The Journal of Maternal-Fetal and Neonatal Medicine, March 2010; 23(3): 229–233

Hypertension in gestational diabetes mellitus: Pathophysiology and

long-term consequences

BAHA M. SIBAI1 & MICHAEL G. ROSS2,3,4

J Matern Fetal Neonatal Med Downloaded from informahealthcare.com by T C Anadolu University on 06/03/10

1
University of Cincinnati College of Medicine, Cincinnati, Ohio, USA, 2Department of Obstetrics and Gynecology,
Harbor-UCLA Medical Center, Torrance, California, USA, 3Department of Obstetrics and Gynecology, Geffen School of
Medicine at UCLA, Torrance, California, USA, and 4Department of of Public Health, UCLA School of Public Health,
Torrance, California, USA

(Received 30 November 2009; revised 7 December 2009; accepted 10 December 2009)

Abstract
Gestational hypertension and gestational diabetes mellitus are the most frequent obstetric disorders during pregnancy. The rates
of both disorders are expected to increase as a result of delayed pregnancy at a later maternal age, the epidemic of obesity and the
For personal use only.

increased frequency of using assisted reproductive technology in women with infertility. Pregnancies complicated one or both of
these disorders are also associated with adverse consequences for the mother and infant (both acute and long-term). The
objectives of this review are to describe the association between gestational hypertension and gestational diabetes, and to discuss
approaches to management and summarize long-term consequences of gestational hypertension.

Keywords: Gestational hypertension, diabetes, management, outcome

twins and triplets have increased rates of both GH

Introduction
Hypertension in pregnancy is classified into four
main categories: (1) chronic hypertension, (2)
preeclampsia-eclampsia, (3) preeclampsia superim-
posed on chronic hypertension and gestational
hypertension (GH). Mild GH often occurs near
term or within 48 h of delivery. It often resolves
within 10 days of the postpartum period without
treatment [1].
GH affects blood flow to organs such as the
placenta, kidneys, brain and liver, and the effects on
these organs vary, depending on the severity of
symptoms and when GH develops during pregnancy
[1]. For example, women who develop mild GH
after 37 weeks have pregnancy outcomes similar to
that of pregnant women who have normal blood
pressure, except they have an increased rate of
induced labor and cesarean section delivery [2].
However, those with GH at 536 weeks’ gestation are
at increased risk to progress to severe GH and to
develop preeclampsia [2]. In addition, patients with
and gestational diabetes mellitus (GDM), and the
progress to severe disease can increase faster than
usual. Moreover, the development of GH and GDM
together increases the risks of both preeclampsia and
adverse pregnancy outcome. Therefore, early detec-
tion of both GH or GDM with appropriate manage-
ment will result in improved pregnancy outcome [2].
This article describes the epidemiology of GH, its
pathophysiology and approaches to managing hyper-
tension in GDM. It also briefly summarizing the
long-term consequences of GH and suggest future
research priorities.
Epidemiology
GH complicates 5–10% of pregnancies. The rate of
hypertension in pregnancy varies by study population
[2]. During the past decade, there has been a
significant increase in the rate of obesity and delayed
pregnancy at a later age (435 years old) in women in
the United States [3,4]. In addition, because of the

