Association of age at menarche, reproductive lifespan and age at menopause with the risk of atrial fibrillation: The HUNT study.

BACKGROUND: Age at menarche, reproductive lifespan, and age at menopause are associated with several cardiovascular diseases, but their relationship with atrial fibrillation (AF) is uncertain. METHODS: We linked information on all women who participated in the third survey of the population-based, longitudinal HUNT study in Norway with medical records from all local hospitals. A total of 14,632 women aged 60 or more were followed for validated incident AF. We retrieved age at menarche and age at menopause from the HUNT questionnaires. Reproductive lifespan was defined as the difference between age at menarche and age at menopause. We used Cox proportional hazards regression models to assess associations between AF and age at menarche, reproductive lifespan, and age at menopause. RESULTS: During a median follow-up of 8.17 years (136,494 person-years), 1217 (8.3 %) participants developed AF. In multivariable-adjusted analyses, we observed no associations between early or late age at menarche and AF (hazard ratios (HRs): <12 years: 0.85 [95 % confidence interval (CI), 0.65-1.12]; ≥16 years: 0.99 [95 % CI, 0.80-1.24] compared to those who attained menarche at 13-14 years). The HR for a reproductive lifespan shorter than 30 years was 0.91 [95 % CI, 0.72-1.15] compared to 34-37 years. Likewise, there was no clear association between premature or early age at menopause and AF (HRs: <40 years: 1.21 [95 % CI, 0.83-1.75]; 40-44 years: 0.97 [95 % CI, 0.77-1.22] compared to 50-54 years). CONCLUSIONS: In this population of women aged 60 years and over, the risk of AF was not associated with age at menarche, reproductive lifespan, or age at menopause.

Postpartum Lifestyle Behaviors among Women with Hypertensive Disorders of Pregnancy: Data from the HUNT Study.

Hypertensive disorders of pregnancy (HDP) are associated with an increased risk of cardiovascular disease later in life. Clinical guidelines for postpartum follow-up after HDP often recommend lifestyle counseling to reduce this risk. However, knowledge about lifestyle behaviors and perceptions among women with a history of HDP is limited. We linked data from the fourth survey of the population-based Trøndelag Health Study (HUNT4) with data from the Medical Birth Registry of Norway. The associations between HDP and postpartum lifestyle behaviors and perceptions were examined using multivariable logistic regression. In a secondary analysis, HUNT4 participants with a recent history of pre-eclampsia were compared with women with a recent history of pre-eclampsia participating in a postpartum pilot intervention study. Lifestyle behaviors and perceptions were self-reported and included diet (intake frequency of fruits, vegetables, meat, fish, and sugar-sweetened beverages), alcohol intake, physical activity, sleep, smoking, lifestyle satisfaction, and the importance of a healthy lifestyle. Among 7551 parous HUNT4 participants, 610 had a history of HDP. We found no differences in lifestyle behaviors between women with and without a history of HDP. However, women with HDP had higher odds of being unsatisfied with their lifestyle. Women with pre-eclampsia participating in a postpartum lifestyle intervention study tended to have a healthier lifestyle at baseline than women participating in HUNT4. Future studies should explore how lifestyle intervention programs could be adapted to the needs of women who have experienced HDP or other pregnancy complications that are associated with an increased risk of CVD.

Undiagnosed diabetes: Prevalence and cardiovascular risk profile in a population-based study of 52,856 individuals. The HUNT Study, Norway.

AIMS: We investigated the current extent of undiagnosed diabetes and prediabetes and their associated cardiovascular risk profile in a population-based study. METHODS: All residents aged ≥20 years in the Nord-Trøndelag region, Norway, were invited to the HUNT4 Survey in 2017-2019, and 54% attended. Diagnosed diabetes was self-reported, and in those reporting no diabetes HbA1c was used to classify undiagnosed diabetes (≥48 mmol/mol [6.5%]) and prediabetes (39-47 mmol/mol [5.7%-6.4%]). We estimated the age- and sex-standardized prevalence of these conditions and their age- and sex-adjusted associations with other cardiovascular risk factors. RESULTS: Among 52,856 participants, the prevalence of diabetes was 6.0% (95% CI 5.8, 6.2), of which 11.1% were previously undiagnosed (95% CI 10.1, 12.2). The prevalence of prediabetes was 6.4% (95% CI 6.2, 6.6). Among participants with undiagnosed diabetes, 58% had HbA1c of 48-53 mmol/mol (6.5%-7.0%), and only 14% (i.e., 0.1% of the total study population) had HbA1c >64 mmol/mol (8.0%). Compared with normoglycaemic participants, those with undiagnosed diabetes or prediabetes had higher body mass index, waist circumference, systolic blood pressure, triglycerides and C-reactive protein but lower low-density lipoprotein cholesterol (all p < 0.001). Participants with undiagnosed diabetes had less favourable values for every measured risk factor compared with those with diagnosed diabetes. CONCLUSIONS: The low prevalence of undiagnosed diabetes suggests that the current case-finding-based diagnostic practice is well-functioning. Few participants with undiagnosed diabetes had very high HbA1c levels indicating severe hyperglycaemia. Nonetheless, participants with undiagnosed diabetes had a poorer cardiovascular risk profile compared with participants with known or no diabetes.

