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 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 134
2. Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 134
3. Maternal Lipid Metabolism During Pregnancy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 134
3.1. Changes in Maternal Lipid Metabolism. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 134
3.2. Maternal Hyperlipidemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 137
3.3. Placental Transfer of Lipids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 138
3.4. How Maternal Hypertriglyceridemia May Benet the Fetus and
the Newborn . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 140
4. Lipid Metabolism and Maternal Pregnancy Complications . . . . . . . . . . . . . . . . . . . . . . 141
4.1. Gestational Diabetes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 141
4.2. Preeclampsia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 141
5. Maternal Hypertriglyceridemia and Fetal Complications . . . . . . . . . . . . . . . . . . . . . . . . 142
5.1. Macrosomia. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 142
5.2. Preterm Birth. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 144
6. Changes in Lipids During Pregnancy and Risk of Cardiovascular Disease . . . . . . . 145
7. Hypertriglyceridemia During Pregnancy: Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 145
7.1. Lifestyle . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 145
7.2. n-3 Fatty Acids Supplementation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 147
8. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 148
References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 148
1
Corresponding author: Alessandra Ghio, e-mail: alessandraghio76@libero.it
133
0065-2423/11 $35.00 Copyright 2011, Elsevier Inc.
DOI: 10.1016/B978-0-12-387042-1.00007-1 All rights reserved.
ADVANCES IN CLINICAL CHEMISTRY, VOL. 55
1. Abstract
During pregnancy, complex changes occur in lipid proles. From the 12th
week of gestation, phospholipids, cholesterol (total, LDL, HDL), and trigly-
cerides (TG) increase in response to estrogen stimulation and insulin resistance.
Transition toa catabolic state favors maternal tissue lipiduse 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 prolif-
eration and development of the growing body. Free-fatty acids (FFA), oxidized
inthe maternal liver as ketone-bodies, represent analternative fuel for the fetus.
Maternal hypertriglyceridemia (vs. other lipids) has many positive effects such
as contributing tofetal growthand 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 sug-
gested that maternal hypertriglyceridemia has a role in increasing cardiovascu-
lar risk later in life. This chapter reviews lipid metabolism during pregnancy to
elucidate its effect on fetal growthand its potential role inpregnancy-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 preg-
nancy, despite the fact that maternal lipids cross to the placenta with difculty
[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 inuence 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 reect a role in future development of
cardiovascular disease [3].
This chapter will review lipid metabolism during normal pregnancy and
evaluate its association with maternalfetal complications. The role of life-
style 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 rst 8 weeks of pregnancy.
134 GHIO ET AL.
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 rst 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 lipopro-
tein particles. Products of this hydrolysis (fatty acids and glycerol), thus,
become available for uptake in adjacent tissues. LPLis located in the capillary
endothelium of extrahepatic tissues. LPL activity decreases during the third
trimester of gestation, thereby reducing uptake of circulating TGinto 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, acyl-
CoA and glycerol-3-phosphate, respectively. Following reesterication for
synthesis of TG, they are subsequently released via VLDL into the circula-
tion. Under fasting conditions, glycerol may also be used for glucose synthe-
sis, whereas FFA is used for b-oxidation, thus producing acetyl-CoA leading
to energy production and ketone body synthesis. Both pathways, gluconeo-
genesis and ketogenesis, are signicantly increased in late pregnancy [13,14].
Maternal fat
accumulation
Hyperfagia
Increased lipid
synthesis
Nourishing
elements
crossing the
placenta
Fetal metabolism
Fetal growth
Late pregnancy
Early pregnancy
Enhanced adipose
tissue lipolytic
activity
Decreased LPL
activity
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].
TRIGLYCERIDE METABOLISM IN PREGNANCY 135
Under fasting conditions, increased glycerol release and its rapid conver-
sion to glucose may benet 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 benet 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 compli-
cations. 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 ketogene-
sis. Women with gestational diabetes (GDM) have peripheral insulin resis-
tance, thus causing increased blood nonessential fatty acids (NEFA) and
ketone bodies concentrations [18,19].
LPL
FFA
Glycerol
Adipose tissue
Liver
Glucose
Ketone
bodies
VLDL
Fetus
FFA
Insulin resistance
Mammary glands
Muscle
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.
136 GHIO ET AL.
3.2. MATERNAL HYPERLIPIDEMIA
During late gestation, the maternal catabolic condition causes hyperlipid-
emia 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 uidity 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 enrich-
ment 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)
Energy
sources
Endogenous and esogenous lipid sources
Cholesterol Free fatty acids
Steroid
hormones
synthesis
Cells
membranes
synthesis
Cells
membranes
synthesis
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].
