The incidence of hypertension among adults in the United States has been estimated at between 29% and 31%. Obesity is commonly associated with treatment-resistant hypertension or hypertension that requires 3 or more antihypertensive agents to achieve blood pressure control by established guidelines.² Among obese individuals, the incidence of hypertension has been reported as high as 50%.³ In the United States, over one-half of reproductive-age women are overweight or obese. More than one-third of these women are obese, with about 8% classified as extremely obese. During pregnancy, these women are expected to be at increased risk for pregnancy complications related to obesity.⁴ Maternal obesity and morbid obesity have been reported to be strongly associated with elevated blood pressure readings during the 3 trimesters of pregnancy, as well as with an increased risk for gestational hypertensive disorders.⁵ To further establish the importance of obesity as a risk factor for hypertensive disorders during pregnancy, one study clearly demonstrated that obesity is a dose-dependent variable: Women with a body mass index (BMI) range of 25–30 kg/m² demonstrated a relative risk (RR) for preeclampsia of 1.88 (with a 95% confidence interval [CI] of 1.34–2.62), while women with BMI greater than 40 kg/m² had a RR of 7.17 with a CI of 5.06–10.16.⁶

The objectives of this chapter include a review of the underlying pathophysiology that predisposes obese women to develop hypertensive disorders, particularly during pregnancy. A review of the definitions of hypertensive disorders occurring during pregnancy is undertaken, as well as the management of mild-to-severe hypertensive disease, including life-threatening complications.

Pathophysiology of Hypertension Related to Obesity

The pathophysiology of hypertension in obesity is complex and multifactorial. Prior to the onset of clinically overt hypertension, there is an increase in cardiac output considered to be a response to the increased demand for peripheral tissue oxygen delivery. The clinical normotensive state is maintained by a compensatory reduction in systemic vascular resistance. Among nulliparous women at risk for development of preeclampsia with marked increase in cardiac output with reduction in systemic vascular resistance, one subgroup at increased risk comparable to women with diabetes mellitus were women with overall increased weight of 14 kg compared to controls not at increased risk.⁷ Over time, an increase in the activation of the renin-angiotensin-aldosterone axis gradually increases systemic vascular resistance, resulting in a rise in blood pressure and the development of clinical hypertension.

Early hypertension among obese individuals is characterized by increased cardiac output and increased systemic vascular resistance.^8,9 The process of moving from clinically normotensive to hypertensive among obese individuals is highly complex and largely speculative. Multiple pathophysiologic pathways have been proposed and have varying relevance depending on patient population characteristics.¹⁰ The end results of these pathophysiologic pathways include increased sympathetic tone, expanded intravascular volume, and endothelial dysfunction. Increased insulin resistance resulting in hyperinsulinemia has been recognized since 1989 as potentially associated with hypertension among obese individuals.¹¹ Increased plasma insulin levels stimulate sympathetic neuron firing, resulting in an increase in sympathetic tone and systemic vascular resistance.¹²

Leptin is a circulating protein that increases in concentration with increasing adipose tissue formation and acts as negative feedback at the level of neurons within the brain. Neurons that are receptive to insulin are also receptive to leptin, resulting in increased expression of melanocortin receptors that participate in the control of energy stores as well as sympathetic tone. With an abnormal response to increasing leptin, there is a disproportionate increase in sympathetic tone in what has been described as the leptin-melanocortin pathway. The effect of increased insulin and leptin is an increase in sympathetic tone and systemic vascular resistance.^13,14,15

Among obese individuals with sleep apnea, episodic hypoxia results in endothelial stress, which increases release of endothelins, a class of proteins with vasoconstrictive properties, resulting in an additional increase in systemic vascular resistance.¹⁶ Increased systemic vascular resistance usually results in diuresis and a reset of the intravascular volume to a point at which overall blood pressure is normalized.

