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1.  ASSOCIATIONS OF BLOOD PRESSURE CHANGE IN PREGNANCY WITH FETAL GROWTH AND GESTATIONAL AGE AT DELIVERY: FINDINGS FROM A PROSPECTIVE COHORT 
Hypertension  2014;64(1):36-44.
Hypertensive disorders of pregnancy are associated with intrauterine growth restriction and preterm birth. However, the associations of patterns of blood pressure change during pregnancy with these outcomes have not been studied in detail. We studied repeat antenatal blood pressure measurements of 9,697 women in the Avon Longitudinal Study of Parents and Children (median (interquartile range) 10 (9, 11) measurements per woman). Bivariate linear spline models were used to relate blood pressure changes to perinatal outcomes.
Higher systolic, but not diastolic, blood pressure at baseline (8 weeks gestation) and a greater increase in systolic and diastolic blood pressure between 18 and 36 weeks gestation were associated with lower offspring birthweight and being smaller for gestational age in confounder-adjusted models. For example, the mean difference (95% CI) in birthweight per 1 mmHg/week greater increase in systolic blood pressure between 18-30 weeks was −71g (−134, −14) and between 30-36 weeks was −175g (−208, −145). A smaller decrease in systolic and diastolic blood pressure prior to 18 weeks and a greater increase between 18 and 36 weeks was associated with a shorter gestation (percentage difference in gestational duration per 1 mmHg/week greater increase in systolic blood pressure between 18-30 weeks: −0.60% (−1.01, −0.18) and 30-36 weeks: −1.01% (−1.36, −0.74)). Associations remained strong when restricting to normotensive women. We conclude that greater increases in blood pressure, from the 18-week nadir, are related to reduced fetal growth and shorter gestation even in women whose blood pressure does not cross the threshold for hypertensive disorders of pregnancy.
doi:10.1161/HYPERTENSIONAHA.113.02766
PMCID: PMC4150069  PMID: 24821945
ALSPAC; Birthweight; Blood pressure; Gestational age; Pregnancy
2.  Grip Strength across the Life Course: Normative Data from Twelve British Studies 
PLoS ONE  2014;9(12):e113637.
Introduction
Epidemiological studies have shown that weaker grip strength in later life is associated with disability, morbidity, and mortality. Grip strength is a key component of the sarcopenia and frailty phenotypes and yet it is unclear how individual measurements should be interpreted. Our objective was to produce cross-sectional centile values for grip strength across the life course. A secondary objective was to examine the impact of different aspects of measurement protocol.
Methods
We combined 60,803 observations from 49,964 participants (26,687 female) of 12 general population studies in Great Britain. We produced centile curves for ages 4 to 90 and investigated the prevalence of weak grip, defined as strength at least 2.5 SDs below the gender-specific peak mean. We carried out a series of sensitivity analyses to assess the impact of dynamometer type and measurement position (seated or standing).
Results
Our results suggested three overall periods: an increase to peak in early adult life, maintenance through to midlife, and decline from midlife onwards. Males were on average stronger than females from adolescence onwards: males’ peak median grip was 51 kg between ages 29 and 39, compared to 31 kg in females between ages 26 and 42. Weak grip strength, defined as strength at least 2.5 SDs below the gender-specific peak mean, increased sharply with age, reaching a prevalence of 23% in males and 27% in females by age 80. Sensitivity analyses suggested our findings were robust to differences in dynamometer type and measurement position.
Conclusion
This is the first study to provide normative data for grip strength across the life course. These centile values have the potential to inform the clinical assessment of grip strength which is recognised as an important part of the identification of people with sarcopenia and frailty.
doi:10.1371/journal.pone.0113637
PMCID: PMC4256164  PMID: 25474696
3.  Predictive models for kidney disease: improving global outcomes (KDIGO) defined acute kidney injury in UK cardiac surgery 
Critical Care  2014;18(6):606.
Introduction
Acute kidney injury (AKI) risk prediction scores are an objective and transparent means to enable cohort enrichment in clinical trials or to risk stratify patients preoperatively. Existing scores are limited in that they have been designed to predict only severe, or non-consensus AKI definitions and not less severe stages of AKI, which also have prognostic significance. The aim of this study was to develop and validate novel risk scores that could identify all patients at risk of AKI.
Methods
Prospective routinely collected clinical data (n = 30,854) were obtained from 3 UK cardiac surgical centres (Bristol, Birmingham and Wolverhampton). AKI was defined as per the Kidney Disease: Improving Global Outcomes (KDIGO) Guidelines. The model was developed using the Bristol and Birmingham datasets, and externally validated using the Wolverhampton data. Model discrimination was estimated using the area under the ROC curve (AUC). Model calibration was assessed using the Hosmer–Lemeshow test and calibration plots. Diagnostic utility was also compared to existing scores.
Results
The risk prediction score for any stage AKI (AUC = 0.74 (95% confidence intervals (CI) 0.72, 0.76)) demonstrated better discrimination compared to the Euroscore and the Cleveland Clinic Score, and equivalent discrimination to the Mehta and Ng scores. The any stage AKI score demonstrated better calibration than the four comparison scores. A stage 3 AKI risk prediction score also demonstrated good discrimination (AUC = 0.78 (95% CI 0.75, 0.80)) as did the four comparison risk scores, but stage 3 AKI scores were less well calibrated.
