Association between maternal thyroid function and risk of gestational hypertension and pre-eclampsia: a systematic review and individual-participant data meta-analysis

Background: Adequate maternal thyroid function is important for an uncomplicated pregnancy. Although multiple observational studies have evaluated the association between thyroid dysfunction and hypertensive disorders of pregnancy, the methods and definitions of abnormalities in thyroid function tests were heterogeneous, and the results were conflicting. We aimed to examine the association between abnormalities in thyroid function tests and risk of gestational hypertension and pre-eclampsia. Methods: In this systematic review and meta-analysis of individual-participant data, we searched MEDLINE (Ovid), Embase, Scopus, and the Cochrane Database of Systematic Reviews from date of inception to Dec 27, 2019, for prospective cohort studies with data on maternal concentrations of thyroid-stimulating hormone (TSH), free thyroxine (FT4), thyroid peroxidase (TPO) antibodies, individually or in combination, as well as on gestational hypertension, pre-eclampsia, or both. We issued open invitations to study authors to participate in the Consortium on Thyroid and Pregnancy and to share the individual-participant data. We excluded participants who had pre-existing thyroid disease or multifetal pregnancy, or were taking medications that affect thyroid function. The primary outcomes were documented gestational hypertension and pre-eclampsia. Individual-participant data were analysed using logistic mixed-effects regression models adjusting for maternal age, BMI, smoking, parity, ethnicity, and gestational age at blood sampling. The study protocol was registered with PROSPERO, CRD42019128585. Findings: We identified 1539 published studies, of which 33 cohorts met the inclusion criteria and 19 cohorts were included after the authors agreed to participate. Our study population comprised 46 528 pregnant women, of whom 39 826 (85·6%) women had sufficient data (TSH and FT4 concentrations and TPO antibody status) to be classified according to their thyroid function status. Of these women, 1275 (3·2%) had subclinical hypothyroidism, 933 (2·3%) had isolated hypothyroxinaemia, 619 (1·6%) had subclinical hyperthyroidism, and 337 (0·8%) had overt hyperthyroidism. Compared with euthyroidism, subclinical hypothyroidism was associated with a higher risk of pre-eclampsia (2·1% vs 3·6%; OR 1·53 [95% CI 1·09–2·15]). Subclinical hyperthyroidism, isolated hypothyroxinaemia, or TPO antibody positivity were not associated with gestational hypertension or pre-eclampsia. In continuous analyses, both a higher and a lower TSH concentration were associated with a higher risk of pre-eclampsia (p=0·0001). FT4 concentrations were not associated with the outcomes measured. Interpretation: Compared with euthyroidism, subclinical hypothyroidism during pregnancy was associated with a higher risk of pre-eclampsia. There was a U-shaped association of TSH with pre-eclampsia. These results quantify the risks of gestational hypertension or pre-eclampsia in women with thyroid function test abnormalities, adding to the total body of evidence on the risk of adverse maternal and fetal outcomes of thyroid dysfunction during pregnancy. These findings have potential implications for defining the optimal treatment target in women treated with levothyroxine during pregnancy, which needs to be assessed in future interventional studies

Marques epigenètiques del desenvolupament prenatal: prevenció del risc cardiovascular i la obesitat en la infància

Epigenètica; Desenvolupament prenatal; Risc cardiovascular en la infància; Obesitat en la infànciaEpigenetics; Prenatal development; Cardiovascular risk in childhood; Childhood obesityEpigenética; Desarrollo prenatal; Riesgo cardiovascular en la infancia; Obesidad en la infanciaComunicació sobre com les marques epigenètiques del desenvolupament prenatal poden ser d'utilitat per a la identificació de nounats amb major susceptibilitat de patir malalties metabòliques en la vida adulta

Central Obesity, Faster Maturation, and 'PCOS' in Girls

Polycystic ovary syndrome (PCOS) development commonly starts with a mismatch between pre- and postnatal weight gain, leading to hepatovisceral fat excess. To escape from such central obesity, girls may accelerate their growth and/or maturation. This homeostatic mechanism is lost upon reaching adult height, and PCOS may ensue. Prevention and/or treatment of PCOS should aim at reducing central fat excess.status: publishe

Low Circulating Levels of miR-451a in Girls with Polycystic Ovary Syndrome: Different Effects of Randomized Treatments

