How do changes in body mass index in infancy and childhood associate with cardiometabolic profile in adulthood? Findings from the Northern Finland Birth Cohort 1966 Study.

BACKGROUND/OBJECTIVE: Postnatal growth patterns leading to obesity may have adverse influences on future cardiometabolic health. This study evaluated age and body mass index (BMI) at infant BMI peak (BMIP) and childhood BMI rebound (BMIR) in relation to adult cardiometabolic outcomes in the Northern Finland Birth Cohort 1966. METHODS: BMI at various ages was calculated from frequent height and weight measurements obtained from child health and welfare clinical records. Age and BMI at BMIP and BMIR were derived from random effect models fitted at >0-1.5 years (N=3 265) and >1.5-13 years (N=4 121). Cardiometabolic outcomes were obtained from a clinical examination at age 31 years. Multiple regression models were used to analyse associations between the derived growth parameters and cardiometabolic outcomes. RESULTS: Age and BMI at BMIP were positively associated with adult BMI and waist circumference (WC), independently of birth weight and infant height growth (P<0.05). Later BMIR was associated with a better cardiometabolic profile: adult BMI and insulin were 14% lower, WC and triglycerides were 10% lower and the odds of metabolic syndrome (MetS) were 74% lower per 2 s.d. (1.86 years) higher age at BMIR (P<0.0001). BMI at rebound had generally weaker associations with cardiometabolic outcomes, which attenuated after adjustment for age at BMIR. CONCLUSIONS: Age and BMI at infant BMIP were associated with adult adiposity but not with other cardiometabolic outcomes. Earlier timing of BMIR was a risk factor of an adverse cardiometabolic profile, independently of early growth or BMI at rebound. Identifying growth patterns harmful to cardiovascular health will give opportunities for early interventions.

The impact of self-reported oligo-amenorrhea and hirsutism on fertility and lifetime reproductive success: results from the Northern Finland Birth Cohort 1966.

STUDY QUESTION: To what extent do self-reported oligo-amenorrhea and hirsutism affect reproductive performance (childlessness, age at first delivery, family size and miscarriage rates)? SUMMARY ANSWER: At the age of 44, among women with both self-reported oligo-amenorrhea and hirsutism the prevalence of childlessness was not significantly different from non-symptomatic women but they had a smaller family size than non-symptomatic women. WHAT IS KNOWN ALREADY: Polycystic ovary syndrome (PCOS) is a common endocrine disorder characterized by oligo-amenorrhea or amenorrhea, hyperandrogenism and hirsutism and it is the most frequent cause of anovulatory infertility, but there are few studies on the reproductive capacity of women with PCOS. In our previous population-based cohort study the women with self-reported oligo-amenorrhea and hirsutism were found to have more infertility problems and smaller family size than non-symptomatic women at the age of 31. STUDY DESIGN, SIZE, DURATION: A prospective population-based cohort study. The population of the study is derived from the prospective Northern Finland Birth Cohort 1966 (NFBC1966), comprising all expected births from the year 1966 in the two northernmost provinces of Finland (n = 12 058). Of them, 5889 were females. Enrollment in this database begun at the 24th gestational week and so far data have been collected from the subjects at the ages of 1, 14 and 31 years. PARTICIPANTS/MATERIALS, SETTING, METHODS: A postal questionnaire including questions about oligo-amenorrhea and hirsutism was sent to all women at the age of 31 (n = 5608, response rate 81%, n = 4535) and a clinical examination was performed (attendance rate 76.5%). Those who reported both hirsutism and oligo-amenorrhea were defined as women with both symptoms (n = 153). Data on pregnancies/deliveries were obtained from the Finnish Medical Birth Register (FMBR) in 2010 when the women were 44 years old. MAIN RESULTS AND THE ROLE OF CHANCE: Women with both symptoms had delivered at least one child as often as non-symptomatic women [75.2 versus 79.0%, adjusted odds ratio (OR) 0.86, 95% confidence intervals (CI) 0.57-1.30], were of similar age [mean (SD)] at first delivery [27.7 (4.81) versus 27.3 (4.71)] and had similar incidence of miscarriages. However, non-symptomatic women had more often ≥2 deliveries (61.6 versus 52.9%, adjusted OR 0.70, 95% CI 0.49-1.00, P = 0.048) and had larger family size [mean (SD)] [2.4 (1.4) versus 1.9 (0.8), P < 0.001]. Women with both symptoms had been treated more often for infertility than non-symptomatic women (6.1 versus 2.4%, adjusted OR 2.74, 95% CI 1.14-6.60, P = 0.024). LIMITATIONS, REASONS FOR CAUTION: The diagnosis of oligo-amenorrhea and hirsutism was based on a questionnaire, suggesting a risk of information bias in reporting the symptoms. However, we have previously shown that self-reported oligo-amenorrhea and hirsutism can distinguish most women with the typical profile of PCOS. Only the women who had delivered at least once were recorded in the FMBR, thus excluding from the study those who had experienced miscarriages and/or infertility treatments but did not have a live birth. This feature could potentially decrease the differences in incidence of miscarriages and/or infertility treatment between symptomatic and non-symptomatic subjects. WIDER IMPLICATIONS OF THE FINDINGS: This is one of the few studies, in which the impact of self-reported oligo-amenorrhea and hirsutism on lifetime reproductive success can be measured. Our results suggest that even at more advanced age, women with both symptoms do not quite match the parity of healthy non-symptomatic women, and that infertility treatment does not always restore normal reproductive capacity in these women. Obese women with both symptoms had the worst prognostic as regards reproduction, which emphasizes the importance of life intervention and preventive politics against obesity in this group of women. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by grants from the Finnish Medical Society Duodecim, the North Ostrobothnia Regional Fund, the Academy of Finland, University Hospital Oulu, Biocenter, University of Oulu, Finland, the European Commission and the Medical Research Council, UK, the National Institute for Health Research (NIHR). None of the authors has any conflict of interest to declare.

