AIM

The aim of this Ph.D.-study is to investigate associations between birth weight, childhood body mass index (BMI), height and growth in weight and height, respectively, and the risk of hemorrhagic stroke later in life. Moreover the question of which biological parameters that underlie the observations made when examining the associations between these particular anthropometric parameters and later risk of hemorrhagic stroke, will also be investigated. As associations between the mentioned anthropometric parameters in childhood and cardiovascular disease (CVD) have been found, and as CVD shares many risk factors with hemorrhagic stroke, it is plausible that associations exist here as well. Thus, low birth weight, high and/or low BMI, height and accelerated gain in weight and/or in height are possible risk factors for hemorrhagic stroke.

BACKGROUND AND SIGNIFICANCE

Stroke causes 9% of all deaths around the world and is the second most common cause of death after ischemic heart disease. Stroke is also a major cause of disability worldwide and consumes about 2-4% of total health-care costs, and in industrialised countries it accounts for more than 4% of direct health-care costs. Approximately 10-15% of all strokes are caused by intracerebral hemorrhage.

Well-established risk factors for hemorrhagic stroke are arterial hypertension, anticoagulant usage, cerebral aneurysms, age, family history of strokes and excessive alcohol intake. Smoking, diabetes, high cholesterol, obesity, and a sedentary lifestyle are risk factors for all types of strokes. The identified risk factors for stroke only explain about 60% of the attributable risk, whereas more than 90% of ischemic heart disease is explained by identifiable risk factors.

The most important of the risk factors for hemorrhagic stroke is arterial hypertension, as it induces degenerative vascular changes that can result in ruptured vessels or micro-aneurysms leading to intracerebral hemorrhage. Excessive use of alcohol is thought to increase the risk of intracerebral hemorrhage by impairing coagulation and directly affecting the integrity of cerebral vessels. High cholesterol levels are known to cause atherosclerosis and thus increase the risk of thrombo-embolic (ischemic) stroke. The vascular degeneration caused by atherosclerosis is, however, likely to increase the risk of rupture and thereby the risk of hemorrhagic stroke. In contrast, some Asian studies have found that low cholesterol levels are associated with the risk of hemorrhagic stroke, suggesting that it causes the arterial wall to weaken and small intra-parenchymal cerebral arteries to subsequently rupture.

Furthermore, it has been found that greater BMI or relative weight in adulthood is strongly associated with the risk of total and ischemic stroke. A J-shaped association between adult BMI and hemorrhagic stroke has been found, thus low and high BMI values increase the risk. Other studies have examined different measures of body size: e.g. adult waist-to-hip ratio and found associations with both ischemic and hemorrhagic stroke. Height is thought to be a surrogate marker of early life and childhood conditions. In studies that have investigated the association between adult height and risk of hemorrhagic stroke an inverse relationship has been found.

Although risk factors for hemorrhagic stroke have been found in adulthood, would it not be better if they could be detected already in childhood? There is evidence that at least a part of the risk may originate in utero as studies consistently find that low birth weight is associated with an increased risk of hemorrhagic stroke. Studies investigating if there are risk factors in childhood, however, are lacking. Childhood BMI, childhood height and growth in height are associated with risk of coronary heart disease (CHD) in adults, and it is therefore likely that these factors also are associated with the risk of hemorrhagic stroke. Despite the plausibility of the associations, few studies have investigated how childhood body size is associated with hemorrhagic stroke. Results from the studies that have are inconsistent, and this is likely due to the low numbers of cases included (less than 100 per study). Therefore, the proposed research will address a gap in the knowledge of childhood body size and growth and its later health consequences.

PROJECT DESCRIPTION

This Ph.D project will be based on data from two epidemiological cohorts. The large Copenhagen School Health Records Register (CSHRR) will serve to investigate the birth weight and childhood anthropometry in relation to risk of hemorrhagic stroke. By using the very detailed data from the smaller Avon Longitudinal Study of Parents and Children (ALSPAC) it will be possible to investigate what biological associations that underlie such particular feature of birth-weight childhood-anthropometry association with later stroke risk. The studies are described in below.

THE CSHRR STUDIES

The CSHRR is an electronic database of information from health examinations on 372.636 schoolchildren who attended school in the capital city of Denmark from 1936 to 2005. The CSHRR contains virtually every school child that attended school in Copenhagen. The children were given full health examinations annually. Essential personal information and dates along with birth weight and height and weight measurements have been computerized.

The CSHRR contains a unique personal identification number, assigned by the Danish Civil Registration System (CRS), for 329,968 (88.5%) of the children. Via the CRS number, the cohort has been linked to the National Cause of Death Register (NCDR) and the National Hospital Discharge Register (NHDR). The size and the prospective and serial measurements of body size along with the age structure of the cohort, where many members have reached middle age, make the CSHRR well suited for studying diseases that occur later in life, such as hemorrhagic stroke.

