Dyslipidemia in Pregnancy

Monica Mukherjee, MD, F.A.C.C. (Disclosure)

May 19, 2014

Introduction

Pregnancy in healthy women is associated with normal changes in lipid metabolism that are essential for fetal growth and development. However, with the obesity epidemic, we more frequently are confronted with patients with cardiovascular disease that precedes gestation, as well as unmasked cardiovascular disease during pregnancy. Moreover, subset populations of gravid women with gestation hypertension and diabetes, and/or preeclampsia have more marked derangement of atherogenic lipid profiles. These alterations in lipogenesis have been linked to perinatal morbidity and mortality by recent studies which are ushering in the field of dyslipidemia in pregnancy as a hot area for outcomes research.

Normal Gestation

Normal pregnancy is associated with predicted changes in lipid metabolism and increases in lipid concentration as gestation progresses.1,2 During the first trimester, there is marked deposition and hypertrophy of maternal adipocytes with increased expression of insulin receptors such that glucose is available to meet the metabolic demand of the growing fetus.3 Increase in maternal insulin in addition to production of progesterone leads to lipogenesis with diminished lipolysis, and increased production of lipids, which then are transported across the placenta and metabolized; this signifies the essential role of lipids to normal fetal development.1,2

While both total cholesterol (TC) and triglycerides (TG) rise throughout pregnancy, TG in particular rise disproportionately in comparison to other lipid fractions reaching two to four times pre-pregnancy levels by the third trimester.1 However, these changes are felt to be generally non-atherogenic, and fall precipitously to pre-pregnancy levels following delivery.1,4 Pregnancy is also associated with alterations in the composition and size of LDL particles. Previous studies have demonstrated that as TG levels increase, there is a decrease in overall LDL size with an increased proportion of smaller, denser LDL particles that are thought to be more atherogenic.4,5

HDL-C levels and apolipoprotein A-I levels also increase during normal gestation, with peak levels during the second trimester. Studies have suggested a potential protective effect to the mother to offset elevations in atherogenic LDL-C and TG levels.4 Multiparous women tend to have relative decrease in HDL-C levels in comparison to their primiparous counterparts.5 These derangements of elevated LDL-C fractions with lower HDL-C levels appear to be more pronounced in women with gestational hypertension and diabetes, and preeclampsia.4,6 Furthermore, women who have higher concentrations of small dense LDL fractions during pregnancy tend to have increased risk of cardiovascular disease later in life.5

Lipoprotein (a)

Lipoprotein [Lp(a)] has long been recognized as an important determinant in the progression of coronary disease, and is comprised of a LDL covalently bound to apolipoprotein (a) along the B100 portion.7,8 Although the exact relationship of elevations in Lp(a) remains unclear, previous studies have suggested a proatherogenic and prothrombotic effects.8 There is also a gender predilection where similar Lp(a) carry greater atherosclerotic risk in women versus age-matched men.7,9 During pregnancy, Lp(a) levels increase with gestational age and similar to other lipid fractions, fall to pre-pregnancy levels within six months postpartum.7,10 Preeclamptic women tend to have increased levels of Lp(a), however no studies to date have demonstrated adverse pregnancy outcomes with elevations in Lp(a) concentration.7

Lipids and Preterm Birth Risk

Recently, the ABCD study showed that atherogenic lipid profiles during the first trimester confer an increased risk of adverse pregnancy outcomes including maternal morbidity, mortality, and preterm delivery.2 Women who deliver preterm are also at an increased risk for cardiovascular disease later in life, as are newborns born preterm who are either too small or too large for gestational age.7,11,12 However, the exact pathophysiology of this relationship of pre-pregnancy and first trimester lipid derangements remains incompletely characterized.

In a large European community-based cohort study comprising nearly 4000 non-diabetic otherwise healthy women with a mean age of 30.9 ± 4.9, investigators found that elevated TG levels, but not TC levels, during the first trimester were independently associated with adverse outcomes for both the mother and the newborn.2 These adverse outcomes are defined as gestational hypertension without proteinuria and preeclampsia in the mother, and preterm babies who are too large for gestational age. Authors suggest that lifestyle modification with a focus on reduction in weight and increase in physical activity in these women may avert hypertensive complications and preterm birth in these women.2,13

In a separate study of the multicenter, longitudinal, observational Coronary Artery Risk Development in Young Adults (CARDIA) cohort, Catov et al examined 1010 women, 49% of whom were African American, with an average age of 24 years.11 There was a U-shaped relationship between pre-pregnancy lipid levels and the risk of preterm birth in normotensive, non-diabetic, otherwise healthy women. Women with pre-pregnancy TC that was low (<156 mg/dl) or high (>195 mg/dl) had the highest incidence of preterm birth between 34 to 37 weeks gestation, independent of race, body mass index, and parity. Furthermore, there were no demonstrable associations between pre-pregnancy levels of LDL-C or HDL-C and the risk of preterm labor.11

The pathways of low versus high TC levels in relation to adverse pregnancy outcomes, however, are quite disparate. Low TC in pre-pregnancy and during early gestation is associated with a blunted increase in TG concentrations, and higher incidence of fetal intrauterine growth retardation in addition to preterm birth.11,14 Higher TC levels either early or late in gestation, on the other hand, may represent a “proatherogenic phenotype” with increased risk of preterm birth, however also with increased cardiovascular risk later in life.11 Authors suggest that pregnancy may function as a cardiometabolic stress test in these patients, and adverse reproductive events may in fact represent future cardiovascular risk.

