methods: In a randomized controlled trial, singleton pregnant women with de novo diagnosis of GDM at 24-28 weeks of gestation were randomized to dietary supplementation of 500 mg DHA per day (intervention, n = 30) until delivery or standard care (control, n = 38). The primary outcomes were cord blood leptin and total adiponectin concentrations. Secondary outcomes included high-molecular-weight (HMW) adiponectin and insulin-like growth factor-1 (IGF-1) concentrations in cord blood, maternal glycemic control post-intervention and birth weight (z score). In parallel, 38 euglycemic pregnant women were recruited for comparisons of cord blood biomarkers. Results: There were no significant differences in cord serum leptin, total and HMW adiponectin and IGF-1 concentrations between DHA supplementation and control groups (all p > 0.05). Maternal fasting and 2-h postprandial blood glucose levels at 12-16 weeks post-intervention were similar between the two groups. The newborns in the DHA group had higher birth weight z scores (p = 0.02). Cord blood total and HMW adiponectin concentrations were significantly lower in GDM vs. euglycemic pregnancies. Conclusion: Docosahexaenoic acid supplementation at 500 mg/day in GDM women did not affect neonatal metabolic biomarkers including leptin, adiponectin and IGF-1. The results are reassuring in light of the absence of influence on neonatal adipokines (leptin and adiponectin), and potential benefits to fetal growth and development. Clinical Trial Registration: Clinicaltrials.gov, NCT03569501.
ABSTRACT
Introduction: Myostatin is a member of the transforming growth factor ß superfamily, and is mainly secreted from skeletal muscle. Animal studies have demonstrated that deficiency in myostatin promotes muscle growth and protects against insulin resistance. In humans, gestational diabetes mellitus (GDM) affects fetal insulin sensitivity. Females are more insulin resistant and weigh less than males at birth. We sought to assess whether cord blood myostatin concentrations vary by GDM and fetal sex, and the associations with fetal growth factors. Methods: In a study of 44 GDM and 66 euglycemic mother-newborn dyads, myostatin, insulin, proinsulin, insulin-like growth factor (IGF)-1, IGF-2 and testosterone were measured in cord blood samples. Results: Cord blood myostatin concentrations were similar in GDM vs. euglycemic pregnancies (mean ± SD: 5.5 ± 1.4 vs. 5.8 ± 1.4 ng/mL, P=0.28), and were higher in males vs. females (6.1 ± 1.6 vs. 5.3 ± 1.0 ng/mL, P=0.006). Adjusting for gestational age, myostatin was negatively correlated with IGF-2 (r=-0.23, P=0.02), but not correlated with IGF-1 (P=0.60) or birth weight (P=0.23). Myostatin was strongly correlated with testosterone in males (r=0.56, P<0.001), but not in females (r=-0.08, P=0.58) (test for difference in r, P<0.001). Testosterone concentrations were higher in males vs. females (9.5 ± 6.4 vs. 7.1 ± 4.0 nmol/L, P=0.017), and could explain 30.0% (P=0.039) of sex differences in myostatin concentrations. Discussion: The study is the first to demonstrate that GDM does not impact cord blood myostatin concentration, but fetal sex does. The higher myostatin concentrations in males appear to be partly mediated by higher testosterone concentrations. These findings shed novel insight on developmental sex differences in insulin sensitivity regulation relevant molecules.
Subject(s)
Diabetes, Gestational , Insulin Resistance , Animals , Infant, Newborn , Humans , Pregnancy , Female , Male , Insulin-Like Growth Factor II , Myostatin , Fetal Blood , Insulin , TestosteroneABSTRACT
BACKGROUND: Small-for-gestational-age (SGA) has a heterogeneous etiology. Our study aimed to examine the childhood health outcomes of etiology-distinct term SGA subgroups. METHODS: Data from the Collaborative Perinatal Project were used. The etiological factors of SGA were categorized into five groups: maternal, fetal, placental, environmental and physiological factors. Primary child outcomes included low IQ and growth restriction. A total of 8417 term infants were eligible. RESULTS: Compared with AGA, SGA children due to fetal factors had the highest risk of low IQ (aOR = 1.94, 95% CI: 1.45-2.59). SGA infants due to physiological factors had the highest risk of growth restriction (aOR = 6.04, 95% CI: 3.93-9.27). SGA children had a higher risk of growth restriction with the aOR ranging from 3.05 (95% CI: 2.36-3.96) to 5.77 (95% CI: 4.29-7.75) for the number of risk factors that the SGA infants had from 1 to 5. SGA children with any risk factor were associated with a higher risk of lower IQ with the aOR ranging from 1.59 (95% CI: 1.31-1.94) to 1.96 (95% CI: 1.50-2.55). SGA without the five types of etiologies was not associated with adverse child outcomes except for growth restriction (aOR = 3.82, 95% CI: 2.62-5.55). CONCLUSION: Term SGA of different etiologies may lead to different child health outcomes. IMPACT: Our study found that SGA of different etiologies may lead to different child health outcomes. Compared with AGA, SGA children due to fetal factors had the highest risk of low IQ. SGA infants due to physiological factors had the highest risk of growth restriction. SGA babies should not be treated the same. In the era of precision medicine, our findings may help pediatricians and parents better manage SGA babies according to different etiologies and the number of risk factors.
