I.

INTRODUCTION

All over the world, since 1980, obesity has doubled and reached epidemic conditions.1
Obesity is a major epidemic in developed countries that is now extending to developing
countries.2 Excessive weight is also a major health problem in the United States and other
affluent societies. For a number of years, obesity was said to be epidemic—strictly defined,
this implies a temporary widespread outbreak of greatly increased frequency and severity.
Unfortunately, obesity more correctly is endemic—a condition that is habitually present. By
1991, approximately a third of adults in the United States were overweight, and thus a stated
goal of Healthy People 2000 was to reduce the prevalence of overweight people to 20 percent
or less by the end of the 20th century (Public Health Service, 1990). Not only was this goal
not achieved, but by 2000, more than half of the population was overweight. In 2010, a third
of all adults were obese (Ogden, 2012). 3 In the United States, the percentage of women who
are overweight or obese has increased by approximately 60% over that last thirty years. The
World Health Organization estimates the prevalence of obese and overweight women (body
mass index ≥ 25 kg/m2) to be 77% in the United States, 73% in Mexico, 37% in France, 32%
in China, 18% in India, and 69% in South Africa with wide variation within each continent.4
Overweight and obesity are prevalent and increasing in the UK. Thirty two percent of
35- to 64-year-old women are overweight (body mass index [BMI] 25–30 kg/m2) and 21%
obese (BMI > 30 kg/m2).1 These proportions are increasing and the percentage of adults who
are obese has roughly doubled since the mid-1980s.5
Based on RISKESDAS 2007, rates of obesity in the population aged more than 15
years in Indonesia was 13.9% in men and 14.8% in women. The prevalence of obesity
sentral, when waist circumference greater than 90 cm in men and 80 cm for women, was
18.8%. Based RISKERDAS 2013, the prevalence of obesity compared RISKERDAS 2007
increased to 19.7% and 32.9% respectively in men and women and normal waist
circumference be 26.6%.1
The global epidemic of obesity is unfolding, resulting in new challenges for all
health-care professionals.6 Due to overweight (obese or overweight) an estimated 3.4 million
deaths occurred, 44% diabetes, 23% of ischemic heart disease and 7-14% of malignancy.1
Obesity is often associated with insulin resistance, dyslipidemia, and hypertension, which has
led to the concept of metabolic syndrome. Recent evidence has suggested that the prevention
of obesity may begin before conception.6

1
 Obesity in pregnancy is associated with increased risk of pregnancy complications
such as miscarriage, congenital abnormalities in infant (such as neural tube defects),
thromboembolism, gestational diabetes, preeclampsia, prematurity, abnormal labor, shoulder
dystocia, postpartum hemorrhage, increased rates of cesarean delivery, surgical site infection
/ perineum, low Apgar scores in stillbirth, as well as maternal and neonatal mortality. The
Confidential Enquiry into Maternal and Child Health reported 28% of maternal deaths in
2003-2005 due to obesity.1,6 Obese women who become pregnant—and their fetuses—are
predisposed to various serious pregnancy-related complications. Moreover, longterm
maternal and fetal effects include significant and increased morbidity and mortality rates.4
Preeclampsia is a pregnancy-specific disorder that affects 2 to 8% of all pregnancies
and remains a leading cause of maternal and perinatal morbidity and mortality worldwide. 4
Each year, an estimated 76,000 maternal and 500,000 child deaths worldwide are attributed to
preeclampsia. Globally preeclampsia is accounting for 10-15% of maternal deaths. It is
responsible for 18% of all maternal deaths in the US alone and 15% of premature births in
developed countries. As the only cure for this condition is delivery, it is one of the main
causes of premature delivery and low birth weight. Preeclampsia occurs in 5-8% of
deliveries, affecting one in every 12 women in the US.7 Diagnosis of preeclampsia is based
on new onset of hypertension and proteinuria. Multiple organ systems can be affected with
severe disease. The wide range of risk factors reflects the heterogeneity of preeclampsia.
Obesity, which is increasing at an alarming rate, is a risk factor for preeclampsia as
well as for later life cardiovascular disease.4 Maternal obesity predisposes a woman to
developing pre-eclampsia and a dose-dependent relationship between increasing body mass
index (BMI) and the risk of developing pre-eclampsia is well established.6,8 Obesity increases
the overall risk of preeclampsia by approximately 2- to 3-fold. The risk of preeclampsia
progressively increases with increasing BMI, even within the normal range. Importantly, it is
not only the late or mild forms of preeclampsia that are increased, but also early and severe
preeclampsia, which are associated with greater perinatal morbidity and mortality. 2,3

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 II. LITERATURE REVIEW

II.1 OBESITY
Definition
Obesity is the accumulation of abnormal or excessive fat that can cause health
problems. Fat is stored throughout the body. Because of that fat can not be measured.1 A
number of systems have been used to define and classify obesity. The body mass index (BMI),
also known as the Quetelet index, is currently most often used. The BMI is calculated as
weight in kilograms divided by the square of the height in meters (kg/m2).3 The National
Institutes of Health (2000) classifies adults according to BMI as follows: normal (18.5 to 24.9
kg/m2); overweight (25 to 29.9 kg/m2); and obese (≥ 30 kg/m2). Obesity is further divided
into: class 1 (30 to 34.9 kg/m2); class 2 (35 to 39.9 kg/m2); and class 3 (≥ 40 kg/m2).3, 9

Table 1. BMI Clasification

Prevalence
Number of obesity worldwide is increasing, today 2 times compared to 1980. In 2008,
over 1.4 billion adults (greater than or equal to 20 years) overweight. More than 200 million
men and nearly 300 million women are obese. 35% overweight and 11% obese.
Approximately 65% of the world population lives in countries where overweight causes more
deaths compared to underweight. In 2012, more than 40 million children are overweight.1
By 2000, 28 percent of men and 33 percent of women were obese (Ogden, 2012). For
the period 2009 to 2010, among men and women these percentages were almost identical at
approximately 35 percent. Shown in Picture 1 are the prevalences of obesity among girls and
women. Obesity increases with age as well as with ethnic minority, and almost 60 percent of
black women were obese in 2010. This is also true among indigent individuals (Drewnowski,
2004).3

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Picture 1. Prevalence of obesity in girls and women in the United States for 2009–2010.
(Data from Flegal, 2012; Ogden, 2012.)

