Triglyceride metabolism in pregnancy

ADVANCES IN CLINICAL CHEMISTRY, VOL. 55

TRIGLYCERIDE METABOLISM IN PREGNANCY Alessandra Ghio,*,1 Alessandra Bertolotto,* Veronica Resi,* Laura Volpe* and Graziano Di Cianni† *Department of Endocrinology and Metabolism, Section of Metabolic Diseases and Diabetes, AOUP, University of Pisa, Pisa, Italy † Diabetology Department, Livorno Hospital, Livorno, Italy

1. Abstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2. Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3. Maternal Lipid Metabolism During Pregnancy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1. Changes in Maternal Lipid Metabolism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2. Maternal Hyperlipidemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3. Placental Transfer of Lipids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.4. How Maternal Hypertriglyceridemia May Benefit the Fetus and the Newborn . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4. Lipid Metabolism and Maternal Pregnancy Complications . . . . . . . . . . . . . . . . . . . . . . 4.1. Gestational Diabetes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2. Preeclampsia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5. Maternal Hypertriglyceridemia and Fetal Complications . . . . . . . . . . . . . . . . . . . . . . . . 5.1. Macrosomia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.2. Preterm Birth. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6. Changes in Lipids During Pregnancy and Risk of Cardiovascular Disease . . . . . . . 7. Hypertriglyceridemia During Pregnancy: Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.1. Lifestyle . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.2. n-3 Fatty Acids Supplementation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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Corresponding author: Alessandra Ghio, e-mail: [email protected] 133

0065-2423/11 $35.00 DOI: 10.1016/B978-0-12-387042-1.00007-1

Copyright 2011, Elsevier Inc. All rights reserved.

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1. Abstract During pregnancy, complex changes occur in lipid profiles. From the 12th week of gestation, phospholipids, cholesterol (total, LDL, HDL), and triglycerides (TG) increase in response to estrogen stimulation and insulin resistance. Transition to a catabolic state favors maternal tissue lipid use as energy sources, thus sparing glucose and amino acids for the fetus. In addition, maternal lipids, that is, cholesterol, are available for fetal use in building cell membranes and as precursor of bile acids and steroid hormones. It is also required for cell proliferation and development of the growing body. Free-fatty acids (FFA), oxidized in the maternal liver as ketone-bodies, represent an alternative fuel for the fetus. Maternal hypertriglyceridemia (vs. other lipids) has many positive effects such as contributing to fetal growth and development and serving as an energy depot for maternal dietary fatty acids. However, increased TG during pregnancy appears to increase risk of preeclampsia and preterm birth. Some have suggested that maternal hypertriglyceridemia has a role in increasing cardiovascular risk later in life. This chapter reviews lipid metabolism during pregnancy to elucidate its effect on fetal growth and its potential role in pregnancy-associated complications and future cardiovascular risk. 2. Introduction Pregnancy is characterized by complex changes in glucose, protein, and lipid metabolism. Interestingly, lipid metabolism is especially affected during pregnancy, despite the fact that maternal lipids cross to the placenta with difficulty [1,2]. The transition from anabolic to catabolic states promotes lipid use as energy sources in maternal tissues, thus sparing other fuels such as glucose and amino acids for fetal use. The influence of maternal lipid metabolism on fetal growth and complications of pregnancy generates considerable debate. For example, it remains unclear if these changes in lipid metabolism are, in fact, exclusive of pregnancy and potentially reflect a role in future development of cardiovascular disease [3]. This chapter will review lipid metabolism during normal pregnancy and evaluate its association with maternal–fetal complications. The role of lifestyle and use of therapeutic intervention to reduce triglycerides (TG) during pregnancy will be addressed. 3. Maternal Lipid Metabolism During Pregnancy 3.1. CHANGES IN MATERNAL LIPID METABOLISM During pregnancy, metabolic changes in the liver and adipose tissue alter circulating TG, fatty acid, cholesterol, and phospholipids. Despite an initial reduction, plasma lipids increase following the first 8 weeks of pregnancy.

