Keywords
pregnancy, superimposed preeclampsia, essential hypertension, pheochromocytoma, primary aldosteronism, renal artery stenosis, Cushing syndrome
Editors’ comments: The fourth edition adds two new authors to the chapter on chronic hypertension and pregnancy. All three authors were members of the recent ACOG task force that elucidated the College’s guidelines published in 2013; the first and second authors particularly act on determining recommendations for managing chronic hypertension in pregnancy, and the diagnosing of superimposed preeclampsia, the editor author (JMR) having chaired the whole report (see Chapter 1 ).
Introduction
Chronic hypertension in pregnancy received but modest attention in the first edition of this text. It was discussed with renal diseases in the final chapter, where Chesley noted briefly that most patients had the “essential variety,” 85% of whom did well, and that many of these women had an exaggerated decrease in blood pressure in early gestation. He cited personal experience to support his view that “accelerated (malignant)” hypertension was an unusual pregnancy complication. He also discussed the difficulty in diagnosing “superimposed preeclampsia” in these women and, by applying his own stringent criteria, suggested an incidence lower than most studies. There were also short discussions of renovascular hypertension, aldosteronism, and pheochromocytoma. Chesley’s summary reflected the paucity of contemporary data, not only in relation to chronic hypertension in pregnancy, but knowledge of the disease in non-pregnant populations as well. Research in both areas has progressed substantially in the last 35 years.
In this chapter, the natural history, diagnosis, and treatment of chronic hypertension complicating pregnancy are reviewed, followed by an overview of specific diagnostic categories including essential, renal, renovascular, and adrenal hypertension. Evaluation and treatment of hypertension postpartum are also discussed.
Background
The prevalence of hypertension in premenopausal women may be as high as 25% in whites and 30% in blacks. Poorly controlled hypertension is a leading cause of cardiovascular disease and global mortality. Elevated blood pressure also has significant implications for pregnancy outcome. Based on current estimates of the prevalence of hypertensive disorders during gestation, chronic hypertension likely complicates about 0.5 to 5% of pregnancies. The wide variation is due to different populations surveyed and the use of different criteria to make the diagnosis. Rates are higher in African-Americans, older women, and those with increased body mass indices (BMI). The global obesity epidemic and the trend towards postponing child-bearing, particularly in urban, industrialized regions, further contribute to the increasing prevalence of hypertension during pregnancy. The prevalence may also be higher, because some multiparous women with unrecognized chronic hypertension may be misdiagnosed with preeclampsia.
Definition
Chronic hypertension complicating pregnancy is defined as high blood pressure known to predate conception, and thus not caused by pregnancy. The US National High Blood Pressure Education Program Guidelines, summarized in the seventh Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure (JNC 7), define normal blood pressure for nonpregnant populations as 120/80 mm Hg, a level also considered “optimal” by virtually every other hypertension society. There is uniform agreement that levels of blood pressure higher than 120/80 mm Hg are associated with increased cardiovascular risk, but the various societies differ in their labeling of elevated blood pressure levels. The American (JNC) guidelines label those with blood pressures 120–139 mm Hg systolic or 80–89 mm Hg diastolic as having prehypertension whereas the European Guidelines, the British Hypertension Society, the World Health Organization, and the International Society of Hypertension Society consider<130/85 mm Hg as normal and 130–139 or 85–89 as “high normal.” Stage 1 hypertension (previously designated “mild”) is defined as a blood pressure of 140 to 159/90 to 99 mm Hg ( Table 18.1 ). The JNC 7 recognizes two stages of hypertension, whereas the European and British societies as well as the WHO distinguish grades 1, 2, and 3, as well as isolated systolic hypertension. Most women with chronic hypertension will have essential (also called primary) hypertension, but as many as 10% may have underlying renal or endocrine disorders, i.e., secondary hypertension. The next JNC report (JNC 8), in press when this book was published, is expected to focus on developing evidence-based systematic reviews focusing on nonpregnant populations only and will probably not be relevant to treatment of hypertension during pregnancy.
| Category | Systolic (mm Hg) | Diastolic (mm Hg) | |
|---|---|---|---|
| Normal | <120 | and | <80 |
| Prehypertension | 120–139 | 80–89 | |
| Stage 1 hypertension | 140–159 | or | 90–99 |
| Stage 2 hypertension | ≥160 | or | ≥100 |
Diagnosis
When hypertension has been clearly documented prior to conception, the diagnosis of chronic hypertension in pregnancy is straightforward. It is also the most likely diagnosis when hypertension is present prior to 20 weeks gestation, although isolated, rare cases of preeclampsia before this time have been reported, particularly in the presence of hydatidiform mole. The clinician should also be aware that if blood pressure was clearly normal at the first antepartum visit (e.g. ~8–12 weeks), then a blood pressure of 140–150/90–100 at 15–20 weeks could represent a pregnancy-related exacerbation including early preeclampsia.
Difficulties may also arise when pregnant women with prepregnancy, undiagnosed stage 1 hypertension present initially in the second trimester with normal blood pressure after having experienced the pregnancy-associated “physiologic” decrease in blood pressure. These women will have been presumed to be normotensive, and if blood pressure rises in the third trimester they will be erroneously diagnosed with either gestational hypertension or, if proteinuria is present, preeclampsia.
Because 15% to 25% of women with chronic hypertension develop superimposed preeclampsia, it may be impossible to diagnose chronic hypertension in this setting until well after delivery. In other instances, women with well-documented hypertension prior to conception will demonstrate normal blood pressures throughout their entire pregnancy, only to return to prepregnancy hypertensive levels postpartum. Thus, an understanding of the normal pregnancy-induced physiologic changes, as well as an appreciation of the clinical and laboratory features of preeclampsia, is essential for correct diagnosis and management of women with chronic hypertension. These principles, reviewed here briefly, are more extensively discussed in Chapter 14 .
