Pregnancy and Perinatal Outcome Among Hypothyroid Mothers: A Population-Based Cohort Study.

BACKGROUND: Maternal hypothyroidism has been associated with adverse pregnancy outcomes. A large nationwide register-based cohort with data on medication purchases was established to study the associations between maternal hypothyroidism, levothyroxine (LT4) use, and pregnancy and perinatal complications. METHODS: The data included all singleton births between 2004 and 2013 (N = 571,785) in Finland. Hypothyroid mothers (n = 16,364) were identified in the Finnish Medical Birth Register. Of these women, 95.8% used LT4 medication, and 37.5% had consistent LT4 use during pregnancy. Hypothyroid mothers were compared to mothers without thyroid disease (N = 550,860) using logistic regression. The main outcome measures were pregnancy and perinatal complications. RESULTS: Maternal hypothyroidism was associated with several pregnancy and perinatal complications, including gestational diabetes mellitus (odds ratio [OR] = 1.19 [confidence interval (CI) 1.13-1.25]), gestational hypertension (OR = 1.20 [CI 1.10-1.30]), severe preeclampsia (OR = 1.38 [CI 1.15-1.65]), cesarean section (OR = 1.22 [CI 1.17-1.27]), preterm births (OR = 1.25 [CI 1.16-1.34]), large-for-gestational age newborns (OR = 1.30 [CI 1.19-1.42]), major congenital anomalies (OR = 1.14 [CI 1.06-1.22]), and neonatal intensive care unit admission (OR = 1.23 [CI 1.17-1.29]). However, among mothers with consistent LT4 purchases, only the associations between gestational diabetes mellitus (OR = 1.12 [CI 1.03-1.22]), cesarean section (OR = 1.13 [CI 1.06-1.21]), neonatal intensive care unit admission (OR = 1.09 [CI 1.01-1.29]), and large-for-gestational age newborns (OR = 1.26 [CI 1.10-1.45]) and maternal hypothyroidism remained. CONCLUSIONS: Maternal hypothyroidism is associated with several pregnancy and perinatal complications, but consistent LT4 use may reduce many of the risks.

Maternal Thyroid Function During Pregnancy and the Child's Linguistic and Sensory Development in the Northern Finland Birth Cohort 1986.

BACKGROUND: Maternal hypothyroidism and hypothyroxinemia are associated with poor neuropsychological development in children. Previous research is lacking on whether maternal thyroid dysfunction affects sensory and linguistic development in childhood. METHODS: The Northern Finland Birth Cohort 1986 included all births within a year (9,362 women, 9,479 children) from the two northernmost Finnish provinces. Maternal serum samples (n = 5,791) were obtained in early pregnancy and analyzed for TSH, free T4, and thyroid peroxidase antibodies (TPO-Abs). Five thousand three hundred and ninety-one parents evaluated their child's sensory and linguistic development at 7 years old via a questionnaire (excluding children with an intelligence quotient ≤85). The prevalence of sensory and linguistic impairments was compared between mothers with and without thyroid dysfunction. RESULTS: There were no statistically significant differences in the prevalence of sensory or linguistic impairment between children of mothers with and without thyroid dysfunction. Children of hypothyroid and hypothyroxinemic mothers had an increased prevalence of vision impairment compared with those of euthyroid mothers (10.8 and 11.7%, respectively, versus 6.5%), but the difference was not significant. All results remained similar after excluding TPO-Ab-positive mothers and premature children. CONCLUSION: We did not find an association between maternal thyroid dysfunction during pregnancy and sensory and linguistic development impairment in childhood. A somewhat higher prevalence of vision impairment was seen in children of hypothyroid and hypothyroxinemic mothers, which merits further research.

Maternal Thyroid Antibodies Associates With Cardiometabolic Risk Factors in Children at the Age of 16.