Cause
Cause of obesity is excess intake of calories compared to usage. This causes 1.
Increased intake of high calorie foods that contain a lot of fat, 2. Reduced physical activity as
a result of changes in work patterns, urbanization and changes in transport.
Generally, changes in diet and physical activity is the estuary of social and environmental
changes caused by development that is not followed by policies in the areas of health,
agriculture, environment, transport, food processing, distribution, marketing and education .1

Patophysiology
Obesity is defined by a BMI over 30 kg / m2, while in Asia, obesity is determined by
the size of BMI over 25 kg / m2. Obesity is caused by positive energy balance within a
certain time due to excess energy intake compared with the body's needs. Mainly due to
excess food intake and physical activity deficiency. Genetic factors did play a role in obesity,
but the obese condition will occur when excess energy is possible to be stored in adipose
cells.1
Energy came out strongly associated with body composition, in this case the amount
of fat-free period than the period of fat. Excess energy is stored in the form of triglycerides in
adipose tissue. At the onset of obesity, causes enlargement of adipose cells, but when energy
intake is still excessive, then the excess energy would cause the formation of new adipose

4
cells. The average adult has 40-50 billion adipose cells. Each adipose cells would save a
maximum of 1.2 mg of triglycerides.1

Adipose Tissue as an Organ System

Fat tissue is much more complex than its energy storage function. Many cell types in
fat tissue communicate with all other tissues via endocrine and paracrine factors—adipokines,
or adipocytokines. Some of those with metabolic functions include adiponectin, leptin, tumor
necrosis factor-α (TNF-α), interleukin 6 (IL-6), resistin, visfatin, apelin, vascular endothelium
growth factor (VEGF), lipoprotein lipase, and insulin-like growth factor (Briana, 2009;
Scherer, 2006). A principal adipokine is adiponectin, which is a 30-kDa protein. It enhances
insulin sensitivity, blocks hepatic release of glucose, and has cardioprotective effects on
circulating plasma lipids. An adiponectin deficit leads to diabetes, hypertension, endothelial
cell activation, and cardiovascular disease.3

Adipocytokines in Pregnancy
Cytokines that result in insulin resistance—leptin, resistin, TNF-α, and IL-6—are increased
during pregnancy. Indeed, these may be the primary stimulant of insulin resistance. Secretion
of the remaining adipokines is either unchanged or decreased. Specific patterns have been
variously described with gestational diabetes, preeclampsia, and fetal-growth restriction
(Briana, 2009). In a longitudinal study of 55 pregnant women, Meyer and associates (2013)
confirmed that higher BMIs are associated with lower adiponectin but higher leptin levels.3

Complication
Obese individuals are at increased risk for an imposing number of complications
(table 2).3 Obesity has been linked to numerous adverse health consequences including,
among others, T2DM, coronary heart disease, sleep apnea and pulmonary dysfunction,
stroke, and liver disease.3 Reproductive function is also affected by obesity. 10 The direct link
between obesity and type 2 diabetes mellitus is well known. Ninety percent of type 2 diabetes
cases are attributable to excess weight, and 75 percent of these diabetics have the metabolic
syndrome (Hossain, 2007). Heart disease due to obesity—adipositas cordis—is caused by
hypertension, hypervolemia, and dyslipidemia. Higher rates of abnormal left ventricular
function, heart failure, myocardial infarction, and stroke have been noted (Chinali, 2004;
Kenchaiah, 2002; Targher, 2010).3

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TABLE 2. Long-Term Complications of Obesity

II.2 OBESITY IN PREGNANCY

The definition of obesity in pregnancy varies by author and includes women who are
110% to 120% of their ideal body weight or > 91 kg (200 lbs) or who have a BMI > 30
kg/m2. 9
Women should set pregnancy weight gain goals based on their pre-pregnancy BMI as
shown in Table 3. To achieve these goals women should be at the healthiest weight possible
when they enter pregnancy. During well-woman checks and other health care interactions,
non-pregnant women of child-bearing age can be advised of their BMI. An evaluation of
dietary intake and exercise habits can provide insight into women at risk. According to the
joint guidelines on exercise in pregnancy by the SOGC and the Canadian Society for Exercise
Physiology, all pregnant women without contraindications should participate in regular
exercise. During prenatal visits women can be questioned and advised about their diet and
exercise habits. Where available, nutritional counselling can be a helpful adjunct for women
not meeting the weight gain guidelines in Table 3. Pregnancy outcomes are related to
maternal weight gain. Fifty-two percent of a Canadian cohort of women gained more than the
recommended weight in pregnancy. Depending on pre-pregnancy BMI, these pregnancies
were at increased risk of macrosomia > 4000 g, augmentation of labour, gestational

6
hypertension, and neonatal metabolic abnormalities. Regardless of BMI, those women who
gained the recommended amount of weight in pregnancy had fewer adverse outcomes
(Caesarean section, gestational hypertension, birth weight < 2500 g or > 4000 g).9

Obesity in pregnancy was recognized to increase the risk of gestational diabetes

mellitus, hypertension, preeclampsia, cesarean delivery, postpartum weight retention, preterm
delivery, still birth, congenital anomalies including neural tube defects, spontaneous abortion,
recurrent miscarriage, macrosomia, birth injury, difficulties related to anesthesia
management, and emergency cesarean section, more than 50 years ago. 6 Overweight and
obesity are common findings in women of reproductive age in the UK; as 32% of 35- to 64-
year-old women are overweight and 21% obese. Obesity causes major changes in many
features of maternal intermediary metabolism. Insulin resistance appears to be central to these
changes and may also be involved in increased energy accumulation by the fetus. Maternal
obesity is associated with many risks to the pregnancy, with increased risk of miscarriage
(three-fold) and operative delivery (20.7 versus 33.8% in the obese and 47.4% in the
morbidly obese group). Other risks to the mother include an increased risk of pre-eclampsia
(3.9 versus 13.5% in the obese group) and thromboembolism (0.05 versus 0.12% in the obese
group). There are risks to the fetus with increased perinatal mortality (1.4 per 1000 versus 5.7
per 1000 in the obese group) and macrosomia (>90th centile; 9 versus 17.5% in the obese
group). Maternal obesity is associated with an increased risk of obesity in the long term.
Obese woman should try to lose weight before pregnancy but probably not during
pregnancy.5

