Puberty timing and markers of cardiovascular structure and function at 25 years: a prospective cohort study

We used data from the Avon Longitudinal Study of Parents and Children (ALSPAC), a prospective birth cohort study based in Southwest England [23‐25]. The women invited to participate in this study were pregnant with an expected delivery date between April 1, 1991, and December 31, 1992, and living in one of the three Bristol-based health districts. A detailed description of this study is available elsewhere [23‐25].

The initial number of pregnancies enrolled was 14,541. When the oldest children were approximately 7 years of age, an attempt was made to increase the initial sample with eligible children who did not join the study originally. This resulted in an additional 913 children being enrolled. Therefore, the total sample size was 15,454 pregnancies. Of these 14,901 were alive at 1 year of age. In the three decades since enrolment, ALSPAC has used questionnaires completed by both parents and children, routine medical data and research clinics as methods of follow-up. The clinics took place when the participants were 7, 9, 10, 11, 13, 15, 17 and 25 years old [23‐27].

Ethical approval for the ALSPAC study was obtained from the ALSPAC Law and Ethics Committee and Local Research Ethics Committees. Informed consent for the use of data collected via questionnaires and clinics was obtained from participants following the recommendations of the ALSPAC Law and Ethics Committee at the time. The study website contains details of all the data that is available through a fully searchable data dictionary and variable search tool: http://​www.​bristol.​ac.​uk/​alspac/​researchers/​our-data/​ [28].

We selected potential confounders a priori and used a directed acyclic graph (DAG) to encode this causal knowledge of this research question. In summary, we have included only covariates in our model, which we believe to be common causes of the exposure and outcome and have excluded any variables that might be potential mediators of the association [38]. Therefore, we considered the following as possible confounders of the association between aPHV and cardiovascular structure and function at age 25 years; maternal age, gestational age at birth, household social class, maternal education, mother’s partner’s education, breastfeeding of baby until 3 months, parity, birthweight, maternal body mass index (BMI), maternal marital status, maternal smoking status during first 3 months of pregnancy, and height and DXA-determined fat mass at age 9.

Maternal age was reported in the mother’s antenatal questionnaires. Gestational age at birth was estimated from clinical records. Household social class was measured as the highest of the mother’s or her partner’s occupational social class using data on job title and details of occupation collected about the mother and her partner from the mother’s questionnaire at 32 weeks gestation. Social class was derived using the standard occupational classification (SOC) codes developed by the UK Office of Population Census and Surveys and classified as I professional, II managerial and technical, IIINM non-manual, IIIM manual and IV&V part skilled occupations and unskilled occupations.

A questionnaire at 32 weeks gestation asked mothers to report on educational attainment, which was categorised as below O-Level (Ordinary Level; exams taken in different subjects usually at age 15–16 at the completion of legally required school attendance, equivalent to today’s UK General Certificate of Secondary Education), O-Level only, A-Level (Advanced-Level; exams taken in different subjects usually at age 18) or university degree or above.

Breastfeeding information was collected via questionnaires administered at 4 weeks, 6 months and 15 months. Parity was defined as the number of previous pregnancies that had resulted in a live or stillborn infant collected at 18 weeks gestation. Birthweight was extracted from medical records. Maternal height and weight data were self-reported from a questionnaire administered at 12 weeks gestation; these were used to calculate maternal BMI. Marital status was obtained from antenatal questionnaires and classified as never married, married and widowed, divorced, or separated. Smoking in the first trimester of pregnancy was self-reported by mothers at 18 weeks gestation; responses to smoking any tobacco (cigarettes, cigars, pipes, or other) were grouped as follows: no smoking, < 10 per day, 10–19 per day or greater than 19 per day, and were re-categorised as a dichotomous variable (smoking: yes/no).

Height and fat mass of offspring was measured at clinics at age 9 years. Standing height was measured to the last complete mm using the Harpenden Stadiometer. Fat mass (in kg, less head) was derived from whole body DXA scans performed using a GE Lunar Prodigy (Madison, WI, USA) narrow fan beam densitometer.

