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Effect of Pregnancy on Lipid Metabolism and Lipoprotein Levels

, MD and , MD, MPH, PhD.

Author Information

Last Update: February 20, 2018.

ABSTRACT

Lipoprotein lipid physiology in pregnancy has important implications for the developing fetus and newborn as well as the mother. Cholesterol is essential for normal fetal development. It is key in the formation of cell membranes. In pregnancy, multiple physiological changes occur that contribute to the alterations in lipid profiles of healthy, gestating women. Initially, there is an anabolic phase with an increase in lipid synthesis and fat storage in preparation for the increases in fetal energy needs in late pregnancy. During the third trimester, lipid physiology transitions to a net catabolic phase with a breakdown of fat deposits. The catabolism increases substrates for the growing fetus. Overall, the changes in lipid physiology throughout the course of pregnancy allow for proper nutrients for the fetus and they reflect increasing insulin resistance in the mother. Our understanding and appreciation of the full scope and implications of dyslipidemia in pregnancy on both maternal and fetal outcomes is not complete; however, it is well known that dyslipidemia in pregnancy is associated with adverse pregnancy outcomes affecting both maternal and fetal health. There are direct implications of dyslipidemia on perinatal outcomes as well as intricate relationships between dyslipidemia and other comorbid intrauterine conditions. There is also developing research indicating that the in utero environment influences susceptibility to chronic diseases later in life, a concept known as “developmental programming.” Given all of these implications of dyslipidemia in pregnancy on maternal and fetal health, it is prudent to screen women for lipid disorders. The ideal time for this is before conception; if a woman has not been screening before pregnancy, the initial obstetrical visit is ideal. Abnormal lipids should be followed through pregnancy. The treatment of dyslipidemia in pregnancy is multifactorial, including diet, exercise and weight management. Medical management is complicated by FDA classifications for medication risks to the fetus, however some evidence indicates there may be permissible pharmacological treatments for dyslipidemia in pregnancy.

INTRODUCTION

Lipoprotein lipid physiology in pregnancy has important implications for the developing fetus and newborn. Cholesterol is important for normal fetal development and is provided to the fetus via both endogenous and exogenous mechanisms. As we begin to understand dyslipidemia in pregnancy, it is clear that dyslipidemia is linked to adverse perinatal outcomes. Dyslipidemia also has profound associations with other pathologies in pregnancy, most notably the hypertensive disorders of pregnancy and gestational diabetes. There is also accumulating evidence of the impact hyperlipidemia in pregnancy has on the epigenetic programming of a fetus and the subsequent risk for atherogenesis for the mother and her offspring. Given the implications, a plan for monitoring and treatment is needed.

CHOLESTEROL IN FETAL DEVELOPMENT

Cholesterol is essential for normal fetal development. It plays a key role in the formation of cell membranes, maintaining membrane integrity and preserving cholesterol-rich domains essential for most membrane-associated signaling cascades, including sonic hedgehog signaling1. It is also the precursor to many important hormones, such as steroids, vitamin D, and bile acids.

There are multiple sources of fetal cholesterol. A significant portion is produced de novo by the fetus. Defects affecting cholesterol biosynthesis are associated with many, sometimes lethal, birth defects2, 3. Both endogenous and exogenous sources are important to fetal cholesterol homeostasis, as illustrated by a number of lines of evidence. Cholesterol in the maternal circulation, which similarly has endogenous and exogenous sources, contributes significantly to the fetal cholesterol pool in animals and in humans4, 5. Interestingly, Vuorio and colleagues6 noted that concentrations of plant stanols in the cord blood of healthy newborns were 40% to 50% lower than the maternal levels. Because the plant stanols evaluated can only be derived from the maternal diet, placental transfer is illustrated. Fetuses with null-null mutations of Smith-Lemli-Opitz syndrome, a disorder characterized by an inability to synthesize endogenous cholesterol at normal rates, have measurable amounts of cholesterol in their bodies. This also illustrates maternal derivation7, 8. The umbilical vein, which carries blood to the fetus, has higher levels of LDL-C than the umbilical artery9.