Context and Objective: The objective of this study was to determine the effects of maternal thyroid dysfunction or antibodies during pregnancy on the cardiometabolic risk factors in children. Design, Setting, and Participants: This prospective population-based cohort study, Northern Finland Birth Cohort 1986, included all pregnancies within a year in the area. Maternal serum samples were collected before the 20th week of gestation and analyzed for thyrotropin, free T4, thyroid-peroxidase antibodies (TPO-Abs), and thyroglobulin antibodies (Tg-Abs). Cardiometabolic risk factors in children at the age of 16 years were evaluated via blood sampling and clinical examination. Data were available for 3229 to 4176 mother-child pairs. Main Outcome Measures: Waist circumference, blood pressure, lipids and lipoproteins, and insulin resistance were measured. Odds ratios (ORs) with 95% confidence intervals (CIs) of cardiometabolic risk factors in children with and without mothers with thyroid dysfunction or antibodies were calculated with logistic regression and adjusted for covariates. Results: Children of TPO-Ab-positive mothers had higher odds of metabolic syndrome (OR, 2.57; 95%, CI 1.26 to 5.25) and waist circumference indicative of metabolic syndrome (OR, 1.69; 95% CI, 1.14 to 2.50). They were also more likely to be overweight or obese (OR, 1.56; 95% CI, 1.04 to 2.34). Maternal thyroid dysfunction or Tg-Ab positivity did not associate with cardiometabolic risk factors in children. Conclusion: Metabolic syndrome, greater waist circumference, and higher body mass index were more prevalent in children of TPO-Ab-positive mothers, indicating an adverse cardiovascular health profile.

Genome-wide association analysis identifies three new susceptibility loci for childhood body mass index.

A large number of genetic loci are associated with adult body mass index. However, the genetics of childhood body mass index are largely unknown. We performed a meta-analysis of genome-wide association studies of childhood body mass index, using sex- and age-adjusted standard deviation scores. We included 35 668 children from 20 studies in the discovery phase and 11 873 children from 13 studies in the replication phase. In total, 15 loci reached genome-wide significance (P-value < 5 × 10(-8)) in the joint discovery and replication analysis, of which 12 are previously identified loci in or close to ADCY3, GNPDA2, TMEM18, SEC16B, FAIM2, FTO, TFAP2B, TNNI3K, MC4R, GPR61, LMX1B and OLFM4 associated with adult body mass index or childhood obesity. We identified three novel loci: rs13253111 near ELP3, rs8092503 near RAB27B and rs13387838 near ADAM23. Per additional risk allele, body mass index increased 0.04 Standard Deviation Score (SDS) [Standard Error (SE) 0.007], 0.05 SDS (SE 0.008) and 0.14 SDS (SE 0.025), for rs13253111, rs8092503 and rs13387838, respectively. A genetic risk score combining all 15 SNPs showed that each additional average risk allele was associated with a 0.073 SDS (SE 0.011, P-value = 3.12 × 10(-10)) increase in childhood body mass index in a population of 1955 children. This risk score explained 2% of the variance in childhood body mass index. This study highlights the shared genetic background between childhood and adult body mass index and adds three novel loci. These loci likely represent age-related differences in strength of the associations with body mass index.

Sixteen new lung function signals identified through 1000 Genomes Project reference panel imputation.

Lung function measures are used in the diagnosis of chronic obstructive pulmonary disease. In 38,199 European ancestry individuals, we studied genome-wide association of forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC) and FEV1/FVC with 1000 Genomes Project (phase 1)-imputed genotypes and followed up top associations in 54,550 Europeans. We identify 14 novel loci (P<5 × 10(-8)) in or near ENSA, RNU5F-1, KCNS3, AK097794, ASTN2, LHX3, CCDC91, TBX3, TRIP11, RIN3, TEKT5, LTBP4, MN1 and AP1S2, and two novel signals at known loci NPNT and GPR126, providing a basis for new understanding of the genetic determinants of these traits and pulmonary diseases in which they are altered.

Maternal and Child's Thyroid Function and Child's Intellect and Scholastic Performance.