Subject(s)
Infant, Small for Gestational Age , Placenta , Infant, Newborn , Infant , Humans , Child , Pregnancy , Female , Fetal Growth Retardation/etiology , Causality , Outcome Assessment, Health Care , Gestational AgeABSTRACT
CONTEXT: Thyroid hormones are essential for fetal brain development. The potential effects of maternal gestational thyroid dysfunction on offspring neuropsychological development remain inconclusive. OBJECTIVE: This work aimed to estimate effects of maternal thyroid dysfunction during pregnancy on offspring neuropsychological development in the first 2 years. METHODS: We prospectively examined 1903 mothers and their children from the Shanghai Birth Cohort. Thyroid hormones were assessed at about 12 gestational weeks. Maternal thyroid function was classified into 7 categories: euthyroid, overt/subclinical hyperthyroidism, overt/subclinical hypothyroidism, hyperthyroxinemia, and hypothyroxinemia. Neuropsychological development was assessed by the Ages and Stages Questionnaire at age 6 months, and Bayley Scales at age 24 months. RESULTS: Compared with children of euthyroid mothers, maternal overt hypothyroidism was associated with 7.0 points (95% CI, 1.7-12.4) lower scores in personal-social domain in girls aged 6 months, 7.3 points (95% CI, 2.0-12.6) lower in motor domain, and 7.7 points (95% CI, 1.1-14.2) lower social-emotional scores in boys at age 24 months; maternal subclinical hypothyroidism was associated with 6.5 points (95% CI, 1.0-12.1) poorer social-emotional domain in boys at age 6 months, and 7.4 points (95% CI, 0.1-14.8) poorer adaptive behavior domain in boys at age 24 months; maternal hypothyroxinemia was associated with 9.3 points (95% CI, 3.5-15.1) lower motor scores in boys at age 24 months; and maternal subclinical hyperthyroidism was associated with 6.9 points (95% CI, 0.1-13.7) lower language scores in girls at age 24 months. CONCLUSION: Maternal overt hypothyroidism, subclinical hypothyroidism/hyperthyroidism, and hypothyroxinemia during early pregnancy were associated with weakened neuropsychological development in infancy, and some effects may be sex specific.
Subject(s)
Hyperthyroidism , Hypothyroidism , Pregnancy Complications , Thyroid Diseases , Pregnancy , Male , Female , Child , Humans , Infant , Child, Preschool , Thyroid Function Tests , Thyrotropin , Cohort Studies , China , Hypothyroidism/complications , Hyperthyroidism/complications , Hyperthyroidism/epidemiology , Thyroid Hormones , Pregnancy Complications/epidemiology , ThyroxineABSTRACT
OBJECTIVE: To examine the effects of prenatal maternal depression, anxiety and stress, and postnatal depression on infant early neurodevelopment, and the sex dimorphism. STUDY DESIGN: We used data from 3379 mother-infant pairs from the Shanghai Birth Cohort. Maternal mental health was assessed using the Center for Epidemiological Studies-Depression Scale, Zung Self-Rating Anxiety Scale, Perceived Stress Scale at mid-pregnancy, and the Edinburgh Postnatal Depression Scale at postpartum. Infant neurodevelopment was evaluated using the Ages & Stages Questionnaires and Bayley Scales at ages 6, 12, and 24 months, respectively. Linear mixed models and linear regression models were used. RESULTS: Among 3379 mothers, 11.07 %, 5.42 %, and 34.85 % of women experienced depression, anxiety, and elevated stress, separately. As maternal prenatal mental scores increased per 1SD, infant social-emotional scores decreased -2.82 (-3.86, -1.79) vs -2.86 (-3.94, -1.79) for depression, -2.34 (-3.38, -1.31) vs -2.72 (-3.81, -1.64) for anxiety, and -2.55 (-3.60, -1.50) vs -3.41 (-4.48, -2.35) for stress among boys and girls at age 24 months, respectively. Associations were also observed on social-emotional and communication scores in boys and girls, and fine motor in girls at age 6 and 12 months. These associations were not observed for postpartum depression. LIMITATION: Generalizability of the results to other population remains to be determined. CONCLUSIONS: Prenatal maternal depression, anxiety, and stress were negatively associated with infant early neurodevelopment, which were not observed for postpartum depression. We underscore the importance of maternal prenatal mental health in optimizing infant neuropsychiatric development.
