Dietary patterns and the risk of pregnancy-associated hypertension in the Danish National Birth Cohort: a prospective longitudinal study.

OBJECTIVE: To examine the association between mid-pregnancy dietary patterns and pregnancy-associated hypertension (PAH). DESIGN: A prospective longitudinal cohort study. SETTING: Denmark. POPULATION: About 55 139 Danish women with single enrolments and recorded food frequency questionnaire dates with complete information on dietary intake. METHODS: Women were eligible if they could speak Danish and were planning to carry to term. Diet was assessed using a validated semi-quantitative 360-item food frequency questionnaire and dietary patterns were derived using factor analysis. MAIN OUTCOME MEASURES: Gestational hypertension (GH) and pre-eclampsia (PE). RESULTS: Disease prevalence was 14% for GH (5491/39 362); 2% for PE (1168/54 778), and 0.4% for severe PE (234/55 086). Seven dietary patterns were characterised in the population, of which two were associated with PAH. The Seafood diet characterised by high consumption of fish and vegetables was inversely associated with the odds of developing GH [odds ratio (OR) 0.86; 95% CI 0.77-0.95)] and PE (OR 0.79; 95% CI 0.65-0.97). The Western diet characterised by high consumption of potatoes (including French fries), mixed meat, margarine and white bread increased the odds of developing GH (OR 1.18; 95% CI 1.05-1.33) and PE (OR 1.40; 95% CI 1.11-1.76). No association was seen with severe PE. CONCLUSIONS: We found protective associations of Seafood diet and harmful associations of Western diet with PAH. Dietary interventions encouraging the reduction of Western diet may contribute to a decrease of PAH. TWEETABLE ABSTRACT: Western diet increases (Seafood diet decreases) the likelihood of developing pre-eclampsia among Danish pregnant women.

Being born small-for-gestational-age is associated with an unfavourable dietary intake in Danish adolescent girls: findings from the Danish National Birth Cohort.

Individuals born small have an increased risk for developing type 2 diabetes. Altered food preferences in these subjects seem to play a role; however, limited evidence is available on the association between being born small-for-gestational-age (SGA) at term and food intake in adolescence. Alterations in leptin, ghrelin and dopamine levels are suggested mechanisms linking SGA with later food intake. From a large prospective Danish National Birth Cohort, we compared dietary intake of adolescents being born SGA with normal-for-gestational-age (NGA) adolescents. Intake of foods and nutrients was assessed by a validated food frequency questionnaire in a subsample of 15,607 14-year-old individuals born at term. SGA was defined by birth weight (BW) <10th percentile (n = 1470) and NGA as BW between 10 and 90th percentile (n = 14,137) according to sex and gestational age-specific BW standard curves. Girls born SGA had a 7% (95% CI: 3-12%, P = 0.002) higher intake of added sugar and a 2-8% lower intake of dietary fibre, vegetables, polyunsaturated fatty acids, and total n-6, compared with NGA girls (P < 0.05). Adjusting for parental socio-occupational status, maternal smoking and diet in pregnancy did not substantially change the differences in dietary intake, except from dietary fibre, which were no longer statistically significant. No significant differences in dietary intake between SGA and NGA boys were found. In summary, girls born SGA had an unfavourable dietary intake compared with NGA girls. These differences persisted after controlling for potential confounders, thus supporting a fetal programming effect on dietary intake in girls born SGA at term. However, residual confounding by other factors operating early in childhood cannot be excluded.

Associations between maternal physical activity in early and late pregnancy and offspring birth size: remote federated individual level meta-analysis from eight cohort studies.

