There is increasing evidence for a developmental origin of bone mass and skeletal development. Peak bone mass, together with later life bone mass loss, is a major determinant of osteoporosis risk in later life.(1) Lower birth weight and earlier gestational age are associated with reduced bone mineral density (BMD) and bone mineral content (BMC) in infancy, childhood and adulthood and with adult fracture risk in a number of studies.(2-5) These findings have led to the exploration for modifiable pre-natal risk factors that affect later bone health.

Maternal pregnancy diet/nutrition and offspring bone health

Variation in maternal vitamin D during pregnancy has been positively associated with offspring total and spinal BMC and with total BMD in a small study (N=198) from the Southampton Women's Survey.(6) In ALSPAC (N=6995) maternal UVB exposure in pregnancy (used as proxy for vitamin D level (7)) is related to bone size at mean age 9.9 years independently of height and lean mass.(8) We will further explore maternal vitamin D in pregnancy with offspring bone phenotypes as agreed with ALSPAC exec. as part of the MRC Vitamin D grant (DAL PI) and so this is not discussed further in this application.

Whilst other constituents of maternal diet/nutrition (other than vitamin D) have been implicated in offspring bone health, a detailed analysis in ALSPAC suggested that variation in folate intake during pregnancy was the only important predictor of future offspring BMC after adjustment for child size and other potential convariables.(9) In a separare ALSPAC publication the child's own C667T MTHFR genotype was found to be associated with spinal BMD at mean age 9.9 years, with each additional T allele of that variant being associated with a 0.10SD decrease in spinal BMD on average (but with no association to total body bone phenotypes).(10) There was some evidence in that study that this association was considerably weakened in children whose mother's diet during pregnancy, and whose own diet in childhood was high in vitamin B, suggesting that high levels of homocysteine adversely affect accrual of trabecuar bone.

Maternal smoking in pregnancy

In the Southamton Women's Survey (N=145 and in later study = 841) maternal smoking in pregnancy was associated with decreased whole body BMC at birth,(11,12) and in the Tasmanian Infant Health Survey (N=330) maternal smoking in pregnancy was associated with reduced size adjusted bone mass at the lumbar spine and femoral neck (but not whole body) at mean age 8 years in children who were born at term.(13) The association of maternal smoking in pregnancy with offspring bone phenotypes has not been examined in detail in the ALSPAC cohort, to our knowledge, though in one publication concerned with diet and bone phenotypes it was noted (but results not presented) that maternal smoking was not associated with DXA determined bone phenotypes at age 9.9 years.(9) Any association of maternal pregnancy smoking with offspring bone phenotypes might be due to intrauterine mechanisms or might be due to the association of maternal smoking in pregnancy with other lifestyle characteristics, that are shared by the offspring (including earlier initiation of smoking) that affect bone development (though for associations with bone phenotype at birth this is unlikely). One way of exploring this that has been used in ALSPAC with other offspring outcomes is to compare the association of maternal smoking in pregnancy with offspring bone phenotype to that of paternal smoking in pregnancy to bone phenotype; a stronger maternal association would be expected if intrauterine mechanisms are important.

Maternal adiposity and weight gain in pregnancy

In the Southampton Women's Survey (N=841) independent predictors of whole body bone area and BMD included maternal own birthweight, height and triceps skinfold thicknes in pregancy.(12) One conclusion of this study was that offspring of women with greater fat stores in pregnancy had better bone development and greater BMC at birth. They speculated that maternal fat stores might influence intrauterine bone mineral acrual through several mechanisms including effects on nutrient availability and endocrine factors such as leptin and oestrogen. The latter would be influenced in pregnancy by both maternal adiposity pre-pregnancy and greater acquisition of fat during pregnancy. This potential advantage of greater maternal fat stores in pregnancy requires further exploration since other studies suggest that greater maternal adiposity in pregnancy might be detremental to offspring future cardiovascular and metabolic risk.(13) As with other phenotypes comparing maternal pre-pregnancy adiposity associations to those of paternal prepregnancy adiposity associations can help to distinguish intrauterine mechanisms from shared familial genetic and lifestyle characteristics.

Given that much of the work to date on potential modifiable pre-natal influences on offspring bone phenotypes has come from the Southampton Women's Survey with a relatively small sample size and with general non-specificity (variation in associations with different bone phenotypes) there is a need for further exploration of this area. This is particulalry important with respect to maternal adiposity and fat stores in pregnancy where associations with potential advantages for bone health may be in the opposite direction to those for cardiovascular health.

Objectives

1. To examine the association of maternal smoking in pregnancy with offspring bone phenotypes and compare these associations with equivalent associations for paternal smoking in pregancy

2. To examine the association of maternal pre-pregnancy BMI with offspring bone phenotypes and compare these associations with equivalent associations for paternal prepregancy BMI

3. To examine the associations of maternal gestational weight gain with offspring bone phenotype

Methods

All applicants will contribute to the analysis protocol. DAL will compile a dataset. CM will complete analyses with supervision from DAL. All applicants will contribute to interpretation of results and writing of papers.

References

1. Hernande CJ, et al. Osteoporosis Int 2003;14:843-847

2. Jones G, Dwyer T. Calcif Tissue Int 2000;67:304-308

3. Yarbrough DE, et al. Osteoporosi Int 2000;11:626-630

4. Dennison EM, et al. Pediatric Research 2005;57:582-86

5. Cooper C, et al. Osteoporosis Int 2001;12:623-629

6. Javaid MK, et al. Lancet 2006;367:36-43

7. Sayers A, et al. IJE; 2009 doi:10.1093/ije/dyp237

8. Sayers A & Tobias JH. J Clin Endocrinol Metab 2009;94:765-771

9. Tobias JH, et al. Osteoporos Int 2005;16:1731-1741

10. Steer CD, et al. J Bone & Mineral Res 2009;24:117-124

11. Godfrey K, et al. J Bone & Mineral Res 2001;9:1694-1703

12. Harvey K, et al. J Developmental Origins of Health & Disease 2009, in press

13. Jones G, et al. J Bone & Mineral Res 1999;14:146-151

14. Viswanthan M et al. Evidence Report/Technology Assessment No. 168. AHRQ Publication No. 08-E009 ed. Rockville, MD: Agency for Healthcare Research and Quality, 2008.