DIAGNOSIS AND EVALUATION IN PREGNANCY
ADVERSE PREGNANCY EFFECTS
ANTIHYPERTENSIVE TREATMENT IN PREGNANCY
PREGNANCY-AGGRAVATED HYPERTENSION OR SUPERIMPOSED PREECLAMPSIA
Chronic hypertension is one of the most common serious complications encountered during pregnancy. This is not surprising because, according to the National Health and Nutrition Examination Survey (NHANES) from the Centers for Disease Control and Prevention (2011), the average prevalence of hypertension in women aged 18 to 39 years is approximately 7 percent. The incidence of chronic hypertension in pregnancy is variable depending on population vicissitudes. In a study of more than 56 million deliveries from the Nationwide Patient Sample, 1.8 percent of births in 2007 and 2008 were in women with chronic hypertension (Bateman, 2012). The incidence was 1.0 percent in more than 530,000 singleton pregnancies in California in 2006 (Yanit, 2012). And according to the American College of Obstetricians and Gynecologists (2012), the incidence may be up 5 percent. Despite this substantive prevalence, optimal management has not been well studied. It is known that chronic hypertension usually improves during early pregnancy. This is followed by variable behavior later in pregnancy and importantly, by its unpredictable development of superimposed preeclampsia, which carries increased risks for maternal and perinatal morbidity and mortality.
To define chronic hypertension, first, the range of normal blood pressure levels must be established. This is not a simple task because, like all polygenic-determined biological variants, blood pressure norms differ between populations. And, within these norms, there are wide variations between individuals. Moreover, these are also greatly influenced by numerous epigenetic factors. For example, blood pressure not only varies between races and gender, but the pressures—especially systolic—increase directly with increasing age and weight. Pragmatically then, normal adults have a wide range of blood pressures, but so do those with chronic hypertension.
After these variables are acknowledged, an important consideration for any population is the attendant risks of chronic hypertension. There is an increasing incremental rate of cardiovascular, cerebrovascular, and renal disease that follows increasing levels of both diastolic and systolic pressures (Kotchen, 2012).
Definition and Classification
For the foregoing reasons, it seems logical that chronic hypertension would be defined as some level of sustained blood pressure that is associated with an increase in acute or long-term adverse effects. For many years in the United States, these values were based primarily on actuarial tables constructed using data derived from white adult males and compiled by life insurance companies. These “norms” disregarded interrelated factors such as ethnicity and gender as well as other important covariants. The importance of race, for example, was emphasized by Kotchen (2012), who cites statistics derived from 65 million American adults. In this study, the incidence of hypertension—defined as blood pressure > 140/90 mm Hg—was 34 percent in blacks, 29 percent in whites, and 21 percent in Mexican Americans.
For many years, guidelines for diagnosis, classification, and management of chronic hypertension have been promulgated by the Joint National Committee. In 2008, the National Heart Lung and Blood Institute discontinued these guidelines, and the Joint National Committee 8 (JNC 8) was instead asked to provide an evidence-based review (James, 2013). Findings pertinent to caring for young women with chronic hypertension are summarized in Table 50-1.
TABLE 50-1. Eighth Joint National Committee (JNC 8)—2014 Chronic Hypertension Guidelines and Recommendations
Evidence-based recommendations from randomized controlled trials
Definitions hypertension and prehypertension not addressed
Lifestyle modifications endorsed from the Lifestyle Work Group (Eckel, 2013)
Recommend selection among four specific medication classes: angiotensin-converting enzyme inhibitors (ACE-I), angiotensin-receptor blockers (ARB), calcium-channel blockers, or diuretics:
General population < 60 years old—initiate pharmacological therapy to lower diastolic pressure ≤ 90 mm Hg and systolic pressure ≤ 140 mm Hg
Diabetics—lower pressure < 140/90 mm Hg
Chronic kidney disease—lower pressure < 140/90 mm Hg. Also add ACE-I or ARB to improve outcomes
General nonblack population—initial therapy should include thiazide-type diuretic, calcium-channel blocker, ACE-I, or ARB
General black population—primary antihypertensive therapy should include thiazide-type diuretic or calcium-channel blocker
Assess monthly, and after 1 month, if goals not met, then increase primary drug dose or add second drug. If no response, increase either or add third drug; then if no response, refer to hypertension specialist
Summarized from James, 2013.
Treatment and Benefits for Nonpregnant Adults
There are proven benefits that accrue with treatment of otherwise normal adults who have sustained hypertension. A myriad studies evaluating many combinations of antihypertensive therapy have been conducted with salutary results. Some of these include the ACCORD, ASCOT, ACCOMPLISH, ALLHAT, SPRINT, TOHMS, TROPHY, and VALUE studies. Importantly, these trials evaluated monotherapy versus combination therapeutic regimens as well as ethnospecific benefits. Most evaluated cardiovascular outcomes, but many also confirmed risk reduction in cerebrovascular accidents, renal insufficiency, and overall mortality rates. Because of these incontrovertible benefits, the JNC 8 recommends the treatment outlined in Table 50-1.