Correspondence: Baha M. Sibai, University of Cincinnati College of Medicine, Cincinnati, OH, USA. E-mail: baha.sibai@uc.edu
ISSN 1476-7058 print/ISSN 1476-4954 online Ó 2010 Informa UK Ltd.
DOI: 10.3109/14767050903550899
 230 B. M. Sibai & M. G. Ross
increased frequency of using assisted reproductive
technology in women with infertility, the rates of
multifetal gestation (twins and triplets) have been
increasing. As a result, it is expected that the rates of
both GH and GDM will continue to increase [2–4].
Women who gain more weight during pregnancy
have higher rates of GH. For example, Crane et al.
[5] evaluated the effects of gestational weight gain on
maternal and neonatal outcomes in different body
mass index (BMI) classes and found that excess
weight gain in women with normal prepregnancy
BMI was associated with increased rates of GH (odd
ratio [OR]: 1.27; 95% confidence interval [CI]:
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1.08–1.49), and birth weight 4000 g (OR: 1.21;
95% CI: 1.10–1.34). In overweight women, excess
weight gain was associated with increased rates of
GH (OR: 1.31; 95% CI: 1.10–1.55) and birth weight
4000 g (OR: 1.30; 95% CI: 1.15–1.47). In women
who were of normal weight, overweight or obese, the
rate of adverse outcome (cesarean section, GH, birth
weight 52500 g or birth weight 4000 g) was lower
in women with recommended weight gain than in
those with excess weight gain [5].
Istwan and coworkers [6] similarly found that rates
of GDM and GH were significantly higher for obese
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versus normal BMI gravidas, respectively. Women
with morbid or severe obesity had a greater incidence
of GDM than women with an obese (30–34.9 kg/m)
or normal BMI (14.1%, 16.4%, 9.6%, and 3.7%,
respectively; P 5 0.05). The incidence of GH in-
creased with maternal BMI (9.0% normal, 25.5%
obese, 33.7% severe, 43.4% morbid; all pairwise
comparisons P 5 0.05).
Other risk factors for GH include insulin resis-
tance [7], advance maternal age, family history and
multifetal gestation [2]. Finally, the rates of both GH
and preeclampsia are both increased in women with
GDM [8–16] (Table I). These rates will depend and
correlate with blood sugar levels during therapy. For
example, adequate control of blood sugars with oral
hypoglycemic agents or insulin is associated with
reduced rate of preeclampsia (Table I) [8–16].
The ongoing HAPO study recently demonstrated
that maternal glucose levels below those diagnostic of
Table I. Rate of hypertension in GDM.
Study No.
Langer et al. [8] 404
Svare et al. [9] 323
Yogev et al. [10] 1813
Jacobson et al. [11] 504
Crowther et al. [12] 1030
Rowan et al. [13] 733
Yogev and Langer [14] 1319
Stella et al. [15] 927
Landon et al. [16] 958
diabetes can predict later incidences of preeclampsia
[17]. Similarly, Yogev et al. [10,14] demonstrated
that the rate of preeclampsia is influenced by the
severity of GDM and prepregnancy BMI. According
to the authors, optimizing glucose control during
pregnancy may decrease the rate of preeclampsia,
even in those with a greater severity of GDM [10].
In addition, two large multicenter randomized
trials comparing treatment versus no treatment
(control of blood sugars with insulin) in patients
with GDM revealed a lower incidence of GH in the
treated group [12–16].
Pathophysiology
GH-preeclampsia and GDM share similar patho-
physiologic abnormalities (Table II). Both GH and
GDM appear to be associated with insulin resistance
and an over expressed innate immune response,
which, in turn, is associated with inflammation,
vascular dysfunction, oxidative stress and vascular
disease. Among women with GDM, markers of
insulin resistance do not appear to correlate with
hypertension in short-term cohort studies. However,
when non-GDM subjects are compared with sub-
jects with GDM, postpregnancy studies do show an
association of insulin resistance with both inflamma-
tory dysregulation and vascular dysfunction [18].
Thus, it appears that GH in patients with GDM is
the result of vascular dysfunction caused by inflam-
matory dysregulation. This inflammatory dysregula-
tion appears to be mediated, at least in part, through
adipose tissue, which produces and releases a variety
of proinflammatory and anti-inflammatory factors,
including the adipokines: leptin, adiponectin, resistin
and visfatin, as well as cytokines and chemokines,
such as TNF-alpha, IL-6, monocyte chemoattractant
protein 1 and others [19–24]. Proinflammatory
molecules produced by adipose tissue have been
implicated as active participants in the development
of insulin resistance and the increased risk of
cardiovascular disease associated with obesity.
Fasshauer et al. [25] recently demonstrated that
maternal adipocyte fatty acid binding protein
Preeclampsia (%) Comment
6 Randomized (2 Rx)
7 Retrospective
9.6 Rate depends on glycemia
8.7 Retrospective (2 Rx)
15.1 Randomized (Rx vs. no Rx)
11.3 (6.3) Randomized (2 Rx)
11.7 Obese/morbid obese
21.4 Retrospective (all hypert.)
8.6 vs. 13.6 Randomized (Rx vs. no Rx)

