Intrauterine exposure to diabetes and risk of cardiovascular disease in adolescence and early adulthood: a population-based birth cohort study.

BACKGROUND: It is unclear whether intrauterine exposure to maternal diabetes is associated with risk factors for cardiovascular disease and related end points in adulthood. We examined this potential association in a population-based birth cohort followed up to age 35 years. METHODS: We performed a cohort study of offspring born between 1979 and 2005 (n = 293 546) and followed until March 2015 in Manitoba, Canada, using registry-based administrative data. The primary exposures were intrauterine exposure to gestational diabetes and type 2 diabetes mellitus. The primary outcome was a composite measure of incident cardiovascular disease events, and the secondary outcome was a composite of risk factors for cardiovascular disease in offspring followed up to age 35 years. RESULTS: The cohort provided 3 628 576 person-years of data (mean age at latest follow-up 20.5 [standard deviation 6.4] years, 49.3% female); 2765 (0.9%) of the offspring experienced a cardiovascular disease end point, and 12 673 (4.3%) experienced a cardiovascular disease risk factor. After propensity score matching, the hazard for cardiovascular disease end points was elevated in offspring exposed to gestational diabetes (adjusted hazard ratio [HR] 1.42, 95% confidence interval [CI] 1.12-1.79) but not type 2 diabetes (adjusted HR 1.40, 95% CI 0.98-2.01). A similar association was observed for cardiovascular disease risk factors (gestational diabetes: adjusted HR 1.92, 95% CI 1.75-2.11; type 2 diabetes: adjusted HR 3.40, 95% CI 3.00-3.85). INTERPRETATION: Intrauterine exposure to maternal diabetes was associated with higher morbidity and risk related to cardiovascular disease among offspring up to 35 years of age.

Cardiac structure and function in youth with type 2 diabetes in the iCARE cohort study: Cross-sectional associations with prenatal exposure to diabetes and metabolomic profiles.

OBJECTIVE: This study aimed to determine the degree of left ventricular (LV) dysfunction and its determinants in adolescents with type 2 diabetes (T2D). We hypothesized that adolescents with T2D would display impaired LV diastolic function and that these cardiovascular complications would be exacerbated in youth exposed to maternal diabetes in utero. METHODS: Left ventricular structure and function, carotid artery intima media thickness and strain, and serum metabolomic profiles were compared between adolescents with T2D (n = 121) and controls (n = 34). Sub-group analyses examined the role of exposure to maternal diabetes as a determinant of LV or carotid artery structure and function among adolescents with T2D. RESULTS: Adolescents with T2D were 15.1 ± 2.5 years old, (65% female, 99% Indigenous), had lived with diabetes for 2.7 ± 2.2 years, had suboptimal glycemic control (HbA1c = 9.4 ± 2.6%) and 58% (n = 69) were exposed to diabetes in utero. Compared to controls, adolescents with T2D displayed lower LV diastolic filling (early diastole/atrial filling rate ratio [E/A] = 1.9 ± 0.6 vs 2.2 ± 0.6, P = 0.012), lower LV relaxation and carotid strain (0.12 ± 0.05 vs 0.17 ± 0.05, P = .03) and elevated levels of leucine, isoleucine and valine. Among adolescents with T2D, exposure to diabetes in utero was not associated with differences in LV diastolic filling, LV relaxation, carotid strain or branched chain amino acids. CONCLUSIONS: Adolescents with T2D display LV diastolic dysfunction, carotid artery stiffness, and elevated levels of select branch chain amino acids; differences were not associated with exposure to maternal diabetes in utero.

Exercise in Pregnancy and Children's Cardiometabolic Risk Factors: a Systematic Review and Meta-Analysis.