Thus, even for mildly elevated blood pressures cited in Table 50-1, interventions to reduce pressure are beneficial. Moreover, it is clear that antihypertensive therapy in nonpregnant reproductive-aged women with sustained diastolic pressures ≥ 90 mm Hg would be considered standard. Not clear from these observations, however, is what constitutes the best management for the woman being treated who contemplates pregnancy, or the best management of the woman undergoing treatment who becomes pregnant, or the woman who is first identified to have chronic hypertension during pregnancy (August, 2014). In these and similar women, the benefits and safety of instituting antihypertensive therapy are less clear, as subsequently discussed.
Women with chronic hypertension should ideally be counseled before pregnancy. The duration of hypertension, degree of blood-pressure control, and current therapy are ascertained. Home measurement devices should be checked for accuracy. Those who require multiple medications for control or those who are poorly controlled are also at increased risk for adverse pregnancy outcomes. General health, daily activities, and dietary habits are also assessed as shown in Table 50-2.
TABLE 50-2. Lifestyle Modifications for Hypertensive Patients—American Heart Association and American College of Cardiology
Consume a dietary pattern that emphasizes intake of vegetables, fruits, and whole grains; includes low-fat dairy products, poultry, fish, legumes, nontropical vegetable oils, and nuts; limits sweets and red meats—e.g. DASH dietary pattern, USDA Food Pattern, or the AHA Diet
Lower sodium intake—consume no more than 2400 mg sodium/day; 1500 mg/day desirable
Engage in aerobic physical activity three to four sessions per week, lasting on average 40 minutes per session, and involving moderate-to-vigorous intensity physical activity
AHA = American Heart Association; DASH = Dietary Approaches to Stop Hypertension; USDA = United States Department of Agriculture.
Summarized from Eckel, 2013.
In those with hypertension for more than 5 years or in diabetic women, cardiovascular and renal function should be assessed (August, 2014; Gainer, 2005). Women with evidence for organ dysfunction or those with prior adverse events such as cerebrovascular accident, arrhythmias, ventricular failure, or myocardial infarction are at markedly increased risk for a recurrence or worsening during pregnancy. Renal function is assessed by serum creatinine measurement, and proteinuria is quantified if the urine spot protein/creatinine ratio is abnormally high (Hladunewich, 2011). The Working Group Report on High Blood Pressure in Pregnancy (2000) of the National Heart, Lung, and Blood Institute concluded that the risks of fetal loss and accelerated deterioration of renal disease are increased if serum creatinine level is above 1.4 mg/dL (Chap. 53, p. 1061).
Although pregnancy is considered by many to be contraindicated in women with severe, poorly controlled hypertension, there is not a consensus regarding this. Certainly, pregnancy is at least relatively contraindicated in women who maintain persistent diastolic pressures of ≥ 110 mm Hg despite therapy, who require multiple antihypertensives, or who have a serum creatinine > 2 mg/dL. Even stronger contraindications include prior cerebrovascular accident, myocardial infarction, or cardiac failure.
DIAGNOSIS AND EVALUATION IN PREGNANCY
Classification of the hypertensive disorders complicating pregnancy is discussed in Chapter 40 (p. 728). Women are diagnosed with chronic hypertension if it is documented to precede pregnancy or if hypertension is identified before 20 weeks’ gestation. In some women without overt chronic hypertension, there is a history of repeated pregnancies complicated by gestational hypertension with or without the preeclampsia syndrome. Each is a risk marker for latent chronic hypertension, and this is especially so for preeclampsia, especially early-onset preeclampsia. In many ways, gestational hypertension is analogous to gestational diabetes in that such women have a chronic hypertensive diathesis, in which heredity plays a major role (Chap. 40, p. 769).
Although uncommon, secondary causes of hypertension are always a possibility in these women. Thus, consideration is given to an underlying pheochromocytoma, connective-tissue disease, Cushing syndrome, chronic renal disease, and myriad other causes. That said, most pregnant women with antecedent hypertension will have uncomplicated disease. As discussed above, some women—especially those with long-term or untreated hypertension—have complications that increase the risk of adverse pregnancy events. Thus, if not already accomplished, assessment during pregnancy is done for the cardiovascular system, the kidneys, and the cerebrovascular circulation.
Associated Risk Factors
Several factors increase the likelihood that pregnant women will have chronic hypertension. Three of those most frequently cited are ethnicity, obesity, and diabetes. As previously discussed, chronic hypertension has a population incidence that is highest in black and lower in white and Mexican-American women (Kotchen, 2012). Related to this, hundreds of blood pressure-related phenotypes and genomic regions have been identified, including candidate genes for preeclampsia and chronic hypertension (Cowley, 2006; Lévesque, 2004).
