9
ORIGINAL ARTICLE Postpartum Weight Retention is Associated with Elevated Ratio of Oxidized LDL Lipids to HDL-Cholesterol Jatta Puhkala Riitta Luoto Markku Ahotupa Jani Raitanen Tommi Vasankari Received: 31 July 2013 / Accepted: 13 September 2013 / Published online: 12 October 2013 Ó AOCS 2013 Abstract Oxidized LDL lipids (ox-LDL) are associated with lifestyle diseases such as cardiovascular diseases, metabolic syndrome and type 2 diabetes. The present study investigated how postpartum weight retention effects on ox-LDL and serum lipids. The study is a nested compara- tive research of a cluster-randomized controlled trial, NELLI (lifestyle and counselling during pregnancy). Dur- ing early pregnancy (8–12 weeks) and 1 year postpartum, 141 women participated in measurements for determining of plasma lipids: total cholesterol (T-C), LDL-cholesterol (LDL-C), HDL-cholesterol (HDL-C), triacylglycerols (TAG) and ox-LDL. Subjects were stratified into tertiles (weight loss, unaltered weight and weight gain groups) based on their weight change from baseline to follow-up. Ox-LDL was determined by baseline level of conjugated dienes in LDL lipids. Among the group of weight gainers, concentration of TAG reduced less (-0.14 vs. -0.33, p = 0.002), HDL-C reduced more (-0.31 vs. -0.16, p = 0.003) and ox-LDL/HDL-C ratio increased (3.0 vs. -0.2, p = 0.003) when compared to group of weight loss. Both T-C and LDL-C elevated more (0.14 vs. -0.21, p = 0.008; 0.31 vs. 0.07, p = 0.015) and TAG and ox- LDL reduced less (-0.33 vs. 0.20, p = 0.033; -3.33 vs. -0.68, p = 0.026) in unaltered weight group compared to weight loss group. The women who gained weight devel- oped higher TAG and ox-LDL/HDL-C ratio as compared to those who lost weight. Postpartum weight retention of 3.4 kg or more is associated with atherogenic lipid profile. Keywords Oxidized LDL to HDL ratio Á Postpartum Á Plasma lipids Á Weight retention Á Weight loss Abbreviations BMI Body mass index GDM Gestational diabetes HDL-C HDL cholesterol LDL-C LDL cholesterol NELLI Name of the study, lifestyle and counselling during pregnancy OGTT Oral glucose tolerance test ox-LDL Oxidized LDL T-C Total cholesterol TAG Triacylglycerols Introduction The high levels of total cholesterol (T-C) and low-density lipoprotein cholesterol (LDL-C), and low levels of high- density lipoprotein cholesterol (HDL-C) are well-known risk factors for atherosclerosis and cardiovascular diseases [1]. In certain circumstances, LDL is oxidatively modified, which has several proatherogenic and proinflammatory effects in arterial wall [2]. Oxidized LDL (ox-LDL) is scavenged by macrophages in endothelium, which J. Puhkala (&) Á R. Luoto Á J. Raitanen Á T. Vasankari UKK Institute for Health Promotion Research, Box 30, 33501 Tampere, Finland e-mail: jatta.puhkala@uta.fi R. Luoto Á T. Vasankari The National Institute for Health and Welfare, Helsinki, Finland M. Ahotupa Department of Physiology, University of Turku, Turku, Finland J. Raitanen School of Health Sciences, University of Tampere, Tampere, Finland 123 Lipids (2013) 48:1227–1235 DOI 10.1007/s11745-013-3852-9

Postpartum Weight Retention is Associated with Elevated Ratio of Oxidized LDL Lipids to HDL-Cholesterol

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ORIGINAL ARTICLE

Postpartum Weight Retention is Associated with Elevated Ratioof Oxidized LDL Lipids to HDL-Cholesterol

Jatta Puhkala • Riitta Luoto • Markku Ahotupa •

Jani Raitanen • Tommi Vasankari

Received: 31 July 2013 / Accepted: 13 September 2013 / Published online: 12 October 2013