With obesity, hyperinsulinemia contributes to direct renal endothelial injury and overall endothelial dysfunction, which result in upregulation of angiotensin II receptors and decreased production of cardiac-derived natriuretic peptides and a resultant increase in sodium retention and expansion of the intravascular volume.^17,18,19 The combination of increased systemic vascular resistance and expanded intravascular volume act to synergistically increase measurable blood pressure.

Pathophysiology of Hypertension Related to Pregnancy

Hypertensive disorders during pregnancy are described as the result of the interaction of factors derived from maternal as well as uteroplacental/fetal origins. Pregnancy-related hypertensive disorders such as preeclampsia begin with conception and the earliest stages of placental vascular development. Instead of placental vasculature, where blood moves through a high-flow, low-resistance circuit as seen in normal placental development, vasculature develops with a low-flow, high-resistance state that results in placental hypoperfusion, which leads to placental hypoxemia and ultimately placental ischemia.

In a normal pregnancy, trophoblastic invasion results in extensive remodeling of maternal spiral arterioles, which produce wide-open vascular channels within the placenta. In the abnormal state that results in a pregnancy-related hypertensive disorder, trophoblastic remodeling of the spiral arterioles is suboptimal in producing the wide-open vascular channels observed in the normal placenta. Placental tissue ischemia results in the release of antiangiogenic factors, which are distributed in the maternal circulation and negatively affect maternal endothelial cell function, resulting in the classic microscopic ultrastructural triad of arteriolar constriction, endothelial cell damage, and tissue hypoxemia.

Pregnancy-related hypertensive disorders are described as a 2-stage process, with the first stage involved with abnormal placental development and the second stage involved with the clinical manifestations of the disorder, including hypertension, proteinuria, and a wide spectrum of organ system issues (e.g., dysfunction of the central nervous, renal, hepatic, or hematologic/coagulation systems).²⁰ Obesity remains a major risk factor for the development of preeclampsia and other hypertensive disorders of pregnancy.²¹

In 2013, the American College of Obstetricians and Gynecologists (ACOG) Task Force on Hypertension in Pregnancy published recommendations based on the available evidence related to hypertension and pregnancy, taking the implications and the confidence in estimates of effect utilizing the strategy developed by the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) Working Group. In this report, the task force made the decision to continue using the classification schema for hypertensive disorders of pregnancy introduced in 1972 by ACOG and modified in 1990 and 2000 by the Working Group of the National High Blood Pressure Education Program.²² The definitions include four broad categories:

1. 
   

   Preeclampsia-eclampsia

   
   
2. 
   

   Gestational hypertension

   
   
3. 
   

   Chronic hypertension of any cause

   
   
4. 
   

   Chronic hypertension with superimposed preeclampsia

The definition of preeclampsia includes the following:

• 
  

  New-onset elevated blood pressure after 20 weeks’ gestation in a woman with normal blood pressure readings prior to pregnancy

  
  
• 
  

  Systolic blood pressure (SBP) of 140 mm Hg or higher or diastolic blood pressure (DBP) of 90 mm Hg or higher on 2 occasions at least 4 hours apart

  
  
• 
  

  New-onset proteinuria determined by 1 of the following:

  
  
  
  
  • 
    

    24-hour urine collection with 300 mg or more of protein or an equivalent amount extrapolated from a shorter, timed collection

    
    
  • 
    

    Ratio of urine total protein to total creatinine 0.3 or greater (each measured as milligrams/deciliter)

    
    
  • 
    

    Urine dipstick reading of 1⁺ or higher (only to be used if other methods are not available)

  
  
• 
  

  In the absence of proteinuria, new-onset hypertension as defined previously with new onset of any one of the following:

  
  
  
  
  • 
    

    Blood platelet count 100,000 or fewer platelets/microliter

    
    
  • 
    

    Blood creatinine concentration greater than 1.1 mg/dL or doubling of baseline creatinine concentration in the absence of any other renal disease

    
    
  • 
    

    Elevated blood transaminase concentrations twice the upper limit of normal range for assay employed

Features consistent with preeclampsia exhibiting severe features include any one of the following:

