Research www. AJOG.

org

OBSTETRICS
Cardiovascular risk factors in women who had hypertensive
disorders late in pregnancy: a cohort study
Wietske Hermes, MD; Arie Franx, MD, PhD; Maria G. van Pampus, MD, PhD; Kitty W. M. Bloemenkamp, MD, PhD;
Michiel L. Bots, MD, PhD; Joris A. van der Post, MD, PhD; Martina Porath, MD, PhD; Gabrielle A. E. Ponjee, MD, PhD;
Jouke T. Tamsma, MD, PhD; Ben Willem J. Mol, MD, PhD; Christianne J. M. de Groot, MD, PhD

OBJECTIVE: The purpose of this study was to determine cardiovascular
risk factors in women with a history of hypertensive pregnancy disor-
ders at term (HTP) 2.5 years after pregnancy.
STUDY DESIGN: In a multicenter cohort study in The Netherlands from
June 2008 through November 2010, cardiovascular risk factors were
compared between women with a history of HTP (HTP cohort, n ⫽ 306)
and women with a history of normotensive pregnancies at term (NTP
cohort, n ⫽ 99). HTP women had participated in a randomized, longitudinal
trial assessing the effectiveness of induction of labor in women with hyper-
tensive pregnancy disorders at term. All women were assessed 2.5 years
after pregnancy for blood pressure, anthropometrics, glucose, glycosylated
hemoglobin, insulin, homeostatic model assessment score, total choles-
terol, high-density lipoprotein cholesterol, triglycerides, high-sensitivity C-
reactive protein, and microalbumin and metabolic syndrome.
RESULTS: After a mean follow-up period of 2.5 years, hypertension
(HTP, 34%; NTP, 1%; P ⬍ .001) and metabolic syndrome (HTP, 25%;
NTP, 5%; P ⬍ .001) were more prevalent in HTP women compared with
NTP women. HTP women had significantly higher systolic and diastolic
blood pressure, higher body mass index, and higher waist circumfer-
ence. Glucose, glycosylated hemoglobin, insulin, homeostatic model
assessment score, total cholesterol, triglycerides, and high-sensitivity
C-reactive protein levels were significantly higher and high-density lipo-
protein cholesterol was significantly lower in HTP women.
CONCLUSION: In women with a history of HTP, hypertension and meta-
bolic syndrome are more common, and they have higher levels of bio-
chemical cardiovascular risk factors 2.5 years after pregnancy.
Key words: cardiovascular risk factors, cohort study, gestational
hypertension, hypertension, preeclampsia, pregnancy.

Cite this article as: Hermes W, Franx A, van Pampus MG, et al. Cardiovascular risk factors in women who had hypertensive disorders late in pregnancy: a cohort
study. Am J Obstet Gynecol 2013;208:474.e1-8.

C ardiovascular disease (CVD) is

the leading cause of death in
women in the Western world.1 Heart
disease symptoms in women are differ-
ent from symptoms in men and diag-
nostic tools in women seem to be less
sensitive and specific than for men.2
Hypertensive disorders are common
complications of pregnancy.3 Observa-
tional studies have shown a relation be-
tween hypertensive disorders in preg-
nancy and CVD morbidity and mortality
later in life.4-10 This suggests that hyper-
tensive disorders in pregnancy share
common risk factors and pathophysio-
logical pathways.11,12 The exact underly-
ing link between hypertensive pregnancy
disorders and future CVD remains un-
clear. It has been suggested that preg-
nancy can potentially be looked upon as
a “stress test,” unmasking underlying de

From the Departments of Obstetrics and Gynecology at Vu University Medical Center (Drs Hermes and de Groot) and Amsterdam Medical Center
(Drs van der Post and Mol), Amsterdam; the Department of Obstetrics and Gynecology (Dr Hermes) and Clinical Laboratory (Dr Ponjee), Medical
Center Haaglanden, The Hague; the Division of Woman and Baby (Dr Franx) and the Julius Center for Health Sciences and Primary Care (Dr Bots),
University Medical Center Utrecht, Utrecht; the Department of Obstetrics and Gynecology, University Medical Center Groningen, Groningen (Dr van
Pampus); the Departments of Obstetrics (Dr Bloemenkamp) and Internal Medicine (Dr Tamsma), Leiden University Medical Center, Leiden; and the
Department of Obstetrics and Gynecology, Maxima Medical Center, Veldhoven (Dr Porath), The Netherlands.
Received Aug. 27, 2012; revised Dec. 25, 2012; accepted Feb. 6, 2013.
This study was supported by a grant from the Nuts Ohra Foundation, The Netherlands.
W.H. is the recipient of a noncommercial grant from the Landsteiner Institute, Medical Center Haaglanden, The Hague, The Netherlands.
The authors report no conflict of interest.
Presented as a poster at the 18th World Congress of the International Society for the Study of Hypertension in Pregnancy, Geneva,
Switzerland, July 9-12, 2012; orally at the 59th annual meeting of the Society for Gynecologic Investigation, Miami, FL, March 16-19, 2011;
and orally at the 31st annual meeting of the Society for Maternal-Fetal Medicine, San Francisco, CA, Feb. 9-12, 2011.
Reprints: Wietske Hermes, MD, Department of Obstetrics and Gynecology, Medical Center Haaglanden, Lijnbaan 32, 2512 VA, The Hague, The
Netherlands. herwie@mchaaglanden.nl.
0002-9378/$36.00 • © 2013 Mosby, Inc. All rights reserved. • http://dx.doi.org/10.1016/j.ajog.2013.02.016

