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Pregnancy-induced Hyperlipoproteinemia: Review of the Literature

Ahmet Basaran
Reproductive Sciences 2009 16: 431 originally published online 20 February 2009
DOI: 10.1177/1933719108330569

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 Pregnancy-induced Hyperlipoproteinemia:
Review of the Literature
Ahmet Basaran, MD

It is well known that with the effect of hormonal changes during pregnancy, plasma lipid levels increase.
Expected elevations for triglyceride and cholesterol levels during a normal gestational period usually do not
exceed 332 mg/dL and 337 mg/dL, respectively (corresponding 95th percentile values). However,
elevations over the 95th percentile values can be observed during pregnancy, and patients with levels over
these expected adaptation levels can be divided into 2 groups: (1) supraphysiologic hyperlipoproteinemia
during pregnancy and (2) extreme hyperlipoproteinemia limited to gestational period (triglyceride level
>1000 mg/dL). Regarding the first group, some of these patients may develop hyperlipoproteinemia
in their future life. What percentage of these women will translate into hyperlipoproteinemia later in life
and how efficiently these women can be screened during pregnancy is an enigma. The underlying disorders
in the second group of patients at least include dysbetalipoproteinemia, partial lipoprotein lipase
deficiency, and apoprotein E3/3 genotype. Pregnancy had been reported to induce severe hyperlipopro-
teinemia that is limited to gestational period in these disorders. Dysbetalipoproteinemia, partial lipopro-
tein lipase deficiency, and apoprotein E3/3 genotype probably bring risks and implications to the future
life of the carrying individuals although the true extent of the risks is yet to be defined. When disorders
unique to gestational period such as gestational diabetes are considered, pregnancy may be accepted as an
opportunity to identify women under risk of cardiovascular morbidity and mortality.

KEY WORDS: Hyperlipoproteinemia, pregnancy, gestational hyperlipoproteinemia,

dysbetalipoproteinemia, lipoprotein lipase deficiency.

INTRODUCTION 2 of the lipolytic enzymes, lipoprotein lipase (LPL), or

During pregnancy, it is well known that with the effects
of estrogen, progesterone, and human placental lactogen,
plasma lipid levels increase.1 Two mechanisms were
proposed to operate to change the lipid profile during
pregnancy. One is estrogen-induced hepatic synthesis of
very low-density lipoprotein (VLDL) triglycerides. The
second mechanism to explain the increase in triglycerides
in all the circulating lipoproteins during gestation could
be impaired removal of lipoprotein triglycerides by 1 or
From the Kulu State Hospital, Obstetrics and Gynecology Department, Konya,
Turkey.
Address correspondence to: Ahmet Basaran, MD, Kulu Devlet Hastanesi, Kadın
hastalıkları ve doğum bölümü Konya-Kulu, Turkiye. E-mail: dr_ahmetbasaran@
yahoo.com.
Reproductive Sciences Vol. 16 No. 5 May 2009 431-437
DOI. 10.1177/1933719108330569
# 2009 by the Society for Gynecologic Investigation
hepatic lipase.2 During the last third trimester of
gestation, activity of hormone-sensitive lipase in adipose
tissue is enhanced and this in turn augments VLDL
production in liver. In addition, decreased activity of 2
lipolytic enzymes also contributes to this augmentation.3
Expected elevations for triglyceride and cholesterol
levels during a normal gestational period usually do not
exceed 332 and 337 mg/dL, respectively (corresponding
95th percentile values).4 However, elevations over the
95th percentile values and extreme hyperlipoproteinemia
(that is defined as triglyceride [TG] >1000 mg/dL5) can
be observed during pregnancy, and these patients may
carry risk of developing hyperlipoproteinemia in their
future life. Hyperlipoproteinemia during pregnancy
could be classified according to clinical implications and
future prospects as in Figure 1. This article will mainly
be focusing on the pregnancy-induced hyperlipoprotei-
nemias with its underlying disorders, their probable

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432 Reproductive Sciences Vol. 16, No. 5, May 2009 Basaran

Figure 1. Classification of hyperlipoproteinemia during pregnancy. Apo indicates apoprotein; LPL ¼ lipoprotein lipase; TG ¼ triglyceride.