Conclusions
This is the first risk score that accurately identifies patients at risk of any stage AKI. This score will be useful in the perioperative management of high risk patients as well as in clinical trial design.
doi:10.1186/s13054-014-0606-x
PMCID: PMC4258283
4.  Modelling Childhood Growth Using Fractional Polynomials and Linear Splines 
Annals of Nutrition & Metabolism  2014;65(3):129-138.
Background
There is increasing emphasis in medical research on modelling growth across the life course and identifying factors associated with growth. Here, we demonstrate multilevel models for childhood growth either as a smooth function (using fractional polynomials) or a set of connected linear phases (using linear splines).
Methods
We related parental social class to height from birth to 10 years of age in 5,588 girls from the Avon Longitudinal Study of Parents and Children (ALSPAC). Multilevel fractional polynomial modelling identified the best-fitting model as being of degree 2 with powers of the square root of age, and the square root of age multiplied by the log of age. The multilevel linear spline model identified knot points at 3, 12 and 36 months of age.
Results
Both the fractional polynomial and linear spline models show an initially fast rate of growth, which slowed over time. Both models also showed that there was a disparity in length between manual and non-manual social class infants at birth, which decreased in magnitude until approximately 1 year of age and then increased.
Conclusions
Multilevel fractional polynomials give a more realistic smooth function, and linear spline models are easily interpretable. Each can be used to summarise individual growth trajectories and their relationships with individual-level exposures.
doi:10.1159/000362695
PMCID: PMC4264511  PMID: 25413651
ALSPAC; Growth; Linear spline models; Longitudinal study; Multilevel models; Repeated measures
5.  Differences in risk factors for self-harm with and without suicidal intent: Findings from the ALSPAC cohort 
Journal of Affective Disorders  2014;168(100):407-414.
Background
There is a lack of consensus about whether self-harm with suicidal intent differs in aetiology and prognosis from non-suicidal self-harm, and whether they should be considered as different diagnostic categories.
Method
Participants were 4799 members of the Avon Longitudinal Study of Parents and Children (ALSPAC), a UK population-based birth cohort who completed a postal questionnaire on self-harm with and without suicidal intent at age 16 years. Multinomial logistic regression analyses were used to examine differences in the risk factor profiles of individuals who self-harmed with and without suicidal intent.
Results
Many risk factors were common to both behaviours, but associations were generally stronger in relation to suicidal self-harm. This was particularly true for mental health problems; compared to those with non-suicidal self-harm, those who had harmed with suicidal intent had an increased risk of depression (OR 3.50[95% CI 1.64, 7.43]) and anxiety disorder (OR 3.50[95% CI 1.72, 7.13]). Higher IQ and maternal education were risk factors for non-suicidal self-harm but not suicidal self-harm. Risk factors that appeared specific to suicidal self-harm included lower IQ and socioeconomic position, physical cruelty to children in the household and parental self-harm.
Limitations
i) There was some loss to follow-up, ii) difficulty in measuring suicidal intent, iii) we cannot rule out the possibility of reverse causation for some exposure variables, iv) we were unable to identify the subgroup that had only ever harmed with suicidal intent.
Conclusion
Self-harm with and without suicidal intent are overlapping behaviours but with some distinct characteristics, indicating the importance of fully exploring vulnerability factors, motivations, and intentions in adolescents who self harm.
doi:10.1016/j.jad.2014.07.009
PMCID: PMC4160300  PMID: 25108277
ALSPAC; Adolescent; Self-harm; Suicide attempt; Longitudinal
6.  Socioeconomic differences in childhood length/height trajectories in a middle-income country: a cohort study 
BMC Public Health  2014;14(1):932.
Background
Socioeconomic disadvantage is associated with shorter adult stature. Few studies have examined socioeconomic differences in stature from birth to childhood and the mechanisms involved, particularly in middle-income former Soviet settings.
Methods
The sample included 12,463 Belarusian children (73% of the original cohort) born in 1996–1997, with up to 14 stature measurements from birth to 7 years. Linear spline multi-level models with 3 knots at 3, 12 and 34 months were used to analyse birth length and growth velocity during four age-periods by parental educational achievement (up to secondary school, advanced secondary/partial university, completed university) and occupation (manual, non-manual).
Results
Girls born to the most (versus least) educated mothers were 0.43 cm (95% confidence interval (CI): 0.28, 0.58) longer at birth; for boys, the corresponding difference was 0.30 cm (95% CI: 0.15, 0.46). Similarly, children of the most educated mothers grew faster from birth-3 months and 12–34 months (p-values for trend ≤0.08), such that, by age 7 years, girls with the most (versus least) educated mothers were 1.92 cm (95% CI: 1.47, 2.36) taller; after controlling for urban/rural and East/West area of residence, this difference remained at 1.86 cm (95% CI: 1.42, 2.31), but after additionally controlling for mid-parental height, attenuated to 1.10 cm (95% CI: 0.69, 1.52). Among boys, these differences were 1.95 cm (95% CI: 1.53, 2.37), 1.89 cm (95% CI: 1.47, 2.31) and 1.16 cm (95% CI: 0.77, 1.55), respectively. Additionally controlling for breastfeeding, maternal smoking and older siblings did not substantively alter these findings. There was no evidence that the association of maternal educational attainment with growth differed in girls compared to boys (p for interaction = 0.45). Results were similar for those born to the most (versus least) educated fathers, or who had a parent with a non-manual (versus manual) occupation.
