ABSTRACT

Lipoprotein lipid physiology in pregnancy has important implications for the developing fetus and newborn as well as the mother. Cholesterol and essential fatty acids are essential for normal fetal development. 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. In a normal pregnancy, total cholesterol levels increase by approximately 50%, LDL-C by 30-40%, HDL-C by 25%, and triglycerides by 2- to 3-fold. 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. In certain instances, plasmapheresis or lipoprotein apheresis can be employed. For complete coverage of all related areas of Endocrinology, please visit our on-line FREE web-text, WWW.ENDOTEXT.ORG.

INTRODUCTION

Lipoprotein lipid physiology before and during pregnancy has important implications for the mother, the developing fetus, the newborn, and their future health. Cholesterol is important for normal fetal development. It is provided to the fetus via both endogenous and exogenous mechanisms. As our understanding of normal and abnormal lipid metabolism in pregnancy improves, it is clear that abnormal lipid metabolism reflected as dyslipidemia is associated with adverse perinatal outcomes. Dyslipidemia has profound associations with other pathologies in pregnancy, most notably hypertensive disorders and gestational diabetes. There is accumulating evidence of the impact of hyperlipidemia in pregnancy on the epigenetic programming of a fetus and the subsequent risk for atherogenesis for the mother and her offspring.

CHOLESTEROL AND OTHER LIPIDS IN FETAL DEVELOPMENT

Cholesterol plays a key role in the formation of cell membranes. It is essential for the formation of cell membranes, maintaining membrane integrity, and preserving cholesterol-rich domains essential for most membrane-associated signaling cascades, including sonic hedgehog signaling (1). It is also the precursor for 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 defects (2,3). 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 humans (4,5). Interestingly, Vuorio and colleagues noted that concentrations of plant stanols in the cord blood of healthy newborns were 40% to 50% lower than the maternal levels (6). Because the plant stanols evaluated can only be derived from the maternal diet, placental transfer is illustrated. Fetuses with null-null mutations of 7-dehydrocholesterol reductase (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 derivation (7,8). The umbilical vein, which carries blood to the fetus, has higher levels of LDL-C than the umbilical artery (9).

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 the transport system between the two (10). Approaching 8 weeks of gestation, the placenta becomes fully functional and takes over as the nutrient transporter (10). The transfer of lipids across the placenta and yolk sac under normal and abnormal circumstances is complex and is still incompletely understood. Cholesterol is taken up on trophoblasts’ apical or maternal side via receptor-mediated and receptor-independent transport processes. Apolipoprotein lipids are then transported across cellular barriers and delivered into the fetal circulation on the basolateral, or fetal, side of trophoblasts (4,10,11). Cultured trophoblast cells express low-density lipoprotein (LDL) receptors (LDLRs), and LDLR-cholesterol taken up by endothelial cells is well understood. How placental endothelial cells transport and deliver substantial amounts of cholesterol to the fetal microcirculation and regulate the efflux of cholesterol is undergoing intense study.

As opposed to adults, high-density lipoprotein (HDL) is the main cholesterol-carrying lipoprotein in fetal circulation. It differs from adult HDL by its higher proportion of apolipoprotein (Apo) E (12), but lower proportion of Apo A1 (13). The major HDL receptor, scavenger receptor class B type I (SR-BI), contributes to local cholesterol homeostasis. Arterial endothelial cells (ECA) from the human placenta are enriched with cholesterol compared to venous endothelial cells (ECV). Moreover, umbilical venous and arterial plasma cholesterol levels differ markedly. There is elevated SR-BI expression and protein abundance in endothelial cell arteries compared to veins in situ and in vitro. Immunohistochemistry demonstrated that SR-BI is mainly expressed on the apical side of placental endothelial cells in situ, allowing interaction with mature HDL circulating in the fetal blood (14). This was functionally linked to a higher increase of selective cholesterol ester uptake from fetal HDL in endothelial arteries than in endothelial veins and resulted in increased cholesterol availability in ECA. SR-BI expression on endothelial veins tended to decrease with shear stress, which, together with heterogeneous immunostaining, suggests that SR-BI expression is locally regulated in the placental vasculature (15).