Cardiac and Hemodynamic Alterations
Normal pregnancy is characterized by generalized vasodilatation, so marked that despite increases in cardiac output and blood volume of 40 to 50%, mean arterial pressure decreases by approximately 10 mm Hg (see Chapter 14 ). The decrement is apparent in the first trimester and reaches a nadir by midpregnancy. Blood pressure then increases gradually, approaching prepregnancy values at term, but may transiently increase to values above the woman’s nonpregnant level during the puerperium. Women with preexisting or chronic hypertension may also develop significantly lower BP during pregnancy with decrements as great as 15 to 20 mm Hg ( Fig. 18.1 ). Also, in light of our previous discussions that focus on the growing awareness that 120–139 mm Hg systolic or 80–89 mm Hg diastolic in nonpregnant populations is labeled “prehypertension,” it may be reasonable to reconsider the designation of all pregnant women with values below 140/90 mm Hg as “normotensive.” Increased clinical vigilance is prudent for all gravidas with blood pressure levels exceeding 120/80 mm Hg. Failure in this respect may result in a delay in diagnosing preeclampsia.
Blood pressure control in normal pregnancy, including the influence of pressor systems (autonomic nerves and catecholamines, renin–angiotensin–aldosterone, and vasopressin), baroreceptor function, endothelial cell function, and volume-mediated changes (detailed elsewhere in this text), has not been well evaluated in pregnant women. Animal studies are frequently contradictory, in part because of species differences. Thus, there continues to be a critical need to better explain normal vascular physiology before we completely understand the blood pressure alterations in chronically hypertensive pregnant women.
There are some data suggesting that the autonomic nervous system is more active in the control of blood pressure during pregnancy, although conflicting results have also been reported. There is little dispute that the renin–angiotensin system is markedly stimulated, and normotensive pregnant women have an exaggerated hypotensive response to angiotensin-converting enzyme inhibition, compared with nonpregnant women. These data suggest that this system is stimulated to help maintain normal blood pressure.
Some evidence exists, mainly from animal models, that basal and stimulated nitric oxide production increases in pregnancy, and may account for the marked vasodilatation and lower blood pressure. There are conflicting data on endothelial cell function in human pregnancy as discussed in Chapter 9 . The link between markedly increased placental hormones, particularly estrogen and progesterone, and alterations in vascular endothelial function is another area of active investigation. Finally, studies of the role of additional vasoactive peptides (vascular endothelial growth factor, placental growth factor, calcitonin gene-related peptide, relaxin) in normal blood pressure regulation or dysregulation in hypertension during pregnancy further suggest that the vasculature in pregnant women is modulated by multiple factors.
Other pregnancy-associated cardiovascular alterations that impact on blood pressure are increased cardiac output and blood volume. The relationship between these changes in women with chronic hypertension has been studied using traditional echocardiography but results are conflicting and confounded by small numbers, varying gestational ages at the time of study, and concomitant use of antihypertensive medications. A limited study of hemodynamic changes prospectively assessed by impedance cardiography in 20 women with chronic hypertension during pregnancy demonstrated increased peripheral vascular resistance and slightly lower stroke volume index compared to normotensive pregnant women, changes that would be expected in hypertension. Larger, prospective, controlled studies are needed to better understand the physiologic alterations in this group of women and potentially to optimize management of individual patients.
The profound alterations in renal hemodynamics in normal pregnancy which include increases in glomerular filtration rate and renal blood flow of ~50% are also detailed elsewhere (see Chapter 16 ). The impact of these changes on blood pressure control and on responsiveness to antihypertensive agents in women with chronic hypertension is not known. It does seem probable, though, that these hemodynamic alterations contribute to the greater ease of blood pressure control during pregnancy, that is, in the absence of superimposed preeclampsia. Finally, there are emerging data indicating that excessive gestational weight gain is associated with higher blood pressure, hypertensive disorders of pregnancy, and later-life cardiometabolic risk. The extent to which excessive weight gain during gestation compromises optimum blood pressure control in pregnant women with chronic hypertension is poorly understood since women with chronic hypertension are usually underrepresented in studies of hypertension in pregnancy. Some dietary habits, such as increased consumption of dairy products high in sodium, may also affect blood pressure control in the chronically hypertensive pregnant woman. Credible investigations of dietary modification have not been performed.
Effect of Chronic Hypertension on the Mother
Chronic hypertension in pregnancy is associated with higher rates of maternal and perinatal morbidity and mortality. This has been confirmed in a number of recent large, population-based studies. However, these and other reports have not consistently distinguished between women with preeclampsia superimposed on chronic hypertension and pregnant women with uncomplicated chronic hypertension alone. While there is little doubt that women with superimposed preeclampsia have higher rates of adverse maternal and fetal/neonatal outcomes, the independent risks associated with uncomplicated chronic hypertension are less clear.