OBJECTIVE: Evidence on the impact of leisure time physical activity (LTPA) in pregnancy on birth size is inconsistent. We aimed to examine the association between LTPA during early and late pregnancy and newborn anthropometric outcomes. DESIGN: Individual level meta-analysis, which reduces heterogeneity across studies. SETTING: A consortium of eight population-based studies (seven European and one US) comprising 72 694 participants. METHODS: Generalised linear models with consistent inclusion of confounders (gestational age, sex, parity, maternal age, education, ethnicity, BMI, smoking, and alcohol intake) were used to test associations between self-reported LTPA at either early (8-18 weeks gestation) or late pregnancy (30+ weeks) and the outcomes. Results were pooled using random effects meta-analyses. MAIN OUTCOME MEASURES: Birth weight, large-for-gestational age (LGA), macrosomia, small-for-gestational age (SGA), % body fat, and ponderal index at birth. RESULTS: Late, but not early, gestation maternal moderate to vigorous physical activity (MVPA), vigorous activity, and LTPA energy expenditure were modestly inversely associated with BW, LGA, macrosomia, and ponderal index, without heterogeneity (all: I2  = 0%). For each extra hour/week of MVPA, RR for LGA and macrosomia were 0.97 (95% CI: 0.96, 0.98) and 0.96 (95% CI: 0.94, 0.98), respectively. Associations were only modestly reduced after additional adjustments for maternal BMI and gestational diabetes. No measure of LTPA was associated with risk for SGA. CONCLUSIONS: Physical activity in late, but not early, pregnancy is consistently associated with modestly lower risk of LGA and macrosomia, but not SGA. TWEETABLE ABSTRACT: In an individual participant meta-analysis, late pregnancy moderate to vigorous physical activity modestly reduced birth size outcomes.

Plasma Concentrations of Long Chain N-3 Fatty Acids in Early and Mid-Pregnancy and Risk of Early Preterm Birth.

BACKGROUND: Fish oil supplementation has been shown to delay spontaneous delivery, but the levels and clinical significance remain uncertain. We examined the association between plasma fatty acids quantified in pregnancy and subsequent risk of early preterm birth. METHODS: In a case-control design nested in the Danish National Birth Cohort, we identified 376 early preterm cases (<34 gestational weeks, excluding preeclampsia cases) and 348 random controls. Plasma eicosapentaenoic acid plus docosahexaenoic acid (EPA+DHA% of total fatty acids), were measured twice in pregnancy, at gestation weeks 9 and 25 (medians). Odds ratios and 95% confidence intervals (CI's) for associations between EPA+DHA and early preterm risk were estimated by logistic regression, adjusted for the woman's age, height, pre-pregnancy BMI, parity, smoking, and socioeconomic factors. Hypotheses and analytical plan were defined and archived a priori. FINDINGS: Analysis using restricted cubic splines of the mean of 1st and 2nd sample measurements showed a strong and significant non-linear association (p < 0.0001) in which the risk of early preterm birth steeply increased when EPA+DHA concentrations were lower than 2% and flattened out at higher levels. Women in the lowest quintile (EPA+DHA < 1.6%) had 10.27 times (95% confidence interval 6.80-15.79, p < 0.0001) increased risk, and women in the second lowest quintile had 2.86 (95% CI 1.79-4.59, p < 0.0001) times increased risk, when compared to women in the three aggregated highest quintiles (EPA+DHA ≥ 1.8%). INTERPRETATION: Low plasma concentration of EPA and DHA during pregnancy is a strong risk factor for subsequent early preterm birth in Danish women.

Birth by cesarean section in relation to adult offspring overweight and biomarkers of cardiometabolic risk.

BACKGROUND: Birth by Cesarean section (C-section) may increase the risk for non-communicable diseases. We aimed to examine the relation of birth by C-section with offspring overweight and markers of cardiometabolic risk in a prospective observational cohort with 20 years of follow-up. METHODS: The Danish Fetal Origins Cohort enrolled 965 pregnant women in 1988-1989. In 2008, a follow-up study of the offspring was completed. The offspring were invited to participate in a clinical examination with measurements of anthropometry and a fasting blood sample (n=443). In addition, 252 offspring completed a self-administered questionnaire with questions on height and weight, leaving us with a study sample of 695 offspring. Offspring overweight at 20 years was defined as body mass index (BMI)⩾25 kg m-2. We also analyzed blood pressure and fasting blood samples for cardiometabolic risk factors including insulin, leptin and adiponectin, and lipid concentrations. RESULTS: In the cohort, 7% were born by C-section, and at age 20 years, 18% of the offspring had a BMI ⩾25 kg m-2. Birth by C-section was associated with increased odds of overweight or obesity at 20 years (Odds ratio=2.17 (95% confidence interval (CI): 1.10, 4.27)) after adjustment for potential confounders. Birth by C-section was also associated with higher serum concentrations of total cholesterol (8.5%, 95% CI: 1.1-16.5), low-density lipoprotein cholesterol (12.6%, 95% CI: 1.0, 25.5), leptin (73.1%, 95% CI: 5.9, 183.1) and Apolipoprotein B (0.08 g l-1, 95% CI: 0.04, 0.15). In contrast, birth by C-section was not related to blood pressure or serum concentrations of insulin, adiponectin, triglycerides, high-density lipoprotein or Apolipoprotein A. CONCLUSION: Birth by C-section was associated with higher frequency of dysmetabolic traits in offspring independently of shared risk factors. Further research aimed at replicating these findings and elucidating the underlying biological mechanisms of this relation is needed.