Menstrual disorders in adolescence: a marker for hyperandrogenaemia and increased metabolic risks in later life? Finnish general population-based birth cohort study.

STUDY QUESTION: Are self-reported menstrual disorders associated with hyperandrogenaemia and metabolic disturbances as early as in adolescence? SUMMARY ANSWER: Menstrual disorders at the age 16 are a good marker of hyperandrogenaemia, and an adverse lipid profile was associated with higher androgen levels. WHAT IS KNOWN AND WHAT THIS PAPER ADDS: Hyperandrogenism per se has been suggested to be a significant metabolic risk factor in women and a cause of physical and psychological morbidity in adolescent girls. A weak positive correlation has been described between hyperandrogenaemia and obesity in adolescent girls, but the clinical consequences are still poorly understood. Hyperandrogenism and insulin resistance are also key features of polycystic ovary syndrome (PCOS), and women with PCOS are consequently at an increased risk of developing type 2 diabetes mellitus and/or metabolic syndrome, and may have increased cardiovascular morbidity. Our findings confirm that the association between menstrual disorders, hyperandrogenism, obesity and metabolic risks is already evident in adolescence. STUDY DESIGN: This population-based, cross-sectional study used postal questionnaires to targeting 15-16-year-old girls in the Northern Finland Birth Cohort 1986 (n= 4567). PARTICIPANTS AND SETTING: There were 3669 girls who answered the postal questionnaire and out of 3373 girls who also underwent clinical examinations and blood tests, 2448 were included in the analyses. The questionnaire included one question about the regularity and length of the menstrual cycle: 'Is your menstrual cycle (the interval from the beginning of one menstrual period to the beginning of the next period) often (more than twice a year) longer than 35 days?' The girls who answered 'yes' to this question were considered to be suffering from menstrual disorders and were classified as 'symptomatic'. The girls who answered 'no' were defined as 'non-symptomatic'. MAIN RESULTS AND THE ROLE OF CHANCE: There were 709 (29%) girls who reported menstrual disorders (symptomatic girls) and 1739 who had regular periods (non-symptomatic girls). In the whole population and in both study groups, there were significant correlations between body mass index (BMI) (and waist-to-hip ratio), hyperandrogenaemia and metabolic parameters. Symptomatic girls exhibited significantly higher serum concentrations of testosterone (P= 0.010), lower levels of sex hormone-binding globulin (P =0.042) and higher free androgen indices [FAIs; geometric mean 3.38 (interquartile range (IQR): 2.27, 5.18) versus 3.08 (IQR: 2.15, 4.74), P= 0.002]. The two groups had comparable BMI and insulin sensitivity, and serum levels of glucose, insulin and lipids. There was a significant linear trend towards higher FAI values in the higher BMI quartiles in both symptomatic and non-symptomatic girls. In the whole population, there was a statistically significant linear decrease in high-density lipoprotein concentrations (P < 0.001) and higher triglyceride concentrations (P =0.004) in the upper FAI quartile. IMPLICATIONS: Information regarding menstrual disorders in adolescence is a good marker of hyperandrogenaemia and may be an early risk factor for the development of PCOS in adulthood. The association between obesity, hyperandrogenism and metabolic risks is already evident in adolescence, which strengthens the importance of noting menstrual disorders at an early stage. BIAS, LIMITATIONS, GENERALIZABILITY: The cross-sectional nature of the study does not allow us to draw conclusions concerning the metabolic risks of this population in later life. The diagnosis of menstrual disorders was based on a questionnaire, suggesting a risk of information bias in reporting the symptoms. This study was not designed to diagnose PCOS, as ultrasonography was not available and there was no clinical evaluation of hyperandrogenism (i.e. hirsutism). However, we were able to take into account potential confounding factors in the analyses. STUDY FUNDING/COMPETING INTERESTS: This work was supported by grants from the Finnish Medical Society Duodecim, the North Ostrobothnia Regional Fund, the Academy of Finland (project grants 104781, 120315, 129269, 1114194, SALVE), University Hospital Oulu, Biocenter, University of Oulu, Finland (75617), the European Commission (EURO-BLCS, Framework 5 award QLG1-CT-2000-01643) and the Medical Research Council, UK (PrevMetSyn/SALVE). None of the authors have any conflict of interest to declare.

