Performance of different fetal growth charts in prediction of large-for-gestational age and associated neonatal morbidity in multiethnic obese population.

OBJECTIVES: To examine the performance of different fetal growth charts in the prediction of large-for-gestational age (LGA) and associated neonatal morbidity at term in a multiethnic, obese population. METHODS: This was a retrospective cohort study of 253 non-anomalous, singleton, term pregnancies that underwent serial third-trimester ultrasound scans due to maternal body mass index ≥ 35 kg/m2 . We compared the performance of the Hadlock, Gestation Related Optimal Weight (GROW), INTERGROWTH-21st (IG-21), World Health Organization (WHO) and Fetal Medicine Foundation (FMF) fetal growth reference charts in the prediction of LGA at birth, defined as birth weight > 90th percentile, and neonatal morbidity, defined as a composite of neonatal intensive care unit admission or 5-min Apgar score < 7. RESULTS: In the study population, 53 (20.9%) infants were born LGA, 27 (10.7%) experienced neonatal morbidity and nine (3.6%) were LGA with associated neonatal morbidity. The Hadlock and GROW charts showed similar performance in predicting LGA, with sensitivity of 66.0% for both and specificity of 82.5% and 83.5%, respectively. The positive likelihood ratios (LR+) were 3.77 (95% CI, 2.64-5.40) and 4.00 (95% CI, 2.77-5.78), respectively. The IG-21, WHO and FMF charts performed similarly and had higher sensitivity of about 85%, with specificity between 66% and 72%. LR+ was 2.74 (95% CI, 2.16-3.47), 2.50 (95% CI, 2.00-3.12) and 3.03 (95% CI, 2.36-3.89), respectively. All charts had high sensitivity for predicting neonatal morbidity associated with LGA, with LR+ ranging between 2.35 and 3.61. CONCLUSIONS: In our multiethnic, obese population, all fetal growth charts performed well in predicting LGA and associated neonatal morbidity. However, the choice of fetal reference chart is likely to affect intervention rates. Copyright © 2019 ISUOG. Published by John Wiley & Sons Ltd.

Evaluation of a simple risk score to predict preterm pre-eclampsia using maternal characteristics: a prospective cohort study.

OBJECTIVES: (1) To derive a simple risk score for preterm pre-eclampsia based on the model used in the ASPRE trial, and (2) to compare it (i) with the original ASPRE algorithm, (ii) with the NICE Guideline score, and (iii) with and without biochemical and ultrasonic predictors. DESIGN: Prospective cohort study. SETTING: Cambridge, UK. POPULATION OR SAMPLE: 4184 nulliparous women from the Pregnancy Outcome Prediction study. METHODS: Maternal history model coefficients from the ASPRE algorithm were translated into a risk score, preserving the relative weight of each coefficient. MAIN OUTCOME MEASURES: Preterm delivery with a diagnosis of pre-eclampsia. RESULTS: The area under the ROC curve (AUC) for preterm pre-eclampsia was 0.846 (95% CI 0.787-0.906) for the risk score and 0.854 (95% CI 0.795-0.914) for the original ASPRE algorithm (P = 0.14). In all, 9.1% of women had a risk score of ≥30 and their risk ratio for preterm pre-eclampsia was 13.3 (95% CI 6.3-27.8), sensitivity 57.1% (37.5-74.8%), false-positive rate (1-specificity) 8.8% (8.0-9.7%), and LR+ 6.5 (4.6-9.1). The score had higher specificity than the NICE Guideline criteria. First trimester levels of PAPP-A and PlGF were not predictive when included in a model with the risk score. In contrast, mean arterial pressure at booking and 20-week uterine artery Doppler were independently associated with preterm pre-eclampsia and the latter modestly increased the AUC (by ~0.02). CONCLUSIONS: A simple risk score derived from the ASPRE screening study predictive model provided clinically useful prediction of the risk of preterm pre-eclampsia. TWEETABLE ABSTRACT: A simple risk score derived from the ASPRE screening study provided clinically useful prediction of the risk of preterm pre-eclampsia.

Blinded ultrasound fetal biometry at 36 weeks and risk of emergency Cesarean delivery in a prospective cohort study of low-risk nulliparous women.