474.e1 American Journal of Obstetrics & Gynecology JUNE 2013

www.AJOG.org
fects, thus identifying women at a young
age at increased risk for cardiovascular
events.13 Determining cardiovascular
risk factors in women who respond to
this stress test with transient hyperten-
sion could be an opportunity for identi-
fying high-risk women for early preven-
tion of modifiable cardiovascular risk
factors.14,15 Until now, most studies have
focused on severe preterm preeclampsia,
which is a rare disease. Most hyperten-
sive disorders develop ⬎ 36 weeks’ ges-
tation. Therefore, we conducted a fol-
low-up study of a randomized controlled
trial in The Netherlands to assess cardio-
vascular risk factors in women with a his-
tory of hypertensive pregnancy disorders
at term (HTP) 2.5 years after their com-
plicated pregnancy.
M ATERIALS AND M ETHODS
Ethics statement
The follow-up study was approved by
the institutional review board of the Uni-
versity of Leiden and locally approved by
the hospital board of the participating
hospitals. The study protocol has previ-
ously been published.16 The current
study is a follow-up of the Hypertension
and Preeclampsia Intervention Trial at
Term (HYPITAT) study (trial registra-
tion: ISRCTN08132825).17
Participants
Hypertension in pregnancy cohort
From October 2005 through March
2008, the HYPITAT study,17 a multi-
center, parallel, open-label randomized
controlled trial of induction of labor
vs expectant management, included
women with gestational hypertension or
preeclampsia at term (n ⫽ 1153). At
baseline (randomization), these women
consented to be contacted 2.5 years after
their delivery to participate in the fol-
low-up study.
The HYPITAT study
The HYPITAT study evaluated whether
induction of labor improved maternal
outcome in women with gestational hy-
pertension or preeclampsia at term and
included women with a singleton preg-
nancy at a gestational age between 36⫹0
and 41⫹0 weeks. The diastolic blood
pressure thresholds for inclusion in the
Obstetrics Research
HYPITAT study differed between gesta- Netherlands (Leiden, Groningen, Am-
tional hypertension and preeclampsia as sterdam, Brabant) participated.
diastolic blood pressure of 90 mm Hg
without proteinuria was discussed and
Normotensive pregnancy cohort
considered too mild and trivial for inclu-
The normotensive pregnancies at term
sion in the HYPITAT trial. Therefore,
(NTP) women were either friends of the
gestational hypertension was defined as a
HTP women or women from midwifery
diastolic blood pressure of ⱖ95 mm Hg
practices. NTP women were required to
measured on 2 occasions at least 6 hours
have had only uncomplicated normo-
apart without proteinuria. Preeclampsia
tensive pregnancies. Exclusion criteria
was defined as diastolic blood pressure of
for the NTP cohort included HELLP
ⱖ90 mm Hg measured on 2 occasions at
syndrome, gestational hypertension,
least 6 hours apart, combined with pro-
preeclampsia, preexisting hypertension,
teinuria (ⱖ2 occurrences of protein on a
(gestational) diabetes, premature deliv-
dipstick, ⬎300 mg total protein within a
ery, delivery of a neonate with intrauter-
24-hour urine collection, or ratio of pro-
ine growth restriction (⬍5th percentile),
tein to creatinine ⬎30 mg/mmol).
renal disease, heart disease, and human
Other exclusion criteria included:
immunodeficiency virus. Initially, we
antihypertensive medication use for
asked HTP women if they had a friend
chronic hypertension, diabetes mellitus,
who had given birth in the same period
gestational diabetes treated with insulin,
as the HTP woman and who could func-
renal disease, heart disease, previous cesar-
tion as NTP woman. We assumed that
ean section, HELLP syndrome (hemolysis,
friends would be similar in terms of age,
elevated liver enzymes, and low platelets),
demographic region, and ethnic origin.
oliguria of ⬍500 mL per 24 hours, pulmo-
If an HTP woman did not have a friend
nary edema or cyanosis, human immuno-
who could function as NTP woman, we
deficiency virus, use of intravenous anti-
searched for a NTP woman in a mid-
hypertensive medication, fetal anomalies,
wifery practice of the same demographic
intrauterine growth restriction, and ab-
region and matched for elapsed time
normal fetal-heart rate monitoring.
since delivery. It is common practice in
In the HYPITAT study, which was an-
The Netherlands for women with no
alyzed according to intention to treat,
medical history or obstetrical history to
women allocated to expectant monitor-
have their antenatal care provided by a
ing were induced if they developed se-
midwife. Data were collected from their
vere preeclampsia. Patients who refused
medical records in midwifery practices.
randomization were analyzed separately
We collected and reviewed the NTP
after informed consent as nonrandom-
women’s blood pressure measurements
ized patients.
and their maternal and fetal outcomes of
index and previous pregnancies and de-
The follow-up study
liveries in thorough detail. Relatives of
From June 2008 through November
the HTP women were excluded from the
2010, women who had participated in
NTP cohort. Furthermore, women who
the HYPITAT study were invited to par-
were pregnant or lactating within the last
ticipate in a longitudinal, follow-up
3 months were excluded from our study
study assessing cardiovascular risk fac-
(n ⫽ 101).
tors 2.5 years after pregnancy. We used a
follow-up period of 2.5 years as this time
interval allows using pregnancy as a Follow-up study procedure and
stress test to identify young women who cardiovascular risk factor assessment
are at high risk for CVD in later life. Fur- The study protocol has been previously
thermore, 2.5 years is long enough to en- published.16 We refer to the Appendix
sure that pregnancy and lactation have for a detailed description of the risk fac-
no influence on biochemical cardiovas- tor assessment methods and the labora-
cular risk factor levels. Three academic tory methods.
hospitals and 17 nonacademic hospitals In short, local research nurses coun-
across 4 geographical regions in The seled the participants, obtained written
JUNE 2013 American Journal of Obstetrics & Gynecology 474.e2
Research Obstetrics
informed consent, monitored the
study protocol in each center, and col-
lected the data. After enrollment all
participants were invited for cardio-
vascular risk factor assessment, includ-
ing blood pressure measurement,
weight, height, and hip and waist
circumference. Furthermore, all par-
ticipants were asked to complete a
questionnaire. This questionnaire in-
cluded: medical history, current use of
medication, obstetric history, subse-
quent pregnancy after index preg-
nancy, and family history, including
CVD.
Venous blood samples were collected af-
ter an overnight fast and assayed for: glu-
cose, glycosylated hemoglobin (HbA1c),
insulin, total cholesterol, high-density li-
poprotein (HDL) cholesterol, triglycer-
ides, and high-sensitivity C-reactive pro-
tein (hs-CRP). Insulin resistance was
assessed by the homeostatic model as-
sessment (HOMA): insulin concentra-
tion/(22.5e–ln glucose concentration).18 Urine
was collected immediately after waking
up for assessment of microalbuminuria.
After immediately centrifuging, the
blood and urine samples were sent to a
central laboratory (Medical Center
Haaglanden, The Hague, The Nether-
lands) and were analyzed within 36
hours after blood draw.
Definitions
Hypertension 2.5 years’ postpartum was
defined as systolic blood pressure ⱖ140
mm Hg, diastolic blood pressure ⱖ90
mm Hg, or current use of antihyperten-
sive medication. Major independent risk
factors were defined according to the
American Heart Association, including
blood pressure ⱖ140/90 mm Hg, HDL
cholesterol ⬍40 mg/dL, current smok-
ing, and a family history of early CVD.19
Metabolic syndrome was defined as
waist circumference ⱖ80 cm plus any 2
of: raised triglycerides (⬎150 mg/dL),
reduced HDL cholesterol (⬍50 mg/dL),
raised blood pressure (systolic ⱖ130 mm