Ten-Year Cardiovascular Disease Risk Trajectories by Obstetric History: A Longitudinal Study in the Norwegian HUNT Study.

Background Women with a history of obstetric complications are at increased risk of cardiovascular disease, but whether they should be specifically targeted for cardiovascular disease (CVD) risk screening is unknown. Methods and Results We used linked data from the Norwegian HUNT (Trøndelag Health) Study and the Medical Birth Registry of Norway to create a population-based, prospective cohort of parous women. Using an established CVD risk prediction model (A Norwegian risk model for cardiovascular disease), we predicted 10-year risk of CVD (nonfatal myocardial infarction, fatal coronary heart disease, and nonfatal or fatal stroke) based on established risk factors (age, systolic blood pressure, total and high-density lipoprotein cholesterol, smoking, antihypertensive use, and family history of myocardial infarction). Predicted 10-year CVD risk scores in women aged between 40 and 60 years were consistently higher in those with a history of obstetric complications. For example, when aged 40 years, women with a history of preeclampsia had a 0.06 percentage point higher mean risk score than women with all normotensive deliveries, and when aged 60 years this difference was 0.86. However, the differences in the proportion of women crossing established clinical thresholds for counseling and treatment in women with and without a complication were modest. Conclusions Findings do not support targeting parous women with a history of pregnancy complications for CVD screening. However, pregnancy complications identify women who would benefit from primordial and primary prevention efforts such as encouraging and supporting behavioral changes to reduce CVD risk in later life.

The role of cardiovascular risk factors in maternal cardiovascular disease according to offspring birth characteristics in the HUNT study.

A history of preterm or small (SGA) or large (LGA) for gestational age offspring is associated with smoking and unfavorable levels of BMI, blood pressure, glucose and lipids. Whether and to what extent the excess cardiovascular risk observed in women with these pregnancy complications is explained by conventional cardiovascular risk factors (CVRFs) is not known. We examined the association between a history of SGA, LGA or preterm birth and cardiovascular disease among 23,284 parous women and quantified the contribution of individual CVRFs to the excess cardiovascular risk using an inverse odds weighting approach. The hazard ratios (HR) between SGA and LGA offspring and CVD were 1.30 (95% confidence interval (CI) 1.15, 1.48) and 0.89 (95% CI 0.76, 1.03), respectively. Smoking explained 49% and blood pressure may have explained ≈12% of the excess cardiovascular risk in women with SGA offspring. Women with preterm birth had a 24% increased risk of CVD (HR 1.24, 95% CI 1.06, 1.45), but we found no evidence for CVRFs explaining any of this excess cardiovascular risk. While smoking explains a substantial proportion of excess cardiovascular risk in women with SGA offspring and blood pressure may explain a small proportion in these women, we found no evidence that conventional CVRFs explain any of the excess cardiovascular risk in women with preterm birth.

GWAS of thyroid stimulating hormone highlights pleiotropic effects and inverse association with thyroid cancer.

Thyroid stimulating hormone (TSH) is critical for normal development and metabolism. To better understand the genetic contribution to TSH levels, we conduct a GWAS meta-analysis at 22.4 million genetic markers in up to 119,715 individuals and identify 74 genome-wide significant loci for TSH, of which 28 are previously unreported. Functional experiments show that the thyroglobulin protein-altering variants P118L and G67S impact thyroglobulin secretion. Phenome-wide association analysis in the UK Biobank demonstrates the pleiotropic effects of TSH-associated variants and a polygenic score for higher TSH levels is associated with a reduced risk of thyroid cancer in the UK Biobank and three other independent studies. Two-sample Mendelian randomization using TSH index variants as instrumental variables suggests a protective effect of higher TSH levels (indicating lower thyroid function) on risk of thyroid cancer and goiter. Our findings highlight the pleiotropic effects of TSH-associated variants on thyroid function and growth of malignant and benign thyroid tumors.

Life Course Trajectories of Maternal Cardiovascular Risk Factors according to Offspring Birthweight: The HUNT Study.

