Regional Committees for Medical and Health Research Ethics (REC)
Project owner/ Project manager
University of Oslo
Participant at FHI
Cardiovascular disease (CVD) caused by atherosclerosis is the main cause of mortality worldwide and in Norway.
Increasing prevalence of obesity and sedentary lifestyle has resulted in an increase in number of young women of fertile age who have considerably elevated blood cholesterol levels during pregnancy. The Forsdahl-Barker hypothesis suggested that the risk of CVD in adult life may be determined by an adverse environment during gestation. The in utero period has therefore emerged as a critical phase influencing disease risk for a range of disorders that develop later in life.
However, while several studies have investigated the relation between maternal adiposity and dysglycemia and adult offspring cardiometabolic health, the relation between maternal dyslipidemia and offspring risk remains much less explored in humans. The link between in utero hypercholesterolemia and later CVD may operate via gestational altered lipid metabolism and epigenome-wide modifications.
By using the Norwegian Mother and Child Cohort Study (MoBa) we will be able to study the relation between maternal and paternal hypercholesterolemia and cardiovascular risk markers in offspring. The “fetal origin of adult disease” identified the relationship (regardless of cholesterol exposure) between impaired in utero growth and risk of adult CVD. This represents a major example of nutritional epigenomics that has key medical impact for the offspring.
These observations have now been extended and correlations between maternal metabolic dysfunction (including increased maternal inflammatory profile) and the intra-uterine environment on the development of adult CVD have been reported. However, the detailed mechanisms of this fetal programming have to be elucidated.
Napoli et al. investigated the relation between fatty streak formation in the aortic arch in children (aged 1-13) who died in non-cardiovascular related events, and who had been born of women with normal- or hypercholesterolemia. They concluded that maternal hypercholesterolemia during pregnancy induces changes in the fetal aorta that confer a long-term susceptibility of children to atherosclerosis.
It has been suggested that the protective “adaptive programming” is a response from the fetus trying to adapt to detrimental conditions in utero, such as maternal hypercholesterolemia. Recent data showed that maternal pre-pregnancy LDL-C levels were associated with adult offspring LDL-C levels and offspring already at the age of 10 years, beyond the influence which could be attributable to measured lifestyle, anthropometric, and inherited genetic factors. Inter-generational maternal epigenetic transmission mechanisms, which currently are poorly understood, may mediate this effect. Hence, the relation between maternal hypercholesterolemia and (epi)genetic risk markers of the offspring needs to be further elucidated. A normal physiological rise (~30%) in cholesterol levels during pregnancy is observed in pregnant women.
Cholesterol lowering treatment is contra-indicated during pregnancy, leading to severely heightened cholesterol levels in hypercholesterolemic women, causing a prothrombotic and proinflammatory environment.
It is not known how exposure to high cholesterol levels in the placenta may influence the offspring. Coincidental statin treatment in the first trimester of pregnancy in 1,152 women did not show any increase in congenital malformations, but data on statin treatment during later course in the pregnancy is lacking. As statin treatment is contra-indicated, it is not possible to perform to investigate the possible effect. However, it is possible to link data from women reporting accidental statin treatment to the birth register for measurement
- Norwegian Institute of Public Health
- Oslo University Hospital – Rikshospitalet
- Norwegian Radium Hospital
- Oslo University Hospital - Ullevaal
- Oslo Economics AS
- Erasmus University Medical Centre
- University of Helsinki