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Increased insulin resistance and estrogen stimulation during pregnancy are responsible for this state of maternal hyperlipidemia [4]. Hyperphagia [5] and increased lipid synthesis [6] contribute to maternal fat accumulation typically associated with the first two-thirds of gestation. In the last third of gestation [7,8], however, fat storage declines or ceases as a consequence of enhanced lipolytic activity and decreased lipoprotein lipase (LPL) activity in adipose tissue (Fig. 1). TG are enzymatically hydrolyzed by LPL in circulating TG-rich lipoprotein particles. Products of this hydrolysis (fatty acids and glycerol), thus, become available for uptake in adjacent tissues. LPL is located in the capillary endothelium of extrahepatic tissues. LPL activity decreases during the third trimester of gestation, thereby reducing uptake of circulating TG into adipose tissue [9]. This transition to a catabolic state favors maternal use of lipids as an energy source and spares glucose and amino acids for the fetus (Fig. 2). In the last trimester, increased adipose tissue lipolysis results in substantial release of FFA and glycerol into the circulation [10,11]. Because placental transfer of these products is poor [12], their primary destination is the maternal liver where they are converted to their active forms, that is, acylCoA and glycerol-3-phosphate, respectively. Following reesterification for synthesis of TG, they are subsequently released via VLDL into the circulation. Under fasting conditions, glycerol may also be used for glucose synthesis, whereas FFA is used for b-oxidation, thus producing acetyl-CoA leading to energy production and ketone body synthesis. Both pathways, gluconeogenesis and ketogenesis, are significantly increased in late pregnancy [13,14].

Early pregnancy

Maternal fat accumulation –Hyperfagia –Increased lipid synthesis

Nourishing elements crossing the placenta

Fetal metabolism

Late pregnancy

Enhanced adipose tissue lipolytic activity Decreased LPL activity

Fetal growth

FIG. 1. Maternal metabolic changes to ensure fetal growth. During early pregnancy, maternal hyperphagia and increased lipids synthesis cause an accumulation of fat stores. In the third trimester, the mother switches to a catabolic condition resulting in an increased breakdown of lipid. All these changes ensure fetal growth [1,2].

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Adipose tissue Insulin resistance ¯LPL Mammary glands

FFA Glycerol

VLDL Liver Glucose Ketone bodies

FFA

Muscle Fetus AA

FIG. 2. Maternal metabolic changes in late pregnancy. LPL activity decreases during the third trimester of gestation, reducing the adipose tissue uptake of circulating TG [8]. FFA and glycerol are used by the liver to synthesize VLDL, glucose, and ketone bodies which should be used by the fetus as fuels. In late pregnancy, VLDL is used by mammary glands to synthesize milk. LPL, lipoprotein lipase enzyme; FFA, free fatty acids; AA, amino acids.

Under fasting conditions, increased glycerol release and its rapid conversion to glucose may benefit the fetus [15]. Although the fetus is unable to synthesize ketone bodies, these compounds easily cross the placenta via simple diffusion [1]. As such, ketone bodies in the fetus mimic maternal levels. During fasting, the increased maternal ketogenesis may benefit the fetus. Ketone bodies may be used by the fetus as oxidative fuels and as substrates for brain lipid synthesis [16]. Use of ketone bodies by maternal tissues provides additional glucose for essential fetal functions (Fig. 2). Rapid activation of ketogenesis in fasting pregnant women and the ability of ketone bodies to freely cross the placenta may cause serious fetal complications. For example, large surveys have shown an association between maternal ketonemia and reduction of intelligence quotient (IQ) in children at 3 and 5 years of age [17]. During late pregnancy, insulin resistance contributes to increased maternal fat breakdown, gluconeogenesis, and ketogenesis under fasting conditions. Insulin action is well known. It increases adipose tissue LPL activity and decreases hormone sensitive lipase (HSL) action, an enzyme with lipolytic activity. In addition, insulin inhibits hepatic gluconeogenesis and ketogenesis. Women with gestational diabetes (GDM) have peripheral insulin resistance, thus causing increased blood nonessential fatty acids (NEFA) and ketone bodies concentrations [18,19].

