Physiology of Pregnancy

Pregnancy is characterized by marked vascular and hemodynamic changes. Early in pregnancy, systemic vasodilation leads to decreased systemic vascular resistance and increased arterial compliance [1]. These changes are evident by 6 weeks of gestation [2]. These primary vascular changes lead to several other hemodynamic changes. Diastolic blood pressure falls by an average of 5 mmHg by the late second trimester [3]. Sympathetic activity is increased, reflected in a 15 % increase in heart rate [4]. The combination of increased heart rate and decreased afterload leads to a large increase in cardiac output by the early first trimester [5], which peaks at 50 % above pre-pregnancy levels in the third trimester [4, 6].

The renin–aldosterone–angiotensin system is activated in pregnancy [3, 7]. This is driven by several factors, including extrarenal renin secretion by the ovaries and maternal decidua, a stimulatory effect of estrogen on renal renin release, and primary vasodilation. This leads to salt and water retention. Increased renal interstitial compliance may also contribute to volume retention, via an attenuation of the renal pressure natriuretic response [8]. Total body water increases by 6–8 l, leading to both plasma volume and interstitial volume expansion—hence most women have demonstrable clinical edema at some point during pregnancy. There is also cumulative retention of about 1000 mmol of sodium distributed between the maternal extracellular compartments and the fetus [9]. The plasma volume increases out of proportion to the red blood cell mass, leading to mild physiologic anemia.

The mechanism of vasodilatation in pregnancy is not fully understood. The decrease in systemic vascular resistance is only partially attributable to the presence of the low-resistance circulation in the pregnant uterus, as blood pressure and systemic vascular resistance are noted to fall before this system is well developed. Reduced vascular responsiveness to vasopressors such as angiotensin 2 and vasopressin is well documented [10–12].

The hormone relaxin contributes to the global vasodilatory response [13]. Relaxin is a 6-kDa peptide hormone, structurally similar to insulin. Relaxin is released predominantly from the corpus luteum, rising early in gestation in response to human chorionic gonadotrophin (hCG) . In the renal circulation, relaxin increases endothelin and nitric oxide production, leading to generalized renal vasodilation and decreased renal afferent and efferent arteriolar resistance [14, 15]. This increases both renal blood flow and glomerular filtration rate, despite high levels of sympathetic activity, renin, angiotensin II, and aldosterone.

Classification of Hypertensive Pregnancy

Hypertension in pregnancy is classified into four categories: preeclampsia-eclampsia, chronic hypertension, chronic hypertension with superimposed preeclampsia , and gestational hypertension . Figure 6.1 outlines the clinical approach to diagnostic evaluation of women with hypertension in pregnancy. The diagnosis of chronic hypertension in pregnancy is based on a history of hypertension prior to pregnancy, or a blood pressure above 140/90 mmHg prior to 20 weeks gestation. Gestational hypertension and preeclampsia are characterized by the new onset of hypertension after 20 weeks gestation, and hypertension resolves after delivery in most cases. Distinguishing chronic hypertension from gestational hypertension /preeclampsia based on the gestational age of the first recorded blood pressure elevation can be subject to pitfalls, however. Some women lack consistent pre-pregnancy and prenatal care, and early pregnancy blood pressure readings are not available. The physiologic dip in blood pressure in the second trimester, which nadirs at about 28 weeks gestation [3], can mask the presence of chronic hypertension in mid-pregnancy. In cases of diagnostic uncertainty, the failure of blood pressure to normalize postpartum confirms the diagnosis of chronic hypertension. The section “Diagnosis of Preeclampsia and Superimposed Preeclampsia” includes a detailed discussion of regarding diagnosis of preeclampsia and superimposed preeclampsia .

Fig. 6.1
figure 1

Diagnostic evaluation of hypertension in pregnancy

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Chronic Hypertension in Pregnancy

The prevalence of chronic hypertension in pregnancy in the USA is increasing, from 1.0 % in 1995–1996 to 1.76 % in 2007–2008 [16]. Hypertension in pregnancy is more common in women of advanced maternal age and black race [17]. It is associated with several medical comorbidities, including obesity, diabetes mellitus, chronic renal disease, thyroid disease, and collagen vascular disease [16].

There are several goals of care in the assessment and management of chronic hypertension in women who are pregnant or planning pregnancy. First, the diagnosis should be established, including assessment for secondary causes of hypertension and end-organ damage. The pregnancy risks (see section “Renovascular Hypertension”) should be communicated to the patient. The blood pressure should be managed, including the appropriate use of antihypertensive medications that are safe in pregnancy. Strategies to reduce the risk of preeclampsia , including the use of low-dose aspirin, should be considered. The patient should be monitored for the development of preeclampsia . These goals of care will be reviewed in detail in the following sections .

Secondary Hypertension

The prevalence of secondary causes of hypertension in pregnancy is unknown, but is probably similar to that seen in healthy non-pregnant hypertensive women of childbearing age. In one retrospective study, 25 % of women in whom hypertension failed to resolve 6 months following preeclampsia were found to have a secondary cause of hypertension (primary aldosteronism and renovascular hypertension) [18]. Findings suggestive of a secondary cause of hypertension include severe or refractory hypertension, onset of hypertension at young age (<35 years), absence of family history, and the presence of hypokalemia or palpitations. Secondary hypertension should also be suspected after preeclampsia , when blood pressure fails to resolve following delivery.