Conclusions
In Belarus, a middle-income former Soviet country, socioeconomic differences in offspring growth commence in the pre-natal period and generate up to approximately 2 cm difference in height at age 7 years. These associations are partly explained by genetic or other factors influencing parental stature.
Trial Registration
Current Controlled Trials: NCT01352247 assigned 9 Sept 2005; ClinicalTrials.gov. Identifier: NCT01561612 received 20 Mar 2012.
Electronic supplementary material
The online version of this article (doi:10.1186/1471-2458-14-932) contains supplementary material, which is available to authorized users.
doi:10.1186/1471-2458-14-932
PMCID: PMC4181044  PMID: 25200513
Length; Height; Growth trajectory; Socioeconomic factors; Belarus
7.  Weight trajectories through infancy and childhood and risk of non-alcoholic fatty liver disease in adolescence: The ALSPAC study 
Journal of Hepatology  2014;61(3):626-632.
Background & Aims
Adiposity is a key risk factor for NAFLD. Few studies have examined prospective associations of infant and childhood adiposity with subsequent NAFLD risk. We examined associations of weight-for-height trajectories from birth to age 10 with liver outcomes in adolescence, and assessed the extent to which associations are mediated through fat mass at the time of outcome assessment.
Methods
Individual trajectories of weight and height were estimated for participants in the Avon Longitudinal Study of Parents and Children using random-effects linear-spline models. Associations of birthweight (adjusted for birth length) and weight change (adjusted for length/height change) from 0–3 months, 3 months–1 y, 1–3 y, 3–7 y, and 7–10 y with ultrasound scan (USS) determined liver fat and stiffness, and serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), and gamma-glutamyl transferase (GGT) at mean age 17.8 y were assessed with linear and logistic regressions. Mediation by concurrent fat mass was assessed with adjustment for fat mass at mean age 17.8 y.
Results
Birth weight was positively associated with liver stiffness and negatively with ALT and AST. Weight change from birth to 1 y was not associated with outcomes. Weight change from 1–3 y, 3–7 y, and 7–10 y was consistently positively associated with USS and blood-based liver outcomes. Adjusting for fat mass at mean age 17.8 y attenuated associations toward the null, suggesting associations are largely mediated by concurrent body fatness.
Conclusions
Greater rates of weight-for-height change between 1 y and 10 y are consistently associated with adverse liver outcomes in adolescence. These associations are largely mediated through concurrent fatness.
doi:10.1016/j.jhep.2014.04.018
PMCID: PMC4139262  PMID: 24768828
NAFLD, Non-alcoholic fatty liver disease; ALT, Alanine aminotransferase; AST, Aspartate aminotransferase; GGT, Gamma-glutamyl transferase; ALSPAC, Avon Longitudinal Study of Parents and Children; AUDIT, Alcohol Use Disorders Identification Tests; ARFI, Acoustic radiation force impulse-imaging; DXA, Dual-energy X-ray absorptiometry; BMI, Body mass index; Infant; Childhood; Growth; Obesity; BMI; NAFLD; Fatty liver
8.  Improving upon the efficiency of complete case analysis when covariates are MNAR 
Biostatistics (Oxford, England)  2014;15(4):719-730.
Missing values in covariates of regression models are a pervasive problem in empirical research. Popular approaches for analyzing partially observed datasets include complete case analysis (CCA), multiple imputation (MI), and inverse probability weighting (IPW). In the case of missing covariate values, these methods (as typically implemented) are valid under different missingness assumptions. In particular, CCA is valid under missing not at random (MNAR) mechanisms in which missingness in a covariate depends on the value of that covariate, but is conditionally independent of outcome. In this paper, we argue that in some settings such an assumption is more plausible than the missing at random assumption underpinning most implementations of MI and IPW. When the former assumption holds, although CCA gives consistent estimates, it does not make use of all observed information. We therefore propose an augmented CCA approach which makes the same conditional independence assumption for missingness as CCA, but which improves efficiency through specification of an additional model for the probability of missingness, given the fully observed variables. The new method is evaluated using simulations and illustrated through application to data on reported alcohol consumption and blood pressure from the US National Health and Nutrition Examination Survey, in which data are likely MNAR independent of outcome.
doi:10.1093/biostatistics/kxu023
PMCID: PMC4173105  PMID: 24907708
Complete case analysis; Missing covariates; Missing not at random; Multiple imputation
9.  Growth trajectories in the children of mothers with eating disorders: a longitudinal study 
BMJ Open  2014;4(3):e004453.
Objective
The aim of this study was to examine longitudinal patterns of growth trajectories in children of women with eating disorders (ED): anorexia nervosa (AN) and bulimia nervosa (BN).
