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Refrat Obesity Pe
Refrat Obesity Pe
INTRODUCTION
All over the world, since 1980, obesity has doubled and reached epidemic conditions.1
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
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 Figure 48-2 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
FIGURE 48-2 Prevalence of obesity in girls and women in the United States for 20092010.
(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 factorsadipokines,
or adipocytokines. Some of those with metabolic functions include adiponectin, leptin, tumor
necrosis factor- (TNF-), 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 resistanceleptin, resistin, TNF-, and IL-6are 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 48-2).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 obesityadipositas cordisis 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
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
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
10
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 2436 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
ParityNulliparity 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 factorsExcess 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
AgeExtremes 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).
RaceThe 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 AfricanAmerican 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 conditionsMany 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.
ObesityElevated 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 preeclampsiaA family history of preeclampsia nearly triples the risk of
preeclampsia.
SmokingParadoxically, cigarette smoking during pregnancy is associated with a reduced
risk of preeclampsia possibly due to modulation of angiogenic factors.
III.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
populations across the globe.
Supporting
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
15
16
increased with obesity as well as with preeclampsia. However, studies demonstrate that TNF 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 midgestation 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 antioxidant 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, obstetriciangynecologists 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
preeclampsia remains poorly elucidated.
2,4
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
(2013a). Some also recommend mini-dose heparin prophylaxis, but we do not routinely use
this (Chap. 52, p. 1044).
FIGURE 48-7 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 volumerestrictive, or by bypassing gastrointestinal absorptionrestrictive
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-forgestational 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-enY 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
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;
24
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.
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
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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
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1. Wallis AB, Saftlas AF, Hsia J, Atrash HK. Secular Trends in the Rates of Preeclampsia,
Eclampsia,
and Gestational Hypertension, United States, 1987-2004. Am J Hypertens. 2008; 21(5):521
526.
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1. Andrea Lausman, et al. Screening, Diagnosis, and Management of Intrauterine
Growth Restriction. J Obstet Gynaecol Can 2012;34(1):1728.
1. Prosiding
2. James M. Roberts, et al. The Role of Obesity in Preeclampsia. Pregnancy Hypertens.
2012: 616.
3. Williams
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):111725. Epub 2006 Aug 10.
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in Pregnancy
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