Vanek and colleagues reported outcomes of 1,807 deliveries after 36 weeks in women with chronic hypertension and observed that, controlling for superimposed preeclampsia, uncomplicated chronic hypertension was associated with a greater risk of cesarean delivery (OR 2.7, 95% CI 2.4–3.0) and postpartum hemorrhage (OR 2.2, 95% CI 1.4–3.7). Tuuli and colleagues reported on pregnancy outcomes of 1,521 women with chronic hypertension. Women with chronic hypertension without superimposed preeclampsia had a higher risk of cesarean delivery (OR 2.1, 95% CI 1.8–2.4) and prolonged maternal hospital stay (OR 1.6, 95% CI 1.3–1.9) compared to normotensive control subjects. In a prospective cohort of pregnant women with chronic hypertension, Chappell and colleagues also reported higher rates of cesarean delivery and longer maternal hospital stay compared to background rates in the general population. The increased cesarean delivery rate may reflect the higher likelihood of iatrogenic intervention in response to elevated blood pressure rather than the disease process itself.
Chronic hypertension is also associated with increased risk of gestational diabetes (OR 1.8, 95% CI 1.4–2.0). This may reflect common risk factors for both conditions such as obesity as well as similar pathogenic mechanisms, e.g., insulin resistance.
Placental abruption, which is associated with life-threatening maternal hemorrhage, is estimated to be three-fold higher in women with chronic hypertension, although most of this risk is associated with superimposed preeclampsia. Other studies have not demonstrated an increased risk of abruption in women with chronic hypertension without superimposed preeclampsia. Differences in sample size and study population may account for the varying results.
Other adverse maternal outcomes include accelerated hypertension during pregnancy with resultant target organ damage, e.g., kidneys, heart, and brain, although in the absence of superimposed preeclampsia this is extremely uncommon. One exception may be women with severe hypertension prior to conception, many of whom have underlying renal disease or secondary hypertension. Some women with secondary forms of hypertension, such as chronic renal disease and collagen disorders, may suffer from irreversible deterioration in renal function during and after pregnancy. In the case of systemic lupus erythematosus, there may be multi-organ morbidity, regardless of the development of superimposed preeclampsia.
Finally, although the expectation is that pregnancies in women with uncomplicated chronic hypertension will be successful, these women are at higher risk of hospitalization due to worsening blood pressures.
Effects of Chronic Hypertension on Fetal/Neonatal Outcome
Perinatal mortality is also higher in pregnancies complicated by chronic hypertension, with most of this increased risk attributable to superimposed preeclampsia and fetal growth restriction. As previously noted, many studies do not precisely distinguish between pregnancies with uncomplicated chronic hypertension alone and those with superimposed preeclampsia. Furthermore, many of these studies lack a normotensive comparison group. Tuuli and colleagues compared women with chronic hypertension only (without superimposed preeclampsia) to normotensive control subjects and reported increased risk of small-for-gestational-age infants (OR 1.8, 95% CI 1.5–2.2), preterm delivery less than 34 weeks (OR 1.93, 95% CI 1.5–2.8), stillbirth (1.9, 95% CI 1.2–2.9), and admission to neonatal intensive care unit (1.4, 95% CI 1.1–1.8). Rey and colleagues also reported a higher relative risk of perinatal death (RR 2.3, 95% CI 1.2–4.6) and SGA (1.7, 95% CI 1.2–2.6) in women with chronic hypertension only compared to the normotensive control group. These findings have also been confirmed by others.
An additional risk to fetal well-being is the in utero exposure to antihypertensive medication. Overall, this risk has been poorly quantified, particularly in regard to long-term follow-up into childhood and beyond. Clinical trials have confirmed the safety of methyldopa with follow-up to 7 years of age. (See Chapter 19 for detailed discussion.)
Chronic Hypertension with Superimposed Preeclampsia
As discussed, pregestational hypertension is a recognized risk factor for preeclampsia. The incidence of superimposed preeclampsia ranges from 13 to 40% among women with chronic hypertension, depending on the diagnostic criteria, etiology (essential versus secondary), duration, and the severity of hypertension. Superimposed preeclampsia is more common in women with secondary causes of hypertension than with essential hypertension (discussed later in this chapter).
A major reason for this wide range in incidence is that the definition of superimposed preeclampsia is used liberally in some studies. The 2013 American College of Obstetricians and Gynecologists (ACOG) Hypertension Task Force described diagnostic criteria similar to those proposed by the National Institutes of Health Working Group Report in 2000 (see below), the latter forming the basis of most studies reviewed here. The criteria included a significant increase in blood pressure, new onset of proteinuria (≥300 mg over 24 hours) or features of HELLP syndrome (hemolysis, elevated liver enzymes, low platelet count). Using these criteria, several well-conducted large surveys report a risk between 15 and 25%. This risk increases with the severity and duration of hypertension as well as the presence of underlying renal disease. Of note, the diagnosis of preeclampsia is often challenging due to the usual gestational increase in blood pressure during the third trimester. The diagnosis is especially problematic in women with preexisting proteinuria. We and others have observed that women with mild (stage 1) hypertension have a risk of superimposed preeclampsia of about 15%, whereas those with stage 2 hypertension have a risk of 25–30%. Analysis of a large database in New York State suggests that these rates may be declining.
An intriguing question is why women with preexisting hypertension are at greater risk of the development of superimposed preeclampsia. There are few studies addressing this, but it has been suggested that women at risk of preeclampsia have genetic, biochemical, and metabolic abnormalities similar to women with essential hypertension. This list includes a higher incidence of polymorphisms in the angiotensinogen gene, obesity, hypertriglyceridemia, and insulin resistance. Such observations raise the possibility that the genesis of “superimposed” preeclampsia in hypertensive pregnant women may be related to the underlying genetic and metabolic disturbances that led to hypertension, rather than the elevated blood pressure itself. This is clearly an exciting area worthy of further investigation.