Design
Prospective longitudinal birth cohort; Avon Longitudinal Study of Parents and Children (ALSPAC).
Setting
South West England, UK.
Participants
The sample consisted of women and their children (n=10 190) from ALSPAC. Patterns of growth among children of women reporting a history of AN (n=137), BN (n=165), both AN and BN (n=68) and other psychiatric disorders (n=920) were compared with an unexposed group of children (n=8900).
Main outcome measures
Height and weight data, from birth to 10 years, were extracted from health visitor records, parental report from questionnaires and clinic attendances. Growth trajectories were analysed using mixed-effects models and constructed separately for male and female children.
Results
Between birth and 10 years, male children of women with BN were taller than children in the unexposed group. Male children of women with a history of AN and BN, and female children of women with AN, were shorter throughout childhood. Between the ages of 2 and 5, higher body mass index (BMI) was observed in male children in all maternal ED groups. Conversely, female children of women with AN had a BMI of −0.35 kg/m2 lower at 2 years compared with the unexposed group, with catch-up by age 10.
Conclusions
Early childhood growth has been found to predict weight gain in adolescence and adulthood, and may be a risk factor for the development of an ED. These findings therefore have public health implications in relation to the prevention of weight-related and eating-related disorders later in life.
doi:10.1136/bmjopen-2013-004453
PMCID: PMC3975767  PMID: 24674996
Epidemiology; Psychiatry; Public Health
10.  Associations of postnatal weight and length/height gain with wheeze, asthma and atopy: The PROBIT Study 
Background
It has been hypothesised that postnatal weight and length/height gain are variously related to wheeze, asthma and atopy, however supporting evidence is limited and inconsistent.
Methods
Weights and lengths/heights of 12,171 term-infants were measured from birth to 12 months and at 6.5 years, and extracted from polyclinic records prospectively obtained between 12 and 60 months. Atopic phenotypes were ascertained at 6.5 years with the International Study of Asthma and Allergy in Childhood questionnaire and skin-prick tests. Logistic regression models investigated whether rates of weight and length/height gain from infancy to mid-childhood were associated with atopy phenotypes that have occurred ever or in the last 12 months.
Results
After controlling for confounders and prior weight and length/height gain, all weight gain variables except birthweight were positively associated with ever having wheezed (p<0.1). A one SD increase in weight gain rate between 0–3 months was associated with a 12% increase (2%–23%) in allergic rhinitis ever. No other consistent patterns of association were found for weight gain or length/height gain rate between 0–60 months with atopic outcomes at 6.5 years. In contrast, all atopy outcomes except for ever having asthma were associated with current weight and height, even after controlling for prior growth.
Conclusion
Current height and weight are more strongly associated with the development of atopic phenotypes in childhood than patterns of infant and early childhood growth, which may well reflect reverse causality (atopy effects on growth) or residual confounding by an unknown common cause of growth and atopy.
doi:10.1111/pai.12049
PMCID: PMC3711479  PMID: 23374010
wheeze; asthma; atopy; postnatal growth; weight gain; length gain
11.  Joint modelling rationale for chained equations 
Background
Chained equations imputation is widely used in medical research. It uses a set of conditional models, so is more flexible than joint modelling imputation for the imputation of different types of variables (e.g. binary, ordinal or unordered categorical). However, chained equations imputation does not correspond to drawing from a joint distribution when the conditional models are incompatible. Concurrently with our work, other authors have shown the equivalence of the two imputation methods in finite samples.
Methods
Taking a different approach, we prove, in finite samples, sufficient conditions for chained equations and joint modelling to yield imputations from the same predictive distribution. Further, we apply this proof in four specific cases and conduct a simulation study which explores the consequences when the conditional models are compatible but the conditions otherwise are not satisfied.
Results
We provide an additional “non-informative margins” condition which, together with compatibility, is sufficient. We show that the non-informative margins condition is not satisfied, despite compatible conditional models, in a situation as simple as two continuous variables and one binary variable. Our simulation study demonstrates that as a consequence of this violation order effects can occur; that is, systematic differences depending upon the ordering of the variables in the chained equations algorithm. However, the order effects appear to be small, especially when associations between variables are weak.
Conclusions
Since chained equations is typically used in medical research for datasets with different types of variables, researchers must be aware that order effects are likely to be ubiquitous, but our results suggest they may be small enough to be negligible.
doi:10.1186/1471-2288-14-28
PMCID: PMC3936896  PMID: 24559129
Chained equations imputation; Gibbs sampling; Joint modelling imputation; Multiple imputation; Multivariate missing data
12.  Association of a Body Mass Index Genetic Risk Score with Growth throughout Childhood and Adolescence 
PLoS ONE  2013;8(11):e79547.
Background
While the number of established genetic variants associated with adult body mass index (BMI) is growing, the relationships between these variants and growth during childhood are yet to be fully characterised. We examined the association between validated adult BMI associated single nucleotide polymorphisms (SNPs) and growth trajectories across childhood. We investigated the timing of onset of the genetic effect and whether it was sex specific.