II.3 PREECLAMPSIA
Hypertensive disorders of pregnancy, including preeclampsia, consist of a broad
spectrum of conditions which are associated with substantial maternal and fetal/neonatal
morbidity and mortality. The incidence is estimated to be between 3 and 10% of all

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pregnancies.Worldwide, preeclampsia and related-conditions are among the leading causes of
maternal mortality.2 While maternal death due to preeclampsia is less common in developed
countries, maternal morbidity is high and is a major contributor to intensive care unit
admissions during pregnancy. Approximately 12 to 25% of fetal growth restriction and small
for gestational age infants as well as 15 to 20% of all preterm births are attributable to
preeclampsia; the associated complications of prematurity are substantial including neonatal
deaths and serious long-term neonatal morbidity. Despite major medical advances, the only
known cure for preeclampsia remains delivery of the fetus and placenta.4

Classification of preeclampsia
Preeclampsia is a pregnancy-specific syndrome that affects many organ systems and
is recognized by new onset of hypertension and proteinuria that occur after 20 weeks’
gestation. It is estimated to complicate 2 to 8% of all pregnancies.2 Although the precise
cause is unknown, the pathophysiologic processes underlying this disorder are described in
two stages. The first stage is characterized by reduced placental perfusion possibly related to
abnormal placentation with impaired trophoblast invasion and inadequate remodeling of the
uterine spiral arteries. The second stage refers to the maternal systemic manifestations with
inflammatory, metabolic, and thrombotic responses converging to alter vascular function
which can result in multi-organ damage.3,4
Precise classification of the various hypertensive disorders of pregnancy has remained
challenging due to the changing nomenclature as well as the geographic variation in accepted
diagnostic criteria. For example, terms such as “toxemia” and “pregnancy-induced
hypertension” are now considered outdated. Furthermore, varying diagnostic criteria are used
in different regions of the world with disagreement regarding the degree of hypertension,
presence/absence of proteinuria, and classification of disease severity. These inconsistencies
have led to challenges in comparing and generalizing epidemiologic and other research
findings. 3,4
The classification system based on the Working Group Report on High Blood
Pressure in Pregnancy is most commonly used in the United States in which four major
categories are defined: gestational hypertension, preeclampsia- eclampsia, chronic
hypertension, and superimposed preeclampsia on chronic hypertension. 3,4

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 TABLE 4. Diagnostic Criteria for Pregnancy-Associated Hypertension

Preeclampsia is defined as new onset of sustained elevated blood pressure

(≥140mmHg systolic or ≥90mm Hg diastolic on at least two occasions 6 hours apart) and
proteinuria (at least 1+ on dipstick or ≥300mg in a 24 hour urine collection) first occurring
after 20 weeks of gestation. Although the symptoms and signs of preeclampsia occur along a
continuum, the syndrome is often categorized as mild or severe to communicate the severity
of disease and management approach. Preeclampsia is considered severe when any of the
following is present in addition to the defining blood pressure and proteinuria criteria:
• Blood pressure ≥160 mmHg systolic or ≥110 mmHg diastolic
• Urine protein excretion of greater than five grams in a 24 hour collection
• Neurologic disturbances (visual changes, headache, seizures, coma)
• Pulmonary edema
• Hepatic dysfunction (elevated liver transaminases or epigastric pain)
• Renal compromise (oliguria or elevated serum creatinine concentration; creatinine
≥ 1.2 is considered abnormal in women without a history of renal disease)
• Thrombocytopenia
• Placental abruption, fetal growth restriction, or oligohydramnios

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TABLE 5. Indicators of Severity of Gestational Hypertensive Disorders

Eclampsia refers to seizures that occur in a preeclamptic woman which cannot be

attributed to other causes. HELLP syndrome is defined by the presence of hemolysis,
elevated liver transaminases, and low platelets. This may or may not occur in the presence of
hypertension or proteinuria, but is considered to be along the spectrum of preeclampsia.3,4
The diagnosis of preeclampsia can be particularly challenging in women with pre-
existing hypertension and/or renal disease since both blood pressure and urinary protein
excretion increase towards the end of pregnancy. Thus, the diagnosis is made based on a
sudden increase in blood pressure or proteinuria and/or evidence of end-organ damage.4
A major criticism of the various classification systems is that none have been
independently evaluated for the ability to identify the subgroup of women who are at
increased risk of adverse pregnancy outcomes. Recent studies have sought to develop
clinically relevant definitions guided by the evidence and based on predictors of adverse
outcomes.4

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Epidemiology of preeclampsia
A systematic review by the World Health Organization indicates that hypertensive
disorders account for 16% of all maternal deaths in developed countries, 9% of maternal
deaths in Africa and Asia, and as high as 26% in Latin America and the Caribbean.10 Where
maternal mortality is high, most of the deaths are attributable to eclampsia, rather than
preeclampsia.4
Based on data from the United States National Hospital Discharge Survey, the rate of
preeclampsia during admission for labor and delivery increased by 25% from 1987 to 2004,
while the rate of eclampsia decreased by 22%, albeit not statistically significant.1 Severe
morbidity associated with preeclampsia and eclampsia include renal failure, stroke, cardiac
dysfunction or arrest, respiratory compromise, coagulopathy, and liver failure.2 In a study of
hospitals managed by Health Care America Corporation, preeclampsia was the second
leading cause of pregnancy-related intensive care unit admissions after obstetric hemorrhage.4

Fetal and Neonatal effects

Fetal and neonatal outcomes related to preeclampsia vary around the world.
Approximately 12 to 25% of fetal growth restriction and small for gestational age infants as
well as 15 to 20% of all preterm births are attributable to preeclampsia. The associated
complications of prematurity are substantial including neonatal deaths and serious long-term
neonatal morbidity. One quarter of stillbirths and neonatal deaths in developing countries are
associated with preeclampsia/eclampsia. Infant mortality associated with preeclampsia is
three times higher in low resource settings compared to high income countries, largely due to
the lack of neonatal intensive care facilities.3,4

Recurrence in subsequent pregnancies4

Studies have reported a 7-20% chance of preeclampsia recurrence in a subsequent
pregnancy.11-13 This risk is further increased if a woman has had two prior preeclamptic
pregnancies and is also influenced by gestational age of onset.14 Estimates of the recurrence
of preeclampsia vary widely based on the quality of the diagnostic criteria used. In a study
done in Iceland using strict diagnostic criteria for preeclampsia and other hypertensive
disorders, the estimated recurrence of preeclampsia or superimposed preeclampsia in a
second pregnancy was 13%.

