Psychiatric disorders and mortality due to external causes following diagnosis of endometriosis at a young age: a longitudinal register-based cohort study in Finland.

BACKGROUND: Endometriosis diagnosed in adults is associated with increased risk of various psychiatric disorders. However, little is known concerning psychiatric comorbidity and mortality due to external causes associated with endometriosis diagnosed at a young age. OBJECTIVE: This longitudinal cohort study aimed to investigate the link between surgical diagnosis of endometriosis at a young age and subsequent psychiatric disorders and mortality due to external causes. In addition, we compared the occurrence of the most common psychiatric disorders between different sites of surgically confirmed endometriosis (ovarian vs other) because of possible differences in pain manifestations. STUDY DESIGN: We conducted a retrospective register-based cohort study. Altogether 4532 women with surgically confirmed diagnosis of endometriosis before the age of 25 years from 1987 to 2012 were identified from the Finnish Hospital Discharge Register. They were matched with women without surgically diagnosed endometriosis for age and municipality on the index day (n=9014). Women were followed up from the index day until the end of 2019 for the outcomes of interest, which included 9 groups of psychiatric disorders (inpatient episodes since 1987, outpatient episodes since 1998) and death due to external causes, including deaths due to accidents, suicides, and violence (Finnish Register of Causes of Death). Cox proportional hazard models were applied to assess the crude and parity-adjusted hazard ratios and 95% confidence intervals. RESULTS: The cohort's median age was 22.9 years (interquartile range, 21.3-24.1) at the beginning and 42.5 years (36.7-48.3) after a median follow-up time of 20.0 years (14.5-25.7). We observed a higher hazard of depressive, anxiety, and bipolar disorders in women with endometriosis compared with the reference cohort, with depressive and anxiety disorders being the two most common psychiatric disorders. These differences appeared early and remained the same during the entire follow-up, irrespective of whether assessed from the data on inpatient episodes only or the data on both in- and outpatient episodes. The corresponding adjusted hazard ratios were 2.57 (95% confidence interval, 2.11-3.14) and 1.87 (1.65-2.12) for depressive disorders, 2.40 (1.81-3.17) and 2.09 (1.84-2.37) for anxiety disorders, and 1.71 (1.30-2.26) and 1.66 (1.28-2.15) for bipolar disorders, respectively. A higher hazard was observed for nonorganic sleeping disorders for the first 10 years only (3.83; 2.01-7.30) when assessed using the data on both in- and outpatient episodes. When based on inpatient records, a higher hazard for alcohol/drug dependence after 15 years of follow-up (2.07; 1.21-3.54) was observed. The difference in hazard for personality disorders tended to increase during follow-up (<10 years, 2.12 [1.28-3.52]; ≥10 years, 3.08 [1.44-6.57]). Depressive and anxiety disorders occurred more frequently in women with types of endometriosis other than ovarian endometriosis. No difference in deaths due to external causes was observed between the endometriosis and reference cohorts. CONCLUSION: Surgical diagnosis of endometriosis at a young age was associated with increased incidence of several psychiatric disorders. Moreover, within the endometriosis population, psychiatric comorbidity was more common in women with types of endometriosis other than ovarian endometriosis. We speculate that chronic pain is essential in the development of these psychiatric disorders, and that early and effective pain management is important in reducing the risk of psychiatric morbidity in young women. More research concerning the associations and management of endometriosis and associated psychiatric disorders is warranted.

Risk of stroke the year following a delivery after using assisted reproductive technologies.

BACKGROUND: Studies indicate that individuals who deliver after assisted reproductive technologies (ART) may have an increased risk of cardiovascular disease (CVD). A recent large study from the U.S. showed a higher risk of stroke during the first year after delivery. OBJECTIVES: To compare the risk of stroke during the first year after delivery according to the use of ART in the Nordic countries. METHODS: Registry-based cohort study using nationwide data from Denmark (1994-2014), Finland (1990-2014), Norway (1984-2015) and Sweden (1985-2015). Data on ART conception were available from ART quality registries and/or Medical Birth Registries (MBRs). National data on stroke were available from hospital and cause-of-death registries. The risk of stroke during the first year after delivery was estimated with Cox proportional hazard regression, adjusting for age, calendar year of delivery, multiple births, and country. RESULTS: A total of 2,659,272 primiparous individuals had a registered delivery in the MBRs during the study period, and 91,466 (4%) of these gave birth after ART. We observed no overall increased risk of stroke during the first year after delivery among individuals conceiving after ART (adjusted hazard ratio [HR] 1.10, 95% CI 0.77, 1.57). Similarly, there was no convincing evidence that the short-term risk of stroke was higher within 1, 2, 3, or 6 months after delivery, with adjusted HRs ranging between 1.23 and 1.33 and confidence intervals including the null value for all time periods. A secondary analysis also including multiparous individuals (n = 3,335,478) at the start of follow-up yielded similar findings. CONCLUSIONS: We found no evidence of an increased short-term risk of stroke among individuals who delivered after using ART.