The metabolic syndrome with superimposed preeclampsia is a risk marker for persistent hypertension postpartum (Spaan, 2012). This is not surprising because obesity may increase the prevalence of hypertension tenfold, and it is an important factor predisposing to chronic hypertension (Chap. 48, p. 963). In addition, obese women are more likely to develop superimposed preeclampsia. Diabetes is also prevalent in chronically hypertensive women, and its interplay with obesity and preeclampsia is overwhelming. In the study of more than 56 million births cited above, the most common comorbidities associated with chronic hypertension were pregestational diabetes—6.6 percent, thyroid disorders—4.1 percent, and collagen-vascular disease—0.6 percent (Bateman, 2012). Similar comorbidities were described by Cruz and associates (2011).
Effects of Pregnancy on Chronic Hypertension
Blood pressure falls in early pregnancy in most women with chronic hypertension. It rises again during the third trimester (Fig. 50-1). According to studies by Tihtonen and coworkers (2007), women with chronic hypertension have persistently elevated vascular resistance and possibly a reduced intravascular volume increase. There is no doubt that adverse outcomes in these women are dependent largely on whether superimposed preeclampsia develops. This may be related to observations reported by Hibbard and colleagues (2005, 2014) that arterial mechanical properties are most marked in women with superimposed preeclampsia.
FIGURE 50-1 Mean systolic and diastolic blood pressures across pregnancy in 107 untreated chronically hypertensive women (yellow) compared with blood pressures across pregnancy in 4589 healthy nulliparous women (blue). (Data from August, 2014; Levine, 1997; Sibai, 1990a.)
ADVERSE PREGNANCY EFFECTS
Chronic hypertension is associated with several adverse maternal and perinatal outcomes listed in Table 50-3. The recurring theme is that these are directly related to severity and duration of hypertension before pregnancy and whether superimposed preeclampsia develops, especially early in gestation. In women with mild chronic hypertension, outcomes are also related to blood pressure levels during pregnancy (Ankumah, 2013).
TABLE 50-3. Some Adverse Effects of Chronic Hypertension on Maternal and Perinatal Outcomes
Maternal Morbidity and Mortality
Most women whose hypertension is well controlled with monotherapy before pregnancy will do well. Even these women, however, are at increased risk for adverse outcomes. Complications are more likely with severe baseline hypertension and especially with documented end-organ damage (Czeizel, 2011; Odibo, 2013). In a study of pregnancy outcomes in nearly 30,000 chronically hypertensive women, Gilbert and associates (2007) reported markedly increased maternal morbidity including stroke, pulmonary edema, and renal failure. These observations were verified in the report from the Nationwide Patient Sample of more than 56 million deliveries by Bateman and colleagues (2012). Complications of hypertension included stroke—2.7 per 1000, acute renal failure—5.9 per 1000, pulmonary edema—1.5 per 1000, mechanical ventilation—3.8 per 1000, and in-house maternal mortality—0.4 per 1000. The contribution of hypertension to pregnancy-related strokes is discussed in Chapter 60 (p. 1191) and to hypertensive and idiopathic peripartum hypertensive cardiomyopathy in Chapter 49 (p. 988).
Pregnancy-aggravated hypertension may be due to gestational hypertension or to superimposed preeclampsia. In either instance, blood pressures can be dangerously elevated. As emphasized by Clark and Hankins (2012), systolic pressure ≥ 160 mm Hg or diastolic pressure ≥ 110 mm Hg will rapidly cause renal or cardiopulmonary dysfunction or cerebral hemorrhage. With superimposed severe preeclampsia or eclampsia, the maternal prognosis is poor unless the pregnancy is ended. Placental abruption is a common and serious complication (Chap. 41, p. 793). In addition to hypertensive heart failure mentioned above, aortic dissection has been described by Weissman-Brenner and coworkers (2004) and is discussed in Chapter 49 (p. 992).
Chronic hypertension has been associated with a fivefold risk for maternal death (Gilbert, 2007). This is emphasized by the report by Berg (2010) describing 4693 pregnancy-related deaths in the United States from 1998 through 2005. Hypertensive disorders, including chronic hypertension and preeclampsia syndrome, accounted for 12.3 percent of these deaths. Undoubtedly related were other causes of death such as cardiovascular conditions—12.4 percent, cerebrovascular conditions—6.3 percent, and cardiomyopathy—11.5 percent. Moodley (2007) reported similar findings with 3406 maternal deaths from South Africa. Interestingly, Sibai and associates (2011) reported that chronically hypertensive women with a history of preeclampsia were not at higher risk for complications compared with hypertensive women without such a history.