CONTEXT: Polycystic ovary syndrome (PCOS) is a prevalent disorder in adolescent girls, purportedly driven by hepato-visceral fat excess, and often followed by subfertility and type 2 diabetes. OBJECTIVE: We studied the baseline microRNA (miRNA) profile of girls with PCOS, and the effects of a randomized treatment with an oral contraceptive (OC) or with spironolactone-pioglitazone-metformin (SPIOMET, aiming at loss of hepato-visceral fat excess) for 1 year. DESIGN & PATIENTS: The miRNA profile was assessed by RNA sequencing in girls with PCOS who had participated in a randomized, open-label, single-center, pilot study (n = 31; age 15.7 years, body mass index (BMI) 23.1 kg/m2). Healthy age- and BMI-matched girls (n = 13) served as controls. Differentially expressed miRNAs were validated by RT-qPCR in the entire study population. Post-treatment ovulation rates were assessed by salivary progesterone in PCOS girls. SETTING: Endocrinology Department, University Hospital. RESULTS: Girls with PCOS, compared with controls, had markedly reduced concentrations of circulating miR-451a, miR-652-3p, miR-106b-5p, and miR-206; pathway enrichment analysis showed that these miRNAs target genes involved in energy homeostasis and cell cycle control. In the present study, miR-451a could diagnose PCOS with 100% sensitivity and 100% specificity. SPIOMET (but not OC) was accompanied by on-treatment normalization of the miRNA profile in girls with PCOS; miR-451a concentrations after 1 year on OC or SPIOMET treatment associated closely (r = 0.66; P < .0001) with post-treatment ovulation rates. CONCLUSION: SPIOMET treatment for 1 year normalizes the miRNA profile of girls with PCOS. Circulating miR-451a may become a biomarker to guide the diagnosis and treatment of PCOS in adolescence.status: publishe

( )Toward a Treatment Normalizing Ovulation Rate in Adolescent Girls With Polycystic Ovary Syndrome

Adolescent polycystic ovary syndrome (PCOS) is characterized by androgen excess and oligomenorrhea, and commonly driven by hepato-visceral fat excess ("central obesity") ensuing from a mismatch between prenatal and postnatal nutrition, on a background of genetic susceptibility. There is no approved treatment for adolescent PCOS. We report the pooled results of 2 pilot studies in nonobese girls with PCOS (N = 62, age 15.8 years) that compared the effects of randomized treatment for 1 year, either with an oral estro-progestogen contraceptive (OC), or with a low-dose combination of spironolactone-pioglitazone-metformin (SPIOMET, targeting the excess of ectopic fat). Auxological and endocrine-metabolic variables (including fasting insulin, androgens, high-molecular-weight adiponectin [HMW-adiponectin], and microRNA [miR]-451a), body composition (dual x-ray absorptiometry) and hepato-visceral fat (magnetic resonance imaging) were assessed on- and posttreatment. Data from menstrual diaries were combined with weekly salivary progesterone measurements to infer ovulation rates during the second and fourth quarter of the posttreatment year. OC and SPIOMET treatment reduced the androgen excess comparably, and had no differential effects on total-body lean or fat mass. However, SPIOMET was accompanied by more broadly normalizing effects, including on hepato-visceral fat and on circulating insulin, HMW-adiponectin, and miR-451a. On average, there were 3-fold more ovulations post-SPIOMET than post-OC; normovulation was only observed after SPIOMET; anovulation was >10-fold more prevalent post-OC. Pooled results of randomized studies in nonobese adolescent girls with PCOS indicate that SPIOMET treatment leads to an overall healthier, more insulin-sensitive condition-with less ectopic fat-than OC treatment, and to a more normal posttreatment ovulation rate.status: publishe

Circulating growth-and-differentiation factor-15 in early life: relation to prenatal and postnatal growth and adiposity measurements

BACKGROUND: Growth-and-differentiation-factor-15 (GDF15) is a regulator of energy homeostasis. To determine the relationship between circulating GDF15 and parameters of metabolic health, we assessed longitudinally GDF15 concentrations in infants born either appropriate- (AGA) or small-for-gestational-age (SGA), the latter population known to be at risk for metabolic alterations, particularly after a rapid postnatal catch-up in weight. METHODS: The study cohort consisted of 103 infants (70 AGA and 33 SGA). Assessments included body length, weight, and ponderal index (PI); fasting glucose, insulin, IGF-I, high-molecular-weight adiponectin, GDF15; and body composition (by absorptiometry) at birth, and at age 4, 12 and 24 months. RESULTS: GDF15 levels at birth were significantly higher than those at each subsequent time point and were similar in AGA and SGA subjects. GDF15 concentrations dropped at age 4 months, more substantially in SGA infants, and continued to decline in both subgroups reaching adult concentrations by age 24 months. GDF15 levels correlated inversely with the changes in PI, IGF-I and body fat throughout follow-up. CONCLUSIONS: Early life is associated with supra-adult concentrations of GDF15. The lower levels of GDF15 in SGA subjects may be an adaptive mechanism to promote catch-up in weight and might increase the risk for obesity later in life.status: publishe

Brown adipose tissue in prepubertal children: associations with sex, birthweight, and metabolic profile

