EHD-04225; No of Pages 6

Early Human Development xxx (2016) xxxxxx

Contents lists available at ScienceDirect

Early Human Development

journal homepage: www.elsevier.com/locate/earlhumdev

Best practice guidelines

Potential benets of physical activity during pregnancy for the reduction

of gestational diabetes prevalence and oxidative stress
Marcela Cid a,1, Marcelo Gonzlez b,c,
a
b
c

Department of Obstetrics & Childcare, Faculty of Biological Sciences, Universidad de Concepcin, P.O. Box 160-C, Concepcin 4070386, Chile
Vascular Physiology Laboratory, Department of Physiology, Faculty of Biological Sciences, University of Concepcin, P.O. Box 160-C, Concepcin 4070386, Chile
Group of Research and Innovation in Vascular Health (GRIVAS-Health), Chilln, Chile

a r t i c l e
Available online xxxx

i n f o

a b s t r a c t
Changes in quality of nutrition, habits, and physical activity in modern societies increase susceptibility to obesity,
which can deleteriously affect pregnancy outcome. In particular, a sedentary lifestyle causes dysfunction in blood
ow, which impacts the cardiovascular function of pregnant women. The main molecular mechanism responsible for this effect is the synthesis and bioavailability of nitric oxide, a phenomenon regulated by the antioxidant
capacity of endothelial cells. These alterations affect the vascular health of the mother and vascular performance
of the placenta, the key organ responsible for the healthy development of the fetus. In addition to the increases in
systemic vascular resistance in the mother, placental oxidative stress also affects the feto-placental blood ow.
These changes can be integrated into the proteomics and metabolomics of newborns.
2016 Elsevier Ireland Ltd. All rights reserved.

Contents
1.
2.
3.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . .
Physical activity and pregnancy . . . . . . . . . . . . . . . . . .
Physical activity, gestational diabetes mellitus, and oxidative stress . .
3.1.
Oxidative stress associated with vascular dysfunction in GDM .
3.2.
Effects of physical activity on oxidative stress induced by GDM .
4.
Perspectives . . . . . . . . . . . . . . . . . . . . . . . . . . .
5.
Key guidelines . . . . . . . . . . . . . . . . . . . . . . . . . .
6.
Research directions . . . . . . . . . . . . . . . . . . . . . . . .
Conict of interest statement . . . . . . . . . . . . . . . . . . . . . .
Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . .
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1. Introduction
Good-quality nutrition and lifestyle (socioeconomic status, exercise,
low stress levels, etc.) are associated with normal body mass index
(BMI), insulin sensitivity, adequate glycemia control, and endothelial
function. All of these parameters are associated with the regulation of

Corresponding author at: Vascular Physiology Laboratory, Department of Physiology,

Faculty of Biological Sciences, University of Concepcin, P.O. Box 160-C, Concepcin
4070386, Chile. Tel.: +56 41 266 1207; fax: +56 41 222 7455.
E-mail addresses: marcecid@udec.cl (M. Cid), mgonzalezo@udec.cl (M. Gonzlez).
1
Tel.: +56 41 220 4575; fax: +56 41 222 3933.

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vascular resistance and cardiovascular health. In adverse conditions

during pregnancy (such as malnutrition, obesity, or sedentary lifestyle)
insulin resistance is associated with endothelial and vascular dysfunction, including placental vascular adaptations. The improvement of
public policies based on scientic knowledge (pathophysiological
mechanisms) and the implementation of low-cost strategies are pivotal
to hinder the progression of these pathologies in the world (Fig. 1)
[13]. Physical activity (PA) during pregnancy is one of the most reliable
strategies to enact positive changes to human health.
In this review, we will summarize the interventions that can impart
positive outcome for mothers and fetuses. Specically, we focus on the
potential benets of these strategies for reducing the effects of oxidative

http://dx.doi.org/10.1016/j.earlhumdev.2016.01.007
0378-3782/ 2016 Elsevier Ireland Ltd. All rights reserved.