BACKGROUND: Maternal hypothyroidism and/or hypothyroxinemia have been associated with child's poor neuropsychological development, but the results have been inconsistent. METHODS: The Northern Finland Birth Cohort 1986 included all expected births within a year (9362 women, 9479 children) from the two northernmost provinces of Finland. Maternal serum samples (n = 5791) were obtained in early pregnancy (M ± SD = 10.7 ± 2.8 weeks' gestation), and serum samples from their children were obtained at 16 years of age (n = 5829). All samples were analyzed for thyrotropin, free thyroxine (fT4), and thyroid peroxidase antibodies. The children's school performance was evaluated by their main teachers at eight years of age, as well as by the adolescents themselves at 16 years of age. Data on possible severe intellectual deficiency and mild cognitive limitation were collected from healthcare records and registries for all children. Logistic regression estimated the odds of poor school performance or severe intellectual deficiency/mild cognitive limitation associated with exposure to maternal thyroid dysfunction. The odds of poor school performance associated with the adolescents' own thyroid function at age 16 were also estimated. Results are presented as odds ratios (OR) with confidence intervals (CI), adjusted for maternal/family covariates and child's sex. RESULTS: Girls of mothers with subclinical hypothyroidism had more self-evaluated difficulties in mathematics than did girls of euthyroid mothers (OR 1.62 [CI 1.06-2.49]). Boys of hypothyroxinemic mothers repeated a school class more often than did boys of euthyroid mothers (OR 5.46 [CI 1.19-25.06]). Adolescents of hyperthyroid mothers had increased odds of poor self-evaluated performance in mathematics (OR 1.61 [CI 1.01-2.49]). Maternal thyroid dysfunction did not increase the odds of a child having severe intellectual deficiency/mild cognitive limitation. At 16 years of age, girls with hyperthyroidism by laboratory measurements had more difficulties in Finnish language (OR 2.82 [CI 1.42-5.61]) than did euthyroid girls. Boys with hypothyroxinemia by laboratory measurement had higher odds of having difficulties in Finnish and/or mathematics (OR 2.13 [CI 1.26-3.62]) than did euthyroid boys. CONCLUSIONS: Maternal thyroid dysfunction during early pregnancy was associated with poorer scholastic performance of the adolescent. Additionally, adolescents' own thyroid dysfunction was associated with difficulties in school performance assessed by self-evaluation.

Farm environment during infancy and lung function at the age of 31: a prospective birth cohort study in Finland.

OBJECTIVES: Farming as an occupation is considered a risk factor for asthma and reduced lung function. By contrast, living on a farm during infancy has been reported to be associated with lower risk of asthma in adulthood. However, little is known about the association between farming environment during infancy and lung function in adulthood. We aimed to study the prospective longitudinal association between farming environment during infancy and lung function in adulthood. DESIGN: A prospective birth cohort study. SETTING: Northern Finland. PARTICIPANTS: 5666 participants born in 1966 were followed up at the age of 31 years. PRIMARY OUTCOME MEASURES: Spirometry at the age of 31 years. RESULTS: To be born into a farmer's family was associated with higher forced expiratory volume in 1 s (FEV1) (36 mL; 95% CI 6 to 67 mL) and forced vital capacity (FVC) (40 mL; 95% CI 5 to 75 mL) at the age of 31 years. Contact with farm animals during infancy was associated with higher FEV1. No associations were seen with FEV1/FVC (FEV1/FVC ratio). Having dogs in childhood revealed similar associations. There was a suggestive dose-dependent association with the number of animal species during childhood and higher FEV1 and FVC at adulthood, especially among women. CONCLUSIONS: Farming environment in early life may have a positive impact on lung function in adulthood.

Life course structural equation model of the effects of prenatal and postnatal growth on adult blood pressure.

BACKGROUND: Fetal and postnatal growth have been associated with adult blood pressure (BP), but findings about the relative importance of growth at different stages of life on BP are inconsistent. METHODS: The study population comprised 5198 participants from the Northern Finland Birth Cohort 1966 with data on birth weight, height and weight measurements until adolescence, systolic and diastolic BP at 31 years and several covariates. Structural equation modelling was used in the analysis. RESULTS: Negative direct effects of birth weight on adult systolic BP were observed (standardised regression coefficients: -0.08 (-0.14 to -0.03) in males and -0.04 (-0.09 to 0.01) in females, equalling -1.99 (-3.32 to -0.65) and -1.01 (-2.33 to 0.32) mm Hg/kg, respectively). Immediate postnatal growth was associated with adult BP only indirectly via growth later in life. In contrast, growth from adiposity rebound onwards had large direct, indirect and total effects on adult BP. Current body mass index was the strongest growth-related predictor of adult BP (0.36 (0.30 to 0.41) in males and 0.31 (0.24, 0.37) in females, equalling 1.29 (1.09 to 1.48) and 0.81 (0.63 to 0.99) mm Hg/(kg/m(2)), respectively). CONCLUSIONS: Our path analytical approach provides evidence for the importance of both fetal growth and postnatal growth, especially from adiposity rebound onwards, in determining adult BP, together with genetic predisposition and behavioural factors.

