Physiologic and Supraphysiologic Increases in Lipoprotein Lipids ...

Physiologic and supraphysiologic increases in lipoprotein lipids and apoproteins in late
pregnancy and postpartum. Possible markers for the diagnosis of "prelipemia".
A Montes, C E Walden, R H Knopp, M Cheung, M B Chapman and J J Albers
Arterioscler Thromb Vasc Biol. 1984;4:407-417
doi: 10.1161/01.ATV.4.4.407
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Physiologic and Supraphysiologic Increases
in Lipoprotein Lipids and Apoproteins
in Late Pregnancy and Postpartum
Possible Markers for the Diagnosis of "Prelipemia"
Agustin Montes, Carolyn E. Walden, Robert H. Knopp, Marian Cheung,
Margaret B. Chapman, and John J. Albers
A supraphysiologic (>95th percentile) rise in plasma lipids in pregnancy may serve
as a marker for "prelipemia" in the same way that gestational diabetes is a marker for
prediabetes. To qualify as prelipemic, subjects with an abnormal lipid rise antepartum
must return to normal postpartum but may have other identifying characteristics. This
paper describes the antepartum-postpartum changes of lipoprotein lipids and apoproteins
at 34 to 38 weeks of gestation and 6 and 20 weeks postpartum in 23 subjects
with physiologic and six subjects with supraphysiologic plasma lipid increases during
pregnancy. These results are compared to measurements in 23 nonpregnant
controls matched for weight, age, and race. In subjects with a physiologic antepartum
lipid rise, postpartum total triglyceride and very low density lipoprotein (VLDL) lipids
(cholesterol and triglyceride) and apo B returned to baseline within 6 weeks. In contrast,
low density lipoprotein (LDL) showed a slow postpartum decline in lipids and
apo B with elevations remaining at 20 weeks postpartum. High density lipoprotein
(HDL) cholesterol concentrations, elevated in pregnancy, remained elevated at 6
weeks postpartum, but fell to baseline by 20 weeks postpartum. HDL triglyceride and
apo A-l concentrations, both elevated in pregnancy, returned to baseline by 6 weeks
postpartum. A supraphysiologic triglyceride rise in pregnancy was associated with a
slower return of total triglycerides and VLDL to baseline, reduced HDL cholesterol
ante- and postpartum, atypical changes in LDL cholesterol during pregnancy and
postpartum, and evidence of hyperlipidemia among family members. Two subjects
with hypercholesterolemia in the nonpregnant state showed no marked exaggeration
of total or LDL cholesterol concentrations in pregnancy. The data support the hypothesis
that a supraphysiologic rise in plasma triglyceride concentrations in late pregnancy
may serve as a marker of prelipemia. Proof of the hypothesis requires further
investigation and longer follow-up.
(Arteriosclerosis 4:407-417, July/August 1984)
Glucose intolerance and hyperlipidemia are physiologic
accompaniments of normal pregnancy.
12 With respect to glucose homeostasis, it is well
known that some women manifest overt diabetes
under the stress of pregnancy but revert to normal
after delivery. The deterioration of glucose homeo-
From the Northwest Lipid Research Clinic and the Department
of Medicine, School of Medicine, University of Washington, and
the Department of Biostatistics, School of Public Health and Community
Medicine, Seattle, Washington.
This work was supported by the Lipid Research Clinic Program
Contract HL 12157 and Grant HD 08960 and by the Council for
Tobacco Research, USA. Dr. Albers is an Established Investigator
of the American Heart Association.
Current address for Dr. Montes: Catedra 2, de Fisiologia, Facultad
de Medicina, Cuidad Universitaria, Madrid 3, Spain.
Address for reprints: Robert H. Knopp, M.D., 326 Ninth Avenue,
Seattle, Washington 98104.
Received August 17, 1983; revision accepted March 14, 1984.
407
stasis in pregnancy, known as gestational diabetes,
134 is considered to be a form of prediabetes
because it predicts later progression to overt diabetes
with a high degree of accuracy. 4 It is not yet
known if a similar deterioration of lipid homeostasis
occurs in pregnancy, reverts to normal postpartum,
and predicts the appearance of overt nongestational
hyperlipidemia years later. Such a condition might be
termed "prelipemia" and if identified would provide
an important tool to study the natural history of hyperlipidemia
from its earliest stages.