TRIGLYCERIDE METABOLISM IN PREGNANCY 137
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 densi-
ty (small and dense LDL) due to HL activity (Fig. 4). These peculiar changes
in lipid prole, occurring in late pregnancy, may promote endothelial dam-
age and subsequent atherogenesis. Small dense LDL particles are more
susceptible to oxidation, demonstrate increased binding to vessel wall pro-
teoglycans 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
LPL

TG-rich
HDL
Small and dense LDL
TG-VLDL
TG-rich
LDL
CETP
Large and buoyant HDL 2
TG
TG
CE
HL HL
CE
TG-VLDL
Estrogens
Insulin-resistance
FIG. 4. Development of an atherogenic prole 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.
138 GHIO ET AL.
components are crucial for fetal growth in general and specically for brain
and retina development.
Similar to esteried FA, most LCPUFA in the maternal circulation are
associated with plasma lipoproteins such as TG, phospholipids, and ester-
ied 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 specic receptors (VLDL, LDL, HDL,
scavenger-receptors, LDLreceptor-related proteins) to allowplacental 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 acid-
binding protein (p-FABPpm) [12,2830] facilitate fetal uptake of LCPUFA-
associated lipoproteins and circulating nonesteried 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 efcient [31].
Following maternal lipoprotein receptor binding, TG are hydrolyzed,
taken up by the placenta and reesteried as fatty acid stores [32]. After
intracellular hydrolysis of glycerides, FFA can diffuse into plasma via a-
fetoprotein [33,34]. Upon reaching the fetal liver, they are reesteried 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 Lipase activity
VLDL LPL
LDL Phospholipase A2
LDL-related proteins Intracellular lipase
HDL Plasma membrane fatty acid-binding protein (FABP/GOT2)
Scavenger 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.
TRIGLYCERIDE METABOLISM IN PREGNANCY 139
In women with GDM, increased TG appear related to signicant 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 dis-
eases. 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 athero-
sclerotic 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 nding during pregnancy.
Although TG do not directly cross the placenta, they may benet the fetus
in various ways.
Maternal TG represent a oating energy depot [1]. Under fasting con-
dition, TG are efciently 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 develop-
ment via increased milk synthesis for subsequent lactation (Fig. 2) [1].
At the time of delivery, LPL expression and activity increase in the mam-
mary glands [1]. These changes are caused by increased insulin and prolactin
in association with enhanced insulin mammary gland sensitivity and de-
creased adipose tissue insulin sensitivity. These metabolic changes drive TG
to the mammary glands where LPL induction facilitates clearance of circu-
lating TG for milk synthesis. EFA (derived from the maternal diet) thus
become available and contribute to newborn development.
140 GHIO ET AL.
4. Lipid Metabolism and Maternal Pregnancy Complications
4.1. GESTATIONAL DIABETES
Diabetic pregnancy appears associated with signicantly increased TG at
all gestational stages [4446]. Recently, some authors have suggested TG
assessment during the rst trimester to improve early screening for gestation-
al glucose intolerance [47]. Interestingly, the presence of both maternal
abdominal obesity and hypertriglyceridemia in the rst trimester was asso-
ciated with signicantly increased risk of glucose intolerance later in preg-
nancy. Conicting 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 rst
trimester in women with GDM versus normal pregnancy [18,48,49], whereas
another reported higher cholesterol concentration [44]. Data remain contradic-
tory even during the second and the third trimesters. Cholesterol was found to
be lower insome studies [45], but unchanged[18,48] or evenhigher [44] inothers.
Women with GDM have been shown to have lower LDL and HDL choles-
terol inthe secondandthirdtrimesters [4448,50] andincreasedsmall size, dense
LDL particles [49,50]. In contrast, other authors found no difference in HDL
and LDLcholesterol in women with GDMversus normal pregnancy [18,48,49].
It should be noted, however, that these discordant reports may be inuenced 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 hormone-
binding 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 melli-
tus, 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 prole (increased TG, decreased HDL, and small dense
LDL) in the months preceding development of clinical preeclampsia [54]. Other
TRIGLYCERIDE METABOLISM IN PREGNANCY 141
authors have found an association between increased TG levels in early preg-
nancy with mild, but not severe eclampsia [55]. Wiznitzer et al. [56] conrmed
this association with a large (n 9911) population-based study. Lipid proles
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 prole. Women with preeclampsia have an
increased FFA/albumin ratio and an increased lipolytic activity, thus promot-
ing increased endothelial FFAuptake that are further esteried 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 prepreg-
nancy BMI [61] and rate of weight gain [39]. We demonstrated a positive
correlation between fasting TG concentration and newborn weight indepen-
dent of glucose concentration and body weight during the third trimester in
Caucasian women with positive diabetic screening but normal glucose toler-
ance. 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 diabe-
tes independent of glycemic control. Langer et al. [63] reported that insulin
effectively reduced macrosomia rate in women with GDM, glycemic prole,
and accelerated fetal growth.