Please cite this article as: Cid M, Gonzlez M, Potential benets of physical activity during pregnancy for the reduction of gestational diabetes
prevalence and oxidative stress, Early Hum Dev (2016), http://dx.doi.org/10.1016/j.earlhumdev.2016.01.007

M. Cid, M. Gonzlez / Early Human Development xxx (2016) xxxxxx

Fig. 1. Insulin resistance and endothelial dysfunction are key factors in the development of cardiovascular diseases. Good quality of nutrition and good quality of life (socioeconomic and
sociocultural environment, physical activity, low stress, etc.) are associated with normal insulin sensitivity and improvement of glucose control and endothelial function. Normal
endothelial function is a key factor for the regulation of vascular resistance and cardiovascular health. In adverse conditions associated with poor quality of nutrition (under- or
overnutrition), obesity, or sedentary lifestyle, insulin resistance is manifested as the rst step in the development of endothelial dysfunction and vascular problems, including placental
vascular adaptations if the insulin resistance or diabetes is manifested in pregnancy. The improvement of public policies based in scientic knowledge about insulin regulation of
vascular function/dysfunction is a pivotal gear for the decline of the progression of these pathologies.

stress associated with gestational diabetes mellitus (GDM) and obesity

during pregnancy.
2. Physical activity and pregnancy
A sedentary lifestyle is the fourth most important risk factor for mortality worldwide. Physical inactivity is increasing in many countries and
is related to the prevalence of non-communicable diseases that impact
the overall health of the world population [4]. People who perform adequate PA on a regular basis have lower rates of heart disease, hypertension, stroke, type 2 diabetes, metabolic syndrome, colon cancer, breast
cancer, and depression. Adults and older people who are physically active have better cardiorespiratory and muscle mass performance,
healthier body composition, and a prole of biomarkers related to the
prevention of cardiovascular disease and type 2 diabetes [5,6].
Although exercise is important in all stages of life, it is especially
important during pregnancy, since it can impact the future health of
both the mother and her offspring. Nonetheless, studies show that
women decrease their PA during pregnancy. The rates of physical
inactivity during pregnancy range between 64.5% and 91.5%, and tend
to be higher in the third trimester of pregnancy [7]. The prevalence of
insufcient activity increases from 12.6% in pre-pregnancy to 21.6% during the second trimester, and remains unchanged at 21.7% at 6 months
postpartum [8]. Research highlights that women who already have a
child at home, who work more than 45 h per week during early pregnancy, and who do not decrease their work hours during pregnancy
have a higher risk of becoming insufciently active during and following
pregnancy [8]. It is important to note that the maintenance of adequate
PA during pregnancy could also depend on pre-pregnancy nutrition and
habits, together with socioeconomic and sociocultural environment.
The establishment of sedentary societies and the increase in highcaloric food intake after the neolithic and industrial revolutions negatively affects physiological processes, particularly those of pregnant
women [9]. Of particular importance is the case of low- and middleincome societies whose economic development relies on women's

contribution to the workforce. For example, a study of Latino women

residing in the USA reported that the absence of support during pregnancy and the postpartum period was the main cause for not engaging
in healthy nutrition and for not meeting the recommended PA level. The
lack of support from their partner or extended family, as well as the
absence of a childcare system, combined with the inability to reduce
their work-load, limited the hours that pregnant women used for selfcare habits [10,11].
Currently, there are many studies that support the prescription of
exercise in pregnant women, ensuring minimal risk and signicant
benet. However, the prevalence of pregnant women with insufcient
leisure PA is still 83% in Chile [12] and 50%60% in the USA [13,14].
Regular engagement in moderate PA during pregnancy in healthy
women has no risk to the health of the mother or fetus, with benets
that are not only restricted to pregnancy, but also extend to the postpartum period [15,16]. Regular PA, when not contraindicated by disease or
a high-risk obstetrics pregnancy, provides a pregnant woman with
better overall tness, improves cardiovascular health and muscle performance, prevents excessive weight gain, improves blood pressure,
and protects against GDM. PA during pregnancy also improves labor
and delivery, and helps reduce the need for obstetric intervention or
cesarean section [16]. Additionally, PA decreases discomfort caused by
the physiological changes of pregnancy, such as digestive problems, insomnia, and psychological problems such as anxiety and depression
[17]. However, the percentage of sedentary women who are of childbearing age seems to be increased, resulting in a sedentary lifestyle
being reported by the majority of pregnant women [14,16,17]. Unfortunately, even women who engage in PA before pregnancy tend to reduce
their activity once they became pregnant [8].
The physical health of women and their engagement in a healthy
lifestyle before and during pregnancy may be important predictors of
their engagement in PA during pregnancy. For example, women with
a BMI above the normal range are more likely to remain inactive and
not do any exercise [18]. The prevalence of obesity varies from 4% in
Japan and Korea, to 30% or more in the USA and Mexico, but there is a