Infant locomotive development and its association with adult blood pressure.

UNLABELLED: Evidence from animal models suggests that locomotion and blood pressure share common neurophysiological regulatory systems. As a result of this common regulation, we hypothesized that the development of locomotion in human infants would be associated with blood pressure levels in adulthood. The study sample comprised 4,347 individuals with measures of locomotive and non-locomotive neuromotor development in infancy and adult blood pressure levels within a longitudinal birth cohort study, the Northern Finland Birth Cohort 1966. Later development in all three stages of locomotive development during infancy was associated with higher systolic and diastolic blood pressure levels at age 31. For age of walking without support, 0.34 (95 % CI 0.07 to 0.60)-mm Hg higher SBP and 0.38 (95 % CI 0.15 to 0.62)-mm Hg higher DBP were estimated for each month of later achievement (P = 0.012 for SBP; P = 0.001 for DBP). No association was identified for non-locomotive neuromotor development. CONCLUSION: These results highlight the positive sequelae of advanced locomotive development during infancy, suggesting that the common regulatory systems between locomotion and blood pressure may influence the development of raised blood pressure over time.

The impact of gestational thyroid hormone concentrations on ADHD symptoms of the child.

CONTEXT: Maternal hypothyroidism during pregnancy is associated with adverse neuropsychological development in the offspring. OBJECTIVE: The objective of the study was to evaluate the effect of maternal thyroid dysfunction during pregnancy on a child's attention-deficit/hyperactivity disorder (ADHD) symptoms. DESIGN, SETTINGS, AND PARTICIPANTS: The prospective, population-based Northern Finland Birth Cohort 1986 (9362 pregnancies; 9479 infants) included analysis of maternal TSH, free T4, and thyroid-peroxidase antibodies (TPO-Abs) from early pregnancy samples (5791 women). Teachers evaluated the children's ADHD symptoms at 8 years using the Rutter B2 scale (5131 mother-child pairs), in which a high score indicated probable psychiatric disorders and three questions focused directly on ADHD. MAIN OUTCOME MEASURES: The odds ratios (ORs) and 95% confidence intervals (95% CIs) of child having ADHD symptoms and/or a high Rutter B2 score after exposure to increases in maternal TSH levels (after logarithmic transformation), low free T4 levels, and TPO-Ab positivity was tested with logistic regression, adjusting for maternal/family covariates. Data were stratified by the child's gender due to interaction. RESULTS: Among girls the odds of inattention (OR 1.18, 95% CI 1.02-1.37), high Rutter B2 total score (OR 1.23, 95% CI 1.03-1.48), and combined ADHD symptoms (OR 1.39, 95% CI 1.07-1.80) significantly increased with every natural log increase in maternal TSH concentrations. Such findings were not evident in boys. No associations were seen between ADHD symptoms and low maternal free T4 levels or TPO-Ab positivity. CONCLUSIONS: Increases in maternal TSH in early pregnancy showed weak but significant association with girls' ADHD symptoms.

Dysregulation of complement system and CD4+ T cell activation pathways implicated in allergic response.