Primary Aldosteronism

A population-based study in the USA reported a diagnosis of primary aldosteronism (PA) in 0.02 % of pregnancies with chronic hypertension [16], and fewer than 50 cases of primary aldosteronism in pregnancy have been described in the literature [19]. However, its true incidence is probably much higher, as primary aldosteronism is estimated to affect up to 10 % of non-pregnant patients with chronic hypertension.

Pregnancy is associated with changes in progesterone and the renin–angiotensin–aldosterone system that provide challenges to diagnosis and affect the clinical course of PA. Progesterone, which is increased throughout pregnancy, acts as a competitive antagonist to aldosterone at the mineralocorticoid receptor in the collecting tubule [20]. This mitigates the hypokalemia and hypertension that might be expected from the high plasma aldosterone concentrations of normal pregnancy. For women with primary aldosteronism, the antagonistic effect of progesterone at the mineralocorticoid receptor sometimes leads to improvement in hypertension and hyperkalemia. However, such remission is not universal and women with primary aldosteronism may have a pregnancy-induced exacerbation of hypertension and hypokalemia [21].

The diagnosis of PA should be considered in all hypertensive women who are pregnant or considering pregnancy, particularly if hypokalemia is present. Screening and diagnosis of PA during pregnancy can be challenging owing to the physiologic activation of the renin–angiotensin–aldosterone system in pregnancy. In normal pregnancy, plasma renin activity and aldosterone concentrations are typically five to tenfold higher than in the non-pregnant state [3]. The major indicator of the presence of PA in pregnancy is suppression of the plasma renin activity [19]. The aldosterone–renin ratio is useful when abnormal, however false negatives can occur, primarily due to pregnancy-induced stimulation of renin production [22]. Standard suppression testing with salt loading is not advisable due to potential exacerbation of hypertension, and adrenal vein sampling during pregnancy is not recommended due to the requisite radiation exposure.

Most cases of PA in pregnancy result from an aldosterone-producing adenoma (APA) [23]. Imaging with MRI or ultrasound is safe. Since non-functional adenomas are rare in women under 50, the diagnosis of APA vs. idiopathic adrenal hyperplasia (IAH) can often be made with imaging alone.

For women diagnosed with aldosterone-producing adenoma during pregnancy, there is little data to favor either immediate surgical adrenalectomy versus medical management until after delivery, though case reports have suggested success with both approaches. Conventional wisdom and expert opinion suggest surgical adrenalectomy is the optimal treatment in the first and early second trimesters, while medical management is often favored after fetal viability (23 weeks gestation) [24].

For women with IAH or APA who are managed medically, adequate blood pressure control is important, as most adverse pregnancy outcomes occur when blood pressure is uncontrolled [19]. Although there are several case reports of the use of spironolactone in pregnancy without adverse fetal effects, there is a theoretical risk of feminization and ambiguous genitalia in male fetuses and it is generally avoided in pregnancy. Eplerenone is a selective mineralocorticoid antagonist without clinically significant antiandrogenic effects. Animal studies have not shown any adverse fetal effects, and case reports describe its safe use in humans [24]. Hence, it is generally considered safe in pregnancy. Blood pressure targets are similar to those recommended in women with chronic primary hypertension in pregnancy: between 120/80 and 160/105 for women without evidence of target organ damage, and below 140/90 for women with evidence of target organ damage.

Renovascular Hypertension

Renovascular hypertension , particularly due to fibromuscular dysplasia, occasionally presents in pregnancy. Published experience with renovascular hypertension in pregnancy is limited to case series and case reports. Renovascular hypertension during pregnancy is characterized by extremely high vascular resistance, likely mediated by high circulating angiotensin 2 levels [25]. Unrecognized renovascular hypertension in pregnancy can present as accelerated hypertension, or early or severe preeclampsia [26]. Neonatal complications are common, including iatrogenic preterm delivery, placental abruption, and fetal demise. Computed tomography (CT) is usually avoided in pregnancy due to fetal radiation exposure, but renal ultrasound with Doppler and magnetic resonance (MR) angiography are both safe diagnostic studies.

With regard to treatment, there is little evidence to guide the decision regarding revasularization vs. medical management. ACE inhibitors and angiotensin receptor antagonists are contraindicated in pregnancy. If blood pressure can be controlled medically with agents suitable for pregnancy, intervention can be deferred until after delivery. Successful angioplasty and stent placement in the second and third trimesters of pregnancy has been described in patients with refractory hypertension [25, 27]. Radiation exposure should be minimized (<5 rad) or avoided, particularly during fetal organogenesis in the first trimester. Surgical repair during pregnancy is not a viable option, as cross clamping of the aorta may result in compromised placental perfusion.

Pheochromocytoma

Although rare, pheochromocytoma can be devastating when it first presents during pregnancy. This syndrome occasionally is unmasked during labor and delivery, when fatal hypertensive crisis can be triggered by labor and spinal anesthesia [28]. Maternal and neonatal morbidity and mortality are as high as 50 % when the diagnosis is made during labor or after delivery, but much lower (less than 15 %) when the diagnosis is made antepartum [29]. Since prenatal diagnosis significantly impacts both perinatal management and fetal and maternal mortality, the clinician needs to have a high level of suspicion for pheochromocytoma despite its low incidence .