Impact of lifestyle intervention for obese women during pregnancy on maternal metabolic and inflammatory markers.

BACKGROUND: Offspring of obese mothers have increased risk of developing obesity and related short- and long-term disease. The cause is multifactorial and may partly be explained by the unfavorable intrauterine environment. Intervention during pregnancy leading to a healthier lifestyle among obese may alter this. OBJECTIVE: To assess the effect of lifestyle intervention on markers of maternal metabolism and inflammation in 'the TOP (Treatment of Obese Pregnant Women) study', a randomized controlled trial. METHODS: In the TOP-study 425 participants with body mass index ⩾30 kg/m2 were randomized to intervention with dietary advices and physical activity assessed by pedometer (PA+D), physical activity assessed by pedometer (PA) or control (C). Of 389 participants completing the study 376 had available blood samples. Serum was analyzed for insulin, c-peptide, lipid profile, leptin, high-sensitivity CRP (hsCRP) and Soluble urokinase Plasminogen Activator Receptor (suPAR), in week 18-20 and 28-30, and simultaneously a 2-h oral glucose-tolerance-test was performed. Diet was assessed in gestational week 11-14 and 36-37 using a validated 360-item Food Frequency Questionnaire. RESULTS: Median levels of hsCRP in gestational week 28-30 were lower in each of the intervention groups (8.3 mg/l in PA+D group, P=0.03; and 8.8 mg/l in PA group, P=0.02) versus the control group (11.5 mg/l). Obtaining 11 000 steps per day as aimed for resulted in a 21% lower hsCRP compared to non-compliant women. Women reporting high carbohydrate intake had around 30% higher hsCRP concentrations in late gestation than women reporting the lowest intake. There were no differences in lipid profile or any of the metabolic markers in gestational week 28-30 when comparing the intervention and control groups. CONCLUSIONS: Lifestyle intervention in obese women can reduce hsCRP representing a marker of inflammation during pregnancy. The effect may partly be mediated by more physical activity and partly by changes in intake of carbohydrates and the glycaemic load.

Maternal fish oil supplementation during lactation is associated with reduced height at 13 years of age and higher blood pressure in boys only.

Dietary long-chain n-3 PUFA (n-3 LCPUFA) in infancy may have long-term effects on lifestyle disease risk. The present follow-up study investigated whether maternal fish oil (FO) supplementation during lactation affected growth and blood pressure in adolescents and whether the effects differed between boys and girls. Mother-infant pairs (n 103) completed a randomised controlled trial with FO (1·5 g/d n-3 LCPUFA) or olive oil (OO) supplements during the first 4 months of lactation; forty-seven mother-infant pairs with high fish intake were followed-up for 4 months as the reference group. We also followed-up 100 children with assessment of growth, blood pressure, diet by FFQ and physical activity by 7-d accelerometry at 13·5 (sd 0·4) years of age. Dried whole-blood fatty acid composition was analysed in a subgroup (n 49). At 13 years of age, whole-blood n-3 LCPUFA, diet, physical activity and body composition did not differ between the three groups. The children from the FO group were 3·4 (95 % CI 0·2, 6·6) cm shorter (P=0·035) than those from the OO group, and tended to have less advanced puberty (P=0·068), which explained the difference in height. There was a sex-specific effect on diastolic blood pressure (P sex×group=0·020), which was driven by a 3·9 (95 % CI 0·2, 7·5) mmHg higher diastolic blood pressure in the FO compared with the OO group among boys only (P=0·041). Our results indicate that early n-3 LCPUFA intake may reduce height in early adolescence due to a delay in pubertal maturation and increase blood pressure specifically in boys, thereby tending to counteract existing sex differences.

Prenatal exposure to persistent organic pollutants and offspring allergic sensitization and lung function at 20 years of age.