BACKGROUND/OBJECTIVES: Individuals born small-for-gestational age (SGA), especially those who experience postnatal catch-up growth, are at increased risk for developing endocrine-metabolic abnormalities before puberty. In adults, brown adipose tissue (BAT) has been associated with protection against metabolic disorders, such as obesity, type 2 diabetes, and dyslipidaemia. Here, we assessed for the first time whether BAT activation differs between prepubertal children born SGA or appropriate-for-gestational age (AGA). SUBJECTS/METHODS: The study population consisted of 86 prepubertal children [41 AGA and 45 SGA; age (mean ± SEM), 8.5 ± 0.1 years], recruited into two prospective longitudinal studies assessing endocrine-metabolic status and body composition in infancy and childhood. The temperature at the supraclavicular region (SCR) before and after a cold stimulus was measured by infrared thermal imaging, and the area of thermally active SCR (increase after cold challenge, ΔAreaSCR) was calculated as a surrogate index of BAT activation. The results were correlated with clinical, endocrine-metabolic, and inflammation variables, and with visceral and hepatic adiposity (assessed by Magnetic Resonance Imaging). RESULTS: No differences in BAT activation index, as judged by ΔAreaSCR, were found between AGA and SGA children. However, girls showed higher baseline and post-cold induction AreaSCR than boys (both p ≤ 0.01). An interaction between gender and birth weight subgroup was observed for BAT activation; AGA girls increased significantly the ΔAreaSCR as compared to AGA boys; this increase did not occur in SGA girls vs SGA boys. Cold-induced ΔAreaSCR negatively correlated with HOMA-IR, us-CRP, liver volume, and liver fat. CONCLUSIONS: Prepubertal AGA girls had significantly greater BAT activation index as compared to AGA boys; this difference was not observed in SGA subjects. Higher BAT activation associated with a lower amount of visceral fat and with a favorable metabolic profile. Long-term follow-up is needed to determine whether those differences relate to pubertal timing, and to the development of obesity and metabolic disorders.status: publishe

Dlk1 expression relates to visceral fat expansion and insulin resistance in male and female rats with postnatal catch-up growth

BACKGROUND: Although prenatal and postnatal programming of metabolic diseases in adulthood is well established, the mechanisms underpinning metabolic programming are not. Dlk1, a key regulator of fetal development, inhibits adipocyte differentiation and restricts fetal growth. METHODS: Assess DLk1 expression in a Wistar rat model of catch-up growth following intrauterine restriction. Dams fed ad libitum delivered control pups (C) and dams on a 50% calorie-restricted diet delivered pups with low birth weight (R). Restricted offspring fed a standard rat chow showed catch-up growth (R/C) but those kept on a calorie-restricted diet did not (R/R). RESULTS: Decreased Dlk1 expression was observed in adipose tissue and skeletal muscle of R/C pups along with excessive visceral fat accumulation, decreased circulating adiponectin, increased triglycerides and HOMA-IR (from p < 0.05 to p < 0.0001). Moreover, in R/C pups the reduced Dlk1 expression in adipose tissue and skeletal muscle correlated with visceral fat (r = -0.820, p < 00001) and HOMA-IR (r = -0.745, p = 0.002). CONCLUSIONS: Decreased Dlk1 expression relates to visceral fat expansion and insulin resistance in a rat model of catch-up growth following prenatal growth restriction. Modulation of Dlk1 expression could be among the targets for the early prevention of fetal programming of adult metabolic disorders.status: publishe

Serum 25-hydroxyvitamin D and cardiovascular disease risk factors in women with excessive weight gain during pregnancy and in their offspring at age 5-6 years

BACKGROUND/OBJECTIVE: Low 25-hydroxyvitamin D levels [25(OH)D] may increase the risk for cardiovascular disease (CVD). In pregnant women excessive weight gain and 25(OH)D deficiency are common complications and both could have deleterious consequences on their children. We aimed to study the relationship between serum 25(OH)D and CVD risk factors in pregnant women and in their offspring at school age. SUBJECTS/METHODS: Fasting serum 25(OH)D and its bioavailable fraction were quantified in 310 healthy pregnant women [with adequate (n = 113), insufficient (n = 113) and excessive (n = 84) weight gain]. A follow-up at 5-6 years was performed in sixty-six children born of these mothers. Lipids, insulin, glucose, and high-sensitivity C-reactive protein (hsCRP) were measured in all subjects. Children's carotid intima-media thickness (cIMT) together with visceral and intra-abdominal fat were measured by ultrasonography. RESULTS: Lower maternal 25(OH)D concentrations were associated with lower maternal age, and higher body mass index, triglycerides and hsCRP (all p < 0.05). In women with excessive weight gain during gestation, serum 25(OH)D concentrations showed independent associations with maternal hsCRP (β = -0.283 p = 0.03) and triglycerides (β = -0.436, p = 0.005). Maternal serum 25(OH)D concentrations were also independently associated with cIMT (β = -0.288, p = 0.04), visceral fat (β = -0.281, p = 0.01) and intra-abdominal fat (β = -0.248, p = 0.01) in their children at 5-6 years. CONCLUSIONS: Lower serum 25(OH)D concentrations were related to CVD risk factors in pregnant woman and in their offspring. The cardiometabolic consequences of low 25(OH)D concentrations during pregnancy could be aggravated by excessive weight gain during gestation.status: publishe