Table II. Preeclampsia and gestational diabetes share similar
pathophysiologic abnormalities.
& Insulin resistance
& Hypertension
& Central obesity/dyslipidemia
& Oxidative stress/endothelial dysfunction
& Exuberant systemic inflammatory process
Abnormal cytokines
Neutrophil activation
& Increased leptin/reduced adinopectin
(AFABP) serum concentrations are significantly
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increased in patients with preeclampsia. Further-
more, BMI and serum creatinine are independent
predictors of circulating AFABP leptin, an adipose
derived adipokine, also appears to play a role in the
development of both GDM and GH [19–25]. Leptin
regulates energy intake and energy expenditure,
including appetite and metabolism. It has been
shown to correlate with adipose tissue mass, and its
levels are elevated in the maternal and newborn
blood in both patients with mild and severe
preeclampsia [26].
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The consequences of gestational hypertension
and gestational diabetes
There is growing evidence that both women and
babies who are exposed to GH during pregnancy
have significant long-term consequences [18]. For
example, in regards to women exposed to GH,
researchers in Finland [27] longitudinally followed
almost 6000 women from birth to age 31, at which
time blood pressure was measured and blood
samples were collected from 2678 women, of which
1463 women had at least one singleton pregnancy.
Of these, 45 had been hospitalized because of GH
and 49 because of preeclampsia. Women who had
either GH or preeclampsia during their first preg-
nancy (average age 25 years) had significantly
increased blood pressure at age 31 compared with
women with a previous normotensive pregnancy,
even after adjustment for BMI.
When compared with the whole female popula-
tion, women with previous GH at some age still had
higher blood pressure, while this difference was
weaker for women with previous preeclampsia.
Women with GH and preeclampsia also had higher
waist circumference, waist/hip ratio and BMI, as well
as increased serum insulin levels and lower glucose/
insulin ratio than women with a previous normoten-
sive pregnancy.
Similarly, Danish researchers [28] have recently
found that GH and preeclampsia are significant risk
factors for later subsequent hypertension and cardi-
ovascular disease. In this study, the investigators
Hypertension in GDM 231
found that the risk of subsequent hypertension after a
hypertensive pregnancy was increased 5.31-fold
(range: 4.90–5.75) after GH, 3.61-fold (range:
3.43–3.80) after mild preeclampsia and 6.07-fold
(range: 5.45–6.77) after severe preeclampsia. In
addition, the risk of subsequent Type 2 diabetes
mellitus was increased 3.12-fold (range: 2.63–3.70)
after GH and 3.68-fold (range: 3.04–4.46) after
severe preeclampsia. Women having two pregnancies
both complicated by preeclampsia had a 6.00-fold
(range: 5.40–6.67) increased risk of subsequent
hypertension compared with 2.70-fold (range:
2.51–2.90) for women having preeclampsia in their
first pregnancy only and 4.34-fold (range: 3.98–4.74)
for women having preeclampsia in their second
pregnancy only. The risk of subsequent thromboem-
bolism was 1.03-fold (range: 0.73–1.45), 1.53-fold
(range: 1.32–1.77) and 1.91-fold (range: 1.35–2.70)
increased after GH and mild and severe preeclamp-
sia, respectively.
Thus, hypertensive pregnancy disorders are
strongly associated with subsequent Type 2 diabetes
mellitus and hypertension, the latter independent of
subsequent Type 2 diabetes mellitus. The severity,
parity and recurrence of these hypertensive preg-
nancy disorders also increased the risk of subsequent
cardiovascular events.
Other studies have found the risk of metabolic
syndrome [29] and Type 2 diabetes [30] is sig-
nificantly elevated among women who have experi-
enced GH even decades after a hypertensive
pregnancy, as is morbidity from cardiovascular
disease [28–30].
Infants who experience GH in utero also appear to
have long-term consequences. A study by Pouta