BACKGROUND: Prenatal exposures to persistent organic pollutants (POPs) have been associated with asthma medication use and self-reported symptoms, but associations with lung function and allergic sensitization have been minimally explored. The aim of the study was to examine the associations between prenatal exposures to POPs and allergic sensitization and lung function in 20-year-old offspring. METHODS: In a Danish cohort of 965 pregnant women established in 1988-1989, six polychlorinated biphenyl (PCB) congeners, hexachlorobenzene (HCB), and dichlorodiphenyldichloroethylene (p,p'-DDE) were quantified in archived maternal serum drawn in gestational week 30 (n = 872). Among those with available maternal exposure information, at age 20, 421 offspring attended attended a clinical examination including measurements of allergic sensitization (serum-specific IgE ≥ 0.35 kUA /L) (n = 418) and lung function [forced expiratory volume in one second (FEV1 ) and forced vital capacity (FVC)] (n = 414). RESULTS: There were no associations between maternal concentrations of POPs and offspring allergic sensitization at 20 years of age. Maternal concentrations of POPs were, however, positively associated with offspring airway obstruction (FEV1 /FVC < 75%). Compared to offspring in the first tertile of exposure, offspring in the third tertile of dioxin-like PCB exposure had an OR of 2.96 (95% CI: 1.14-7.70). Similar associations for non-dioxin-like PCBs, HCB, and p,p'-DDE were 2.68 (1.06-6.81), 2.63 (1.07, 6.46), and 2.87 (1.09, 7.57), respectively. No associations were observed with reduced lung function (FEV1 % of predicted value < 90%). CONCLUSION AND CLINICAL RELEVANCE: Our data indicate that prenatal exposure to POPs appears to be associated with airway obstruction but not allergic sensitization at 20 years of age. The findings support that chronic obstructive lung diseases may have at least part of their origins in early life.

Pregnancy and Infants' Outcome: Nutritional and Metabolic Implications.

Pregnancy is a complex period of human growth, development, and imprinting. Nutrition and metabolism play a crucial role for the health and well-being of both mother and fetus, as well as for the long-term health of the offspring. Nevertheless, several biological and physiological mechanisms related to nutritive requirements together with their transfer and utilization across the placenta are still poorly understood. In February 2009, the Child Health Foundation invited leading experts of this field to a workshop to critically review and discuss current knowledge, with the aim to highlight priorities for future research. This paper summarizes our main conclusions with regards to maternal preconceptional body mass index, gestational weight gain, placental and fetal requirements in relation to adverse pregnancy and long-term outcomes of the fetus (nutritional programming). We conclude that there is an urgent need to develop further human investigations aimed at better understanding of the basis of biochemical mechanisms and pathophysiological events related to maternal-fetal nutrition and offspring health. An improved knowledge would help to optimize nutritional recommendations for pregnancy.

Gestational weight gain in normal weight women and offspring cardio-metabolic risk factors at 20 years of age.

OBJECTIVE: Limited knowledge exists on the long-term implications of maternal gestational weight gain (GWG) on offspring health. Our objective was to examine whether high GWG in normal weight women is associated with adult offspring cardio-metabolic risk factors. METHODS: We used a cohort of 308 Danish women who gave birth in 1988-89 and whose offspring participated in a clinical examination at 20 years of age. Main outcome measures were offspring body mass index (BMI), waist circumference, weight-regulating hormones, blood lipids and glucose metabolism. Associations were assessed using multivariable linear and logistic regression models. RESULTS: A weak positive association was observed between GWG during the first 30 weeks and offspring anthropometry. Each 1-kg increase in maternal GWG was associated with 0.1-kg m(-2) higher (95% confidence interval (CI): 0.01, 0.2) offspring BMI and 10% (95% CI: 0.1%, 20%) higher odds of offspring overweight at the age of 20 years, with similar associations observed in both sexes. However, sex differences were observed for the association between maternal GWG and specific cardio-metabolic risk factors. Hence, a 1-kg increase in GWG was associated with 3.4% (95% CI; 0.8, 6.0%) higher homeostasis model assessment-estimated insulin resistance (HOMA-IR), 3.7% (95% CI: 1.4%, 6.2%) higher insulin and 10.7% (95% CI: 5.7%, 15.9%) higher leptin levels in male offspring. These associations were not observed in females, which may partly be explained by more frequent reports of dieting and physical exercise at follow-up among female offspring. CONCLUSIONS: In normal-weight women, high GWG may have modest long-term implications on offspring cardio-metabolic risk factors at adult age.