For exogenous cholesterol to be available for fetal use, it must be transported across the tissues separating the mother and fetus. Early in pregnancy, the yolk sac is the site of transport system between the two. Approaching 8 weeks of gestation, the placenta becomes fully functional and takes over as the nutrient transporter. The transfer of lipids across the yolk sac and placenta is complex and incompletely understood. Cholesterol is taken up on the apical or maternal side of trophoblasts via receptor-mediated and receptor-independent transport processes. Lipids are then transported across cellular barriers and delivered into the fetal circulation on the basolateral, or fetal, side of trophoblasts10, 11. Cultured trophoblast cells express low-density lipoprotein (LDL) receptors (LDLRs), LDLR-related proteins, scavenger receptor A, and high-density lipoprotein (HDL)-binding scavenger receptor B1 (SR-B1s), on their apical side. Cholesterol is taken up by internalization of receptor bound ApoB- or ApoE- carrying lipoproteins. Oxidized LDL, and cholesterol from SR-B1-bound HDL, is then released into fetal circulation4. It is thought that cholesterol exits into fetal circulation through direct secretion of lipoprotein particles, as a complex with apolipoprotein or is effluxed to various acceptors through diffusion or protein-mediated export12. The uptake of cholesterol by endothelial cells is well understood, but it is incompletely known how placental endothelial cells transport and deliver substantial amounts of cholesterol to the fetal microcirculation and regulate efflux of cholesterol.

NORMAL LIPID CHANGES IN PREGNANCY

Figure 1 shows the average values of total cholesterol, triglycerides, low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C) measured in normal women from pre-conception through several months postpartum. These values were measured in a cohort of women proceeding through normal pregnancy and delivery. Most of the women in the cohort are of young reproductive age and thus their values before pregnancy are in what is considered the normal range for a nonpregnant woman. In the first trimester, there is a discernible decrease in levels during the first 6 weeks. As pregnancy progresses, there is a noticeable increase by the third month or at the end of the first trimester. This begins a steady increase throughout pregnancy in the major lipoprotein lipids. By the end of pregnancy, or the third trimester, levels peak to maximize near term13. This lipid metabolism throughout pregnancy allows for proper nutrients for the fetus and the normal, steady increase throughout pregnancy reflects increasing insulin resistance in the mother as noted above.

Figure 1. Lipid and Lipoprotein Levels During Pregnancy.

Figure 1Lipid and Lipoprotein Levels During Pregnancy

(Adapted From: Wiznitzer A, Mayer A, Novack V, et al. Association of lipid levels during gestation with preeclampsia and gestational diabetes mellitus: a population-based study. Am J Obstet Gynecol 2009; 201(5):482.e1-8;)

Regardless of dietary differences in cholesterol, by late pregnancy, plasma cholesterol levels are 50% higher than routinely seen pre-pregnancy while triglyceride levels are doubled. These changes can be viewed as important for enhanced availability of substrates for the fetus14. For understanding clinical management, it is important to note that the maximum plasma cholesterol value never exceeds 250 mg/dL at any time during normal pregnancy even with the marked increases in triglyceride levels that occur normally. If abnormal pregnancies are included in cross sectional evaluations, levels reach 300 mg/dL or higher. In other words, higher levels are consistent with some of the population not being normal having a variety of maternal pathological conditions. In normal pregnant women however, the atherogenic index, LDL/HDL, remains essentially unchanged during pregnancy. This suggests that while the total lipoprotein levels increase, the lipoprotein fractions are evenly distributed15. Physiological hyperlipidemia/hypertriglyceridemia is distinguished from pathological dyslipidemias by a paralleled increase in HDL-C in normal women as they progress through pregnancy. During pregnancy LDL and HDL are enriched in triglycerides16.

MECHANISMS FOR THE HYPERLIPIDEMIA OF PREGNANCY

Multiple physiological changes occur during pregnancy. Hormonal and metabolic changes that occur in the mother contribute to changes in the lipid profile in healthy, gestating women. It is useful to think of two phases of lipid metabolism in normal pregnancy. During the first two trimesters, lipid metabolism is ‘primarily anabolic.’ There is an increase in lipid synthesis and fat storage in preparation for the exponential increases in fetal energy needs in late pregnancy. This increase in lipid synthesis between 10 and 30 weeks of pregnancy is promoted by maternal hyperphagia seen in early pregnancy as well as an increase in insulin sensitivity. The increase in insulin sensitivity stimulates fatty acid synthesis in adipocytes and stimulates the expression of lipoprotein lipase, which results in the increased uptake of fatty acids from circulating triglyceride rich lipoproteins. Additionally, the increased production of progesterone, cortisol, leptin, and prolactin contributes to the increased fat storage13,14. There is also significant hypertrophy of the adipocytes to accommodate increased fat storage14.