Hg and diastolic ⱖ85 mm Hg), treat-
ment of previously diagnosed hyperten-
sion, raised fasting plasma glucose
(ⱖ100 mg/dL), or previously diagnosed
type 2 diabetes.20
474.e3 American Journal of Obstetrics & Gynecology JUNE 2013
www.AJOG.org
TABLE 1
Baseline characteristics at index pregnancy
NTP cohort HTP cohort
Characteristic (n ⴝ 99) (n ⴝ 306) P value
Maternal age, y 31 (4.5) 31 (5.1) .70
..............................................................................................................................................................................................................................................
Ethnic origin
.....................................................................................................................................................................................................................................
Caucasian 94 (95%) 273 (89%) .15
.....................................................................................................................................................................................................................................
Other 5 (5%) 30 (10%)
.....................................................................................................................................................................................................................................
Unknown 0 (0%) 3 (1%)
..............................................................................................................................................................................................................................................
Nulliparous 30 (30%) 211 (69%) ⬍ .001
..............................................................................................................................................................................................................................................
Systolic blood pressure at booking, mm Hg 113 (11) 120 (12) ⬍ .001
..............................................................................................................................................................................................................................................
Diastolic blood pressure at booking, mm Hg 66 (7.6) 73 (9.0) ⬍ .001
..............................................................................................................................................................................................................................................
Body mass index at booking, kg/m 2
24 (4.2) 26 (4.9) ⬍ .001
..............................................................................................................................................................................................................................................
Gestational age at delivery, wk 39.9 (1.2) 39.4 (1.3) ⬍ .001
..............................................................................................................................................................................................................................................
Birthweight, g 3630 (465) 3395 (519) ⬍ .001
..............................................................................................................................................................................................................................................
Table shows mean (SD) or number (%). Differences between groups were tested with Student t test and categorical data with
␹2 test.
HTP, hypertensive disorders at term pregnancy; NTP, normotensive pregnancies at term.
Hermes. Cardiovascular risk factors after hypertensive pregnancy disorders at term. Am J Obstet Gynecol 2013.
Sample size considerations homogeneous outcome of cardiovascu-
Our power analysis was based on indi- lar risks.
vidual risk estimation from the Framing-
ham Heart Study,21 rather than on car- Statistical analysis
diovascular risk factors alone.22 Due to Data were analyzed using software
the young age of our participants, the es- (SPSS, version 18.0; IBM Corp, Armonk,
timated absolute 10-year cardiovascular NY). Baseline continuous data are ex-
risk was likely to be low. Therefore, our pressed as means and SD or as medians
approach was to estimate the risk for with 25th–75th percentile (interquartile
each woman as if the woman was 60 range) for the not normally distributed
years old. This approach has been rec- values; dichotomous data are presented
ommended in the cardiovascular risk as numbers and percentages. Differences
factor management guidelines for young between groups were tested with the Stu-
women with elevated risk factor levels.23
dent t test and categorical data with ␹2
For detecting an estimated absolute
test. Comparisons of continuous data
10-year cardiovascular risk difference
with a skewed distribution were per-
between the HTP and NTP cohorts of
formed using the nonparametric Mann-
10% increase after extrapolation, we
Whitney U test. We used logistic regres-
needed a sample size of 456 women for
sion analyses and results were reported
80% power and a 5% type 1 error prob-
ability (2-sided) for inclusion in 3:1 ratio as odds ratios (ORs) with corresponding
(3 HTP: 1 NTP). This method was used 95% confidence intervals (CIs). We
according to an earlier study performed made adjustments for potential con-
in severe early preeclampsia.22 Accord- founders, where appropriate, ie, parity,
ing to earlier studies24-26 we expected a body mass index (BMI), smoking, and
homogeneous effect with low prevalence age at follow-up; and BMI, systolic and
of unfavorable cardiovascular risk fac- diastolic blood pressure, and parity at
tors in NTP women. Therefore, we used booking. Furthermore, we performed
a 3:1 inclusion ratio instead of 1:1 as we a multicenter analysis that resulted in
assumed that including more NTP an intraclass correlation coefficient of
women in 1:1 ratio would have no addi- 2-4%. Therefore, we did not use a mul-
tional value in this study as a result of tilevel model for our analyses. For all
www.AJOG.org Obstetrics Research
friends of the HTP women and 59
TABLE 2 women who were identified from mid-
Outcome characteristics at 2.5-year follow-up wifery practices.
NTP cohort HTP cohort Baseline characteristics of the subjects
Characteristic (n ⴝ 99) (n ⴝ 306) P value are shown in Table 1. At index preg-
Maternal age at follow-up, y 34 (4.7) 34 (5.2) .67 nancy, HTP women were more often
..............................................................................................................................................................................................................................................
Time elapsed since delivery, d 965 (387) 921 (161) .11 nulliparous and had higher BMI at
..............................................................................................................................................................................................................................................
booking, higher systolic and diastolic
Primiparous 30 (30%) 123 (40%) .04
.............................................................................................................................................................................................................................................. blood pressures at booking, lower gesta-
Antihypertensive medication use 0 (0%) 29 (9%) ⬍ .001 tional age at delivery, and lower birth-
..............................................................................................................................................................................................................................................
Systolic blood pressure at follow-up, mm Hg 110 (9.3) 124 (13) ⬍ .001 weight compared with NTP women.