Long-term effects of prenatal exposure to perfluoroalkyl substances on female reproduction.

STUDY QUESTION: Does prenatal exposure to perfluoroalkyl substances (PFASs) have long-term effects on female reproductive function?. SUMMARY ANSWER: Our results suggest an association between in utero exposure to perfluorooctanoic acid (PFOA) and delay in age of menarche. WHAT IS KNOWN ALREADY: Previous cross-sectional studies have reported possible effects of PFASs on female reproduction including reduced fecundity, delayed puberty and accelerated age at menopause. Only limited data exist from follow-up studies on long-term implications of prenatal exposure to PFASs. STUDY DESIGN, SIZE, DURATION: In this study we used data from a Danish population-based cohort established in 1988-1989. Of 1212 eligible pregnant women, 965 participated. Follow-up was initiated in 2008 on the female offspring at ∼20 years of age. Three hundred and sixty seven (84%) daughters answered a questionnaire and 267 (61%) daughters furthermore attended clinical examinations which were conducted in 2008-2009. PARTICIPANTS/MATERIALS, SETTING, METHODS: The final study population consisted of 343 daughters of which 254 had attended the clinical examinations and 89 had answered the questionnaire only. Levels of PFASs in maternal serum from pregnancy week 30 were used as a measure of prenatal exposure and related to age of menarche, menstrual cycle length, levels of reproductive hormones and follicle number of the daughters. Data were divided into three groups according to tertiles of maternal concentrations of PFASs (low, medium, high). MAIN RESULTS AND THE ROLE OF CHANCE: In adjusted regression analyses, daughters exposed to higher levels of PFOA in utero had a 5.3 (95% confidence interval: 1.3; 9.3) months later age of menarche compared with the reference group of lower PFOA. Crude (P = 0.05) and adjusted (P = 0.01) trend tests also indicated a relationship between higher prenatal PFOA exposure and delay of menarche. LIMITATIONS, REASONS FOR CAUTION: We did not measure the exact amount of PFASs to which the daughters had been exposed prenatally. Instead we used PFAS concentrations in maternal serum as surrogates. However, PFASs are efficiently transferred to the fetus via placenta. Information on age of menarche was collected retrospectively but the time interval for recall in our study was relatively short (2-10 years). The remaining outcome measures depended on participation in clinical examination which reduced the number of observations leading to limited statistical power and risk of selection bias. WIDER IMPLICATIONS OF THE FINDINGS: Since PFASs can be detected in humans all over the world, effects of prenatal exposure on female reproductive function later in life may have wide health implications. STUDY FUNDING/COMPETING INTEREST(S): The study was supported by the Danish Council for Independent Research (271-05-0296, 09-065631), the Danish Ministry of Interior and Health (0-302-02-18/5), the Danish Council for Strategic Research (09-067124 (Centre for Fetal Programming), 09-063072, 2101-06-0005), the Novo Nordisk Foundation, the Aarhus University Research Foundation, the Frimodt-Heineke Foundation, the Foundation of Maria Dorthea and Holger From, the Beckett-Foundation, the Research Grant of Organon and the Foundation of Lily Benthine Lund. There are no competing interests. TRIAL REGISTRATION NUMBER: Not applicable.

Deep phenotyping of the unselected COPSAC2010 birth cohort study.