Lipid metabolism in the third trimester is in a ‘net catabolic phase’, which is driven by a decrease in insulin sensitivity (i.e. insulin resistance). This decrease in insulin sensitivity enhances the lipolysis of stored triglycerides in adipocytes. The third trimester elevation of human placental lactogen (Hpl) also stimulates lipolysis in adipocytes. In addition, insulin resistance results in a decrease in lipoprotein lipase in adipocytes leading to a decrease in the uptake of fatty acids from plasma triglyceride rich lipoproteins. These changes result in a reduction in fat stored in adipocytes.

The hypertriglyceridemia that occurs during pregnancy is due to both the increased production of triglyceride rich lipoproteins and the decreased clearance of triglyceride rich lipoproteins. The increased production of triglyceride rich lipoproteins by the liver is due to the increased lipolysis of triglycerides that occurs in adipocytes, which results in an increase in free fatty acids that are transported to the liver. In the liver, these free fatty acids are used in the synthesis of triglycerides, which are then packaged into VLDL and secreted by the liver. The high estrogen levels in the third trimester stimulate lipogenesis and VLDL production in the liver. The decrease in clearance of triglyceride rich lipoproteins is due to a decrease in lipoprotein lipase and hepatic lipase16. The decrease in hepatic lipase is due to the elevated estrogen levels17 while the decrease in lipoprotein lipase is likely due to a combination of factors including insulin resistance and elevated estrogen levels. The triglyceride enrichment of LDL and HDL is due to an increase in CETP activity18,19 resulting in the transfer of triglyceride from VLDL to LDL and HDL and a decrease in hepatic lipase, which decreases the removal of triglycerides from these lipoprotein particles.

At term, LPL activity increases in the mammary glands, which will enhance the uptake of fatty acids to increase the formation of triglycerides for lactation14. The increase in plasma cholesterol levels is likely due to increased hepatic cholesterol synthesis20,21.

Table 1Role of Hormones in Inducing Hyperlipidemia in the Third Trimester

Estrogen increaseInhibits Hepatic Lipase
Stimulates VLDL production
Stimulates lipogenesis in liver
Human Placental Lactogen increaseInduces insulin resistance
Increases lipolysis
Insulin ResistanceDecreases LPL activity
Increases lipolysis
Increase CETP

IMPLICATIONS FOR THE FETUS

Our understanding and appreciation of the full scope and implications of dyslipidemia in pregnancy on both maternal and fetal outcomes is not complete. Dyslipidemia is associated with adverse pregnancy outcomes that affect the health of both the mother and the fetus. The best-studied pathologies are pre-eclampsia and gestational diabetes. Newer information suggests that dyslipidemia in pregnancy may have highly significant implications for developmental programming in infants, increasing their risk and their offspring’s risk for atherosclerosis and cardiovascular disease later in life. This is best studied in animal model systems, and in conjunction with epidemiological associations keeping with a line of investigation based on long term effects of nutritional deprivation albeit from under or over feeding.

Direct Implications

Maternal dyslipidemia is linked to adverse perinatal outcomes. In animal studies, mice fed a hypercholesterolemic diet had increased rates of abortion, mortality, small litter sizes and lower birth weights of offspring. The offspring of hypercholesterolemic mothers also showed growth impairment and reduced renal function, effects only partially reversed by being fed a standard diet after delivery22. Hypercholesterolemia and elevated triglycerides in early pregnancy have been associated with an increased risk for spontaneous preterm delivery. Pregestational high lipid levels are associated with premature birth and low birth weight, indicating that maternal health status before conception has an impact on fetal health23. Variations in maternal lipid metabolism have an impact on fetal growth. In pregnancies of non-diabetic mothers, maternal triglyceride levels are correlated with fetal birth weight. Concentration of triglycerides in the third trimester is a stronger predictor of birth weight than glucose parameters24-26. Schaefer-Graf et al27 followed a cohort of women with gestational diabetes (GDM) throughout pregnancy and found that triglycerides (TGs) and free fatty acids (FFAs) were both significantly correlated with abdominal circumference (AC) size at 28 weeks and at delivery. Both are correlated with neonatal birth weight, BMI and fat mass. After adjusting for other maternal confounding factors, only maternal FFAs and TGs were independently related to large for gestational age (LGA). Other studies have corroborated this evidence that elevated levels of maternal TGs predict macrosomia independently of other maternal factors, such as BMI and glucose levels24-26. Some studies suggest that high levels of maternal HDL-C are significantly associated with a decreased risk for macrosomia, perhaps indicating that HDL might have protective qualities for more than just maternal benefit28.