..............................................................................................................................................................................................................................................
Diastolic blood pressure at follow-up, mm Hg 72 (8.8) 82 (9.6) ⬍ .001 At the 2.5-year follow-up study, HTP
..............................................................................................................................................................................................................................................
women were found to use more antihy-
Body mass index at follow-up, kg/m 2
24 (4.6) 28 (5.5) ⬍ .001
.............................................................................................................................................................................................................................................. pertensive medication and had higher
Waist circumference, cm 81 (12) 90 (13) ⬍ .001 BMI, higher systolic and diastolic blood
..............................................................................................................................................................................................................................................
Hip circumference, cm 104 (11) 109 (12) ⬍ .001 pressures, and higher waist circumfer-
..............................................................................................................................................................................................................................................
Smoking 19 (19%) 60 (20%) .89 ences compared with NTP women.
.............................................................................................................................................................................................................................................. There were no significant differences in
Table shows mean (SD) or number (%). Differences between groups were tested with Student’s t test and categorical data with
␹2 test. maternal age, elapsed time since deliv-
HTP, hypertensive disorders at term pregnancy; NTP, normotensive pregnancies at term. ery, or smoking rates (Table 2).
Hermes. Cardiovascular risk factors after hypertensive pregnancy disorders at term. Am J Obstet Gynecol 2013. Table 3 shows biochemical cardiovas-
cular risk factors 2.5 years after index
tests, a P value ⬍ .05 indicated statisti- at term were included in the follow-up pregnancy in HTP and NTP women.
cal significance. study. Fasting blood glucose, HbA1c, insulin,
Of the 751 eligible HTP women for the HOMA scores, total cholesterol, triglyc-
R ESULTS 2.5-year follow-up study, 168 women re- erides, and hs-CRP were all significantly
From June 2008 through November fused participation, 175 women were higher in HTP compared with NTP
2010, 306 women with a history of gesta- lost to follow-up, and 101 pregnant or women. HDL cholesterol was signifi-
tional hypertension or preeclampsia at lactating women were excluded. One cantly lower in HTP women. We found
term and 99 women with a history of un- woman died in a car accident. The NTP higher microalbumin levels in urine in
complicated normotensive pregnancies cohort consisted of 40 women who were HTP women, however this difference
was not significant (P ⫽ .06).
The prevalence of 4 major cardiovas-
TABLE 3 cular risk factors, multiple major cardio-
Biochemical cardiovascular risk factors 2.5 years after pregnancy vascular risk factors, and metabolic syn-
Biochemical cardiovascular NTP cohort HTP cohort drome in HTP and NTP women are
risk factor (n ⴝ 99) (n ⴝ 306) P value summarized in Table 4. The adjusted OR
Microalbumin urine,a mmol/L 4.0 (3.0–8.0) 5.0 (3.0–10.0) .06 of HTP women for hypertension 2.5
..............................................................................................................................................................................................................................................
b
years’ postpartum was 48. On the con-
Fasting blood glucose, mg/dL 85 (79–88) 85 (81–92) .01
.............................................................................................................................................................................................................................................. trary, there were no significant differ-
c
HbA , % 1c 5.3 (5.1–5.5) 5.3 (5.1–5.6) .04 ences between HTP and NTP women in
..............................................................................................................................................................................................................................................
Insulin, mU/L d
2.9 (2.0–5.0) 4.4 (2.0–7.6) .003 the other 3 major independent risk fac-
..............................................................................................................................................................................................................................................
HOMA score e
0.6 (0.4–1.0) 1.0 (0.4–1.6) .001 tors: HDL cholesterol, currently smok-
..............................................................................................................................................................................................................................................
ing, or family history of early CVD. Mul-
hs-CRP, mg/L f
0.9 (0.4–2.2) 2.2 (1.0–5.0) ⬍ .001
.............................................................................................................................................................................................................................................. tiple risk factors were present in 18% of
g
Total cholesterol, mg/dL 178 (151–197) 182 (162–207) .02 the HTP women compared with 7% of
..............................................................................................................................................................................................................................................
HDL cholesterol, mg/dL h
56 (50–63) 54 (46–62) .03 NTP women (P ⫽ .01), including 4%
..............................................................................................................................................................................................................................................
Triglycerides, mg/dL h
63 (48–91) 81 (58–110) ⬍ .001 of HTP women with ⱖ3 independent
.............................................................................................................................................................................................................................................. risk factors compared to 0% in NTP
HbA1c, glycosylated hemoglobin; HDL, high-density lipoprotein; HOMA, homeostatic model assessment; hs-CRP, high-
sensitivity C-reactive protein; HTP, hypertensive disorders at term pregnancy; NTP, normotensive pregnancies at term. women. Metabolic syndrome was found
a
Missing data of 6 NTP women and 9 HTP women; b Missing data of 11 NTP women and 15 HTP women. Majority of missing data in 25% of HTP and in 5% of NTP
was caused by fact that urine and blood samples were only processed within 36 h after sampling. Samples that arrived after this women (OR, 6.0; 95% CI, 2.3–15.3) even
period were cancelled for analysis. Table shows median (interquartile range, 25th–75th percentile). Differences were tested with
nonparametric Mann-Whitney U test. HTP women; c Missing data of 6 NTP women and 14 HTP women; d Missing data of 9 NTP after adjustment for maternal age and
women and 24 HTP women; e Missing data of 11 NTP women and 25 HTP women; f Missing data of 7 NTP women and 10 HTP baseline differences.
women; g Missing data of 5 NTP women and 5 HTP women; h Missing data of 5 NTP women and 4 HTP women.
Hermes. Cardiovascular risk factors after hypertensive pregnancy disorders at term. Am J Obstet Gynecol 2013.
Surprisingly, we found a prevalence of
chronic hypertension of 34% in the HTP