Because there is no precise definition of superimposed preeclampsia in women with chronic hypertension, the reported incidence is variable. The risk is directly related to the severity of baseline hypertension. In a Maternal-Fetal Medicine Units Network trial, Caritis and coworkers (1998) identified superimposed preeclampsia in 25 percent. It was 29 percent in the California database study cited above (Yanit, 2012). According to the American College of Obstetricians and Gynecologists (2012), mild chronic hypertension has a 20-percent incidence for superimposed preeclampsia, whereas with severe hypertension, it is 50 percent. August and colleagues (2014) posit that this predilection may be because of similarities of genetic, biochemical, and metabolic abnormalities. In the study cited above, a history of superimposed preeclampsia did not increase the risk for recurrence, however, it was a marker for increased preterm delivery (Sibai, 2011).
Thus far, prognostic and predictive tests for superimposed preeclampsia have been disappointing when used clinically (American College of Obstetricians and Gynecologists, 2012; Conde-Agudelo, 2014; Zeeman, 2003). For example, Di Lorenzo and colleagues (2012) studied serum markers for Down syndrome and reported a sensitivity of 60 percent with a 20-percent false-positive rate. Similar results were found using antiangiogenic factors to discriminate among chronic hypertension, gestational hypertension, and preeclampsia (Sibai, 2008; Woolcock, 2008). According to Elovitz and coworkers (2013), microRNA assays may prove valuable as predictors of pregnancy-associated hypertension. This subject is discussed further in Chapter 40 (p. 747).
Prevention of Superimposed Preeclampsia
Trials of various substances to prevent preeclampsia in women with chronic hypertension have generally been disappointing. Low-dose aspirin has been evaluated most frequently. In the Network study by Caritis and associates (1998) cited above, the incidence of superimposed preeclampsia, fetal-growth restriction, or both was similar in women given low-dose aspirin or placebo. That said, Duley (2007) and Meads (2008) and their colleagues performed Cochrane reviews and found that low-dose aspirin was beneficial in some high-risk women. Minimal benefits were also found from a metaanalysis (Askie, 2007). To the contrary, however, the PARIS Collaborative Group (2007) reviewed individual data from 33,897 pregnant women enrolled in 33 randomized trials of low-dose aspirin and reported that women with chronic hypertension derived no benefits.
Spinnato and coworkers (2007) randomly assigned 311 women with chronic hypertension to antioxidant treatment with vitamins C and E or to a placebo. A similar number in both groups developed preeclampsia—17 versus 20 percent, respectively.
There seems to be no doubt that chronic hypertension increases the risk two- to threefold for premature placental separation (American College of Obstetricians and Gynecologists, 2012). As discussed in Chapter 41 (p. 793), the overall risk is one in 200 to 300 pregnancies, and this is increased to 1 in 60 to 120 pregnancies in women with chronic hypertension (Ananth, 2007; Cruz, 2011; Madi, 2012; Tuuli, 2011). This risk is increased further if the woman smokes or if she develops superimposed preeclampsia. The risk is highest with severe hypertension, and Vigil-De Gracia and colleagues (2004) reported it to be 8.4 percent. Most abruptions are in women with worsening gestational hypertension or superimposed preeclampsia. From the Norwegian Birth Registry, supplemental folic acid slightly decreased the abruption incidence in women with chronic hypertension (Nilsen, 2008).
Perinatal Morbidity and Mortality
From the foregoing, it is not surprising that almost all adverse perinatal outcomes are increased in women with chronic hypertension. Some of those from a Network study are shown in Figure 50-2. The increasing incremental adverse effects of rising blood pressure levels are apparent. Interestingly, Bánhidy and colleagues (2011) have provided data suggesting that severe hypertension may be associated with fetal esophageal atresia or stenosis. As expected, for the entire group of women, those who developed preeclampsia had substantially increased adverse outcome rates compared with those without preeclampsia.
FIGURE 50-2 Perinatal outcomes in 759 women with midrange chronic hypertension enrolled in a Maternal-Fetal Medicine Units Network study (Ankumah, 2013).
The stillbirth frequency is substantively greater in most reports (Chap. 35, p. 663). In the Nationwide Patient Sample study, the stillbirth rate was 15.1 per 1000 births (Bateman, 2012). This is similar to the frequency of 18 per 1000 from a Norwegian study (Ahmad, 2012). The rate was increased two- to threefold in the California database study by Yanit and associates (2012).
Low-birthweight infants are common and due to preterm delivery, fetal-growth restriction, or both. In the California study, a fourth of fetuses were delivered preterm (Yanit, 2012). This and other studies attest to the increased risk for fetal-growth restriction, and the incidence averages 20 percent. Zetterström and coworkers (2006) reported a 2.4-fold risk for fetal-growth restriction in 2754 chronically hypertensive Swedish women compared with the risk in normotensive women. Broekhuijsen and associates (2012) found a 1.3-fold increased risk for 1609 Dutch nulliparas with chronic hypertension compared with that in normotensive controls. Fetal-growth dysfunction is more likely in the chronically hypertensive women who develop superimposed preeclampsia. In one study, Chappell and colleagues (2008) reported an almost 50-percent incidence of growth-restricted fetuses born to women with superimposed preeclampsia compared with only 21 percent in women without preeclampsia. Because worsening hypertension frequently mandates preterm delivery, neonates born to these women have a correspondingly high rate of intensive-care nursery admission.
