Pål Romundstad

Incidence and mortality of venous thrombosis: a population-based study

Background:  Estimates of the incidence of venous thrombosis (VT) vary, and data on mortality are limited.

Prepregnancy cardiovascular risk factors as predictors of pre-eclampsia: population based cohort study

Objective To examine the effect of cardiovascular risk factors before pregnancy on risk of pre-eclampsia. Design Population based prospective study. Setting Linkage between a Norwegian population based study (Nord-Tr�ndelag health study, HUNT-2) and Norways medical birth registry. Participants 3494 women who gave birth after participating in the Nord-Tr�ndelag health study at baseline; of whom 133 (3.8%) delivered after a pre-eclamptic pregnancy. Main outcome measure Odds ratio of developing pre-eclampsia. Results After adjustment for smoking; previous pre-eclampsia; parity; maternal age, education, and socioeconomic position; and duration between baseline measurements and delivery, positive associations were found between prepregnancy serum levels of triglycerides, cholesterol, low density lipoprotein cholesterol, non-high density lipoprotein cholesterol, and blood pressure and risk of pre-eclampsia. The odds ratio of developing pre-eclampsia for women with baseline systolic blood pressures greater than 130 mm Hg (highest fifth) was 7.3 (95% confidence interval 3.1 to 17.2) compared with women with systolic blood pressures less than 111 mm Hg (lowest fifth). Similar results were found for nulliparous and parous women. Women who used oral contraceptives at baseline had half the risk of pre-eclampsia compared with never or former users (0.5, 0.3 to 0.9). Conclusion Women with cardiovascular risk factors may be predisposed to pre-eclampsia.

Effects of technology or maternal factors on perinatal outcome after assisted fertilisation: a population-based cohort study

BACKGROUND Research suggests that singleton births following assisted fertilisation are associated with adverse outcomes; however, these results might be confounded by factors that affect both fertility and pregnancy outcome. We therefore compared pregnancy outcomes in women who had singleton pregnancies conceived both spontaneously and after assisted fertilisation. METHODS In a population-based cohort study, we assessed differences in birthweight, gestational age, and odds ratios (OR) of small for gestational age babies, premature births, and perinatal deaths in singletons (gestation >/=22 weeks or birthweight >/=500 g) born to 2546 Norwegian women (>20 years) who had conceived at least one child spontaneously and another after assisted fertilisation among 1 200 922 births after spontaneous conception and 8229 after assisted fertilisation. FINDINGS In the whole study population, assisted-fertilisation conceptions were associated with lower mean birthweight (difference 25 g, 95% CI 14 to 35), shorter duration of gestation (2.0 days, 1.6 to 2.3) and increased risks of small for gestational age (OR 1.26, 1.10 to 1.44), and perinatal death (1.31, 1.05 to 1.65) than were spontaneous conceptions. In the sibling-relationship comparisons, the spontaneous versus the assisted-fertilisation conceptions showed a difference of only 9 g (-18 to 36) in birthweight and 0.6 days (-0.5 to 1.7) in gestational age. For assisted fertilisation versus spontaneous conception in the sibling-relationship comparisons, the OR for small for gestational age was 0.99 (0.62 to 1.57) and that for perinatal mortality was 0.36 (0.20 to 0.67). INTERPRETATION Birthweight, gestational age, and risks of small for gestational age babies, and preterm delivery did not differ among infants of women who had conceived both spontaneously and after assisted fertilisation. The adverse outcomes of assisted fertilisation that we noted compared with those in the general population could therefore be attributable to the factors leading to infertility, rather than to factors related to the reproductive technology.

Hypertensive disorders in pregnancy and subsequently measured cardiovascular risk factors.

OBJECTIVE: To study the association of hypertensive pregnancy disorders with modifiable risk factors for cardiovascular and metabolic diseases and to estimate the feasibility for early detection and prevention. METHODS: This was a prospective study of 15,065 women with a first singleton birth between 1967 and 1995, who later participated in a population study that included standardized measurements of blood pressure, serum lipids, and body mass index (BMI). RESULTS: Women with a history of hypertensive disorders in pregnancy (preeclampsia or gestational hypertension) had higher BMI, higher blood pressure, and unfavorable levels of total cholesterol, low-density lipoprotein cholesterol, and triglycerides. Preeclampsia was associated with substantially higher risk of developing diabetes (odds ratio 3.8, 95% confidence interval [CI] 2.1–6.6), and if the hypertensive disorder occurred in more than one pregnancy, or in a relatively late pregnancy, the associations with later cardiovascular risk factors were substantially stronger. Thus, women with two episodes of preeclampsia were approximately 10 times more likely to use blood pressure medication at follow-up (adjusted odds ratio, 11.6, 95% CI 7.1–26.3), and in women with gestational hypertension in three consecutive pregnancies, systolic pressure was on average 27 mm Hg (95% CI 18–37 mm Hg) higher, and diastolic pressure was 12 mm Hg (95% CI 5–19 mm Hg) higher, compared with women without a history of hypertensive disorders. Adjustment for current body mass index partly attenuated these associations, suggesting that BMI may play an important mediating role. CONCLUSION: Women with a history of hypertensive disorders in pregnancy, and particularly women with recurrent pregnancy disorders, should be candidates for intervention intended to prevent premature cardiovascular disease. LEVEL OF EVIDENCE: II