This paper presents information to support the
hypothesis that prelipemia is identified by a supraphysiologic
lipid rise in pregnancy. The postpartum
return of plasma lipids and lipoproteins to baseline is
described in normal subjects. These results are compared
to women with supraphysiologic elevations in
triglyceride or cholesterol in pregnancy but with de-
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408 ARTERIOSCLEROSIS VOL 4, No 4, JULY/AUGUST 1984
monstrable normolipidemia before or after pregnancy.
Relatives of these subjects were examined for
evidence of familial hyperlipidemia. The distinction
between physiologic and supraphysiologic antepartum
increases in lipoprotein lipids in pregnancy was
made on the basis of the 95th percentile outpoints for
lipoprotein triglyceride and cholesterol concentrations
in late gestation that we have recently described.
5
Subjects
Methods
Twenty-three pregnant women with a physiologic
plasma lipid increase in pregnancy were recruited for
this study from the classes of the Childbirth Education
Association (CEA) in Seattle and King County.
Six other pregnant women with supraphysiologic lipid
increases in pregnancy were referred or found
through surveys. Two of these subjects, one hypertriglyceridemic
(Subject DR), and one hypercholesterolemic
(Subject AM), were identified in the original
CEA survey. All subjects gave informed written consent.
A physiologic increase in plasma lipids in pregnancy
was defined as a total plasma triglyceride and
cholesterol concentration less than the 95th percentile
at 36 weeks of gestation (387 mg/dl for triglyceride
and 318 mg/dl for cholesterol). 5 A supraphysiologic
increase in plasma lipids in pregnancy was
defined as a total plasma triglyceride or cholesterol
concentration at or above the 95th percentile at 36
weeks of gestation. The pregnant subjects were
compared with 23 nonpregnant subjects matched for
age and Quetelet Index (body mass index calculated
as weight/height 2 x 1000) with the 20-week postpartum
body mass index of the study subjects used for
matching to controls. Control subjects were drawn
from a random sample of female Pacific Northwest
Bell Company employees whose characteristics
were described previously. 8 " 8 The nonpregnant controls
and 20-week postpartum subjects having antepartum
physiological increases in blood lipids were
closely matched for age, weight, height, and body
mass index (Table 1). Women with supraphysiologic
lipid increases were generally heavier and had a
higher Quetelet Index.
Length of gestation was estimated from the first
day of the last menstrual period. Pregnant subjects
were studied within 2 weeks of the antepartum target
week and within 1 week of the postpartum target
week. All subjects were free-living and consuming
their customary diets; there was no systematic attempt
to restrict calories in these subjects. All fasting
glucose concentrations were normal in the pregnant
subjects (mean 72.6 ± 1.6 mg/dl, range 60-87) and
in nonpregnant subjects (91.5 ± 7.6 mg/dl, range
79-108). No medications except multivitamins were
taken during pregnancy. All newborn infants were
healthy and of normal weight (mean 3581 g ± 87.6,
range 2727-3949 g), except one who was anencephalic.
The lipid and apoprotein measurements in
the mother of this infant were typical. Of the women
with physiological hyperlipidemia, 19 women breastfed
postpartum and four did not. None took oral contraceptives
during the postpartum study period. One
other woman (Subject EW) was studied before, as
well as during and after, pregnancy. Her results are
considered separately. She was normoglycemic and
delivered a normal infant weighing 3580 g. The lactational
status of the women with supraphysiologic lipid
increases are noted in the tables or text. None used
oral contraception postpartum.
Table 1. Characteristics of Pregnant Subjects with Physiologic or Supraphysiologic Lipid
Increases and Nonpregnant Normal Controls
Physiologic increase
Antepartum week 34-38
Postpartum week 6
Postpartum week 20
Nonpregnant controls
Supraphysiologic increase
Triglyceride
D.R.
F.S.
Y.F.
C.B.
Cholesterol
M.R.
N.C.
Values are means ± SD.
*Prepregnant body weight.
No.