Women with small or large for gestational age offspring are at increased risk of cardiovascular disease later in life. How their cardiovascular risk factors develop across the life course is incompletely known. We linked data from the population-based HUNT Study (1984-2008) and the Medical Birth Registry of Norway (1967-2012) for 22,487 women. Mixed effect models were used to compare cardiovascular risk factor trajectories for women according to first offspring birthweight for gestational age. Women with small for gestational age (SGA) offspring had 1-2 mmHg higher systolic and diastolic blood pressure across the life course, but lower measures of adiposity, compared to women with offspring who were appropriate for gestational age (AGA). In contrast, women with large for gestational age (LGA) offspring had higher measures of adiposity, ~0.1 mmol/l higher non-HDL cholesterol and triglycerides and 0.2 mmol/l higher non-fasting glucose, compared with mothers of AGA offspring. These differences were broadly stable from prior to first pregnancy until 60 years of age. Our findings point to different cardiovascular risk profiles in mothers of SGA versus LGA offspring, where giving birth to SGA offspring might primarily reflect adverse maternal vascular health whereas LGA offspring might reflect the mother's metabolic health.

Association of Conventional Cardiovascular Risk Factors With Cardiovascular Disease After Hypertensive Disorders of Pregnancy: Analysis of the Nord-Trøndelag Health Study.

Importance: Women with a history of hypertensive disorders of pregnancy (HDP) have higher risk of cardiovascular disease (CVD). It is not known how much of the excess CVD risk in women with a history of HDP is associated with conventional cardiovascular risk factors. Objective: To quantify the excess risk of CVD in women with a history of HDP and estimate the proportion associated with conventional cardiovascular risk factors. Design, Setting, and Participants: Prospective cohort study with a median follow-up of 18 years. Population-based cohort of women participating in the Nord-Trøndelag Health Study in Norway. We linked data for 31 364 women from the Nord-Trøndelag Health Study (1984-2008) to validated hospital records (1987-2015), the Cause of Death Registry (1984-2015), and the Medical Birth Registry of Norway (1967-2012). A total of 7399 women were excluded based on selected pregnancy characteristics, incomplete data, or because of emigrating or experiencing the end point before start of follow-up, leaving 23 885 women for study. Data were analyzed between January 1, 2018, and June 6, 2018. Exposures: Experiencing 1 or more pregnancies complicated by HDP before age 40 years vs only experiencing normotensive pregnancies. Main Outcomes and Measures: We used Cox proportional hazards models to estimate the hazard ratios (HRs) for the association between HDP and CVD. The proportion of excess risk associated with conventional cardiovascular risk factors was estimated using an inverse odds ratio weighting approach. Results: Our study population consisted of 23 885 parous women from Nord-Trøndelag County, Norway. A total of 21 766 women had only normotensive pregnancies, while 2199 women experienced ever having an HDP. From age 40 to 70 years, women with history of HDP had an increased risk of CVD compared with women with only normotensive pregnancies (HR, 1.57; 95% CI, 1.32-1.87) but not at older age (ß = 0.98; 95% CI, 0.96-1.00; P for interaction by age = .01). Blood pressure and body mass index were associated with up to 77% of the excess risk of CVD in women with history of HDP, while glucose and lipid levels were associated with smaller proportions. Conclusion and Relevance: In this study, the risk of excess CVD in women with history of HDP was associated with conventional cardiovascular risk factors, indicating that these risk factors are important targets for cardiovascular prevention in these women.

Does pregnancy complication history improve cardiovascular disease risk prediction? Findings from the HUNT study in Norway.

AIM: To evaluate whether history of pregnancy complications [pre-eclampsia, gestational hypertension, preterm delivery, or small for gestational age (SGA)] improves risk prediction for cardiovascular disease (CVD). METHODS AND RESULTS: This population-based, prospective cohort study linked data from the HUNT Study, Medical Birth Registry of Norway, validated hospital records, and Norwegian Cause of Death Registry. Using an established CVD risk prediction model (NORRISK 2), we predicted 10-year risk of CVD (non-fatal myocardial infarction, fatal coronary heart disease, and non-fatal or fatal stroke) based on established risk factors (age, systolic blood pressure, total and HDL-cholesterol, smoking, anti-hypertensives, and family history of myocardial infarction). We evaluated whether adding pregnancy complication history improved model fit, calibration, discrimination, and reclassification. Among 18 231 women who were parous, ≥40 years of age, and CVD-free at start of follow-up, 39% had any pregnancy complication history and 5% experienced a CVD event during a median follow-up of 8.2 years. While pre-eclampsia and SGA were associated with CVD in unadjusted models (HR 1.96, 95% CI 1.44-2.65 for pre-eclampsia and HR 1.46, 95% CI 1.18-1.81 for SGA), only pre-eclampsia remained associated with CVD after adjusting for established risk factors (HR 1.60, 95% CI 1.16-2.17). Adding pregnancy complication history to the established prediction model led to small improvements in discrimination (C-index difference 0.004, 95% CI 0.002-0.006) and reclassification (net reclassification improvement 0.02, 95% CI 0.002-0.05). CONCLUSION: Pre-eclampsia independently predicted CVD after controlling for established risk factors; however, adding pre-eclampsia, gestational hypertension, preterm delivery, and SGA made only small improvements to CVD prediction among this representative sample of parous Norwegian women.