OBJECTIVES: To compare the association between risk of emergency Cesarean delivery (CD) and non-customized vs customized ultrasound estimated fetal weight (EFW) at 36 weeks' gestation, determine whether addition of ultrasound EFW to a model based on maternal characteristics alone improved prediction of emergency CD, assess the screening performance of a multivariable model using both EFW and maternal characteristics to predict emergency CD, and determine whether women at high predicted risk of emergency CD based on this model had higher risk of maternal and perinatal morbidity compared with screen-negative women. METHODS: We studied 3047 low-risk (no pre-existing medical conditions or acquired complications of pregnancy) nulliparous women from the prospective Pregnancy Outcome Prediction study (Cambridge, UK) cohort, who underwent ultrasound EFW at ∼36 weeks' gestation. Both the women and their clinicians were blinded to fetal biometry results. Emergency CD was defined as delivery by Cesarean section in pregnancies in which the date of delivery had not been prearranged. Additional candidate predictors of emergency CD evaluated were maternal age, height, body mass index (BMI), weight gain, fetal abdominal circumference growth velocity and fetal sex. External validation of the predictive model was performed using routinely collected data from 55 337 births in Scotland between 2003 and 2008. Women with an estimated risk of emergency CD ≥ 40% were defined as screen positive. RESULTS: Blinded EFW was associated strongly with the risk of emergency CD (coefficient for increase of 1 SD in EFW, 0.39 (95% CI, 0.30-0.48); odds ratio (OR), 1.48 (95% CI, 1.35-1.62)). The coefficient for customized EFW was similar (0.42 (95% CI, 0.33-0.51); OR, 1.53 (95% CI, 1.39-1.67)); hence, for simplicity, non-customized EFW was employed subsequently. A multivariable logistic regression model combining maternal characteristics (age, height, BMI and weight gain between 12 and 36 weeks) was moderately predictive of emergency CD (area under the receiver-operating characteristics curve (AUC) = 0.68). Addition of blinded EFW to the model increased the AUC to 0.71 and improved prediction (likelihood-ratio test P < 0.0001). Based on this model, 189 (6.2%) women were screen positive and 48% of these delivered by CD. Screen-positive women had elevated risks of severe postpartum hemorrhage (relative risk (RR), 2.49; 95% CI, 1.83-3.38), any adverse neonatal outcome (RR, 1.86; 95% CI, 1.22-2.82) and severe adverse neonatal outcome (RR, 4.03; 95% CI, 1.35-12.03) compared with screen-negative women. The risks of these events were also higher compared with women who had a term CD for breech presentation. The model was similarly predictive of the risk of emergency CD and perinatal morbidity when evaluated using the dataset from Scotland. CONCLUSIONS: Ultrasound EFW at 36 weeks, combined with maternal characteristics, can identify women who are at increased risk of subsequent emergency CD. These women are at increased risk of maternal and perinatal morbidity compared with women at low risk of emergency CD and those having CD for breech presentation at term. Copyright © 2017 ISUOG. Published by John Wiley & Sons Ltd.

Universal vs selective ultrasonography to screen for large-for-gestational-age infants and associated morbidity.

OBJECTIVES: To compare the diagnostic effectiveness of selective vs universal ultrasonography as a screening test for large-for-gestational-age (LGA) infants, and to determine whether previously described ultrasound markers of excessive fetal growth could identify suspected LGA fetuses that are at increased risk of adverse neonatal outcome. METHODS: Data from the Pregnancy Outcome Prediction study, a prospective cohort study of nulliparous women with a viable singleton pregnancy at the time of the dating ultrasound scan, were analyzed. Women were selected for clinically indicated ultrasound assessment in the third trimester as per routine clinical care, and the results of these scans were reported ('selective ultrasonography'). In addition, all participants underwent research ultrasound scans, including estimated fetal weight (EFW) assessment, at around 36 weeks' gestation, in which both the women and their clinicians were blinded to the results ('universal ultrasonography'). Participants who attended the 36-week research scan and had a live birth at the Rosie Hospital were included in the study. Screen positive for LGA was defined as EFW > 90th percentile at ≥ 34 weeks. RESULTS: The current analysis included 3866 eligible women, of whom 1354 (35%) had a clinically indicated ultrasound scan at or after 34 weeks' gestation. A total of 177 (4.6%) infants had a birth weight > 90th percentile. The sensitivity for detection of LGA infants was 27% for selective ultrasonography and 38% for universal ultrasonography. The specificity of both approaches was high (99% and 97%, respectively). Using universal ultrasonography, neonatal outcome differed (P for interaction) by abdominal circumference growth velocity (ACGV) for both any neonatal morbidity (P = 0.08) and severe adverse neonatal outcome (P = 0.03). LGA fetuses with increased ACGV had a relative risk of any neonatal morbidity of 2.0 (95% CI, 1.1-3.6; P = 0.04) and of severe adverse neonatal outcome of 6.5 (95% CI, 2.0-21.1; P = 0.01), whereas LGA fetuses with normal ACGV were not at increased risk. CONCLUSIONS: Third-trimester screening of nulliparous women by universal ultrasound fetal biometry increases the detection rate of LGA infants and, combined with ACGV, identifies those at increased risk of adverse neonatal outcome. Copyright © 2017 ISUOG. Published by John Wiley & Sons Ltd.