Lipids and Hypertensive Complications in Pregnancy

There is a spectrum of hypertensive disorders that can occur in pregnancy. First is chronic hypertension, where elevations in blood pressure precede conception. Gestational hypertension, on the other hand, is elevated blood pressure without proteinuria occurring during pregnancy. This may be evidence of an underlying hypertensive disorder uncovered with gestation and increased cardiometabolic stress, or may resolve with delivery. Preeclampsia is a well-defined syndrome, defined by new-onset gestational hypertension and proteinuria occurring in approximately 5-8% of pregnancies and is a major source of maternal and fetal morbidity and mortality.6,15,16 When preeclampsia becomes associated with neurologic deficits, this syndrome is known as eclampsia, and emergent delivery is indicated given exceedingly high maternal and fetal mortality.

Preeclampsia has been defined as a two-staged process during which the initiating mechanism during Stage 1 is inadequate remodeling of the placental vasculature, leading to reduced placental perfusion.17 Uterine vascular hypoplasia in addition to maternal factors of genetics, hypertension, diabetes, obesity, androgen secretion, and black race, then lead to the maternal manifestation of preeclampsia, with associated endothelial dysfunction and marked systemic inflammation.16,17 Preeclampsia has different gradations from mild disease to severe, delineated by degree of blood pressure elevation and proteinuria.15,16 Preeclampsia that is associated with more pronounced hypertension, oliguria, noncardiogenic pulmonary edema, elevated liver enzymes, thrombocytopenia of less than 100,000/m3, and neurologic deficits is classified as severe disease.15,16,18

Several studies have identified proatherogenic patterns in lipid concentrations that precede clinical manifestations of preeclampsia.4,6,7,15 Preeclamptic women tend to have increased levels of Lp(a), of uncertain significance.7 These gestations are also marked by higher levels of TG, lower levels of HDL-C, and greater fractionation of small dense atherogenic LDL particles.4,6,15 Elevated LDL fractions with lower HDL-C levels appear to be more pronounced in women with gestational hypertension and diabetes, and preeclampsia.4,6 Furthermore, women who have higher concentrations of small dense LDL fractions during pregnancy tend to have increased risk of cardiovascular disease later in life.5 Dyslipidemia, especially during mid-gestation, is associated with mild preeclampsia.6,15 Severe preeclamptic women tend to have low LDL-C levels with less atherogenic profiles suggesting a different pathologic mechanism between mild and severe disease.15

Lipids and Diabetes Mellitus in Pregnancy

Similar to hypertension, there is a range of diabetic disease that occurs in pregnancy including preexisting type 1 and type 2 diabetes mellitus (DM), and gestational diabetes.

Lipid profiles in women with uncomplicated preexisting type 1 DM are similar to healthy women without diabetes.19 However when confounded by other maternal metabolic risk factors such as obesity, hypertension, poor glycemic control, and preeclampsia, type 1 DM is associated with higher elevations in first trimester TG levels and lower levels of HDL-C in comparison to healthy counterparts.1,19,20

There are subtle differences in type 1 DM and co-morbid conditions of unclear clinical significance. For example, renal dysfunction and type 1 DM is associated with higher TC and LDL fractions while women with poor glycemic control and type 1 DM have higher TG levels and lower HDL-C without significant changes in LDL fractions from normal.19-21 Similarly, women with preexisting type 2 DM have higher TG and lower HDL-C levels during the first trimester without significant change in LDL-C and Lp(a) levels in comparison to normal.1,19,21 Women with gestational diabetes may have increased to unchanged TG and TC levels and stable LDL fractions throughout gestation although these results have been equivocal.19-21

Maternal obesity, on the other hand, with or without overt gestational diabetes, is linked with atherogenic lipid profiles and adverse pregnancy outcomes, in part due to inflammation and endothelial dysfunction.13,19 Gestation in obese women is more frequently associated with elevated TG and small, dense LDL fractions with low HDL-C levels.19,21 Newborns born to obese mothers also tend to be large for gestational age, and may have increased risk of cardiovascular events later in life.9,19,22

Anti-Hyperlipidemic Therapies in Pregnancy

Unfortunately, despite the known benefits of many anti-hyperlipidemic therapies on atherogenic lipid profiles, and clinical outcomes, there is a paucity of studies that have been performed in pregnancy. In fact, pregnant women are routinely excluded from clinical trials. As a result, recommendations on the treatment of significant dyslipidemia in pregnant women are limited. Omega-3 fatty acids can be used safely in pregnancy as monotherapy, and function to decrease maternal TG levels.19,23 Nicotinic acid (Niacin) decreases TG levels while also increasing HDL-C levels;  however, it has only been studied in case reports of pregnant women, and are therefore not recommended.23,24

Fibrates, which function to decrease TG concentration, increase LDL clearance, and increase HDL-C levels, have also not been well studied in pregnant women and similarly are not recommended.19,23 Studies on the use of HMG-CoA- reductase inhibitors, otherwise known as statins, in pregnancy have had conflicting reports of teratogenicity and congenital malformation and are therefore not generally recommended.23

Conclusion

Pregnancy represents a unique opportunity for the detection of subclinical dyslipidemia. Normal gestation is characterized by increase in lipid production to foster the healthy fetal development. However, evidence is emerging that the presence in pre-pregnancy and early gestation of atherogenic dyslipidemia – characterized by high TG, small dense LDL, and low HDL-C levels – confers an increased risk of adverse pregnancy outcomes as well as cardiovascular risk later in life. Co-morbid conditions of preeclampsia, gestational hypertension and diabetes, as well as maternal obesity may accentuate these unfavorable changes in lipid patterns and clinical outcomes.

Atherogenic lipid profiles during pregnancy are also associated with preterm birth and newborns that are large for gestational age. These children also appear to have an increased risk of cardiovascular disease later in life, which further signifies the importance of early detection and risk modification of dyslipidemia during pregnancy. Further studies are needed to delineate the role of anti-hyperlipidemic therapies in pregnant women with dyslipidemia.

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