23
—
—
23
Age
(yrs)
28.0 ±4.2
—
—
27.8±4.2
26
32
27
27
34
30
Weight
(kg)
70.6±7.1
62.2±7.7
60.6±8.7
60.3 ±8.1
64.5*
84.5
80.4
69.6
64.5
55.2
Height
(cm)
167.6 ±6.4
—
—
166.5±6.0
162.6
172.7
162.6
165.0
154.9
165.1
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Body mass
index
(kg/cm 2 x
1000)
2.52 ±0.30
2.22 + 0.22
2.16±0.29
2.17±0.23
0.244*
0.283
0.304
0.256
0.269
0.203

Blood Sampling
PREGNANCY HYPERLIPIDEMIA AND PRELIPEMIA Montes et al. 409
Blood samples in pregnant and postpartum women
were obtained by a research nurse in each subject's
home to minimize the effects of stress on fuel
and lipoprotein homeostasis. Nonpregnant subjects
came to the Northwest Lipid Research Clinic for
blood drawing. All subjects had fasted for 12 to 14
hours before the sampling. About 35 ml of venous
blood were obtained from subjects who were sitting.
The blood for lipid analysis contained 1.5 mg EDTA
per ml blood and was kept on ice until centrifuged in
the laboratory. The blood for glucose estimation was
collected in tubes containing 2.5 mg sodium fluoride
and 2.0 mg potassium oxalate per ml blood.
Lipoprotein and Apoproteln Analyses
Plasma samples were overlain with 0.9% saline
and ultracentrifuged in a 40.3 rotor at 40,000 rpm at
17° C for 18 hours. 9 The top 2 ml were analyzed as
very low density lipoprotein (VLDL). The bottom fraction
was brought to a measured 5 ml with saline and
analyzed as the d > 1.006 fraction. Another 3 ml of
whole plasma was treated with heparin and MnCLg
to precipitate VLDL and low density lipoprotein
(LDL), allowing measurement of high density lipoprotein
(HDL) lipids in the supernatant. 9 ' 10 The apo B
content of the supernatant fraction never exceeded 2
mg/dl by immunoassay. LDL lipid concentrations
were determined as the difference between the d <
1.006 infranatant and HDL. Triglyceride and cholesterol
were measured using the AutoAnalyzer II
method. 9
Apolipoprotein B (apo B) was measured in total
plasma and VLDL by a double antibody radioimmu-
noassay as previously described. 11 LDL apo B was
calculated as the difference between total plasma
and VLDL apo B. Apolipoprotein A-l was measured
on whole plasma by a radial immunodiffusion method
after tetramethylurea delipidation. 12
The ratios of triglyceride/cholesterol and lipid/apoprotein
in each lipoprotein fraction are presented as
indices of lipoprotein composition.
Statistical Analyses
The mean, standard deviation, and median described
lipoprotein lipids, apoproteins and ratios for
the nonpregnant controls and the antepartum and
postpartum subjects. Nonparametric statistical
methods were used for significance testing because
of the small sample sizes. Wilcoxon's matched pairs
test 13 was performed to determine if significant differences
existed between antepartum and postpartum
measurements and between 6- and 20-week postpartum
values. The Wilcoxon rank sum test 13 was
used to detect differences between controls and antepartum,
6-week, and 20-week postpartum subjects.
Mean values and 95% confidence intervals
were used to graphically illustrate antepartum-topostpartum
changes.
Results
Physiologic Hyperllpldemla In Pregnancy
Table 2 presents the antepartum-postpartum lipoprotein
observations in subjects with physiologic
hyperlipidemia in pregnancy and matched nonpregnant
controls. Selected lipoprotein lipid and apoprotein
changes are illustrated in Figure 1. Ratios of
Table 2. Plasma Lipoprotein Lipid and Apoproteln Concentrations (mg/dl) in 23 Women In Late
Pregnancy and Postpartum and in 23 Age- and Body-Mass-Matched Nonpregnant Controls
Total
Triglyceride
Cholesterol
Pregnant
Weeks 34-38
Mean±SD Median Mean
222 ±60
251 ±32
223*
244*
VLDL
Triglyceride 107 ±41 100*
Cholesterol 22 ± 9 20*
ApoB 20±11 23*
LDL
Triglyceride
Cholesterol
ApoB
HDL
Triglyceride
Cholesterol
ApoA-1
72 ±21
161 ±39
84±23
29 ±9
64 ± 9
164+16
70
151*
81*
26*
65*
167*
Week 6 Week 20
±SD
71 ±23
205 + 23
Postpartum
Median Mean ± so
66t
204*t
29±18 23t
7±4 6*f
4±3 4t
27 + 10
124±21
104±17
8±3
64±12
127±22
26*t
127*t
103*f
9*t
62*
130t
'Significantly different from controls at p s 0.05.
tSignificantly different from antepartum at p < 0.05.