Methods
Children from the ALSPAC and Raine birth cohorts were used for analysis (n = 9,328). Genotype data from 32 adult BMI associated SNPs were investigated individually and as an allelic score. Linear mixed effects models with smoothing splines were used for longitudinal modelling of the growth parameters and measures of adiposity peak and rebound were derived.
Results
The allelic score was associated with BMI growth throughout childhood, explaining 0.58% of the total variance in BMI in females and 0.44% in males. The allelic score was associated with higher BMI at the adiposity peak (females  =  0.0163 kg/m2 per allele, males  =  0.0123 kg/m2 per allele) and earlier age (-0.0362 years per allele in males and females) and higher BMI (0.0332 kg/m2 per allele in females and 0.0364 kg/m2 per allele in males) at the adiposity rebound. No gene:sex interactions were detected for BMI growth.
Conclusions
This study suggests that known adult genetic determinants of BMI have observable effects on growth from early childhood, and is consistent with the hypothesis that genetic determinants of adult susceptibility to obesity act from early childhood and develop over the life course.
doi:10.1371/journal.pone.0079547
PMCID: PMC3823612  PMID: 24244521
13.  Gestational weight gain as a risk factor for hypertensive disorders of pregnancy 
American Journal of Obstetrics and Gynecology  2013;209(4):327.e1-327.e17.
Objective
Pregnancy interventions to limit gestational weight gain (GWG) have been proposed as a means of preventing hypertensive disorders of pregnancy (HDP); however, it is currently unclear whether GWG has a causal influence on the development of HDP. Thus, we aimed to determine whether GWG in early pregnancy is a risk factor for preeclampsia and gestational hypertension and whether GWG precedes the increases in blood pressure in normotensive women across pregnancy.
Study Design
We examined repeat antenatal clinic measurements of weight and blood pressure (median of 12 and 14 per woman, respectively) of 12,522 women in the Avon Longitudinal Study of Parents and Children.
Results
Greater prepregnancy weight was associated with an increased risk of gestational hypertension and preeclampsia per 10 kg of prepregnancy weight: odds ratio (OR), 1.80; 95% confidence interval (CI), 1.70–1.91 and OR, 1.71; 95% CI, 1.49–1.95, respectively, for women weighing 90 kg or less before pregnancy; OR, 1.24; 95% CI, 1.03–1.49 and OR, 1.61; 95% CI, 1.18–2.19 for women weighing more than 90 kg. Fully adjusted odds ratios for gestational hypertension and preeclampsia per 200 g per week GWG up to 18 weeks were OR, 1.26; 95% CI, 1.16–1.38 and OR, 1.31; 95% CI, 1.07–1.62. In normotensive women, GWG in early pregnancy was associated positively with blood pressure change in midpregnancy and negatively with blood pressure change in late pregnancy. In all gestational periods, GWG was positively associated with concurrent blood pressure change. However, there was no evidence that blood pressure changes in any period were associated with subsequent GWG.
Conclusion
These findings suggest that GWG in early pregnancy may be a potential target for interventions aimed at reducing the risk of HDP.
doi:10.1016/j.ajog.2013.05.042
PMCID: PMC3807791  PMID: 23711667
Avon Longitudinal Study of Parents and Children; blood pressure; gestational weight gain; hypertensive disorder of pregnancy; preeclampsia
14.  Area Deprivation Across the Life Course and Physical Capability in Midlife: Findings From the 1946 British Birth Cohort 
American Journal of Epidemiology  2013;178(3):441-450.
Physical capability in later life is influenced by factors occurring across the life course, yet exposures to area conditions have only been examined cross-sectionally. Data from the National Survey of Health and Development, a longitudinal study of a 1946 British birth cohort, were used to estimate associations of area deprivation (defined as percentage of employed people working in partly skilled or unskilled occupations) at ages 4, 26, and 53 years (residential addresses linked to census data in 1950, 1972, and 1999) with 3 measures of physical capability at age 53 years: grip strength, standing balance, and chair-rise time. Cross-classified multilevel models with individuals nested within areas at the 3 ages showed that models assessing a single time point underestimate total area contributions to physical capability. For balance and chair-rise performance, associations with area deprivation in midlife were robust to adjustment for individual socioeconomic position and prior area deprivation (mean change for a 1-standard-deviation increase: balance, −7.4% (95% confidence interval (CI): −12.8, −2.8); chair rise, 2.1% (95% CI: −0.1, 4.3)). In addition, area deprivation in childhood was related to balance after adjustment for childhood socioeconomic position (−5.1%, 95% CI: −8.7, −1.6). Interventions aimed at reducing midlife disparities in physical capability should target the socioeconomic environment of individuals—for standing balance, as early as childhood.
doi:10.1093/aje/kwt003
PMCID: PMC3727343  PMID: 23788665
geography; Great Britain; health status disparities; longitudinal studies; multilevel analysis; physical endurance; residence characteristics; socioeconomic factors
15.  Associations of Maternal Weight Gain in Pregnancy With Offspring Cognition in Childhood and Adolescence: Findings From the Avon Longitudinal Study of Parents and Children 
American Journal of Epidemiology  2013;177(5):402-410.