Preclampsia and later life cardiovascular disease4

11
 Dr. Leon Chesley, a pioneer in the field of preeclampsia, and his co-workers
demonstrated that women who had eclampsia in any pregnancy after their first had a
mortality risk that was two- to five-fold higher over the next 35 years compared to
controls.16 Following this early report, others have demonstrated an association between
preeclampsia and later life cardiovascular disease and related mortality. Cardiovascular
disease risk was increased eight-fold in a Scandinavian population of healthy nulliparous
women who developed preeclampsia severe enough to necessitate a preterm delivery. In a
cohort of women delivering in Jerusalem, there was a two-fold higher risk of mortality at 24-
36 year followup in women with prior preeclampsia compared to women who did not have
this diagnosis. The deaths were largely related to cardiovascular causes. These findings have
also been confirmed in other populations. Hypertension, dyslipidemia, insulin resistance,
endothelial dysfunction and vascular impairment have all been observed months to years after
preeclampsia, further supporting the link between preeclampsia and subsequent
cardiovascular disease. It remains unresolved as to whether these common risk factors lead to
the development of preeclampsia and later life cardiovascular disease or whether
preeclampsia itself may contribute to this future risk. Based on these data, preeclampsia
should be considered a cardiovascular risk factor and women with a history of preeclampsia
should have ongoing, close surveillance to prevent and/or detect future cardiovascular
disease.

Risk factors for preeclampsia4

The epidemiology of preeclampsia reflects a wide range of risk factors as well as the
complexity and heterogeneity of the disease. Risk factors can be classified into pregnancy
specific characteristics and maternal pre-existing features. The incidence of preeclampsia is
increasing in the United States and may be related to the higher prevalence of predisposing
disorders such as hypertension, diabetes, obesity, delay in child-bearing, and the use of
artificial reproductive technologies with associated increase in multi-fetal gestation.

Pregnancy-specific features
Parity—Nulliparity is a strong risk factor, almost tripling the risk of preeclampsia (odds ratio
of 2.91, 1.28 to 6.61) based on a systematic review of controlled studies. It is estimated that
two-thirds of cases occur in first pregnancies that progress beyond the first trimester.
New paternity also increases the risk of preeclampsia in a subsequent pregnancy. The
association between primiparity and preeclampsia suggests an immunological mechanism

12
such that later pregnancies are protected against those paternal antigens.24 Supporting this
concept, previous pregnancy loss, increased duration of sexual activity prior to pregnancy or
prolonged pre-pregnancy cohabitation confer a lower risk of preeclampsia.25 Conversely, the
risk of preeclampsia is increased with the use of barrier contraceptives, new paternity, and
with donor sperm insemination.
Placental factors—Excess placental volume as with hydatidiform moles and multi-fetal
gestations is also associated with the development of preeclampsia. The disease process may
occur earlier and have more severe manifestations in these cases. The risk progressively
increases with each additional fetus.

Maternal characteristics
Age—Extremes of childbearing age have been associated with preeclampsia.1 However,
once adjustments for parity are made in the younger age group (since most first pregnancies
occur at a younger age), the association between younger age and preeclampsia is lost.
Multiple studies demonstrate a higher incidence of preeclampsia among older women
independent of parity; however, many of these do not control for pre-existing medical
conditions. After controlling for baseline differences, women who were 40 years of age or
older had almost twice the risk of developing preeclampsia (risk ratio of 1.68, 1.23 to 2.29
among primiparas and 1.96, 1.34 to 2.87 among multiparas).
Race—The association between African-American merican race and preeclampsia has been
confounded by the higher prevalence of chronic hypertension, often undiagnosed, in this
group. While some studies demonstrate a higher risk of preeclampsia among African-
American women, larger prospective studies which controlled for other risk factors and
rigorously defined preeclampsia did not find a significant association between preeclampsia
and African-American race. More severe forms of preeclampsia may be associated with
maternal non-white race.
Pre-existing conditions—Many of the maternal risk factors for preeclampsia are similar to
those for cardiovascular disease. Pre-existing hypertension, diabetes, obesity, and vascular
disorders (renal disease, autoimmune conditions) are associated with preeclampsia. Risk is
correlated with the severity of the underlying disorder. Women with underlying chronic
hypertension have a 10-25% risk of developing preeclampsia compared to the general
population. This risk is increased to 31% in women with a longer duration of hypertension of
at least four years or more severe hypertension at baseline. With pre-gestational diabetes, the
overall risk of developing preeclampsia is approximately 21%. However, the risk is 11-12%

13
with diabetes of less than 10 years duration, which increases to 36 to 54% among women
with longer-standing diabetes associated with microvascular disease. For mild renal disease
(serum creatinine of less than 1.5mg/dL), the risk of preeclampsia is estimated at 20 to 25%
but greater than 50% for pregnant women with severe renal disease. Preeclampsia also
occurs more frequently among pregnant women with autoimmune conditions such as
systemic lupus erythematosus and antiphospholipid antibody syndrome.
Obesity—Elevated body mass index (BMI, kg/m2) is also associated with preeclampsia.
Given the obesity epidemic in the United States and around the world, this is one of the
largest attributable and potentially modifiable risk factors for preeclampsia. This will be
discussed in further detail below.
Family history of preeclampsia—A family history of preeclampsia nearly triples the risk of
preeclampsia.
Smoking—Paradoxically, cigarette smoking during pregnancy is associated with a reduced
risk of preeclampsia possibly due to modulation of angiogenic factors.