All of these aforementioned adverse perinatal effects of chronic hypertension contribute to the increased perinatal mortality rate, which is three- to fourfold higher in pregnancies complicated by chronic hypertension compared with those of normotensive women (American College of Obstetricians and Gynecologists, 2012). In the Network study shown in Figure 50-2, the perinatal death rate was 31 per 1000 with mild hypertension, 72 per 1000 with moderate disease, and 100 per 1000 in women with severe chronic hypertension. Again as expected, the highest rates are in women who develop superimposed preeclampsia, for whom the risk doubled from 4 to 8 percent. And, if diabetes coexists with chronic hypertension, then preterm delivery, fetal-growth restriction, and perinatal mortality rates are increased even more (Gonzalez-Gonzalez, 2008; Yanit, 2012).
MANAGEMENT DURING PREGNANCY
The diagnosis of chronic hypertension in pregnancy should be confirmed. For example, Brown and associates (2005) reported “white-coat” hypertension in a third of 241 women diagnosed in early pregnancy. Within this third, pregnancy outcomes were good, and only 8 percent developed preeclampsia.
Management goals for chronic hypertension include reductions of adverse maternal or perinatal outcomes just discussed. Treatment is targeted to prevent moderate or severe hypertension and to delay or ameliorate pregnancy-aggravated hypertension. To some extent, these goals can be achieved pharmacologically. Blood-pressure self-monitoring is encouraged, but for accuracy, automated devices must be properly calibrated (Brown, 2004; Staessen, 2004). Personal health modification includes dietary counseling and reduction of behaviors such as tobacco, alcohol, cocaine, or other substance abuse (see Table 50-2).
Blood Pressure Control
Women with severe hypertension must be treated for maternal neuro-, cardio-, and renoprotection regardless of pregnancy status (American College of Obstetricians and Gynecologists, 2012). This includes women with prior adverse outcomes such as cerebrovascular events, myocardial infarction, and cardiac or renal dysfunction. We agree with the philosophy of beginning antihypertensive treatment in otherwise healthy pregnant women with persistent systolic pressures > 150 mm Hg or diastolic pressures of 95 to 100 mm Hg or greater (August, 2014; Working Group Report, 2000). With end-organ dysfunction, treatment of diastolic pressures ≥ 90 mm Hg is reasonable to mitigate further organ damage.
There are only sparse data indicating salutary effects on pregnancy outcomes with simply lowering blood pressure. These studies are relatively small and have widely varying inclusion and outcome criteria. In a Cochrane review of 46 of these studies that included a total of 4282 women, Abalos and coworkers (2007) confirmed that the risk for severe hypertension was lowered with therapy. There were, however, no differences in the frequencies of superimposed preeclampsia, eclampsia, abruption, preterm birth, fetal-growth restriction, or perinatal or maternal mortality. These studies do attest to the apparent safety of antihypertensive therapy except for angiotensin-converting enzyme (ACE) inhibitors and angiotensin-receptor blockers (Chap. 12, p. 247). As emphasized by the Working Group Report (2000), there is a need for further trials in chronically hypertensive women.
During the past decade, the concept of tight control of blood pressure has been espoused as a means of optimizing maternal and perinatal outcomes. Such control is compared with that of glycemic control for management of the pregnant diabetic. In one study, El Guindy and Nabhan (2008) randomly assigned 125 pregnant women with mild chronic hypertension or gestational hypertension to rigid versus less strict blood pressure control. More women in the latter group developed severe hypertension, they had more hospital admissions, and they were delivered of infants at a lower mean gestational age than the tight-control group. Other than these preliminary observations, there are limited data concerning this type of treatment.
As concluded by the American College of Obstetricians and Gynecologists (2012), treatment during pregnancy has included every drug class, but there still is limited information regarding safety and efficacy (Czeizel, 2011; Podymow, 2011). Although many studies indicate increased perinatal adverse effects in treated women, it is still not known whether this is due to cause or effect (Orbach, 2013). The following summary of antihypertensive drugs is abstracted from several sources, including the 2014 Physicians’ Desk Reference. Many of these drugs are also discussed throughout Chapter 12 (p. 247) and have been recently reviewed by Umans and associates (2014).
