BACKGROUND

1. Pregnancy complications and subsequent metabolic profiles in mid-life.

Pregnancy complications, including hypertensive disorders of pregnancy (HDP), gestational diabetes (GDM), preterm birth, small for gestational age (SGA) and large for gestational age (LGA) are associated with subsequent increased cardiovascular and diabetes risk in the mother, though the precise mechanims underlying these associations are unclear.[1] In ALSPAC we have previously shown that HDP is associated with a wide range of cardiometabolic risk factors (greater body mass index, fat mass, waist circumference, blood pressure and fasting lipid levels and adverse fasting lipids) approximately 18 years postnatal, whereas GDM was associated only with greater fasting glucose and insulin. However, both were associated with the same increased risk (~30%) of predicted CVD based on the Frammingham equation.[2] Preterm birth and SGA were associated with higher blood pressure 18 years later and LGA with higher waist circumference and fasting glucose.[2]

A number of small studies (commongly fewer than 100 participants) have shown that blood based metabolites (either maternal gestational or fetal assessed in cord blood), including amino acids, fatty acids, lipids and phospholipids, are associated with pre-eclampsia.[3-8] One study found differences in sphingolipids, phospholipids, carnitines and fatty acids in early pregnancy maternal serum comparing those who had a SGA infant to those with a normal for gestational infant,[9] and one differences in cord-blood glucose, several amino acids, lipids and lipoproteins between infants of mothers who did, and those who did not, have GDM.[10] To our knowledge no study to date has examined the relationship of pregnancy complications with future metabolic profiles in the mother some years after delivery and the extent to which these might explain any association of these complications with atherosclerosis.

2. Menopausal transition and metabolic profiles

There is increasing interest in the role of the menopausal transition and health ageing in women.[11,12] Endogenous oestrogen levels are cardioprotective and a large number of cross sectional studies have shown that cardiovascular events and risk factors are higher in women who are post- compared to pre-menopausal.[13] From the small number of relatively small (N ~ 50 to 1000) studies with repeat measurements of cardiovascular risk factors there is evidence that as women go through the perimenopausal transition adiposity, fasting glucose, insulin, LDLc and triglycerides increase and HDLc decreases independently of age-related changes, whereas blood pressure changes at this time appear to reflect age effects.[13] Recently a meta-analysis of cross sectional associations in greater than 10,000 participants

found metabolic profile differences between women and men, with a sex*age interaction that supported adverse (in relation to atherosclerosis) changes in women around the time of the menopausal transition. In cross-sectional analyses in a subgroup of the women they showed adverse levels of lipids, lipoproteins, fatty acids and amino acids in between age matched women who were pre-, peri- and postmenopausal.[14] To our knowledge no one to date has examined prospective associations of menopausal status and change in this with change in metabolic profiles.

OBJECTIVES

1. Pregnancy complications and subsequent metabolic profiles

1. To determine the associations of HDP, GDM, preterm birth, SGA and LGA with subsequent (~18 years later) metabolomic profiles, including identifying the extent to which the different pregnancy complications overlap with each other in terms of relating to similar future metabolic disruptions.

2. To determine the cross-sectional association of metabolic profiles with atherosclerosis, as measured by cIMT, in middle-aged women.

3. To determine the extent to which metabolic profiles mediate any associations of complications of pregnancy with future cIMT

2. Menopausal transition and metabolomic profiles

1. To determine the cross-sectional associations of menopausal status and hormone use (women will be categorised into mutually exclusive categories of: hysterectomy/oophorectomy; using HRT; using hormonal contraception; pre-menopausal; in menopausal transition; early post-menopause; late post-menopause, according to STRAW criteria for menopausal/reproductive status) with metabolic profiles.

2. To determine the prospective change in menopausal status with change in metabolomic profiles.

METHODS

1. Pregnancy complications and metabolomic profiles

For this paper obstetric and early pregnancy questionnaire data will be combined with data from FoM1

Analyses will be done by Qin Wang with supervision from Mika Ala-Korpella and Debbie Lawlor

2. Menopausal status and metabolomic profiles

For this paper data from FoM1 and FoM2 will be primarily used

Analyses will be done by Qin Wang (as above)

Data preparation

Debbie Lawlor will work with Kate Northstone to put some of the non-metabolomic data together, Kate / someone from her team will link these data to the metabolomic data and add a research collaborator number before they are transferred to Mika Ala-Korpella at the University of Oulu.

REFERENCES

1. Rich-Edwards JW, Fraser A, Lawlor DA, Catov JM. Pregnancy Characteristics and Women's Future Cardiovascular Health: An Underused Opportunity to Improve Women's Health? Epidemiol Rev 2014; 36: 57-70

2. Fraser A,

3. Kenny LC, et al. Novel biomarkers for pre-eclampsia detected using metabolomics and machine learning. Metabolomics 2005; 1: 277-

4. Kenny LC, et al. Robust early pregnancy predictors of later pre-eclampsia using metabolomic biomarkers. Hypertension 2010; 56: 741-49.

5. Aitkinson KR, et al. An altered pattern of circulating apolipoprotein E3 isoforms is implicated in pre-eclampsia. J Lipid Research 2009; 50:71-80.

6. Turner E, et al. Plasma from women with pre-eclampsia has a low lipid and high ketone body content - A nuclear magnetic resonance study. Hypertension in Pregnancy 2007; 26:329-42.

7. Odibo AO, et al. First-trimester prediction of pre-eclampsia using metabolomics: a discovery phase study. Prenatal Diagnosis 2011; 31:990-94.

8. Bahado-Singh RO, et al. Metabolomics and first-trimester prediction of early-onset pre-eclampsia. Journal of Maternal-Fetal and Neonatal Medicine 2012;25:1840-47.

9. Horgan RP, et al. Metabolic profiling uncovers a phenotypic signature of small for gestational age in early pregnancy. Journal of Proteome Research 2011; 3660-73.

10. Dani C, et al. Metabolic profile of term infants of gestational diabetic mothers. Journal of Maternal-Fetal and Neonatal Medicine 2013 doi: 10.3109/1476058.2013.823941.

11. Bittner V. Menopause and cardiovascular risk cause or consequence? J Am Coll Cardiol 2006;47:1984-86.

12. Report of the WHO Scientific Group. Research on the menopause in the 1990s. Geneva: World Health Organisation; 1996. Report No.: 886

13. Lawlor DA, Hardy R. A life course approach to metabolic and vascular function. Kuh D, Cooper R, Hardy R, Richards M, Ben-Shlomo Y, eds. A life course approach to healthy ageing. OUP; 2013.

14. Finish menopausal metabolomics study