BACKGROUND: Maternal metabolic health during the prenatal period is an established determinant of cardiometabolic disease risk. Many studies have focused on poor offspring outcomes after exposure to poor maternal health, while few have systematically appraised the evidence surrounding the role of maternal exercise in decreasing this risk. The aim of this study is to characterize and quantify the specific impact of prenatal exercise on children's cardiometabolic health markers, at birth and in childhood. METHODS: A systematic review of Scopus, MEDLINE, EMBASE, CENTRAL, CINAHL, and SPORTDiscus up to December 2017 was conducted. Randomized controlled trials (RCTs) and prospective cohort studies of prenatal aerobic exercise and/or resistance training reporting eligible offspring outcomes were included. Four reviewers independently identified eligible citations and extracted study-level data. The primary outcome was birth weight; secondary outcomes, specified a priori, included large-for-gestational age status, fat and lean mass, dyslipidemia, dysglycemia, and blood pressure. We included 73 of the 9804 citations initially identified. Data from RCTs was pooled using random effects models. Statistical heterogeneity was quantified using the I2 test. Analyses were done between June and December 2017 and the search was updated in December 2017. RESULTS: Fifteen observational studies (n = 290,951 children) and 39 RCTs (n = 6875 children) were included. Observational studies were highly heterogeneous and had discrepant conclusions, but globally showed no clinically relevant effect of exercise on offspring outcomes. Meta-analyzed RCTs indicated that prenatal exercise did not significantly impact birth weight (mean difference [MD] - 22.1 g, 95% confidence interval [CI] - 51.5 to 7.3 g, n = 6766) or large-for-gestational age status (risk ratio 0.85, 95% CI 0.51 to 1.44, n = 937) compared to no exercise. Sub-group analyses showed that prenatal exercise reduced birth weight according to timing (starting after 20 weeks of gestation, MD - 84.3 g, 95% CI - 142.2, - 26.4 g, n = 1124), type of exercise (aerobic only, MD - 58.7 g, 95% CI - 109.7, - 7.8 g; n = 2058), pre-pregnancy activity status (previously inactive, MD - 34.8 g, 95% CI - 69.0, - 0.5 g; n = 2829), and exercise intensity (light to moderate intensity only, MD - 45.5 g, 95% CI - 82.4, - 8.6 g; n = 2651). Fat mass percentage at birth was not altered by prenatal exercise (0.19%, 95% CI - 0.27, 0.65%; n = 130); however, only two studies reported this outcome. Other outcomes were too scarcely reported to be meta-analyzed. CONCLUSIONS: Prenatal exercise does not causally impact birth weight, fat mass, or large-for-gestational-age status in a clinically relevant way. Longer follow up of offspring exposed to prenatal exercise is needed along with measures of relevant metabolic variables (e.g., fat and lean mass). PROTOCOL REGISTRATION: Protocol registration number: CRD42015029163 .

Associations of Maternal Leptin with Neonatal Adiposity Differ according to Pregravid Weight.

BACKGROUND: During pregnancy, maternal circulating leptin is released by maternal adipose tissue and the placenta, and may have a role in fetal development. OBJECTIVES: We investigated maternal leptinemia and glycemia associations with neonatal adiposity, taking into account pregravid weight status. METHODS: We included 235 pregnant women from the Genetics of Glucose Regulation in Gestation and Growth prospective cohort with data: blood samples collected during the 2nd trimester, an oral glucose tolerance test (OGTT), and the measured leptin and glucose levels. As an integrated measure of maternal leptin exposure, we calculated the area under the curve for maternal leptin at the OGTT (AUCleptin). Within 72 h of delivery, we measured the triceps, biceps, subscapular, and suprailiac skinfold thicknesses (SFTs); the sum of these SFTs represented neonatal adiposity. We conducted a regression analysis to assess the maternal metabolic determinants of neonatal adiposity, adjusting for parity, smoking status, maternal triglyceride levels, gestational weight gain, placental weight, delivery mode, neonate sex, and gestational age at delivery. RESULTS: The pregravid BMI of the participating women was 23.3 (21.2-27.0). In the 2nd trimester, maternal AUCleptin was 1,292.0 (767.0-2,222.5) (ng × min)/mL, and fasting glucose levels were 4.2 ± 0.4 mmol/L. At delivery, the neonatal sum of 4 SFTs was 17.9 ± 3.3 mm. Higher maternal leptinemia was associated with higher neonatal adiposity (ß = 4.23 mm [SE = 1.77] per log-AUCleptin; p = 0.02) in mothers with a BMI ≥25, independently of confounders and maternal glycemia, but not in mothers with a BMI <25. Higher maternal fasting glucose was associated with higher neonatal adiposity (ß = 0.88 mm [SE = 0.30] per SD glucose; p = 0.005) in mothers with a BMI <25, independently of confounders and maternal leptinemia. CONCLUSION: Maternal leptinemia may be associated with neonatal adiposity in offspring from overweight/obese mothers, independently of maternal glycemia.

Maternal inhaled fluticasone propionate intake during pregnancy is detected in neonatal cord blood.