Birth weight to placenta weight ratio and its relationship to ultrasonic measurements, maternal and neonatal morbidity: A prospective cohort study of nulliparous women.

INTRODUCTION: Birth weight to placenta weight (BWPW)-ratio is an indicator of the ability of the placenta to maintain adequate nutrient supply to the fetus. We sought to investigate the relationship between BWPW-ratio with fetal growth, utero-placental Doppler and neonatal and maternal morbidity. METHODS: We studied a group of 3311 women recruited to a prospective cohort study of nulliparous women (Rosie Hospital, Cambridge, UK) who delivered a live born infant at term and whose placental weight and birth weight were known. Ultrasonic indices and BWPW ratio were converted to gestational age adjusted z scores. Analysis of continuous variables was by multivariable linear regression. BWPW ratio was also categorized (lowest or highest quintile, both referent to quintiles 2 to 4) and associations with adverse outcomes analyzed using multivariable logistic regression. RESULTS: Lowest quintile of BWPW-ratio was associated (adjusted odds ratio [95% CI], P) with both neonatal morbidity (1.55 [1.12-2.14], 0.007) and maternal diabetes (1.75 [1.18-2.59], 0.005). Highest quintile of BWPW ratio was associated with a reduced risk of maternal obesity (0.71 [0.53 to 0.95], 0.02) and preeclampsia (0.51 [0.31 to 0.84], 0.008), but higher (adjusted z score [95% CI], P) uterine artery Doppler mean pulsatility index (PI) at 20 weeks of gestation (0.09 [0.01-0.18], 0.04) and umbilical artery Doppler PI at 36 weeks of gestation (0.16 [0.07-0.25], <0.001). CONCLUSION: BWPW-ratio is related to ultrasonic measurements and both neonatal and maternal morbidity. Therefore, this ratio may be an indicative marker of immediate and longer term health risks for an individual.

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.

The relationship between human placental morphometry and ultrasonic measurements of utero-placental blood flow and fetal growth.

INTRODUCTION: Ultrasonic fetal biometry and arterial Doppler flow velocimetry are widely used to assess the risk of pregnancy complications. There is an extensive literature on the relationship between pregnancy outcomes and the size and shape of the placenta. However, ultrasonic fetal biometry and arterial Doppler flow velocimetry have not previously been studied in relation to postnatal placental morphometry in detail. METHODS: We conducted a prospective cohort study of nulliparous women in The Rosie Hospital, Cambridge (UK). We studied a group of 2120 women who had complete data on uterine and umbilical Doppler velocimetry and fetal biometry at 20, 28 and 36 weeks' gestational age, digital images of the placenta available, and delivered a liveborn infant at term. Associations were expressed as the difference in the standard deviation (SD) score of the gestational age adjusted ultrasound measurement (z-score) comparing the lowest and highest decile of the given placental morphometric measurement. RESULTS: The lowest decile of placental surface area was associated with 0.87 SD higher uterine artery Doppler mean pulsatility index (PI) at 20 weeks (95% CI: 0.68 to 1.07, P < 0.001). The lowest decile of placental weight was associated with 0.73 SD higher umbilical artery Doppler PI at 36 weeks (95% CI: 0.54 to 0.93, P < 0.001). The lowest decile of both placental weight and placental area were associated with reduced growth velocity of the fetal abdominal circumference between 20 and 36 weeks (both P < 0.001). CONCLUSION: Placental area and weight are associated with uterine and umbilical blood flow, respectively, and both are associated with fetal growth rate.

Do eating disorders in parents predict eating disorders in children? Evidence from a Swedish cohort.

OBJECTIVE: We investigated whether parental eating disorders (ED) predict ED in children, using a large multigeneration register-based sample. METHOD: We used a subset of the Stockholm Youth Cohort born 1984-1995 and resident in Stockholm County in 2001-2007 (N = 286,232), The exposure was a diagnosed eating disorder in a parent; the outcome was any eating disorder diagnosis in their offspring, given by a specialist clinician, or inferred from an appointment at a specialist eating disorder clinic. A final study sample of 158,697 (55.4%) had data on these variables and confounding factors and contributed a total of 886,241 person years to the analysis. RESULTS: We found good evidence in support of the hypothesis that ED in either parent are independently associated with ED in their female children (HR 1.97 (95% CI: 1.17-3.33), P = 0.01) and that ED in mothers are independently associated with ED in their female children (HR 2.35 (95% CI: 1.39-3.97) P = 0.001). Numbers were too low to permit separate analysis of ED in parents and their male children. CONCLUSION: Eating disorders in parents were associated with ED in children. This study adds to our knowledge about the intergenerational transmission of ED, which will help identify high-risk groups and brings about the possibility of targeted prevention.