Comorbid Intrauterine Conditions

Adverse pregnancy outcomes impact both maternal and fetal health. Pre-eclampsia and gestational diabetes are not only two of the most common adverse pregnancy outcomes, they each have short and long term consequences for both the mother and the fetus. Pre-eclampsia is a rapidly progressive condition that affects 5-8% of pregnancies. It is characterized by hypertension and proteinuria. Risks to the fetus with preeclampsia include poor fetal growth and sometimes devastating consequences of preterm birth, whether spontaneous or induced. These can manifest as cerebral palsy, epilepsy, small size, and even death. Gestational diabetes (GDM) is diabetes secondary to insulin resistance of pregnancy. Risks to the fetus from GDM include brachial plexus injuries, hypoglycemia, respiratory distress, hyperbilirubinemia and cardiomyopathy.

Numerous studies have explored the relationships between maternal dyslipidemia, pre-eclampsia and GDM. In observational studies and larger population cohort studies in women normal prior to pregnancy, increasing maternal triglycerides in early pregnancy is associated with increased rates of pre-eclampsia29,30 and GDM31,32. Enquobahrie et. al33 followed a cohort of women from early pregnancy onward and found that women who developed pre-eclampsia had significantly higher concentrations of LDL-C, TG, and LDL/HDL ratios as early as 13 weeks of gestation compared to women who remained normotensive. They also found that HDL-C was 7.0% lower in pre-eclamptic women than the control group. Furthermore, they noted a 3.6-fold increase in risk for pre-eclampsia in women with total cholesterol >205 mg/dL, compared to women whose total cholesterol levels were <172 mg/dL, even after adjusting for confounders. These studies and others34-37, indicate that dyslipidemia, particularly hypertriglyceridemia, precedes the clinical recognition of this relatively common complication of pregnancy.

Lipid abnormalities in pregnancies complicated by diabetes are associated with poorer health outcomes for both mom and baby38. Maternal hyperlipidemia early in pregnancy is independently associated with an increased rate of GDM31,32, but women with pre-gestational and GDM have an increased risk of developing preeclampsia than women with a normal pregnancy. This relationship is partially due to glycemic control and its impact on endothelial function. There also appears to be a role for lipids. In a cohort of women with type I DM, early LDL-C was elevated in those who later developed preeclampsia39. Given the intertwining associations between maternal hyperlipidemia, preeclampsia and GDM, there is a suggestion that this is a form of pregnancy metabolic syndrome, marked by the same characteristics as metabolic syndrome outside of pregnancy. It is thought that the dyslipidemia, while individually asymptomatic, might be an early sign that metabolic syndrome could be developing40. Gestational metabolic syndrome has clear implications for maternal vascular health, but also presents a multitude of health concerns for the fetus and the mom again both short term and long term.

Developmental Programming

The in utero period is a time of dynamic growth, when the fetus is sensitive to external factors. A large body of literature indicates that the in utero environment influences susceptibility to chronic diseases later in life, a concept known as “developmental programming.” Genetic, metabolic and environmental factors surrounding maternal and paternal lifestyles are all potential contributors to fetal developmental programming. Hypercholesterolemia is a well-known risk factor for development of atherosclerosis, which typically manifests clinically in adult life. However, accruing evidence indicates that atherosclerosis may begin in utero.