Table 1. Lipid Levels in Uncomplicated Pregnancies12,13,14

Controls (mg/dL) First Trimester (mg/dL) Second Trimester (mg/dL) Third Trimester (mg/dL)

Total cholesterol 183 + 25 173 + 18 243 + 53 267 + 30

HDL-C 69 + 10 67 + 12 83 + 19 81 + 17
LDL-C 99 + 23 90 + 17 130 + 46 136 + 33
Triglycerides 77 + 34 79 + 27 151 + 80 245 + 73
ApoA-1 163 + 24 170 + 27 204 + 22 196 + 28
ApoA-2 47 + 6 49 + 7 52 + 6 49 + 5
ApoB 61 + 22 70 + 21 91 + 25 113 + 29
ApoC-II 237 + 11 265 + 13 299 + 18 314 + 21
ApoC-III 121 + 19 141 + 3 188 + 5 217 + 6
ApoE 42 + 20 41 + 12 42 + 9 49 + 19
Lipoprotein(a) 86 (11-473) 60 (0-1440) 63 (2-1210) 54 (0-1230)
VLDL1a 23 (5-85) 19 (12-55) 47 (26-110) 109 (38-170)
VLDL2a 23 (13-44) 17 (7-45) 36 (20-77) 103 (46-168)
IDLa 35 (18-62) 26 (13-54) 58 (24-100) 124 (79-157)
LDLa 207 (150-363) 200 (135-323) 292 (206-410) 353 (244-534)
LDL-Ia 50 (22-130) 33 (16-52) 49 (37-70) 67 (27-96)
LDL-IIa 135 (72-258) 143 (95-231) 160 (103-287) 201 (59-316)
LDL-IIIa 31 (5-68) 28 (15-56) 32 (24-165) 123 (43-192)
Abbreviations: Apo, apoprotein; HDL-C, high-density lipoprotein cholesterol; IDL, intermediate-density lipoprotein; LDL-C, low-density
lipoprotein cholesterol; VLDL, very low-density lipoprotein.
a
For VLDL1, VLDL2, IDL, LDL, LDL-I, LDL-II, and LDL-III, 10th week, 20th week, and 35th week values are taken as first, second, and third
trimester values, respectively.

mechanisms and properties unique to pregnancy, and the
chances of preventive measures. Management of preexist-
ing hyperlipoproteinemias during pregnancy is discussed
elsewhere in the literature.
LIPID LEVELS IN UNCOMPLICATED PREGNANCIES
Normal lipid metabolism during pregnancy had been
investigated in several studies.6-11 First trimester lipid
levels are concordant with nonpregnant women and sig-
nificant deviation from nonpregnant level occurs mainly
in second and third trimesters.4,12 Plasma triglyceride
levels rise markedly during pregnancy, whereas increments
in phospholipids and cholesterol are more moderate
(Table 1). In normal pregnancies without accompanying
morbidities such as diabetes and preeclampsia, under
physiologic conditions, plasma cholesterol levels increase
by 50%, while triglyceride levels rise between 2- and
4-fold.1,15 Although elevated plasma triglycerides are
found in all the lipoprotein fractions during late gestation,
the triglyceride/cholesterol ratio remains stable in VLDL
despite significant changes in both low-density lipopro-
teins (LDL; 358% change between postpartum and third
trimester values) and high-density lipoproteins (HDL;
241% change between postpartum and third trimester