Associations Between Sedentary Time, Physical Activity, and Cardiovascular Health in 6-Year-Old Children Born to Mothers With Increased Cardiometabolic Risk.

PURPOSE: To assess associations between sedentary time (ST), physical activity (PA), and cardiovascular health in early childhood. METHOD: Cross-sectional study including 160 children (age 6.1 y [SD 0.5], 86 boys, 93 maternal body mass index ≥ 30 kg/m2, and 73 gestational diabetes) assessed for pulse wave velocity, echocardiography, ultra-high frequency 48-70 MHz vascular ultrasound, and accelerometery. RESULTS: Boys had 385 (SD 53) minutes per day ST, 305 (SD 44) minutes per day light PA, and 81 (SD 22) minutes per day moderate to vigorous PA (MVPA). Girls had 415 (SD 50) minutes per day ST, 283 (SD 40) minutes per day light PA, and 66 (SD 19) minutes per day MVPA. In adjusted analyses, MVPA was inversely associated with resting heart rate (ß = -6.6; 95% confidence interval, -12.5 to -0.7) and positively associated with left ventricular mass (ß = 6.8; 1.4-12.3), radial intima-media thickness (ß = 11.4; 5.4-17.5), brachial intima-media thickness (ß = 8.0; 2.0-14.0), and femoral intima-media thickness (ß = 1.3; 0.2-2.3). MVPA was inversely associated with body fat percentage (ß = -3.4; -6.6 to -0.2), diastolic blood pressure (ß = -0.05; -0.8 to -0.1), and femoral (ß = -18.1; -32.4 to -0.8) and radial (ß = -13.4; -24.0 to -2.9) circumferential wall stress in boys only. ST and pulse wave velocity showed no significant associations. CONCLUSIONS: In young at-risk children, MVPA is associated with cardiovascular remodeling, partly in a sex-dependant way, likely representing physiological adaptation, but ST shows no association with cardiovascular health in early childhood.

Surgically confirmed endometriosis in adolescents in Finland-A register-based cross-sectional cohort study.

INTRODUCTION: Increasing awareness of endometriosis in adolescents requires data on the nature of the disease and its management. Our objective was to investigate the subtypes of surgically confirmed endometriosis in adolescents (aged <20 years) and trends in the incidence rates and endometriosis-related procedures during the study period, 1987-2012. MATERIAL AND METHODS: In this register-based cohort study, we identified 526 adolescents receiving their initial surgical diagnosis of endometriosis between 1987 and 2012 from the Finnish Hospital Discharge Register. The age-specific incidence rate of surgically confirmed endometriosis was calculated by dividing the number of adolescents during specific periods by person-years. We calculated the relative differences in incidence rates between the periods using crude incidence ratios. RESULTS: Adolescents were divided into three age groups, <17, 17-18, and 19 years, which comprised 8.2% (43/526), 39.7% (209/526), and 52.1% (274/526) of the study cohort, respectively. Peritoneal endometriosis and ovarian endometriosis were the most common types (379/526 [72%] and 119/526 [23%], respectively). The incidence rate of surgically confirmed endometriosis per 100 000 person-years varied from 5.63 (95% confidence interval [CI] 4.24-7.33) to 11.42 (95% CI 9.64-13.44). The incidence rate in 2001-2005 was significantly higher and was 1.6- to 2.0-fold that of the periods 1987-1990 and 2006-2012, respectively. Comparing the periods in which International Classification of Diseases, Ninth Revision (ICD-9; 1987-1995) and Tenth Revision (ICD-10; 1996-2012) codes were used, the use of laparoscopy (78.2% vs 88.9%), day surgery (10.3% vs 31.6%), and procedures for ovarian (18.8% vs 34.1%) and deep (0.6% vs 10.8%) endometriosis increased. The types of endometriosis and procedures did not differ between the age groups. CONCLUSIONS: Peritoneal endometriosis was the most common type of endometriosis overall and by age group. During the 26-year period, the incidence rate of initial surgical diagnosis of endometriosis peaked in 2001-2005 and decreased thereafter. The proportion of procedures performed for ovarian and deep endometriosis increased, as did the use of laparoscopy and day surgery.

Effect of lifestyle counselling on health-related quality of life in women at high risk for gestational diabetes.