et al. [27] observed an important effect of gestational
programming on the incidence of GH. Women who
themselves were born prematurely (before
gestational week 37) had a 2-fold risk for GH in
their first pregnancy (RR: 2.53; 95% CI: 1.0–6.2). As
GH and preeclampsia results in an increased risk
of premature delivery, GH appears to have long-
term consequences for the fetus as well as the
mother.
Additional effects of GH and GDM on offspring
have been reported. Stella et al. [15], for example,
studied the combined effects of GH and GDM on
perinatal outcomes among a group of almost 15,000
nulliparous women with singleton pregnancies deli-
vering at 37–40 weeks of gestation from 1995 to
2004. Of 14,880 women, there were 11,349 controls,
2604 with GH, 728 with GDM and 199 with both
GH/GDM during their preganancy. After controlling
for covariates, GH significantly increased cesarean
section (C/S) rate (OR: 1.62; 95% CI: 1.47–1.78),
rates of admittance to the neonatal intensive care
unit (NICU) and birth of large-for-gestational age
 232 B. M. Sibai & M. G. Ross
(LGA) infants. GDM significantly increased C/S
(OR: 1.42; CI: 1.21–1.66), rates of NICU admission
(OR: 1.32; CI: 1–1.75), birth of LGA babies (OR:
1.51; CI: 1.14–1.98) and macrosomic infants
(OR: 1.53; CI: 1.12–2.08). Rates of LGA infants
(OR: 1.85; CI: 1.19–2.86) and C/S (OR: 2.03; CI:
1.52–2.71) were significantly increased with GH/
GDM. The authors of this study concluded that GH
or GDM is associated with increased rates of adverse
outcomes, and their coexistence further increases
adverse perinatal outcomes [15].
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Management of mild hypertension in
pregnancies complicated by GDM
There is general agreement to treat severe levels of
blood pressures during pregnancy (systolic  160 mm
Hg and/or diastolic 105 mm Hg); however, there is
no agreement regarding treatment of mild hyperten-
sion during pregnancy [31]. Indeed, there are no
prospective observational studies or randomized trials
evaluating the benefits or risks of treating mild
hypertension in patients with GDM. On the other
hand, because of the proven benefits of treating mild
values of hypertension in nonpregnant diabetic sub-
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jects, there is agreement that maternal blood pressure
should be treated to levels below 130/80 mm Hg in
those with Type 1 and 2 diabetes mellitus during
pregnancy [31]. However, no such data exist for
women with GDM in association with GH. Thus,
there is an urgent need for research in this area.
Unanswered questions
Although recent studies have given us a great deal of
additional insights into the pathophysiology, con-
sequences and effective management of GH and
GDM, many unanswered questions remain. Should
all women be screened for risk factors before
conception [32]? Should all women with GDM or
GH be screened for cardiovascular risk factors at 3–6
months postpartum [32,33]?
In addition, if they test positive, what is the
appropriate course of action? In addition to the
management of GH or GDM, should the physician
also seek to treat or attenuate long-term complica-
tions, such as metabolic syndrome, Type 2 diabetes
or cardiovascular disease (e.g., prescribing an in-
tensive weight reduction program statins for the at-
risk patient) [33].
Conclusions
Pregnancies complicated by GH or GDM are
associated with adverse consequences for the mother
and fetus (both acute and long-term). Future studies
should address the impact of aggressive management
of these pregnancies (control of mild hypertension
and mild glucose intolerance) and reducing the long-
term consequences for both the mothers and
children later in life. Finally, we are only beginning
to recognize the long-term health and disease impact
among the offspring of women who experience GH
or GDM.
Declaration of interest: The authors report no
conflicts of interest. The authors alone are respon-
sible for the content and writing of the paper.
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