Abigail Fraser

Cohort Profile: The ‘Children of the 90s’—the index offspring of the Avon Longitudinal Study of Parents and Children

The Avon Longitudinal Study of Parents and Children (ALSPAC) is a transgenerational prospective observational study investigating influences on health and development across the life course. It considers multiple genetic, epigenetic, biological, psychological, social and other environmental exposures in relation to a similarly diverse range of health, social and developmental outcomes. Recruitment sought to enrol pregnant women in the Bristol area of the UK during 1990–92; this was extended to include additional children eligible using the original enrolment definition up to the age of 18 years. The children from 14 541 pregnancies were recruited in 1990–92, increasing to 15 247 pregnancies by the age of 18 years. This cohort profile describes the index children of these pregnancies. Follow-up includes 59 questionnaires (4 weeks–18 years of age) and 9 clinical assessment visits (7–17 years of age). The resource comprises a wide range of phenotypic and environmental measures in addition to biological samples, genetic (DNA on 11 343 children, genome-wide data on 8365 children, complete genome sequencing on 2000 children) and epigenetic (methylation sampling on 1000 children) information and linkage to health and administrative records. Data access is described in this article and is currently set up as a supported access resource. To date, over 700 peer-reviewed articles have been published using ALSPAC data.

Cohort Profile: The Avon Longitudinal Study of Parents and Children: ALSPAC mothers cohort

Summary The Avon Longitudinal Study of Children and Parents (ALSPAC) was established to understand how genetic and environmental characteristics influence health and development in parents and children. All pregnant women resident in a defined area in the South West of England, with an expected date of delivery between 1st April 1991 and 31st December 1992, were eligible and 13 761 women (contributing 13 867 pregnancies) were recruited. These women have been followed over the last 19–22 years and have completed up to 20 questionnaires, have had detailed data abstracted from their medical records and have information on any cancer diagnoses and deaths through record linkage. A follow-up assessment was completed 17–18 years postnatal at which anthropometry, blood pressure, fat, lean and bone mass and carotid intima media thickness were assessed, and a fasting blood sample taken. The second follow-up clinic, which additionally measures cognitive function, physical capability, physical activity (with accelerometer) and wrist bone architecture, is underway and two further assessments with similar measurements will take place over the next 5 years. There is a detailed biobank that includes DNA, with genome-wide data available on >10 000, stored serum and plasma taken repeatedly since pregnancy and other samples; a wide range of data on completed biospecimen assays are available. Details of how to access these data are provided in this cohort profile.

Association of Maternal Weight Gain in Pregnancy With Offspring Obesity and Metabolic and Vascular Traits in Childhood

Background— We sought to examine the association of gestational weight gain (GWG) and prepregnancy weight with offspring adiposity and cardiovascular risk factors. Methods and Results— Data from 5154 (for adiposity and blood pressure) and 3457 (for blood assays) mother-offspring pairs from a UK prospective pregnancy cohort were used. Random-effects multilevel models were used to assess incremental GWG (median and range of repeat weight measures per woman: 10 [1, 17]). Women who exceeded the 2009 Institute of Medicine-recommended GWG were more likely to have offspring with greater body mass index, waist, fat mass, leptin, systolic blood pressure, C-reactive protein, and interleukin-6 levels and lower high-density lipoprotein cholesterol and apolipoprotein A1 levels. Children of women who gained less than the recommended amounts had lower levels of adiposity, but other cardiovascular risk factors tended to be similar in this group to those of offspring of women gaining recommended amounts. When examined in more detail, greater prepregnancy weight was associated with greater offspring adiposity and more adverse cardiovascular risk factors at age 9 years. GWG in early pregnancy (0 to 14 weeks) was positively associated with offspring adiposity across the entire distribution but strengthened in women gaining >500 g/wk. By contrast, between 14 and 36 weeks, GWG was only associated with offspring adiposity in women gaining >500 g/wk. GWG between 14 and 36 weeks was positively and linearly associated with adverse lipid and inflammatory profiles, with these associations largely mediated by the associations with offspring adiposity. Conclusions— Greater maternal prepregnancy weight and GWG up to 36 weeks of gestation are associated with greater offspring adiposity and adverse cardiovascular risk factors. Before any GWG recommendations are implemented, the balance of risks and benefits of attempts to control GWG for short- and long-term outcomes in mother and child should be ascertained.