^Significantly different from 6 week postpartum at p < 0.05.
66±18
190±28
Median
62t
187*t*
28±16 21t
6±5 5't
4±2 4t
23±7 21*t
120 ±24 120't
88 ±16 90*tt
8±4
56±11
132±16
10t
131f
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Nonpregnant controls
Mean±sD
59±19
171+26
33±14
11+6
7 + 6
14±10
104±23
61 ±10
12±6
56±12
128±23
Median
58
165
31
10
6
13
103
62
11
53
124

410 ARTERIOSCLEROSIS VOL 4, No 4, JULY/AUGUST 1984
50-
LDL:
150-
2* 100 H
HDL:
150-
100-
50-
Weeks. 36

PREGNANCY HYPERLIPIDEMIA AND PRELIPEMIA Montes et al. 411
Table 3. LIpoprotein Lipid and Apoproteln Ratios In 23 Women in Late Pregnancy and Postpartum and In 23
Age- and Body-Mass-Matched Nonpregnant Controls
VLDL
TG/chol
TG/apo B
Chol/apo B
LDL
TG/chol
TG/apo B
Chol/apo B
HDL
TG/chol
TG/apo A-1
Chol/apo A-1
Pregnant
Weeks 34-38
Mean±SD Median Mean
5.10±1.10 5.00*
7.79 ±5.07 5.21
1.57 ±0.98 0.99
0.46±0.10
0.91 ±0.30
2.02 + 0.65
0.44*
0.87*
1.93
0.46 ±0.15 0.50*
0.18±0.05 0.16*
0.39 ±0.07 0.40*
Week 6 Week 20
±SD
4.88 ±2.40 4.00*
9.30±9.08 7.00
2.31+3.07 1.60
0.23 ±0.08
0.26 + 0.08
1.21 ±0.25
0.14±0.06
0.07 ±0.03
0.51 ±0.11
Postpartum
Median Mean±sD
0.22*t
0.25f
1.14*t
0.13*t
0.07t
0.48*t
'Significantly different from controls at p s 0.05.
tSignificantly different from antepartum at p == 0.05.
^Significantly different from 6 weeks postpartum at p ^ 0.05.
80-
60-
I6O-
80-
mg/dl
240-
I6O
80-
O- 1
Glucose
Triglycerkje
Cholesterol
8 16 24
Pregnancy
6.14±3.76
7.56 ±4.01
1.50 ±1.02
0.20 ±0.07
0.26 ±0.08
1.38 ±0.29
0.15 ±0.08
0.07 + 0.03
0.42 ±0.08
32 40
Weeks
Median
5.67*
6.18
1.15
0.20*t
0.25f
1.43*t
0.16*t
0.07*t
-VLDL
Nonpregnant controls
Mean±sD
3.69 ±3.48
10.88± 14.86
3.06 ±3.32
0.14 + 0.08
0.23±0.17
1.72 ±0.28
0.21 ±0.09
0.09 ±0.04
0.44 + 0.06
LDL
6 20
Posfpartum
Figure 2. Plasma glucose, triglyceride, and cholesterol and lipoprotein cholesterol
concentrations in subject EW before, during, and after pregnancy. Glucose declined
while all lipids increased throughout pregnancy. Postpartum, triglyceride and VLDL
cholesterol fell to slightly below prepregnancy levels by 6 weeks of gestation and HDL
cholesterol fell to normal by 20 weeks. LDL cholesterol declined more slowly and
remained above prepregnancy levels at 20 weeks postpartum.
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Median
2.99
4.11
1.50
0.12
0.22
1.74
0.20
0.09
0.44

412 ARTERIOSCLEROSIS VOL 4, No 4, JULY/AUGUST 1984
Table 4. Hypertrlglycerldemla In Pregnancy: Subject D.R.