BACKGROUND: The incidence of gestational diabetes (GDM) is increasing and interventions to curb the detrimental effects of GDM are needed. We have previously reported that a combined diet and physical activity intervention has the potential to reduce GDM among high-risk women. It is also important to know whether the intervention affects health-related quality of life (HRQoL). METHODS: A total of 378 women at high risk for GDM were randomized into an intervention (lifestyle counselling four times during pregnancy, n=192), or a control group (n=186) before 20 gestational weeks. HRQoL was assessed with the 15D-instrument six times: once during each trimester and at six weeks, six months and 12 months postpartum. RESULTS: In this study population, the cumulative incidence of GDM was similar in the intervention and the control group (45.7 vs. 44.5%). There was no difference between the 15D scores of the control and intervention groups at any of the time points. CONCLUSIONS: Combined diet and physical activity intervention did not provide HRQoL benefits in the study. A high prevalence of GDM in both study groups may have confounded the effect of the intervention.

Long-term effects of a preconception lifestyle intervention on cardiometabolic health of overweight and obese women.

BACKGROUND: The global prevalence of obesity in women keeps increasing. The preconception period may be a window of opportunity to improve lifestyle, reduce obesity and improve cardiometabolic health. This study assessed the effect of a preconception lifestyle intervention on long-term cardiometabolic health in two randomized controlled trials (RCTs). METHODS: Participants of the LIFEstyle and RADIEL preconception lifestyle intervention studies with a baseline body mass index (BMI) ≥29 kg/m2 were eligible for this follow-up study. Both studies randomized between a lifestyle intervention targeting physical activity, diet and behaviour modification or usual care. We assessed cardiometabolic health 6 years after randomization. RESULTS: In the LIFEstyle study (n = 111) and RADIEL study (n = 39), no statistically significant differences between the intervention and control groups were found for body composition, blood pressure, arterial stiffness, fasting glucose, homeostasis model assessment of insulin resistance, HbA1c, lipids and high sensitive C-reactive protein levels 6 years after randomization. Participants of the LIFEstyle study who successfully lost ≥5% bodyweight or reached a BMI <29 kg/m2 during the intervention (n = 22, [44%]) had lower weight (-8.1 kg; 99% CI [-16.6 to -0.9]), BMI (-3.3 kg/m2; [-6.5 to -0.8]), waist circumference (-8.2 cm; [-15.3 to -1.3]), fasting glucose (-0.5 mmol/L; [-1.1 to -0.0]), HbA1c (-4.1 mmol/mol; [-9.1 to -0.8]), and higher HDL-C (0.3 mmol/L; [0.1-0.5]) compared with controls. CONCLUSION: We found no evidence of improved cardiometabolic health 6 years after a preconception lifestyle intervention among overweight and obese women in two RCTs. Women who successfully lost weight during the intervention had better cardiometabolic health 6 years later, emphasizing the potential of successful preconception lifestyle improvement.

Effects of maternal lifestyle interventions on child neurobehavioral development: Follow-up of randomized controlled trials.

Obesity is a major public health problem. Children of women who were obese before or during pregnancy are at increased risk for neurobehavioral developmental problems. Whether a maternal lifestyle intervention conducted before and during pregnancy in obese women affects child neurobehavioral development is unknown. This study reports on the follow-up of a subsample of two randomized controlled trials, the Finnish RADIEL (n = 216) and Dutch LIFEstyle (n = 305) trial. Women with a pre-pregnancy BMI ≥29 kg/m2 wishing to conceive or who were already pregnant (<20 weeks) were allocated to a lifestyle intervention or to care as usual. Child neurodevelopment was measured with the Ages and Stages Questionnaire and child behavioral problems were measured with the Childhood Behavior Checklist (RADIEL) or the Strengths and Difficulties Questionnaire (LIFEstyle) at age 3-6 years. We used linear and binary logistic regression analyses to assess the effects of the lifestyle interventions on children's neurobehavioral developmental scores. Follow-up data was available from 161(38%) RADIEL and 96(32%) LIFEstyle children. Child neurodevelopmental scores did not differ significantly between children in the intervention and the control group (RADIEL:median = 275 vs. 280; LIFEstyle:median = 270 vs 267). Child behavioral problem scores did not differ significantly between children in the intervention and the control group (RADIEL:median = 22 vs. 21; LIFEstyle:median = 8 vs. 8). We did not observe considerable effects of the lifestyle interventions before or during pregnancy in obese women on child neurobehavioral development. With our sample sizes, we were not able to detect subtle differences in neurobehavioral development however.

Diet quality as assessed by the Healthy Food Intake Index and relationship with serum lipoprotein particles and serum fatty acids in pregnant women at increased risk for gestational diabetes.

