The objective of this paper is to review the extent and mechanisms of lipoprotein alterations in pregnancy, present new data relating to placental lipid transport in. normal humans and diabetic animals and consider possible effects on fetal growth and development in normal and diabetic pregnancy. The concentration of all lipoprotein fractions increases during pregnancy. VLDL cholesterol and triglyceride increase 2.5-fold over prepregnancy levels and LDL cholesterol increases 1.6-fold, all with peak levels at term. HDL cholesterol is maximally increased in midgestation by 1.45-fold and subsequently declines to 1.15-fold at term. The mechanisms of these lipoprotein changes have not been studied in humans but the hypertriglyceridemia in animal models is related to enhanced VLDL entry into the circulation. In addition, diminished adipose tissue lipoprotein lipase (LPL) activity in late gestation may cause a rerouting of triglyceride fatty acids to other tissues such as muscle and uterus for oxidation, rather than storage, since triglyceride transport is not reduced in pregnancy. All of these changes appear to be sex hormone mediated. In diabetic pregnancies, the available data indicate that triglyceride concentrations are increased and HDL cholesterol concentrations are decreased with reference to lipoproteins in nondiabetic pregnant women. Previously unpublished data show that a transplacental FFA gradient exists across the umbilical circulation in the direction of the fetus and is proportional to the maternal FFA concentration. No gradient is seen for triglyceride or total plasma cholesterol. However, transport of unmeasured amounts of triglyceride fatty acids may still occur via placental LPL and be exaggerated in diabetes where LPL declines in adipose tissue but not in placenta. The mechanism of transplacental cholesterol transport remains to be defined. Preliminary studies suggest that it depends on HDL as well as LDL since both can provide cholesterol for placental progesterone synthesis. In addition, fetal weight and length are associated with maternal apoproteins A-I and A-II, both major apoproteins of HDL. By lowering HDL in pregnancy, diabetes mellitus could negatively affect these relationships. In conclusion, sex hormone mediated modifications of lipoprotein physiology are described in pregnancy which may enhance triglyceride fatty acid transport to muscle for oxidation and LDL and HDL cholesterol delivery to growing maternal and fetal tissues, a process that diabetes could globally disrupt.

The hyperlipidemia of pregnancy consists primarily of an increase in triglyceride with lesser rises in cholesterol and phospholipid. As a further characterization, we have analyzed all lipids in the major lipoprotein subfractions in fasting pregnant and non-pregnant women. An elevated triglyceride in the major lipoprotein fractions in pregnancy is confirmed. The triglyceride rises in VLDL and IDL (density 1.006-1.019 lipoprotein) are associated with proportional rises in cholesterol and phospholipid. The result is a 3-4-fold increase of compositionally unchanged lipoprotein lipid. Contrasting changes are seen in LDL, density 1.019-1.063 lipoprotein, and HDL. In these fractions, triglyceride rises more than cholesterol and phospholipid. As a result, an increase in triglyceride on a percentage basis tends to reduce the contribution of the other two lipids. Nonetheless, on an absolute basis HDL cholesterol is not significantly reduced. The proportional increases in all lipids of VLDL and IDL fractions are consistent with increased VLDL production in pregnancy as suggested by data from animal systems. However, alterations in removal are not rules out. Maintenance of the HDL cholesterol level distinguishes pregnancy from other endogenous hypertriglyceridemias where HDL cholesterol is reduced. One may speculate that these physiological adaptations in material lipid transport can serve the increased energy needs of the mother, supply steroid hormone precursors for the placenta, and provide cholesterol and essential fatty acids for the fetus.

The available data have been examined to determine if plasma lipids or lipoproteins are altered in pregnant subjects with adult-onset (type II) diabetes, gestational diabetes, or the hyperglycemic extreme of a randomly selected group of pregnant women attending a prepaid health plan. In each of these groups, a trend is observed toward an increase in total plasma and very low density lipoprotein triglycerides and a decrease in high density lipoprotein (HDL) cholesterol. These observations indicate that measurements of plasma triglyceride and HDL cholesterol may be valuable in identifying and quantifying the metabolic abnormality in gestational diabetes and in prognosticating fetal outcome.

Plasma triglycerides increase two-to-three-fold in normal pregnancy. If mechanistically similar to the atherosclerosis-associated hypertriglyceridemias, hypertriglyceridemia in pregnancy should be exaggerated by diabetes, obesity, and high carbohydrate feeding. A failure to exaggerate would point to a different physiologic mechanism. To study this matter, we measured fasting plasma triglyceride and cholesterol In 38 normal, 22 gestational-diabetic, and 27 overtly diabetic women in the third trimester, measuring the concomitant effects of age and body weight and, in four subjects, high carbohydrate feeding.Compared with controls, fasting plasma triglyceride and cholesterol were unchanged hi gestational diabetics and hi 10 of the 27 overtly diabetic pregnant women treated with insulin and diet. However, 17 of 27 diabetic women treated with an estrogenprogestin supplement during gestation had a 36 per cent higher triglyceride and a 15 per cent higher cholesterol than control. Body weight, age, duration of diabetes, or length of gestation could not account for the observations. In non-hormone-treated subjects, regression analysis showed a positive correlation of triglycerides with age but not with body weight. High carbohydrate feeding in pregnancy produced a triglyceride increase (mean±S.D.) of 9±19 per cent in whole plasma and 17 ±13 per cent in very-low-density Upoprotein. Respective postpartum increases were 41 and 68 per cent, similar to the responses reported in nonpregnant Individuals.Conclusion: Lack of a major effect of diabetes, body weight, and high carbohydrate feeding on blood lipids hi gestation distinguishes pregnancy from the atherosclerosis-associated hypertriglyceridemias and points to a different physiologic control mechanism. DIABETES 26:1056-62, November, 1977.The endogenous hypertriglyceridemia of pregnancy is a physiologic event 1 2 distinguished from From the 1056 atherosclerosis-associated hypertriglyceridemias 3 by an increased h i g h -d e n s i t y -l i p o p r o t e i n (HDL)* cholesterol. 4 ' 6 This change resembles that seen in oral contraceptive steroid therapy, suggesting that the hypertriglyceridemia of pregnancy is hormonally cont r o l l e d . 2 4 7 8In this paper we attempt to characterize the hypertriglyceridemia of pregnancy by its response to diabetes, body weight, and high carbohydrate feeding, factors known to aggravate the atherosclerosisassociated hypertriglyceridemias. 9 " 11 An exaggerated response in pregnancy would suggest a mechanistic similarity to hypertriglyceridemias in general. A failure to exaggerate would point to a different physiologic control mechanism, presumably related to the sex hormones of pregnancy. The results support the latter possibility. Some of the results have been presented in abstract form. 12 METHODS Fasting Lipid Measurements; Subjects and ProceduresThree-hour oral glucose tolerance tests (OGTT) were performed in 64 pregnant women who were referred to the Diabetes Clinic of the Boston City Hospital. One hundred grams of glucose was given a...