Please cite this article as: Cid M, Gonzlez M, Potential benets of physical activity during pregnancy for the reduction of gestational diabetes
prevalence and oxidative stress, Early Hum Dev (2016), http://dx.doi.org/10.1016/j.earlhumdev.2016.01.007

M. Cid, M. Gonzlez / Early Human Development xxx (2016) xxxxxx

global escalation in these values. It is estimated that 2/3 of people will be

overweight or obese in 2020, with the majority being women. According to the 2010 National Health Survey in Chile, the prevalence of obesity in individuals over the age of 15 is 25% (19% in men and 31% in
women) and the prevalence of overweightness is 39% [19]. Globally, it
is estimated that pre-pregnancy overweightness and obesity have 34%
and 25% prevalence, respectively; though, these may be underestimated
[19]. In the USA, more than half of pregnant women are overweight or
obese, and 8% of reproductive-age women are extremely obese [20].
Being overweight during pregnancy is associated with an increased
risk of GDM, gestational hypertension, preeclampsia, fetal macrosomia,
and a high rate of cesarean delivery [20]. Furthermore, children of
mothers who gained too much weight during pregnancy are more likely
to be born prematurely, be macrosomic, and become obese during
childhood, adolescence, or adulthood [21]. A study in Greece concluded
that women who gained excessive weight during pregnancy and did
not engage in PA were more likely to have a child that is obese by
8 years of age. Given these statistics and clinical outcomes, physicians
have started advising women to perform moderate exercise during
pregnancy [22]. The American College of Obstetricians and Gynecologists (ACOG) currently recommends performing at least 30 min of
moderate daily exercise [23]. Similarly, the American College of Sports
Medicine recommends a minimum of 15 min of exercise at least three
times per week, with the aim of gradually increasing to 30 min of
exercise per day [23].
In addition to helping control gestational weight gain, PA has been
demonstrated to be effective for reducing depression symptoms and
improving overall maternal quality of life [24]. Furthermore, contrary
to traditional beliefs, gestational PA is not associated with prematurity.
Studies have shown that women who perform recreational PA regularly
(such as swimming, tness programs, yoga, etc.) for over two trimesters
of their pregnancy give birth to babies of gestational age similar to those
who do not exercise. Additionally, women who participate in regular
gestational PA have babies with lower birth weights than those of
sedentary women [25].
The hemodynamic changes during exercise are the basis for theories
about why PA during pregnancy can cause decreased oxygen delivery to
the fetus and potential fetal growth restriction. Although studies have
shown a decrease in uterine circulation due to exercise during pregnancy, many mechanisms act to maintain a relatively constant oxygen
delivery to the fetus. These mechanisms include an increased maternal
hematocrit and oxygen transport in the blood, an inverse relationship
between blood ow and the tissue extraction of oxygen, as well as a redistribution of blood ow to the placenta rather than to the uterus [26].
The current literature indicates that gestational exercise is not associated with any complications, neither for the mother nor the fetus [27].
While uterine blood ow is reduced during exercise, studies indicate
that this does not affect the blood ow to the fetus. It is still unclear
what the underlying mechanisms are, though they may be related to
the preservation of both umbilical and placental blood ow during PA.
One hypothesis is that local regulation of placental circulation protects
the fetus against hemodynamic changes [26,28,29]. The next section
will further describe the potential mechanisms that underlie the
physiological adaptations and benets of PA during pregnancy and the
postpartum period.
3. Physical activity, gestational diabetes mellitus, and oxidative
stress
With the changes in the lifestyle and quality of nutrition of Western
civilization, there has been a consistent increase in the risk of GDM, a
carbohydrate intolerance of varied severity that begins, or is rst
recognized, during pregnancy [30]. According to the American Diabetes
Association, the prevalence of GDM is 18% among all pregnancies in the
USA [31]. The global percentage of hyperglycemia in pregnancy is 16.9%,
representing 21.4 million births per year [32]. The growing incidence of