Maternal weight gain during the first half of pregnancy and offspring obesity at 16 years: a prospective cohort study.

OBJECTIVE: To assess the association between maternal gestational weight gain (GWG) during the first 20 weeks of gestation and overweight/obesity and abdominal obesity of offspring at the age of 16 years. DESIGN: A prospective cohort study. SETTING: The two northernmost provinces of Finland. POPULATION: Mothers and their adolescent offspring born from singleton pregnancies (3265 boys; 3372 girls) in the Northern Finland Birth Cohort 1986. METHODS: Maternal weight at 20 weeks of gestation was measured in municipal maternity clinics. Maternal GWG was based on the difference between the measured weight and self-reported pre-pregnancy weight, and was classified into quartiles. Offspring weight, height and waist circumference were measured by study nurses during a clinical examination. Logistic regression analyses [with and without adjustment for maternal pre-pregnancy body mass index (BMI), glucose metabolism, education level, haemoglobin, smoking status, parity, and gender of offspring] were performed. MAIN OUTCOME MEASURE: Offspring overweight/obesity, based on BMI and abdominal obesity at 16 years. RESULTS: The highest quartile of maternal weight gain (>7.0 kg during the first 20 weeks of gestation) was independently associated with BMI-based overweight/obesity and abdominal obesity in the 16-year-old offspring (OR 1.46, 95% CI 1.16-1.83, and OR 1.37, 95% CI 1.10-1.72, respectively). Among all covariates, maternal pregravid obesity showed the highest odds for both overweight/obesity and abdominal obesity (OR 4.57, 95% CI 3.18-6.57, and OR 4.43, 95% CI 3.10-6.34, respectively). CONCLUSIONS: Maternal overnutrition during the first half of gestation predicts offspring overweight/obesity and abdominal obesity in adolescence, yet a high pregravid BMI appears to be a more important determinant of both outcomes.

The association of body mass index, waist and hip circumference, and waist-hip ratio with Chlamydia pneumoniae IgG antibodies and high-sensitive C-reactive protein at 31 years of age in Northern Finland Birth Cohort 1966.

BACKGROUND: Viruses and bacteria like Chlamydia pneumoniae and Helicobacter pylori have been suggested to have a role in pathogenesis of overweight and obesity. OBJECTIVE: We studied whether C. pneumoniae-specific IgG antibodies are associated with elevated body mass index (BMI), waist and hip circumference, and/or waist-hip ratio (WHR), and whether the risk is more pronounced in the simultaneous presence of an ongoing inflammation as measured by elevated high-sensitive C-reactive protein (hsCRP) levels. SUBJECTS AND METHODS: Our study population was derived from the Northern Finland Birth Cohort 1966 (NFBC1966), a general population sample of 12,058 live-born children. This cross-sectional study consisted of 5044 persons at 31 years of age. Serum C. pneumoniae IgG titers were measured by microimmunofluorescence test, and hsCRP levels by immunoenzymometric assay. RESULTS: C. pneumoniae IgG positivity (titer ≥ 32), both alone and jointly with elevated hsCRP (≥ 1.64 mg l(-1), an upper quartile), was found to significantly associate with elevated BMI in the whole study population and with elevated hip and waist circumference in women, yet no association with WHR was seen. The analyses were adjusted for sex (when appropriate), smoking, socioeconomic position, glucose, insulin, high- and low-density lipoprotein cholesterols, triglycerides, leukocytes and pulse pressure. CONCLUSION: These findings suggest that especially in women, persistent C. pneumoniae infection may be associated with overweight/obesity, independently of more traditional risk factors.

Treating miscarriages: a randomised study of cost-effectiveness in medical or surgical choice.