Allergy is a complex disease that is likely to involve dysregulated CD4+ T cell activation. Here we propose a novel methodology to gain insight into how coordinated behaviour emerges between disease-dysregulated pathways in response to pathophysiological stimuli. Using peripheral blood mononuclear cells of allergic rhinitis patients and controls cultured with and without pollen allergens, we integrate CD4+ T cell gene expression from microarray data and genetic markers of allergic sensitisation from GWAS data at the pathway level using enrichment analysis; implicating the complement system in both cellular and systemic response to pollen allergens. We delineate a novel disease network linking T cell activation to the complement system that is significantly enriched for genes exhibiting correlated gene expression and protein-protein interactions, suggesting a tight biological coordination that is dysregulated in the disease state in response to pollen allergen but not to diluent. This novel disease network has high predictive power for the gene and protein expression of the Th2 cytokine profile (IL-4, IL-5, IL-10, IL-13) and of the Th2 master regulator (GATA3), suggesting its involvement in the early stages of CD4+ T cell differentiation. Dissection of the complement system gene expression identifies 7 genes specifically associated with atopic response to pollen, including C1QR1, CFD, CFP, ITGB2, ITGAX and confirms the role of C3AR1 and C5AR1. Two of these genes (ITGB2 and C3AR1) are also implicated in the network linking complement system to T cell activation, which comprises 6 differentially expressed genes. C3AR1 is also significantly associated with allergic sensitisation in GWAS data.

The role of adiposity in cardiometabolic traits: a Mendelian randomization analysis.

BACKGROUND: The association between adiposity and cardiometabolic traits is well known from epidemiological studies. Whilst the causal relationship is clear for some of these traits, for others it is not. We aimed to determine whether adiposity is causally related to various cardiometabolic traits using the Mendelian randomization approach. METHODS AND FINDINGS: We used the adiposity-associated variant rs9939609 at the FTO locus as an instrumental variable (IV) for body mass index (BMI) in a Mendelian randomization design. Thirty-six population-based studies of individuals of European descent contributed to the analyses. Age- and sex-adjusted regression models were fitted to test for association between (i) rs9939609 and BMI (n  =  198,502), (ii) rs9939609 and 24 traits, and (iii) BMI and 24 traits. The causal effect of BMI on the outcome measures was quantified by IV estimators. The estimators were compared to the BMI-trait associations derived from the same individuals. In the IV analysis, we demonstrated novel evidence for a causal relationship between adiposity and incident heart failure (hazard ratio, 1.19 per BMI-unit increase; 95% CI, 1.03-1.39) and replicated earlier reports of a causal association with type 2 diabetes, metabolic syndrome, dyslipidemia, and hypertension (odds ratio for IV estimator, 1.1-1.4; all p < 0.05). For quantitative traits, our results provide novel evidence for a causal effect of adiposity on the liver enzymes alanine aminotransferase and gamma-glutamyl transferase and confirm previous reports of a causal effect of adiposity on systolic and diastolic blood pressure, fasting insulin, 2-h post-load glucose from the oral glucose tolerance test, C-reactive protein, triglycerides, and high-density lipoprotein cholesterol levels (all p < 0.05). The estimated causal effects were in agreement with traditional observational measures in all instances except for type 2 diabetes, where the causal estimate was larger than the observational estimate (p  =  0.001). CONCLUSIONS: We provide novel evidence for a causal relationship between adiposity and heart failure as well as between adiposity and increased liver enzymes.

Meta-analysis of genome-wide association studies identifies ten loci influencing allergic sensitization.

Allergen-specific immunoglobulin E (present in allergic sensitization) has a central role in the pathogenesis of allergic disease. We performed the first large-scale genome-wide association study (GWAS) of allergic sensitization in 5,789 affected individuals and 10,056 controls and followed up the top SNP at each of 26 loci in 6,114 affected individuals and 9,920 controls. We increased the number of susceptibility loci with genome-wide significant association with allergic sensitization from three to ten, including SNPs in or near TLR6, C11orf30, STAT6, SLC25A46, HLA-DQB1, IL1RL1, LPP, MYC, IL2 and HLA-B. All the top SNPs were associated with allergic symptoms in an independent study. Risk-associated variants at these ten loci were estimated to account for at least 25% of allergic sensitization and allergic rhinitis. Understanding the molecular mechanisms underlying these associations may provide new insights into the etiology of allergic disease.

Rare genomic structural variants in complex disease: lessons from the replication of associations with obesity.