obesity and insulin resistance (metabolic syndrome) stresses the need

to understand the underlying cellular and molecular mechanisms of
GDM. In addition to obstetric and perinatal complications, gestational
obesity and insulin resistance are associated with increased prevalence
of postnatal disorders, such as cardiovascular diseases (atherosclerosis,
hypertension, etc.) and/or metabolic diseases (type 2 diabetes mellitus,
obesity, etc.) [33,34] (Fig. 2). This relationship between prenatal
environmentas dictated by maternal healthand adult disease has
been referred to as fetal origin of adult disease.
In pregnancy, there is a 50%60% decrease in insulin sensitivity, with
a signicant decrease in late gestation in women with GDM. A study
that assessed the response to insulin infusion noted a 32% reduction in
the uptake of 2-deoxyglucose in rectus abdominis muscles of normal
glucose-tolerant pregnant women but a 54% decrease in GDM women,
as compared with non-pregnant women. These reductions were correlated with a 37% decrease in the maximal effect of insulin on insulinreceptor phosphorylation in GDM compared with normal pregnancy
[35]. This association of GDM and maternal insulin resistance also has
an impact on placental physiology in late pregnancy. Specically, angiogenesis and microvascular remodeling in the placenta can alter insulin
resistance, as evidenced by increased capillary branching and capillary
surface area. These alterations may be caused by high expression of vascular endothelial growth factor (VEGF) receptor 1 (VGFR1/Flt1) and
VEGF receptor 2 (VGFR2/Kdr), which act as compensatory mechanisms.
Other potential mechanisms include up-regulation of stress and
inammatory factors, such as interleukin 6 (IL6) and tumor necrosis
factor alpha (TNF), which are increased in the placenta due to GDM
[35,36].
3.1. Oxidative stress associated with vascular dysfunction in GDM
The main causes of mortality and morbidity in diabetic patients are
cardiovascular diseases (CVD), which primarily involve loss of vascular
tone. Vascular tone is maintained by equilibrium between endothelialderived relaxing factors (EDRFs) and endothelial-derived contracting
factors (EDCFs). These are molecules released from endothelial cells
(ECs), which act on vascular smooth muscle cells (VSMCs) [37,38].
The most relevant EDRF is nitric oxide (NO), a molecule involved in
the regulation of vasodilation, blood ow, vascular resistance, platelet
aggregation, and VSMCs proliferation [39]. NO is synthesized from the
semi-essential amino acid L-arginine, a molecule transported by cationic
amino acids transporters (CATs), and primarily by human CAT 1
(hCAT-1) [40]. This amino acid is the substrate for endothelial NO synthase (eNOS), an enzyme that catalyzes the synthesis of L-citrulline
and NO [41].
CVD is associated with high levels of reactive oxygen species (ROS)
and low levels of antioxidant activity [42,43]. The mechanism involved
in vascular dysfunction associated with ROS includes the neutralization
of NO, by a quick reaction with superoxide anion (O
2 ), and peroxinitrite
(ONOO) synthesis [44,45]. High extracellular concentration of D-glucose
(25 mM) increases the expression and activity of hCAT-1, elevating the
synthesis of NO associated with NADPH oxidase-dependent O
2 in
human umbilical vein endothelial cells (HUVECs) [46]. On the other
hand, in normoglycemia, insulin increases L-arginine transport and NO
synthesis without changes in O
2 levels, inducing relaxation of umbilical
and placental vessels [47]. Interestingly, the effect of high D-glucose is
associated with high contractile response to U46619 (thromboxane A2
analog) and hydrogen peroxide (H2O2). Under these experimental conditions, co-incubation with insulin recovers adequate response to vasoconstrictors and decreases the NADPH oxidase-dependent ROS in HUVECs
from normoglycemic pregnant women [46]. This evidence shows that in
pregnancies with a well-regulated glucoseinsulin axis, insulin signaling
controls oxidative stress in placental endothelial cells, therefore inducing
relaxation and lowering vascular resistance. However, in GDM, vascular
dysfunction occurs due to increased insulin resistance and reduction of
NO bioavailability (Fig. 2).