Changes in maternal vasculature enable an increased uterine blood flow, placental nutrient, and oxygen exchange, and subsequent fetal development. Potassium (K+) channels seem to be important modulators of vascular function, promoting vasodilation, inducing cell proliferation, and regulating cell signaling (16). Different types of K(+) channels, such as Ca(2+)-activated, ATP-sensitive, and voltage-gated, have been implicated in the adaptation of maternal vasculature during pregnancy. Conversely, K(+) channel dysfunction has been associated with vascular-related complications of pregnancy, including intrauterine growth restriction and pre-eclampsia. It is thought that vascular ischemia may lead to inflammation important in pregnancy complications. Abnormalities in these pregnancy-associated vascular dilation and remodeling processes are associated with the pregnancy complications of intrauterine growth restriction (IUGR) and pre-eclampsia, in which, the normal vasodilatory effects of acetylcholine (ACh), bradykinin, Nitric oxide (NO), endothelium-derived hyperpolarizing factor (EDHF), and thromboxane-mediated responses are impaired (16).

Placental lipid metabolism may influence pregnancy outcomes, fetal growth, development, and life-long health (17). The placenta converts circulating maternal lipids to free fatty acids (FFAs) for uptake and processing by trophoblast cells, for metabolic demands, to produce hormones for pregnancy maintenance, and to transfer them to the developing fetus. Robust lipid uptake and metabolism early in gestation are vital to meeting the high energetic demands needed to simultaneously grow the placenta and develop embryonic organ systems. Late in gestation the human fetus requires lipids for neurodevelopment and growth, so as pregnancy progresses, metabolic adaptations in the mother and placenta uniquely support increasing lipid transport and biomagnification of essential long-chain polyunsaturated fatty acids in the last trimester (18). These fatty acids serve as local mediators of metabolism, inflammation, immune function, platelet aggregation, signal transduction, neurotransmission, and neurogenesis for the developing fetal brain and retina (19). Because these fatty acids cannot be synthesized de novo, the fetus relies on increasing placental transport, especially during the last trimester when the peak in utero accretion can surpass maternal intake to support rapid fetal brain growth. Placental lipid uptake and metabolism is a critical, highly-regulated, and surprisingly dynamic process as gestation proceeds.

Lipids are crucial structural and bioactive components that sustain embryo, fetal, and placental development, and growth. Intrauterine development can be disturbed by several diseases that impair maternal lipid homeostasis and lead to abnormal lipid concentrations in fetal circulation. Deficiency in essential fatty acids can lead to congenital malformations and visual and cognitive problems in the newborn. Either deficient mother-to-fetus lipid transfer or abnormal maternal-fetal lipid metabolism can cause fetal growth restriction. On the other hand, excessive mother-to-fetus fatty acid transfer can induce fetal overgrowth and lipid overaccumulation in different fetal organs and tissues. The placenta plays a fundamental role in the transfer of lipid moieties to the fetal compartment and is affected by maternal diseases associated with impaired lipid homeostasis. Studies investigating the relationship between gestational dyslipidemia and small for gestational age (SGA) have reported differing results. A recent meta-analysis found that gestations complicated with lower concentrations of TC, TG, and LDL-C, were at significantly higher risk of delivery of SGA (20). Postnatal consequences may be evident in the neonatal period or later in life. Indeed, both defects and excess of different lipid species can lead to the intrauterine programming of metabolic and cardiovascular diseases in the offspring (21)