An association of gestational weight gain (GWG) with offspring cognition has been postulated. We used data from the Avon Longitudinal Study of Parents and Children, a United Kingdom prospective cohort (1990 through the present) with a median of 10 maternal weight measurements in pregnancy. These were used to allocate participants to 2009 Institute of Medicine weight-gain categories and in random effect linear spline models. Outcomes were School Entry Assessment score (age, 4 years; n = 5,832), standardized intelligence quotient assessed by Wechsler Intelligence Scale for Children (age, 8 years; n = 5,191), and school final-examination results (age, 16 years; n = 7,339). Offspring of women who gained less weight than recommended had a 0.075 standard deviation lower mean School Entry Assessment score (95% confidence interval: −0.127, −0.023) and were less likely to achieve adequate final-examination results (odds ratio = 0.88, 95% confidence interval: 0.78, 0.99) compared with offspring of women who gained as recommended. GWG in early pregnancy (defined as 0–18 weeks on the basis of a knot point at 18 weeks) and midpregnancy (defined as 18–28 weeks on the basis of knot points at 18 and 28 weeks) was positively associated with School Entry Assessment score and intelligence quotient. GWG in late pregnancy (defined as 28 weeks onward on the basis of a knot point at 28 weeks) was positively associated with offspring intelligence quotient and with increased odds of offspring achieving adequate final-examination results in mothers who were overweight prepregnancy. Findings support small positive associations between GWG and offspring cognitive development, which may have lasting effects on educational attainment up to age 16 years.
doi:10.1093/aje/kws239
PMCID: PMC3581073  PMID: 23388581
ALSPAC; cognition; gestational weight gain
16.  BLOOD PRESSURE CHANGE IN NORMOTENSIVE, GESTATIONAL HYPERTENSIVE, PREECLAMPTIC AND ESSENTIAL HYPERTENSIVE PREGNANCIES 
Hypertension  2012;59(6):1241-1248.
We compared patterns of blood pressure (BP) change between normotensive women, women who developed gestational hypertension or preeclampsia and women who had essential hypertension to examine how distinct these conditions are and whether rates of BP change may help to identify women at risk of hypertensive disorders. We used antenatal clinic BP measurements (median 14 per woman) of 13,016 women from the Avon Longitudinal Study of Parents and Children (ALSPAC) who had a singleton or twin live birth surviving until at least 1 year. Linear spline models were used to describe changes in systolic and diastolic BP in different periods of pregnancy (8-18, 18-30, 30-36 and 36+ weeks gestation). Women who had essential hypertension, and those who developed gestational hypertension or preeclampsia had higher BP at 8 weeks gestation (baseline) compared with normotensive women. The decrease in BP until 18 weeks was smaller in gestational hypertensive compared with normotensive pregnancies. BP rose more rapidly from 18 weeks onwards in gestational hypertensive and preeclamptic pregnancies and from 30 weeks onwards in essential hypertensive compared with normotensive pregnancies. Women who developed preeclampsia had a more rapid increase in BP from 30 weeks onwards than those who developed gestational hypertension or had essential hypertension. Our findings indicate notable patterns of BP change that distinguish women with essential hypertension, gestational hypertension and preeclampsia from each other and from normotensive women, even from early pregnancy. These distinct patterns may be useful for identifying women at risk of developing a hypertensive disorder later in pregnancy.
doi:10.1161/HYPERTENSIONAHA.111.187039
PMCID: PMC3378662  PMID: 22526257
blood pressure; preeclampsia; gestational hypertension; pregnancy; ALSPAC
17.  Association of maternal weight gain in pregnancy with offspring obesity and metabolic and vascular traits in childhood 
Circulation  2010;121(23):2557-2564.
Background
We aimed to examine the association of gestational weight gain (GWG) and pre-pregnancy weight with offspring adiposity and cardiovascular risk factors.
Methods and results
Data from 5,154 (for adiposity and blood pressure) and 3,457 (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, CRP and IL-6 levels, and lower HDLc and Apolipoprotein A1 levels. Children of women who gained less than the recommended amounts had lower levels of adiposity, but other cardiovascular risk factor tended to be similar in this group to offspring of women gaining recommended amounts. When examined in more detail greater pre-pregnancy weight was associated with greater offspring adiposity and more adverse cardiovascular risk factors at age 9. GWG in early pregnancy (0 to 14 weeks) was positively associated with offspring adiposity across the entire distribution, but strengthened in women gaining more than 500g/week. By contrast, between 14 and 36 weeks GWG was only associated with offspring adiposity in women gaining at least 500g/week. GWG between 14-36 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 pre-pregnancy weight and GWG up to 36 weeks gestation are associated with greater offspring adiposity and adverse cardiovascular risk factors. Before implementing any GWG recommendations, the balance of risks and benefits of attempts to control GWG for short- and long-term outcomes in mother and child should be ascertained.
doi:10.1161/CIRCULATIONAHA.109.906081
PMCID: PMC3505019  PMID: 20516377
Pregnancy; Gestational Weight Gain; Offspring cardiovascular risk factors; ALSPAC
18.  Is infant weight associated with childhood blood pressure? Analysis of the Promotion of Breastfeeding Intervention Trial (PROBIT) cohort 
Background Weight gain during infancy may programme later health outcomes, but examination of this hypothesis requires appropriate lifecourse methods and detailed weight gain measures during childhood. We examined associations between weight gain in infancy and early childhood and blood pressure at the age of 6.5 years in healthy children born at term.
