Introduction
During gestation, the maternal metabolism undergoes several transformations due to
hormonal changes and nutritional demands. This period is characterized by changes
in lipid metabolism that are essential to satisfy nutritional demands and fetal development.[1 ]
[2 ] It has two distinct phases: the initial phase is characterized by fatty acids accumulation,
which results in triglycerides deposition in the maternal adipose tissue; the late
phase is characterized by accelerated adipose tissue catabolism with increased availability
of fatty acids and glycerol in the circulation, which causes hypertriglyceridemia.[3 ] Maternal hyperlipidemia, especially hypertriglyceridemia, may be associated with
very low-density lipoprotein (VLDL) increased hepatic synthesis as a role of high
estrogen concentration during gestation, and triglycerides (TG) rich lipoproteins
catabolism reduction due to reduced lipoprotein lipase (LPL) and hepatic lipase (LH)
activities.[4 ]
[5 ]
[6 ] Such changes can provide development of atherogenic phenotype that is characterized
by small and dense low-density lipoprotein (LDL) particles, associated with triglycerides
levels increase, and a decrease of high-density lipoprotein (HDL) cholesterol levels.[5 ]
Maternal hyperlipidemia may be associated with fetal development complications (preterm
birth, preeclampsia, vascular complications) and early cardiovascular diseases, when
evaluated long term.[3 ]
[5 ] In women, the progression and evolution of pregnancy represent an early opportunity
to identify cardiovascular risk factors and serum markers.[7 ] Studies suggest that gestation constitutes a “stress test” to the carbohydrates
and lipids metabolic pathways, which causes inflammatory markers synthesis hyper-regulation
and changes vascular function. Thus, this period may be the most adequate time for
a long-term prediction of hemodynamic complications of the cardiocirculatory system.[8 ]
[9 ]
[10 ]
To better understand the lipoprotein metabolism changes that occur during pregnancy
(especially those associated with the development of dyslipidemias with atherogenic
phenotype and maternal-fetal complications), we reported here some metabolic implications,
such as alterations of LPL and cholesterol ester transfer protein (CEPT), that are
associated with cardiovascular risk increase during pregnancy, as well as the long-term
repercussions of those changes that are related to pregnant woman and newborn health.
To describe these major metabolic changes that occur during pregnancy, a literature
review was performed by using scientific articles from the following databases: PUBMED,
MEDLINE and SCIELO. The main health sciences descriptors (DeCS) were: cardiovascular
diseases, lipid metabolism, lipoproteins, gestation, maternal-fetal complications,
biomarkers, dyslipidemias and hypertriglyceridemia.
Maternal Hyperlipidemia
Pregnancy is characterized by hormonal changes such as progressive hyperinsulinemia,
associated with estrogen, progesterone, cortisol, chorionic gonadotrophin and placental
lactogen hormone increases, among other markers. On the other hand, serum adiponectin
concentration is reduced.[11 ] The major hormonal changes accountable for metabolic alterations are insulin resistance
and the increased estrogen concentration.[12 ] Lipoproteins and apolipoproteins serum concentrations increase significantly in
pregnancy in response to hormonal changes.[13 ]
[14 ] Estrogen increases hepatic VLDL synthesis, reduces hepatic lipoprotein lipase activity,
and plays an important role in the accumulation of TG into HDL.[6 ]
Hypertriglyceridemia is the main manifestation associated with hormonal alterations
due to increased adipose tissue lipolytic activity, which contributes to the physiological
hyperlipidemia observed during pregnancy.[11 ] This mechanism occurs mainly during the third trimester of pregnancy to ensure nutrient
supply and essential fatty acids in adequate quantities to the placental-fetal unit.[11 ] The mother's TG and non-esterified fatty acids concentrations show a positive correlation
with the newborn's body mass.[15 ]
[16 ] According to Emet et al (2013)[3 ] there are numerous changes in the lipid profile, especially in the third trimester
of gestation. In their study, the total cholesterol (TC), low-density lipoprotein
cholesterol (LDL-C), TG and high-density lipoprotein cholesterol (HDL-C) mean value
during the first trimester was significantly lower (p < 0.05) than in the third trimester of pregnancy. Wild et al (2016)[17 ] affirm that these lipoprotein profile alterations may cause important clinical disorders.
For example, severe hypertriglyceridemia may result in pancreatitis, and hypercholesterolemia
may result in precocious atherosclerosis.