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Pregnancy-induced Hyperlipoproteinemia
values) as gestation advances.2 During the second and
third trimesters, apoprotein (Apo) A-1, ApoB100, lipo-
protein(a), and plasma cholesteryl ester transfer protein
(CETP) activity increases, while postheparin lipase
activities (LPL and hepatic lipase activity) decrease.2,12
During late gestation, activity of the hormone-sensitive
lipase in adipose tissue is enhanced and this in turn
augments VLDL production in liver. Very low-density
lipoprotein 1 and VLDL2 rose together during pregnancy
so that their ratio remains constant.13 Thus, the increase
in the level of VLDL triglycerides in the presence of an
enhanced CETP activity during pregnancy facilitates a pro-
portional enrichment of triglycerides in LDL and HDL.2,3
Brizzi et al showed significant increase in ApoA
during the 3 trimesters of pregnancy only in women with
large isoforms (S3 and S4 bands on sodium dodecyl
sulfate–polyacrylamide gel electrophoresis), whereas in
women with small isoforms (F, S1, and S2), ApoA levels
did not change significantly. Moreover, Brizzi et al
showed that women having higher triglyceride increase
had appearance of small, dense LDL-III.4 This was also
demonstrated by Sattar et al. They had suggested a
presence of a critical triglyceride threshold at which
significant changes in LDL subclasses may occur. They
showed that the alteration in profile toward small, dense
LDL-III was earliest in those individuals with the highest
initial 10-week triglyceride concentrations.13 Appearance
of small, dense LDL-III had been associated with the
increased activity of hepatic lipase.16 Apoprotein A and
small, dense LDL-III had been shown to be associated
with atherosclerosis.4
Changes in lipid metabolism during pregnancy
promote the accumulation of maternal fat stores in early
and mid pregnancy and enhance fat mobilization in late
pregnancy.17 Cholesterol is used by the placenta for
steroid synthesis, and fatty acids are used for placental
oxidation and membrane formation.17 The anabolic phase
of early pregnancy encourages lipogenesis and fat storage in
preparation for rapid fetal growth in late pregnancy.18
LIPID LEVELS IN PATIENTS WITH ACCOMPANYING MEDICAL
CONDITIONS DURING PREGNANCY
Risk factors for hyperlipidemia in the nonpregnant state
are also true for pregnancy, which at least include obesity,
weight gain, hypothyroidism, both gestational and nonges-
tational diabetes, alcohol consumption, and prescription
medications such as low-molecular-weight heparin14 and
glucocorticoids.19 Among these risk factors, diabetes has
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Reproductive Sciences Vol. 16, No. 5, May 2009 433
been the most commonly investigated factor. Toescu
et al compared the lipid levels between diabetic (groups
include type I and type II diabetes, gestational diabetes)
and nondiabetic pregnant patients; they did not observe
any significant differences among these groups according
to trimesters. They suggested that the observed
hyperlipoproteinemia during pregnancy is independent
of diabetic status.17 Kilby et al had also showed higher
lipid levels in pregnant type I diabetics, and although total
TGs, VLDL/LDL, HDL cholesterol increased with gesta-
tion in those with type I diabetes, there was no significant
difference from gestationally matched controls.20 Other
authors reported lower median maternal total cholesterol
(TC) and HDL cholesterol in type I diabetic pregnan-
cies.20-22 Moreover, Koukkou et al reported higher
triglyceride and lower LDL cholesterol levels in gestational
diabetes, and HDL cholesterol, TC, ApoA1, ApoB, HDL/
LDL cholesterol ratio were not different between
groups.23
METABOLIC DISORDERS UNIQUE TO
GESTATIONAL PERIOD
Pregnancy has been suggested as a stress test for life. Dur-
ing pregnancy, almost every organ of the mother has to
work more to meet the needs of developing conceptus.
Maternal organ systems adapt to these changes at differing
paces; and when these organ systems are unable to meet
the increased physiological demands of pregnancy, gesta-
tional syndromes develop. For these disorders, delivery
induces remission, but it is usually transient. The compo-
nents or full-blown clinical picture of the gestational
syndrome or disorder may reappear later in life.24 The
gestational syndromes that have been linked to diseases
later in life at least includes the following:
(a) Gestational diabetes mellitus (GDM): Women
with GDM have a 17% to 63% risk of nongesta-
tional diabetes within 5 to 16 years after the index
pregnancy. The risk of diabetes is particularly high
in women who have marked hyperglycemia
during or soon after pregnancy, women who are
obese, and women whose gestational diabetes was
diagnosed before 24 weeks of gestation.25
(b) Gestational hypertension: Preeclampsia and
pregnancy-induced hypertension had been found
to be related with cardiovascular disease later in
life.24 There is a 5-fold increased risk of death
from stroke and a 8-fold increased risk of death
434 Reproductive Sciences Vol. 16, No. 5, May 2009 Basaran