BACKGROUND: We hypothesize that perinatal exposures, in particular the human microbiome and maternal nutrition during pregnancy, interact with the genetic predisposition to cause an abnormal immune modulation in early life towards a trajectory to chronic inflammatory diseases such as asthma and others. OBJECTIVE: The aim of this study is to explore these interactions by conducting a longitudinal study in an unselected cohort of pregnant women and their offspring with emphasis on deep clinical phenotyping, exposure assessment, and biobanking. Exposure assessments focus on the human microbiome. Nutritional intervention during pregnancy in randomized controlled trials are included in the study to prevent disease and to be able to establish causal relationships. METHODS: Pregnant women from eastern Denmark were invited during 2008-2010 to a novel unselected 'COPSAC2010 ' cohort. The women visited the clinic during pregnancy weeks 24 and 36. Their children were followed at the clinic with deep phenotyping and collection of biological samples at nine regular visits until the age of 3 and at acute symptoms. Randomized controlled trials of high-dose vitamin D and fish oil supplements were conducted during pregnancy, and a trial of azithromycin for acute lung symptoms was conducted in the children with recurrent wheeze. RESULTS: Seven hundred and thirty-eight mothers were recruited from week 24 of gestation, and 700 of their children were included in the birth cohort. The cohort has an over-representation of atopic parents. The participant satisfaction was high and the adherence equally high with 685 children (98%) attending the 1 year clinic visit and 667 children (95%) attending the 2 year clinic visit. CONCLUSIONS: The COPSAC2010 birth cohort study provides longitudinal clinical follow-up with highly specific end-points, exposure assessments, and biobanking. The cohort has a high adherence rate promising strong data to elucidate the interaction between genomics and the exposome in perinatal life leading to lifestyle-related chronic inflammatory disorders such as asthma.

Maternal milk consumption, birth size and adult height of offspring: a prospective cohort study with 20 years of follow-up.

BACKGROUND/OBJECTIVES: Previous studies have suggested that milk consumption during pregnancy may have growth-promoting effects on the offspring in utero. Whether this effect tracks beyond the prenatal period remains unclear. We examined whether milk consumption during pregnancy is associated with infant size at birth and offspring's height- and growth-related biomarkers at ∼20 years of age. SUBJECT/METHODS: A prospective cohort of 809 Danish pregnant women was recruited in 1988-1989, with offspring follow-up at ∼20 years of age (n=685). Milk consumption was assessed at gestational week 30 using a food frequency questionnaire. Birth weight and birth length were measured according to standard procedures at delivery and converted to specific z-scores, adjusted for gestational age and gender. RESULTS: In adjusted models, maternal milk consumption of ≥150 ml/day vs <150 ml/day was associated with 0.32 higher z-scores for birth weight (95% confidence interval (CI) 0.06; 0.58) and 0.34 higher z-scores for birth length (95% CI 0.04; 0.64). At follow up, ∼20 years later, those offspring whose mothers had consumed < 150 ml milk/day tended to have 0.19 higher z-scores for height (P=0.16), ∼8% higher levels of insulin-like growth factor I (P=0.12) and ∼14% higher insulin levels (P=0.11) compared with offspring whose mothers consumed <150 ml milk/day. CONCLUSIONS: Our findings add to recent observations that maternal milk consumption may have a growth-promoting effect with respect to weight and length at birth. Furthermore, the results provide some suggestion that this effect may even track into early adult age, although further studies with more statistical power are needed for that purpose.

Maternal smoking during pregnancy and reproductive health of daughters: a follow-up study spanning two decades.