JUNE 2013 American Journal of Obstetrics & Gynecology 474.e4

Research Obstetrics www.AJOG.org

TABLE 4
Major independent cardiovascular risk factors, multiple risk factors, and metabolic syndrome
Independent CVD risk factor and NTP cohort HTP cohort Unadjusted OR Adjusted ORa Adjusted ORb
metabolic syndrome (n ⴝ 99) (n ⴝ 306) (95% CI) (95% CI) (95% CI) P value
Blood pressure, ⱖ140/90 mm Hg c
1 (1%) 105 (34%) 51.5 (7.1–374) 47.5d (6.5–350) 36.4 (4.8–276) ⬍ .001
................................................................................................................................................................................................................................................................................................................................................................................
HDL cholesterol, ⬍40 mg/dL e
10 (11%) 37 (12%) 1.2 (0.6–2.5) d
0.8 (0.3–1.8) 1.1 (0.4–2.8) .53
................................................................................................................................................................................................................................................................................................................................................................................
f g
Current smoking, % 19 (19%) 60 (21%) 1.1 (0.6–1.9) 1.01 (0.6–1.1) 1.1 (0.5–2.1) .98
................................................................................................................................................................................................................................................................................................................................................................................
h g
Family history of early CVD, % 11 (11%) 48 (16%) 1.6 (0.8–3.1) 1.7 (0.8–3.5) 2.0 (0.9–4.2) .15
................................................................................................................................................................................................................................................................................................................................................................................
ⱖ1 independent risk factor e
32 (34%) 184 (61%) 3.0 (1.9–4.9) 3.2 (1.9–5.3) 2.7 (1.5–4.9) ⬍ .001
................................................................................................................................................................................................................................................................................................................................................................................
ⱖ2 independent risk factors e
7 (7%) 54 (18%) 2.7 (1.2–6.2) i
3.1 (1.3–7.5) 3.0 (1.0–9.0) .01
................................................................................................................................................................................................................................................................................................................................................................................
Metabolic syndrome j
5 (5%) 73 (25%) 6.0 (2.3–15) k
5.9 (2.3–15) 3.3 (1.2–9.1) ⬍ .001
................................................................................................................................................................................................................................................................................................................................................................................
Logistic regression analyses; adjustments made for potential confounders 2.5 y after pregnancy. Majority of missing data was caused by fact that urine and blood samples were only processed within
36 h after sampling. Samples that arrived after this period were cancelled for analysis. Table shows number (%) and OR (95% CI).
CI, confidence interval; CVD, cardiovascular disease; HDL, high-density lipoprotein; HTP, hypertensive disorders at term pregnancy; NTP, normotensive pregnancies at term; OR, odds ratio.
a
Adjusted for parity, body mass index (continuous variable), smoking, age at follow-up; b Adjusted for differences at baseline, including body mass index at booking, systolic and diastolic blood pressures
at booking, and parity at booking; c Missing data of 1 HTP woman; d Adjusted for age, body mass index, parity, and smoking; e Missing data of 5 NTP women and 4 HTP women; f Missing data of 1
NTP women and 13 HTP women; g Adjusted for age; h Missing data of 1 NTP women and 14 HTP women; i Adjusted for age and parity; j Missing data of 4 NTP women and 14 HTP women; k Adjusted
for age, parity, and smoking.
Hermes. Cardiovascular risk factors after hypertensive pregnancy disorders at term. Am J Obstet Gynecol 2013.