Table 2. Triglyceride Levels of 4 Patients in the Study of Montes et al27

Triglyceride (mg/dL)

Prepregnant Pregnant Postpartum

Week 36 Week 6 Week 20 Week 40 Week 100

95th percentile 127 387 157 127 127 127

D.R. – 600 211 102 – –
F.S. – 434 179 124 – –
Y.F. – 716 221 151 – –
C.B. 126 1195 392 – 570 173

Table 3. Total Cholesterol Levels of 4 Patients in the Study of Montes et al27

Total Cholesterol (mg/dL)

Prepregnant Pregnant Postpartum

Week 36 Week 6 Week 20 Week 40 Week 100

95th percentile 225 318 265 225 225 225

D.R. – 329 169 163 – –
F.S. – 184 212 169 – –
Y.F. – 257 267 205 – –
C.B. 223 274 260 – 232 213

from cardiovascular diseases compared with
women who had a normotensive pregnancy.26
In addition, patients with preeclampsia during
their pregnancy have a 8-fold increased risk of
death from cardiovascular diseases.26
(c) Gestational diabetes insipidus: Placenta produces
vasopressinase that degrades vasopressin. In response,
the maternal posterior pituitary produces up to
4 times as much vasopressin to sustain water home-
ostasis during pregnancy. Women who are unable to
increase their pituitary output develop diabetes insi-
pidus during pregnancy. Although there are no long-
term follow-up studies of these women, transient
gestational diabetes insipidus recurs in the third
trimester of subsequent pregnancies.24
Nevertheless, it is not clearly elucidated that pregnancy
also presents a challenge for the homeostasis of lipid levels.
When the above gestational syndromes are taken into
account, maternal adaptation during pregnancy can be
overwhelmed with regard to lipid metabolism also. In
addition, underlying metabolic disorders can be revealed
during pregnancy. Accordingly, English literature search
provides few articles to enlighten this gap. In this context,
2 groups can be identified that may have normal lipid lev-
els before and/or after the index pregnancy (Figure 1).
Patients having higher lipid levels than the expected
adaptation constitute the first group that can be named
as supraphysiologic hyperlipoproteinemia. The second
group is comprised of patients with extreme hyperlipo-
proteinemia revealed only during pregnancy.
SUPRAPHYSIOLOGIC HYPERLIPOPROTEINEMIA DURING
PREGNANCY
Some patients may not be able to adapt to gestational
changes occurring in lipid metabolism. In addition, in
homology with other gestational metabolic syndromes
that are previously stated, some patients may develop a
state of supraphysiologic hyperlipoproteinemia because
of failed adaptation to requirements of pregnancy. In
addition, supraphysiologic hyperlipoproteinemia may be
defined as patients with lipid levels greater than 95th per-
centile for the corresponding gestational age. This group
of patients had also been cited in the English literature as
‘‘prelipemic’’ by Montes et al.27 In the study of Montes
et al consisting of 29 pregnant participants, 4 cases had
elevations over the 95th percentile.27 Details of the 4 par-
ticipants are given in Tables 2 and 3. These patients were
associated with a slower return of total triglycerides and
VLDL to baseline, reduced HDL cholesterol antepartum
and postpartum, and atypical changes in LDL cholesterol
during pregnancy and postpartum. Moreover, Sattar et al