Methods We carried out an observational analysis of data from a cluster-randomized breastfeeding promotion trial in Belarus. Of 17 046 infants enrolled between June 1996 and December 1997, 13 889 (81.5%) had systolic and diastolic blood pressure measured at 6.5 years; 10 495 children with complete data were analysed. A random-effects linear spline model with three knot points was used to estimate each individual's birthweight and weight gain from birth to 3 months, 3 months to 1 year and 1–5 years. Path analysis was used to separate direct effects from those mediated through subsequent weight gain.
Results In boys, after controlling for confounders and prior weight gain, the change in systolic blood pressure per z-score increase in weight gain was 0.09 mmHg [95% confidence interval (95% CI) −0.14 to 0.31] for birthweight; 0.41 mmHg (95% CI 0.19–0.64) for birth to 3 months; 0.69 mmHg (95% CI 0.47–0.92) for 3 months to 1 year and 0.82 mmHg (95% CI 0.58–1.06) for 1–5 years. Most of the associations between weight gain and blood pressure were mediated through weight at the age of 6.5 years. Findings for girls and diastolic blood pressure were similar.
Conclusions Children who gained weight faster than their peers, particularly at later ages, had higher blood pressure at the age of 6.5 years, with no association between birthweight and blood pressure.
doi:10.1093/ije/dyr119
PMCID: PMC3383097  PMID: 22039193
Birthweight; blood pressure; lifetime; multi-level model; path analysis; weight gain
19.  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.
doi:10.1093/ije/dys066
PMCID: PMC3600619  PMID: 22507742
20.  Challenges in examining area effects across the life course on physical capability in mid-life: Findings from the 1946 British Birth Cohort 
Health & Place  2012;18(2-2):366-374.
A major limitation of past work linking area socioeconomic conditions to health in mid-life has been the reliance on single point in time measurement of area. Using the MRC National Survey of Health and Development, this study for the first time linked place of residence at three major life periods of childhood (1950), young adulthood (1972), and mid-life (1999) to area-socioeconomic data from the nearest census years. Using objective measures of physical capability as the outcome, the purpose of this study was to highlight four methodological challenges of attrition bias, secular changes in socio-economic measures, historical data availability, and changing reporting units over time. In general, standing balance and chair rise time showed clear cross-sectional associations with residing in areas with high deprivation. However, it was the process of overcoming the methodological challenges, which led to the conclusion that in this example percent low social class occupations was the most appropriate measure to use when extending cross-sectional analysis of standing balance and chair rise to life course investigation.
doi:10.1016/j.healthplace.2011.11.007
PMCID: PMC3315018  PMID: 22209408
Life course; Area; Capability; Methodology; Deprivation
21.  Maternal smoking during pregnancy and offspring trajectories of height and adiposity: comparing maternal and paternal associations 
Background Maternal smoking during pregnancy is associated with reduced offspring birth length and has been postulated as a risk factor for obesity. Causality for obesity is not established. Causality is well-supported for birth length, but evidence on persistence of height deficits is inconsistent.
Methods We examined the association between maternal smoking during pregnancy and trajectories of offspring height (0–10 years, N = 9424), ponderal index (PI) (0–2 years, N = 9321) and body mass index (BMI) (2–10 years, N = 8887) in the Avon Longitudinal Study of Parents and Children. To strengthen inference, measured confounders were controlled for, maternal and partner smoking associations were compared, dose–response and associations with post-natal smoking were examined.
Results Maternal smoking during pregnancy was associated with shorter birth length, faster height growth in infancy and slower growth in later childhood. By 10 years, daughters of women who smoke during pregnancy are on average 1.11 cm (SE = 0.27) shorter after adjustment for confounders and partner smoking; the difference is 0.22 cm (SE = 0.22) for partner's smoking. Maternal smoking was associated with lower PI at birth, faster PI increase in infancy, but not with BMI changes 2–10 years. Associations were stronger for maternal than partner smoking for PI at birth and PI changes in infancy, but not for BMI changes after 2 years. A similar dose–response in both maternal and partner smoking was seen for BMI change 2–10 years.