II.4 OBESITY AND PREECLAMPSIA

In the United States, the percentage of women who are overweight or obese has
increased by approximately 60% over that last thirty years. The World Health Organization
estimates the prevalence of obese and overweight women (body mass index ≥ 25 kg/m2) to
be 77% in the United States, 73% in Mexico, 37% in France, 32% in China, 18% in India,
and 69% in South Africa with wide variation within each continent. The high prevalence of
obesity and projected increase have substantial implications for pregnancy since obesity is
associated with infertility, spontaneous miscarriage, fetal malformations, thromboembolic
complications, gestational diabetes, stillbirth, preterm delivery, cesarean section, fetal
overgrowth and hypertensive complications.4
Preeclampsia has increased in both the youngest and oldest women of the
reproductive generation. The incidence of preeclampsia has increased from 2.5% in 1987 to
3.2% in 2004in the United States .This increase may have been influenced by a variety of
factors, including age groups, period effect, changes in diagnostic criteria, and the earlier
identification of symptoms during pregnancy. Women born in the “older” cohorts may have
different lifestyle factors, such as smoking or illicit drug use, than women born in more
recent cohorts. Among these numerous factors, an increase in obesity among women of

14
reproductive age is expected to be one of the strongest risk factors underlying the increasing
prevalence of preeclampsia.6
Obesity increases the overall risk of preeclampsia by approximately 2- to 3-fold. The
risk of preeclampsia progressively increases with increasing BMI, even within the normal
range. Importantly, it is not only the late or mild forms of preeclampsia that are increased, but
also early and severe preeclampsia, which are associated with greater perinatal morbidity
andmortality. The increased risk is present in both Caucasian and African-American women.
The association between preeclampsia risk and obesity has also been demonstrated in varying
Supporting
populations across the globe. the concept that obesity may play a causal role is the
finding that weight loss reduces the risk of preeclampsia. Some studies suggest that excessive
maternal weight gain is associated with the risk of preeclampsia, although these may be
confounded by the increase in fluid retention with preeclampsia contributing to the higher
weight. Although weight loss is discouraged in pregnancy, obesity is a potential modifiable
risk factor for preeclampsia. Weight loss prior to pregnancy is encouraged in overweight and
obese women to decrease the risk of adverse outcomes. In our population (Pittsburgh,
Pennsylvania), it is estimated that 30% of the preeclampsia risk is attributable to obesity. 4
Maternal obesity predisposes a woman to developing pre-eclampsia and a dose-dependent
relationship between increasing body mass index (BMI) and the risk of developing
pre-eclampsia is well established.8
Obesity is associated with significant metabolic and physiologic alterations. Adipose
tissue is not simply storage of fat, but rather is a hormonally active tissue producing
endocrine mediators such as cytokines and adipokines.These mediators have been associated
with a proinflammatory and prothrombotic state, insulin resistance and oxidative stress, all of
which have been associated with pathogenesis of preeclampsia, as well as lifetime risk of
maternal cardiovascular disease.
Obesity is a risk factor for both preeclampsia and cardiovascular disease. Exploring
common mechanisms may provide insight into the pathophysiology of preeclampsia,
potential areas for further investigation, and possible targets for therapy. Here, we will briefly
highlight a few features that are shared by these conditions including insulin resistance,
inflammation, oxidative stress and vascular dysfunction, adipokines, and angiogenic factors.4

Insulin resistance

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 Insulin resistance is estimated to be present in two-thirds of obese individuals. It is
also a risk factor for cardiovascular disease and type 2 diabetes. Insulin resistance is more
common with preeclampsia and can persist for as long as seventeen years after a preeclamptic
pregnancy, thus increasing cardiovascular risk. Features of the metabolic syndrome (obesity,
hypertension, insulin resistance, impaired glucose tolerance and dyslipidemia) are also
observed more commonly with preeclampsia. With metabolic syndrome, it has been proposed
that obesity contributes to hypertension by multiple mechanisms including reduction in
available nitric oxide due to oxidative stress, increase in sympathetic tone, and increased
angiotensinogen by adipose tissue. Dyslipidemia and the increase in free fatty acids released
from adipocytes have also been posited to contribute to oxidative stress and insulin
resistance.2,4

Inflammation
Inflammation is a common feature of obesity, cardiovascular disease and
preeclampsia. Adipose tissue generates several inflammatory mediators that can alter
endothelial function and are produced more actively in obese individuals. 2 The role of
inflammation in cardiovascular diseases is indicated by increased concentrations of
inflammatory markers.4
Several of these are also increased in preeclampsia C-reactive protein (CRP), an
inflammatory mediator produced by the liver as well as adipocytes, is higher in obese
individuals and associated with cardiovascular morbidity. Circulating CRP is elevated early in
pregnancy prior to the development of preeclampsia and appears to have a stronger
association with preeclampsia among obese women. Studies from our group indicate that
CRP is more associated with preeclampsia in obese women than lipids and could account for
about one third of the relationship between BMI and the risk of preeclampsia.4
Interleukin-6 is another potent inflammatory mediator that can lead to vascular
damage and is associated with obesity, insulin resistance and later life cardiovascular disease.
Circulating concentrations are also higher with obesity and with preeclampsia, indicating a
potential link.2,4 24 It is a major stimulator of acute phase reactants with consequent effects on
vessel wall function blood clotting. IL-6 has been proposed as a major mediator of
inflammation induced vascular damage.2
Tumor necrosis factor alpha (TNF-α) is also produced in adipose tissue and associated
with insulin resistance, endothelial damage and oxidative stress. Circulating levels are

16
increased with obesity as well as with preeclampsia. However, studies demonstrate that TNF-
α is not higher in obese pregnant women compared to non-obese controls.2,4

Oxidative stress
In preeclampsia, oxidative stress is postulated to lead to altered endothelial function
and resulting vascular dysfunction. Obesity is also associated with oxidative stress possibly
secondary to increased inflammation and free fatty acids as well as lower concentration of
circulating anti-oxidants. oxidative stress may be a factor that predisposes obese women to
developing preeclampsia.4 The origin of oxidative stress is proposed to be secondary to
increased free fatty acids and inflammation. It is also suggested that diet can contribute to
oxidative stress. Obese individuals have lower blood concentrations of antioxidants. This
could be due to reduced dietary intake of antioxidants, but increased consumption by reactive
oxygen species is also possible. Ingestion of large quantities of fats or carbohydrates is
associated with increased generation of leukocyte free radicals. Interestingly, this dietary
pattern is more prevalent with obesity and during pregnancy in women who develop
preeclampsia.2

Adipokines
Leptin and adiponectin, two substances produced by adipose tissue, affect metabolism
have been linked with cardiovascular disease. Obesity is associated with elevated leptin and
decreased adiponectin concentrations. Circulating leptin is increased in preeclampsia and
correlates with maternal BMI. Of note, leptin is also produced by the placenta and is likely a
major contributor to circulating concentrations during pregnancy. Adiponectin, has insulin
sensitizing effects, is decreased with obesity, and inversely correlated with cardiovascular
risk. There is not yet a consensus on adiponectin concentrations in preeclampsia, as studies
have reported higher as well as lower concentrations. Based on the mechanism of action and
association with cardiovascular disease and obesity, these adipokines s may be relevant in
preeclampsia, particularly among obese and overweight women.2,4