STUDY QUESTION: Does in utero exposure to constituents of cigarette smoke have a programming effect on daughters' age of menarche and markers of long-term reproductive health? SUMMARY ANSWER: In utero exposure to constituents of cigarette smoke was associated with earlier age of menarche and--to a lesser extent--changes in the testosterone profile of the young women. WHAT IS KNOWN ALREADY: Studies observe potential effects of in utero exposure to constituents of cigarette smoke on the intrauterine formation of female gonads, but the consequences on long-term reproductive health in daughters remain unclear. STUDY DESIGN, SIZE AND DURATION: A prospective cohort study was designed using data from 965 pregnant women enrolled prior to a routine 30th-week antenatal examination at a midwifery practice in Denmark from 1988 to 1989 and a follow-up of their 19-21-year-old daughters in 2008. PARTICIPANTS/MATERIALS, SETTING AND METHODS: The pregnant women provided information on lifestyle factors during pregnancy, including the exact number of cigarettes smoked per day during the first and the second trimesters. A total of 438 eligible daughters were asked to complete a web-based questionnaire on reproductive health and subsequently invited to participate in a clinical examination during 2008. Of the 367 daughters (84%) who answered the questionnaire, 267 (61%) agreed to further examination. Information on menstrual pattern was provided at examination, blood samples were drawn to be analyzed for serum levels of reproductive hormones [FSH, LH, estradiol (E(2)), sex hormone-binding globulin, anti-Müllerian hormone, dehydroepiandrosterone-sulphate (DHEAS), free testosterone and free E(2)] and number of follicles (2-9 mm) were examined by transvaginal ultrasound. The daughters were divided into three exposure groups according to the level of maternal smoking during first trimester [non-exposed (reference), low-exposed (mother smoking >0-9 cigarettes/day) and high-exposed (mother smoking ≥ 10 cigarettes/day)]. Data were analyzed by multiple regression analyses in which we adjusted for potential confounders. Both crude and adjusted test for trend were carried out using maternal smoking during the first trimester as a continuous variable. MAIN RESULTS AND THE ROLE OF CHANCE: We observed an inverse association between in utero exposure to constituents of cigarette smoke and age of menarche (P = 0.001). Daughters exposed to >0-9 cigarettes/day debuted with -2.7 [95% confidence interval (CI) -5.2 to -0.1] percentage earlier age of menarche, whereas daughters exposed to ≥ 10 cigarettes/day had -4.1 (95% CI: -6.6 to -1.5) percentage earlier age of menarche corresponding to 6.5 (95% CI: -10.7 to -2.2) months. There was a non-significant tendency towards lower levels of testosterone and DHEAS with increasing in utero exposure to constituents of cigarette smoke but no associations with follicle number, cycle length or serum levels of the other reproductive hormones were observed. LIMITATIONS AND REASONS FOR CAUTION: We collected information on age of menarche retrospectively but the recall time was relatively short (2-10 years) and the reported values were within the normal range of Caucasians. Analyses of reproductive hormones are presented only for the group of daughters who were non-users of hormonal contraceptives because users were excluded, leaving only a low number of daughters available for the analyses (n = 75), as reflected in the wide CIs. The analyses of hormones were further adjusted for menstrual phase at time of clinical examination (follicular, ovulation and luteal phase) because blood samples were not collected on a specific day of the menstrual cycle. WIDER IMPLICATIONS OF THE FINDINGS: This study supports the limited evidence of an inverse association between maternal smoking during pregnancy and age of menarche and further addresses to what extent reproductive capacity and hormones may be programmed by maternal smoking during pregnancy. A trend toward earlier maturation of females is suggested to have implications on long-term reproductive function. STUDY FUNDING/COMPETING INTEREST(S): Supported by a scholarship from The Lundbeck Foundation (R93-A8476). No conflict of interest declared.

A prospective study of trans fat intake and risk of preeclampsia in Denmark.

BACKGROUND/OBJECTIVES: An association between biomarkers of trans fat intake and greater risk of preeclampsia has been reported, but research in this area is scant. Thus, we examined the association of second trimester intake of trans fats with risk of preeclampsia and severe preeclampsia. SUBJECTS/METHODS: We followed 67,186 pregnancies of women participating in the Danish National Birth Cohort between 1998 and 2003. Diet was assessed with a food frequency questionnaire at gestation week 25, and preeclampsia diagnosis was obtained by linkage with the Danish National Patient Registry. RESULTS: There were 1804 cases of preeclampsia and 402 cases of severe preeclampsia identified in the cohort. Intake of trans fats decreased during the study period as a consequence of a reduction in industrial trans fat intake. Second trimester intake of trans fats was unrelated to risk of preeclampsia or severe preeclampsia. The relative risk (95% confidence interval; P, trend) of preeclampsia and severe preeclampsia comparing top to bottom quintiles of trans fat intake were 0.95(0.81; 1.11, 0.33) and 1.07 (0.78; 1.48, 0.92), respectively. CONCLUSION: Second trimester intake of trans fats is unrelated to risk of preeclampsia within the intake range observed in a period of gradual reduction of industrial trans fats from the Danish food supply.

A very large proportion of young Danish women have polycystic ovaries: is a revision of the Rotterdam criteria needed?