Statistical analysis was performed using Stata MP 14.2. Linearity of association between aPHV and cardiovascular structure and function in males and females was assessed by comparing fit of models regressing carotid intima-media thickness, left ventricular mass index and relative wall thickness, pulse wave velocity, and systolic blood pressure on fourths of aPHV (treated as a continuous exposure) to models regressing carotid intima-media thickness, left ventricular mass index and relative wall thickness, pulse wave velocity and systolic blood pressure on fourths of aPHV (treated as a categorical exposure); models were then formally compared using a likelihood ratio test. Data on aPHV and all cardiovascular outcomes were normally distributed. We used linear regression to examine the association between aPHV and each measure of cardiac structure and function. All analyses were stratified by sex to examine whether associations of aPHV and each outcome differed for males and females.

Several studies to date have examined the association between puberty timing and clinical endpoints such as CVD and traditional cardiovascular risk factors such as blood pressure and adiposity, with conflicting findings [11‐13, 18, 20, 21, 43]. However, these studies used different measures of puberty timing (objective vs. self-report) [43, 44] and had varying degrees of adjustment for confounding (particularly early childhood adiposity) [11‐13, 18] and different ranges in follow-up and age of measurement of outcomes [17, 21, 45].

In contrast, fewer studies have examined associations of puberty timing with measures of cardiac structure and function, which are used clinically to assess arterial stiffness, left ventricular hypertrophy and cardiac remodelling [44]. Hardy and colleagues found evidence of an association between later puberty timing (measured using age at menarche) and lower left ventricular mass and relative wall thickness in females in the National Study of Health and Development (NSHD) (N = 1385), though results attenuated after adjustment for childhood or adult adiposity [44]. In contrast, there was no strong evidence of an association between puberty timing (measured via physical examination) and any measure of cardiac structure or function in males in the NSHD, a finding comparable to ours [44]. Our findings are also comparable to results from the Young Finns Cohort (N = 794) which demonstrated no strong evidence of associations between puberty timing (measured via age at menarche) and carotid intima-media thickness in females at age 30–39 years [17]. Similarly, in a study of 800 women aged 50 to 81 years in Southern Germany, age at menarche was not associated with carotid intima-media thickness in both unadjusted and confounder-adjusted analyses [45].

Strengths of this study include use of an objective measure of puberty timing (aPHV) based on prospective, repeated measures of height from age 5 years to 20 years which is a more accurate marker of puberty timing than self-reported measures. We also used measures of pre-clinical CVD, which strongly predict later cardiovascular risk. We adjusted for childhood adiposity using DXA fat mass at age 9, allowing us to adjust for directly measured pre-pubertal adiposity, a key limitation in several previous studies [11‐13, 18]. However, there are also several limitations; a limitation of our adiposity adjustment may include the possibility that DXA fat mass is measured after pubertal onset for a small proportion of participants (N = 1 for males, N = 41 for females) giving rise to the possibility of collider bias if DXA fat mass at age 9 is a mediator of the puberty timing-cardiac risk association. However, we believe that any bias introduced due to this is minimal, given that prior work in this cohort has shown that puberty has little impact on post-pubertal fat mass gain [32] (suggesting fat mass is an unlikely mediator of any associations of puberty timing with health outcomes) and that analyses without adjustment for fat mass were similar to confounder-adjusted results. Nevertheless, though we have shown that our approach to adjustment for adiposity here is not likely to have introduced bias to our results, the direction of causality of the relationship between adiposity and puberty timing is complex given the potential shared genetic architecture between the traits. In addition, the outcome measures used may be subject to measurement error which may have led to biased estimates. However, any measurement error is likely to be non-differential and would therefore bias our results towards to the null [46, 47]. Further limitations include potential for selection bias due to missing data and attrition from the cohort. However, the use of multivariate multiple imputation aimed to minimise bias and a loss of statistical power by imputing missing covariate and outcome data, and results in multiply imputed and complete-case data were similar. However, replication of findings in studies with larger sample sizes may be needed in order to provide more precise estimates of associations. Moreover, our outcomes were measured at age 25 years, and while the pre-clinical measures of CVD used here are strong predictors of later cardiovascular risk [33, 48], young adulthood might be too early to detect changes in cardiac structure and function that progress with age. Therefore, future studies examining a puberty timing and CVD risk relationship in older populations may be worthwhile. Finally, the vast majority of the ALSPAC cohort are of White ethnicity [23], and a key limitation of our study is the generalisability of the findings to non-White ethnicities.