NORMAL LIPID CHANGES IN A PREGNANT MOTHER

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 from measurements in a cohort of women proceeding through normal pregnancy and delivery in the U.S. Circulating levels may differ depending upon the nutritional environment. It is reported that most lipoprotein concentrations increase throughout pregnancy in Gambian women for example yet are lower vs. U.S. women, the exception being medium-sized LDL and HDL particle concentrations which decrease during gestation and are similar in both cohorts (22). In a careful evaluation of normal pregnant women in Oklahoma traversing through pregnancy and delivering normal viable infants, we found that non-HDL particles, very small highly atherogenic LDL particles (small dense LDL), and total and active pcsk9 levels increase as pregnancies progress (23). BMI, an indicator of obesity, was associated with higher levels of atherogenic lipoproteins during each trimester. Most of the women in the Wiznitzer and Wild cohorts were of young reproductive age at the time of sampling and thus their values overlap values before pregnancy and are considered in the normal range for a nonpregnant woman. In the first trimester, there is a discernible decrease in levels during the first 6 weeks of pregnancy. As pregnancy progresses, there is a noticeable increase by the third month or at the end of the first trimester. There is a steady increase throughout pregnancy. By the third trimester or near the end of pregnancy (term), levels peak (24,25). Levels of lipoprotein particles and lipids, particularly in the later part of pregnancy, are in the atherogenic range when compared to non-pregnant levels in women of comparable ages without medical conditions. After delivery, lipid and lipoprotein levels rapidly return to normal. The changes in lipid metabolism throughout pregnancy allow for proper nutrients for the fetus and the normal, steady increase throughout pregnancy is associated with increased insulin resistance in the mother. Regardless of dietary differences in cholesterol, by late pregnancy, plasma cholesterol levels are approximately 50% higher than routinely seen pre-pregnancy while triglyceride levels are increased 2-3 times (see figure 1 and table 1) (25). These changes can be viewed as important for the enhanced availability of substrates for the fetus (26,27). However, derangements in lipids are associated with adverse pregnancy outcomes and likely are associated with residual vascular damage after some key obstetrical adverse events which may put the mother at risk for later cardiovascular disease.

Figure 1.

Lipid 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;).

For understanding clinical management including healthy targets, maximum plasma cholesterol values usually do not exceed 250 mg/dL during normal pregnancy, even with the marked increases in triglyceride levels that occur normally as pregnancy progresses. If abnormal pregnancies are included in cross-sectional evaluations, cholesterol levels are commonly 300 mg/dL or higher. Higher levels are consistent with a variety of maternal adverse pregnancy conditions. In normal pregnant women, the atherogenic index, LDL/HDL, remains essentially unchanged during pregnancy. This suggests that while the total lipoprotein levels increase, the cholesterol-containing lipoprotein fractions are evenly distributed (28). 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 triglycerides (29). There is an increase in large HDL late in gestation and a decrease in medium HDL (30).

Small dense LDL levels increase during pregnancy, particularly in individuals who have a large increase in triglyceride levels (32,33). As one would expect given the increase in triglycerides, LDL-C, and HDL-C, apolipoprotein B, and A-I levels are also increased (table 1). In most cross-sectional studies Lp(a) levels are not elevated in pregnancy (33-35). However, in some studies that measured Lp(a) serially throughout pregnancy an increase in Lp(a) levels was observed near term (table 1) (31,36,37) (23). The failure of cross-sectional studies to find a difference in Lp(a) levels is likely due to the wide variation in Lp(a) levels between individuals. Values in individuals range from 1mg/dL to over 200mg/dL and are largely determined by genetic factors.

MECHANISMS ACCOUNTING FOR THE CHANGES IN LIPIDS DURING PREGNANCY

Multiple physiological changes occur during pregnancy (27,38). 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 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 increased uptake of fatty acids from circulating triglyceride-rich lipoproteins. Additionally, the increased production of progesterone, cortisol, leptin, and prolactin contributes to increased fat storage (24,26,27,38). There is also significant hypertrophy of the adipocytes to accommodate increased fat storage (26,27,38).