Therefore, using the CSHRR, the following hypotheses will be investigated:

* Low birth weight increases the risk of hemorrhagic stroke

* High and/or low BMI in childhood increases the risk of hemorrhagic stroke

* Accelerated weight gain increases the risk of hemorrhagic stroke

* Short height in childhood increases the risk of hemorrhagic stroke

* Accelerated growth in height increases the risk of hemorrhagic stroke

Childhood will be defined as 7 to 13 years of age as these are the ages of children in the CSHRR. There are 3.458 cases of hemorrhagic stroke among the cohort members, however these numbers will increase as this is from an older linkage to the NCDR and the NHDR. Furthermore, a sub-set of the CSHRR will be augmented by the use of data from the Danish National Indicator Project (DNIP) that now contains detailed information on prior medical history, diagnostic methods (i.e. CT or MR scannings and severity by the Scandinavian Stroke Scale) and supplemental test, interventions and treatment during hospitalization on more than 4000 cases of hemorrhagic stroke after year 2001. Since other studies on this subject have had less than 100 cases of hemorrhagic stroke, results from this study will contribute to what is known in this area of research. However, an important issue is that the methods used to diagnose hemorrhagic stroke have changed during the given period due to the technical development and implementation of CT scannings in the 1990s. Since hemorrhagic stroke in most cases appear late in life, and given the age structure of the CSHRR, only a small number of cases in this cohort will have had the diagnosis made solely on the basis of a clinical examination.

The proposed research will be conducted at the Institute of Preventive Medicine. The group that will supervise the Ph.D. project has extensive experience in the area of researching long-term health consequences of childhood body size, has a successful history of collaboration, and is skilled in the statistical techniques required. The proposed research is feasible, as the data resource has been used for similar types of projects. With the support of the team, the proposed research is achievable within the timeframe of the Ph.D.

Statistical methods: Associations between birth weight, BMI and height at each age and hemorrhagic stroke will be investigated using Cox regression. Growth will be investigated using the life course analysis technique. Analyses will be conducted separately for men and women. Additionally, analyses will be conducted with the inclusion of birth weight to see if this changes the observed associations. Interactions between birth weight and body size in childhood will be investigated. The assumptions of the Cox regression model will be assessed as will the linearity of the associations. Sensitivity analyses will be conducted to examine the effect of diagnostic changes for hemorrhagic strokes.

Ethical aspects: The Danish Data Protection Agency has approved the use of the CSHRR for these studies

THE ALSPAC STUDY

The ALSPAC resource has a richness of detail that is incredibly valuable as it contains genetic and biological samples collected at multiple time points ranging from the prenatal period through to adolescence and young adulthood of the subjects, thus allowing the assessment of developmental trajectories and critical periods of development. The study recruited 14,541 pregnant women who resided in the former Avon Health Authority area of southwest England with an expected date of delivery between April 1991 and December 1992, resulting in a total birth cohort of 14,062 live births of whom 13,970 were alive at 1 year of age. These children have been followed, initially with questionnaires throughout childhood, and at regular annual clinic visits since the age of 7 years. The UK Medical Research Council, the Wellcome Trust, and the University of Bristol provide core support for ALSPAC, and there have been more than 850 articles published by February 2013; details of these can be found on the ALSPAC study website (enter the website here).

Information on weight and height, puberty, social background medical history for parents and grant parents and exposure to passive smoking, as well as health care examinations, multiple blood samples (including blood lipids) and cardiovascular health parameters (such as blood pressure and pulse rate, intima-media thickness, pulse wave, flow-mediated dilation and scan of the carotid arteries) is available for more than 5000 children.

Using information from ALSPAC, the current study will investigate the hypothesis:

* Childhood body composition and growth are associated with biological risk factors for hemorrhagic stroke

The proposed research will investigate these factors in the ALSPAC-children using the collected data and blood samples. Information from records of preceding measurements of height and weight, including birth weight will be used. Associations between body size and the known risk factors for hemorrhagic stroke such as hypertension, family history of stroke and diabetes will be examined. Associations with blood pressure will be investigated as well. Furthermore, associations of body size with the blood lipid-profile will be investigated. The study will examine both known and also more uncertain risk factors as the lipid profile will, in addition to the traditionally examined lipids like low density lipoprotein (LDL), total cholesterol, triglyceride and high density lipoprotein (HDL), include apolipoprotein B and apolipoprotein A-I which have been found to provide more useful information on the risk cardiovascular disease in adults than traditional lipids do. Also IGF-I levels, which have been hypothesized to promote structural integrity of cerebral arteries and thereby offering protection from hemorrhagic stroke, will also be examined.

It will thus be possible to investigate how different anthropometric parameters are biologically mediated to hemorrhagic stroke.

Statistical methods:

Longitudinal modelling of the relations between rates and patterns of growth in body weight and height from birth through adolescence and the pertinent potential biological mediators of the asscociation between birth-weight-childhood antropometrics and stroke risk will be carried out in collaboration with statisticians with particualr expertise in this type of analyses in Bristol and Copenhagen

Ethical aspects: Approval for the study was obtained from the ALSPAC ethics and law committee, and written informed consent and assent was obtained from both the parent or guardian and the child.

FUTURE ASPECTS

This PhD. study will, with the possible findings of childhood risk factors of hemorrhagic stroke, provide leads for future research aimed at targeted prevention already in childhood and clinical research within the areas of vascular disease.