Maternal Metabolic and Vascular Adaptation to Healthy, Obese and Complicated Pregnancy

During pregnancy the mother adapts her metabolism and physiology in a number of ways to help support and feed her fetus. In early pregnancy, maternal fat is laid down and in later pregnancy, the fats stored in adipose tissue are mobilised to provide the mother and baby with essential nutrients and fuels for energy. The maternal blood vessels also adapt and can become more responsive to signals allowing them to relax and this helps provide good blood flow to the placenta. The mechanisms by which these adaptations are achieved are not well understood. Furthermore, in obese pregnancy and pregnancies complicated by preeclampsia, intrauterine growth restriction and gestational diabetes, the metabolic and blood vessel adaptation to pregnancy is not optimal leading to hypertension, poor placental blood perfusion, failure to respond properly to hormones such as insulin. This can have immediate consequences for the health of mother and baby, but also may impact on their future health.

Maternal adaptation to pregnancy includes increased storage of fatty acids in adipose tissue in early gestation, and mobilisation of fatty acids from adipose tissue in response to maternal insulin resistance induced by pregnancy hormones, in mid-to-late gestation. Obese mothers have higher fasting insulin, plasma triglycerides and lower high density lipoprotein concentrations in the third trimester of pregnancy in combination with increased markers of inflammation. Thus, the physiologically normal insulin resistance is much more pronounced in overweight and obese women. Obese women also have a compromised vascular adaptation to pregnancy and vascular function fails to show the same extent of improvement as that of normal weight pregnant women. Maternal obesity is a risk factor for preeclampsia and gestational diabetes. The combination of an adverse metabolic/inflammatory profile and vascular dysfunction may impact on both placental development and the maternal response to pregnancy, leading these adverse outcomes such as GDM and PE. Intrauterine growth restriction (IUGR) is failure of a fetus to reach its full growth potential during gestation. Several key aspects of the maternal metabolic adaptation to pregnancy are altered in IUGR. Gestational weight gain is lower in IUGR than control pregnancies, there is no late gestational increase in lipolysis, plasma LDL concentrations and size are reduced and long chain polyunsaturated fatty acid concentrations in maternal erythrocytes are up to 60% lower. Thus there is suboptimal nutrient supply to the placenta. In addition, vascular function is abnormal in IUGR compared to healthy pregnancies with similar pre-pregnancy BMI. In some cases of IUGR there is a very abnormal metabolic adaptation to pregnancy and preeclampsia, a condition of widespread maternal endothelial dysfunction, occurs leading to proteinuria, oedema and hypertension.

Our research addresses the following questions:

• How is the healthy metabolic and vascular adaptation to pregnancy orchestrated?
• How and why do these processes fail in pregnancy complications?
• What are the short- and long-term consequences for mother and baby?

Publications

1. Meyer BJ, Stewart FM, Brown EA, Cooney J, Nilsson S, Olivecrona G, Ramsay JE, Griffin BA, Caslake MJ, Freeman DJ. Maternal obesity is associated with the formation of small dense LDL and hypoadiponectinaemia in the third trimester. JCEM 2013;98:643-652

2. Hodson L, Neville M, Chong M, Rogers I, Huda SS, Freeman DJ, Frayn KN, Fielding BA. Micro-techniques for analysis of human adipose tissue fatty acid composition in dietary studies Nutrition, Metabolism and Cardiovascular Diseases 2012 Dec 7 [Epub ahead of print]

3. Mackenzie RM, Sandrim VC, Carty DM, McClure JD, Freeman DJ, Dominiczak AF, McBride MW, Delles C. Endothelial FOS expression and preeclampsia. BJOG 2012;119:1564-7

4. Mackay VA, Huda SS, Stewart FM, Tham K, McKenna L, Martin I, Jordan F, Brown E.A, Hodson L, Greer IA, Meyer BJ, Freeman DJ. Preeclampsia is associated with compromised maternal synthesis of long chain polyunsaturated fatty acids leading to offspring deficiency Hypertension 2012;60:1078-85

5. Carty DM, Anderson LA, Freeman DJ, Welsh PI, Brennand JE, Dominiczak AF, Delles C. Early pregnancy soluble E-selectin concentrations and risk of pre-eclampsia. J Hypertens 2012;30:954-9

6. Potential mechanisms contributing to gestational diabetes and preeclampsia in the obese woman. Sattar N, Freeman DJ. Chapter 5, pg 45-55 in Maternal obesity Ed Matthew W. Gillman, Lucilla Poston. Cambridge Press 2012 

7. Jarvie E, Hauguel-de-Mouzon S, Nelson SM, Sattar N, Catalano PM, Freeman DJ Lipotoxicity in obese pregnancy and its potential role in adverse pregnancy outcome. Clinical Science 2010;119:123-9