142 GHIO ET AL.
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 strong-
ly predicted increased fetal lipids in poorly controlled type 1 diabetes [65].
Another study, by the same author, reported altered lipid proles only in
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.
TRIGLYCERIDE METABOLISM IN PREGNANCY 143
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 conrmed 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 proles are predictive for those in later adult life. As
such, we can reasonably propose that alterations in lipid prole 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 [6872]. Despite this nding, the mechanism that links preterm birth
and maternal cardiovascular risk remains uncertain. Some authors propose
that inammation and altered lipid proles are involved. Catov et al. [73]
found increased cholesterol and TG at 8th week of gestation in women with
subsequent spontaneous preterm birth. This nding likely precedes pregnan-
cy-induced changes in blood lipids. The same authors attempted to link
maternal inammation 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 inammation and
infection may also induce changes in lipids, hypertriglyceridemia may be
considered part of innate immunity and increased inammatory proteins
may cause hypercholesterolemia. In consideration of these ndings, Catov
et al. [73] proposed that dyslipidemia and inammation were biologically
144 GHIO ET AL.
related and operated with synergic, but incompletely understood mechan-
isms, ultimately resulting in preterm birth.
6. Changes in Lipids During Pregnancy and Risk of
Cardiovascular Disease
During pregnancy, changes in lipid prole 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 primip-
arous women. They proposed that these changes in lipid prole led to an
atherogenic prole (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 rst pregnancy was unrelated to weight, adipose distribu-
tion, 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 [7981]. 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.
TRIGLYCERIDE METABOLISM IN PREGNANCY 145
TABLE 3
CHANGES IN LIPID PROFILE DURING PREGNANCY AND CARDIOVASCULAR RISK LATER IN LIFE
Authors Population number Design of study Changes in lipids levels Cardiovascular risk
Brizzi [75] 22 Pregnant
women 24
nulliparous women
Controlled study to evaluate lipid prole in
pregnant women versus nulliparous
"TG, T-CH, LDL in pregnant women
versus nulliparous
"TG, # HDL in multiparous women
versus nulliparous
Increased in
multiparous
women
Mankuta [74] 1752 Women Retrospective study to evaluate lipid
proles before, during, and after
pregnancy
"T-CH, LDL, VLDL during
pregnancy
#HDL, TG after pregnancy
Pregnancy increases
cardiovascular risk
CARDIA
study [76,77]
1952 Women Prospective study to evaluate changes in
lipid prole during 10 years
#HDL in the years after pregnancy in
parous versus nulliparous women
Increased in parous
women
Catov et al. [3] 540 Women 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
#HDL, "TG in parous women with
perinatal complications
Parous women had higher CVD
prevalence
Increased in parous
women
Many studies have evaluated pregnancy effects on cardiovascular risk later in life.
The participants were queried as to type, frequency, and duration of physical
activity during the previous 7 days.
Mean TGwere 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 pregnan-
cy-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 nding.
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 inter-
view was performed to assess n-3LCPUFA dietary intake during pregnancy.
Plasma n-3LCPUFA, erythrocyte phospholipid, and lipid proles 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 sh
consumption and women who consumed sh more than twice weekly had
lower plasma TG and higher HDL cholesterol versus women who consumed
sh 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 signicant reduction in TG (39861860 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 sh oil or olive oil
supplementation (4 g/day, from 20 weeks of pregnancy until delivery). Ma-
ternal 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.
TRIGLYCERIDE METABOLISM IN PREGNANCY 147
8. Conclusions
Lipid levels, especially TG, increase during pregnancy. Changes in lipid
metabolism are mediated by estrogen concentration and insulin resistance.
The state of maternal hypertriglyceridemia has many positive effects and
contributes to fetal growth and development. Maternal TG serves as a
reservoir for dietary fatty acids and as a oating energy depot.
Despite these benets, increased maternal TG appear involved in develop-
ment of preeclampsia and contributes to preterm birth. In addition, LGA
newborns have a higher risk for development of adulthood diseases such as
hypertension, dyslipidemia, and insulin resistance. TG are also associated
with increased risk of future cardiovascular disease (Table 4).
Based on these ndings, it is clear that additional more comprehensive and
well-controlled studies are warranted to more fully explore and elucidate the
complicated role of lipid metabolism in pregnancy.
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POSITIVE AND NEGATIVE EFFECTS OF MATERNAL HYPERTRIGLYCERIDEMIA
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