Most women diagnosed with pheochromocytoma during pregnancy present in the second or third trimester with hypertension, palpitations, chest pain, pallor, sweating, nausea, or abdominal pain [29]. Paroxysmal, orthostatic, or severe hypertension with complications such as pulmonary edema and heart failure should lead to consideration of pheochromocytoma. Although standard diagnostic testing for pheochromocytoma has not been specifically validated in pregnancy, there are no significant alterations in catecholamine metabolism in pregnancy [23]. Thus, diagnosis is established as with non-pregnant individuals, with the measurement of abnormally high levels of plasma or urine catecholamines. Ultrasound and MRI can be used for imaging and tumor localization.

Once the diagnosis of pheochromocytoma has been established, management options include timely surgical removal or medical management with alpha-blockade until delivery. Among women diagnosed prior to 23 weeks, laparoscopic removal of the tumor during pregnancy appears to result in somewhat better neonatal outcomes in case reports and case series [29]. Alpha-adrenergic blockers such as phenoxybenzamine can be safely used in pregnancy. Beta-blockade, with labetalol or selective beta-blockers such as propranolol, should be initiated only after alpha-blockade is established. Sodium restriction should not be prescribed, especially in the weeks preceding surgical resection, as volume depletion increases the likelihood of postoperative hypotension [23].

If medical management until delivery is elected, labor and vaginal delivery should be avoided, as labor can trigger severe hypertensive crisis. Prenatal consultation should be obtained with an anesthesiologist with expertise in pheochromocytoma. Resection of the pheochromocytoma can be successfully performed at the time of cesarean section, or following delivery [30].

Genetic Causes of Hypertension and Hypokalemia

Glucocorticoid-remediable aldosteronism , or familial hyperaldosteronism type 1 (FH-1), results from a hybrid recombination of the 11beta-hydroxylase and aldosterone synthase genes. This leads to an abnormal aldosterone synthase protein in which aldosterone synthesis is regulated by adrenocorticotropin (ACTH) . Most women with FH-1 have stabilization or improvement in their hypertension and hyperkalemia during pregnancy [31]. This may be due to the antagonistic effects of progesterone on the mineralocorticoid receptor, as noted above. Progesterone also appears to directly inhibit both wild-type and chimeric aldosterone synthase genes, which may lead to amelioration of aldosterone production during pregnancy [32].

Geller syndrome is a rare cause of early onset hypertension arising from an activating mutation of the mineralocorticoid receptor. This results in inappropriate receptor activation by progesterone, and affected women develop a marked exacerbation of hypertension and hypokalemia in pregnancy, but without proteinuria or other features of preeclampsia [33]. Geller syndrome clinically resembles primary aldosteronism, but aldosterone levels are low-normal, with a normal aldosterone:renin ratio.

Cushing Syndrome

Hypercortisolism , or Cushing syndrome , is a relatively uncommon cause of hypertension in pregnancy. The clinical clues that usually suggest the diagnosis of Cushing syndrome may not be recognized, as they resemble symptoms of pregnancy itself: weight gain, edema, moon facies, abdominal striae, and glucose intolerance. Diagnosis is challenging, as both serum and urine cortisol are increased in normal pregnancy. The best initial screening test is a 24-hour urine collection for free cortisol, with cortisol excretion greater than 2 times the upper limit of normal strongly suggesting hypercortisolism [34]. Further details on the evaluation and management of Cushing syndrome in pregnancy are reviewed elsewhere [23].

Evaluation for End-Organ Damage

The presence of end-organ damage in women with chronic hypertension in pregnancy may impact the therapeutic blood pressure target (see Pharmacotherapy: Blood Pressure Target). Initial evaluation should always include measurement of a basic metabolic panel and quantification of urine protein. The presence of an elevated serum creatinine concentration or proteinuria can signify chronic kidney disease, which may be both a cause and a consequence of hypertension. If chronic kidney disease is present without apparent cause, renal ultrasound should be performed to evaluate for renal atrophy or polycystic kidneys. Proteinuria in early pregnancy in women with chronic hypertension is associated with an increased risk of intrauterine growth restriction and preterm delivery [35]. The detection of hypokalemia can indicate the presence of other secondary forms of hypertension, such as primary aldosteronism or renovascular hypertension. Early measurement of creatinine and proteinuria establishes a baseline, which can be helpful in the subsequent diagnosis of superimposed preeclampsia . Echocardiogram to evaluate for left ventricular hypertrophy should be considered, particularly in women with severe or longstanding hypertension .