OBJECTIVE: The aim was to carry out a cost effectiveness analysis (CEA) of medical and surgical treatment of miscarriage using quantitative and qualitative indicators. DESIGN: A prospective study where the data of the clinical course of the treatment and the patients; experiences (pain and satisfaction) were collected from a previous randomised study. SETTING: Department of Obstetrics and Gynecology, Oulu University Hospital, Oulu, Finland. POPULATION: Ninety-eight eligible women with a diagnosed miscarriage. METHODS: The incremental cost-effectiveness ratio (ICER) was calculated by using institutional prices (provider's aspect) of the medical care and the number of patients who experienced pain, dissatisfaction or unsuccessful treatment while treated for the miscarriage. MAIN OUTCOME MEASURES: Primary (uncomplicated treatment) and secondary (complications and other unplanned events) costs of the treatments. RESULTS: Primary costs of the surgical treatment were higher, but the more frequent unplanned events and complications in the medical group brought the costs to the same level. In the medical group, based on the ICER, 12 patients more experienced pain, 7 patients more were dissatisfied with the treatment and 5 patients more had unsuccessful treatment compared with surgically treated patients. In theory, these negative outcomes could have been avoided by investing euro1688 more in the surgical treatment. CONCLUSIONS: Medical treatment of miscarriage was not more cost-effective, when the adverse events were considered. As neither of these two methods was economically superior, the treatment choice should be made on an individual basis by respecting the patient's choice.

Fecundability and spontaneous abortions in women with self-reported oligo-amenorrhea and/or hirsutism: Northern Finland Birth Cohort 1966 Study.

BACKGROUND: Women with polycystic ovary syndrome (PCOS) suffer from anovulatory infertility and hospital-based studies suggest that they have an increased risk of spontaneous abortion. Our aim was to investigate the proportion of women, with self-reported oligo-amenorrhea and/or hirsutism in a general population, who had suffered from infertility, the percentage of them managing to conceive and their rate of spontaneous abortion. METHODS: At age 31, a postal questionnaire including questions about hirsutism and oligo-amenorrhea was sent to all women from the population-based Northern Finland Birth Cohort 1966 (total n = 5889). Of these, 4535 (79.5%) answered the questionnaire, 1103 reported hirsutism and/or oligo/amenorrhea (symptomatic women) and 3420 were non-symptomatic. The fecundability ratio (FR) was defined as the probability of conception of a clinically detectable pregnancy within 12 months. RESULTS: The overall pregnancy (77.7% versus 75.6%) and spontaneous abortion (19.3% versus 18.6%) rates did not differ between the two groups and the risk of spontaneous abortion was not associated with body mass index (BMI), waist-to-hip ratio (WHR) or waist circumference. Symptomatic women had suffered more often from infertility than non-symptomatic women (19.4% versus 11.1%, P < 0.01). Oligo-amenorrhea and/or hirsutism (FR = 0.74, P < 0.001) and obesity (FR = 0.68, P = 0.002) were both independently associated with decreased fecundability, but symptomatic women had become pregnant and had one or two successful deliveries as often as non-symptomatic women. CONCLUSIONS: Women with self-reported oligo-amenorrhea and/or hirsutism had lower fecundability and suffered more often from infertility, but had at least one delivery as often as non-symptomatic women, and did not exhibit an increased risk of spontaneous abortion.

Does vitamin D supplementation in infancy reduce the risk of pre-eclampsia?

Vitamin D has been suggested to affect the balance between T helper (Th1) and (Th2) type cytokines by favouring Th2 domination. We investigated the association between infant vitamin D supplementation and later pre-eclampsia, a disorder suggested to be dominated by Th1 response. We used data on 2969 women born in the Northern Finland Birth Cohort 1966 of whom 68 (2.3%) had pre-eclampsia in their first pregnancy. Risk of pre-eclampsia was halved (OR 0.49, 95% confidence interval (CI) 0.26-0.92) in participants who had received vitamin D supplementation regularly during the first year of life and this association was not affected by adjustment for own birth order, birth weight, gestational age, social class in 1966 and hospitalizations or pregnancy-induced hypertension of their mothers. Together with earlier observations on a reduced risk of type 1 diabetes after vitamin D supplementation, these data suggest that vitamin D intake in infancy may affect long-term programming of the immune response pattern.

Body mass index trajectories from 2 to 18 years - exploring differences between European cohorts.