Please cite this article as: Cid M, Gonzlez M, Potential benets of physical activity during pregnancy for the reduction of gestational diabetes
prevalence and oxidative stress, Early Hum Dev (2016), http://dx.doi.org/10.1016/j.earlhumdev.2016.01.007

M. Cid, M. Gonzlez / Early Human Development xxx (2016) xxxxxx

Fig. 2. Benets of physical activity during pregnancy to avoid the pathophysiological mechanisms associated with maternal obesity and gestational diabetes mellitus (GDM). Sedentary
lifestyle, before and during pregnancy, increases the rate of overweightness and obesity in the mother and affect the development of the placenta. Placenta dysfunction is leading by
high oxidative stress and inammatory cytokines, lower availability of nitric oxide (NO), and high vascular resistance. This condition can be related with GDM, inducing alterations in
the mother related with lower ow-mediated dilatation (FMD), high systemic vascular resistance (SVR), or high insulin resistance (IR). This placental environment can affect the fetus,
resulting in a newborn with higher tendency to oxidative stress, vascular resistance, and early life complications associated with growth restriction or macrosomy (depending on the
time and strength of stress during placentation). In later life, both mother and fetus, have an increased probability of developing cardiometabolic diseases. Physical activity can avoid
these deleterious mechanisms, especially if the exercise is performed regularly before and during pregnancy, as well as in the postpartum period. To ensure this goal, pregnant women
need leisure time, a good childcare system (when they have children at home), a progressive reduction in workload, and adequate support from her family and national health
services (NHS).

Taken together, vascular dysfunction can be dened as the

impairment in NO function as a vasodilator. Vascular dysfunction
is also related to an antioxidant/oxidant imbalance leading to
oxidative stress [48] and insulin resistance [49]. Insulin resistance
and hyperglycemia are the main pathophysiological factors leading
to GDM and type 2 diabetes in pregnant and non-pregnant women,
respectively [35,50]. In GDM, maternal hyperglycemia is believed to
cause hyperplasia and hypertrophy of fetal pancreatic beta cells,
affecting fetal organ development and function, as well as placental
vasculature [51,52]. This hypothesized mechanism is supported by
molecular changes in GDM placentas. Studies analyzing arteries
and veins isolated from the chorionic plate of placentas of women
with GDM, revealed a decrease in lactate-induced relaxation [53],
an increase in H 2 O 2 -induced contractions [53] and alterations in
placental vascular response to hypoxia/reoxygenation [54]. As
mentioned previously, it has also been demonstrated that insulin
induces relaxation in endothelium-intact vessels in normoglycemic
human umbilical veins [47], an effect that was decreased in GDM
pregnancies [55]. These data show that GDM placental vasculature
has high sensitivity for endogenous vasoconstrictors and that the
mechanisms could be related to high levels of ROS, mainly those
dependent on NADPH oxidase expression. The main catalytic
subunits of NADPH oxidase expressed in endothelium are the
isoforms NOX2 and NOX4 [56], both expressed in HUVEC and
stimulated by 24 h incubation with high D-glucose [57]. Additionally in GDM-HUVECs, it has been determined that there is a decrease
in L -arginine transport associated with lower activity hCATs [58],
supporting the hypothesis that the oxidative stress associated
with hyperglycemia affects the L-arginine/NO pathway in GDM.
3.2. Effects of physical activity on oxidative stress induced by GDM
PA can help to prevent GDM and therefore postnatal complications,
including childhood obesity and diabetes in adult life [59]. Exercise