Subject(s)
Depression, Postpartum , Humans , Pregnancy , Infant , Male , Female , Child, Preschool , Depression, Postpartum/epidemiology , Depression, Postpartum/psychology , Depression/epidemiology , Depression/psychology , China/epidemiology , Anxiety/epidemiology , Anxiety/psychology , Anxiety Disorders/epidemiology , Anxiety Disorders/psychology , Mothers/psychologyABSTRACT
BACKGROUND: Fetal overgrowth "programs" an elevated risk of type 2 diabetes in adulthood. Epigenetic alterations may be a mechanism in programming the vulnerability. We sought to characterize genome-wide alterations in placental gene methylations in fetal overgrowth and the associations with metabolic health biomarkers including leptin, adiponectin and fetal growth factors. RESULTS: Comparing genome-wide placental gene DNA methylations in large-for-gestational-age (LGA, an indicator of fetal overgrowth, n = 30) versus optimal-for-gestational-age (OGA, control, n = 30) infants using the Illumina Infinium Human Methylation-EPIC BeadChip, we identified 543 differential methylation positions (DMPs; 397 hypermethylated, 146 hypomethylated) at false discovery rate < 5% and absolute methylation difference > 0.05 after adjusting for placental cell-type heterogeneity, maternal age, pre-pregnancy BMI and HbA1c levels during pregnancy. Twenty-five DMPs annotated to 20 genes (QSOX1, FCHSD2, LOC101928162, ADGRB3, GCNT1, TAP1, MYO16, NAV1, ATP8A2, LBXCOR1, EN2, INCA1, CAMTA2, SORCS2, SLC4A4, RPA3, UMAD1,USP53, OR2L13 and NR3C2) could explain 80% of the birth weight variations. Pathway analyses did not detect any statistically significant pathways after correcting for multiple tests. We validated a newly discovered differentially (hyper-)methylated gene-visual system homeobox 1 (VSX1) in an independent pyrosequencing study sample (LGA 47, OGA 47). Our data confirmed a hypermethylated gene-cadherin 13 (CDH13) reported in a previous epigenome-wide association study. Adiponectin in cord blood was correlated with its gene methylation in the placenta, while leptin and fetal growth factors (insulin, IGF-1, IGF-2) were not. CONCLUSIONS: Fetal overgrowth may be associated with a large number of altered placental gene methylations. Placental VSX1 and CDH13 genes are hypermethylated in fetal overgrowth. Placental ADIPOQ gene methylations and fetal circulating adiponectin levels were correlated, suggesting the contribution of placenta-originated adiponectin to cord blood adiponectin.
Subject(s)
Diabetes Mellitus, Type 2 , Diabetes, Gestational , Pregnancy , Female , Humans , Adult , Placenta/metabolism , DNA Methylation , Leptin/genetics , Adiponectin , Diabetes, Gestational/genetics , Diabetes Mellitus, Type 2/genetics , Fetal Macrosomia/genetics , Fetal Macrosomia/metabolism , Gestational Age , Fetal Blood/metabolism , Intercellular Signaling Peptides and Proteins/genetics , Fetal Development/genetics , Carrier Proteins/genetics , Membrane Proteins/geneticsABSTRACT
Aims: Our objective is to identify first-trimester plasmatic miRNAs associated with and predictive of GDM. Methods: We quantified miRNA using next-generation sequencing in discovery (Gen3G: n = 443/GDM = 56) and replication (3D: n = 139/GDM = 76) cohorts. We have diagnosed GDM using a 75-g oral glucose tolerance test and the IADPSG criteria. We applied stepwise logistic regression analysis among replicated miRNAs to build prediction models. Results: We identified 17 miRNAs associated with GDM development in both cohorts. The prediction performance of hsa-miR-517a-3p|hsa-miR-517b-3p, hsa-miR-218-5p, and hsa-let7a-3p was slightly better than GDM classic risk factors (age, BMI, familial history of type 2 diabetes, history of GDM or macrosomia, and HbA1c) (AUC 0.78 vs. 0.75). MiRNAs and GDM classic risk factors together further improved the prediction values [AUC 0.84 (95% CI 0.73-0.94)]. These results were replicated in 3D, although weaker predictive values were obtained. We suggest very low and higher risk GDM thresholds, which could be used to identify women who could do without a diagnostic test for GDM and women most likely to benefit from an early GDM prevention program. Conclusions: In summary, three miRNAs combined with classic GDM risk factors provide excellent prediction values, potentially strong enough to improve early detection and prevention of GDM.