The limited ability of common variants to account for the genetic contribution to complex disease has prompted searches for rare variants of large effect, to partly explain the 'missing heritability'. Analyses of genome-wide genotyping data have identified genomic structural variants (GSVs) as a source of such rare causal variants. Recent studies have reported multiple GSV loci associated with risk of obesity. We attempted to replicate these associations by similar analysis of two familial-obesity case-control cohorts and a population cohort, and detected GSVs at 11 out of 18 loci, at frequencies similar to those previously reported. Based on their reported frequencies and effect sizes (OR≥25), we had sufficient statistical power to detect the large majority (80%) of genuine associations at these loci. However, only one obesity association was replicated. Deletion of a 220 kb region on chromosome 16p11.2 has a carrier population frequency of 2×10(-4) (95% confidence interval [9.6×10(-5)-3.1×10(-4)]); accounts overall for 0.5% [0.19%-0.82%] of severe childhood obesity cases (P = 3.8×10(-10); odds ratio = 25.0 [9.9-60.6]); and results in a mean body mass index (BMI) increase of 5.8 kg.m(-2) [1.8-10.3] in adults from the general population. We also attempted replication using BMI as a quantitative trait in our population cohort; associations with BMI at or near nominal significance were detected at two further loci near KIF2B and within FOXP2, but these did not survive correction for multiple testing. These findings emphasise several issues of importance when conducting rare GSV association, including the need for careful cohort selection and replication strategy, accurate GSV identification, and appropriate correction for multiple testing and/or control of false discovery rate. Moreover, they highlight the potential difficulty in replicating rare CNV associations across different populations. Nevertheless, we show that such studies are potentially valuable for the identification of variants making an appreciable contribution to complex disease.

Identification of seven loci affecting mean telomere length and their association with disease.

Interindividual variation in mean leukocyte telomere length (LTL) is associated with cancer and several age-associated diseases. We report here a genome-wide meta-analysis of 37,684 individuals with replication of selected variants in an additional 10,739 individuals. We identified seven loci, including five new loci, associated with mean LTL (P < 5 × 10(-8)). Five of the loci contain candidate genes (TERC, TERT, NAF1, OBFC1 and RTEL1) that are known to be involved in telomere biology. Lead SNPs at two loci (TERC and TERT) associate with several cancers and other diseases, including idiopathic pulmonary fibrosis. Moreover, a genetic risk score analysis combining lead variants at all 7 loci in 22,233 coronary artery disease cases and 64,762 controls showed an association of the alleles associated with shorter LTL with increased risk of coronary artery disease (21% (95% confidence interval, 5-35%) per standard deviation in LTL, P = 0.014). Our findings support a causal role of telomere-length variation in some age-related diseases.

Elevated blood pressure in pregnancy and subsequent chronic disease risk.

BACKGROUND: Preeclampsia, a new-onset hypertensive disorder of pregnancy, is associated with lifetime cardiovascular disease risk, but less is known about risk after other pregnancy-related hypertension. METHODS AND RESULTS: The Northern Finland Birth Cohort 1966 included all expected births from 1 year (N=12 055 women). Blood pressure measurements and other prospective data were determined from prenatal care records and questionnaires for 10 314 women. Subsequent diagnoses were ascertained from Finnish registries (average follow-up, 39.4 years). Adjusted hazard ratios (HRs) with 95% confidence intervals (CIs) estimate risks in hypertensive women compared with normotensive women. Hypertension during pregnancy was associated with increased risk of subsequent cardiovascular disease and arterial hypertension. Women with chronic hypertension and superimposed preeclampsia/eclampsia had high risk for future diseases. Gestational hypertension was associated with increased risk of ischemic heart disease (HR, 1.44 [95% CI, 1.24-1.68]), myocardial infarcts (HR, 1.75 [95% CI, 1.40-2.19]), myocardial infarct death (HR, 3.00 [95% CI, 1.98-4.55]), heart failure (HR, 1.78 [95% CI, 1.43-2.21]), ischemic stroke (HR, 1.59 [95% CI, 1.24-2.04]), kidney disease (HR, 1.91 [95% CI, 1.18-3.09]), and diabetes mellitus (HR, 1.52 [95% CI, 1.21-1.89]). Isolated systolic hypertension was associated with increased risk of myocardial infarct death (HR, 2.15 [95% CI, 1.35-3.41]), heart failure (HR, 1.43 [95% CI, 1.13-1.82]), and diabetes mellitus (HR, 1.42 [95% CI, 1.13-1.78]), whereas isolated diastolic hypertension was associated with increased risk of ischemic heart disease (HR, 1.26 [95% CI, 1.05-1.50]). Results were similar in nonsmoking women aged <35 years with normal weight and no diabetes mellitus during pregnancy. CONCLUSIONS: Elevated blood pressure during pregnancy, regardless of type and even without known risk factors, signals high risk of later cardiovascular disease, chronic kidney disease, and diabetes mellitus. Clinical monitoring, risk factor evaluation, and early intervention could benefit women with hypertension in pregnancy.