Lipid metabolism in the third trimester is in a ‘net catabolic phase’, associated with a decrease in insulin sensitivity (i.e., insulin resistance) (27,38). This decrease in insulin sensitivity is associated with enhanced 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 during pregnancy is due to both the increased production and the decreased clearance of triglyceride-rich lipoproteins (27). The increased production of triglyceride-rich lipoproteins by the liver is due to the increased lipolysis of triglycerides that occurs in adipocytes, which increases free fatty acids transported to the liver. These free fatty acids are then packaged into VLDL and secreted by the liver. The high estrogen levels in the third trimester stimulate liver lipogenesis and VLDL production. Insulin resistance may also play a role in the increase in fatty acid synthesis in the liver as inhibition of glucose production can be resistant to insulin while lipogenesis is not. The increase in insulin levels that occur can stimulate hepatic fatty acid synthesis as shown in a mouse model (39). The decrease in clearance of triglyceride-rich lipoproteins is due to a decrease in lipoprotein lipase and hepatic lipase (29). The decrease in hepatic lipase is due to elevated estrogen levels (40). The decrease in lipoprotein lipase is believed to be 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 activity (29) 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 lactation (26). The increase in plasma cholesterol levels is likely due to increased hepatic cholesterol synthesis (41,42). The increase in PCSK9 during pregnancy suggests an additional mechanism. The PCSK9 could result in a decrease in hepatic LDL receptors leading to increased LDL-C levels (23).

IMPLICATIONS FOR THE FETUS AND MOTHER

Our understanding and appreciations of the full scope and implications of dyslipidemia in pregnancy on both maternal and fetal outcomes are not complete. Maternal dyslipidemia, particularly, high triglyceride and low HDL-C levels, are associated with several adverse perinatal outcomes. To demonstrate that lipid abnormalities are causative, intervention studies to lower lipid levels demonstrating a reduction in adverse perinatal outcomes are needed. This is difficult because the study of pregnant women is protected, underfunded, and understudied, in part because of medical legal concerns and the first rule of do no harm.

Dyslipidemia, while asymptomatic, is an integral factor in the metabolic syndrome (MetS). Having the MetS has clear implications for maternal vascular health, and this portends a multitude of other health concerns for the mom and her fetus.

LIPID SCREENING

The National Lipid Association (NLA) supports checking lipids routinely if there is no normal current pre-pregnancy lipid profile (78). Screening for reproductive-aged women, in general, remains deficient in part due to disparities in health services (79). Identifying pregnant women with prior atherosclerotic cardiovascular disease (ASCVD), familial hypercholesterolemia, or hypertriglyceridemia is important to allow for multi-disciplinary collaborative care. Increased knowledge and awareness are needed at both the patient and provider levels. In a survey study of 200 pregnant women within the University of Pennsylvania Health System, 59% self-reported previous lipid screening; non- Hispanic Black women were less likely to report screening (43% vs. 67%) and they had lower awareness of high cholesterol as a risk factor for ASCVD (66% vs 92%) (80). The perinatal period, when a woman sees a physician most regularly, is an opportunity to screen for lipid disorders and facilitate prevention by bringing lipid values to normal age specific target ranges. Hypertensive disorders of pregnancy are among the leading causes of maternal morbidity and mortality in the US. Pre-eclampsia, which includes hypertension and proteinuria during pregnancy, is thought to result from placental ischemia. Risk factors for pre-eclampsia parallel those for cardiovascular disease and recent studies point to hyperlipidemia, specifically hypertriglyceridemia. Current practice does not routinely include lipid testing pre-conception or during pregnancy. Professional and societal recommendations should advocate for hyperlipidemia screening, followed by appropriate management, pre-conception, and during pregnancy as an important evaluation for risk of preeclampsia during pregnancy (48).

A recent review recommended measuring lipids at the first visit and if normal at the beginning of third trimester (81). High risk patients should have lipids measured at first visit, beginning of second trimester, and monthly during the 3rd trimester. If triglyceride levels are greater than 250mg/dl at any time the lipid panel should be measured monthly. When and if more specialized lipid testing such as NMR or ion mobility to measure small dense LDL levels, apo B and apo A1 levels, and Lp(a) levels is needed is not defined and further studies are required. Measuring Lp(a) levels at the first visit is reasonable in patients who have not had their Lp(a) levels determined previously. If lipid abnormalities are noted during pregnancy follow-up lipid panels post-pregnancy should be obtained.

