Elsevier

The Lancet

Volume 354, Issue 9186, 9 October 1999, Pages 1234-1241
The Lancet

Articles
Influence of maternal hypercholesterolaemia during pregnancy on progression of early atherosclerotic lesions in childhood: Fate of Early Lesions in Children (FELIC) study

https://doi.org/10.1016/S0140-6736(99)02131-5Get rights and content

Summary

Background

Children generally have low cholesterol and no clinical manifestations of atherosclerosis, but fatty-streak formation begins in fetuses and is greatly increased by maternal hypercholesterolaemia during pregnancy. In the FELIC study we assessed the evolution of such lesions during childhood.

Methods

Computer-assisted imaging was used to measure the area of the largest individual lesion and the cumulative lesion area per section in serial cross-sections through the entire aortic arch and abdominal aorta of 156 normocholesterolaemic children aged 1–13 years, who died of trauma and other causes. Children were classified by whether their mother had been normocholesterolaemic (n=97) or hypercholesterolaemic (n=59) during pregnancy. Atherosclerosis was correlated with 13 established or potential risk factors.

Findings

The largest fatty streaks in the aortic arch of children younger than 3 years of hypercholesterolaemic mothers were 64% smaller than those previously found in corresponding fetuses (p<0·0001), which suggests that fetal fatty streaks mayregress afterbirth. In the two groups, lesion size in the aortic arch and abdominal aorta increased linearly with age (r=0·87–0·98). However, lesions progressed strikingly faster in children of hypercholesterolaemic mothers than in those of normocholesterolaemic mothers (p<0·0001). Conventional risk factors for atherosclerosis in children or mothers correlated with lesion size, but did not account for the faster progression of atherogenesis in normocholesterolaemic children of hypercholesterolaemic mothers.

Interpretation

Our results suggest that maternal hypercholesterolaemia during pregnancy induces changes in the fetal aorta that determine the long-term susceptibility of children to fatty-streak formation and subsequent atherosclerosis. If so, cholesterol-lowering interventions in hypercholesterolaemic mothers during pregnancy may decrease atherogenesis in children.

Introduction

Hypercholesterolaemia is associated with an increased incidence of atherosclerosis and its common clinical sequelae, coronary heart disease, and ischaemic stroke.1, 2 Clinical trials with cholesterol-lowering drugs have substantially decreased cardiovascular morbidity and mortality,3, 4, 5, 6 and the mechanisms by which hypercholesterolaemia and lipoprotein oxidation induce and promote atherogenesis are increasingly understood.7, 8, 9, 10, 11 Current guidelines for the prevention of atherosclerosis therefore emphasise detection of hypercholesterolaemia and lowering of cholesterol.12

In the absence of genetic defects, such as familial hypercholesterolaemia, children generally have low cholesterol concentrations and do not develop clinically important atherosclerosis. However, some atherosclerotic lesions have been seen in young adults and, occasionally, children.13, 14 We have shown previously that the earliest lesions of atherosclerosis, fatty streaks, are already formed in fetal arteries and that maternal hypercholesterolaemia during pregnancy greatly increases their number and size.15, 16 Even the earliest fetal fatty streaks contained native and oxidised LDL, as well as macrophage-derived foam cells, and analysis of lesion composition showed that LDL oxidation contributed to the initiation of the atherogenic process. Oxidation increases atherogenicity of LDL9, 10, 11 and has substantial immunological consequences.17 We have also seen that fetal cholesterol concentrations were highest in earlier pregnancy and decreased with increasing fetal age. Since fatty-streak formation was related to hypercholesterolaemia, this finding suggested that fetal lesions would regress in infancy, when cholesterol concentrations are low.

We designed the Fate of Early Lesions in Children (FELIC) study to investigate whether such regression occurs and whether the events in the arterial wall during pregnancy influence the extent of lesion formation during childhood.

Section snippets

Patients

We studied 156 children, aged 1–13 years, who died of acute trauma, cancer, and cerebral aneurysms. Children were allocated to groups according to whether their mothers had been normocholesterolaemic (n=97) or hypercholesterolaemic (n=59) during pregnancy. Mothers were asked to provide all medical records and we obtained current lipid profiles. To be classified as hypercholesterolaemic according to the joined recommendations of the Task Force of the European Society of Cardiology, European

Results

In all children, lipid-rich lesions were found in the aortic arch and abdominal aorta. Lesions in younger children consisted mostly of fatty streaks with only minimal intimal thickening, whereas in children older than 10 years, especially those from hypercholesterolaemic mothers, transitional lesions and even some classical atheromas were seen (figure 1), consistent with previous reports.12, 13, 14 Intimal lipid accumulations in the aorta of younger children visible only under the microscope

Discussion

Little is known about the progression of fatty streaks in human beings. It is assumed that fatty streaks can progress to more advanced atherosclerotic lesions because they occur at the same anatomical sites and because transitional stages have been seen.32 Conversely, the assumption that fatty streaks may regress rests on observations in animal studies and angiographic studies which show that some advanced human lesions may partially regress as a result of hypolipidaemic intervention.33 The

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