BACKGROUND: In recent decades, there has been an increase in the prevalence of childhood overweight in most high-income countries. Within northern Europe, prevalence tends to be higher in the UK compared with the Scandinavian countries. We aimed to study differences in body mass index (BMI) trajectories between large cohorts of children from UK and Scandinavian populations. METHODS: We compared BMI trajectories in participants from the English Avon Longitudinal Study of Parents and Children born in 1991-1993 (ALSPAC) (N = 6517), the Northern Finland Birth Cohorts born in 1966 (NFBC1966) (N = 3321) and 1986 (NFBC1986) (N = 4764), and the Danish Aarhus Birth Cohort born in 1990-1992 (ABC) (N = 1920). We used multilevel models to estimate BMI trajectories from 2 to 18 years. We explored whether cohort differences were explained by maternal BMI, height, education or smoking during pregnancy and whether differences were attributable to changes in the degree of skew in the BMI distribution. RESULTS: Differences in mean BMI between the cohorts were small but emerged early and persisted in most cases across childhood. Girls in ALSPAC had a higher BMI than all other cohorts throughout childhood, e.g. compared with the NFBC1986 BMI was 2.2-3.5% higher. For boys, the difference emerging over time (comparing the two NFBC's) exceeded the differences across populations (comparing NFBC1986, ABC and ALSPAC). BMI distribution demonstrated increasing right skew with age. CONCLUSION: Population-level differences between cohorts were small, tended to emerge very early, persisted across childhood, and demonstrated an increase in the right-hand tail of the BMI distribution.

Does parity affect mortality among parous women?

OBJECTIVE: To find out whether there is an association between parity and mortality. DESIGN: Prospective cohort study. SETTING: Northern Finland, 1966-2001. PARTICIPANTS AND METHODS: 12,055 women in the two northernmost provinces of Finland were followed up from pregnancy in 1966-2001, the coverage percentage being 96%. The data on age, smoking, body mass index, socioeconomic position, age at menarche and age at first birth were collected during pregnancy, and data on deaths were obtained from the National Cause of Death Statistics, maintained by Statistics Finland. The Cox proportional hazard model was used to estimate relative mortality between parity groups. RESULTS: Total mortality was lowest among the women with 2-4 children (reference group). High parity was associated with an up to twofold risk of mortality from vascular complications, but after adjustment for all background factors, this significance disappeared. Mortality from haemorrhagic stroke was fourfold higher among the women with > or = 10 births compared with those of the reference group. No differences in cerebral infarction or total cancer mortality were seen between the groups. Primiparity was associated with increased mortality from accidental death (relative risk 2.6, 95% confidence interval 1.6 to 4.4). CONCLUSIONS: High parity was associated with an increased risk of mortality from vascular complications, especially haemorrhagic stroke, and primiparity with an increased risk of accidental death.

Radioimmunoassay of plasma ouabain in healthy and pregnant individuals.

Ouabain was recently isolated from human plasma, bovine hypothalamus and bovine adrenal in attempts to identify endogenous substances inhibiting the cell membrane sodium pump. A number of radioimmunoassays have been developed in order to study the clinical significance of ouabain. The results have been controversial with regard to the presence and chemical nature of plasma ouabain-like immunoreactivity. We have now measured ouabain in healthy and pregnant individuals using solid-phase extraction of plasma samples followed by a new radioimmunoassay with the extraordinary sensitivity of at least 2 fmol/tube (5 pmol/l). Plasma extracts, a previously isolated human plasma ouabain-like compound and bovine hypothalamic inhibitory factor displaced the tracer in parallel and eluted identically with ouabain in high-performance liquid chromatography. Plasma ouabain immunoreactivity was found to be much lower than reported previously: 12.6+/-1.3 pmol/l in healthy men (mean+/-s.e., n=20) and 9.4+/-0.7 pmol/l in women (n=14). In pregnant women (n=28) plasma ouabain concentration was 16.3+/-4.0 pmol/l during the first trimester, 18.8+/-4.3 pmol/l during the second trimester and 24.3+/-4.0 pmol/l during the third trimester (all P<0.01 compared with non-pregnant women). Plasma ouabain 3-5 days after the delivery was 13.6+/-1.1 pmol/l (n=10, P<0.05-0.01 compared with second and third trimesters). The pregnancy-related changes in the plasma concentrations of ouabain resembled those of cortisol. Therefore cortisol was measured from the same plasma samples and a significant positive correlation was found (r=0.512, P=0.006). The similar profiles of plasma ouabain and cortisol during pregnancy and their rapid decreases postpartum are consistent with the adrenal cortical origin of ouabain and also show that the secretions of these hormones are possibly under the control of same factors.

An increase of the plasma N-terminal peptide of proatrial natriuretic peptide in preeclampsia.