Conclusion Maternal smoking during pregnancy has an intrauterine effect on birth length, and possibly on adiposity at birth and changes in height and adiposity in infancy. We do not find evidence of a specific intrauterine effect on height or adiposity changes after the age of 2 years.
doi:10.1093/ije/dys025
PMCID: PMC3396309  PMID: 22407859
Smoking; growth; obesity; pregnancy; child; ALSPAC
22.  Patterns of Alcohol Use in Early Adolescence Predict Problem Use at Age 16 
Aims: Teenagers in the UK report some of the highest rates of alcohol use in Europe. We identify patterns of alcohol use in early adolescence and relate these to hazardous and harmful alcohol use at age 16. Methods: In a UK birth cohort, we analysed repeated measures of alcohol use from age 13 to 15 in a sample of 7100 adolescents. Data on drinking frequency and typical consumption when drinking were modelled separately using a pair of latent class models. Classes of alcohol-use behaviour were contrasted across a range of risk factors and then to hazardous and harmful alcohol use as assessed using the Alcohol Use Disorders Identification Test scale at age 16. Results: Heterogeneity in drinking frequency and consumption could each be captured with three classes corresponding to low, medium and high levels. In total, 14.2% were classified as high-frequency and 8.9% as high consumption alcohol users. Socio-demographic factors, maternal substance use and the young persons' use of tobacco and cannabis were associated with class membership. At age 16, 29% were drinking hazardously and a further 5.6% were assessed as harmful drinkers. Young people in the high drinking frequency or consumption class had a 9-fold increased risk of reporting harmful drinking at age 16. Conclusions: By the age of 16, a substantial proportion of teenagers in this sample were drinking at levels that could be considered hazardous or harmful for an adult. Patterns of alcohol exposure in early adolescence were strongly associated with later alcohol use. Altering drinking patterns in middle adolescence has the potential to reduce harmful use in later adolescence.
doi:10.1093/alcalc/agr156
PMCID: PMC3284685  PMID: 22215001
23.  Relationships of Risk Factors for Pre-Eclampsia with Patterns of Occurrence of Isolated Gestational Proteinuria during Normal Term Pregnancy 
PLoS ONE  2011;6(7):e22115.
Background
Isolated gestational proteinuria may be part of the pre-eclampsia disease spectrum. Confirmation of its association with established pre-eclampsia risk factors and higher blood pressure in uncomplicated pregnancies would support this concept.
Methods
Data from 11,651 women from the Avon Longitudinal Study of Parents and Children who had a term live birth but did not have pre-existing hypertension or diabetes or develop gestational diabetes or preeclampsia were used. Proteinuria was assessed repeatedly (median 12 measurements per woman) by dipstick and latent class analysis was used to identify subgroups of the population with different patterns of proteinuria in pregnancy.
Results
Higher maternal pre-pregnancy body mass index (BMI), younger age, nulliparity and twin pregnancy were independently associated with increased odds of any proteinuria in pregnancy. Women who experienced proteinuria showed five patterns: proteinuria in early pregnancy only (≤20 weeks gestation), and onset at 21–28 weeks, 29–32 weeks, 33–36 weeks and ≥37 weeks gestation. There were higher odds of proteinuria onset after 33 weeks in obese women and after 37 weeks in nulliparous women compared with normal weight and multiparous women respectively. Smoking in pregnancy was weakly negatively associated with odds of proteinuria onset after 37 weeks. Twin pregnancies had higher odds of proteinuria onset from 29 weeks. In women with proteinuria onset after 33 weeks blood pressure was higher in early pregnancy and at the end of pregnancy.
Conclusions
Established pre-eclampsia risk factors were related to proteinuria occurrence in late gestation in healthy term pregnancies, supporting the hypothesis that isolated gestational proteinuria may represent an early manifestation of pre-eclampsia.
doi:10.1371/journal.pone.0022115
PMCID: PMC3138774  PMID: 21789220
24.  Adult height variants affect birth length and growth rate in children 
Human Molecular Genetics  2011;20(20):4069-4075.
Previous studies identified 180 single nucleotide polymorphisms (SNPs) associated with adult height, explaining ∼10% of the variance. The age at which these begin to affect growth is unclear. We modelled the effect of these SNPs on birth length and childhood growth. A total of 7768 participants in the Avon Longitudinal Study of Parents and Children had data available. Individual growth trajectories from 0 to 10 years were estimated using mixed-effects linear spline models and differences in trajectories by individual SNPs and allelic score were determined. The allelic score was associated with birth length (0.026 cm increase per ‘tall’ allele, SE = 0.003, P = 1 × 10−15, equivalent to 0.017 SD). There was little evidence of association between the allelic score and early infancy growth (0–3 months), but there was evidence of association between the allelic score and later growth. This association became stronger with each consecutive growth period, per ‘tall’ allele per month effects were 0.015 SD (3 months–1 year, SE = 0.004), 0.023 SD (1–3 years, SE = 0.003) and 0.028 SD (3–10 years, SE = 0.003). By age 10, the mean height difference between individuals with ≤170 versus ≥191 ‘tall’ alleles (the top and bottom 10%) was 4.7 cm (0.8 SD), explaining ∼5% of the variance. There was evidence of associations with specific growth periods for some SNPs (rs3791675, EFEMP1 and rs6569648, L3MBTL3) and supportive evidence for previously reported age-dependent effects of HHIP and SOCS2 SNPs. SNPs associated with adult height influence birth length and have an increasing effect on growth from late infancy through to late childhood. By age 10, they explain half the height variance (∼5%) of that explained in adults (∼10%).
doi:10.1093/hmg/ddr309
PMCID: PMC3177650  PMID: 21757498
25.  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)1234 
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.
doi:10.3945/ajcn.110.008326
PMCID: PMC3095501  PMID: 21471282

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