Recent paradigms of the pathogenesis of preeclampsia emphasize that there are necessary fetal as well as maternal susceptibility factors. Elevated blood pressure, considered to be a “maternal susceptibility factor,” clearly increases risk; however, most would agree that coincident fetal/placental pathologic abnormalities are necessary for the full expression of the disease. (Further aspects of this intriguing subject are discussed in several other chapters, including Chapter 4 , Chapter 5 , Chapter 6 , Chapter 10 .)
In 2013, the American College of Obstetricians and Gynecologists’ Task Force on Hypertension in Pregnancy released updated and evidence-based definitions and guidelines for the hypertensive disorders in pregnancy including superimposed preeclampsia. The Task Force, consisting of obstetricians, maternal-fetal medicine specialists, nephrologists, an anesthesiologist, a physiologist, and a patient representative, utilized the GRADE approach to evaluate the quality of the evidence and convey the strength of its recommendations. Given the higher risk of adverse pregnancy outcomes with superimposed preeclampsia, overdiagnosis was deemed to be preferable, with the goal of increasing vigilance and preventing catastrophic maternal and fetal outcomes. However, it was recognized that a more specific and stratified approach along with predictors of adverse outcomes would be useful in guiding clinical management and avoiding unnecessary preterm births. Therefore, superimposed preeclampsia was stratified into two groups (superimposed preeclampsia and superimposed preeclampsia with severe features) to guide clinical management ( Table 18.2 ).
| Superimposed preeclampsia is likely when any of the following are present: |
|
| The diagnosis of superimposed preeclampsia with severe features is confirmed when any of the following are present: |
|
Importantly, it should be recognized that there is often ambiguity in the diagnosis and that clinical vigilance should be high when superimposed preeclampsia is suspected. Furthermore, women with preeclampsia can progress and develop end-organ involvement and adverse outcomes. Superimposed preeclampsia without severe features mandates increased maternal and fetal surveillance given the progressive nature of preeclampsia. The presence of severe features directs further management and timing of delivery. Delivery decisions must carefully balance maternal and fetal well-being. Management considerations are detailed in the Task Force recommendations.
Effects of Superimposed Preeclampsia on the Mother and Fetus/Neonate
As noted previously, maternal and fetal/neonatal morbidity and mortality are clearly higher with superimposed preeclampsia compared to chronic hypertension alone. C-section rates, length of hospital stay, placental abruption with hemorrhage, and HELLP syndrome are all increased. In addition, seizures, strokes, pulmonary edema, and renal dysfunction are all associated with superimposed preeclampsia.
Rey and colleagues reported a relative risk of perinatal death of 3.6 in women with superimposed preeclampsia compared to women with uncomplicated chronic hypertension. Fetal growth restriction is also higher with superimposed preeclampsia. Chappell and colleagues reported fetal growth restriction less than the 5th percentile in 42% of women with superimposed preeclampsia compared to 14% in women with chronic hypertension alone. Preterm delivery, with the associated neonatal complications of prematurity, is also higher with superimposed preeclampsia. Preterm delivery is usually indicated by worsening maternal status or fetal growth restriction. While the details vary, the pattern of these findings is fairly consistent across a number of studies and varying populations and is the basis for recommending increased maternal and fetal surveillance.
Specific Hypertensive Disorders
Essential Hypertension
One in four adults has hypertension worldwide, which equates to approximately 1 billion individuals. Based on data from the US National Health and Nutrition Examination Survey (NHANES), which included 26,349 adults aged 30 years and older, and from the Behavioral Risk Factor Surveillance System from 1997 to 2009, including 1,283,722 adults aged 30 years and older, the prevalence of hypertension was estimated at 37.6% in men and 40.1% in women. Hypertension is more prevalent in non-Hispanic blacks and older persons. The prevalence of hypertension in women is estimated to be 3.8% between ages 20 and 34, 14.2% between 35 and 44, and 31.2% between 44 and 54 years of age based on recent US Health statistics. A recent study reported the prevalence of chronic hypertension in US reproductive-age women to be approximately 8%. Overall, chronic hypertension is estimated to affect 0.5 to 5% of all pregnancies. The wide variation is likely to be due to the population studied and the criteria used to establish the diagnosis. Using a database that included 56 million hospitalizations for delivery in the United States, approximately 1.8% of all pregnancies were complicated by chronic hypertension in 2007–2008, with a progressive increase since 1995. The increasing rates of obesity as well as the trend towards postponing child-bearing, particularly in urban, industrialized regions, contribute to the increasing rates of hypertension during pregnancy. The rates may even be higher, because some multiparous women with unrecognized chronic hypertension may be misdiagnosed with preeclampsia.
Before age 50 most people with hypertension have elevated diastolic pressure. After age 50, systolic pressure continues to rise and diastolic pressure tends to fall, and isolated systolic hypertension is prevalent. Poorly controlled hypertension is the leading cause of death globally. Reduction of blood pressure reduces cardiovascular disease and death by amounts predicted from data associating elevations in blood pressure with adverse events.
Essential hypertension is a heterogeneous, polygenic disorder resulting from dysregulation of hormones, proteins, and neurogenic factors involved in blood pressure regulation interacting with diet, level of activity, and other environmental influences. About 30–60% of blood pressure variability is inherited; however, genetic studies of essential hypertension have not yet uncovered common genes with large effects on blood pressure. Rather, polymorphisms in alleles at many different loci, interacting with behavioral and environmental factors, contribute to the final disease trait.