Risk Assessment and Counseling

Women with chronic hypertension in pregnancy have an increased risk of several adverse pregnancy outcomes. Superimposed preeclampsia complicates approximately 25 % of these pregnancies [35], and risk is even higher when other preeclampsia risk factors such as diabetes, obesity, or prior preeclampsia are present (see Table 6.1) [36–47]. Hypertension is associated with an increased risk of premature delivery (23–35 %), intrauterine growth restriction (13–21 %), placental abruption (1–3 %), and perinatal mortality (3–5 %) [36]. However, most adverse fetal and neonatal outcomes occur in women with uncontrolled hypertension (diastolic blood pressure >110 mmHg), superimposed preeclampsia , or preexisting cardiovascular and renal disease (ACOG practice bulletin 2013) [48]. Although the duration and the severity of hypertension are correlated with perinatal morbidity and preeclampsia risk [49, 50], the treatment of hypertension with medications does not appear to prevent these adverse outcomes (see Sect. 6.3.4.3). Women with mild, uncomplicated chronic hypertension usually have obstetric outcomes comparable to the general population [17]. The presence of baseline proteinuria increases the risk of preterm delivery and IUGR, but not preeclampsia per se [35].

Table 6.1 Risk factors for preeclampsia
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Management of Chronic Hypertension in Pregnancy

Minimizing Preeclampsia Risk

The most effective measure for reducing preeclampsia risk among high-risk women, including those with chronic hypertension, is the early initiation of low-dose aspirin (pooled relative risk 0.76, 95 % CI, 0.62–0.95) [51]. When started early in pregnancy (before 16 weeks), aspirin may reduce the relative risk of preeclampsia by nearly 50 %[52]. Whether later initiation of aspirin provides benefit is less clear. Early ASA appears to be particularly effective in preventing severe and early onset preeclampsia , and also reduces risk of intrauterine growth restriction [52, 53]. Most trials demonstrating benefit used dosages of 60–100 mg/d [51]. Aspirin is typically held after 36 weeks gestation, to minimize theoretical risk of postpartum hemorrhage.

Daily calcium supplementation (1.5–2.0 g/d) appears to lower preeclampsia risk, particularly in populations with low baseline calcium intake and women at high preeclampsia risk [54]. Low-dose calcium (<1 g/d) may be similarly effective [55].

Other interventions to reduce preeclampsia risk have generally demonstrated little or no beneficial effect. These include vitamin C and vitamin E, bed rest, and dietary sodium restriction. A large randomized controlled trial is currently underway to assess the effect of folic acid supplementation on preeclampsia risk [56]. Vitamin D deficiency is associated with increased preeclampsia risk [57], but trials demonstrating a benefit of vitamin D supplementation are lacking. Neither sodium restriction nor diuretics appear to reduce the risk of preeclampsia [58, 59].

Non-Pharmacologic Interventions for Hypertension Control

In non-pregnant individuals , non-pharmacologic management strategies for hypertension include regular aerobic exercise, weight loss (for overweight and obese individuals), and a diet low in sodium and rich in fruits and vegetables (DASH diet). None of these interventions has been rigorously evaluated in pregnant women with hypertension. A meta-analysis of 15 observational studies found reduced preeclampsia risk with increasing levels of physical activity before and during pregnancy [60]. Hence, regular aerobic exercise is recommended for hypertensive pregnant women, so long as they are accustomed to exercise and their blood pressure is well controlled [61].

Weight loss during pregnancy is not recommended, even in obese individuals. The 2009 Institute of Medicine (IOM) guidelines specifies gestational weight gain targets based on pre-pregnancy body mass index [62]. Normal weight women are advised to gain between 25 and 35 lbs during the course of gestation; obese women (BMI ≥ 30 kg/m2) are advised to gain between 11 and 20 lbs. Weight gain in excess of these amounts is associated with an increased risk of preeclampsia and eclampsia [63]. Although gestational weight gain has not been specifically studied in hypertensive women, avoiding weight gain in excess of the IOM guidelines should be avoided.

Dietary sodium restriction lowers blood pressure and is associated with a decreased risk of cardiovascular disease in non-pregnant individuals [64]. Thus, dietary sodium restriction (<2.0 g/day) is recommended in non-pregnant hypertensive individuals by several major national and international organizations. In pregnancy, dietary sodium restriction could theoretically interfere with the physiologic plasma volume expansion of pregnancy. There are no studies on the effects of dietary sodium restriction in hypertensive pregnant women. The American College of Obstetrics and Gynecology 2013 Task Force suggests that dietary sodium restriction not be used in this setting [65].

Pharmacotherapy : Blood Pressure Target

When hypertension is severe (>160/105 mmHg), antihypertensive therapy is clearly indicated for the prevention of acute stroke and cardiovascular complications [61]. Treatment of mild and moderate hypertension in pregnancy is controversial. The 8th Joint National Commission recommends treating hypertension in members of the general population <60 years to a target blood pressure of less than 140/90 mmHg [66]. However, the strength of recommendation for the 18–29 age group is weak (grade E, expert opinion). Even for women over age 30, the evidence upon which the JNC guidelines are based uniformly excluded pregnant women.

There is little evidence that treatment of mild to moderate hypertension has a short-term benefit for either mother or fetus. Several small clinical trials have evaluated the impact of antihypertensive therapy vs. no treatment in such women, and these have been evaluated in meta-analyses [67–69]. Although antihypertensive therapy lowers the risk of severe hypertension, there is no beneficial effect on the development of preeclampsia , neonatal death, preterm birth , small for gestational age babies, or other adverse outcomes [70].