Pregnant
Week 36
Week 6
Whole plasma (mg/dl)
Triglyceride
Cholesterol
VLDL (mg/dl)
Triglyceride
Cholesterol
Apo B
LDL (mg/dl)
Triglyceride
Cholesterol
Apo B
HDL (mg/dl)
Triglyceride
Cholesterol
Apo A-1
600
329
382
79
44
164
240
181
10
14
158
(387)*
(318)
(246)
(47)
(113)
(218)
121
(21)
(42)
95
211
169
131
23
9
34
114
99
7
12
95
(157)*
(265)
(122)
(29)
(36)
(177)
(4)
(44)
Postpartum
Week 20
102
163
69
15
7
24
109
6
36
116
(127)*
(225)
(83)
(28)
(35)
(157)
(5)
(35)
Week 40
115
154
71
17
25
97
15
40
(127)*
(225)
(83)
(28)
(35)
(157)
D.R.'s infant's birth weight was 3239 g. D.R. elected not to breast feed postpartum or use oral
contraceptives. See text for family study lipids.
'Denotes 95th percentiles for total, VLDL, and LDL lipids and 5th percentile for HDL lipids. Values for
36 weeks of gestation and 6 weeks postpartum are based on a study of 553 pregnant women (see
reference 5); values are from reference 6 for 20- to 29-year-old nonpregnant, nonhormone-taking subjects
(Weeks 20 and 40).
Table 5. Summary of Endogenous Hypertrlglycerldemic Subjects Studied In Pregnancy
Pre-
Pregnant
Postpartum
pregnant Week 36 Week 6 20 40 100
Total triglyceride (mg/dl)
(95th percentile)
D.R.
F.S.
Y.F.
C.B.
Total cholesterol (mg/dl)
(95th percentile)
D.R.
F.S.
Y.F.
C.B.
LDL cholesterol (mg/dl)
(95th percentile)
D.R.
F.S.
Y.F.
C.B.
HDL cholesterol (mg/dl)
(95th percentile)
D.R.
F.S.
Y.F.
C.B.
(127)*
—
—
—
116
(225)
—
—
—
223
(157)
—
—
160
(35)
—
—
40
(387)t
600
434
716
1195
(318)
329
184
257
274
(218)
240
70
60
61
(42)
14
40
43
38
(157)t
211
179
221
392
(265)
169
212
267
260
(177)
114
152
187
163
(44)
12
34
36
36
(127)*
102
124
151
—
(225)
163
169
205
—
(157)
109
124
124
—
(35)
36
29
32
—
(127)*
115
—
—
570
(225)
154
—
—
232
(157)
97
—
—
—
*Percentiles from a population of nonpregnant subjects (see reference 6).
tPercentiles from a population study of pregnant and postpartum subjects (see reference 5).
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(35)
40
—
—
34
(5)
(35)
(127)*
—
—
—
173
(225)
—
—
—
213
(157)
—
—
—
139
(35)
—
—
—
39

PREGNANCY HYPERLIPIDEMIA AND PRELIPEMIA Montes et al. 413
/ /
£• £• 6
20 40 60
Weeks Postpartum
Figure 3. Plasma total triglyceride and LDL and HDL cholesterol concentrations
antepartum, at 36 weeks of gestation, and at various times postpartum in four hypertriglyceridemic
subjects in pregnancy compared with the 95th or 5th percentiles of a
random population of pregnant women or nonpregnant women aged 20 to 29 years.
Total triglyceride for subject YF (aged 33) is above the 95th percentile for women aged
20-29 at 20 weeks postpartum, but below the 95th percentile for women aged 30-39.
Supraphysiologic Hyperlpidemia in Pregnancy
The results are considered by the individual subject
in the text and are summarized in Tables 4 to 6
and Figure 3. Subject DR was studied in detail (Table
4 and Figure 3). She was markedly hypertriglyceridemic
and slightly hypercholesterolemic in late gestation
as compared to 95th percentile reference values.
5 The VLDL triglyceride level of 382 mg/dl was
well above the 95th percentile in pregnancy (246 mg/
dl). The LDL triglyceride and cholesterol concentrations
both exceeded the 95th percentile at 36 weeks
of gestation, but the relative amounts of her triglyceride,
cholesterol, and apo B in LDL remained approximately
the same as in the 23 normal subjects (Table
2). Her HDL triglyceride and cholesterol concentrations
were markedly reduced in pregnancy, while the
apo A-l concentrations remained at a level typical for
pregnancy (158 mg/dl).