Thiazide diuretics are sulfonamides, and these were the first drug group used to successfully treat chronic hypertension (Beyer, 1982). These agents and loop-acting diuretics such as furosemide are commonly used in nonpregnant hypertensives. In the short term, they provide sodium and water diuresis with volume depletion. But with time, there is sodium escape, and volume depletion is corrected. Some aspect of lowered peripheral vascular resistance likely contributes to their effectiveness in reducing long-term morbidity (Umans, 2014; Williams, 2001).
Thiazide drugs may be mildly diabetogenic, and expected volume expansion may be curtailed in pregnant women. Sibai and colleagues (1984) showed that plasma volume expanded only about 20 percent over time in hypertensive pregnant women who continued diuretic therapy compared with a 50-percent expansion in women who discontinued treatment. Although perinatal outcomes were similar in these women, such concerns have led to practices of withholding diuretics as first-line therapy, particularly after 20 weeks (Working Group Report, 2000). Even so, in a Cochrane review, Churchill and associates (2007) reported no differences in perinatal outcomes in 1836 nonhypertensive women randomly assigned to a thiazide diuretic or placebo for primary preeclampsia prevention. Overall, thiazide diuretics are considered safe in pregnancy (Briggs, 2011; Umans, 2014).
This was the second class of effective antihypertensives. Peripherally acting β-adrenergic receptor blockers cause a generalized decrease in sympathetic tone. Examples are propranolol, metoprolol, and atenolol. Labetalol is a commonly used α/β-adrenergic blocker. Some adrenergic-blocking drugs act centrally by reducing sympathetic outflow to effect a generalized decreased vascular tone. Some of these are clonidine and α-methyldopa. The drugs most frequently used in pregnancy to treat hypertension are methyldopa or a β- or α/β-receptor blocking agent.
Hydralazine relaxes arterial smooth muscle and has been used parenterally for decades to safely treat severe peripartum hypertension (Chap. 40, p. 767). Oral hydralazine monotherapy for chronic hypertension is not generally used because of its weak antihypertensive effects and resultant tachycardia. It may be an effective adjunct for long-term use with other antihypertensives, especially if there is chronic renal insufficiency. In the study by Su and coworkers (2013), vasodilator treatment of chronically hypertensive women was associated with a twofold increase in low-birthweight and growth-restricted neonates.
Calcium-Channel Blocking Agents
These drugs are divided into three subclasses based on their modification of calcium entry into cells and interference with binding sites on voltage-dependent calcium channels. Common agents include nifedipine—a dihydropyridine, and verapamil—a phenylalkyl amine derivative. These agents have negative inotropic effects and thus can worsen ventricular dysfunction and congestive heart failure. Theoretically, they may potentiate the actions of magnesium sulfate that is given for eclampsia neuroprophylaxis. There is minimal published experience with these agents during pregnancy (Abalos, 2007). That said, calcium-channel blockers appear to be safe for therapy for chronic hypertension (Briggs, 2011; Podymow, 2011; Umans, 2014).
The safety of acute peripartum nifedipine treatment has been questioned. The drug is used by some for rapid control of severe peripartum hypertension, and it is also widely used for tocolysis in preterm labor (Chap. 42, p. 853). Nifedipine for tocolysis should not be combined with intravenous β-agonists (Oei, 2006). Adverse outcomes reported in women given nifedipine for tocolysis or severe gestational hypertension include myocardial infarction and pulmonary edema (Abbas, 2006; Bal, 2004; Oei, 1999; Verhaert, 2004). Severe maternal hypotension with resultant fetal compromise necessitating cesarean delivery and fetal death have also been reported (Johnson, 2005; Kandysamy, 2005; van Veen, 2005).
Angiotensin-Converting Enzyme Inhibitors
These drugs inhibit the conversion of angiotensin-I to the potent vasoconstrictor angiotensin-II. They can cause severe fetal malformations when given in the second and third trimesters. These include hypocalvaria and renal dysfunction (Chap. 12, p. 247). Some preliminary studies have also suggested teratogenic effects, and because of this, they are not recommended during pregnancy (Briggs, 2011; Podymow, 2011).
Angiotensin-receptor blockers act in a similar manner. But, instead of blocking the production of angiotensin-II, they inhibit binding to its receptor. They are presumed to have the same fetal effects as ACE inhibitors and thus are also contraindicated.
Antihypertensive Treatment in Pregnancy
As discussed, continuation of prepregnancy antihypertensive treatment when women become pregnant is debated. Although blood-pressure reduction is certainly beneficial to the mother long term, it at least theoretically can decrease uteroplacental perfusion. According to older observational reports, in general, most pregnancy outcomes in women with mild to moderate hypertension were good without treatment and unless superimposed preeclampsia developed (Chesley, 1978; Umans, 2014).
There are no large randomized trials to settle the questions surrounding empirical treatment. Abalos and associates (2007) performed a Cochrane database review of 46 small trials enrolling a total of 4282 women. These studies varied widely in definitions of hypertension severity, use of placebos, gestational age at entry, and the type of drug(s) used. The salient results are shown in Table 50-4. These led the investigators to conclude again that treatment reliably lowered risk for severe hypertension during pregnancy.