Subject(s)
Diabetes Mellitus, Type 2 , Diabetes, Gestational , MicroRNAs , Pregnancy , Humans , Female , Diabetes, Gestational/diagnosis , Diabetes, Gestational/genetics , Pregnancy Trimester, First , Diabetes Mellitus, Type 2/complications , MicroRNAs/genetics , Glucose Tolerance TestABSTRACT
Gestational diabetes mellitus (GDM) "program" an elevated risk of metabolic syndrome in the offspring. Epigenetic alterations are a suspected mechanism. GDM has been associated with placental DNA methylation changes in some epigenome-wide association studies. It remains unclear which genes or pathways are affected, and whether any placental differential gene methylations are correlated to fetal growth or circulating metabolic health biomarkers. In an epigenome-wide association study using the Infinium MethylationEPIC Beadchip, we sought to identify genome-wide placental differentially methylated genes and enriched pathways in GDM, and to assess the correlations with fetal growth and metabolic health biomarkers in cord blood. The study samples were 30 pairs of term placentas in GDM vs. euglycemic pregnancies (controls) matched by infant sex and gestational age at delivery in the Shanghai Birth Cohort. Cord blood metabolic health biomarkers included insulin, C-peptide, proinsulin, IGF-I, IGF-II, leptin and adiponectin. Adjusting for maternal age, pre-pregnancy BMI, parity, mode of delivery and placental cell type heterogeneity, 256 differentially methylated positions (DMPs,130 hypermethylated and 126 hypomethylated) were detected between GDM and control groups accounting for multiple tests with false discovery rate <0.05 and beta-value difference >0.05. WSCD2 was identified as a differentially methylated gene in both site- and region-level analyses. We validated 7 hypermethylated (CYP1A2, GFRA1, HDAC4, LIMS2, NAV3, PAX6, UPK1B) and 10 hypomethylated (DPP10, CPLX1, CSMD2, GPR133, NRXN1, PCSK9, PENK, PRDM16, PTPRN2, TNXB) genes reported in previous epigenome-wide association studies. We did not find any enriched pathway accounting for multiple tests. DMPs in 11 genes (CYP2D7P1, PCDHB15, ERG, SIRPB1, DKK2, RAPGEF5, CACNA2D4, PCSK9, TSNARE1, CADM2, KCNAB2) were correlated with birth weight (z score) accounting for multiple tests. There were no significant correlations between placental gene methylations and cord blood biomarkers. In conclusions, GDM was associated with DNA methylation changes in a number of placental genes, but these placental gene methylations were uncorrelated to the observed metabolic health biomarkers (fetal growth factors, leptin and adiponectin) in cord blood. We validated 17 differentially methylated placental genes in GDM, and identified 11 differentially methylated genes relevant to fetal growth.
Subject(s)
Diabetes, Gestational , Adiponectin/metabolism , Biomarkers , China , DNA Methylation , Diabetes, Gestational/metabolism , Female , Fetal Blood/metabolism , Fetal Development , Humans , Infant , Leptin/metabolism , Parity , Placenta/metabolism , Pregnancy , Proprotein Convertase 9/geneticsABSTRACT
BACKGROUND: Trace elements may affect neurodevelopment. There is a lack of data on breast-milk rubidium (Rb) in relation to neurodevelopment in infants. The associations of copper (Cu), zinc (Zn) and strontium (Sr) with neurodevelopment in infants remain uncertain. OBJECTIVES: We sought to evaluate the associations of breast-milk Rb (primary exposure), Cu, Zn, and Sr with neurodevelopment in infants at age 8 months. METHODS: The study cohort included 117 breastfed infants. Breast-milk samples were collected at 42 days and 8 months postpartum. Breast-milk Rb, Zn, Cu, and Sr were measured by inductively coupled plasma mass spectrometer. Neurodevelopment was assessed at age 8 months. The primary outcomes were attention and working memory scores, as evaluated by the A-not-B task. Other outcomes included the Mental Development Index (MDI) and Psychomotor Development Index (PDI) as evaluated by the Bayley Scale of Infant Development III. Generalized linear models and restricted cubic spline regression were used to assess the associations between trace elements and neurodevelopment indices. Bonferroni correction was conducted on all data presented. RESULTS: A nonlinear association was observed between breast-milk Rb at 42 days and infant's attention at age 8 months (nonlinearity P = 0.037). Positive associations were observed with infant MDI scores and breast-milk Rb at 42 days (ß = 4.46; P = 0.06) and 8 months (ß = 3.79; P = 0.009) postpartum. Breast-milk Zn at 42 days was positively associated with infant's attention (ß = 0.31; P = 0.039). Sr at 42 days was positively correlated with attention (ß = 0.18; P = 0.043) and MDI scores (ß = 2.18; P = 0.015) at 8 months. Inverted U-shape associations were observed for breast-milk Cu at 42 days with infant attention and PDI scores. All associations were not significant after correction for multiple tests. CONCLUSIONS: Our data suggest that Rb, Zn, Cu, and Sr in breast milk at certain concentrations are associated with neurodevelopment in breastfed infants. Further studies are warranted to validate the findings.