Potential maternal benefits of antihypertensive treatment need to be balanced against potential adverse fetal effects. Some evidence suggests that aggressive treatment of mild to moderate hypertension in pregnancy may impair fetal growth. Treatment-induced falls in mean arterial pressure are associated with decreased birth weight and fetal growth restriction, presumably as a result of decreased uteroplacental perfusion [71]. For this reason, the American College of Obstetrics and Gynecology Task Force on Hypertension in Pregnancy recommends against antihypertensive medication use in pregnant women with chronic hypertension and BP less than 160/105 mmHg in the absence of evidence of end-organ damage [61]. Similarly, the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood pressure (JNC7) recommends initiating antihypertensive therapy only when maternal blood pressure exceeds 150/100 mmHg [72]. JNC 8 provides no recommendation regarding treatment of hypertension in pregnancy [66]. For women with end-organ damage, such as cardiac hypertrophy or chronic kidney disease, the ACOG Task Force suggests a blood pressure goal of less than 140/90 mmHg [61].

The Control of Hypertension in Pregnancy Study (CHIPS) recently added to the evidence base on this issue [73]. This was an open, multicenter, randomized trial in 987 women with mild to moderate, nonproteinuric gestational or chronic hypertension. Women were randomized to treatment with pharmacotherapy to achieve tight (DBP target <85 mmHg) vs. less-tight (DBP target <100 mmHg) blood pressure control. There were no significant differences in adverse neonatal outcomes (pregnancy loss or need for high-level neonatal care) between treatment groups. However, the less-tight control group had a higher incidence of severe hypertension, thrombocytopenia, elevated AST or ALT with symptoms, and a trend toward a higher incidence of HELLP syndrome. There was no difference between treatment groups in the incidence of IUGR or preeclampsia . The study was not powered to detect a difference in maternal cardiovascular events, and follow-up was short. A major contribution of this trial, the largest and most well designed to date, was the assurance that tight blood pressure control was not associated with intrauterine growth restriction or other adverse neonatal effects. Based on these data, it is reasonable to treat hypertension in pregnancy to a diastolic blood pressure goal of less than 85 mmHg.

Monitoring of Women with Chronic Hypertension in Pregnancy

Close monitoring of blood pressure is important throughout pregnancy. Blood pressure often falls through the first half of pregnancy, and rises in the last trimester, requiring adjustments in medication. After 20 weeks gestation, monitoring for superimposed preeclampsia is required (see section “Diagnosis of Preeclampsia and Superimposed Preeclampsia”). This is accomplished through close blood pressure monitoring, frequent urinalysis for detection of proteinuria, and screening for preeclampsia symptoms. Dipstick testing is routinely used for preeclampsia screening; results ≥1+ should be confirmed with a random urine protein:creatinine ratio or 24-hour urine collection for proteinuria. Women with chronic hypertension in pregnancy should be educated regarding signs and symptoms of preeclampsia , including headache, visual changes, edema, and upper abdominal pain. The use of home blood pressure monitoring using an automated cuff is useful both for ensuring appropriate dosing of antihypertensive medication and for preeclampsia surveillance [61]. Patients should be instructed on proper use of home blood pressure monitors, and instructed to call their provider if they have an increase in blood pressure, particularly when associated with signs or symptoms of preeclampsia . Women with suspected superimposed preeclampsia should be hospitalized for maternal and fetal evaluation and monitoring [61].

Hypertension in pregnancy should be managed by an obstetrician with expertise in high risk pregnancies. Consultation with a maternal–fetal medicine physician is often helpful. Due to the increased risk for intrauterine growth restriction , fetal monitoring with ultrasound and antenatal fetal testing is recommended in women with chronic hypertension.

Intrapartum and Postpartum Care

Oral antihypertensive medications are frequently held during labor and delivery without adverse effects if hypertension is relatively mild. For women with more severe hypertension in pregnancy, intravenous agents can be used in the peripartum period (see section “Intravenous Agents”). Medications should be resumed following delivery, unless blood pressure is low. Blood pressure should be reassessed within 6 weeks postpartum. For women with an indication for an ACE-I or ARB, these medications are safe in breastfeeding and can be safely started immediately following delivery.

Gestational Hypertension and Preeclampsia

Gestational Hypertension

Gestational hypertension is defined as the new onset of hypertension, without proteinuria, after 20 weeks gestation. A subset of women with gestational hypertension have unrecognized preexisting chronic hypertension. In such cases, if the woman presents for medical care during the second-trimester nadir in blood pressure, she may be inappropriately presumed to be previously normotensive. In such a circumstance the diagnosis of chronic hypertension is established postpartum, when blood pressure fails to return to normal.

Gestational hypertension progresses to overt preeclampsia in 10–25 % of cases [74]. When gestational hypertension is severe, it carries similar risks for adverse outcomes as preeclampsia , even in the absence of proteinuria [75]. A renal biopsy study suggests that a significant proportion of women with gestational hypertension have renal glomerular endothelial damage [76]. Hence, gestational hypertension may share the same pathophysiologic underpinnings as preeclampsia , and should be monitored and treated as such. For these reasons, the American College of Obstetric and Gynecology guidelines no longer require proteinuria for the diagnosis of preeclampsia if severe features are present (see Table 6.2).