TABLE 50-4. Comparison of Pregnancy Outcomes in Women with and without Antepartum Treatment for Mild to Moderate Chronic Hypertension
This Cochrane review does raise concern for fetal-growth restriction with β-blocking drugs. It is not resolved, however, because diminished placental perfusion secondary to lowered maternal blood pressure is confounded by the fact that worsening blood pressure itself is associated with abnormal fetal growth. Some also posit that the drugs have a direct fetal action (Umans, 2014). In two of the larger randomized trials, however, the incidence of growth restriction was not altered in women randomly assigned to treatment (Gruppo di Studio Ipertensione in Gravidanza, 1998; Sibai, 1990a).
Severe Chronic Hypertension
Most data suggest that the prognosis for pregnancy outcome with chronic hypertension is dependent on the severity of disease antedating pregnancy. This may be related to findings that many women with severe hypertension have renal disease—as either cause or effect (Cunningham, 1990). One report by Sibai and coworkers (1986) described outcomes from 44 pregnancies in women whose blood pressure at 6 to 11 weeks was ≥ 170/110 mm Hg. All were given oral treatment with α-methyldopa and hydralazine to maintain pressures < 160/110 mm Hg. If dangerous hypertension developed, then the woman was hospitalized and treated with parenteral hydralazine. Of the 44 pregnancies, superimposed preeclampsia developed in half, and all adverse perinatal outcomes were in this group. Moreover, all neonates of women in the latter group were delivered preterm, nearly 80 percent were also growth restricted, and they had a 48-percent perinatal mortality rate. Conversely, those women with severe chronic hypertension who did not develop superimposed preeclampsia had reasonably good outcomes. There were no perinatal deaths, and only 5 percent of fetuses were growth restricted.
Recommendations for Therapy in Pregnancy
The Working Group on High Blood Pressure in Pregnancy (2000) concluded that there were limited data from which to draw conclusions concerning any decision to treat mild chronic hypertension in pregnancy. As discussed on page 1005, the Group did recommend empirical therapy in women whose blood pressures exceed threshold levels of 150 to 160 mm Hg systolic or 100 to 110 mm Hg diastolic or in women with target-organ damage such as left ventricular hypertrophy or renal insufficiency. They also concluded that early treatment of hypertension would probably reduce subsequent hospitalization rates during pregnancy.
Some women will have persistently worrisome hypertension despite usual therapy (Samuel, 2011; Sibai, 1990a). In these women, primary attention is given to the likelihood of pregnancy-aggravated hypertension, with or without superimposed preeclampsia. Other possibilities include inaccurate blood-pressure measurements, suboptimal treatment, and antagonizing substances (Moser, 2006). Causes reported in nonpregnant cohorts were nonsteroidal antiinflammatory drugs including cyclooxygenase-2 inhibitors and alcohol consumption (Sowers, 2005; Xin, 2001).
Pregnancy-Aggravated Hypertension or Superimposed Preeclampsia
As discussed, the incidence of superimposed preeclampsia for women with chronic hypertension varies depending on the study population and hypertension severity. A reasonable average is 20 to 30 percent. The incidence of superimposed preeclampsia may be underreported if the diagnosis is based solely on urine protein dipstick testing (Gangaram, 2005; Lai, 2006). Importantly, in approximately half of chronically hypertensive women, superimposed preeclampsia develops before 37 weeks (Chappell, 2008).
The diagnosis may be difficult to make, especially in women with hypertension who have underlying renal disease with chronic proteinuria (Cunningham, 1990). As discussed in Chapter 40 (p. 730), conditions that support the diagnosis of superimposed preeclampsia include worsening hypertension, new-onset proteinuria, neurological symptoms such as severe headaches and visual disturbances, generalized edema, oliguria, and certainly, convulsions or pulmonary edema. Supporting laboratory abnormalities are increasing serum creatinine levels, thrombocytopenia, serum hepatic transaminase elevations, or the triad of HELLP—hemolysis, elevated liver enzyme levels, low platelet count—syndrome. For women with chronic hypertension and superimposed preeclampsia with severe features, magnesium sulfate for maternal neuroprophylaxis is recommended (American College of Obstetricians and Gynecologists, 2013).
Some pregnant women with chronic hypertension have worsening hypertension with no other findings of superimposed preeclampsia. This is most commonly encountered near the end of the second trimester. In the absence of other supporting criteria for superimposed preeclampsia, including fetal-growth restriction or decreased amnionic fluid volume, this likely represents the higher end of the normal blood-pressure curve shown in Figure 50-1. In such women, if preeclampsia can be reasonably excluded, then it is reasonable to begin or to increase the dose of antihypertensive therapy.