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Pregnancy-induced Hyperlipoproteinemia
have shown that triglyceride increments are minimal in
those participants who enter pregnancy with low basal
triglyceride levels, whereas those with higher basal
triglycerides show the greatest increase.13 This difference
was independent of the degree of increments in estrogen
levels, and authors had attributed this condition to
increased susceptibility to estrogen-induced hyperlipo-
proteinemia in the latter group.
In our view, pregnant women showing over the 95th
percentile triglyceride and cholesterol elevations are
analogous to GDM. Pregnancy is characterized, in part,
by insulin resistance and hyperinsulinemia, thus it may
predispose some women to develop diabetes during
gestation. Nearly all women with GDM are normoglyce-
mic after delivery. However, they are at risk for recurrent
GDM, impaired glucose tolerance, and overt diabetes.
As in the case of GDM, patients showing over the 95th
percentile triglyceride and cholesterol elevations may be
at risk of developing future hyperlipoproteinemia.
Qualifying patients in a group such as supraphysiolo-
gic hyperlipoproteinemia can be questioned because what
percentage of these patients will develop hyperlipoprotei-
nemia later in their life is unknown. In addition, there are
no long-term follow-up studies for this group. However,
this categorization (Figure 1) might help to determine
prognosis and outcome via future studies that may
enlighten this gap. The next question that comes in our
minds is that ‘‘could a test like 50-g oral glucose challenge
test be developed for this group?’’ By this way, a cutoff
triglyceride or cholesterol level can be determined and
this level may indicate patients under risk of hyperlipo-
proteinemia later in life. In addition, preventive measures
such as diet restriction, exercise, and pharmacological
treatment can be undertaken at a very early stage before
the development of complications. For the time being,
before definitive studies, routine screening to identify this
group of patients during pregnancy is unnecessary and
impractical.
EXTREME HYPERLIPOPROTEINEMIA LIMITED TO
GESTATIONAL PERIOD
In this group of patients, during pregnancy, plasma lipid
levels can be found to be extremely elevated and these
patients’ plasma lipid levels may return to normal in the
postpartum period. In a patient without a history of classic
forms of familial hyperlipoproteinemia, severe asympto-
matic hyperlipoproteinemia with level of triglyceride
over 1000 mg/dL is a rare complication of pregnancy.
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Reproductive Sciences Vol. 16, No. 5, May 2009 435
These cases usually come to attention in the second half
of pregnancy concordant with the physiologic rise.
Underlying disorders at least include dysbetalipoproteine-
mia, partial lipoprotein lipase deficiency (PLPLD), and
ApoE3/3 genotype. In these genetic disorders, hyperlipo-
proteinemia develops when a secondary metabolic factor
takes place such as pregnancy.
Ma et al reported 4 patients with severe hyperlipo-
proteinemia during pregnancy, 3 of them with PLPLD
and the fourth with ApoE3/3 genotype; also, the same
authors previously had reported another case with partial
LPLD with 12% of the normal activity.28 The range of
triglyceride levels in these patients was between 2314 and
14 596 mg/dL during pregnancy and 80 and 623 mg/dL
before pregnancy. The range of TC in these patients
was 132 to 320 mg/dL in nonpregnant state and 251 to
970 mg/dL in the third trimester of pregnancy.28 In our
experience, we had confronted with a patient belonging
to this group; she was incidentally diagnosed at 30th week
of gestation because of turbid cloudy supernatant appear-
ance of the blood samples.29 Severe hyperlipidemia was
demonstrated on further investigation with levels of
triglyceride 1411 mg/dL. At 37th week of gestation,
measured triglyceride level was 1866 mg/dL. In the con-
trol visit at the fourth postpartum week, triglyceride,
HDL, LDL, VLDL, and TC were declined completely
into the same levels as in prepartum status, that is, 262,
30, 55, 52, and 138 mg/dL, respectively. A similar patient
had also been reported by Eskandar et al as ‘‘severe, gesta-