Using the candidate gene approach, studies where authors report polymorphisms in genes regulating the renin–angiotensin system, the adrenergic system, G protein signaling, nitric oxide synthase, and kallikreins have been inconclusive. Rather than focusing on simple single nucleotide polymorphism (SNP) based association studies of candidate genes, ongoing research is utilizing more complex haplotype-based association studies, genome-wide linkage analysis and genome-wide SNP analyses of multiple SNPs. Rare monogenic forms of hypertension have been described. The genes identified so far confirm the importance of renal sodium excretion in the pathogenesis of hypertension, as almost all cause alterations in renal sodium handling. These studies have also identified potential mechanisms that can be studied in essential hypertension, in particular, alterations in WNK kinases, aldosterone synthase, and the epithelial sodium channel (ENaC).
Renal Basis for Essential Hypertension
Despite the complexity of blood pressure regulation, the central role of impaired renal sodium excretion in the genesis of hypertension is undisputed and continues to be supported by experimental and clinical studies. Subclinical renal abnormalities observed in some individuals with essential hypertension include focal renal ischemia leading to chronic non-suppressible renin secretion, renal sodium retention, reduced renal mass, decreased glomerular filtration rate, and a compromised sodium excretory capacity.
Therapeutically, the role for renal sodium retention in the pathogenesis of hypertension is supported by the efficacy in many hypertensive individuals of diuretic therapy. Similarly, a role for non-suppressible renin secretion is supported by the efficacy of agents that interrupt the renin–angiotensin system. The relationship between subtle abnormalities in renal function and pregnancy outcome has not been investigated in detail. Given the significant impact of reduced renal function on the risk of preeclampsia, this is an area of investigation of potential importance.
Hormonal Basis for Essential Hypertension
Alterations in the renin–angiotensin system are important aspects of the pathophysiology of primary aldosteronism and renovascular hypertension. Conversely, in essential hypertension there is considerable heterogeneity in circulating renin and aldosterone levels. Some patients have normal or high plasma renin activity, whereas about one-third of hypertensive individuals have low or suppressed plasma renin activity. The latter values are those expected if volume overload is present, and, indeed, low-renin hypertension is often associated with increased sensitivity to salt restriction or diuretic therapy. Because pregnancy is characterized by activation of the renin–angiotensin system, adverse perinatal outcomes in women with essential hypertension who have alterations in the renin system is a real possibility.
Sympathetic Nervous System and Essential Hypertension
The role of the sympathetic nervous system in the pathogenesis of primary hypertension is supported by a large number of indirect experimental and clinical observations. These include increased heart rate and plasma catecholamine levels in response to a variety of stimuli in hypertensive individuals and in animals. While sympathetic nervous system activity and function are difficult to measure accurately in humans, there are a few studies that link preeclampsia to its activation.
Vascular Structure and Function and Hypertension
It is beyond the scope of this chapter to review the expanding field of vascular biology and the role of abnormalities of vascular structure and function that are important in the genesis and the maintenance of elevated blood pressure. However, several key areas of investigation are worth mentioning, particularly those with relevance to the pathophysiology of preeclampsia. Mechanisms for vascular hypertrophy and blood vessel remodeling, as well as alterations in ion transport and signal transduction in vascular smooth muscle and endothelial cells are the focus of active investigation. Current evidence supports a role for dysregulation of these processes and suggests that there is significant overlap between processes involved in generalized atherosclerosis and the pathogenesis of preeclampsia. (See Chapter 9 .) The role of these processes in the increased tendency of women with preexisting hypertension to develop preeclampsia deserves study.
Metabolic Disturbances and Hypertension
The common occurrence of obesity, type 2 diabetes, and hypertension, all features of the metabolic syndrome, as well as the observation that a significant number of non-obese hypertensives will have insulin resistance and hyperinsulinemia have led to the concept of insulin resistance in the genesis of primary hypertension. This has relevance to hypertension in pregnancy because insulin resistance appears more prevalent in preeclamptic women, and women with overt and gestational diabetes are reported to be at greater risk of preeclampsia. (See Chapter 7 for additional discussion).
Dietary Factors
The role of sodium in the pathogenesis of some, if not most, cases of primary hypertension is established. Other dietary components possibly involved are calcium and potassium. Inverse relationships between dietary calcium intake and blood pressure have been documented, while calcium supplementation lowers blood pressure in experimental models and in clinical trials. Calcium requirements are increased in normal pregnancy, and there are data suggesting an association between inadequate calcium intake and hypertension during pregnancy. Supplemental calcium has been shown to prevent preeclampsia and adverse pregnancy outcomes in women ingesting a low-calcium diet. However, a small study of calcium supplementation in pregnant women with essential hypertension but eating a calcium-replete diet failed to demonstrate a reduction in superimposed preeclampsia in the calcium-supplemented group.
Environment and Behavior
Obesity and excess alcohol intake contribute to hypertension. Conversely, weight loss, increased physical activity, and decreased alcohol intake have been demonstrated to be effective strategies for lowering blood pressure. As noted in Chapter 7 , obesity is also an independent risk factor for preeclampsia. Excessive gestational weight gain is also associated with adverse clinical outcomes including hypertensive disorders. In 2009 the Institute of Medicine released updated guidelines for weight gain in pregnancy. These guidelines reduced the recommended weight gain in obese women during pregnancy to improve pregnancy and maternal outcomes.
Physiology and Pathophysiology of Essential Hypertension During Pregnancy
The cardiovascular, renal, and hemodynamic alterations in pregnancy pertinent to blood pressure regulation were summarized above. Surprisingly, few detailed investigations of the physiology of essential hypertension in pregnancy have been performed. Women with essential hypertension are an intriguing group to investigate because they have a high incidence of superimposed preeclampsia. Thus, longitudinal studies of chronic hypertensive women may be helpful in elucidating early pregnancy phenomena important in the pathophysiology of preeclampsia.