The importance of overall diet in modifying circulating lipoprotein particles and fatty acids during pregnancy is unclear. We examined the relationships of diet quality as assessed by the validated Healthy Food Intake Index (HFII) with serum HDL, LDL and VLDL particle concentrations and sizes and proportions of serum fatty acids in pregnant women at high risk for gestational diabetes mellitus (GDM). Overall, 161 women with a BMI of ≥30 kg/m2 and/or a history of GDM were drawn from the Finnish Gestational Diabetes Prevention Study, which is a dietary and exercise intervention trial to prevent GDM. At baseline, the HFII score was inversely related to concentrations of HDL particles (P=0·010) and MUFA (P=0·010) and positively related to concentrations of n-3 (P<0·001) and n-6 (P=0·003) PUFA. The significance for MUFA disappeared after adjustments. An increase in the HFII score from the first to second trimester of pregnancy correlated with reduced VLDL particle size (r -0·16, 95 % CI -0·31, -0·01), decreased MUFA concentrations (r -0·17, 95 % CI -0·31, -0·01) and elevated n-6 PUFA concentrations (r 0·16, 95 % CI 0·01, 0·31). In the maximum-adjusted model, the results remained significant except for VLDL particle size. These findings suggest that higher diet quality as defined by the HFII is related to a more favourable serum fatty acid profile, whereas the relationship with serum lipoprotein profile is limited in pregnant women at increased GDM risk.

Is improvement in the Healthy Food Intake Index (HFII) related to a lower risk for gestational diabetes?

The aim was to analyse whether changes in the Healthy Food Intake Index (HFII) during pregnancy are related to gestational diabetes (GDM) risk. The 251 pregnant women participating had a pre-pregnancy BMI≥30 kg/m2 and/or a history of GDM. A 75 g oral glucose tolerance test (OGTT) was performed during the first and second trimesters of pregnancy for assessment of GDM. A normal OGTT result at first trimester was an inclusion criterion for the study. FFQ collected at first and second trimesters served for calculating the HFII. A higher HFII score reflects higher adherence to the Nordic Nutrition Recommendations (NNR) (score range 0-17). Statistical methods included Student's t test, Mann-Whitney U test, Fisher's exact test and linear and logistic regression analyses. The mean HFII at first trimester was 10·1 (95 % CI 9·7, 10·4) points, and the mean change from the first to the second trimester was 0·35 (95 % CI 0·09, 0·62) points. The range of the HFII changes varied from -7 to 7. The odds for GDM decreased with higher HFII change (adjusted OR 0·83 per one unit increase in HFII; 95 % CI 0·69, 0·99; P=0·043). In the analysis of the association between HFII-sub-indices and GDM, odds for GDM decreased with higher HFII-Fat change (fat percentage of milk and cheese, type of spread and cooking fats) but it was not significant in a fully adjusted model (P=0·058). Dietary changes towards the NNR during pregnancy seem to be related to a lower risk for GDM.

Interaction between rs10830963 polymorphism in MTNR1B and lifestyle intervention on occurrence of gestational diabetes.

AIMS/HYPOTHESIS: The aim of this study was to assess the interaction between melatonin receptor 1B gene (MTNR1B) rs10830963 polymorphism and lifestyle intervention during pregnancy on occurrence of gestational diabetes mellitus (GDM) in high-risk women. METHODS: This is a secondary analysis of the randomised controlled gestational diabetes prevention trial 'RADIEL', conducted between 2008 and 2014 in four maternity hospitals in southern Finland. A total of 226 women with a history of GDM and/or a pre-pregnancy BMI ≥ 30 kg/m(2) were enrolled at <20 weeks of gestation (mean 13 weeks) and randomised into an intervention group receiving counselling on diet, physical activity and weight control and a control group receiving standard antenatal care. The main outcome was incidence of GDM, defined as one or more pathological glucose values in a standard 75 g 2-h OGTT. The MTNR1B rs10830963 was genotyped for further analyses. RESULTS: No significant differences were found in the genotype distribution between the intervention and the control group. A significant interaction was observed between the rs10830963 genotypes and the lifestyle intervention on age-adjusted occurrence of gestational diabetes (p = 0.038). Among women homozygous for the C allele of rs10830963, the OR for GDM was significantly lower in the intervention group than in the control group (OR 0.16 [95% CI 0.03, 0.85], p = 0.014). This difference was not seen in women heterozygous (OR 0.88 [95% CI 0.32, 2.41], p = 0.798) or homozygous (OR 2.25 [95% CI 0.34, 14.69], p = 0.384) for the risk allele G. CONCLUSIONS/INTERPRETATION: In women at high risk of GDM, only those not carrying the risk allele G benefited from the lifestyle intervention. Our results indicate that certain genetic risk variants may modify the effectiveness of lifestyle interventions. This may provide important information when planning GDM prevention studies in the future.

Elevated serum squalene and cholesterol synthesis markers in pregnant obese women with gestational diabetes mellitus.