OBJECTIVE: To determine whether increased concentrations of the N-terminal peptide of proatrial natriuretic peptide and of atrial natriuretic peptide are related to the severity of preeclampsia and gestational hypertension. METHODS: Blood samples were collected from 70 healthy pregnant women, 48 women with preeclampsia, and 19 women with gestational hypertension in the third trimester. We used a specific radioimmunoassay (RIA) method suitable for the determination of the plasma N-terminal peptide of proatrial natriuretic peptide in unextracted plasma. The atrial natriuretic peptide was measured by RIA from Sep-Pak C18-extracted plasma. RESULTS: The N-terminal peptide of proatrial natriuretic peptide levels were significantly higher in preeclamptic women than in healthy pregnant controls (median 571 [range 189-2000] versus 266 pmol/L [80-634], P < .001) and also significantly higher in women with severe preeclampsia than in women with mild preeclampsia (766 [431-2000] versus 492 pmol/L [189-1283], P = .01). The N-terminal peptide of proatrial natriuretic peptide values were significantly elevated in the subgroup of hypertensive pregnancies with abnormal Doppler velocimetry. At entry into the study the values for the N-terminal peptide of proatrial natriuretic peptide were higher in the subgroup of women who developed severe preeclampsia and/or gave birth to a small for gestational age (SGA) infant compared to the values in the subgroup of women in whom the hypertensive condition remained stable (710 [271-1475] versus 407 pmol/L [189-1067], P = .006). Similar comparisons of atrial natriuretic peptide values did not reach significant differences. CONCLUSION: The levels of N-terminal peptide of proatrial natriuretic peptide were higher in women with preeclampsia than in those with gestational hypertension and higher in women with gestational hypertension than in those with normal pregnancies. A marked elevation in N-terminal peptide of proatrial natriuretic peptide may predict development of severe preeclampsia and/or an SGA infant.

Midtrimester N-terminal proatrial natriuretic peptide, free beta hCG, and alpha-fetoprotein in predicting preeclampsia.

OBJECTIVE: To determine whether maternal midtrimester serum N-terminal peptide of proatrial natriuretic peptide, free beta subunit of human chorionic gonadotropin (hCGbeta), or alpha-fetoprotein (AFP) levels can predict preeclampsia. METHODS: A population-based cohort included 1037 nulliparous women, of whom 637 (61%) participated in a maternal serum Down syndrome screening program. Measurements of hCGbeta, AFP, and N-terminal peptide of proatrial natriuretic peptide were made from maternal serum collected at 15-19 weeks' gestation. Sensitivity, specificity, and predictive values were calculated for elevated AFP (at least 2.0 multiples of the median [MoM]) and hCGbeta (at least 2.0 MoM) values. RESULTS: No difference was found in the concentrations of the N-terminal peptide of proatrial natriuretic peptide among the 30 women in whom preeclampsia developed later (median 270 [range 142-604] pmol/L) compared with 536 women who remained normotensive (274 [51-2626] pmol/L). The sensitivity and specificity of elevated AFP in predicting preeclampsia were 3% and 98% and those of elevated hCGbeta were 20% and 84%, respectively. When a stepwise multiple logistic regression model was used, only mean arterial pressure was an independent risk factor in predicting preeclampsia. CONCLUSION: Determinations of the proposed new marker N-terminal peptide of proatrial natriuretic peptide, as well as serum hCGbeta or AFP, are not helpful in predicting preeclampsia.

Serum sex hormone-binding globulin and testosterone in relation to cardiovascular disease risk factors in young men: a population-based study.

OBJECTIVE: Reduced sex hormone-binding globulin (SHBG) concentration predicts insulin resistance and type 2 diabetes, but its association with cardiovascular disease (CVD) risk is unclear. We examined the association between SHBG and cardiovascular risk factors, independently of total testosterone (TT), in young men. DESIGN: Observational, cross-sectional study. SETTING: General community. PARTICIPANTS: The study included 2716 men aged 31 years in the Northern Finland Birth Cohort in 1996 with clinical examination data and fasting blood samples. OUTCOME VARIABLES: Blood pressure (BP), lipids and C-reactive protein (CRP) as biological CVD risk markers. RESULTS: SHBG concentration was significantly and inversely related to systolic and diastolic BP, triglycerides and CRP, but positively to HDL cholesterol after adjusting for insulin, BMI, waist circumference, smoking, education and physical activity (all P<0.05). These linearly graded associations persisted with additional adjustment for TT. SHBG was significantly associated with total cholesterol only with adjustment for covariates and TT (P<0.05). The direction and magnitude of associations between TT and risk factors were variable, but further adjustment for insulin, adiposity and SHBG showed positive associations between TT and BP, total and LDL-cholesterol and triglycerides and an inverse association with CRP (all P<0.05), but its relation with HDL-cholesterol was no longer significant. CONCLUSIONS: In this cohort of young adult men, higher SHBG concentration was associated with a more favourable CVD risk profile, independently of TT. SHBG concentration modified the associations of TT with CVD risk factors.