Blood Pressure Patterns and Hemodynamic Measurements
Women with essential hypertension normally demonstrate the expected decrease in blood pressure in early and mid-pregnancy, although compared to normotensive women they have increased peripheral vascular resistance. In women who develop superimposed preeclampsia, blood pressure may start to increase in the late second trimester, whereas women who have uncomplicated pregnancies will frequently demonstrate even lower blood pressures at this time of gestation. It has been suggested that absence of a second-trimester decrease in blood pressure is associated with more gestational complications and predictive of development of preeclampsia. We reported that systolic blood pressure greater than 140 mm Hg at 20 weeks gestation and increased uric acid and suppressed plasma renin activity predict superimposed preeclampsia with a high sensitivity and specificity. Ambulatory blood pressure monitoring techniques have not been extensively studied in pregnant women with essential hypertension, although preliminary studies suggest that they will have limited utility in predicting superimposed preeclampsia.
Cardiac function has not been investigated extensively during pregnancy in women with essential hypertension. Increased left ventricular mass has been reported in third-trimester chronic hypertensives. In a small, longitudinal study of 20 pregnant women with chronic hypertension the authors reported increased peripheral vascular resistance and lower stroke volume index compared to normotensive women. Atrial natriuretic peptide levels were lower in the women with hypertension, suggesting decreased plasma volume expansion. Larger longitudinal studies are needed. Similarly, there is a paucity of information concerning renal function and hemodynamics during pregnancies complicated by chronic hypertension (see Chapter 16 ). In one study there was a normal increase in creatinine clearance and urinary calcium excretion in most women with uncomplicated essential hypertension during pregnancy, but, as expected, when superimposed preeclampsia developed, renal function decreased modestly while marked hypocalciuria supervened. We have observed increased mid-trimester hyperuricemia in women with chronic hypertension prior to development of superimposed preeclampsia, which raises the question of whether subtle alterations in renal hemodynamics precede the development of preeclampsia. A preliminary study of Doppler analysis of the renal artery in hypertensive pregnant women noted an increase in renal blood flow with chronic hypertension, consistent with abnormal autoregulation. These intriguing observations are not surprising given the alterations that have been reported in nonpregnant essential hypertensives.
Hormonal and Biochemical Alterations
Most investigations of pregnant women with chronic essential hypertension demonstrate that until superimposed preeclampsia develops, levels of hormones and other circulating substances associated with blood pressure regulation are similar to values in normotensive pregnancy. The stimulation of the renin–angiotensin systems in these two groups are also similar, as is platelet angiotensin II binding. Of further interest, pregnant women with essential hypertension destined to develop superimposed preeclampsia also manifest reductions in plasma renin activity in midpregnancy, again in a fashion similar to that described in nulliparas who subsequently become preeclamptic. The decrease in plasma renin activity is accompanied by a decrease in urinary aldosterone excretion, and is an expected response to increased vasoconstriction. Furthermore, some women who developed superimposed preeclampsia and had low plasma renin activity also had a marked decrease in plasma estradiol. Others have reported that plasma estradiol levels are decreased in women with uncomplicated chronic hypertension in pregnancy. Finally, we have noted similar plasma progesterone levels in women with chronic hypertension, with and without preeclampsia, and in normotensive pregnant women.
Several studies of nitric oxide production in normal and preeclamptic pregnant women have been conducted with conflicting results. As of the middle of 2013, we were aware of only one that focuses on essential hypertension in pregnancy. In this study, the authors reported significantly decreased levels of nitric acid metabolites compared to normotensive gestation. This finding, consistent with observations in nonpregnant essential hypertensives, is surprising in view of the frequently observed pregnancy-induced vasodilatation and decrease in blood pressure in pregnant women.
Platelet and lymphocyte intracellular calcium concentrations are increased in nonpregnant essential hypertensives, as well as in preeclamptics. The rationale for such studies is the belief that platelets are surrogates for vascular smooth muscle, an increase in their intracellular calcium implying similar increments in the vascular cells suggesting increased tone or vasoconstriction. Kilby et al. reported increased platelet cytosolic calcium levels in five pregnant chronic hypertensives, while Hojo et al. noted no differences in the lymphocyte intracellular free calcium levels of pregnant women with essential hypertension compared to normotensives, although levels were higher in preeclampsia.
Pathophysiology of Superimposed Preeclampsia
Women with essential hypertension are at greater risk of developing superimposed preeclampsia, but the reason for this is not known. Dysregulation of angiogenic factors is a feature of preeclampsia developing in previously normotensive women (see Chapter 6 ). Elevations of soluble fms-like tyrosine kinase-1 (sFlt-1) and endoglin, have been reported prior to and at the time of clinical disease. Soluble Flt-1 is a circulating antagonist of vascular endothelial growth factor (VEGF) released from the placenta, and is hypothesized to contribute to maternal vascular endothelial dysfunction and glomerular endotheliosis. Placental growth factor, an angiogenic factor similar to VEGF, is decreased in women with preeclampsia. We and others have recently reported that maternal serum levels of angiogenic factors are altered in women with chronic hypertension and superimposed preeclampsia, similar to women with preeclampsia without preexisting hypertension. In particular, we found that the ratio of sFlt-1/PlGF was highest in midpregnancy in women with chronic hypertension who developed preterm preeclampsia, compared with those who developed preeclampsia close to term, or not at all. In a secondary analysis of the Maternal-Fetal Medicine Units Network trial of aspirin to prevent preeclampsia in high-risk pregnancies, we reported on 313 women with chronic hypertension. Soluble Flt-1 and endoglin were significantly elevated between 26 and 30weeksgestation in women who later developed superimposed preeclampsia compared to women with chronic hypertension who did not develop superimposed preeclampsia. However, there were no significant differences at other time points in gestation, including at the time of diagnosis. The variability in these studies may be related to sample size, differing criteria for the diagnosis of superimposed preeclampsia, and varying populations. Overall, the aggregate of observations suggest possible similarities in pathogenesis between preeclampsia in previously normotensive women and those with superimposed preeclampsia. Further study is needed to determine whether angiogenic factors play a causal role in the pathogenesis of superimposed preeclampsia and the contribution of other etiologies in this subgroup of women.