Maternal hypertensive disorders during pregnancy and mild cognitive limitations in the offspring.

BACKGROUND: It remains unclear whether maternal hypertensive disorders could impact cognitive development of the child. The aim of this study was to explore the association between hypertensive disorders and other maternal biological and social factors on the risk of mild cognitive limitations (intelligence quotient 50-85) in the offspring. METHODS: An 11.5-year follow-up study of the Northern Finland Birth Cohort 1986 (n = 9432) was utilised. The analysis included 8847 singleton children, of whom 198 had mild cognitive limitations. Gestational hypertension was defined as de novo hypertension (blood pressure ≥ 140/90), diagnosed mid-pregnancy in a previously normotensive woman. Data on intelligence level of the children were based on standardised intelligence test results. RESULTS: Eleven per cent (n = 20) of mothers having a child with mild cognitive limitations had gestational hypertension. Maternal gestational hypertension was independently associated with increased odds of mild cognitive limitation in the offspring (odds ratio 2.4 [95% confidence interval 1.4, 3.9]). Other independent maternal risk factors for mild cognitive limitation were high pre-pregnancy body mass index (≥30 kg/m(2)), multiparity (≥4) and low education. In addition family's socio-economic status lower than professional, male gender and small birthweight-for-gestational age appeared as independent risk factors for mild cognitive limitation. CONCLUSIONS: Gestational hypertension should be considered as one of the adverse early risk factors that may predispose to impaired cognitive development in childhood.

Preeclampsia, gestational hypertension and subsequent hypothyroidism.

OBJECTIVES: To evaluate the effect of preeclampsia (PE) and gestational hypertension (GH) on subsequent hypothyroidism. Recent studies suggest that women with PE have increased risk for reduced thyroid function, but the association between PE and GH with overt hypothyroidism has not been examined. STUDY DESIGN: Two prospective population-based cohort studies, the Northern Finland Birth Cohorts 1966 and 1986, followed women who had PE (N=955), GH (N=1449) or were normotensive (N=13531) during pregnancy. Finnish national registers were used to confirm subsequent hypothyroidism. Adjusted hazard ratios (aHRs) with 95% confidence intervals (CIs) estimated hypothyroidism risk when comparing women with PE or GH with normotensive women. MAIN OUTCOME MEASURES: Primary hypothyroidism during follow-up of 20-40 years. RESULTS: The subsequent prevalence of hypothyroidism was higher among women with PE (4.0%) and GH (4.5%) compared with normotensive women (3.5%), but the risk increase was not significant (aHR for PE 1.13, 95%CI 0.80-1.59 and aHR for GH 1.11, 95%CI 0.85-1.45). Subgroup analysis among nulliparous women revealed a significant association between late PE and subsequent hypothyroidism (aHR 1.82, 95%CI 1.04-3.19). Early or recurrent PE were not associated with hypothyroidism (aHR 0.93, 95%CI 0.46-1.81 and aHR 1.35, 95%CI 0.63-2.88, respectively). CONCLUSIONS: Overall, PE or GH during pregnancy was not significantly associated with subsequent hypothyroidism in Finnish women after 20-40 years of follow-up. However, late PE in nulliparous women was associated with a 1.8-fold increased risk of subsequent hypothyroidism, a finding that merits further study in other populations.

Maternal thyroid dysfunction during pregnancy and thyroid function of her child in adolescence.