At 6 weeks postpartum, DR's plasma triglyceride
concentrations remained above the 95th percentile,
but at 20 and 40 weeks postpartum they fell within
the 95th percentile of triglyceride for nonpregnant,
nonhormone-using subjects. 6 A similar slow postpartum
decline was seen for VLDL triglyceride. LDL tri-
100
glycerides had dropped more abruptly by 6 weeks
postpartum, while HDL triglyceride declined slowly.
LDL cholesterol showed a continuing decline
through 40 weeks postpartum but was within the
95th percentile by 6 weeks postpartum. HDL cholesterol
was still low at 6 weeks postpartum, rose by 20
weeks postpartum, but even at 40 weeks postpartum
was only marginally above the 5th percentile for HDL
cholesterol in nonpregnant women aged 20-29. In
contrast, apo A-l concentrations at 6 and 20 weeks
postpartum were only slightly below the mean for
nonpregnant, nonhormone-treated normal subjects
(125 mg/dl). 12
Two years later, subject DR was observed in a
second pregnancy at 36 weeks of gestation. Total
plasma triglyceride was 400 mg/dl (>95th percentile),
LDL cholesterol was 167 mg/dl (

414 ARTERIOSCLEROSIS VOL 4, No 4, JULY/AUGUST 1984
Table 6. Hypercholesterolemla In Pregnancy:
Subject A.M.
Whole plasma
Triglyceride
Cholesterol
VLDL (mg/dl)
Triglyceride
Cholesterol
Apo B
LDL (mg/dl)
Triglyceride
Cholesterol
Apo B
HDL (mg/dl)
Triglyceride
Cholesterol
Apo A-1
Pregnant
Week 36
(mg/dl)
226 (387)
326 (318)
87 (246)
15 (47)
20
98 (113)
230 (218)
116
23 (21)
60 (42)
164
Postpartum
Week 6 Week 20
118 (157)
250 (265)
40 (122)
9 (29)
11
50 (36)
167 (177)
184
13 (4)
59 (44)
150
105 (160)
254 (240)
20 (112)
4 (28)
4
68 (28)
181 (159)
103
11 (4)
52 (33)
150
A.M.'s infant's birth weight was 2789 g. A.M. breast fed
for 8 weeks postpartum.
Parentheses denote 95th percentiles for total, VLDL,
and LDL lipids and 5th percentile for HDL lipids. Values for
36 weeks of gestation and 6 weeks postpartum are based
on a study of 553 pregnant women (see reference 5);
values for age 30-39 nonpregnant, nonhormone-taking
subjects (Week 20) are from reference 6.
242 (>90th age-specific percentile), a total-cholesterol
of 257 (>75th percentile), an LDL cholesterol of
181 (~90th percenile), and an HDL cholesterol of 37
(~15th percentile). The mother's lipoproteins were
close to the median values for her age and sex: total
triglyceride, 149; total cholesterol, 227; LDL cholesterol,
175; while her HDL cholesterol, 72 mg, was
near the 75th percentile. Thus, there is evidence for
elevated total triglyceride and LDL cholesterol in a
first degree relative of DR.
Three other subjects with supraphysiologic triglyceride
increases in pregnancy are compared to DR in
Table 5 and are also illustrated in Figure 3. One of
these women, subject CB, was the mother of two
hypertriglyceridemic children with fasting chylomicronemia
and plasma triglyceride levels of 6460 and
796 mg/dl at ages 3 and 1, respectively, on an unrestricted
diet. CB's parents had triglycerides at the
75th and 90th percentiles and cholesterol at the 75th
percentile. 68 CB therefore appears to be an obligate
heterozygote for the Type I phenotype. YF's brother
(aged 29) had total and LDL cholesterol concentrations
(237 and 163 mg/dl, respectively) at or above
the age- and sex-specific 95th percentiles (222 and
165 mg/dl) and a total triglyceride concentration (135
mg/dl) >90th percentile. YF's father had average
lipoprotein lipid concentrations. Thus, there is an association
of hyperlipidemia in a first degree relative
of YF. The relatives of FS were not available for
study.