BACKGROUND: Despite recommendations to use inhaled corticosteroids as treatment to control asthma during pregnancy, it is unknown whether inhaled fluticasone propionate (FP) reaches the fetus. Results & methodology: We collected maternal blood on the morning following delivery. FP was detected by ultra-performance LC-MS/MS (UPLC-MS/MS) in 9/17 asthmatic women using FP. Delay between last FP inhalation and maternal blood sampling ranged between 3 and 33 h and FP was detected in a range of 1.572-46.440 pg/ml. Among the nine offspring of these FP users, FP was detected in five cord blood samples. Delay between last predelivery FP inhalation and cord blood sampling ranged from 4 to 20 h and FP was detected in a range of 0.423-4.510 pg/ml. CONCLUSION: Our findings demonstrate placental passage of inhaled FP.

Timing of Excessive Weight Gain During Pregnancy Modulates Newborn Anthropometry.

OBJECTIVE: Excessive gestational weight gain (GWG) is associated with increased birth weight and neonatal adiposity. However, timing of excessive GWG may have a differential impact on birth outcomes. The objective of this study was to compare the effect of early and mid/late excessive GWG on newborn anthropometry in the context of the Canadian clinical recommendations that are specific for first trimester and for second/third trimesters based on maternal pre-pregnancy BMI. METHODS: We included 607 glucose-tolerant women in our main analyses, after excluding women who had less than the recommended total GWG. Maternal body weight was measured in early pregnancy, mid-pregnancy, and late pregnancy. Maternal and fetal clinical outcomes were collected, including newborn anthropometry. Women were divided into four groups according to the Canadian guidelines for GWG in the first and in the second/third trimesters: (1) "overall non-excessive" (reference group); (2) "early excessive GWG"; (3) "mid/late excessive GWG"; and (4) "overall excessive GWG." Differences in newborn anthropometry were tested across GWG categories. RESULTS: Women had a mean (±SD) pre-pregnancy BMI of 24.7 ± 5.2 kg/m(2) and total GWG of 15.3 ± 4.4 kg. Women with mid/late excessive GWG gave birth to heavier babies (gestational age-adjusted birth weight z-score 0.33 ± 0.91) compared with women in the reference group (0.00 ± 0.77, P = 0.007), whereas women with early excessive GWG gave birth to babies of similar weight (gestational age-adjusted z-score 0.01 ± 0.86) to the reference group (0.00 ± 0.77, P = 0.84). When we stratified our analyses and investigated women who gained within the recommendations for total GWG, mid/late excessive GWG specifically was associated with greater newborn size, similar to our main analyses. CONCLUSION: Excessive GWG in mid/late pregnancy in women who did not gain weight excessively in early pregnancy is associated with increased birth size, even in those who gained within the Canadian recommendations for total GWG.

Higher maternal leptin levels at second trimester are associated with subsequent greater gestational weight gain in late pregnancy.

BACKGROUND: Excessive gestational weight gain (GWG) is associated with adverse pregnancy outcomes. In non-pregnant populations, low leptin levels stimulate positive energy balance. In pregnancy, both the placenta and adipose tissue contribute to circulating leptin levels. We tested whether maternal leptin levels are associated with subsequent GWG and whether this association varies depending on stage of pregnancy and on maternal body mass index (BMI). METHODS: This prospective cohort study included 675 pregnant women followed from 1(st) trimester until delivery. We collected anthropometric measurements, blood samples at 1(st) and 2(nd) trimester, and clinical data until delivery. Maternal leptin was measured by ELISA (Luminex technology). We classified women by BMI measured at 1(st) trimester: BMI < 25 kg/m(2) = normal weight; 25 ≤ BMI < 30 kg/m(2) = overweight; and BMI ≥ 30 kg/m(2) = obese. RESULTS: Women gained a mean of 6.7 ± 3.0 kg between 1(st) and 2(nd) trimester (mid pregnancy GWG) and 5.6 ± 2.5 kg between 2(nd) and the end of 3(rd) trimester (late pregnancy GWG). Higher 1(st) trimester leptin levels were associated with lower mid pregnancy GWG, but the association was no longer significant after adjusting for % body fat (%BF; ß = 0.38 kg per log-leptin; SE = 0.52; P = 0.46). Higher 2(nd) trimester leptin levels were associated with greater late pregnancy GWG and this association remained significant after adjustment for BMI (ß = 2.35; SE = 0.41; P < 0.0001) or %BF (ß = 2.01; SE = 0.42; P < 0.0001). In BMI stratified analyses, higher 2(nd) trimester leptin levels were associated with greater late pregnancy GWG in normal weight women (ß = 1.33; SE = 0.42; P =0.002), and this association was stronger in overweight women (ß = 2.85; SE = 0.94; P = 0.003--P for interaction = 0.05). CONCLUSIONS: Our results suggest that leptin may regulate weight gain differentially at 1(st) versus 2(nd) trimester of pregnancy: at 2(nd) trimester, higher leptin levels were associated with greater subsequent weight gain--the opposite of its physiologic regulation in non-pregnancy--and this association was stronger in overweight women. We suspect the existence of a feed-forward signal from leptin in second half of pregnancy, stimulating a positive energy balance and leading to greater weight gain.