Alanine Aminotransferase, γ-Glutamyltransferase, and Incident Diabetes The British Women's Heart and Health Study and meta-analysis

OBJECTIVE To estimate and compare associations of alanine aminotransferase (ALT) and γ-glutamyltransferase (GGT) with incident diabetes. RESEARCH DESIGN AND METHODS ALT and GGT were studied as determinants of diabetes in the British Womens Heart and Health Study, a cohort of 4,286 women 60–79 years old (median follow-up 7.3 years). A systematic review and a meta-analysis of 21 prospective, population-based studies of ultrasonography, which diagnosed nonalcoholic fatty liver disease (NAFLD), ALT, and GGT as determinants of diabetes, were conducted, and associations of ALT and GGT with diabetes were compared. RESULTS Ultrasonography-diagnosed NAFLD was associated with more than a doubling in the risk of incident diabetes (three studies). ALT and GGT both predicted diabetes. The fully adjusted hazard ratio (HR) for diabetes per increase in one unit of logged ALT was 1.83 (95% CI 1.57–2.14, I2 = 8%) and for GGT was 1.92 (1.66–2.21, I2 = 55%). To directly compare ALT and GGT as determinants of diabetes, the fully adjusted risk of diabetes in the top versus bottom fourth of the ALT and GGT distributions was estimated using data from studies that included results for both markers. For ALT, the HR was 2.02 (1.59–2.58, I2 = 27%), and for GGT the HR was 2.94 (1.98–3.88, I2 = 20%), suggesting that GGT may be a better predictor (P = 0.05). CONCLUSIONS Findings are consistent with the role of liver fat in diabetes pathogenesis. GGT may be a better diabetes predictor than ALT, but additional studies with directly determined liver fat content, ALT, and GGT are needed to confirm this finding.OBJECTIVE To estimate and compare associations of alanine aminotransferase (ALT) and gamma-glutamyltransferase (GGT) with incident diabetes. RESEARCH DESIGN AND METHODS ALT and GGT were studied as determinants of diabetes in the British Womens Heart and Health Study, a cohort of 4,286 women 60-79 years old (median follow-up 7.3 years). A systematic review and a meta-analysis of 21 prospective, population-based studies of ultrasonography, which diagnosed nonalcoholic fatty liver disease (NAFLD), ALT, and GGT as determinants of diabetes, were conducted, and associations of ALT and GGT with diabetes were compared. RESULTS Ultrasonography-diagnosed NAFLD was associated with more than a doubling in the risk of incident diabetes (three studies). ALT and GGT both predicted diabetes. The fully adjusted hazard ratio (HR) for diabetes per increase in one unit of logged ALT was 1.83 (95% CI 1.57-2.14, I(2) = 8%) and for GGT was 1.92 (1.66-2.21, I(2) = 55%). To directly compare ALT and GGT as determinants of diabetes, the fully adjusted risk of diabetes in the top versus bottom fourth of the ALT and GGT distributions was estimated using data from studies that included results for both markers. For ALT, the HR was 2.02 (1.59-2.58, I(2) = 27%), and for GGT the HR was 2.94 (1.98-3.88, I(2) = 20%), suggesting that GGT may be a better predictor (P = 0.05). CONCLUSIONS Findings are consistent with the role of liver fat in diabetes pathogenesis. GGT may be a better diabetes predictor than ALT, but additional studies with directly determined liver fat content, ALT, and GGT are needed to confirm this finding.

Gamma-Glutamyltransferase Is Associated With Incident Vascular Events Independently of Alcohol Intake: Analysis of the British Women’s Heart and Health Study and Meta-Analysis

Objective—&ggr;-glutamyltransferase (GGT) is a marker of alcohol intake but may also reflect oxidative stress and nonalcoholic fatty liver disease. Alanine aminotransferase (ALT) is the enzyme most closely associated with liver fat content. Methods and Results—Associations of GGT and ALT with incident CHD, stroke, and a combined outcome of CHD or stroke were examined in the British Women’s Heart and Health study (n=2961), and a meta-analysis of population based studies examining these associations was performed. In pooled analyses of fully adjusted results of 10 prospective studies, a change of 1 U/L of GGT was associated with a HR=1.20 (95% CI: 1.02, 1.40) for CHD; a HR=1.54 (95% CI: 1.20, 2.00) for stroke; and HR=1.34 (95% CI: 1.22, 1.48) for CHD or stroke. Heterogeneity was substantially decreased when 2 studies in Asian populations were excluded. In a subgroup of nondrinkers results were similar to the main analysis. Meta analyses of the only 2 studies that examined the association of ALT with incident cardiovascular events found a HR=1.18, 95% CI: 0.99, 1.41) for CHD and a HR=1.10 (95% CI: 0.89, 1.36) for CHD or stroke (combined). Conclusion—GGT is associated with incident vascular events independently of alcohol intake. The mechanisms underlying this association remain unclear and require future study.

Association between general and central adiposity in childhood, and change in these, with cardiovascular risk factors in adolescence: prospective cohort study.