� AOCS 2013

Abstract Oxidized LDL lipids (ox-LDL) are associated

with lifestyle diseases such as cardiovascular diseases,

metabolic syndrome and type 2 diabetes. The present study

investigated how postpartum weight retention effects on

ox-LDL and serum lipids. The study is a nested compara-

tive research of a cluster-randomized controlled trial,

NELLI (lifestyle and counselling during pregnancy). Dur-

ing early pregnancy (8–12 weeks) and 1 year postpartum,

141 women participated in measurements for determining

of plasma lipids: total cholesterol (T-C), LDL-cholesterol

(LDL-C), HDL-cholesterol (HDL-C), triacylglycerols

(TAG) and ox-LDL. Subjects were stratified into tertiles

(weight loss, unaltered weight and weight gain groups)

based on their weight change from baseline to follow-up.

Ox-LDL was determined by baseline level of conjugated

dienes in LDL lipids. Among the group of weight gainers,

concentration of TAG reduced less (-0.14 vs. -0.33,

p = 0.002), HDL-C reduced more (-0.31 vs. -0.16,

p = 0.003) and ox-LDL/HDL-C ratio increased (3.0 vs.

-0.2, p = 0.003) when compared to group of weight loss.

Both T-C and LDL-C elevated more (0.14 vs. -0.21,

p = 0.008; 0.31 vs. 0.07, p = 0.015) and TAG and ox-

LDL reduced less (-0.33 vs. 0.20, p = 0.033; -3.33 vs.

-0.68, p = 0.026) in unaltered weight group compared to

weight loss group. The women who gained weight devel-

oped higher TAG and ox-LDL/HDL-C ratio as compared

to those who lost weight. Postpartum weight retention of

3.4 kg or more is associated with atherogenic lipid profile.

Keywords Oxidized LDL to HDL ratio �Postpartum � Plasma lipids � Weight retention �Weight loss

Abbreviations

BMI Body mass index

GDM Gestational diabetes

HDL-C HDL cholesterol

LDL-C LDL cholesterol

NELLI Name of the study, lifestyle and counselling

during pregnancy

OGTT Oral glucose tolerance test

ox-LDL Oxidized LDL

T-C Total cholesterol

TAG Triacylglycerols

Introduction

The high levels of total cholesterol (T-C) and low-density

lipoprotein cholesterol (LDL-C), and low levels of high-

density lipoprotein cholesterol (HDL-C) are well-known

risk factors for atherosclerosis and cardiovascular diseases

[1]. In certain circumstances, LDL is oxidatively modified,

which has several proatherogenic and proinflammatory

effects in arterial wall [2]. Oxidized LDL (ox-LDL) is

scavenged by macrophages in endothelium, which

J. Puhkala (&) � R. Luoto � J. Raitanen � T. Vasankari

UKK Institute for Health Promotion Research, Box 30,

33501 Tampere, Finland

e-mail: [email protected]

R. Luoto � T. Vasankari

The National Institute for Health and Welfare, Helsinki, Finland

M. Ahotupa

Department of Physiology, University of Turku, Turku, Finland

J. Raitanen

School of Health Sciences, University of Tampere, Tampere,

Finland

123

Lipids (2013) 48:1227–1235

DOI 10.1007/s11745-013-3852-9

accelerates the pathogenesis of atherosclerosis [3–5]. Ele-

vated ox-LDL level is associated with atherosclerosis [6].

Ox-LDL accumulates excessively into the arterial wall in

an unregulated fashion, whereas native LDL has no similar

properties [7]. HDL may protect LDL from oxidization and

attenuate the effects of ox-LDL in endothelium [8, 9].

HDL-C has multiple antiatherogenic and antioxidative

features [8–10]. Previous studies have shown that the ratio

of ox-LDL to HDL-C is a potential biomarker for increased

risk of coronary artery disease and all-cause mortality

[11, 12].

Being overweight is associated with many diseases,

including cardiovascular diseases [13], and it is also con-

nected to elevated plasma ox-LDL as well as decreased

HDL-C levels [14]. Obese individuals often tend to have

co-morbidities like metabolic syndrome and type 2 diabe-

tes that also are associated with same kind of alterations of

lipid profile [15]. There are only a few studies about effect

of weight change on ox-LDL levels. In a previous study,

the oxidation of LDL was reduced after weight reduction in

obese premenopausal women [16]. In obese middle-aged

men, ox-LDL was reduced after weight reduction and also

remained reduced among those who could maintain the

weight loss for 2 years [17]. Many other studies instead

have shown that weight reduction positively affects plasma

lipids like T-C, LDL-C, HDL-C and TAG [18, 19].