Table 6.2 Features of severe preeclampsia
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Preeclampsia

Preeclampsia is a pregnancy-specific syndrome characterized by hypertension and proteinuria, with onset in the second half of pregnancy. Preeclampsia affects 3–5 % of all pregnancies [49]. Although most cases of preeclampsia occur in healthy nulliparous women, several maternal and pregnancy risk factors are associated with a marked increase in preeclampsia risk (Table 6.1). Preeclampsia can lead to the development of severe maternal and fetal/neonatal complications. Maternal complications may include liver failure, hepatic hematoma or rupture, pulmonary edema, seizures (eclampsia), hypertensive encephalopathy, intracranial hemorrhage, renal failure, placental abruption, and death. For the fetus, preeclampsia can lead to intrauterine growth restriction , placental abruption, stillbirth, and neonatal death [77, 78]. Severe maternal complications can usually be avoided with careful prenatal monitoring and expedient delivery when severe features emerge. Since delivery is the definitive treatment for preeclampsia , premature delivery for maternal or fetal distress is often required, with consequent neonatal morbidity.

Pathogenesis

The preeclampsia syndrome is characterized by widespread maternal endothelial dysfunction [79]. Inadequate placental vascular development is an early event, particularly in early onset preeclampsia [80]. This early placental vascular insufficiency is incompletely understood, with genetic, immunologic, and environmental factors all playing a role. Preeclampsia is a state of sympathetic overactivity. Maternal vascular reactivity to the vasopressors angiotensin II and norepinephrine is increased [81]. In normal pregnancy, the renin–angiotensin–aldosterone system is activated; in preeclampsia , plasma renin levels are low [82].

The full-blown preeclampsia syndrome culminates in oxidative stress, endothelial damage, and maternal end-organ dysfunction. Maternal diseases characterized by vascular dysfunction, such as diabetes mellitus, chronic hypertension, chronic kidney disease, and obesity, are associated with increased preeclampsia risk. This suggests that maternal susceptibility contributes to pathogenesis. Molecular and cellular pathways linking placental insufficiency to subsequent maternal endothelial dysfunction include angiogenic factors such as sFlt1 (VEGFR1), angiotensin-2 receptor autoantibodies, immunologic factors, and oxidative stress. A full discussion of the pathogenesis of preeclampsia is beyond the scope of this book and is reviewed elsewhere [83].

Diagnosis of Preeclampsia and Superimposed Preeclampsia

The diagnostic criteria for preeclampsia are in evolution. Historically, preeclampsia was defined by the new onset of hypertension (SBP >140 mmHg or DBP >90 mmHg) and proteinuria (>0.3 g/day in a 24-hour collection or random urine protein:creatinine ratio >0.3 mg protein/mg creatinine) after 20 weeks gestation. However, preeclampsia complications are more strongly associated with the severity of hypertension than the presence or severity of proteinuria [75, 84]. Following the lead of other national and international organizations [85–87], the 2013 American College of Obstetrics and Gynecology Task Force on Hypertension in Pregnancy recommended that proteinuria should no longer be required for the diagnosis of preeclampsia (Table 6.3) [61, 88, 89]. These broader criteria allow for the diagnosis of preeclampsia in the absence of proteinuria when one or more other features of end-organ damage are present. In addition, the presence of severe proteinuria (>5 g/day) is no longer considered indicative of severe preeclampsia , as the degree of proteinuria is poorly correlated with adverse outcomes [84]. The HELLP syndrome (hemolytic anemia, elevated liver enzymes, and low platelets) is a severe form of preeclampsia , not a distinct pathologic and clinical entity.

Table 6.3 Diagnostic criteria for preeclampsia [61, 88]
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The use of spot urine protein:creatinine ratio to quantify proteinuria in pregnancy has slowly gained broader use in the obstetric community. Suggested cutoffs for the diagnosis of abnormal proteinuria are >0.3 mg protein/mg creatinine, or >30 mg protein/mmol creatinine, ideally performed on a first morning voided sample [88].

The diagnosis of superimposed preeclampsia in the setting of chronic hypertension can be challenging. The presence of preexisting hypertension robs the clinician of preeclampsia ’s key diagnostic feature. Clinical practice guidelines variably define superimposed preeclampsia as worsening hypertension, resistant hypertension, new or worsening proteinuria, or the presence of one or more systemic features of preeclampsia in a woman with previously diagnosed chronic hypertension [88]. In the absence of baseline proteinuria, the new onset of proteinuria (>300 mg/day), usually with worsening hypertension, may be the most reliable sign of superimposed preeclampsia . When preexisting proteinuria is present, diagnosis is even more difficult. In these cases, a sudden, substantial increase in proteinuria, accompanied by worsening blood pressure, should suggest superimposed preeclampsia . Features of severe preeclampsia such as headache, visual changes, epigastric pain, pulmonary edema, thrombocytopenia, renal insufficiency, and elevated liver enzymes (Table 6.2) should also prompt consideration of superimposed preeclampsia .