Genetics of Glucose regulation in Gestation and Growth (Gen3G): a prospective prebirth cohort of mother-child pairs in Sherbrooke, Canada.

PURPOSE: We initiated the Genetics of Glucose regulation in Gestation and Growth (Gen3G) prospective cohort to increase our understanding of biological, environmental and genetic determinants of glucose regulation during pregnancy and their impact on fetal development. PARTICIPANTS: Between January 2010 and June 2013, we invited pregnant women aged ≥ 18 years old who visited the blood sampling in pregnancy clinic in Sherbrooke for their first trimester clinical blood samples: 1034 women accepted to participate in our cohort study. FINDINGS TO DATE: At first and second trimester, we collected demographics and lifestyle questionnaires, anthropometry measures (including fat and lean mass estimated using bioimpedance), blood pressure, and blood samples. At second trimester, women completed a full 75 g oral glucose tolerance test and we collected additional blood samples. At delivery, we collected cord blood and placenta samples; obstetrical and neonatal clinical data were abstracted from electronic medical records. We also collected buffy coats and extracted DNA from maternal and/or offspring samples (placenta and blood cells) to pursue genetic and epigenetic hypotheses. So far, we have found that low adiponectin and low vitamin D maternal levels in first trimester predict higher risk of developing gestational diabetes. FUTURE PLANS: We are now in the phase of prospective follow-up of mothers and offspring 3 and 5 years postdelivery to investigate the consequences of maternal dysglycaemia during pregnancy on offspring adiposity and metabolic profile. TRIAL REGISTRATION NUMBER: NCT01623934.

Preeclampsia is associated with an increased pro-inflammatory profile in newborns.

Hypertensive disorders of pregnancy (HDP) lead to high rates of maternal and fetal morbidity. Existing studies on inflammatory marker TNFα in HDP offspring are inconsistent. We performed a population-based cohort study of 636 pregnancies, including normotensive (NT) women and women with preeclampsia (PE) or gestational hypertension (GH). TNFα was measured in maternal blood in the first and second trimesters and in cord blood at the time of delivery. Cord blood TNFα was higher in offspring delivered of women with PE (6.53 [4.94-8.38]pg/mL) versus those delivered of NT women (5.13 [4.11-6.72]pg/mL; p=0.01), independent of confounders. Maternal TNFα levels were not different among groups (p>0.1) in either the first or second trimester.

TNFα dynamics during the oral glucose tolerance test vary according to the level of insulin resistance in pregnant women.

INTRODUCTION: TNFα is suspected to play a role in inflammation and insulin resistance leading to higher risk of metabolic impairment. Controversies exist concerning the role of TNFα in gestational insulin resistance. We investigated the interrelations between TNFα and insulin resistance in a large population-based cohort of pregnant women. METHODS: Women (n = 756) were followed prospectively at 5-16 weeks and 24-28 weeks of pregnancy. Anthropometric measures and blood samples were collected at both visits. A 75-g oral glucose tolerance test (OGTT) was conducted at the second trimester to assess insulin sensitivity status (homeostasis model of assessment of insulin resistance and Matsuda index). TNFα was measured at the first trimester (nonfasting) and at each time point of the OGTT. RESULTS: Participants were 28.4 ± 4.4 years old and had a mean body mass index of 25.5 ± 5.5 kg/m(2) at first trimester. Median TNFα levels were 1.56 (interquartile range, 1.18-2.06) pg/mL at first trimester and 1.61 (interquartile range, 1.12-2.13) pg/mL at second trimester (1 h after glucose load). At second trimester, higher TNFα levels were associated with higher insulin resistance index levels (r = 0.37 and -0.30 for homeostasis model of assessment of insulin resistance and Matsuda index, respectively; P < .0001), even after adjustment for age, body mass index, triglycerides, and adiponectin. Women with higher insulin resistance showed a continuing decrease in TNFα levels during the OGTT, whereas women who were more insulin sensitive showed an increase in TNFα at hour 1 and a decrease at hour 2 of the test. CONCLUSION: Higher insulin resistance is associated with higher levels of circulating TNFα at first and second trimesters of pregnancy. TNFα level dynamics during an OGTT at second trimester vary according to insulin-resistance state.