Pregnancy plays an important role in development of

excessive weight among many women. The magnitude of

parity-associated gained weight is around 0.5–3.2 kg,

estimated as 7 % increase of obesity risk with each addi-

tional child [20–22]. Variation in weight retention is large

and some women may retain over 17 kg [21]. The

triggering effect has turned into a cumulative effect among

multiparous women with at least three children, who can be

considered a special risk group. In Finland, 10-year trends

in obesity by parity have been associated with visceral

obesity [23].

We have earlier reported the main results of the lifestyle

trial, showing that intervention was effective in producing

positive changes in diet and physical activity [24]. The aim

of the current study is to perform an analysis of the trial

and follow-up data in order to investigate how postpartum

weight retention effects on concentration of ox-LDL and

serum conventional lipids.

Materials and Methods

The study is a nested comparative research of a gestational

diabetes (GDM) preventive trial, NELLI (lifestyle and

counselling during pregnancy) [24]. A more detailed

description of the design and methods has been reported

previously [25]. The primary aim of the trial was to prevent

GDM among pregnant women who were assessed in early

pregnancy to have increased risk for GDM. Women were

eligible if they had at least one of the following GDM risk

factors: age C40 years, pre-pregnancy body mass index

(BMI) C25 kg/m2, GDM or any sign of glucose intolerance

or a macrosomic baby (C4,500 g) in any previous preg-

nancy, or diabetes in first or second grade relatives. The

study was conducted in primary health care maternity

clinics in 2007–2009. The intervention included structured

individual counselling on weight gain, diet and physical

activity by public health nurses during five routine visits to

Table 1 Baseline (pre-

pregnancy or 8–12 weeks’

gestation) characteristics of

women by weight change from

baseline to 1 year follow-up

Means and standard deviations

or frequencies (and proportions)

of participants (n = 141) and

p values for differences between

the groups (one-way ANOVA

or v2 test)a n = 137b n = 139

Weight loss

group -16.6

to -0.5 kg

(n = 45)

Unaltered weight

group -0.4

to 3.4 kg

(n = 46)

Weight gain

group 3.5

to 18.0 kg

(n = 50)

p value

Age, years 31.6 ± 5.2 29.9 ± 4.9 29.8 ± 4.6 0.150

Height, cm 167.3 ± 6.8 167.0 ± 6.8 165.6 ± 5.4 0.365

Parity

0 13 (29) 13 (29) 23 (48) 0.140

1 24 (53) 24 (53) 16 (33)

C2 8 (18) 8 (18) 9 (19)

Educationa

University degree 16 (36) 13 (29) 11 (23) 0.456

Polytechnic education 15 (34) 22 (49) 21 (44)

Basic or secondary education 13 (30) 10 (22) 16 (33)

Smoking half a year before pregnancyb

No 37 (82) 32 (71) 36 (74) 0.767

Occasionally 5 (11) 7 (16) 7 (14)

Frequently 3 (7) 6 (13) 6 (12)

1228 Lipids (2013) 48:1227–1235

123

maternity clinics. The women in the control clinics

received usual maternal care including some dietary and

physical activity advice.

A total of 604 pregnant women participated in baseline

assessments (8–12 weeks’ gestation), of whom 442 (69 %)

were eligible for the randomized intervention study

(intensified counselling or usual care). The rest, 198

(31 %), were excluded, most of them (88 %) due to diag-

nosis of GDM [26] in early pregnancy. A total of 464

women participated in follow-up assessments 1 year post-

partum. Women with new pregnancies were excluded from

follow-up measurements. Current data consisted of results

from 141 women, who had information available for both

the lipids and weight at early pregnancy and 1 year post-

partum. Of these, 50 (36 %) of them had been in the ori-

ginal intensified counselling group, 59 (41 %) in the usual

care and 32 (23 %) had abnormal OGTT at baseline. The

participants with abnormal OGTT at baseline had got usual

care of GDM. For the analysis of changes in plasma lipids

according to weight change, the 141 women were stratified

into tertiles: subjects in first tertile, ‘‘weight loss group’’

(n = 45) reduced weight more than 0.4 kg; subjects in

second tertile, ‘‘unaltered weight group’’ (n = 46) reduced

weight max 0.4 kg or gained max 3.4 kg and subjects in

third tertile, ‘‘weight gain group’’ (n = 50) gained weight

more than 3.4 kg between the baseline (8–12 weeks’ ges-

tation) and follow-up (1 year postpartum) measurements.