8. Madigan J, Freeman DJ, Menzies F, Forrow S, Nelson SM, Young A, Sharkey A, Moffett A, Graham GJ, Greer IA, Rot A, Nibbs RJB. The chemokine scavenger D6 is expressed by trophoblasts and aids the survival of mouse embryos transferred into allogeneic recipients. Journal Immunology 2010;184(6):3202-12

9. Nelson SM, Fleming R, Stewart F, Freeman DJ. Longitudinal assessment of Anti-Müllerian hormone during pregnancy – relationship with maternal adiposity, insulin and adiponectin Fertility and Sterility 2010:93(4):1356-8

10. Freeman DJ. The effects of maternal obesity on foetal growth and body composition: implications for programming and future health. Seminars in Fetal and Neonatal Medicine 2010;15:113-8

11. Huda SS, Freeman DJ, Nelson SM Short and Long Term Strategies for the Management of Hypertensive Disorders of Pregnancy. Expert Review in Cardiovascular Therapy 2009;7:1581-94

12. Nelson SM, Freeman DJ, Sattar N, Lindsay RS. Erythrocytosis in offspring of mothers with type 1 diabetes – Are factors other than insulin critical determinants? Diabetic Medicine 2009;26:887-92

13. Huda SS, Sattar N, Freeman DJ. Lipid metabolism and vascular complications in pregnancy. Clinical Lipidology 2009;4(1):91-102

14. Kanagalingham MG, Nelson SM, Freeman DJ, Ferrell WR, Lowe GD, Greer IA and Sattar N. Vascular dysfunction and alteration of novel and classic cardiovascular risk factors in mothers of growth restricted offspring: evidence of higher vascular risk even in reproductive years Atherosclerosis 2009;205:244-50.

15. The effect of pregnancy on energy metabolism, body composition and endothelial function. Freeman DJ, Sattar N. in Diabetes in Women: Pathophysiology and Therapy Edited by: A. Tsatsoulis et al. Humana Press 2009 

16. Meyer BJ, Freeman DJ. Role of omega-3 polyunsaturated fatty acids in pregnancy: Need for increasing awareness among women. AgroFood Industry Hi-tech 2008;19:17-19

17. Nelson SM, Freeman DJ, Sattar N, Lindsay RS. Role of adiponectin in matching of fetal and placental weight in mothers with type 1 diabetes. Diabetes Care 2008;31:1123-5

18. Freeman DJ, Tham K, Brown EA, Rumley A, Lowe GD, Greer IA. Fetal CRH mRNA, but not phosphatidylserine exposing microparticles, in maternal plasma are associated with FVII activity in preeclampsia. Journal of Thrombosis and Haemostasis 2008 6:421-7

19. Nelson SM, Freeman DJ, Sattar N, Walker JD, Lindsay RS. IGF-1 and leptin associate with fetal HDL-cholesterol at birth: examination in offspring of mothers with type 1 diabetes Diabetes 2007 56(11):2705-9

20. Nelson SM, Sattar N, Freeman DJ, Lindsay RS. Inflammation and endothelial activation are evident at birth in offspring of mothers with type I diabetes. Diabetes 2007;56:2697-704

21. Stewart F, Rodie VA, Ramsay JE, Greer IA, Freeman DJ, Meyer BJ. Longitudinal assessment of erythrocyte fatty acid composition throughout pregnancy and post partum. Lipids 2007;42:335-44

22. Stewart FM, Freeman DJ, Ramsay JE, Greer IA, Caslake M, Ferrell, WR. Longitudinal assessment of maternal endothelial function and markers of inflammation & placental function throughout pregnancy in lean and obese mothers. JCEM 2007;92:969-75

23. Freeman DJ. Update on gestational hypertension. Women’s Health 2006;2:695-698

24. Rodie VA, Young A, Jordan F, Sattar N, Greer IA, Freeman DJ Human placental peroxisome proliferator-activated receptor delta and gamma expression in healthy pregnancy and in pre-eclampsia and intrauterine growth restriction. J Soc Gynecoc Investig 2005;12:320-9

25. Freeman DJ, McManus F, Brown EA, Cherry L, Norrie J, Ramsay JE, Clark P, Walker ID, Sattar N, Greer IA. Short and long term changes in plasma inflammatory markers associated with pre-eclampsia. Hypertension 2004;44:708-14

26. Rodie VA, Caslake MJ, Stewart F, Sattar N, Greer IA, Freeman DJ. Fetal cord plasma lipoprotein status in uncomplicated human pregnancies and in pregnancies complicated by pre-eclampsia and intrauterine growth restriction. Atherosclerosis 2004 176:181-187

27. Rodie VA, Freeman DJ, Sattar N, Greer IA. Pre-eclampsia and cardiovascular disease: metabolic syndrome of pregnancy? Atherosclerosis 2004 175:189-202

28. Clark P, Freeman DJ, Streja E, Sattar N, Walker ID, Greer IA. The G-to-T point mutation in codon 34 of the Factor XIII gene and the risk of pre-eclampsia Blood Coagulation & Fibrinolysis 2003;14:155-7