All four subjects were below the 95th percentile
values for total plasma triglycerides either before
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pregnancy or 20 weeks postpartum, but were markedly
above the 95th percentile in late gestation. All
subjects showed a delay in the postpartum decline of
total triglyceride concentrations compared with normal
subjects, in that at 6 weeks postpartum, total
triglyceride concentrations were consistently above
the 95th percentile (Table 5 and Figure 3). Similar
trends were observed in VLDL triglyceride and cholesterol
(data not shown). Disparate responses were
seen among the four subjects with respect to total
and LDL cholesterol ante- and postpartum. DR was
the only subject showing a combined elevation of
triglyceride and cholesterol in pregnancy. All others
had abnormal increases only in total and VLDL triglyceride.
Another distinction was the LDL cholesterol
fall at 6 weeks postpartum in DR, but a rise in the
other three. The 20-week postpartum or prepregnancy
LDL cholesterol concentrations in these three
subjects were also higher than the pregnancy levels.
HDL cholesterol concentrations were not as low in
subjects FS, YF, and CB as in subject DR, but were
near or below the 5th percentiles both ante- and
postpartum.
Hypercholesterolemic subject AM is presented in
Table 6 and in Figure 3. She was not on a cholesterol-restricted
diet at the time of the study. Total plasma
cholesterol concentrations were similar at 6 and
20 weeks postpartum, but were near or above the
95th percentile value. VLDL lipids and apo B were
consistently normal (compare the apo B results with
those in Table 2). The LDL cholesterol concentration
was above the 95th percentile at 36 weeks of gestation,
5 fell postpartum to slightly below the 95th percentile
at 6 weeks, but exceeded the 95th percentile
at 20 weeks. 6 Compared with 6 and 20 weeks postpartum,
the LDL cholesterol rise due to pregnancy
was 49 to 63 mg/dl. The apo B concentration was
about 40 mg/dl above the average at 36 weeks of
gestation and 20 weeks postpartum, but increased to
80 mg/dl above the average at 6 weeks postpartum,
an exaggeration of the pattern observed in normal
subjects at 6 weeks postpartum (Table 2). HDL lipids
were fairly typical in this patient; however, apo A-l did
not fall postpartum as much as expected.
A familial heterozygous hypercholesterolemic
woman with tendonous xanthomas (subject NC) was
studied at 37 weeks of gestation and 6 and 20 weeks
postpartum. The patient was on a cholesterol-restricted
and polyunsaturate-supplemented diet
throughout. Total cholesterol was 614 mg/dl and total
triglyceride, 232 mg/dl at 37 weeks of gestation.
Postpartum, 6- and 20-week total cholesterol concentrations
were 554 mg/dl and 530 mg/dl with cholesterol
concentrations in VLDL of 20 mg/dl and 24
mg/dl; LDL, of 484 mg/dl and 444 mg/dl; and HDL, of
60 mg/dl and 62 mg/dl. In NC the total cholesterol
rise in pregnancy (comparing 36 weeks of gestation
and 20 weeks postpartum) was 84 mg/dl, only slightly
higher than the total cholesterol increment observed
in 23 normal women over the same interval
(61 mg/dl). The conclusion from hypecholesterole

PREGNANCY HYPERLIPIDEMIA AND PRELIPEMIA Montes et al. 415
mic subjects AM and NC is that plasma cholesterol in
hypercholesterolemic subjects is not disproportionately
exaggerated in pregnancy in contrast to plasma
triglyceride in hypertriglyceridemics.
Discussion
Women with physiologic or supraphysiologic increases
in plasma triglyceride or cholesterol in pregnancy
were studied at 34 to 38 weeks of gestation
and at 6 and 20 weeks or longer postpartum to answer
the following questions: How rapidly do the
changes in plasma lipoproteins return to normal
postpartum in subjects who have a physiologic lipid
increase antepartum? Do subjects with supraphysiologic
increases antepartum return to normal postpartum
in the same manner and do they return to normal
at all? Are there identifying characteristics in lipoprotein
concentrations or family history that would suggest
that the supraphysiologic lipid rise in pregnancy
is a pathophysiologic process indicative of a subclinical
or prelipemic trait that may eventually progress to
overt hyperlipidemia?