The number of women of the original intensified counsel-

ling group was 15 in ‘‘weight loss group’’, 20 in ‘‘unaltered

weight group’’ and 15 in ‘‘weight gain group’’. The cor-

responding numbers of usual care group were 20, 14 and 23

and of abnormal OGTT group 9, 11 and 12.

Information on maternal measurements was obtained

from the standard maternity cards. Height was measured at

the first maternity care visit (8–12 weeks’ gestation) and

weight was measured at each maternity care visit and

1 year postpartum. Because 23 % of weight measurements

at first visit were missing, self-reported pre-pregnancy

weight was used as the baseline weight. Blood specimens

were taken after 12-h fast. For lipid analyses venous blood

was drawn into EDTA tubes. Plasma samples were stored

frozen at -80 �C until analyzed. T-C, HDL-C and TAG

concentrations were measured with enzymatic assays using

Roche Cobas Mira Plus analyzer. All analyses were made

in duplicate.

Assay of ox-LDL was based on analysis of oxidized

lipids in isolated LDL [27, 28]. LDL was isolated by pre-

cipitation with buffered heparin. The isolation procedure

was validated for the purpose, and did not affect the level

of oxidized lipids [28]. Lipids were extracted from isolated

LDL by chloroform–methanol, dried under nitrogen and

redissolved in cyclohexane. The amount of peroxidized

lipids in LDL was assessed spectrophotometrically at

234 nm. Validation studies for the assay have ruled out

interference by nonspecific substances, and shown that the

assay is a measure of oxidative modifications found in all

LDL lipid classes. The coefficient of variation (CV) for

within-assay precision for determination of oxidized LDL

lipids (ox-LDL) was 4.4 %, and the CV for the between-

assay precision was 4.5 %. The isolated LDL fraction was

used for direct measurement of LDL-cholesterol (LDL-C)

(CHOD-PAP method).

Background characteristics and descriptive information

are reported as means and standard deviations (SDs) or

frequencies and proportions. The differences between ter-

tiles of weight change at baseline were tested by variance

analysis and chi-square test. Unadjusted and adjusted linear

regression models were constructed to estimate the asso-

ciation between weight change tertiles and changes in lipid

Fig. 1 Correlation between weight change and change in a LDL

cholesterol and b HDL cholesterol from 8 to 12 weeks’ gestation to

1 year postpartum (n = 140–141)

Lipids (2013) 48:1227–1235 1229

123

outcomes from baseline to follow-up. In the adjusted

analyses we controlled for baseline lipid level, maternal

age, BMI, parity and smoking status. Normality of distri-

bution of outcome variables was tested using Kolmogorov–

Smirnov test. Results were considered statistically signifi-

cant if the p-values were \0.05. IBM SPSS Statistics

(version 20) were used to perform all analyses.

Results

Background Characteristics of the Participants

(Table 1)

There were no significant differences in any variable at

the baseline data between the three groups. The mean age

of all subjects at 8–12 weeks’ gestation was 30.4 years.

One-third of the women had no previous deliveries. One-

fourth were smoking occasionally or frequently before

pregnancy.

The Changes in Plasma Lipids Associated with Weight

Change

Figures 1, 2 and 3 show the correlations between change in

weight and change in plasma lipids from 8 to 12 weeks’

gestation to 1 year postpartum. The figures demonstrate

that weight gain correlates slightly with TAG (R = 0.27,

p = 0.001), ox-LDL (R = 0.17, p = 0.046), and ox-LDL/

HDL-C ratio (R = 0.25, p = 0.003) and conversely with

HDL-C (R = -0.23, p = 0.008). There were no correla-

tions between weight change and the change of T-C

(R = 0.07, p = 0.47), LDL-C (R = 0.13, p = 0.13) or ox-

LDL/LDL-C ratio (R = 0.07, p = 0.43).