Management

The definitive treatment for preeclampsia is delivery. However, early preterm delivery carries a high morbidity for the neonate. Mild preeclampsia remote from term can sometimes be managed for a few weeks with bed rest, antihypertensive medication, and close maternal and fetal monitoring [90]. However, progression to severe preeclampsia over days to weeks is typical. Expectant management of severe preeclampsia leads to a high rate of maternal morbidity and fetal and neonatal mortality [91]. Immediate delivery should be considered with women with uncontrolled severe hypertension or other severe features of preeclampsia (Table 6.2). Delivery is also appropriate in those who develop even mild preeclampsia at or near term [92].

Patients who develop preeclampsia with severe features should be monitored in a hospital setting. Hypertension should be treated with medication when severe (>150–160/100–110) [88]. Intravenous magnesium sulfate prevents the development of seizures in women with preeclampsia [93], and is recommended when severe features are present. Magnesium is also used for the treatment of seizures if eclampsia occurs. Administration of antenatal corticosteroids to enhance fetal lung maturity is recommended prior to 34 weeks gestation [88].

Following delivery, preeclampsia generally remits over a period of days to weeks. Antihypertensive therapy should generally be continued, and tapered as dictated by the maternal blood pressure. Continued monitoring is important, as complications—particularly seizures—can occur in the postpartum period. A spontaneous diuresis usually ensues within days after delivery. Diuretics during this period may hasten improvement in hypertension but do not affect hospital length of stay or adverse outcomes [94].

Postpartum Hypertension and Preeclampsia

Newly recognized hypertension presenting in the postpartum period can be due to either postpartum preeclampsia or the new recognition of chronic hypertension. Since pregnancy itself can lower blood pressure, chronic hypertension is sometimes unmasked and first diagnosed following delivery.

Postpartum preeclampsia can present up to 4 weeks following delivery, and can be severe: up to 1/3rd of eclampsia occurs in the postpartum period [95]. Most women who present with eclampsia or stroke in the postpartum period have prodromal symptoms, which can include headache, visual changes, nausea, vomiting, or epigastric pain [95]. For this reason, it is important that both pregnant women and their providers be informed regarding the signs and symptoms of postpartum preeclampsia . As with antepartum preeclampsia , early recognition and treatment with magnesium sulfate and antihypertensive medications may prevent severe complications .

Long-Term Outcomes After Preeclampsia

In the past, women with preeclampsia were reassured that the disease is cured by delivery, and future risk was limited to the higher probability of preeclampsia in subsequent pregnancies. There is now strong epidemiologic data to show that women with a history of preeclampsia have a substantially increased risk of cardiovascular, cerebrovascular, and renal disease later in life.

Hypertension and proteinuria begin to improve soon after delivery in the majority of women with preeclampsia , and resolve completely an average of 5–6 weeks postpartum. However, up to 20 % of women have persistent hypertension 6 months postpartum [18]. Women who have had preeclampsia are more likely to have physical and biochemical markers of cardiovascular risk, such as obesity, hypercholesterolemia, hypertension, and albuminuria, as compared with women who had normotensive pregnancies [96–98]. Long-term cardiovascular complications, including ischemic heart disease, cerebrovascular disease, and cardiovascular mortality, are increased two to threefold in women with a history of preeclampsia , as compared to women with no such history [99, 100]. Severe preeclampsia , recurrent preeclampsia , preeclampsia with preterm birth , and preeclampsia with intrauterine growth restriction are associated with the highest risk of adverse cardiovascular outcomes. The 2011 American Heart Association Guidelines now include a history of preeclampsia as a risk factor for cardiovascular disease [101].

Preeclampsia, especially in association with low neonatal birth weight, also carries an increased risk of subsequent maternal kidney disease [102]. A Norwegian study using birth and renal registry data on over 570,000 women showed that preeclampsia is associated with a nearly fivefold increase in the risk of subsequent ESRD [103]. Familial aggregation of risk factors does not seem to explain this risk [104].

The mechanism underlying the link between preeclampsia and subsequent cardiovascular and renal disease is unknown. Preeclampsia and cardiovascular disease share many common risk factors, such as chronic hypertension, diabetes, obesity, renal disease, and the metabolic syndrome. Still, the increase in long-term cardiovascular mortality holds even for women who develop preeclampsia in the absence of any overt vascular risk factors. Whether cardiovascular complications in these women result from vascular damage caused by preeclampsia , or simply reflect the common subclinical risk factors shared by preeclampsia and cardiovascular disease, remains speculative. Regardless of etiology, it is recommended that women who with a history of preeclampsia , especially with preterm birth or intrauterine growth restriction , be screened for potentially modifiable cardiovascular and renal disease risk factors (hypertension, diabetes mellitus, hyperlipidemia, obesity) at their postpartum obstetrician visit and yearly thereafter [61, 105].

Antihypertensive Drugs in Pregnancy

Treatment of blood pressure in pregnancy is frequently required for women with chronic hypertension in pregnancy, gestational hypertension , preeclampsia , and superimposed preeclampsia . General principles of treatment are similar for all four disorders. The selection of oral vs. intravenous medications should be driven by the severity of hypertension and presence of end-organ damage, rather than by the underlying etiology of hypertension. Even severe hypertension can frequently be managed with oral agents [106]. Thresholds for initiation of pharmacologic agents and therapeutic targets are discussed in Sects. 6.3.4.3 and “Management” .