BACKGROUND: According to the Rotterdam 2003 criteria, an ovary is defined as polycystic if 12 or more follicles of 2-9 mm are present, when evaluating the ovary by ultrasonography on Days 3-5 of the menstrual cycle in women not using hormonal contraceptives. The aim of this population-based study was to estimate the prevalence of polycystic ovaries (PCO) in a representative sample of young Danish women according to the Rotterdam criteria. METHODS: From a Danish pregnancy cohort established in 1988-1989, 267 (61%) young adult daughters agreed to participate in a clinical examination and 174 (40%) consented to vaginal ultrasound. Sufficient image quality in at least one ovary was obtained from 154 women. Both users and non-users of hormonal contraceptives were included and the examination was not restricted to a particular time of the menstrual cycle. RESULTS: The median (range) age was 20.1 (19.5-21.0) years. The median follicle number per ovary was 14 (6-30) and 12 or more follicles were counted in 104 of the 154 women. Thus, the prevalence was estimated to 68% [95% confidence interval (CI): 60-74%]. PCO were present in 80% (95% CI: 65-89%) of non-users (n = 44) of hormonal contraceptives. Of the 104 women with PCO, 41% (95% CI: 32-51%) could be defined as having polycystic ovary syndrome. CONCLUSIONS: A very large proportion of the young women had PCO according to the Rotterdam 2003 criteria. As the number of follicles is higher at a younger age, we believe the Rotterdam criteria should be revised, particularly to avoid misdiagnosis in this age group.

Intake of vitamin C and E in pregnancy and risk of pre-eclampsia: prospective study among 57 346 women.

OBJECTIVE: It has been suggested that vitamin C, alone or in combination with vitamin E, may protect against pre-eclampsia, whereas the safety of high-dose vitamin E supplements has been questioned. We investigated dietary intakes of vitamins C and E to see if they correlated with the incidence of pre-eclampsia. DESIGN: Prospective cohort study. SETTING: The Danish National Birth Cohort; a population-based pregnancy cohort; analyses were based on 57 346 pregnancies. METHODS: Vitamin intake was estimated from a food frequency questionnaire completed in gestational week 25, recording intake from diet and supplements during the previous four weeks. Pre-eclampsia diagnoses were obtained from the Danish National Patient Registry; we worked with two entities, 'pre-eclampsia (all types)' and 'severe pre-eclampsia/eclampsia/HELLP'. We adjusted for confounding factors by logistic regression. MAIN OUTCOME MEASURES: A small increase in the incidence of severe disease was also seen in the group of women (64, n = 49 373) with a high intake of vitamin E from supplements and dietary sources. RESULTS: The incidence of 'pre-eclampsia (all types)' did not correlate with dietary vitamin C and E intake. There was a decreasing trend (P = 0.01) in the incidence of 'severe pre-eclampsia/eclampsia/HELLP' with increasing dietary vitamin C intake; with an intake of 130-170 mg/day as reference, odds ratios ranged from 1.21 (95% confidence interval 0.83 to 1.75) for an intake below 70 mg/day to 0.70 (0.40 to 1.23) for an intake exceeding 275 mg/day (total n = 57 346). For vitamin E intake aggregated from diet and supplements (n = 49 373), with an intake of 10.5-13.5 mg/day as reference, the 'severe pre-eclampsia/eclampsia/HELLP' odds ratio was 1.46 (1.02 to 2.09) for an intake exceeding 18 mg/day. CONCLUSIONS: Low dietary intake of vitamin C was associated with a trend towards an increased incidence of either severe pre-eclampsia, eclampsia or HELLP. A small increase in the incidence of severe disease was also seen in the group of women with a high intake of vitamin E from supplements and dietary sources.

Associations of maternal prenatal dietary intake of n-3 and n-6 fatty acids with maternal and umbilical cord blood levels.

Maternal n-3 and n-6 polyunsaturated fatty acid (PUFA) status may influence birth outcomes and child health. We assessed second trimester maternal diet with food frequency questionnaires (FFQs) (n=1666), mid-pregnancy maternal erythrocyte PUFA concentrations (n=1550), and umbilical cord plasma PUFA concentrations (n=449). Mean (SD) maternal intake of total n-3 PUFA was 1.17 g/d (0.43), docosahexaenoic and eicosapentaenoic acids (DHA+EPA) 0.16 g/d (0.17), and total n-6 PUFA 12.25 g/d (3.25). Mean maternal erythrocyte and cord plasma PUFA concentrations were 7.0% and 5.2% (total n-3), 5.0% and 4.6% (DHA+EPA), and 27.9% and 31.4% (total n-6). Mid-pregnancy diet-blood and blood-blood correlations were strongest for DHA+EPA (r=0.38 for diet with maternal blood, r=0.34 for diet with cord blood, r=0.36 for maternal blood with cord blood), and less strong for n-6 PUFA. The FFQ is a reliable measure of elongated PUFA intake, although inter-individual variation is present.