cohort 2.5 years’ postpartum, of which 29 in the HYPITAT study of some women vided the HTP cohort into mean arterial
women (28%) had started antihyperten- with chronic hypertension, which was ini- pressure at booking and blood pressure at
sive medication at 2.5 years after preg- tially masked by the physiological fall of booking subgroups. As can be seen from
nancy. This unexpected high prevalence blood pressure in early pregnancy. There- Table 5, even when we studied the sub-
might partially be explained by inclusion fore, we performed subanalyses and di- group of women who had a blood pressure
of ⬍120/70 mm Hg at booking, the prob-
ability of hypertension after 2.5 years was
TABLE 5 still as high as 27%. In all, 94 HTP women
Prevalence of hypertension per blood pressure subgroup 2.5 years’ (31%) had developed severe hypertensive
postpartum disease during their index pregnancy.
Cutoff value for subgroup based on blood pressure at booking in index pregnancy
MAP at booking ⱖ100 mm Hg C OMMENT
.....................................................................................................................................................................................................................................
Criterion Yes No The main finding of the follow-up study
.....................................................................................................................................................................................................................................
No of women (%) 35 (11%) 271 (89%) is that women with a history of gesta-
.....................................................................................................................................................................................................................................
tional hypertension or preeclampsia at
Prevalence of hypertension 2.5 y postpartum 57% 32%
.............................................................................................................................................................................................................................................. term have a high risk of hypertension 2.5
MAP at booking ⱖ90 mm Hg years after their pregnancy. Additionally,
.....................................................................................................................................................................................................................................
Criterion Yes No women with a history of gestational hy-
.....................................................................................................................................................................................................................................
No of women (%) 147 (48%) 159 (52%) pertension or preeclampsia at term ex-
.....................................................................................................................................................................................................................................
hibit more cardiovascular risk factors 2.5
Prevalence of hypertension 2.5 y postpartum 44% 25%
.............................................................................................................................................................................................................................................. years after their pregnancy compared
Blood pressure at booking ⱖ130/75 mm Hg with women with a history of uncompli-
.....................................................................................................................................................................................................................................
Criterion Yes No cated normotensive pregnancies. They
.....................................................................................................................................................................................................................................
No of women (%) 167 (55%) 139 (45%) have higher waist circumferences; higher
.....................................................................................................................................................................................................................................
BMI; higher systolic and diastolic
Prevalence of hypertension 2.5 y postpartum 44% 23%
.............................................................................................................................................................................................................................................. blood pressures; higher prevalence of
Blood pressure at booking ⱖ120/70 mm Hg metabolic syndrome; higher levels of
.....................................................................................................................................................................................................................................
Criterion Yes No biochemical risk factors, including
.....................................................................................................................................................................................................................................
No of women (%) 251 (82%) 55 (18%) glucose, HbA1c, insulin, insulin resis-
.....................................................................................................................................................................................................................................
tance (HOMA), total cholesterol, trig-
Prevalence of hypertension 2.5 y postpartum 36% 27%
.............................................................................................................................................................................................................................................. lycerides, and hs-CRP; and lower levels
Table shows number (%). of HDL cholesterol 2.5 years’ postpar-
MAP, mean arterial pressure.
Hermes. Cardiovascular risk factors after hypertensive pregnancy disorders at term. Am J Obstet Gynecol 2013.
tum compared with women with a his-
tory of normotensive pregnancies.