The HUNT study: participation is associated with survival and depends on socioeconomic status, diseases and symptoms

BackgroundPopulation based studies are important for prevalence, incidence and association studies, but their external validity might be threatened by decreasing participation rates. The 50 807 participants in the third survey of the HUNT Study (HUNT3, 2006-08), represented 54% of the invited, necessitating a nonparticipation study.MethodsQuestionnaire data from HUNT3 were compared with data collected from several sources: a short questionnaire to nonparticipants, anonymous data on specific diagnoses and prescribed medication extracted from randomly selected general practices, registry data from Statistics Norway on socioeconomic factors and mortality, and from the Norwegian Prescription Database on drug consumption.ResultsParticipation rates for HUNT3 depended on age, sex and type of symptoms and diseases, but only small changes were found in the overall prevalence estimates when including data from 6922 nonparticipants. Among nonparticipants, the prevalences of cardiovascular diseases, diabetes mellitus and psychiatric disorders were higher both in nonparticipant data and data extracted from general practice, compared to that reported by participants, whilst the opposite pattern was found, at least among persons younger than 80 years, for urine incontinence, musculoskeletal pain and headache. Registry data showed that the nonparticipants had lower socioeconomic status and a higher mortality than participants.ConclusionNonparticipants had lower socioeconomic status, higher mortality and showed higher prevalences of several chronic diseases, whilst opposite patterns were found for common problems like musculoskeletal pain, urine incontinence and headache. The impact on associations should be analyzed for each diagnosis, and data making such analyses possible are provided in the present paper.

Metformin Versus Placebo from First Trimester to Delivery in Polycystic Ovary Syndrome: A Randomized, Controlled Multicenter Study

CONTEXT Metformin is widely prescribed to pregnant women with polycystic ovary syndrome (PCOS) in an attempt to reduce pregnancy complications. Metformin is not approved for this indication, and evidence for this practice is lacking. OBJECTIVES Our objective was to test the hypothesis that metformin, from first trimester to delivery, reduces pregnancy complications in women with PCOS. DESIGN AND SETTING We conducted a randomized, placebo-controlled, double-blind, multicenter study at 11 secondary care centers. PARTICIPANTS The participants were 257 women with PCOS, in the first trimester of pregnancy, aged 18-42 yr. INTERVENTION We randomly assigned 274 singleton pregnancies (in 257 women) to receive metformin or placebo, from first trimester to delivery. MAIN OUTCOME MEASURES The prevalence of preeclampsia, gestational diabetes mellitus, preterm delivery, and a composite of these three outcomes is reported. RESULTS Preeclampsia prevalence was 7.4% in the metformin group and 3.7% in the placebo group (3.7%; 95% CI, -1.7-9.2) (P=0.18). Preterm delivery prevalence was 3.7% in the metformin group and 8.2% in the placebo group (-4.4%; 95%, CI, -10.1-1.2) (P=0.12). Gestational diabetes mellitus prevalence was 17.6% in the metformin group and 16.9% in the placebo group (0.8%; 95% CI, -8.6-10.2) (P=0.87). The composite primary endpoint prevalence was 25.9 and 24.4%, respectively (1.5%; 95% CI, -8.9-11.3) (P=0.78). Women in the metformin group gained less weight during pregnancy compared with those in the placebo group. There was no difference in fetal birth weight between the groups. CONCLUSIONS Metformin treatment from first trimester to delivery did not reduce pregnancy complications in PCOS.