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3.2. MATERNAL HYPERLIPIDEMIA During late gestation, the maternal catabolic condition causes hyperlipidemia consisting of increased TG, phospholipids and cholesterol. Increased lipids are predominated by TG [20]. Cholesterol is used in the placenta to synthesize steroid hormones and precursor of bile acids. FFA is oxidized by the maternal liver. Both, however, are critical for fetal cellular membrane synthesis. Cholesterol is essential to maintain fluidity of cell membranes and FFA is required for phospholipid synthesis (Fig. 3) [21]. Increased estrogens cause an increase in HDL starting with the 12th gestational week, while increased total and LDL cholesterol such as VLDL and TG occur during the second and third trimesters. Increased VLDL is caused by:
enhanced liver production (sustained by increased estrogen) [22];
decreased circulatory removal due to decreased adipose tissue LPL activity (caused by insulin resistance and increased apo C-III, an inhibitor of LPL) [9,23];
increased intestinal absorption of dietary lipids [24]. TG are increased in VLDL. Interestingly, this property causes TG enrichment in HDL and LDL particles that typically have low TG content under nonpregnant conditions. Accelerated transfer of TG to lipoproteins of higher density is due to an increased length of exposure to cholesteryl ester transfer protein (CETP)

Endogenous and esogenous lipid sources

Cholesterol

Steroid hormones synthesis

Cells’ membranes synthesis

Free fatty acids

Cells’ membranes synthesis

Energy sources

FIG. 3. Cholesterol and FFA utilization in the fetus. Cholesterol is used in the placenta to synthesize steroid hormones while FFAs are oxidized; both are used to synthesize cellular membranes [20].

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activity. Decreased hepatic lipase (HL) activity contributes to the shift of HDL particles to larger more buoyant TG-rich HDL subclasses [23,25]. During late pregnancy, there is an incremental TG increase in the HDL2b and a TG reduction in cholesterol-rich HDL2a and HDL3 subfractions [23]. During gestation, TG-enriched LDL has reduced size and increased density (small and dense LDL) due to HL activity (Fig. 4). These peculiar changes in lipid profile, occurring in late pregnancy, may promote endothelial damage and subsequent atherogenesis. Small dense LDL particles are more susceptible to oxidation, demonstrate increased binding to vessel wall proteoglycans and have reduced uptake via the LDL receptor [26].

3.3. PLACENTAL TRANSFER OF LIPIDS 3.3.1. FFA and TG Transfer The fetus can synthesize lipids or use maternal lipids that cross the placenta. In early pregnancy, however, the fetus is unable to synthesize lipids. As such, essential fatty acids (EFA) and long-chain polyunsaturated fatty acids (LCPUFA) arrive via the maternal circulation. These

ØLPL

≠≠ TG-VLDL

TG

TG-VLDL

TG

CE

CE CETP

≠

TG-rich LDL ØHL

TG-rich HDL

ØHL Estrogens Insulin-resistance

Small and dense LDL

Large and buoyant HDL 2

FIG. 4. Development of an atherogenic profile during pregnancy. An accelerated transfer of TG to lipoproteins of higher density is caused by accumulation of TG in VLDL lipoproteins, reduced LPL activity, and increased time of exposure to the cholesteryl ester transfer protein (CETP) activity. A decrease in hepatic lipase (HL) activity contributes to generate larger, buoyant, and TG-rich HDL and small and dense LDL [22,24]. These peculiar changes may favor endothelial damage and activation of atherogenesis.

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components are crucial for fetal growth in general and specifically for brain and retina development. Similar to esterified FA, most LCPUFA in the maternal circulation are associated with plasma lipoproteins such as TG, phospholipids, and esterified cholesterol. Only a minor fraction is present as FFA [27]. Despite fetal need, maternal lipoproteins do not freely cross the placenta [12]. They can, however, interact with specific receptors (VLDL, LDL, HDL, scavenger-receptors, LDL receptor-related proteins) to allow placental uptake. The placenta does have lipase activity (LPL, phospholipase A2, intracellular lipase). Plasma membrane fatty acid-binding protein (FABP/GOT2), fatty acid translocase (FAT/CD36), fatty acid transport proteins (FATP), fatty acid-binding proteins (FABP), and placental plasma membrane fatty acidbinding protein (p-FABPpm) [12,28–30] facilitate fetal uptake of LCPUFAassociated lipoproteins and circulating nonesterified forms (FFA; Table 1). Although the exact process by which those receptors, enzymes, and FABP facilitate placental fatty acid transfer remains unclear, the mechanism appears to be very efficient [31]. Following maternal lipoprotein receptor binding, TG are hydrolyzed, taken up by the placenta and reesterified as fatty acid stores [32]. After intracellular hydrolysis of glycerides, FFA can diffuse into plasma via afetoprotein [33,34]. Upon reaching the fetal liver, they are reesterified and released back into circulation as TG. Fetal lipogenesis begins in the liver and adipose tissue at the pregnancy term [35,36]. In diabetic pregnancy, impaired maternal lipid metabolism affects the amount and type of lipids available to cross the placenta and reach the fetus. Data have shown a direct relationship between maternal TG during the third trimester and neonatal birth weight [37] in women with normal glucose tolerance and GDM. TABLE 1 MOLECULES ON THE PLACENTA SURFACE Receptors VLDL LDL LDL-related proteins HDL Scavenger