We examined serum cholesterol synthesis and absorption markers and their association with neonatal birth weight in obese pregnancies affected by gestational diabetes mellitus (GDM). Pregnant women at risk for GDM (BMI >30 kg/m²) were enrolled from maternity clinics in Finland. GDM was determined from the results of an oral glucose tolerance test. Serum samples were collected at six time-points, one in each trimester of pregnancy, and at 6 weeks, 6 months, and 12 months postpartum. Analysis of serum squalene and noncholesterol sterols by gas-liquid chromatography revealed that in subjects with GDM (n = 22), the serum Δ8-cholestenol concentration and lathosterol/sitosterol ratio were higher (P < 0.05) than in the controls (n = 30) in the first trimester, reflecting increased cholesterol synthesis. Also, subjects with GDM had an increased ratio of squalene to cholesterol (100 × µmol/mmol of cholesterol) in the second (11.5 ± 0.5 vs. 9.1 ± 0.5, P < 0.01) and third (12.1 ± 0.8 vs. 10.0 ± 0.7, P < 0.05) trimester. In GDM, the second trimester maternal serum squalene concentration correlated with neonatal birth weight (r = 0.70, P < 0.001). In conclusion, in obesity, GDM associated with elevated serum markers of cholesterol synthesis. Correlation of maternal serum squalene with neonatal birth weight suggests a potential contribution of maternal cholesterol synthesis to newborn weight in GDM.

Prevention of gestational diabetes through lifestyle intervention: study design and methods of a Finnish randomized controlled multicenter trial (RADIEL).

BACKGROUND: Maternal overweight, obesity and consequently the incidence of gestational diabetes are increasing rapidly worldwide. The objective of the study was to assess the efficacy and cost-effectiveness of a combined diet and physical activity intervention implemented before, during and after pregnancy in a primary health care setting for preventing gestational diabetes, later type 2 diabetes and other metabolic consequences. METHODS: RADIEL is a randomized controlled multi-center intervention trial in women at high risk for diabetes (a previous history of gestational diabetes or prepregnancy BMI ≥30 kg/m2). Participants planning pregnancy or in the first half of pregnancy were parallel-group randomized into an intervention arm which received lifestyle counseling and a control arm which received usual care given at their local antenatal clinics. All participants visited a study nurse every three months before and during pregnancy, and at 6 weeks, 6 and 12 months postpartum. Measurements and laboratory tests were performed on all participants with special focus on dietary and exercise habits and metabolic markers.Of the 728 women [mean age 32.5 years (SD 4.7); median parity 1 (range 0-9)] considered to be eligible for the study 235 were non-pregnant and 493 pregnant [mean gestational age 13 (range 6 to 18) weeks] at the time of enrollment. The proportion of nulliparous women was 29.8% (n = 217). Out of all participants, 79.6% of the non-pregnant and 40.4% of the pregnant women had previous gestational diabetes and 20.4% of the non-pregnant and 59.6% of the pregnant women were recruited because of a prepregnancy BMI ≥30 kg/m2. Mean BMI at first visit was 30.1 kg/m2 (SD 6.2) in the non-pregnant and 32.7 kg/m2 (SD 5.6) in the pregnant group. DISCUSSION: To our knowledge, this is the first randomized lifestyle intervention trial, which includes, besides the pregnancy period, both the prepregnancy and the postpartum period. This study design also provides an opportunity to focus upon the health of the next generation. The study is expected to produce novel information on the optimal timing and setting of interventions and for allocating resources to prevent obesity and diabetes in women of reproductive age.

The risk of Type 1 diabetes in children born after ART: a Nordic cohort study from the CoNARTaS group.

STUDY QUESTION: Do children born after ART have a higher risk of developing Type 1 diabetes (DM1) than children conceived without ART? SUMMARY ANSWER: The risk of DM1 was similar for children conceived with and without ART, and there were no clear differences in risk according to method of fertility treatment. WHAT IS KNOWN ALREADY: ART is associated with a higher risk of adverse perinatal outcomes, and the risk depends on the method of ART. The Developmental Origins of Health and Disease theory proposes that prenatal stress can provoke changes in endocrine processes which impact health later in life. STUDY DESIGN SIZE DURATION: A Nordic register-based cohort study was carried out, including all children born in Denmark (birth years 1994-2014), Finland (1990-2014), and Norway (1984-2015). The study included 76 184 liveborn singletons born after ART and 4 403 419 born without ART. Median follow-up was 8.3 and 13.7 years in the ART and non-ART group, respectively. PARTICIPANTS/MATERIALS SETTING METHODS: The cohort, initiated by the Committee of Nordic Assisted Reproductive Technology and Safety (CoNARTaS), was established by linking national registry data from the medical birth registries and national patient registries available in the Nordic countries. We performed multivariable logistic regression analyses for the birth year intervals 1984-1990, 1991-1995, 1996-2000, 2001-2005, 2006-2010, and 2011-2015, while adjusting for year of birth within each interval, sex of the child, parity, maternal age, maternal diabetes, and maternal smoking during pregnancy as potential confounders. MAIN RESULTS AND THE ROLE OF CHANCE: During follow-up, 259 (3.4‰) children born after ART were diagnosed with DM1, while this was the case for 22 209 (5.0‰) born without ART, corresponding to an adjusted odds ratio of 0.98 (95% CI: 0.861.11). Within the different birth year intervals, no significant difference in risk of DM1 between the two groups was found, except for the youngest cohort of children born 2011-2015 where ART was associated with a higher risk of DM1. We found no significant differences in risk of DM1 when comparing children born after IVF versus ICSI or fresh versus frozen embryo transfer, but with only few cases in each group. LIMITATIONS REASONS FOR CAUTION: The main limitation of the study is the relatively short follow-up time. The incidence rate of DM1 peaks during ages 10-14 years, hence a longer follow-up would benefit all analyses and, in particular, the subgroup analyses. WIDER IMPLICATIONS OF THE FINDINGS: Overall, our findings are reassuring especially considering the concomitantly increasing number of children born from ART and the increasing incidence of DM1 globally. STUDY FUNDING/COMPETING INTERESTS: This Nordic registry study has been supported by the Nordic Trial Alliance/NORDFORSK and Rigshospitalets Research Foundation. The funding sources had no role in study design; in the collection, analysis, and interpretation of data; in the writing of the report; and in the decision to submit the article for publication. None of the authors has any conflicts of interest to declare regarding this study. TRIAL REGISTRATION NUMBER: ISRCTN11780826.