Angiogenic factors
The balance of circulating angiogenic factors is altered in preeclampsia compared to
normal pregnancy, even weeks prior to development of the clinical condition. Placental
growth factor (PGF), a member of the vascular endothelial growth factor (VEGF) family, is
lower in preeclamptic women. This is likely due to higher circulating concentrations of

17
soluble Flt-1, an anti-angiogenic factor that binds and inactivates PGF and VEGF. Some
studies have demonstrated that sFlt-1 and PGF are both lower in obese pregnant women,
while others have shown that higher BMI is associated with higher sFlt-1 concentrations and
a higher sFlt-1/PGF ratio indicative of an anti-angiogenic milieu even in early pregnancy.
Although findings are not consistent across studies, the altered angiogenic milieu with
obesity may have implications in the development of preeclampsia.4
Lifestyle factors such as diet, sleep disorders, and physical activity are also associated
with obesity and cardiovascular disease. Many of these factors have also been implicated
with preeclampsia; thus, raising the possibility of a mechanistic link whereby obesity may
increase the risk of preeclampsia.4

Exploring common mechanisms

Perturbation in the nitric oxide (NO) synthesis and bioavailability leading to vascular
dysfunction has been a key mechanistic pathway that has garnered attention in the context of
cardiovascular disease and obesity. Asymmetric dimethylarginine (ADMA) is a competitive
agonist of L-arginine, the precursor of nitric oxide synthesis. ADMA functions as a nitric
oxide synthase inhibitor resulting in reduced NO production and increased superoxide
generation. Elevated ADMA concentrations are associated with inflammation, insulin
resistance, dyslipidemia, obesity, and cardiovascular disease. Interestingly, circulating ADMA
has been shown to decrease with weight loss. Several studies have demonstrated higher
concentrations of ADMA with preeclampsia and even prior to the onset of disease at mid-
gestation L-arginine has been used to reverse some of the effects of ADMA in clinical
studies. It has been used safely in pregnancy. One randomized controlled trial demonstrated
that preeclampsia was reduced with administration of a combination of arginine and anti-
oxidant therapy in a high risk population compared to placebo or anti-oxidants alone.86
Further study is needed to elucidate the effects of Larginine administration on the risk of
preeclampsia in other populations including obese women. Thus, a better understanding the
relationship between obesity, preeclampsia and cardiovascular disease may shed light on
common mechanisms and potential targets for therapy.4

18
ADMA as a convergence point for obesity related mechanisms to increase the risk of
preeclampsia2
ADMA is an endogenous inhibitor of nitric oxide synthase. ADMA is elevated in
individuals at risk for cardiovascular disease. Virtually all of the factors that are considered
risk factors for cardiovascular disease are associated with elevated ADMA. Inflammation,
dyslipidemia, insulin resistance, elevated homocystein and even sleep disorders, all are
associated with increased ADMA.
The pathophysiological changes induced by obesity that are relevant to cardiovascular
disease or preeclampsia all would be expected to increase ADMA (Figure 2). This is
supported by data demonstrating increased ADMA concentration with obesity. ADMA is a
dimethylated analogue of arginine. The methylated arginines are synthesized on proteins and
are only available as modified amino acids with protein breakdown. The major mechanism to
modify ADMA concentration is by regulation of its degradatory enzyme, dimethylarginine
dimethylaminohydrolase (DDAH). Impaired DDAH activity is a central mechanism by which
cardiovascular risk factors increase ADMA and disrupt NOS activity. DDAH, is regulated by
oxidative stress and by inflammatory cytokines and hyperglycemia. Oxidative stress modifies
a crucial sulfhydryl group in the active site of the enzyme and may be involved in the activity
of some of the other factors to increase circulating ADMA.
ADMA appears to exert its activities through its role as an antagonist of the
conversion of arginine to nitric oxide (NO) by NOS. There are two results of this antagonism.
The first is reduced NO production and the second the uncoupling of NOS. ADMA
“uncouples” endothelial NOS, such that molecular oxygen becomes the substrate for electron
transfer rather than the guanidino nitrogen of L-arginine. Under these conditions, endothelial
NOS generates superoxide anion, increases oxidative stress, attenuates NO bioactivity, and
induces additional endothelial dysfunction. Thus, ADMA is both increased by oxidative stress
and by uncoupling NO has the capacity to increase oxidative stress. Several studies have
reported that plasma ADMA concentrations are higher in women withpreeclampsia. Plasma
ADMA concentrations are also significantly higher in midpregnancy in women who later
develop preeclampsia.157162 ADMA concentrations remain high in these same women when
they develop preeclampsia compared to women with an uncomplicated pregnancy and
women who have growth restricted infants in the absence of developing preeclampsia. These
data are particularly interesting given the central role ADMA plays in the regulation of
endothelial-dependent vascular function, angiogenesis and arteriogenesis, and the known
deficiencies in these activities in preeclampsia.

19
 Consistent with a role for ADMA in the increased risk of cardiovascular disease and
preeclampsia, circulating plasma ADMA concentrations are higher in obese subjects. While
the exact mechanism for the increase in plasma ADMA in with obesity is unknown, it is
likely mediated in part by a change in DDAH activity. Interestingly, a recent study reported
that plasma ADMA concentrations correlate positively with the acute inflammatory marker
CRP in obese subjects both before and after weight loss suggesting a role for inflammation.
In addition, ADMA is higher in obese insulin resistant women compared to similarly obese
insulin sensitive women. ADMA concentrations are inversely related to insulin sensitivity,
and ADMA concentrations decrease in response to weight loss. It is possible that
preeclampsia develops in obese women with the highest ADMA concentrations. As a
competitive antagonist of L-arginine many of the effects of ADMA can be reversed with
modest increases in L-arginine intake. Arginine at concentrations that increase NO production
has been used safely in pregnancy. ADMA provides targets for subsequent randomized
controlled trials in obese women.