• 
  

  SBP of 160 mm Hg or higher or DBP of 110 mm Hg or higher on two occasions at least 4 hours apart while the patient is at bed rest (note that this is also the definition for severe acute hypertension; blood pressure reading should be repeated within 15 minutes and if persistently elevated in the severe range should be followed immediately by antihypertensive therapy²³)

  
  
• 
  

  Thrombocytopenia (blood platelet count of 100,000 or fewer platelets/microliter)

  
  
• 
  

  Impaired liver function:

  
  
  
  
  • 
    

    Elevated blood transaminase concentrations twice the upper limit of normal range for assay employed

    
    
  • 
    

    Right upper quadrant or epigastric pain not responsive to medication and not attributable to another cause

  
  
• 
  

  Progressive renal insufficiency (blood creatinine concentration greater than 1.1 mg/dL or doubling of baseline creatinine concentration in the absence of any other renal disease)

  
  
• 
  

  New-onset pulmonary edema

  
  
• 
  

  New-onset cerebral or visual disturbances

The definition of gestational hypertension is elevation of blood pressure after 20 weeks’ gestation without proteinuria or other systemic findings.

The ACOG Task Force on Hypertension in Pregnancy defined the goals of treatment for hypertension during pregnancy to include prevention of acute complications of hypertension while maintaining the pregnancy in a state of health for as long as possible safely. These goals include the recognition and reduction of risks to the pregnant woman and her fetus attributable to hypertension and related vascular compromise. For the fetus, this approach also includes the recognition and reduction of adverse risk potentially attributable to the effects of antihypertensive agents on maternal hemodynamics, uteroplacental perfusion, and potential to cross the maternal-placental interface. Presently, the anticipated long-term benefit of antihypertensive management on maternal cardiovascular morbidity and mortality is not a primary concern during pregnancy.²²

Nonpharmacological Interventions

Many nonpharmacological interventions and strategies have been utilized to reduce blood pressure in nonpregnant hypertensive patients; these interventions and strategies include regular aerobic exercise, attaining/maintaining ideal body weight; moderating alcohol intake; and modifying the diet to include such things as abundant fruits and vegetables, low-fat dairy products, high-fiber items, and reduced sodium, such as what constitute the Dietary Approaches to Stop Hypertension (DASH) diet. These interventions have appeal for use during pregnancy due to their nonpharmacological basis; however, most are not appropriate for pregnancy or have not been evaluated during pregnancy.²² Strategies and interventions that are potentially applicable during pregnancy due to supporting evidence include the following:

• 
  

  Weight loss and diets with less than 100 mEq/d (extremely low) sodium are not recommended.

  
  
• 
  

  Moderate-level physical activity is recommended.

  
  
• 
  

  Home blood pressure monitoring is recommended.

Weight loss and extreme sodium restriction are not recommended; however, the quality of the evidence is reported as low and the recommendation is qualified in scope. The recommendation regarding moderate-level physical activity is also reported as having low-quality evidence.^24,25 Exercise during pregnancy may reduce the risk of developing preeclampsia.²⁶ Obese women are considered at extraordinarily high risk for developing severe hypertension, which often requires multiple antihypertensive agents to achieve control.²⁷

Home blood pressure monitoring for this group is reasonable, with the quality of the evidence described as low. Despite recognized advantages of ambulatory blood pressure monitoring and home blood pressure monitoring, it is likely office blood pressure monitoring will remain the most common method to screen and monitor blood pressure in outpatient medicine. This is due to the lack of reimbursement for ambulatory and home monitoring equipment, limited availability of the equipment needed, and a lack of detailed guidelines for monitoring strategies other than office blood pressure monitoring. Attention to the recognized factors that contribute to accurate blood pressure assessment include time of measurement, type of device used, cuff size, patient positioning, cuff placement, technique for obtaining measurement, the number of measurements taken, and recent use of tobacco or caffeine.^28,29 Proper selection of appropriate blood pressure cuff size is an essential component of accurate reproducible measurements. For example, too small a cuff leads to increased pressure within the cuff bladder compared to the occluding pressure of the brachial artery, resulting in overestimation of the patient’s blood pressure.^30,31 Please see Table 24-1 for details of blood pressure cuff selection based on a patient’s upper arm circumference.