The concept of “shared risk factors” for both essential hypertension and preeclampsia, e.g., insulin resistance, has already been mentioned. It is also worth considering whether some forms of essential hypertension, for example those characterized as high or low renin, may be particularly predisposed to preeclampsia. This appears to be the case with secondary hypertension: for instance, women with renovascular hypertension, in whom the renin–angiotensin system is activated, appear to have an unusually high incidence of preeclampsia. Women with hyperaldosteronism, a low-renin form of hypertension, may have a lower incidence of preeclampsia compared to those with renovascular hypertension. Currently, there is little information regarding the association of baseline renin levels and development of superimposed preeclampsia in women with essential hypertension although we have reported that suppressed plasma renin activity and elevated serum uric acid levels at mid pregnancy (20 weeks) are associated with an increased risk of later development of superimposed preeclampsia.
Secondary Hypertension
Secondary forms of hypertension are uncommon compared with essential hypertension, and comprise only 2 to 5% of hypertensives diagnosed and treated at specialized centers. In routine primary care settings, however, their numbers are even lower. The most common etiologies are renal disease, aldosteronism, renovascular hypertension, Cushing syndrome, and pheochromocytoma. The prevalence of secondary hypertension in women of childbearing age has not been precisely determined, but is estimated to be 10% of women with prepregnancy hypertension. Of importance, prognosis is best when a diagnosis of secondary hypertension is made prior to conception, because most forms of secondary hypertension are associated with increased maternal and fetal morbidity and mortality.
Renal Disease
A detailed discussion of renal disease and pregnancy has not been undertaken in this text, except those discussions relating to superimposed preeclampsia. We suggest ref. for our review of this topic. There are, however, points to emphasize regarding management of hypertension associated with intrinsic renal disease. Kidney disease is the most common cause of secondary hypertension in nonpregnant populations, in which high blood pressure is often found in patients with anatomic or congenital abnormalities, glomerulonephritis, diabetes, systemic lupus erythematosus, or interstitial nephritis.
All young women with newly diagnosed hypertension should be screened for intrinsic renal disease including measurements of renal function, and urinalysis for detection of proteinuria or red blood cells. Those with a strong family history of renal disease should be screened with renal ultrasound for polycystic kidney disease. This autosomal dominant disorder often presents with hypertension in the third and fourth decades. When renal disease is detected, regardless of its cause, these women should be counseled about the increased maternal and fetal risks associated with impaired renal function (preconception serum creatinine level≥1.4 mg/dL) or poorly controlled hypertension. Differentiating between worsening renal disease and superimposed preeclampsia is often challenging in this group of women.
Women with renal disease are best managed by a multidisciplinary team including high-risk obstetricians and nephrologists. This is extremely important in the case of renal transplant recipients, in whom concerns regarding immunosuppression and risk of infection and rejection require coordinated specialty care. Therapy of hypertension is similar to that in gravidas with essential hypertension, although maintaining normal levels of blood pressure in women with renal disease may be more important in order to protect the kidneys from further deterioration.
Renovascular Hypertension
This entity refers to hypertension caused by stenotic lesions of the renal arteries. The narrowing of the arterial lumen leads to diminished blood flow to one or both kidneys, with resulting renal ischemia, stimulation of the renin–angiotensin system, and ensuing hypertension. It is important to emphasize that not all stenotic lesions of the renal artery result in hypertension, because they may not be severe enough to compromise renal blood flow. Thus, demonstration (by angiography) of a lesion does not necessarily establish the diagnosis of renovascular hypertension. Cure of hypertension after renal artery revascularization with either bypass surgery or angioplasty remains the most reliable proof of renovascular hypertension.
The causes of renovascular hypertension are many. Atherosclerotic renovascular disease is primarily observed in postmenopausal women, especially those with a history of tobacco use and diffuse vascular disease, whereas fibromuscular dysplasia is more likely to be present in young women, making it the form most likely to be encountered in pregnancy. Fibromuscular dysplasia is three times more common in women than men (but infrequent in black or Asian populations), and is a nonatherosclerotic, noninflammatory vascular occlusive disease, most often presenting as medial fibroplasia. Fibromuscular dysplasia has a prevalence of approximately 1% in hypertensive populations. Although the renal arteries are most commonly involved, other vessels including carotid, coronary, abdominal aorta, and peripheral arteries may also be affected.
Clinical features suggestive of renovascular hypertension are severe hypertension, which may be resistant to medical therapy, and which first appears in the second, third, or fourth decades. Abdominal bruit and a high peripheral venous plasma renin activity are among the findings traditionally associated with the disorder. Several noninvasive screening tests are also useful. These include captopril renography, Doppler ultrasonography of the renal arteries, and magnetic resonance angiography with gadolinium contrast enhancement. The gold-standard test remains conventional angiography. These tests are justified for use in pregnant women because the hypertension is potentially curable with either angioplasty or surgery, and without adequate treatment these women are at increased risk of doing poorly in pregnancy. In addition the fetal radiation dose during angiography is small and in the range permissible for pregnancy. We prefer angiography to noninvasive testing, as the latter may not detect the smaller branch lesions which are more frequent when fibromuscular dysplasia is present. Angiography may reveal either a single area of stenosis, or multiple stenotic lesions with intervening aneurysmal outpouchings, the “string of beads” image.