TREATMENT OF OBESITY
Weight loss is tremendously difficult for obese individuals. If achieved, long-term
maintenance poses equivalent or even more daunting difficulties. Even the most legitimate
nonsurgical methods are fraught with frequent failure. If they are successful, slow and
inexorable return to preintervention weight usually follows (Yanovski, 2005). Successful
weight loss approaches include behavioral, pharmacological, and surgical techniques or a
combination of these methods (Eckel, 2008; Zimmet, 2012). As such, obstetrician-
gynecologists are encouraged to aid assessment and management of obesity in adult women.
Weight loss and lifestyle changes have been shown to reduce the associated metabolic
syndrome (Crist, 2012). When used in conjunction with bariatric surgery, there is improved
glucose control with type 2 diabetes (Mingrone, 2012; Schauer, 2012). 3

Life style factors associated with obesity

Life style factors such as diet and physical activity have been associated with obesity
and risk of cardiovascular diseases, however the association of these factors with
2,4
preeclampsia remains poorly elucidated. The associatoin of diet, sleep disorders and
physical activity with cardiovascular disease is well established. There is much less
information available for the relevance of these factors to preeclampsia. We present evidence
for the involvement of life style in cardiovascular disease and its relationship to obesity.

20
Diet—Poor nutrition is a major contributor to cardiovascular disease. Diets high in
antioxidants, fruits and vegetables, B vitamins, omega-3 polyunsaturated fatty acids (PUFAs),
fish and seafood, whole grains, and dietary fiber protect against heart disease, and
excessive intakes of saturated fat, trans fatty acids, refined grains and sweets increase the risk
of heart disease. After decades of research in this area, healthy diet is now a cornerstone of
cardiovascular disease prevention. Despite the similarities between preeclampsia and
cardiovascular disease, few investigators have studied the role of diet in the pathophysiology
of preeclampsia. Vitamin C, vitamin E, and the carotenoids are important physiologic
antioxidants. Folate reverses endothelial dysfunction in patients with some chronic diseases,
reduces oxidative stress, and restores the activity of nitric oxide.
Physical activity-- is known to reduce the risk of obesity and cardiovascular diseases. In
addition, data from observational studies show that exercise may reduce the risk of
preeclampsia. Studies have shown association between physical activity (leisure time and
occupational activities) during and before pregnancy to be associated with reduced risk of
preeclampsia.. Data from these studies show that physical activity including recreational
activities one year before pregnancy and in early pregnancy is associated with reduced risk of
preeclampsia. According to these studies, reduced physical activity may explain the
association between obesity and risk of preeclampsia as well as cardiovascular diseases risk.
As preeclampsia is associated with significant morbidity and the literature suggests
commonalities in the pathogenesis of adverse effects of obesity and preeclampsia,
prepregnancy BMI may be a target for pubic health focus to reduce the risk of preeclampsia.7

Antepartum Management3
Dietary Intervention in Pregnancy
Weight reduction is not advisable during pregnancy (Catalano, 2013). As noted,
recommended weight gain in obese women is 11 to 20 pounds, and several dietary
interventions to limit weight gain to these targets have been reported. These include lifestyle
interventions and physical activity (Petrella,2013). Reviews by Quinlivan (2011) and
Tanentsapf (2011) found that randomized trials generally reported successful results with
intervention. On the other hand, in many other studies, either these have been unsuccessful or
the results were insufficient to permit a conclusion (Campbell, 2011; Dodd, 2010; Guelinckx,
2010; Nascimento, 2011; Ronnberg, 2010). Special attention to psychological aspects of
pregnancy has been recommended by some (Skouteris, 2010).

21
Prenatal Care
Close prenatal surveillance detects most early signs of diabetes or hypertension.
Standard screening tests for fetal anomalies are sufficient, while being mindful of
sonographic limitations for detection of fetal anomalies. Accurate assessment of fetal growth
usually requires serial sonography. Antepartum and intrapartum external fetal heart rate
monitoring are likewise more difficult, and sometimes these are even impossible.
Surgical and Anesthetic Concerns
Evaluation by the anesthesia team is performed at a prenatal visit or on arrival at the
labor unit (American College of Obstetricians and Gynecologists, 2013b). Special attention is
given to that might arise during labor and delivery. Vricella and coworkers (2010) reported
the following frequencies of anesthetic complications in 142 morbidly obese women at
caesarean delivery. These included technical problems with regional analgesia—up to 6
percent; use of general anesthesia—6 percent; hypotension—3 percent; and overall anesthetic
complications of 8.4 percent.
For cesarean delivery, forethought is given to optimal placement and type of abdominal
incision to allow access to the fetus and to effect the best wound closure with the least
intervening tissue (Alexander, 2006). One technique is shown in Figure 48-7. Others prefer a
transverse abdominal incision (Alanis, 2010). Individual differences in maternal body habitus
preclude naming any one approach as superior (Gilstrap, 2002; McLean, 2012). Although
some have reported similar wound complications with either incision, others reported a
fourfold wound complication rate when a vertical abdominal incision was compared with a
transverse incision—31 versus 8 percent (Houston, 2000; Thornburg, 2012; Wall, 2003).
Finally, a mid-abdomen transverse incision has been advocated performed a metaanalysis of
subcutaneous closure in 887 women undergoing cesarean delivery whose wound thickness
was greater than 2 centimeters. Subcutaneous closure resulted in a modest but significant 6-
percent decrease in wound disruption. The frequency of abdominal wound infections is
directly related to BMI (Norman, 2013). Comorbid diabetes apparently increases this risk
(Leth, 2011). Several reports describe a wound complication rate of 15 to 45 percent. Alanis
and colleagues (2010) reported a 30-percent rate in 194 women whose BMI was > 50 kg/m2.
Of these, 90-percent were wound disruptions to the fascia, but there was only one
evisceration. As indicated above, the transverse abdominal incision had fewer complications.
Walsh and coworkers (2009) have reviewed the prevention and management of surgical site
infections in morbidly obese women. To lower thromboembolic complications, graduated
compression stockings, hydration, and early mobilization after cesarean delivery in obese

22
women are recommended by the American College of Obstetricians and Gynecologists
(2013a). Some also recommend “mini-dose” heparin prophylaxis, but we do not routinely use
this (Chap. 52, p. 1044).

Picture 2 Abdominal incision for the obese woman. A. Frontal view. The dotted line
indicates an appropriate skin incision for abdominal entry relative to the panniculus. As
shown by the uterus in the background, selection of this periumbilical site permits access to
the lower uterine segment. B. Sagittal view. Attention to closure of the subcutaneous layer is
important. Chelmow and associates (2004)

23
Bariatric Surgery
Several surgical procedures have been designed to treat morbid obesity either by decreasing
gastric volume—restrictive, or by bypassing gastrointestinal absorption—restrictive
malabsorptive (Adams, 2007; Kushner, 2012). In nonpregnant patients, these procedures
have been shown to improve or resolve diabetes, hyperlipidemia, hypertension, and
obstructive sleep apnea (Buchwald, 2007; Mingrone, 2012; Schauer, 2012).