In subjects with a physiologic triglyceride rise in
pregnancy, plasma total triglyceride and all VLDL
constituents reached a baseline level by 6 weeks
postpartum essentially identical to nonpregnant
con In subjects with a physiologic triglyceride rise
in pregnancy, plasma total triglyceride and all VLDL
constituents reached a baseline level by 6 weeks
postpartum essentially identical to nonpregnant control
subjects. All subjects with a supraphysiological
triglyceride rise in pregnancy had normal total plasma
triglyceride concentrations (

416 ARTERIOSCLEROSIS VOL 4, No 4, JULY/AUGUST 1984
A final argument that a supraphysiologic rise in
plasma triglyceride antepartum is a pathophysiologic
process signifying an underlying prelipemic trait is
based on the fact that all three subjects for whom
relatives were available show evidence of hyperlipidemia
among family members. The difference
among the subjects' responses to pregnancy, as well
as the available information among relatives, suggests
that the designation of prelipemia could represent
several distinct and possibly genetic underlying
disorders of lipoprotein metabolism. Further investigations
of larger numbers of prelipemic women with
in-depth family studies are necessary to resolve this
question. In addition, long-term follow-up will be necessary
to verify the hypothesis that the hyperlipidemic
stress of pregnancy can unmask a prelipemic
trait. Nonetheless, it is noteworthy that subject CB
has remained hyperlipidemic for almost 2 years
since delivery, her only normal value having been
obtained before the pregnancy we observed.
While the postpartum observations made at specific
times and the distinctions between subjects with
physiologic and supraphysiologic lipid increases in
pregnancy are entirely new, our antepartum observations
confirm several previously described features
of hyperlipidemia in pregnancy. These include
an increase in total and VLDL apo B, 24 little or no
change in VLDL composition, 2 2425 an increase in
triglyceride content of LDL and HDL, 22425 and an
increase in apo A-l. 26 Thus, conclusions drawn from
this paper can be considered to be generally representative
of the body of information on hyperlipidemia
in pregnancy.
The possibility that the hyperlipidemia of pregnancy
might confer added arteriosclerosis risk has
recently been raised. 2728 While it is true that an increase
in LDL cholesterol could enhance arteriosclerosis,
usually this change is associated with an apo
B-rich 29 and triglyceride-poor LDL, 30 which is the opposite
of that seen in pregnancy. In addition, HDL
cholesterol and apo A-l concentrations were increased,
which may facilitate cholesterol removal
from tissues. In light of these results, it is perhaps not
surprising that the epidemiologic evidence 31 that
arteriosclerosis is more common in multiparous
women is inconclusive. It is more likely that the observed
lipoprotein changes serve a physiological
purpose to support growth of maternal and fetal tissues
and production of large quantities of steroid
hormones. 5 ' 16 The extent to which the postpartum
lipoprotein changes are atherogenic is deserving of
further study.
In summary, evidence is presented to support the
hypothesis that the hyperlipidemic stress of pregnancy
can unmask a latent hypertriglyceridemia, by
using as a basis for recognition a triglyceride rise in
pregnancy exceeding the 95th percentile. Women
with such a supraphysiologic triglyceride rise antepartum
may return to normal levels postpartum more
slowly than normal, have LDL lipids that change in an
atypical manner antepartum and postpartum, have
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HDL cholesterol concentrations that are persistently
low antepartum and postpartum, and have hyperlipidemic
family members. In contrast, hypercholesterolemia
is not greatly exaggerated in pregnancy. Longterm
follow-up studies of women with genetically
well-characterized disorders of lipoprotein metabolism
are required to determine if an abnormal lipoprotein
response in pregnancy can identify prelipemic
subjects and distinguish among the major disorders
of lipoprotein metabolism. Identification of prelipemia
will provide an opportunity to study prospectively
the natural progression, potential for atherosclerosis,
and possible treatment of hyperlipidemia from
early adulthood.
Acknowledgments
The authors express their thanks to the staff of the Northwest
Liptd Research Clinic Core Laboratory who performed analyses;
to Susan Irvine who carefully obtained the samples; to the gracious
women of the Childbirth Education Association who volunteered
for participation in the study; and to Donna Gola and Lori
Lebon for excellent secretarial assistance.
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Index Terms, lipoproteins • apoproteins • pregnancy • hyperiipidemia • prelipemia
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