474.e5 American Journal of Obstetrics & Gynecology JUNE 2013

www.AJOG.org
Our results after hypertensive preg-
nancy disorders at term are in line with
results from previous studies. These
studies reported higher blood pressure,
higher BMI, and higher concentrations
of lipids and insulin resistance in women
with previous hypertensive pregnancy
disorders.7,24,27-46 However, previous
studies included only women with severe
preterm preeclampsia,29,36,37 gestational
age was not reported,27,28,38,39,41,42,45
and distinction was not made between
preterm preeclampsia and term pre-
eclampsia.24,32-34,38,40,43,44,46 This makes
it difficult to draw a conclusion about the
association of hypertensive disorders in
term pregnancy and the presence of car-
diovascular risk factors after pregnancy.
In the literature, 2 other studies have
determined cardiovascular risk factors
after “mainly” term hypertensive pre-
gnancy disorders.34,43 These studies
showed similar results to our study, de-
spite the fact that both studies are small
(n ⫽ 43 and n ⫽ 30, respectively). Dif-
ferences between our study and previous
studies can be explained by differences in
follow-up periods, study population (eg,
nulliparous and multiparous women),
or chronic hypertension. While other
studies, which mostly included women
with severe preterm preeclampsia, found
significantly higher microalbumin levels
postpartum compared to control sub-
jects (mean difference, 8.55; 95% CI,
2.11–14.98),47 we showed a trend toward
higher microalbumin levels in HTP
women compared to NTP women (P ⫽
.06). Due to the sample size, our finding
did not reach statistical significance.
We found an unexpected high preva-
lence of hypertension 2.5 years’ postpar-
tum in the HTP cohort, namely 34%
compared with 1% in the NTP cohort.
The high prevalence was unexpected,
especially because women with preex-
isting hypertension with antihyperten-
sive medication use (before index preg-
nancy) were excluded from our study.
Due to physiological blood pressure re-
duction in the first trimester, inclusion
of women with (sub) clinical chronic hy-
pertension without the use of antihyper-
tensive medication might explain, at
least partly, the high prevalence of
hypertension 2.5 years’ postpartum in
our study. However, the prevalence of
chronic hypertension 2.5 years’ postpar-
tum in the lowest blood pressure at
booking subcategory ⱕ130/75 mm Hg
was still as high as 23% and thus of clinical
interest. We assumed that women with a
blood pressure at booking ⬍130/75 mm
Hg do not have chronic hypertension. An-
other consideration is that we performed
the follow-up of only 306 HTP women
(27% of the HYPITAT cohort [n ⫽ 1153]),
which might have resulted in selection
bias. The selection bias might result in an
overestimation of the prevalence of
chronic hypertension in HTP women.
However, the fact that women who were
not included in the follow-up study had
higher diastolic blood pressures at book-
ing compared to included women argues
against overestimation of chronic hyper-
tension in HTP women. Women who
were included in the follow-up study
were significantly older at baseline com-
pared to women who were not included.
All other baseline characteristics were
comparable between included and non-
included women (data not shown). If the
resulting 847 women, who were not in-
cluded in the follow-up study, would all
have been normotensive 2.5 years’ post-
partum, we would have introduced the
most extreme selection bias. Even then,
the minimum detection rate for chronic
hypertension for HTP women is 9%. To
put these percentages in perspective: the
prevalence of chronic hypertension in
The Netherlands, among women in a
comparable age group between 30-40
years in 2010, was 5.5%. Thus, a detec-
tion rate between a minimum of 9% and
a maximum of 34% in women with a his-
tory of gestational hypertension or pre-
eclampsia at term is of great interest for
health care providers.
The major strength of our study is
2-fold. First, we focused on women with
a history of hypertensive pregnancy dis-
orders at term, which are common dis-
orders in pregnancy and of daily ob-
stetric care. Second, we longitudinally
followed up HTP women who were in-
cluded in a randomized controlled trial
and we had a prespecified hypothesis
and objective at baseline, providing a
large and strong HTP cohort.
JUNE 2013 American Journal of Obstetrics & Gynecology
Obstetrics Research
The finding, that the common preg-
nancy disorders gestational hypertension
and preeclampsia at term are associated
with a high risk of hypertension and more
cardiovascular risk factors, makes this
study original and of interest for not only
obstetricians, but also for internists, cardi-
ologists, and general physicians.
Our study has a few limitations. First,
the study design of the HYPITAT trial was
to compare 2 different strategies at term in
women with 1 pregnancy complication,
namely gestational hypertension or pre-
eclampsia, without comparison to a con-
trol group. To compare cardiovascular risk
factors after 2.5 years, we secondarily
added a control group. For that purpose,
baseline data of the index pregnancy of
NTP women were collected from review of
medical records at the time of inclusion in
the follow-up study. The information on
the variables addressed in this manuscript
was nearly all complete in the medical
charts. HTP and NTP women were com-
parable according to age, race, and demo-
graphic region. From etiological perspec-
tive, it would have been ideal to have
matched HTP and NTP women for BMI at
booking, blood pressure at booking, and
parity. Instead, we preferred a pragmatic
approach as we aimed to study whether
hypertensive pregnancy disorders in term
pregnancy can be used as a stress test for
cardiovascular risk factor screening to
identify women who are at risk for CVD
later. We performed a multivariate analysis
taking all the differences at baseline into
account (Table 4). The results of that ap-
proach showed that even after adjustment