TREATMENT OF DYSLIPIDEMIA DURING PREGNANCY

MANAGEMENT OF PREGNANT WOMEN WITH PRE-EXISTING LIPID ABNORMALITIES

Patients with the following disorders are best managed using a team approach that includes a lipid and maternal-fetal specialist. Persons with these disorders should be provided with genetic counseling in addition to multi-specialty team management and pregnancy offers an important opportunity to address the impact in families and how to recognize, prevent, and treat these disorders.

CONSIDERATIONS FOR BREASTFEEDING

The postpartum period is a critical time requiring proactive counseling and shared decision-making regarding plans for lactation. Enabling women to breastfeed is a public health priority because, on a population level, interruption of lactation is associated with adverse health outcomes for the woman and her child, including higher maternal risks of breast cancer, ovarian cancer, diabetes, hypertension, and heart disease, and greater infant risks of infectious disease, sudden infant death syndrome, and metabolic disease. Contraindications to breastfeeding are few. Most medications and vaccinations are safe for use during breastfeeding, with few exceptions. Breastfeeding confers medical, economic, societal, and environmental advantages; however, each woman is uniquely qualified to make an informed decision surrounding infant feeding.

Risks vs. benefits need to be considered to determine the optimal management of lipid disorders, as all lipid-lowering medications are contraindicated during pregnancy and remain contraindicated during breastfeeding. Breastfeeding has enormous benefits and is encouraged. Medications taken by the mother can transfer into breast milk through passive diffusion or active transport by membrane proteins and therefore expose the baby to the medication. Therefore, continuing breastfeeding given its benefits in metabolic health needs to be balanced with stopping breastfeeding to resume lipid-lowering therapies and the progression of atherosclerosis (112). Shared decision-making and discussions of risks and benefits of both time without statin treatment and breastfeeding vs. treatment during pregnancy and lactation are best initiated before delivery and every visit in the fourth-trimester period (after delivery) (113,114). The LactMed database (National Institute of Child Health and Development) contains information on drugs and other chemicals to which breastfeeding mothers may be exposed. It includes information on the levels of such substances in breast milk and infant blood and the possible adverse effects in the nursing infant. Suggested therapeutic alternatives to those drugs are provided, where appropriate. All data are derived from the scientific literature and fully referenced. A peer review panel reviews the data to assure scientific validity and currency. The consensus opinion is that women taking a statin should not breastfeed because of a concern with disruption of infant lipid metabolism. However, others have argued that children homozygous for familial hypercholesterolemia are treated with statins beginning at 1 year of age, that statins have low oral bioavailability, and that risks to the breastfed infant are low, especially with pravastatin and rosuvastatin.

In a recent systematic review of 33 articles from 15 randomized controlled trials limited evidence suggests that omega-3 fatty acid supplementation during pregnancy may result in favorable cognitive development in the child. There was insufficient evidence to evaluate the effects of omega-3 fatty acid supplementation during pregnancy and/or lactation on other developmental outcomes (115).

CONCLUSION

There is an increase in lipid levels in normal gestation. Dyslipidemia in pregnancy beyond physiologic levels is associated with adverse pregnancy outcomes. Adverse pregnancy events enhance the risk of clinical ASCVD events in later life. Screening for and adequately addressing atherogenic dyslipidemia before and during pregnancy is a priority. Major barriers to the management of hyperlipidemia during pregnancy and the postpartum period include limited studies in pregnant patients. Many therapeutic agents are categorized as contraindicated without adequate evidence. Future research is needed to allow for evidence-based decisions to guide therapeutic options. Pregnancy is a unique opportunity for multidisciplinary and collaborative care across various specialties to improve rates of screening and optimize the long-term cardiovascular health of women. Many women are overwhelmed post-partum. They need to be encouraged to prioritize ASCVD risk reduction as integral to their care. Improving access to quality preventive care is still in need of improvement.

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