The Changes in Plasma Lipids According to Tertiles

of Weight Change

At baseline, the mean BMI was 26.7 kg/m2 and at follow-up

27.4 kg/m2 (Table 2). The proportion of being overweight

or obese at 1 year postpartum was the same as at baseline,

64.5 %. The mean change from weight before pregnancy to

weight at 1 year postpartum was quite moderate, ?1.6 kg,

but it varied from -16.1 to ?18.0 kg. The changes in lipids

from 8 to 12 weeks’ gestation to 1 year postpartum were

less advantageous in weight gain group than in weight loss

group. According to linear regression model, the concen-

tration of TAG reduced less (-0.14, vs. -0.33, p = 0.004),

Fig. 2 Correlation between weight change and change in a triacyl-

glycerols and b oxidized LDL from 8 to 12 weeks’ gestation to 1 year

postpartum (n = 140–141)

Fig. 3 Correlation between weight change and change in oxidized

LDL/HDL cholesterol ratio from 8 to 12 weeks’ gestation to 1 year

postpartum (n = 140)

1230 Lipids (2013) 48:1227–1235

123

HDL-C reduced more (-0.31, vs. -0.16, p = 0.003), and

the ox-LDL/HDL-C ratio elevated (3.0 vs. -0.2,

p = 0.007) in weight gain group compared to the weight

loss group, when adjusted by only baseline lipid level.

These differences persisted in all variables after adjusting

the results with maternal age, BMI, parity and smoking

(Figs. 4, 5, 6, 7). Between the weight loss and the unaltered

weight groups, the only difference was T-C and LDL-C,

which both elevated more in the unaltered weight group

(T-C: 3.0 % vs. -4.4 %, p = 0.007; LDL-C: 14.3 % vs.

3.2 %, p = 0.010, baseline level as a covariate). When

results were adjusted also by baseline level, maternal age,

BMI and smoking, the differences were seen in T-C, LDL-

C, TAG and ox-LDL between the weight loss and the

unaltered weight groups.Ta

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Fig. 4 Changes in a total cholesterol and b LDL cholesterol

according to tertiles of weight change from baseline (pre-pregnancy

or 8–12 weeks’ gestation) to follow-up (1 year postpartum). Means

(95 % CI). p values for differences of changes in lipids are analyzed

by linear regression model adjusted by baseline level, age, body mass

index, parity and smoking

Lipids (2013) 48:1227–1235 1231

123

Discussion

Present study demonstrated that marked postpartum weight

retention (3.4 kg or more) was associated with elevated

concentration of TAG, ox-LDL/HDL-C ratio, and

decreased concentration of HDL-C. These results indicate

that postpartum weight retention might also cause athero-

genic lipid profile. Further, the correlations between weight

change and changes in blood lipids support these findings.

Elevated ox-LDL/HDL-C ratio is a predictor for coro-

nary artery disease [29]. In a Finnish population study,

elevated ox-LDL/HDL-C ratio was also connected with a

higher overall mortality among elderly [12]. The major

cardioprotective mechanism of HDL is the removal of

cholesterol from cells, but HDL also inhibits LDL

oxidation [8, 9]. Thus, decreased concentration or impaired

function of HDL-C is connected with increased concen-

tration of ox-LDL [1, 30]. Therefore, the ox-LDL/HDL-C

ratio considering both atherogenic ox-LDL and cardio-

protective HDL-C, stands out as a valuable biomarker for

evaluating the risk of cardiovascular diseases.

To our knowledge, this study is the first one to inves-

tigate the effects of postpartum weight retention on ox-

LDL. Compared to the few previous studies of men and

women without pregnancies, the association between

weight change and change in TAG, HDL-C and ox-LDL

was similar: favourable change in weight was accompanied

with favourable change in serum lipids and ox-LDL [16,

17]. Nevertheless, the current study did not show correla-

tion between postpartum weight retention and T-C or LDL-

Fig. 5 Changes in a HDL cholesterol and b triacylglycerols accord-

ing to tertiles of weight change from baseline (pre-pregnancy or

8–12 weeks’ gestation) to follow-up (1 year postpartum). Means

(95 % CI). p values for differences of changes in lipids are analyzed

by linear regression model adjusted by baseline level, age, body mass

index, parity and smoking

Fig. 6 Changes in a oxidized LDL lipids and b oxidized LDL/LDL

cholesterol ratio according to tertiles of weight change from baseline

(pre-pregnancy or 8–12 weeks’ gestation) to follow-up (1 year

postpartum). Means (95 % CI). p values for differences of changes

in lipids are analyzed by linear regression model adjusted by baseline

level, age, body mass index, parity and smoking

1232 Lipids (2013) 48:1227–1235

123

C, unlike several previous studies about weight change in

men and women without pregnancies [18, 19].