for baseline factors HTP women had a sig-
nificantly higher prevalence of hyperten-
sion and metabolic syndrome 2.5 years af-
ter pregnancy. A problem with a
multivariate model like that is that the dif-
ferences were based on definitions of the
cohort. However, it does not invalidate our
findings showing that women with a his-
tory of hypertensive pregnancy disorders
at term still have unfavorable risk factors
2.5 years after pregnancy.
A second limitation concerns the vol-
untary contribution of NTP women,
which may have introduced selection
bias. NTP women with a family history
of CVD are probably more likely to par-
ticipate in a study on risk of CVD than
474.e6
Research Obstetrics
women with a healthy family history.
However, family history of first degrees
with a cardiovascular event ⬍60 years of
age was not significantly different be-
tween both groups. Moreover, this po-
tential bias underestimates the differ-
ences between HTP and NTP women.
Finally, as a consequence of the relatively
young age of the study participants, this
study evaluated surrogate endpoints: car-
diovascular risk factors rather than cardio-
vascular clinical outcomes.
Our study results strongly suggest
that women with a history of gesta-
tional hypertension or preeclampsia at
term may be offered screening and
counseling for cardiovascular risk fac-
tors after their pregnancy. Before wide
implementation in practice however,
strategies of cardiovascular risk factor
screening and subsequent tailored pre-
ventive interventions need to be evalu-
ated for feasibility, clinical effective-
ness, and cost-effectiveness.
Clara Kolster, research nurse from the
Department of Obstetrics at the Leiden
University Medical Center, Leiden, The
Netherlands, is acknowledged for her
contribution to the study. f history of eclampsia. BJOG 2000;107:776-84.
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A PPENDIX
Detailed description of the risk factor
assessment methods and the
laboratory methods
Hypertension Risk Assessment Study
procedure and cardiovascular risk
factor assessment
Local research nurses counseled the par-
ticipants, obtained written informed
consent, monitored the study protocol
in each center, and collected the data. Af-
ter enrollment, all participants were in-
vited to their local center for cardiovas-
cular risk factor assessment and were
asked to complete a questionnaire. This
questionnaire included questions about
their medical history, current use of
medication, obstetric history, subse-
quent pregnancy after index pregnancy,
and family history, including cardiovas-
cular disease.
Assessment of cardiovascular risk fac-
tors was performed by trained research
nurses in their respective local centers.
Blood pressure was measured manually
with a validated sphygmomanometer in
sitting position at the right upper arm
using the equipment and methodology
of the Hypertension and Preeclampsia
Intervention Trial at Term (HYPITAT)
study. The mean of 2 measurements was
used in the analyses. Height and weight
were measured wearing light clothes and
shoes (no heels); height was measured to
the nearest 1 cm and weight to the near-
est 1 kg. Body mass index was calculated
as weight/length2; hip and waist circum-
ference were measured with the partici-
pant standing upright, using a steel band
to measure horizontally at the height of
the umbilicus, and rounded to the near-
est 1 cm. Venous blood samples were
collected after an overnight fast and as-
sayed for glucose, glycosylated hemoglo-
bin (HbA1c), insulin, total cholesterol,
high-density lipoprotein (HDL) choles-
terol, triglycerides, and high-sensitivity
C-reactive protein (hs-CRP). Insulin re-
sistance was assessed by the homeostatic
model assessment: insulin concentra-
tion/(22.5e-ln glucose concentration).20 Urine
was collected for assessment of mi-
croalbuminuria immediately after wak-
ing up. After immediate centrifuging,
the blood and urine samples were sent to
a central laboratory (Medical Center
Haaglanden, The Hague, The Nether-
lands) and analyzed within 36 hours af-
ter blood draw.
JUNE 2013 American Journal of Obstetrics & Gynecology
Obstetrics Research
Laboratory methods
We used a Modular P800, E170 analyzer
and corresponding reagents (Roche Di-
agnostics, Almere, The Netherlands) to
determine blood plasma levels of glucose
(in a tube containing sodium fluoride),
total cholesterol, HDL cholesterol, trig-
lycerides, and urine concentrations of al-
bumin. HbA1c levels in blood were deter-
mined by high-performance lipid
chromatography on a Variant II Turbo
(Bio-Rad, Veenendaal, The Nether-
lands) using corresponding buffers and
reagents. Insulin serum levels were de-
termined using an enzyme-labeled im-
munometric assay on the Immulite 2000
and corresponding reagents (Siemens
Healthcare Diagnostics, Breda, The
Netherlands). For the analysis of hs-CRP a
plasma sample was snap frozen at ⫺70°C
until the batch analysis was performed.
Glucose was measured spectrophoto-
metrically with an enzymatic hexokinase
method, and total cholesterol and trig-
lycerides with an enzymatic colorimet-
ric method. HbA1c was separated from
other hemoglobin forms on a cation
exchange column and detected spec-
trophotometrically. HDL cholesterol
levels were quantified using an enzy-
matic colorimetric test after complex-
ation of the chylomicrons, low density
lipoprotein and very low density lipo-
protein cholesterol with dextran sul-
fate and magnesium sulfate. The hs-
CRP levels were determined with a
particle-enhanced immunoturbidimet-
ric assay. Microalbumin levels in urine
were measured turbidimetrically after
agglutination with sheep antihuman al-
bumin antibodies. Interassay coeffi-
cients of variation were 0.9-1.0% for glu-
cose, 0.8-1.3% for HbA1c, 4.1-6.4% for
insulin, 0.8-0.9% for total cholesterol,
2.1-3.0% for HDL cholesterol, 1.0% for
triglycerides, 1.5-3.2% for hs-CRP, and
1.4-5.5% for microalbumin. All analyses
were performed by technicians who were
blinded for outcome.
474.e8