Prevalence of metabolic syndrome at age 16 using the International Diabetes Federation paediatric definition.

OBJECTIVE: We estimated the prevalence of metabolic syndrome (MS) in adolescents, using the new International Diabetes Federation (IDF) paediatric definition and compared this with prevalence estimated using the IDF adult definition and five other previously published definitions. DESIGN: Cross-sectional survey in the prospective general population-based Northern Finland Birth Cohort 1986 (NFBC 1986) at age 16 years. SETTING: Birth cohort in Finland. PARTICIPANTS: 5665 adolescents (2862 males and 2803 females) clinically examined in 2001-2002. MAIN OUTCOME MEASURES: The prevalence of MS using different definitions. RESULTS: The overall prevalence of MS using the IDF paediatric definition was 2.4% (95% CI 2.0 to 2.8%) at the age of 16 years. Using the IDF adult definition the overall prevalence was lower, 1.7% (CI 1.3 to 2.0%, European cut-offs for waist circumference) and 1.0% (CI 0.7 to 1.3%, North American cut-offs). CONCLUSION: In 16-year-old adolescents, the paediatric IDF definition rendered a higher prevalence estimate than the adult definition.

No evidence that established type 2 diabetes susceptibility variants in the PPARG and KCNJ11 genes have pleiotropic effects on early growth.

AIMS/HYPOTHESIS: The P12A variant in the PPARG gene and the E23K polymorphism in KCNJ11 are both known to influence individual predisposition to type 2 diabetes. If the effect of these variants on insulin secretion and action were to extend to an influence on early growth (which is largely mediated by insulin), it would offer an explanation for observed associations between low birthweight and subsequent diabetes. Since previous studies of the effects of these variants on early growth have been limited and conflicting, we examined these associations in a large, well-characterised birth cohort. METHODS: The P12A and E23K variants were genotyped in (respectively) 5,652 and 5,632 individuals from the Northern Finland Birth Cohort of 1966 and we sought associations with early growth phenotypes. RESULTS: Neither variant was associated with birthweight (P12A, p = 0.42; E23K, p = 0.44, additive models) or other measures of early growth. Although a previous report had suggested that the P12A effect on adult insulin sensitivity was restricted to small babies, we were unable to reproduce this finding (p = 0.40), nor did we confirm a previous report of an association with gestational age (p = 0.23). CONCLUSIONS/INTERPRETATION: Despite a larger sample size than previous studies, we were unable to detect any effect of these variants on early growth. These findings do not support the notion that there are shared genetic determinants of low birthweight and adult diabetes.

Association of variants in the fat mass and obesity associated (FTO) gene with polycystic ovary syndrome.

AIMS/HYPOTHESIS: Variants in the fat-mass and obesity-associated gene (FTO) influence susceptibility to type 2 diabetes via an effect on adiposity/obesity. Given the important role of obesity in the aetiology of both polycystic ovary syndrome (PCOS) and type 2 diabetes mellitus, our aim was to establish whether FTO variants are also implicated in PCOS susceptibility. METHODS: We performed a genetic association study of FTO variant rs9939609 using case-control analyses, conducted in 463 PCOS patients (geometric mean BMI 27.5 kg/m(2)) and 1,336 female controls (geometric mean BMI 25.3 kg/m(2)) of UK British/Irish origin. We also sought evidence for associations between FTO variation and circulating testosterone levels in 324 UK PCOS patients and 1,000 women from the Northern Finland Birth Cohort of 1966. Outcome measures included FTO rs9939609 genotype frequencies by participant group and androgen measures (testosterone, free androgen index) by genotype. RESULTS: There was a significant association between FTO genotype and PCOS status in the UK case-control analysis, which was attenuated by adjustment for BMI (Cochran-Armitage test, odds ratio [per minor allele copy] 1.30 [95% CI 1.12, 1.51], p = 7.2 x 10(-4) [unadjusted], p = 2.9 x 10(-3) [adjusted]). This association was most evident in obese PCOS patients (PCOS patients below median BMI vs UK controls, p = 0.11; above median BMI vs controls, p = 2.9 x 10(-4)). No relationship between FTO genotype and androgen levels was seen. CONCLUSIONS/INTERPRETATION: We provide the first evidence that variants that predispose to common obesity also result in altered susceptibility to PCOS, confirming the mechanistic link between these conditions. The predominant effect of FTO variants on PCOS susceptibility is probably mediated through adiposity.

Disparate genetic influences on polycystic ovary syndrome (PCOS) and type 2 diabetes revealed by a lack of association between common variants within the TCF7L2 gene and PCOS.