Lipase activity LPL Phospholipase A2 Intracellular lipase Plasma membrane fatty acid-binding protein (FABP/GOT2) Fatty acid translocase (FAT/CD 36) Fatty acid transport protein (FABP) Placental plasma membrane fatty acid-binding protein (p-FABPpm)

The placenta has a lot of receptors and lipase activities that allow lipid transport to the fetus.

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In women with GDM, increased TG appear related to significant risk for large-for-gestational-age (LGA) newborns [38]. Fasting TG concentration in the third trimester of pregnancy is considered a stronger predictor of birth weight than fasting glucose [38,39]. 3.3.2. Cholesterol Transfer Cholesterol needs are very high in the embryo and the fetus. In early pregnancy, the fetus is unable to synthesize cholesterol. Although most fetal cholesterol is derived endogenously at term, placental mechanisms of maternal transfer satisfy fetal cholesterol needs at early stages of pregnancy [12]. Impaired maternal cholesterol metabolism appears related to fetal diseases. Low maternal cholesterol concentration is associated with impaired neurological development [40] and low birth weight in term infants [41]. Increased maternal cholesterol is associated with increased risk of atherosclerotic disease development [42]. Recent data have shown a U-shaped relationship between maternal cholesterol concentration and preterm birth risk [43].

3.4. HOW MATERNAL HYPERTRIGLYCERIDEMIA MAY BENEFIT THE FETUS AND THE NEWBORN Increased maternal blood TG are a typical finding during pregnancy. Although TG do not directly cross the placenta, they may benefit the fetus in various ways. Maternal TG represent a ‘‘floating energy depot’’ [1]. Under fasting condition, TG are efficiently used by the maternal liver to synthesize ketone bodies. This mechanism spares glucose for use by the fetus for energy. Maternal TG should be considered a ‘‘reservoir for maternal fatty acids’’ derived from the diet. Placenta uptake of maternal TG is concentration dependent [1]. Hydrolysis by LPL and other lipases releases FFA for the fetus. Maternal hypertriglyceridemia may also contribute to newborn development via increased milk synthesis for subsequent lactation (Fig. 2) [1]. At the time of delivery, LPL expression and activity increase in the mammary glands [1]. These changes are caused by increased insulin and prolactin in association with enhanced insulin mammary gland sensitivity and decreased adipose tissue insulin sensitivity. These metabolic changes drive TG to the mammary glands where LPL induction facilitates clearance of circulating TG for milk synthesis. EFA (derived from the maternal diet) thus become available and contribute to newborn development.

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4. Lipid Metabolism and Maternal Pregnancy Complications 4.1. GESTATIONAL DIABETES Diabetic pregnancy appears associated with significantly increased TG at all gestational stages [44–46]. Recently, some authors have suggested TG assessment during the first trimester to improve early screening for gestational glucose intolerance [47]. Interestingly, the presence of both maternal abdominal obesity and hypertriglyceridemia in the first trimester was associated with significantly increased risk of glucose intolerance later in pregnancy. Conflicting reports on the role of diabetes in pregnancy-associated hypertriglyceridemia, however, continue to emerge. Some studies have shown no difference in total cholesterol during the first trimester in women with GDM versus normal pregnancy [18,48,49], whereas another reported higher cholesterol concentration [44]. Data remain contradictory even during the second and the third trimesters. Cholesterol was found to be lower in some studies [45], but unchanged [18,48] or even higher [44] in others. Women with GDM have been shown to have lower LDL and HDL cholesterol in the second and third trimesters [44–48,50] and increased small size, dense LDL particles [49,50]. In contrast, other authors found no difference in HDL and LDL cholesterol in women with GDM versus normal pregnancy [18,48,49]. It should be noted, however, that these discordant reports may be influenced by degree of metabolic control, stage of pregnancy, and type of diabetes. Maternal hyperlipidemia during normal pregnancy is caused by increased insulin resistance and changes in synthesis of steroid hormones. Pregnant women with GDM have lower steroid hormones [18] and sex hormonebinding globulin [51] versus women without GDM. As such, differences in steroid hormones, sex hormone dysfunction, as well as degree of metabolic control likely contribute individually or cumulatively to development of hyperlipidemia in diabetic pregnancy. With respect to pregestational diabetes, a recent trial demonstrated a less pronounced increase in serum lipids (total cholesterol, HDL, LDL, and TG) in pregnant women with type 2 versus type 1 diabetes [52].