Renal angioplasty is a highly effective method in treating non-pregnant patients with fibromuscular dysplasia. There is a high rate of technical success with cure, or significant improvement in blood pressure exceeding 80%.
Knowledge of renovascular hypertension in pregnancy is based on a handful of case reports and a few limited series of patients totaling approximately 30 cases. Many of the patients presented with early and severe preeclampsia and poor pregnancy outcomes. One retrospective comparison of pregnancy outcomes in four patients with known renovascular hypertension matched to 20 women with essential hypertension demonstrated that those with renovascular hypertension were younger (age 25 versus 36) and had higher blood pressure levels during pregnancy. Of interest, the four women with renovascular hypertension all developed superimposed preeclampsia, in contrast to 30% of those with essential hypertension. Plasma renin activity in one woman with renovascular hypertension was, as expected, quite elevated when measured early in pregnancy, but decreased when preeclampsia developed. There have been a number of case reports of successful angioplasty in the setting of renal artery stenosis during pregnancy, with good pregnancy outcome. We and others have also documented the experiences of women with untreated renovascular hypertension whose pregnancies were complicated by severe preeclampsia. Both had successful angioplasty postpartum and their subsequent pregnancies were normal. In view of the dramatic clinical improvement which usually follows revascularization, as well as the anecdotal experience described above, it seems justified and preferable to rule out renovascular hypertension before conception in young women with suggestive clinical features. Furthermore, based on the observations that hypertension mediated by renal ischemia and stimulation of the renin–angiotensin system increases the risk of preeclampsia, the role of these factors in the pathogenesis of preeclampsia warrants further investigation.
In summary, pregnant women with renovascular hypertension who have not undergone renal artery revascularization are at considerable risk, especially for superimposed preeclampsia and fetal complications. Temporizing therapy with angiotensin-converting enzyme inhibitors or angiotensin II receptor blocking agents is not an option in pregnancy because these drugs are associated with major malformations and significant fetal toxicity (see Chapter 19 ), but treatment of hypertension with other drugs that suppress renin secretion is possible. Those most likely to be effective are methyldopa and beta-adrenergic receptor blockers.
Primary Aldosteronism
Primary aldosteronism consists of a heterogeneous group of disorders characterized by mineralocorticoid hypertension coexisting with anatomical abnormalities of the adrenal glands. Surgically curable forms of primary aldosteronism include unilateral aldosterone-producing adenoma (APA, or Conn syndrome), unilateral adrenal hyperplasia, and, rarely, aldosterone-producing carcinoma. Surgical cure (with adrenalectomy) is associated with younger age and shorter duration of hypertension, observations which emphasize the importance of early identification. Those with bilateral adrenal abnormalities – either adenomas or hyperplasia – are not surgically curable. A rare form of non-primary aldosteronism, glucocorticoid remediable aldosteronism (GRA), is an autosomal dominant familial condition that is characterized by excess aldosterone production which is suppressible by exogenous steroids. This disorder is not surgically curable.
Primary aldosteronism may be the most common curable endocrine form of hypertension, present in as many as 5 to 15% of patients with elevated blood pressure. The classic clinical features are hypertension, hypokalemia, suppressed plasma renin activity, excessive urinary potassium excretion, hypernatremia, and metabolic alkalosis. Manifestation of each of these features is variable, and even hypokalemia, once thought of as the sine qua non for diagnosing aldosterone excess, may be initially absent in as many as 25–50% of patients. Diagnosis is made by demonstrating biochemical and hormonal abnormalities, followed by computerized tomography (CT) or magnetic resonance imaging (MRI) of the adrenal glands (helpful in differentiating an adenoma from hyperplasia). If an adenoma is detected, radiologic imaging may be followed by adrenal vein sampling to document unilateral aldosterone secretion prior to surgery. Surgery is indicated for unilateral disease, with a cure rate of about 65%, and an improvement in an additional 33%. Medical therapy with aldosterone blockade (in nonpregnant individuals) is usually effective for patients with hyperplasia, although high doses may be necessary. Calcium-channel blockers have also been reported to be effective.
There are a number of case reports describing primary aldosteronism in pregnancy. Some of these have been complicated by considerable morbidity, including severe hypertension, hypokalemia, preeclampsia, and poor fetal outcome, but there are also instances where hypertension and hypokalemia have been ameliorated during gestation. It is hypothesized that such improvement, when it occurs, is a consequence of the high levels of progesterone which antagonize the actions of aldosterone.
Primary aldosteronism may be difficult to diagnose in pregnant women because of the marked alterations in the renin–angiotensin–aldosterone system that occur in normal pregnancy. Both renin and aldosterone production are markedly increased, with a five-fold increase in urine aldosterone excretion compared to that observed in nonpregnant patients with primary aldosteronism. Moreover, mild hypokalemia is not unusual in the course of a normal pregnancy. Greater degrees of hypokalemia (≤3 mEq/L), however, are unusual and should be investigated. In one case involving a pregnant women with an aldosteronoma, reported by us ( Fig. 18.2 ), plasma renin activity was not totally suppressed, but became undetectable postpartum. Her plasma renin levels, however, were approximately one-third to one-half of those routinely observed in other pregnant women with essential hypertension. Her urinary aldosterone excretion was well above the increases recorded in most women with uncomplicated gestations.