Lipid metabolism changes during pregnancy and may

both accentuate and defuse the effects of weight retention

on the changes in plasma lipids when comparing the levels

of the early pregnancy to the levels of 1 year postpartum.

During pregnancy, total, LDL- and HDL-cholesterol

(HDL-C) and TAG elevate [31], and ox-LDL also elevates,

especially in complicated pregnancies [32–34]. This would

explain why in the present study the concentration of ox-

LDL lipids decreased slightly even in the weight gain

group, although in the weight loss group a fivefold decrease

was seen compared to the weight gain group.

Women participating in the present study were all

evaluated to have had more or less risk factors for devel-

oping GDM at early pregnancy. When compared to women

at the same age in Finland or in other industrial countries,

these women, for example, had higher BMI [35], they were

more often obese, and they more often had a history of

GDM at the follow-up point [36]. Our previous study

showed that as many as almost one-fifth (18 %) of these

had metabolic syndrome according to the International

Diabetes Federation (IDF) criteria [37]. Metabolic syn-

drome is associated with increased levels of ox-LDL [15,

38]. It also might be the case that postpartum changes in

weight affect plasma lipids differently in this group than in

healthier women at the same age. Still, the study shows a

clear benefit of weight loss and disadvantage of weight

gain after pregnancy in terms of plasma lipids.

One limitation of this study is that at the follow-up,

the subjects were not specially queried about hormonal

contraception and medication for dyslipidemia, which

both have effects on lipid metabolism. However, when

medication for dyslipidemia was queried at the baseline,

none of the women reported such medication. Thus, it is

very improbable that lipid-lowering therapy was used in

postpartum stage 1-year after pregnancy. Further, statins

as a lipid lowering medication decrease the concentration

of serum lipids (particularly T-C and LDL-C), but the

effect of statins on the concentration of ox-LDL lipids is

contradictory and seems to depend on statins and

methods used to measure ox-LDL lipids [39–42]. The

effects of hormonal contraception on ox-LDL are not

properly known. However, it is known that hormonal

replacement therapy may somewhat influence on con-

centrations of ox-LDL [43]. In the present study, the

differences of the lipid results between the weight groups

are obviously not caused by the possible use of hormonal

contraception. On the contrary, the possible use of hor-

monal contraception within the weight groups would

rather make the study design more conservative and

diminished the differences.

We used self-reported weight before pregnancy, which

is not as reliable a measurement as using a scale. When

self-reported weight was compared to the available weight

measurement at the first maternity clinic visit, the mean

difference was\1 kg, which could easily be explained by a

minimal early-pregnancy weight gain. Thus the self-

reported weight is concluded to be quite accurate.

There is a need for further study about effect of post-

partum weight retention on cardiovascular events or on

other atherosclerosis risk markers than LDL oxidation. That

information would be valuable in investigating the rele-

vance of weight retention on cardiovascular health after

delivery. To our knowledge it has not been studied yet.

To conclude, postpartum weight retention is associated

with higher TAG and ox-LDL/HDL-C ratio as compared to

those who lost weight. Postpartum weight retention of

3.4 kg or more is associated with atherogenic lipid profile.

The present study shows that postpartum weight manage-

ment or weight reduction is important in management of

anti-atherogenic lipid profile.

Acknowledgments This study was funded by Competitive

Research Funding of the Tampere University Hospital, Juho Vainio

Foundation, Academy of Finland, Ministry of Education and Culture,

and Ministry of Social Affairs and Health. We are thankful to Tiina

Solakivi, PhD, associate professor at the Medical School at the

University of Tampere, who was responsible for the laboratory

testing.

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