Maternal Risk of Cardiovascular Disease After Use of Assisted Reproductive Technologies.

Importance: The use of assisted reproductive technologies (ARTs) is steadily increasing worldwide. The outcomes associated with treatment for an individual's long-term health, including risk of cardiovascular disease (CVD), remain largely unknown, due to the small number of studies and their limited follow-up time. Objective: To study whether the risk of CVD is increased among individuals who have given birth after ART compared with those who have given birth without ART. Design, Setting, and Participants: A registry-based cohort study was conducted using nationwide data from Denmark (1994-2014), Finland (1990-2014), Norway (1984-2015), and Sweden (1985-2015). Data analysis was conducted from January to August 2022. A total of 2 496 441 individuals with a registered delivery in the national birth registries during the study period were included, and 97 474 (4%) of these gave birth after ART. Exposures: Data on ART conception were available from ART quality registries and/or medical birth registries. Main Outcomes and Measures: Information on CVD was available from patient and cause of death registries. The risk of CVD was estimated with Cox proportional hazards regression, adjusting for age, calendar year of start of follow-up, parity, diagnosis of polycystic ovary syndrome, diabetes, chronic hypertension, and country. Results: Median follow-up was 11 (IQR, 5-18) years. The mean (SD) age of women with no use of ART was 29.1 (4.9) years, and the age of those who used ART was 33.8 (4.7) years. The rate of any CVD was 153 per 100 000 person-years. Individuals who gave birth after using ART had no increased risk of CVD (adjusted hazard ratio [AHR], 0.97; 95% CI, 0.91-1.02), with evidence of heterogeneity between the countries (I2 = 76%; P = .01 for heterogeneity). No significant differences in the risk of ischemic heart disease, cerebrovascular disease, stroke, cardiomyopathy, heart failure, pulmonary embolism, or deep vein thrombosis were noted with use of ART. However, there was a tendency for a modest reduction in the risk of myocardial infarction (AHR, 0.80; 95% CI, 0.65-0.99), with no notable heterogeneity between countries. Conclusions and Relevance: The findings of this study suggest that women who gave birth after ART were not at increased risk of CVD over a median follow-up of 11 years compared with those who conceived without ART. Longer-term studies are needed to further examine whether ART is associated with higher risk of CVD.

Ultra-high frequency ultrasound delineated changes in carotid and muscular artery intima-media and adventitia thickness in obese early middle-aged women.

Obesity is linked to increased arterial size, carotid intima-media thickness and arterial stiffness. The effects of obesity and body composition on muscular artery intima-media and adventitia thickness has previously not been established. The aim of this study was to explore associations between carotid and muscular artery wall layer thickness with body composition and cardiovascular risk factors in early middle-aged women. This is a cross-sectional study including 199 women aged 40±4 years. Arterial lumen (LD), intima-media (IMT) and adventitia thickness (AT) were measured from carotid, brachial and radial arteries using ultra-high frequency ultrasound (22-71 MHz). Women with obesity had increased IMT in carotid (0.47 vs 0.45 mm), brachial (0.19 vs 0.17 mm) and radial arteries (0.16 vs 0.15 mm) and increased brachial AT (0.14 vs 0.13 mm). In multiple regression models all arterial LD (ß-range 0.02-0.03 mm/kg/m2), IMT (ß-range 0.91-3.37 µm/kg/m2), AT (ß-range 0.73-1.38 µm/kg/m2) were significantly associated with BMI. The IMT of all arteries were significantly associated with systolic blood pressure (ß-range 0.36-0.85 µm/mmHg), attenuating the association between IMT and BMI (ß-range 0.18-2.24 µm/kg/m2). Obese early middle-aged women have increased arterial intima media thickness and brachial artery adventitia thickness compared to non-obese counterparts. The association between BMI and intima-media thickness is partly mediated through blood pressure levels.