AIMS/HYPOTHESIS: Common variants of the gene encoding transcription factor 7-like 2 (TCF7L2) have a powerful effect on individual risk of type 2 diabetes (per allele odds ratio approximately 1.35). Polycystic ovary syndrome (PCOS) and type 2 diabetes are familial conditions sharing common features. Based on this, the aim of the present study was to establish whether variation in TCF7L2 also influences the development of PCOS. METHODS: We conducted a genetic association study of variants of TCF7L2 (rs7903146 and rs12255372) using both case-control and quantitative trait approaches. Case-control analyses were conducted in (1) 369 PCOS cases and 2574 controls of UK British/Irish origin, and (2) 540 women with PCOS symptoms and 1083 controls from the Northern Finland Birth Cohort of 1966. Quantitative trait analyses (androgen levels) were also performed (1249 individuals). RESULTS: There was no association between rs7903146 and PCOS in the UK case-control study (Cochran-Armitage test, p = 0.51); nor with symptomatic status in the Finnish cohort (p = 0.36). In addition, there were no relationships between the TCF7L2 single nucleotide polymorphism rs7903146 and androgen levels (UK cases, p = 0.99; Finnish controls, p = 0.57; Finnish symptomatic cases, p = 0.80). Results at rs12255372 were similar, reflecting strong linkage disequilibrium with rs7903146. CONCLUSIONS/INTERPRETATION: Our study was powered to detect an effect on PCOS susceptibility similar to that previously reported for these variants on type 2 diabetes. Failure to detect any evident association with PCOS provides the strongest evidence yet that the genetic architecture of these related conditions is qualitatively distinct.

No association between insulin gene variation and adult metabolic phenotypes in a large Finnish birth cohort.

AIMS/HYPOTHESIS: Although the variable number tandem repeat (VNTR) minisatellite 5' to the insulin gene is among the most studied polymorphisms in diabetes, the relationships between VNTR variation, diabetes-related traits and predisposition to type 2 diabetes remain unclear. Since inadequate sample size is likely to have been an obstacle to reliable inference, we examined the relationship between VNTR variation and a range of diabetes-related traits in a cohort of 5,753 Finnish adults. MATERIALS AND METHODS: VNTR genotypes were derived, by typing at the -23HphI variant site, for 5,646 individuals from the Northern Finland Birth Cohort 1966. Associations were sought between these genotypes and a range of anthropometric (BMI, WHR), physiological (blood pressure) and biochemical (fasting glucose, insulin, lipids, indices of insulin sensitivity and beta cell function) measures obtained at clinical examination at 31 years. RESULTS: We found no evidence that VNTR genotype was significantly associated with measures of insulin secretion, insulin sensitivity, glycaemia, adiposity or blood pressure. CONCLUSIONS/INTERPRETATION: Despite evidence from several relatively small studies suggesting that INS-VNTR genotypes are associated with predisposition to type 2 diabetes, reduced beta cell function and measures of adiposity, the present study failed to detect any association with a range of diabetes-related traits. Taken with other recent studies in large population-based cohorts, these data suggest that previous studies have, at the very least, overestimated the influence of the INS-VNTR on type 2 diabetes-related traits. The effects of INS-VNTR variation on insulin transcription observed in vitro appear not to translate into detectable differences in basal insulin secretion in humans.

Pre-eclampsia: the effect of intravenous fluid preload on atrial natriuretic peptide secretion during caesarean section under spinal anaesthesia.

BACKGROUND: The haemodynamic effect of volume load at elective Caesarean delivery may be modulated by atrial natriuretic peptide (ANP) especially in pre-eclamptic women in whom basal ANP levels are increased. METHODS: We followed the haemodynamic parameters and determined the peripheral venous levels of ANP before and after an intravenous volume preload of 1000 ml of Ringer's acetate solution, followed by a further load of the same volume under spinal anaesthesia in 7 healthy and in 6 pre-eclamptic women. RESULTS: During the preload period the median ANP level increased more (from 14.8 to 22.1 pmol/l, P = 0.03) in pre-eclamptic than in healthy women (from 8.0 to 8.5 pmol/l, NS); while an increment in central venous pressure (CVP) was also greater in pre-eclamptic than in healthy women. The increase in the concentrations of ANP correlated significantly (P < 0.05) with the increase in CVP in the total study group. A significant increase in ANP levels in healthy pregnant women was not seen until during the second infusion period under spinal anaesthesia; in pre-eclamptic women the levels increased further during that period. CONCLUSION: These findings concur with the theory that atrial stretch is a stimulus for ANP release. An exaggerated release of ANP in response to volume loading may aid in the adaptation of maternal circulation to volume load at elective Caesarean delivery in pre-eclamptic women.