improves insulin sensitivity and can prevent excessive gestational weight

gain in the rst trimester, which is strongly associated with GDM (Fig. 2).
Engaging in regular PA for three to twelve months prior to pregnancy decreases the incidence of GDM by 30%74%. This decrease is directly correlated with the intensity and/or duration, with vigorous exercise causing
the most reduction in GDM risk [60]. However, despite clinical evidence
showing that PA is benecial for reducing excessive weight gain and decreasing the incidence of GDM, the underlying mechanisms are still unclear. While a few studies have shown that PA alters oxidative stress
pathways induced by GDM, no explicit study has been published on this
matter. For example, a PubMed search using the words gestational diabetes, oxidative stress, and physical activity (or exercise) has no results. Two relevant rodent studies were found when searching for implicit
studies on the role of PA on oxidative stress in pregnancy. In the rst
study, pregnant obese rats who voluntarily exercised had reduced adiposity index and testicular oxidative stress markers (malondialdehyde and
glutathione peroxidase), decreased liver nitrotyrosine levels, and gave
birth to male offspring with increased fertility rate [61,62]. In the second
animal study, Marcelino et al. showed that PA (swimming) after and during pregnancy reduced brain oxidative stress in rat offspring inicted with
hypoxic ischemia [63]. In a rat model of reduced uteroplacental perfusion
(RUPP), exercise was shown to restore placental efciency (fetal weight/
placental weight), decrease mean arterial pressure, restore placental angiogenic balance and antioxidant capacity, and elevate expression of superoxide dismutase (SOD) [64].
Contrary to these reports, a recent study on the effect of PA on rats
with type 1 diabetes mellitus (induced through streptozotocin
injections), showed that swimming was ineffective at reducing the
overall oxidative stress, but still induced elevation of SOD [65].
Together, these studies may help elucidate the possible mechanisms
for the link between PA and GDM. The sparse and somewhat conicting
reports also provide impetus for future research in this eld so as to
properly understand how PA alters oxidative stress and hyperglycemia
in different types of diabetes.

Please cite this article as: Cid M, Gonzlez M, Potential benets of physical activity during pregnancy for the reduction of gestational diabetes
prevalence and oxidative stress, Early Hum Dev (2016), http://dx.doi.org/10.1016/j.earlhumdev.2016.01.007

M. Cid, M. Gonzlez / Early Human Development xxx (2016) xxxxxx

4. Perspectives
Despite numerous scientic reports demonstrating a positive relationship between PA and pregnancy, especially in pathological pregnancies, many pregnant women do not meet the minimum recommended
level of PA during and after pregnancy [66]. The current high prevalence
of maternal overweightness and obesity, insulin resistance, and GDM,
necessitate establishing public policies that support gestational and
leisure-time PA. These are essential for reducing the prevalence of cardiovascular and metabolic diseases in the future. Future research should
focus on understanding the effects of PA on the expression and activity
of various pro- and anti-oxidant pathways in the placentas of women
with GDM. In addition to research, efforts should be made to encourage
women to engage in PA prior to, during, and after pregnancy.
5. Key guidelines
The increases of overweightness and obesity in pregnancy necessitate physical activity-based interventions before, during, and
after pregnancy.
Gestational diabetes induces placental oxidative stress and
lowers nitric oxide availability. These alter the cardiometabolic
status in the mother and her fetus.
Moderate physical activity improves the antioxidant capacity of
the placenta, restoring nitric oxide signaling and reducing the
probability of feto-placental blood ow dysfunction.

6. Research directions
Future studies should aim at understanding the mechanisms by
which physical activity regulates placental vasculature. Elucidating
these mechanisms will enable to construct clinical interventions
that are exercise-based and would reduce overweightness, obesity,
and GDM in pregnancy.
Specically, it is important to determine if moderate PA reduces
NADPH oxidase activity and improves NO availability in placental
vasculature.

Conict of interest statement

The authors declare that they have no conict of interest, nancial or
otherwise, pertaining to this article.
Acknowledgements
We would like to thank all research staff at the Vascular Physiology
Laboratory of Universidad de Concepcin for their technical support
and the Departments of Obstetrics & Childcare and Physiology of
Universidad de Concepcin for administrative support. MC and MG
are nancially supported by VRID-Asociativo 213.A84.014-1.0
(Universidad de Concepcin, Chile).
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Please cite this article as: Cid M, Gonzlez M, Potential benets of physical activity during pregnancy for the reduction of gestational diabetes
prevalence and oxidative stress, Early Hum Dev (2016), http://dx.doi.org/10.1016/j.earlhumdev.2016.01.007