Pregnancy
Because of these successes, bariatric surgery currently has become popular, and many
women are becoming pregnant following weight-reduction surgery (Abodeely, 2008). Several
observational studies have reported improved fertility rates and reduced risks of obstetrical
complications in women following bariatric surgery and compared with morbidly obese
controls (Alatishe, 2013; Guelinckx, 2009; Kjaer, 2013a; Lesko, 2012; Tan, 2012). The
largest of these studies is from the Swedish Birth Register, which included 681 women with a
pregnancy following bariatric surgery (Josefsson, 2011). Despite surgical treatments, half of
these women were still obese by the time of their first pregnancy following bypass, however,
the proportion with morbid obesity was smaller. The frequency of large-for-gestational age
infants decreased from 9.1 to 3.2 percent and that of smallfor- gestational age neonates
increased from 2.1 to 5.6 percent. In a recent systematic review, Kjaer and Nilas (2013b)
reported a decreased risk after bariatric surgery for diabetes, preeclampsia, and large-for-
gestational age infants. Most studies confirmed a higher risk for small-for-gestational age
fetuses.

Restrictive Procedures
There are three procedures to accomplish gastric restriction and selective
malabsorption. The most commonly used is the laparoscopically performed Roux-en-Y
gastric bypass and biliopancreatic diversion with duodenal switch. With the Roux-en-Y
procedure, the proximal stomach is completely to leave a 30-mL pouch. A gastroenterotomy
is then created by connecting the proximal end of the distal jejunum to the pouch. A Roux-en-
Y enteroenterostomy is also completed 60 cm distal to this gastrojejunostomy to allow
drainage of the unused stomach and proximal small intestine. As with other bariatric
procedures, pregnancy outcomes are changed remarkably following Rouxen- Y bypass
(Wittgrove, 1998). As shown in Table 48-4, rates of hypertension, gestational diabetes, and

24
fetal macrosomia are reduced. Serious complications are uncommon. Intussusception and
small bowel obstruction develop from internal herniation, and maternal deaths from
herniation and obstruction have been reported (Kakarla, 2005; Moore, 2004; Renault, 2012;
Wax, 2007). Bowel obstruction is notoriously difficult to diagnose, and Wax and associates
(2013) caution for a high index of suspicion.

Recommendations
The American College of Obstetricians and Gynecologists (2013a) recommends that
women who have undergone bariatric surgery be assessed for vitamin and nutritional
sufficiency. When indicated, vitamin B12 and D, folic acid, and calcium supplementation are
given. Vitamin A deficiency has also been reported (Chagas, 2013). Women with a gastric
band should be monitored by their bariatric team during pregnancy because adjustments of
the band may be necessary. Finally, special vigilance is appropriate for signs of intestinal
obstruction.

25
 III. CONCLUSION

Obesity causes significant complications during pregnancy for the mother and fetus.
Interventions promoting pre-pregnancy weight loss and the prevention of excessive weight
gain during pregnancy must begin in the preconception period. Obstetrical care providers
need to counsel their obese patients about the risks and complications conferred by obesity
and the importance of weight loss before pregnancy. Surveillance may need to be heightened
during pregnancy, and a multidisciplinary approach to the management of obese women
during pregnancy is useful. Women need to be informed about both maternal and fetal
complications and about the measures that are necessary to optimize outcome. 10
Large population studies have shown that obese women are two to three times more
likely to develop preeclampsia than their leaner counterparts. Therefore, the recent marked
increase in obesity in women of childbearing age has raised specific concerns regarding the
risk management of preeclampsia. Since maternal obesity appears to shift their offspring
toward a predisposition to obesity, this cycle may continuously increase not only the
incidence of preeclampsia, but also numerous risk factors associated with pregnancy during
the next half century. Lifestyle interventions before conception as well as postpartum until
attempting another pregnancy is the most effective strategy to reduce the risks associated with
pregnancy in obese women; however, this has not been very successful. Since global
preventive medical care programs have been unsuccessful in protecting against the
overwhelming prevalence of the “Obesity Tsunami” in developed as well as developing
countries, new medical care strategies, such as preemptive medicine are needed. 6 Whether
weight reduction prior to pregnancy or restricting weight gain during pregnancy will reduce
the risk of preeclampsia is not established. However, the general health benefits of weight
loss in obese individuals justify weight loss before pregnancy. Similarly the Institute of
Medicine recommended reduced weight gain for obese pregnant women. Whether these
behavioral modifications will reduce the risk of preeclampsia will be established over time
but is unlikely to be tested in randomized controlled trials.2

REFERENCES
26
1. Biran, Affandi, Pengaruh Obesitas terhadap gangguan Obstetri dan Ginekologi.

Prosiding Kongres Obstetri dan Ginekologi Indonesia XVI Bandung. Dept Obstetri

dan Ginekologi FK UNPAD dan POGI 2015. 53-81

2. James M. Roberts, et al. The Role of Obesity in Preeclampsia. Pregnancy

Hypertension. 2012: 6–16.

3. Cuningham, leveno, Bloom et all, Williams Obstetric 24th edition. McGraw-Hill

Education. 2014
4. Arun Jeyabalan, MD. Epidemiology of preeclampsia: Impact of obesity. Nutr Rev,

2014
5. Yu CK1, Teoh TG, Robinson S. Obesity in pregnancy. BJOG. 2006 Oct;113 (10) :

1117 -25 . Epub 2006 Aug 10.

6. Itoh H, Kanayama N. Obesity and Risk of Preeclampsia. Med J Obstet Gynecol , 2014

2(2): 1024.
7. Zabih, Weda. PREPREGNANCY BMI AND PREECLAMPSIA.
8. NH Anderson, et al. The impact of maternal body mass index on the phenotype of

pre-eclampsia: a prospective cohort study. BJOG 2012

9. Gregory A.L. Davies, MD, et al. Obesity in Pregnancy
10. Arendas K1, Qiu Q, Gruslin A Obesity in pregnancy: pre-conceptional to postpartum

consequences. J Obstet Gynaecol Can. 2008 Jun;30(6):477-88.

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