4.2. PREECLAMPSIA Features of metabolic syndrome including maternal obesity, diabetes mellitus, and hypertension have been associated with development of preeclampsia [53]. Studies have shown a concentration-dependent association between increased maternal TG and the risk of preeclampsia. Some authors reported a proatherogenic lipid profile (increased TG, decreased HDL, and small dense LDL) in the months preceding development of clinical preeclampsia [54]. Other

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authors have found an association between increased TG levels in early pregnancy with mild, but not severe eclampsia [55]. Wiznitzer et al. [56] confirmed this association with a large (n ¼ 9911) population-based study. Lipid profiles were assessed in women without cardiovascular disease before, during, and after singleton pregnancy. This study found an association between increased TG and increased risk for development of preeclampsia and GDM. The association between dyslipidemia and preeclampsia may be explained by a variety of mechanisms (Table 2). Increased lipids may induce oxidative stress via endothelial dysfunction, that is, decreased prostacyclin resulting in endothelial cell TG accumulation [57]. On the other hand, insulin resistance may be associated with development of preeclampsia. Resistance causes a compensatory increase in insulin concentration, decreased LPL activity, and increased TG [58]. Another explanation may involve LPL disregulation, thus resulting in a dislipidemic lipid profile. Women with preeclampsia have an increased FFA/albumin ratio and an increased lipolytic activity, thus promoting increased endothelial FFA uptake that are further esterified to TG [59,60].

5. Maternal Hypertriglyceridemia and Fetal Complications 5.1. MACROSOMIA TG are important contributors to fetal growth during pregnancy. Reports clearly link maternal TG concentration during the third trimester to neonatal birth weight. Others have shown a positive correlation between nonfasting serum TG and birth weight in women with GDM independent of prepregnancy BMI [61] and rate of weight gain [39]. We demonstrated a positive correlation between fasting TG concentration and newborn weight independent of glucose concentration and body weight during the third trimester in Caucasian women with positive diabetic screening but normal glucose tolerance. The same relationship was found in Japanese women with positive diabetic screening test, but normal oral glucose tolerance test (OGTT) [38]. In a recent study conducted on women with GDM, Schaefer-Graf et al. [62] measured TG, cholesterol, FFA, glycerol, glucose, and insulin in maternal serum and cord blood at different time points during the third trimester. Data were correlated with fetal and neonatal anthropometric data. This study found an independent relationship between maternal FFA and TG with LGA rate. Recently, Go¨bl et al. [52] demonstrated a positive association between maternal TG and LGA rate in women with type 1 and type 2 diabetes independent of glycemic control. Langer et al. [63] reported that insulin effectively reduced macrosomia rate in women with GDM, glycemic profile, and accelerated fetal growth.

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TABLE 2 MATERNAL TG LEVELS AND PREECLAMPSIA RISK Hypothesis to explain the relationship between maternal TG levels and risk for preeclampsia Oxidative stress Insulin resistance

Increased insulin levels

Decreased LPL activity Increased FFA/albumin ratio and increased lipolytic activity

Increased endothelial FFA uptake

Increased TG synthesis The association between maternal TG levels and preeclampsia risk involves different mechanisms.

These data suggest that impaired lipid metabolism, not hyperglycemia, should be a risk factor for macrosomia in pregnancy complicated by diabetes. The role of insulin in reducing macrosomia rate may be related to its antilipolytic activity, thus reducing FFA and TG and their potential impact on fat mass. In response, Son et al. [64] suggested that measurement of maternal serum TG during mid-pregnancy would help to identify women likely to give birth to LGA newborns. Although the important role of maternal lipids on fetal development is supported by the interrelationship between maternal and fetal FFA and TG concentration, only few studies have examined this phenomenon. Merzouk et al. [65] reported that maternal TG concentration in late pregnancy strongly predicted increased fetal lipids in poorly controlled type 1 diabetes [65]. Another study, by the same author, reported altered lipid profiles only in