Objectives To examine the prospective associations between body mass index (BMI), waist circumference, and fat mass in childhood and cardiovascular risk factors at age 15-16. Design Prospective cohort study. Setting Avon Longitudinal Study of Parents and Children. Participants 5235 children aged 9-12 at start of study. Main exposures BMI, waist circumference, and fat mass determined by dual energy x ray absorptiometry, assessed at age 9-12 and at age 15-16. Main outcome measures Systolic and diastolic blood pressure and concentrations of fasting glucose, insulin, triglycerides, low density lipoprotein cholesterol, and high density lipoprotein cholesterol assessed at age 15-16. Results In girls a 1 SD greater BMI at age 9-12 was associated with cardiovascular risk factors at age 15-16 in fully adjusted models: odds ratio 1.23 (95% confidence interval 1.10 to 1.38) for high systolic blood pressure (≥130 mm Hg); 1.19 (1.03 to 1.38) for high concentration of low density lipoprotein cholesterol (≥2.79 mmol/l); 1.43 (1.06 to 1.92) for high concentration of triglycerides (≥1.7 mmol/l); 1.25 (1.08 to 1.46) for low concentration of high density lipoprotein cholesterol (<1.03 mmol/l); and 1.45 (1.22 to 1.73) for high concentration of insulin (≥16.95 IU/l). Equivalent results in boys were 1.24 (1.13 to 1.37) for systolic blood pressure; 1.30 (1.07 to 1.59) for low density lipoprotein cholesterol; 1.96 (1.51 to 2.55) for triglycerides; 1.39 (1.22 to 1.57) for high density lipoprotein cholesterol, and 1.84 (1.56 to 2.17) for insulin. BMI was associated with high fasting glucose (≥5.6 mmol/l) only in boys (1.18, 1.03 to 1.36). With these binary outcomes there was statistical evidence that associations differed between girls and boys for fasting glucose (P=0.03) and insulin (P<0.001). When risk factors were examined as continuous outcomes there was evidence for stronger associations of BMI with more adverse levels in boys than girls for fasting insulin, glucose, and triglyceride concentrations (all interaction P≤0.03). BMI, waist circumference, and fat mass were all strongly correlated with each other (r=0.89-0.94), and associations of the three with cardiovascular outcomes were of similar magnitude with statistical evidence of consistency in associations (all P>0.2 for heterogeneity). When waist circumference or fat mass or both were added to models including BMI they did not increase the variation in cardiovascular risk factors already explained by BMI and confounders alone. Girls who were overweight/obese at age 9-12 but were normal weight by 15-16 had similar odds of adverse levels of risk factors to those who were normal weight at both ages. In boys odds of high systolic blood pressure, high concentrations of triglycerides and insulin, and low concentrations of high density lipoprotein cholesterol remained higher in this group compared with those who were normal weight at both ages but were lower than in those who remained overweight/obese at both ages. Conclusions Measurements of waist circumference or directly assessed fat mass in childhood do not seem to be associated with cardiovascular risk factors in adolescence any more strongly than BMI. Girls who favourably alter their overweight status between childhood and adolescence have cardiovascular risk profiles broadly similar to those who were normal weight at both time points, but boys who change from overweight to normal show risk factor profiles intermediate between those seen in boys who are normal weight at both ages or overweight at both ages.

Associations of Pregnancy Complications With Calculated Cardiovascular Disease Risk and Cardiovascular Risk Factors in Middle Age The Avon Longitudinal Study of Parents and Children

Background— The nature and contribution of different pregnancy-related complications to future cardiovascular disease (CVD) and its risk factors and the mechanisms underlying these associations remain unclear. Methods and Results— We studied associations of pregnancy diabetes mellitus, hypertensive disorders of pregnancy, preterm delivery, and size for gestational age with calculated 10-year CVD risk (based on the Framingham score) and a wide range of cardiovascular risk factors measured 18 years after pregnancy (mean age at outcome assessment, 48 years) in a prospective cohort of 3416 women. Gestational diabetes mellitus was positively associated with fasting glucose and insulin, even after adjustment for potential confounders, whereas hypertensive disorders of pregnancy were associated with body mass index, waist circumference, blood pressure, lipids, and insulin. Large for gestational age was associated with greater waist circumference and glucose concentrations, whereas small for gestational age and preterm delivery were associated with higher blood pressure. The association with the calculated 10-year CVD risk based on the Framingham prediction score was odds ratio 1.31 (95 confidence interval, 1.11–1.53) for preeclampsia and 1.26 (95 confidence interval, 0.95–1.68) for gestational diabetes mellitus compared with women without preeclampsia and without gestational diabetes mellitus, respectively. Conclusions— Hypertensive disorders of pregnancy and pregnancy diabetes mellitus are independently associated with an increased calculated 10-year CVD risk. Preeclampsia may be the better predictor of future CVD because it was associated with a wider range of cardiovascular risk factors. Our results suggest that pregnancy may be an important opportunity for early identification of women at increased risk of CVD later in life.