Maternal hyperlipidemia, with hypertriglyceridemia, may be associated with reduced
LPL activity at the end of gestation. Lipoprotein lipase drives the TG hydrolysis
into TG-rich lipoproteins, such as chylomicrons and VLDL. The hydrolysis products,
like glycerol and fatty acids, are mainly captured by the underlying tissue. The reduction
of LPL activity leads to TG-rich lipoproteins accumulation by compromised lipoprotein
catabolism.[12 ]
[18 ] The significant increase in TG and LDL-C levels during gestation can be used as
a biomarker of lipoprotein atherogenic phenotype to identify women at risk for developing
cardiovascular atherogenic disease later in life.[5 ]
The hypertriglyceridemia during pregnancy is implicated in different types of lipid
metabolism pathways modification. The CETP activity has been associated with increased
HDL esterified cholesterol (EC) transfer to other lipoproteins. To maintain mass balance,
while exchanging EC, HDL receives TG, by the action of CETP and phospholipid transfer
protein (PLTP). Thus, the mass balance maintaining alter HDL particle composition
and function. In addition, LDL particles become TG-richer, with a higher prevalence
of smaller and denser LDL (sdLDL), phenotype B, more atherogenic.[19 ]
[20 ] The sdLDL accumulation during pregnancy increases the risk of vascular endothelial
damage. ([Fig. 1 ])[1 ]
Fig. 1 The main changes that occur in the third trimester of gestation that contribute to
cardiovascular diseases risk. Abbreviations: CETP, cholesterol ester transfer protein;
HDL-C, high-density lipoprotein cholesterol; LDL, low-density lipoprotein; LPL, lipoprotein
lipase; QM, chylomicron; QMr, remaining chylomicron; TG, triglycerides; VLDL, very
low-density lipoprotein; VLDLr, very low-density lipoprotein receptor. Source: The
author
Cardiovascular Risk Biomarkers
Cardiovascular risk may be related not only to the lipoproteins cholesterol content,
but also to the number of circulating atherogenic particles that enter the arterial
wall.[21 ]
[22 ] Apolipoprotein B (apoB) and apolipoprotein A-I (apoA-I) serum concentrations can
be used to calculate the apoB/apoA-I ratio, which has been used as a cardiovascular
risk surrogate marker.[23 ]
[24 ] It reflects the balance between circulating particles and represents the amount
of cholesterol that reaches the tissues and is removed back to the liver.[25 ]
[26 ] Besides, high HDL cholesterol content does not exclude the possibility of cardiovascular
risk, the analysis of HDL biomarkers as apoA-I, which can be used to estimate the
number of antiatherogenic particles, and HDL particles size must be performed.[27 ] Consequently, serum HDL-C determination plus HDL particle functionality should be
performed as an essential protocol for cardiovascular risk assessment.[28 ]
[29 ] The determination of particle functionality brings the information about HDL function
to exert antiatherogenic, antioxidant and antiinflammatory activities; in addition,
it is possible to evaluate the performance of HDL on reverse cholesterol transport
(RCT). By the way, the HDL protective function may be compromised in the presence
of proinflammatory conditions that can cause lipoprotein structural modifications,
such as in the presence of oxidative status.[27 ]
In addition to the structural and functional HDL evaluations, the determination of
other biomarkers has been used, for example, the serum antioxidant potential can be
measured from paraoxonase-1 activity (PON-1) (EC 3.1 0.8.1) determination, an enzyme
belonging to the paraoxonase family. It is an enzyme associated with the HDL particle,
esterase calcium-dependent, synthesized by the liver, which contains 354 amino acids
with molecular mass of 43 KDa.[30 ]
[31 ] According to Aviram et al (2013),[31 ] PON-1 has a protective action that supports the following functions: lipoproteins
oxidative stress attenuation and reduced oxidized LDL macrophages uptake by stimulating
HDL mediated cholesterol efflux.[32 ]
[33 ]
During pregnancy, all of these cardiovascular risk biomarkers, like apoA and apoB
concentration, PON-1 activity, HDL and LDL particle size may be changed. Belo et al
(2002)[34 ] performed a longitudinal study in pregnant women. They concluded that there was
an increase in apoB concentration in the third trimester of gestation, while apoA
presented a slight reduction. They also observed an increased in sdLDL particle numbers
at the end of gestation.[34 ] Stefanovic et al (2012)[35 ] showed in a longitudinal study the PON-1 activity changes during normal gestation.
There was a significant PON-1 activity reduction from the 32nd week of gestation,
thus a greater susceptibility to oxidative damage.[35 ]
Maternal-fetal Complications
The presence of abdominal obesity and hypertriglyceridemia in the first trimester
of pregnancy are associated with an increased risk of developing glucose intolerance
in the third trimester. Gestational diabetes is a public health priority, as it is
a serious metabolic complication that aggressively impair both the mother's and the
child's vital health.[36 ]
In obese pregnant women, hyperlipidemia is more pronounced.[37 ]
[38 ] Total cholesterol (TC) and VLDL-C are in higher concentration, HDL cholesterol is
reduced, and LDL lipoprotein is more susceptible to oxidation.[39 ]
The high TG concentration during pregnancy is associated with preeclampsia, preterm
birth and cardiovascular disease increased risk.[5 ]
[40 ] Pregnancy complications and adverse events in newborns are reported in hypertriglyceridemia
and hypercholesterolemia cases.[41 ]
[42 ] In addition, there is evidences that altered maternal lipid profile may be associated
with congenital and developmental anomalies.[43 ]
[44 ]
[45 ]
[46 ]
The study by Han et al (2016)[45 ] concluded that pregnant women who developed gestational diabetes had an atherogenic
lipid profile, such as a predominance of sdLDL particles, even before becoming pregnant.