The first indication that maternal lipid status may program adult cardiovascular disease came from observations that maternal hypercholesterolemia, even when temporary and limited to only pregnancy, is associated with a marked increase in size of fatty streaks in the human fetal aortas41. Given that term-born children had low cholesterol levels even in the presence of maternal hypercholesterolemia, it was thought that these fetal lesions would regress over time. However, the Fate of Early Lesions in Children (FELIC) study assessed the progression of atherosclerosis in normocholesterolemic children and showed that maternal hypercholesterolemia was associated with increased atherogenesis throughout childhood42. Furthermore, the progression of atherosclerosis is much faster in children of hypercholesterolemic mothers than in children of normocholesterolemic mothers43.

Much of the work exploring the effect of the uterine environment on fetal programming has been done in animal models. Frantz et al. showed that in offspring of rabbits fed hypercholesterolemic diets, there is an increased amount of collagen in the abdominal aorta and coronary arteries as compared to offspring of mothers fed normal diets, a finding that was directly correlated to increased maternal plasma levels of lipoproteins. There were also concentrations of collagen found in the placentas of hypercholesterolemic mothers44. Further evidence showed that rabbit offspring of hypercholesterolemic mothers had 1.5 to 3 fold larger aortic lesions than offspring of mothers of normocholesterolemic mothers at birth, 6 months and 12 months. This was even with all offspring being fed mildly hypercholesterolemic diets, indicating that the developmental programming that occurs in utero may initiate a cascade of pathogenic events ending in atherosclerosis, even with adjustments of modifiable risk factors after birth43.

Several theories have been proposed as to how maternal hypercholesterolemia pathogenically affects fetal risk for atherosclerosis. Murine models indicate that permanent changes in DNA methylation, chromatin modification, or both, may be responsible for epigenetic programming of increased atherosclerotic susceptibility45-47. For example, maternal hypercholesterolemic in Apo-E deficient mice leads to activation of genes involved in cholesterol synthesis and LDLR activity in adult offspring42,48. There is early evidence that maternal hypercholesterolemia may reprogram the set point for cholesterol homeostasis in the liver of offspring49. There is evidence in the mouse model that because of excessive fat and sugar in the diet ovarian genetic changes occur throughout generations.

Another theory is that decreased antioxidant capacity impacts atherosclerosis risk. Leiva et al50 showed that maternal supra-physiological hyperlipidemia was associated with umbilical vein endothelial dysfunction by reducing endothelium-derived NO-dependent dilation of the umbilical veins. Increased intake of certain long chain fatty acids may enhance lipid peroxidation, leading to reduced antioxidant capacity51. Eventually, maternal hyperlipidemia creates an abnormal feto-placental vascular response52. This theory is supported by studies demonstrating that antioxidant therapies have reduced atherosclerosis in animal models by up to 39%43,52.

Our understanding of the mechanisms underlying the effects of maternal dyslipidemia on fetal outcomes and risk for atherosclerosis is incomplete and needs further research.

MONITORING FOR HYPERLIPIDEMIA

Maternal hyperlipidemia has for the most part been considered physiological and is not routinely screened for in pregnancy. Reference ranges for lipids in pregnancy are not universally understood or reported. While maternal hypertriglyceridemia in pregnancy has a clear impact on adverse pregnancy outcomes, there is evidence that pre-conception maternal dyslipidemia is correlated with adverse pregnancy outcomes. Because of this, the ideal time to screen for and treat maternal dyslipidemia is before conception. Yet, since many women are not seen before they become pregnant, we should not ignore the importance of controlling dyslipidemia during pregnancy given the implications for mother and fetus in both the short and long term.

When a woman has not been screened before pregnancy for dyslipidemia, the National Lipid Association (NLA) recommends obtaining these at her first obstetrical visit. The values should be followed throughout pregnancy if they are initially abnormal, and should be re-evaluated by 6 weeks post-partum. Given that dyslipidemia is often seen in concert with other metabolic disorders, such as diabetes and hypertensive disorders, it is not unreasonable to screen early for both of these conditions in women who have abnormal lipid panels53.

TREATMENT OF HYPERLIPIDEMIA

The treatment of dyslipidemia in pregnancy is multifactorial. Appropriate diet, alongside exercise and weight management continues to be the mainstay of therapy. The medical management of dyslipidemia in pregnancy has always been complicated by the FDA classifications for medication risks to the fetus. For women who are on lipid-lowering agents before pregnancy, it has been recommended to stop agents before becoming pregnant or as soon as a patient finds out she is pregnant.