The neurodevelopmental morbidity of children born after assisted reproductive technology: a Nordic register study from the Committee of Nordic Assisted Reproductive Technology and Safety group.

OBJECTIVE: To assess the risk of neurodevelopmental disorders in singletons born after the use of assisted reproductive technology (ART) compared with singletons born without the use of ART. DESIGN: Nordic register-based study. SETTING: Cross-linked data from Medical Birth Registers and National ART and Patient Registers; liveborn singletons in 1995-2014 in Denmark and Finland, 2005-2015 in Norway, and 1995-2015 in Sweden with follow-up to 2014 (Denmark and Finland) or 2015 (Norway and Sweden). PATIENTS: A total of 5,076,444 singletons: 116,909 (2.3%) born with and 4,959,535 (97.7%) born without the use of ART (non-ART). INTERVENTIONS: In vitro fertilization, intracytoplasmic sperm injection, and fresh and frozen embryo transfer. MAIN OUTCOME MEASURES: The primary outcomes (International Statistical Classification of Diseases and Related Health Problems, Tenth Revision, codes) were learning and motor functioning disorders (F80-F83), autism spectrum disorder (F84), attention-deficit/hyperactivity disorder and conduct disorders (F90-F92), and tic disorders (F95). Crude hazard ratios (HRs) and adjusted hazard ratios (aHRs) with 95% confidence intervals were calculated. RESULTS: Singletons in the ART cohort had a higher adjusted risk of learning and motor functioning disorders (HR, 1.01 [0.96-1.07]; aHR, 1.17 [1.11-1.24]) and a tendency toward a higher risk of autism spectrum disorder (HR, 1.12 [1.04-1.21]; aHR, 1.07 [0.98-1.16]) and attention-deficit/hyperactivity disorder and conduct disorders (HR, 0.82 [0.77-0.86]; aHR, 1.17 [0.99-1.12]) but not of tic disorders (HR, 1.21 [1.06-1.38]; aHR, 1.17 [0.96-1.27]). No differences in risk were found between children born after in vitro fertilization and intracytoplasmic sperm injection or after fresh and frozen embryo transfer. CONCLUSIONS: Our findings of only small differences in neurodevelopment between ART and non-ART singletons are reassuring and in line with previous studies.

Ideal Cardiovascular Health and Vascular Phenotype Associations in Mothers with Obesity and Their Six-Year-Old Children.

BACKGROUND: Heredity and family-shared lifestyle contribute to cardiovascular risk, but the magnitude of their influence on arterial structure and function in early childhood is unknown. We aimed to assess associations between child and maternal ideal cardiovascular health, maternal subclinical atherosclerosis, and child arterial phenotype. METHODS: Cross-sectional analysis of 201 mother-child pairs originating from the Finnish Gestational Diabetes Prevention Study (RADIEL) longitudinal cohort was done at child age 6.1 ± 0.5 years with assessments of ideal cardiovascular health (BMI, blood pressure, fasting glucose, total cholesterol, diet quality, physical activity, smoking), body composition, very-high frequency ultrasound of carotid arteries (25 and 35 MHz), and pulse wave velocity. RESULTS: We found no association between child and maternal ideal cardiovascular health but report evidence of particular metrics correlations: total cholesterol (r=0.24, P=0.003), BMI (r=0.17, P=0.02), diastolic blood pressure (r=0.15, P=0.03), and diet quality (r=0.22, P=0.002). Child arterial phenotype was not associated with child or maternal ideal cardiovascular health. In the multivariable regression explanatory model adjusted for child sex, age, systolic blood pressure, lean body mass, and body fat percentage, child carotid intima-media thickness was independently associated only with maternal carotid intima-media thickness (0.1 mm increase [95% CI 0.05, 0.21, P=0.001] for each 1 mm increase in maternal carotid intima-media thickness). Children of mothers with subclinical atherosclerosis had decreased carotid artery distensibility (1.1 ± 0.2 vs 1.2 ± 0.2%/10 mmHg, P=0.01) and trend toward increased carotid intima-media thickness (0.37 ± 0.04 vs 0.35 ± 0.04 mm, P=0.06). CONCLUSION: Ideal Cardiovascular Health metrics are heterogeneously associated in mother-child pairs in early childhood. We found no evidence of child or maternal Ideal Cardiovascular Health effect on child arterial phenotype. Maternal carotid intima-media thickness predicts child carotid intima-media thickness, but the underlying mechanisms remain unclear. Maternal subclinical atherosclerosis is associated with local carotid arterial stiffness in early childhood.