Antihypertensive Agent Management

The ACOG Task Force on Hypertension in Pregnancy provides limited guidance for the use of antihypertensive agents during pregnancy. Oral antihypertensive agents are only indicated for control of chronic hypertension, where the SBP is greater than or equal to 160 or DBP is greater than or equal to 105 mm Hg based on evidence of moderate quality while making a strong recommendation. Meanwhile, if the SBP is less than 160 mm Hg, DBP is less than 105 mm Hg, and evidence for end-organ damage is absent, then antihypertensive medication management is not recommended, a recommendation based on low-quality evidence.

Antihypertensive agents discussed for use during pregnancy include labetalol, nifedipine, methyldopa, and thiazide diuretics. The use of each agent is summarized in a table that lists a dosage range from initial to maximum toxic dose and a few notes.²² The only classes of agents discussed as second-line therapy for managing chronic hypertension during pregnancy are diuretics, specifically thiazide-class agents.^32,33 Given the difficult and complex nature of controlling hypertension among women with obesity, and the lack of direct evidence to guide more complex management during pregnancy, an approach that extrapolates lessons learned among nonpregnant hypertensive patients can be used to enhance our understanding of how subpopulations respond to specific agents and how the difference between the standard dose and the maximum dose can guide the organization of first-, second-, and third-line management.

When considering and initiating antihypertensive management, an essential component of care is what to select as a target range for blood pressure. The ACOG Task Force on Hypertension in Pregnancy proposed, based on low-quality evidence, a target range for control that includes SBP between 120 and 160 and DBP between 80 and 105 mm Hg.²² The National Institute for Health and Care Excellence (NICE) in the United Kingdom has published guidelines for the management of chronic hypertension that recommend a target SBP less than 150 and DBP between 80 and 100 mm Hg.³⁴ The Control of Hypertension in Pregnancy Study (CHIPS) conducted an open, international, multicenter trial that studied two treatment targets for chronic hypertension, with one group having a target DBP at 100 mm Hg and a second group having a target DBP at 85 mm Hg. There was no difference in outcomes, except the group with DBP at 100 mm Hg had an increased frequency of severe maternal hypertension.³⁵

Given that severe acute hypertension is associated with serious maternal complications, such as intracranial hemorrhage, congestive heart failure, and acute renal failure, controlling hypertension in a manner that reduces the incidence of severe hypertension is reasonable: target SPB 130–150 and DBP 80–90 mm Hg for uncomplicated hypertension. For obese women with complicated hypertension (1 or more of the following: secondary hypertension, left ventricular hypertrophy, microalbuminuria, retinopathy, dyslipidemia, maternal age greater than 40 years, history of stroke, previous perinatal loss, or diabetes mellitus), target treatment of SBP is lower, at 120–140 mm Hg, while DBP is the same, at 80–90 mm Hg.³⁶

Table 24-2 summarizes the antihypertensive agents that can be considered for control of hypertension during pregnancy. The classic agents used during pregnancy as outlined by the ACOG Task Force on Hypertension in Pregnancy are listed first and include labetalol, methyldopa, and nifedipine and hydrochlorothiazide as a representative member of the thiazide diuretic agent category. As older agents, their efficacy and safety during pregnancy have been documented over time. The standard dose is the range where the medication has efficacy with limited side effects. The maximum dose, if exceeded, will result in toxic effects. If the upper limit of the standard dose is exceeded, one can expect little increase in effect while increasing the risk for side effects. The standard dose ranges have not been determined in pregnant women; it would be reasonable to expect, with the physiologic increase in medication clearance, that the standard dose range during pregnancy may be wider for some of these agents. With endothelial dysfunction expected among obese women during pregnancy, it is also possible that medication clearance due to target-organ dysfunction may as likely be compromised.