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obese women and their macrosomic infants [66]. Others have found increased TG in small-for-gestational-age (SGA) newborns [67,68]. These data have recently been confirmed by Schaefer-Graf et al. [62], who found an inverse correlation between fetal TG and birth weight in newborns from mothers with GDM. SGA infants had increased TG versus AGA and LGA infants. The authors suggested that this difference was caused by impaired LPL activity and subsequent fetal fat mass development. They suggested that SGA newborns might have a decreased LPL activity, thus increasing TG. In contrast, LGA babies have decreased TG as result of increased LPL activity derived from their increased fat mass. These data suggest a role of maternal TG levels as a ‘‘strong determinant of fetal environment and growth’’ [62]. Disproportionate fetal growth is related to adverse intrauterine conditions that cause adulthood diseases such as hypertension, dyslipidemia, and insulin resistance. Abnormalities in childhood lipoprotein profiles are predictive for those in later adult life. As such, we can reasonably propose that alterations in lipid profile during pregnancy could predispose LGA and SGA newborns to later development of obesity, diabetes, and cardiovascular disease. Clearly, more conclusive studies are required to comprehend this correlation and more fully elucidate the exact molecular mechanisms of this disease.

5.2. PRETERM BIRTH Epidemiologic evidence indicates that women who deliver preterm babies have two- to threefold increased risk to develop cardiovascular disease later in life [68–72]. Despite this finding, the mechanism that links preterm birth and maternal cardiovascular risk remains uncertain. Some authors propose that inflammation and altered lipid profiles are involved. Catov et al. [73] found increased cholesterol and TG at 8th week of gestation in women with subsequent spontaneous preterm birth. This finding likely precedes pregnancy-induced changes in blood lipids. The same authors attempted to link maternal inflammation and dyslipidemia to preterm birth [74]. In this subsequent study, C-reactive protein (CRP), cholesterol, and TG was measured in 337 women prior to week 21 of gestation. Of these, 109 women delivered before 37 weeks and 228 women delivered after 37 weeks. Increased CRP, cholesterol, and TG early in pregnancy were independently associated with increased risk of preterm birth. Because inflammation and infection may also induce changes in lipids, hypertriglyceridemia may be considered part of innate immunity and increased inflammatory proteins may cause hypercholesterolemia. In consideration of these findings, Catov et al. [73] proposed that dyslipidemia and inflammation were biologically

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related and operated with synergic, but incompletely understood mechanisms, ultimately resulting in preterm birth. 6. Changes in Lipids During Pregnancy and Risk of Cardiovascular Disease During pregnancy, changes in lipid profile may have a role in endothelial damage and activation of atherogenesis (Table 3) [26]. Brizzi et al. [75] investigated the changes in lipoproteins and lipids in women during normal pregnancy and compared their results with those obtained in nulliparous women of similar age. Pregnant women had increased TG, total cholesterol, and LDL cholesterol versus nulliparous women. Multiparous women had higher TG and lower HDL versus primiparous women. They proposed that these changes in lipid profile led to an atherogenic profile (appearance of small dense LDL). As such, increased plasma TG and LDL during pregnancy might identify women likely to develop atherogenic disease later in life. Other studies reported that the decline in HDL cholesterol for up to 10 years after the first pregnancy was unrelated to weight, adipose distribution, and behavioral changes [76]. A recent study evaluated lipids before, during, and after pregnancy in a cohort of 1752 women. Increased total cholesterol, LDL, and VLDL was observed during pregnancy. Consecutive pregnancies had a cumulative effect in lowering HDL cholesterol, but no differences were observed for TG. These changes were suggested to have a negative effect on cardiovascular risk later in life [74]. Interestingly, these results are similar to those reported in the CARDIA study in which lipids were evaluated in 1952 women for over 10-year period [77,78]. As such, TG changes during pregnancy may have a key role in atherogenic damage despite their return to normal levels following pregnancy. In contrast, Catov et al. [3] found increased TG and decreased HDL in older parous women with perinatal complications and higher cardiovascular risk (vs. nulliparous). 7. Hypertriglyceridemia During Pregnancy: Treatment 7.1. LIFESTYLE Physical activity is effective in preventing GDM, gestational hypertension, and preeclampsia [79–81]. Only one study, however, evaluated the effect of physical activity on lipids [82]. In this study, lipids were evaluated in 925 normotensive, nondiabetic women at the 13th week of gestation.