tional, nonfamilial, nongenetic hypertriglyceridemia.’’30
The other condition that may cause severe hyperlipo-
proteinemia limited to gestational period is dysbetalipo-
proteinemia for which the differential diagnosis from
PLPLD and ApoE3/3 genotype may prove difficult.
Dysbetalipoproteinemia is a genetic disorder of lipid
metabolism and it is characterized by elevated plasma
cholesterol and triglycerides that are elevated approximately
to equal levels and usually over 300 to 400 mg/dL.31
Dysbetalipoproteinemia is caused either by the expression
of forms of ApoE that are defective in binding to lipopro-
tein receptors or by ApoE deficiency. More than 90% of
individuals with dysbetalipoproteinemia are homozygous
for ApoE2 (‘‘classical’’ type); the remainder is ApoE2
heterozygous or carriers of rare ApoE mutants (‘‘nonclas-
sical’’ type).32 However, only a minority (1 in 20) of
ApoE2 homozygotes will be overtly hyperlipidemic.33
Diagnosis of dysbetalipoproteinemia is often suspected
when both the TC and TG concentrations are increased
and the TC/TG molar ratio approximates 2:1. However,
there are no simple diagnostic tests. Electrophoresis of
436 Reproductive Sciences Vol. 16, No. 5, May 2009
plasma samples typically demonstrates a broad band in the
(-migrating lipoprotein region. Patients can also be tested
for ApoE2 homozygosity either by isoelectric focusing
of plasma or by ApoE genotyping with PCR-based
methods.33 Remnant accumulation sufficient to cause
hyperlipidemia usually occurs only when a second meta-
bolic hit increases lipoprotein production (eg, diabetes) or
further decreases remnant clearance (eg, hypothyroidism).
Although scarcely reported in the English literature,
women with dysbetalipoproteinemia may have exacer-
bation during pregnancy. Glueck et al reported an
entirely asymptomatic participant; triglyceride levels greater
than 5000 mg/dL were discovered incidentally at term. In
addition, plasma triglyceride levels abruptly had fallen
postpartum to less than 500 mg/dL with a fat-restricted
diet, and subsequent studies revealed the so-called
dysbetalipoproteinemia.34
According to the reported cases in the English litera-
ture, management of patients in this group with extremely
low fat diet is usually adequate.28-30,34 However, an indivi-
dualized approach may be required regarding the clinical
condition and lipid profile of the patients. With progressive
increase of the triglycerides (to over 2000 to 3000) and
cholesterol in patients that are unresponsive to dietary man-
agement, acute pancreatitis and other hyperlipoproteinemia-
associated complications may develop.30 Although the drug
therapy is contraindicated during pregnancy, antihyperlipi-
demics may be administered after a careful risk-benefit
analysis.35,36 Other treatment options for nonresponsive
patients include total parenteral nutrition (associated with
severe side effects), lipoprotein apheresis (heparin-induced
extracorporeal LDL precipitation [HELP], double filtration
plasmapheresis [DFPP], recently named lipidfiltration,
direct adsorption of lipoproteins [DALI], dextran sulfate
adsorption [DSA], and LDL immunoadsorption), and
plasma exchange.37 Performance of the indicated methods
of lipoprotein apheresis in patients with familial hypercholes-
terolemia showed decrease in LDL cholesterol by 60% and
triglyceride between 20% and 50%.37 In addition, this expe-
rience can be extrapolated to the management of this group
of patients according to their lipid levels.
In conclusion, hyperlipoproteinemia during preg-
nancy could be classified according to clinical implications
and future prospects as in Figure 1. Groups peculiar to
pregnancy are supraphysiologic hyperlipoproteinemia and
extreme hyperlipoproteinemia limited to gestational
period. These 2 groups may have overlapping clinical
presentations and these gestational entities may have an
impact on the future life of women. However, these
issues can only be answered via further studies. When
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Basaran
disorders unique to gestational period are considered, preg-
nancy may be accepted as an opportunity to identify
women under cardiovascular morbidity and mortality risk.
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