BMI and all cause mortality: systematic review and non-linear dose-response meta-analysis of 230 cohort studies with 3.74 million deaths among 30.3 million participants

Objective To conduct a systematic review and meta-analysis of cohort studies of body mass index (BMI) and the risk of all cause mortality, and to clarify the shape and the nadir of the dose-response curve, and the influence on the results of confounding from smoking, weight loss associated with disease, and preclinical disease. Data sources PubMed and Embase databases searched up to 23 September 2015. Study selection Cohort studies that reported adjusted risk estimates for at least three categories of BMI in relation to all cause mortality. Data synthesis Summary relative risks were calculated with random effects models. Non-linear associations were explored with fractional polynomial models. Results 230 cohort studies (207 publications) were included. The analysis of never smokers included 53 cohort studies (44 risk estimates) with >738 144 deaths and >9 976 077 participants. The analysis of all participants included 228 cohort studies (198 risk estimates) with >3 744 722 deaths among 30 233 329 participants. The summary relative risk for a 5 unit increment in BMI was 1.18 (95% confidence interval 1.15 to 1.21; I2=95%, n=44) among never smokers, 1.21 (1.18 to 1.25; I2=93%, n=25) among healthy never smokers, 1.27 (1.21 to 1.33; I2=89%, n=11) among healthy never smokers with exclusion of early follow-up, and 1.05 (1.04 to 1.07; I2=97%, n=198) among all participants. There was a J shaped dose-response relation in never smokers (Pnon-linearity <0.001), and the lowest risk was observed at BMI 23-24 in never smokers, 22-23 in healthy never smokers, and 20-22 in studies of never smokers with ≥20 years’ follow-up. In contrast there was a U shaped association between BMI and mortality in analyses with a greater potential for bias including all participants, current, former, or ever smokers, and in studies with a short duration of follow-up (<5 years or <10 years), or with moderate study quality scores. Conclusion Overweight and obesity is associated with increased risk of all cause mortality and the nadir of the curve was observed at BMI 23-24 among never smokers, 22-23 among healthy never smokers, and 20-22 with longer durations of follow-up. The increased risk of mortality observed in underweight people could at least partly be caused by residual confounding from prediagnostic disease. Lack of exclusion of ever smokers, people with prevalent and preclinical disease, and early follow-up could bias the results towards a more U shaped association.

Circumferential resection margin as a prognostic factor in rectal cancer

This study examined the prognostic impact of the circumferential resection margin (CRM) in patients with rectal cancer treated by total mesorectal excision (TME) with or without radiotherapy.

Regular Exercise During Pregnancy to Prevent Gestational Diabetes A Randomized Controlled Trial

OBJECTIVE: To assess whether exercise during pregnancy can prevent gestational diabetes and improve insulin resistance. METHODS: A total of 855 women in gestational week 18–22 were randomly assigned to receiving a 12-week standard exercise program (intervention group) or standard antenatal care (control group). The exercise program followed standard recommendations and included moderate-intensity to high-intensity activity 3 or more days per week. Primary outcomes were gestational diabetes and insulin resistance estimated by the homeostasis model assessment method. For the power calculation, we assumed a gestational diabetes prevalence of 9% in the control group and a prevalence of 4% in the exercise group (risk difference of 5%). Under these assumptions, a two-sample comparison with a 5% level of significance and power of 0.80 gave a study population of 381 patients in each group. RESULTS: At 32–36 weeks of gestation there were no differences between groups in prevalence of gestational diabetes: 25 of 375 (7%) in the intervention group compared with 18 of 327 (6%) in the control group (P=.52). There were no differences in insulin resistance between groups when adjusting for baseline values. Only 55% of women in the intervention group managed to follow the recommended exercise protocol. No serious adverse events related to physical exercise were seen, and the outcomes of pregnancy were similar in the two groups. CONCLUSION: There was no evidence that offering women a 12-week standard exercise program during the second half of pregnancy prevents gestational diabetes or improves insulin resistance in healthy pregnant women with normal body mass indexes. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, www.clinicaltrials.gov, NCT00476567. LEVEL OF EVIDENCE: I

Intrauterine exposure to preeclampsia and adolescent blood pressure, body size, and age at menarche in female offspring.

OBJECTIVE To investigate whether female offspring of preeclamptic pregnancies have higher blood pressure, lower height, higher body mass index (BMI), and later age at menarche compared with offspring of normotensive pregnancies. METHODS Questionnaire information on age at menarche and measurements of blood pressure, height, and weight were collected among 4096 Norwegian girls 13–19 years old. Individual linkage to perinatal data registered at the national Medical Birth Registry allowed us to study the relationship of preeclampsia in the mother with adolescent blood pressure, body size, and age at menarche of daughters. RESULTS Maternal preeclampsia was associated in the female offspring with higher systolic (2.9 mm Hg difference, P < .001) and diastolic (1.7 mm Hg difference, P = .001) blood pressure during adolescence and higher weight (3.4 kg difference, P < .001) and BMI (22.6 versus 21.5, P < .001). After adjustment for adolescent BMI, the difference in systolic blood pressure was attenuated from 2.9 to 1.7 mm Hg (P = .017), and from 1.7 to 0.9 mm Hg (P = .08) for diastolic blood pressure. CONCLUSION Intrauterine exposure to preeclampsia was associated with increased adolescent blood pressure. The association may be causally related to adult hypertension but could also be confounded by higher BMI during adolescence.