Life Course Trajectories of Cardiovascular Risk Factors in Women With and Without Hypertensive Disorders in First Pregnancy: The HUNT Study in Norway.

Background Women with hypertensive pregnancy disorders have adverse levels of cardiovascular risk factors. It is unclear how this adverse risk factor profile evolves during adult life. We compared life course trajectories of cardiovascular risk factors in women with preeclampsia or gestational hypertension in their first pregnancy to normotensive women. Methods and Results We linked information on cardiovascular risk factors from the population-based HUNT (Nord-Trøndelag Health Study) surveys with pregnancy information from the Medical Birth Registry of Norway. Trajectories of cardiovascular risk factors were constructed for 22 308 women with a normotensive first pregnancy; 1092 with preeclampsia, and 478 with gestational hypertension in first pregnancy. Already before first pregnancy, women with preeclampsia in their first pregnancy had higher measures of adiposity, blood pressure, heart rate, and serum lipids and glucose compared with women with a normotensive first pregnancy. After first pregnancy, there was a parallel development in cardiovascular risk factor levels, but women with a normotensive first pregnancy had a time lag of >10 years compared with the preeclampsia group. There were no clear differences in risk factor trajectories between women with gestational hypertension and women with preeclampsia. Conclusions Women with hypertensive pregnancy disorders in their first pregnancy had an adverse cardiovascular risk factor profile before pregnancy compared with normotensive women, and the differences persisted beyond 50 years of age. Hypertensive disorders in pregnancy signal long-term increases in modifiable cardiovascular risk factors, and may be used to identify women who would benefit from early prevention strategies.

Does pregnancy alter life-course lipid trajectories? Evidence from the HUNT Study in Norway.

We examined the association between pregnancy and life-course lipid trajectories. Linked data from the Nord-Trøndelag Health Study and the Medical Birth Registry of Norway yielded 19,987 parous and 1,625 nulliparous women. Using mixed-effects spline models, we estimated differences in nonfasting lipid levels from before to after first birth in parous women and between parous and nulliparous women. HDL cholesterol (HDL-C) dropped by -4.2 mg/dl (95% CI: -5.0, -3.3) from before to after first birth in adjusted models, a 7% change, and the total cholesterol (TC) to HDL-C ratio increased by 0.18 (95% CI: 0.11, 0.25), with no change in non-HDL-C or triglycerides. Changes in HDL-C and the TC/HDL-C ratio associated with pregnancy persisted for decades, leading to altered life-course lipid trajectories. For example, parous women had a lower HDL-C than nulliparous women at the age of 50 years (-1.4 mg/dl; 95% CI: -2.3, -0.4). Adverse changes in lipids were greatest after first birth, with small changes after subsequent births, and were larger in women who did not breastfeed. Findings suggest that pregnancy is associated with long-lasting adverse changes in HDL-C, potentially setting parous women on a more atherogenic trajectory than prior to pregnancy.

Correction to: The impact of parity on life course blood pressure trajectories: the HUNT study in Norway.

The article was originally published electronically on the publisher's internet portal (currently SpringerLink) on 24 January 2018 without open access.

The impact of parity on life course blood pressure trajectories: the HUNT study in Norway.

The drop in blood pressure during pregnancy may persist postpartum, but the impact of pregnancy on blood pressure across the life course is not known. In this study we examined blood pressure trajectories for women in the years preceding and following pregnancy and compared life course trajectories of blood pressure for parous and nulliparous women. We linked information on all women who participated in the population-based, longitudinal HUNT Study, Norway with pregnancy information from the Medical Birth Registry of Norway. A total of 23,438 women were included with up to 3 blood pressure measurements per woman. Blood pressure trajectories were compared using a mixed effects linear spline model. Before first pregnancy, women who later gave birth had similar mean blood pressure to women who never gave birth. Women who delivered experienced a drop after their first birth of - 3.32 mmHg (95% CI, - 3.93, - 2.71) and - 1.98 mmHg (95% CI, - 2.43, - 1.53) in systolic and diastolic blood pressure, respectively. Subsequent pregnancies were associated with smaller reductions. These pregnancy-related reductions in blood pressure led to persistent differences in mean blood pressure, and at age 50, parous women still had lower systolic (- 1.93 mmHg; 95% CI, - 3.33, - 0.53) and diastolic (- 1.36 mmHg; 95% CI, - 2.26, - 0.46) blood pressure compared to nulliparous women. The findings suggest that the first pregnancy and, to a lesser extent, successive pregnancies are associated with lasting and clinically relevant reductions in systolic and diastolic blood pressure.