Hypercholesterolemia

Hypercholesterolemia, due to familial hypercholesterolemia, polygenic hypercholesterolemia, or other disorders, is relatively common in women of childbearing age. Therefore, a significant number of women will be on therapy for elevated cholesterol levels prior to pregnancy. Statins, which are the mainstay of treatment for elevated cholesterol levels, were labeled as category X. This was before the FDA mandated new labeling changes, which give more guidance to the clinician when determining medical management in pregnant, lactating or reproductive aged women53. Two systematic reviews have evaluated current literature to date. Karalis et al and Kusters et al both found no evidence that statins cause congenital anomalies independent of concomitant medical conditions associated with their use54,55. Recently pravastatin has been used in the mid trimester to successfully reduce preeclampsia in persons with a prior history of preeclampsia56. Given the FDA changes, the use of statins to keep LDL levels in the normal ranges during pregnancy is not prohibited. Lipid soluble statins are theoretically more likely to be associated with fetal risk mechanistically and therefore some have encouraged water soluble statins as the preferred drugs. However, definitive data are lacking. Thus, the clinician after discussion with the patient, can weigh the risks and benefits of statin therapy and thereby decide on whether to continue statin therapy. An alternative to statins are bile acid sequestrants. These drugs are not absorbed and have a safe track record. Bile acid sequestrants can cause GI symptoms, inhibit the absorption of certain drugs, and in some patients induce an increase in plasma triglyceride levels. We have little other than anecdotal case reports for the use of ezetimibe and PCSK9 inhibitors given to pregnant women. In patients with homozygous familial hypercholesterolemia or severe heterozygous familial hypercholesterolemia lipoprotein apheresis has been employed to lower LDL cholesterol levels55. PCSK9 inhibitors were not labeled as prohibited in pregnancy. In future these agents may have theoretical benefits. Because no randomized clinical trial data exists about the use of any lipid lowering agents (except for pravastatin for patients with prior pre-eclampsia) all women who lipid lowering agents are encouraged to join a registry. The FDA has directed manufacturers of PCSK9 inhibitors to encourage any pregnant patient taking one of these agents to enroll in a registry so they can be followed to better inform safety.

Hypertriglyceridemia

Marked hypertriglyceridemia is a cause of pancreatitis in pregnant women and usually occurs in women with familial chylomicronemia syndromes, other genetic disorders of triglyceride metabolism, or other disease states that increase plasma triglyceride levels such as diabetes or after medications that can precipitate it in persons at risk. The hypertriglyceridemia can be exaggerated by the normal alterations in lipid metabolism that occur during pregnancy and therefore increasing the risk of marked elevations in triglyceride levels leading to pancreatitis. Lifestyle changes such as a low fat diet, avoidance of simple sugars, avoidance of excessive glucocorticoids or retinoic acid (contraindicated in pregnancy) , avoidance of alcohol , increased exercise, and weight loss can be all very beneficial in avoiding severe hypertriglyceridemia. In patients with diabetes, glycemic control is crucial. If hypertriglyceridemia is severe, the use of medium chain triglyceride therapy can be helpful in treating pancreatitis associated with hypertrigyceridemia. The use of fibrates, omega 3 fatty acids, and niacin can be considered in patients with marked elevations in triglycerides who are at high risk of pancreatitis. At times parenteral nutrition or hospitalization to limit fat intake is needed. In patients unresponsive to therapy or with severe pancreatitis with markedly elevated triglyceride levels therapeutic plasma exchange may be required to lower triglyceride levels57-59.

SUMMARY

Because of the evolution of increasing levels of cholesterol and triglycerides during pregnancy in normal and abnormal pregnancies, individualized risk benefit decisions are made on whether to provide a lipid lowering agent. It is useful to know that the potential for congenital anomaly risk is lower after the first trimester of pregnancy. Certainly use of a statin in a patient who becomes pregnant is not an indication for termination of her pregnancy because of potential risk.

In animal studies, vitamin E and cholestyramine treatment of hypercholesterolemic mothers reduces aortic lesions in offspring, compared to untreated hypercholesterolemic mothers37, 39. The concept of protecting the infant through maternal control of dyslipidemia is a relatively new concept in need of more investigation. Because many are needlessly fearful of studying this question investigations are limited and need to be expanded.

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