CONTEXT: Normal maternal thyroid function is important for fetal development. No knowledge exists on how maternal thyroid function and thyroid antibodies during early pregnancy affect thyroid function of the offspring. OBJECTIVE: The aim of this study was to investigate the relationship between maternal and adolescent thyroid function parameters. DESIGN, SETTING, AND PARTICIPANTS: A total of 3673 mother-child pairs from the prospective, population-based Northern Finland Birth Cohort 1986 participated in the study. Maternal serum samples were drawn in early pregnancy (<20th gestational week), and children's samples were drawn at the age of 16 years and analyzed for TSH, free T4 (fT4), and thyroid peroxidase antibodies (TPO-Abs). MAIN OUTCOME MEASURES: TSH, fT4, and TPO-Ab concentrations were measured at the age of 16 years. Children of mothers with thyroid dysfunction (hypothyroidism, hyperthyroidism, or hypothyroxinemia) or TPO-Ab positivity were compared to those of euthyroid or TPO-Ab-negative mothers. The distributions are expressed as medians with 5th to 95th percentiles. RESULTS: Boys of hypothyroid mothers had higher TSH concentrations than those of euthyroid mothers: 2.0 (0.9-4.0) vs 1.7 (0.8-3.3) mU/L; P = .001. Children of hyperthyroid mothers had lower TSH concentrations than those of euthyroid mothers: 1.3 (0.6-4.2) vs 1.7 (0.8-3.3) mU/L, P = .013, for boys; and 1.3 (0.5-3.5) vs 1.6 (0.7-3.4) mU/L, P = .034, for girls. There were no differences in TSH or fT4 concentrations between children of hypothyroxinemic and euthyroid mothers. TPO-Ab-positive mothers more often had TPO-Ab-positive children (prevalence, 9.0 vs 3.7% among boys, and 22.7 vs 7.5% among girls). CONCLUSIONS: Maternal thyroid dysfunction and TPO-Ab positivity during pregnancy seem to modify thyroid function parameters of offspring even in adolescence. Whether this increases the thyroid disease risk of the children is still unknown.

Causal relationship between obesity and vitamin D status: bi-directional Mendelian randomization analysis of multiple cohorts.

BACKGROUND: Obesity is associated with vitamin D deficiency, and both are areas of active public health concern. We explored the causality and direction of the relationship between body mass index (BMI) and 25-hydroxyvitamin D [25(OH)D] using genetic markers as instrumental variables (IVs) in bi-directional Mendelian randomization (MR) analysis. METHODS AND FINDINGS: We used information from 21 adult cohorts (up to 42,024 participants) with 12 BMI-related SNPs (combined in an allelic score) to produce an instrument for BMI and four SNPs associated with 25(OH)D (combined in two allelic scores, separately for genes encoding its synthesis or metabolism) as an instrument for vitamin D. Regression estimates for the IVs (allele scores) were generated within-study and pooled by meta-analysis to generate summary effects. Associations between vitamin D scores and BMI were confirmed in the Genetic Investigation of Anthropometric Traits (GIANT) consortium (n = 123,864). Each 1 kg/m(2) higher BMI was associated with 1.15% lower 25(OH)D (p = 6.52×10⁻²7). The BMI allele score was associated both with BMI (p = 6.30×10⁻6²) and 25(OH)D (-0.06% [95% CI -0.10 to -0.02], p = 0.004) in the cohorts that underwent meta-analysis. The two vitamin D allele scores were strongly associated with 25(OH)D (p≤8.07×10⁻57 for both scores) but not with BMI (synthesis score, p = 0.88; metabolism score, p = 0.08) in the meta-analysis. A 10% higher genetically instrumented BMI was associated with 4.2% lower 25(OH)D concentrations (IV ratio: -4.2 [95% CI -7.1 to -1.3], p = 0.005). No association was seen for genetically instrumented 25(OH)D with BMI, a finding that was confirmed using data from the GIANT consortium (p≥0.57 for both vitamin D scores). CONCLUSIONS: On the basis of a bi-directional genetic approach that limits confounding, our study suggests that a higher BMI leads to lower 25(OH)D, while any effects of lower 25(OH)D increasing BMI are likely to be small. Population level interventions to reduce BMI are expected to decrease the prevalence of vitamin D deficiency.