Women with well-controlled chronic hypertension and who have no complicating factors can generally be expected to have a good pregnancy outcome. Because even those with mild hypertension have an increased risk of superimposed preeclampsia and fetal-growth restriction, serial antepartum assessment of fetal well-being is recommended by many. That said, according to the American College of Obstetricians and Gynecologists (2012), with the exception of sonographic fetal-growth monitoring, there are no conclusive data to address either benefit or harm associated with various antepartum surveillance strategies.
Given that half of these women develop superimposed preeclampsia before term, considerations for expectant management may be reasonable in some cases. In a study from Magee-Women’s Hospital, 41 carefully selected women with a median gestational age of 31.6 weeks were expectantly managed (Samuel, 2011). Despite liberal criteria to mandate delivery, 17 percent developed either placental abruption or pulmonary edema. The latency period was extended by a mean of 9.7 days, and there were no perinatal deaths. These investigators recommended randomized trials to study expectant management.
For chronically hypertensive women who have complications such as fetal-growth restriction or superimposed preeclampsia, the decision to deliver is made by clinical judgment. The route of delivery is dictated by obstetrical factors. Certainly, most women with superimposed severe preeclampsia are better delivered even when there is a markedly preterm pregnancy. These women are at increased risk for placental abruption, cerebral hemorrhage, and peripartum heart failure (Cunningham, 1986, 2005; Martin, 2005).
For women with mild to moderate chronic hypertension who continue to have an uncomplicated pregnancy, there are at least two options for timing of delivery (American College of Obstetricians and Gynecologists, 2012). The first is delivery at term, that is, ≥ 39 completed weeks. Another option is from consensus committee findings by Spong and associates (2011), which recommend consideration for delivery at 38 to 39 weeks, that is, ≥ 37 completed weeks. A trial of labor induction is preferable, and many of these women respond favorably and will be delivered vaginally (Alexander, 1999; Atkinson, 1995).
For women with severe preeclampsia, peripartum management is the same as described in Chapter 40 (p. 761). Epidural analgesia for labor and delivery is optimal with the caveat that it is not given to treat hypertension (Lucas, 2001). That said, women with severe superimposed preeclampsia are more sensitive to the acute hypotensive effects of epidural analgesia (Vricella, 2012). Magnesium sulfate neuroprophylaxis is initiated for prevention of eclampsia (Alexander, 2006). Severe hypertension—diastolic blood pressure ≥ 110 mm Hg or systolic pressure ≥ 160 mm Hg—is treated with either intravenous hydralazine or labetalol. Some prefer to treat women with a diastolic pressure of 100 to 105 mm Hg. Vigil-De Gracia and colleagues (2006) randomized 200 women to intravenous hydralazine or labetalol to acutely lower severe high blood pressure in pregnancy. Outcomes were similar except for significantly more maternal palpitations and tachycardia with hydralazine and significantly more neonatal hypotension and bradycardia with labetalol.
In most respects, postpartum observation, prevention, and management of adverse complications are similar in women with severe chronic hypertension and in those with severe preeclampsia–eclampsia (Chap. 40, p. 767). For persistent severe hypertension, consideration is given for a cause such as pheochromocytoma or Cushing disease (Sibai, 2012). And because of chronic end-organ damage, certain complications are more common. These include cerebral or pulmonary edema, heart failure, renal dysfunction, or cerebral hemorrhage, especially within the first 48 hours after delivery (Martin, 2005; Sibai, 1990b). These frequently are preceded by sudden increases—“spikes”—of mean arterial blood pressure, especially the systolic component (Cunningham, 2000, 2005).
Following delivery, as maternal peripheral resistance increases, left ventricular workload also increases. This rise is further aggravated by appreciable and pathological amounts of interstitial fluid that are mobilized to be excreted as endothelial damage from preeclampsia resolves. In these women, sudden hypertension—either moderate or severe—exacerbates diastolic dysfunction, causes systolic dysfunction, and leads to pulmonary edema (Cunningham, 1986; Gandhi, 2001). Prompt hypertension control, along with furosemide-evoked diuresis, usually quickly resolves pulmonary edema. It is possible in many women to forestall this by the administration of intravenous furosemide to augment the normal postpartum diuresis. Daily weights are helpful in this regard. On average, a woman should weigh 15 pounds less immediately after delivery. Excessive extracellular fluid can be estimated by subtracting the postpartum weight from the predelivery weight—if not determined on hospital admission, the weight at the last prenatal visit provides a relatively accurate estimate. In one study, 20-mg oral furosemide given daily to postpartum women with severe preeclampsia aided blood-pressure control (Ascarelli, 2005).
Women with chronic hypertension have special considerations for contraceptive and sterilization choices. These are discussed in detail throughout Chapters 38 and 39. These women are also at ultimate high risk for lifetime cardiovascular complications, especially when accompanied by diabetes, obesity, and the metabolic syndrome.
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