TABLE 3 CHANGES IN LIPID PROFILE DURING PREGNANCY AND CARDIOVASCULAR RISK LATER IN LIFE Authors

Population number

Design of study

Changes in lipids levels "TG, T-CH, LDL in pregnant women versus nulliparous "TG, # HDL in multiparous women versus nulliparous "T-CH, LDL, VLDL during pregnancy #HDL, TG after pregnancy #HDL in the years after pregnancy in parous versus nulliparous women #HDL, "TG in parous women with perinatal complications Parous women had higher CVD prevalence

Brizzi [75]

22 Pregnant women þ 24 nulliparous women

Controlled study to evaluate lipid profile in pregnant women versus nulliparous

Mankuta [74]

1752 Women

CARDIA study [76,77] Catov et al. [3]

1952 Women

Retrospective study to evaluate lipid profiles before, during, and after pregnancy Prospective study to evaluate changes in lipid profile during 10 years Cross-sectional study to evaluate CVD prevalence, number of births, perinatal complications determined by self-report and hospital report for women enrolled in the ABC study

540 Women

Many studies have evaluated pregnancy effects on cardiovascular risk later in life.

Cardiovascular risk Increased in multiparous women Pregnancy increases cardiovascular risk Increased in parous women Increased in parous women

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The participants were queried as to type, frequency, and duration of physical activity during the previous 7 days. Mean TG were lower in women performing any physical activity. Mean TG and total cholesterol were lower in women in the highest tertiles associated with length of physical activity, energy expenditure, and peak intensity. These data indicate that habitual physical activity may attenuate pregnancy-associated dyslipidemia. As such, it is reasonable to suggest that even mild physical activity during pregnancy should be useful to prevent TG-associated complications such as preeclampsia, preterm birth, LGA newborn, and increased future cardiovascular risk. It is clear that additional studies are indicated to more fully elucidate explore this finding. Only two studies have evaluated the role of diet in reducing TG during pregnancy. Results from these studies, however, appear contradictory. Matorras et al. [83] evaluated n-3 long-chain polyunsaturated fatty acids (n-3LCPUFA) in 162 maternal-neonatal pairs during pregnancy. An interview was performed to assess n-3LCPUFA dietary intake during pregnancy. Plasma n-3LCPUFA, erythrocyte phospholipid, and lipid profiles were measured. Interestingly, n-3LCPUFA intake was not associated with changes in maternal or neonatal lipids [83]. Contrasting results were reported by Williams et al. [84]. This study evaluated 923 pregnant women who reported periconception dietary habits and provided a blood sample before 20 weeks of gestation. This study found that mean erythrocyte PUFA was positively associated with frequency of fish consumption and women who consumed fish more than twice weekly had lower plasma TG and higher HDL cholesterol versus women who consumed fish only once a week. 7.2.

N-3

FATTY ACIDS SUPPLEMENTATION

Little data exist on the effect of n-3 fatty acid supplementation on reducing TG during pregnancy. In 1996, Glueck et al. [85] reported that n-3 fatty acid supplementation reduced TG in a 31-year-old pregnant woman with severe familial hypertriglyceridemia. Treatment with a very low fat content diet (10.7% of total calories) and supplementation with n-3 fatty acid (12 g/day) resulted in a significant reduction in TG (3986–1860 mg/dL). Treatment was maintained till the end of pregnancy. In 2006, Barden et al. [86] studied 83 pregnant women with allergic disease. Study participants were randomly selected to receive fish oil or olive oil supplementation (4 g/day, from 20 weeks of pregnancy until delivery). Maternal lipids and blood pressure were measured during and after pregnancy. Fetal lipids were measured at birth. Unfortunately, no differences were noted in any of these parameters.

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GHIO ET AL. TABLE 4 POSITIVE AND NEGATIVE EFFECTS OF MATERNAL HYPERTRIGLYCERIDEMIA Maternal triglycerides

Positive effects

Negative effects

Represent a floating energetic deposit Should be considered a reservoir for maternal fatty acids Are important elements contributing to fetal growth May contribute to newborn development because they are involved in milk synthesis

Increase preeclampsia risk Increase preterm birth risk Macrosomia Increase maternal cardiovascular risk later in life

During pregnancy, TG increase in maternal circulation is very high. Even if TG do not directly cross the placenta, they may have a lot of effects on the fetus and the newborn.

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