Antibiotic prophylaxis in neutropenic patients: new evidence, practical decisions.

New evidence shows that antibiotic prophylaxis in neutropenic patients reduces mortality, febrile episodes, and bacterial infections. For patients with acute leukemia or those who undergo bone marrow transplantation, prophylaxis with fluoroquinolones diminished the risk of death from any cause by 33% (95% confidence interval [95% CI], 2–54%). Thus, 55 patients who have acute leukemia or who undergo bone marrow transplantation must receive prophylaxis to prevent 1 death. In 4 studies that included patients with solid tumors or lymphoma, prophylaxis reduced the rate of death during the first month (relative risk, 0.51; 95% CI, 0.27–0.97), and 82 patients had to receive prophylaxis to prevent 1 death. The main argument brought against prophylaxis is the induction of resistance. Patients who received prophylaxis did not experience more infections caused by resistant strains than patients in the control group. The recent GIMEMA study was conducted in a population with a nearly 50% resistance to fluoroquinolones in all pathogens and 20% resistance in gram‐negative isolates, thus indicating that prophylaxis should be offered in settings with similar or less resistance. Prophylaxis with fluoroquinolones was efficacious in reducing infections caused by gram‐positive bacteria. Patients who are treated for acute leukemia should be offered prophylaxis with ciprofloxacin or levofloxacin. Prophylaxis to cover the expected period of neutropenia may be considered for the first cycle of treatment in patients with solid tumors or lymphoma who regularly receive regimens that cause severe neutropenia. Excessive local levels of resistance to fluoroquinolones or high local incidence of infections caused by Clostridium difficile and related to fluoroquinolones should prompt a reconsideration of this policy. Cancer 2006.

Associations of gestational weight gain with maternal body mass index, waist circumference, and blood pressure measured 16 y after pregnancy: the Avon Longitudinal Study of Parents and Children (ALSPAC)

Background: Little is known about associations of gestational weight gain (GWG) with long-term maternal health. Objective: We aimed to examine associations of prepregnancy weight and GWG with maternal body mass index (BMI; in kg/m2), waist circumference (WC), systolic blood pressure (SBP), and diastolic blood pressure (DBP) 16 y after pregnancy. Design: This is a prospective study in 2356 mothers from the Avon Longitudinal Study of Parents and Children (ALSPAC)—a population-based pregnancy cohort. Results: Women with low GWG by Institute of Medicine recommendations had a lower mean BMI (−1.56; 95% CI: −2.12, −1.00) and WC (−3.37 cm; −4.91, −1.83 cm) than did women who gained weight as recommended. Women with a high GWG had a greater mean BMI (2.90; 2.27, 3.52), WC (5.84 cm; 4.15, 7.54 cm), SBP (2.87 mm Hg; 1.22, 4.52 mm Hg), and DBP (1.00 mm Hg; −0.02, 2.01 mm Hg). Analyses were adjusted for age, offspring sex, social class, parity, smoking, physical activity and diet in pregnancy, mode of delivery, and breastfeeding. Women with a high GWG had 3-fold increased odds of overweight and central adiposity. On the basis of estimates from random-effects multilevel models, prepregnancy weight was positively associated with all outcomes. GWG in all stages of pregnancy was positively associated with later BMI, WC, increased odds of overweight or obesity, and central adiposity. GWG in midpregnancy (19–28 wk) was associated with later greater SBP, DBP, and central adiposity but only in women with a normal prepregnancy BMI. Conclusions: Results support initiatives aimed at optimizing prepregnancy weight. Recommendations on optimal GWG need to balance contrasting associations with different outcomes in both mothers and offspring.

Pregnancy Characteristics and Women's Future Cardiovascular Health: An Underused Opportunity to Improve Women's Health?

Growing evidence indicates that women with a history of common pregnancy complications, including fetal growth restriction and preterm delivery (often combined as low birth weight), hypertensive disorders of pregnancy, and gestational diabetes, are at increased risk for cardiovascular disease later in life. The purpose of this paper was to review the associations of parity and these 4 pregnancy complications with cardiovascular morbidity and mortality; to review the role of cardiovascular risk factors before, during, and after pregnancy complications in explaining these associations; and to explore the implications of this emerging science for new research and policy. We systematically searched for relevant cohort and case-control studies in Medline through December 2012 and used citation searches for already published reviews to identify new studies. The findings of this review suggest consistent and often strong associations of pregnancy complications with latent and future cardiovascular disease. Many pregnancy complications appear to be preceded by subclinical vascular and metabolic dysfunction, suggesting that the complications may be useful markers of latent high-risk cardiovascular trajectories. With further replication research, these findings would support the utility of these prevalent pregnancy complications in identifying high-risk women for screening, prevention, and treatment of cardiovascular disease, the leading cause of morbidity and mortality among women.