There is a possible relationship between dyslipidemia, preterm delivery and maternal
health risk in the long term.[40 ]
[47 ] The mechanisms that link preterm delivery to maternal cardiovascular risk are still
not well understood, although the inflammatory process has been pointed out.[8 ] The presence of inflammatory or proinflammatory phenotypes may predispose women
to preterm birth during reproductive age, and it is also related to an increased risk
of cardiovascular disease development in subsequent years.[47 ]
[48 ]
According to Smith et al (2001),[48 ] women who have experienced preterm birth show two to three times greater risk of
developing cardiovascular disease later in their lives.[49 ] The evidence related to dyslipidemia, a precursor of cardiovascular disease, as
well as preeclampsia, such as pregnancy physiologic changes are associated to metabolic
abnormalities.[50 ]
To exemplify, [Table 1 ] shows the results achieved in the study of Jin et al (2016)[50 ] about the associations between maternal third-trimester TG concentration and pregnancy
complications. They concluded that 7.6% of mothers developed gestational diabetes,
1.5% preeclampsia and 6.3% intrahepatic cholestasis of pregnancy. Every unit elevation
of TG concentration in the third semester was associated with increased risk for gestational
diabetes, preeclampsia and intrahepatic cholestasis of pregnancy. Serum TG concentration
increased as pregnancy advanced (p < 0.001).[50 ]
Table 1
Associations between maternal third-trimester TG concentration and main pregnancy
complications[50 ]
Outcomes
TG (mmol/L)
AOR (95%CI)
p value
Gestational diabetes mellitus
1.37 (1.18–1.58)
0.000
Preeclampsia
1.50 (1.16–1.93)
0.002
Intrahepatic cholestasis of pregnancy
1.28 (1.09–1.51)
0.002
Preterm birth
1.04 (0.77–1.38)
0.818
Abbreviations: AOR, adjusted odds ratio; TG, triglycerides.
There is an association between maternal hyperlipidemia, mainly hypertriglyceridemia,
and preeclampsia.[50 ]
[51 ] Elevated serum TG concentrations during pregnancy increases the risk of developing
preeclampsia, as well as preterm birth.[5 ] High TG concentrations are associated with a 4-fold preeclampsia increased risk
when compared with women with normal TG concentrations, according to the lipid profile
reference values.[50 ]
[51 ]
[52 ]
[53 ]
[54 ] It is also known that high concentration of oxidative stress markers and reduction
of antioxidant enzymes activity, such as PON-1, are highly associated to preeclampsia
etiology.[52 ]
Studies have shown that hypertriglyceridemia together with maternal obesity, diabetes
mellitus and hypertension, which characterize metabolic syndrome, correlate positively
with preeclampsia.[55 ]
[56 ] In addition, if these problems persist up to 6 months postpartum, they may influence
future gestation as well as the cardiovascular risk long-term.[20 ]
[57 ] Women who developed preeclampsia showed more changes in their lipid profile, like
dyslipidemia, formation of particles more susceptible to oxidation and endothelial
dysfunction.[34 ]
[58 ]
[59 ] They also showed a more atherogenic lipid profile, with more marked hypertriglyceridemia,
containing a greater sdLDL proportion, a more pronounced HDL-C and apoA-I reductions.[60 ]
Conclusion
The physiological changes in the cardiovascular system, proatherogenic lipid profile,
changes in carbohydrate metabolism and PON-1 antioxidant profile contribute to the
hypothesis that pregnant women are at higher risk of developing cardiovascular diseases
later in their lives. Given the evidence, both particles number and lipoprotein structure,
that is, the lipid composition and lipoprotein functionality, can be modified during
the course of gestation. There is a need to find a better strategy to instruct the
population about the risk of cardiovascular complications that could affect pregnant
women long term so that the preventive and behavioral policies can be implemented.
We suggest evaluating the lipid profile during the course of the trimesters of gestation
to identify pregnant women at high risk of maternal-fetal and cardiovascular complications.
Once the risk factors and markers have been identified, behavioral and nutritional
changes must be introduced to achieve healthy and safe pregnancy outcomes in the long
term.