The impact of educational attainment on the occurrence of gestational diabetes mellitus in two successive pregnancies of Finnish primiparous women: a population-based cohort study.

AIMS: To assess the impact of educational attainment on the occurrence and recurrence of gestational diabetes mellitus (GDM) in two successive pregnancies in primiparous women. METHODS: This is a population-based observational cohort study including all 2347 Finnish women without previously diagnosed diabetes, aged ≥ 20 years from the city of Vantaa, Finland, who gave birth to their first and second child between 2009 and 2015. National registries provided data on study participants. We divided the population into four groups according to the presence of GDM in the two pregnancies (GDM-/-, n = 1820; GDM-/+, n = 223; GDM+/-, n = 113; GDM+/+, n = 191). RESULTS: The occurrence of GDM in the first pregnancy was 13.0% (n = 304) and 17.6% (n = 414) in the second. The recurrence rate of GDM was 62.8%. The four groups did not differ in relation to educational attainment (p = 0.11). In multinomial regression analysis, educational attainment protected from GDM in the second pregnancy [relative risk ratio 0.93 (95% confidence interval (CI) 0.86-0.99) per year of schooling for being GDM-/+ compared with GDM-/-]. In multivariate logistics models, prepregnancy body mass index at the first pregnancy [odds ratio (OR) 1.53 per 1-standard deviation (SD) (95% CI 1.22-1.91)], first-born birth weight z-score [OR 1.30 per 1-SD (95% CI 1.00-1.67)], and inter-pregnancy weight change [OR 1.66 per 1-SD (95% CI 1.27-2.16)], but not educational attainment, predicted recurrence of GDM. CONCLUSIONS: The recurrence rate of GDM was high. Education protected from novel GDM in the second pregnancy, but was not associated with GDM recurrence.

No effect of gestational diabetes or pre-gestational obesity on 6-year offspring left ventricular function-RADIEL study follow-up.

AIMS: We aimed to investigate associations between pre-pregnancy obesity, gestational diabetes (GDM), offspring body composition, and left ventricular diastolic and systolic function in early childhood. METHODS: This is an observational study, including 201 mother-child pairs originating from the Finnish Gestational Diabetes Prevention Study (RADIEL; 96 with GDM, 128 with pre-pregnancy obesity) with follow-up from gestation to 6-year postpartum. Follow-up included dyads anthropometrics, body composition, blood pressure, and child left ventricular function with comprehensive echocardiography (conventional and strain imaging). RESULTS: Offspring left ventricular diastolic and systolic function was not associated with gestational glucose concentrations, GDM, or pregravida obesity. Child body fat percentage correlated with maternal pre-pregnancy BMI in the setting of maternal obesity (r = 0.23, P = 0.009). After adjusting for child lean body mass, age, sex, systolic BP, resting HR, maternal lean body mass, pre-gestational BMI, and GDM status, child left atrial volume increased by 0.3 ml (95% CI 0.1, 0.5) for each 1% increase in child body fat percentage. CONCLUSIONS: No evidence of foetal cardiac programming related to GDM or maternal pre-pregnancy obesity was observed in early childhood. Maternal pre-pregnancy obesity is associated with early weight gain. Child adiposity in early childhood is independently associated with increased left atrial volume, but its implications for long-term left ventricle diastolic function and cardiovascular health remain unknown.

Oral glucose tolerance test results in early pregnancy: A Finnish population-based cohort study.

AIMS: To analyze early-pregnancy oral glucose tolerance test (OGTT) results and differences between early- and late-pregnancy OGTT results in a population-based cohort. METHODS: From 3/2013 to 12/2016, pregnant women in South Karelia, Finland, were invited to undergo a 2-hour 75 g OGTT at 12-16 weeks' gestation (OGTT1) and, if normal, repeat testing at 24-28 weeks (OGTT2). Early and late gestational diabetes (GDM) were diagnosed using the same nationally endorsed criteria (fasting [FPG], 1- or 2-hour plasma glucose ≥5.3, ≥10.0 or ≥8.6 mmol/L, respectively). RESULTS: In OGTT1 (n = 1401), the mean (SD) FPG, 1- and 2-hour values were 4.85 (0.34), 6.63 (1.73) and 5.60 (1.28) mmol/L, respectively. Early GDM was diagnosed in 209 (14.9%). In OGTT2 (n = 1067), late GDM was diagnosed in 114 (10.6%). In women without GDM (n = 953), the mean FPG values were higher and post-load values lower in OGTT1 vs. OGTT2. No interaction effects of gestational timepoint and maternal BMI on OGTT results were detected, except for the 2-hour value. In women with late GDM, both mean FPG and post-load values were lower in OGTT1 vs. OGTT2. Results were similar employing the IADPSG GDM criteria. CONCLUSIONS: Our findings suggest that gestational-age specific OGTT thresholds for early GDM diagnosis need to be generated.