Comparison of fully and semi-automated area-based methods for measuring mammographic density and predicting breast cancer risk.

BACKGROUND: Mammographic density is a strong risk factor for breast cancer but the lack of valid fully automated methods for quantifying it has precluded its use in clinical and screening settings. We compared the performance of a recently developed automated approach, based on the public domain ImageJ programme, to the well-established semi-automated Cumulus method. METHODS: We undertook a case-control study within the intervention arm of the Age Trial, in which ∼54,000 British women were offered annual mammography at ages 40-49 years. A total of 299 breast cancer cases diagnosed during follow-up and 422 matched (on screening centre, date of birth and dates of screenings) controls were included. Medio-lateral oblique (MLO) images taken closest to age 41 and at least one year before the index case's diagnosis were digitised for each participant. Cumulus readings were performed in the left MLO and ImageJ-based readings in both left and right MLOs. Conditional logistic regression was used to examine density-breast cancer associations. RESULTS: The association between density readings taken from one single MLO and breast cancer risk was weaker for the ImageJ-based method than for Cumulus (age-body mass index-adjusted odds ratio (OR) per one s.d. increase in percent density (95% CI): 1.52 (1.24-1.86) and 1.61 (1.33-1.94), respectively). The ImageJ-based density-cancer association strengthened when the mean of left-right MLO readings was used: OR=1.61 (1.31-1.98). CONCLUSIONS: The mean of left-right MLO readings yielded by the ImageJ-based method was as strong a predictor of risk as Cumulus readings from a single MLO image. The ImageJ-based method, using the mean of two measurements, is a valid automated alternative to Cumulus for measuring density in analogue films.

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.

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.

Common genetic variation near MC4R is associated with eating behaviour patterns in European populations.

Both rs17782313 (near MC4R) and rs1421085 (FTO) polymorphisms have been consistently associated with increased risk of obesity and with body mass index (BMI) variation. An effect of both polymorphisms on satiety has recently been suggested. We genotyped rs17782313 and rs1421085 in 5764 relatives from 1109 French pedigrees with familial obesity, 1274 Swiss class III obese adults as well as in 4877 French adults and 5612 Finnish teenagers from two randomly selected population cohorts. In all subjects, eating behaviour traits were documented through questionnaires. We first assessed the association of both single nucleotide polymorphisms with BMI and then studied eating behaviour. Under an additive model, the rs17782313-C MC4R allele showed a trend towards higher percentages of snacking in both French obese children (P=0.01) and Swiss obese adults (P=0.04) as well as in adolescents from the Finnish general population (P=0.04). In French adults with familial obesity, this allele tended to be also associated with a higher Stunkard hunger score (P=0.02) and in obese children with a higher prevalence of eating large amounts of food (P=0.04). However, no consistent association of the FTO rs1421085-C allele and available eating behaviour trait was found in our studied populations. The rs17782313-C allele nearby MC4R may modulate eating behaviour-related phenotypes in European obese and randomly selected populations, in both children and adults, supporting a regulatory role of this genetic variant on eating behaviour, as previously shown for MC4R non-synonymous loss-of-function mutations. The potential effect of the obesity-associated FTO gene on eating behaviour deserves additional investigation.

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.

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.

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.

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.

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.

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.

Body size from birth to adulthood and bone mineral content and density at 31 years of age: results from the northern Finland 1966 birth cohort study.

The purpose of this study was to evaluate the association between body size from birth to adulthood and bone mineral content (BMC) and bone mineral density (BMD) at the age of 31 years in a longitudinal study of the Northern Finland birth cohort for 1966. Data were collected at birth, 1, 14, and 31 years. This analysis was restricted to a subsample of individuals (n =1,099) for whom the BMC (g) and BMD measurements (g/cm(2)) were performed on the distal and ultradistal radius by dual-energy X-ray absorptiometry (DXA) at the age of 31 years. Determinants of low BMC and BMD were analyzed using multivariate logistic regression. Growth retardation at birth, being underweight (BMI < or =20.0 kg/m(2)) at 31 years, and having a low calcium intake at 31 years were associated independently with low BMD at 31 years. Additionally, the proportion of subjects with low BMD was higher among those who had low standardized body weight (< or =1 SD) both at birth and at 14 years, and both at 14 and 31 years. Body weight at 31 years was the strongest associating factor of BCM at 31 years. Growth retardation at birth has long-lasting effects on adult bone mineral content and density of the distal and ultradistal radius independently of later body size, although adult body weight seems to be a most important determinant of BMC at the age of 31 years. Thinness and a low calcium intake are associated with low bone mineral content and density at 31 years of age. Further studies are needed to evaluate if these groups are at increased risk of osteoporosis in old age.