Oral Agents

Recommended antihypertensive agents in pregnancy are summarized in Table 6.4. The major classes of medication used for treatment of hypertension in pregnancy are calcium channel blockers, beta-blockers, methyldopa, and hydralazine.

Table 6.4 Antihypertensive medications in pregnancy
Full size table

Beta-adrenergic antagonists have been used extensively in pregnancy and are effective without known teratogenicity or known adverse fetal effects. Labetalol has found widespread use and acceptance, both as an oral and an intravenous agent [107]. Labetalol is preferred over pure beta-blockers, as the alpha-blocking effect may augment placental perfusion. Some data suggest atenolol is associated with fetal growth restriction, so this agent is usually avoided [108].

There is extensive clinical experience supporting the safety of calcium channel blockers in pregnancy. Long-acting nifedipine is the most well studied, and is both safe and effective [109]. Non-dihydropyridine calcium channel blockers such as verapamil and diltiazem have also been used without apparent adverse effects.

Methyldopa continues to be widely used for the management of hypertension in pregnancy. Methyldopa is a centrally acting alpha-2 adrenergic agonist, now seldom used outside of pregnancy. Of all antihypertensive agents, it has the most extensive safety data and has no apparent adverse fetal effects. Limitations include short duration of action, sedation, and rare adverse effects include elevated liver enzymes and hemolytic anemia. Clonidine appears to be comparable to methyldopa in terms of mechanism and safety, but data are fewer.

Diuretics are usually avoided in preeclampsia , since blood volume is already low. In pregnant women with chronic hypertension, diuretics could theoretically impede the physiologic volume expansion of pregnancy. However, there is no evidence that diuretics are associated with adverse fetal or maternal outcomes. Thus, although not considered first-line, it is reasonable to continue thiazide diuretics when these agents are part of a stable pre-pregnancy antihypertensive regimen [58]. When hypertension in pregnancy or preeclampsia is complicated by pulmonary edema, loop diuretics are appropriate and effective [110]. Aldactone can lead to feminization of male fetuses and are usually avoided. Eplerenone is a more specific antagonist to the mineralocorticoid receptor and theoretically would not lead to antiandrogenic effects. Although experience with eplerenone in pregnancy is limited, case reports have described its successful use in the management of both primary aldosteronism and Gitelman syndrome in pregnancy [24, 111].

Angiotensin-converting enzyme inhibitors (ACE-I) and angiotensin receptor antagonists (ARB) are contraindicated in pregnancy. Exposure during the second and third trimesters leads to major fetal malformations including renal dysgenesis, perinatal renal failure, oligohydramnios, pulmonary hypoplasia, hypocalvaria, and intrauterine growth restriction [112]. Evidence for teratogenicity with first trimester exposure is less compelling. A large population-based study reported congenital malformations of the central nervous and cardiovascular systems were higher among women with first trimester exposure to ACE inhibitors [113]. However, this study has been criticized for the presence of potential confounders and ascertainment bias. Women with a compelling indication for ACE-I or ARB (such as diabetic nephropathy) can probably be continued on these agents while attempting conception, with discontinuation as soon as pregnancy is diagnosed. However, risks and benefits of this strategy should be discussed with the patient, with shared and individualized decision-making. Women inadvertently exposed in early pregnancy can be reassured by a normal mid-trimester ultrasound examination. Fewer data are available on the effects of angiotensin receptor blockers, but a case series strongly suggests fetal effects are similar to ACE-I [114]. The American College of Obstetrics and Gynecology recommends that ACE-I and ARBs be avoided in all women of reproductive age with chronic hypertension unless there is a compelling indication, such as proteinuric chronic kidney disease [61].

Intravenous Agents

When hypertension in pregnancy is severe, treatment with intravenous agents is appropriate. This most frequently occurs in the setting of preeclampsia and superimposed preeclampsia . All intravenous medications commonly used for urgent control of severe hypertension are classified as pregnancy class C by the U.S. Food and Drug Administration (risk not ruled out). Nevertheless, there is extensive clinical experience with several agents, which are widely used with no clinical evidence of adverse effects. Options for intravenous use include labetalol , nicardipine, hydralazine, and diazoxide.

Intravenous labetalol , like oral labetalol , is safe and effective, with the major drawback being its short duration of action. Intravenous nicardipine is also short acting, and requires a continuous infusion treatment of hypertension [115]. The use of oral short-acting nifedipine is controversial due to well-documented adverse effects in the non-pregnant population. However, a recent trial suggests oral short-acting nifedipine is safe in hypertensive emergencies in pregnancy [116], and it may be an option in areas where intravenous agents are unavailable.

Hydralazine has been widely used as a first-line agent for severe hypertension in pregnancy. However, a recent meta-analysis of 21 trials comparing IV hydralazine to either labetalol or nifedipine for acute management of hypertension in pregnancy suggested an increased risk of maternal hypotension, maternal oliguria, placental abruption, and low APGAR scores with hydralazine [117]. Hence, hydralazine should be considered second-line and its use limited. Nitroprusside continues to be used in many low and middle income countries [118], but must be used with great caution due to risks of maternal and fetal cyanide toxicity when used for more than short periods (>4 h).

Diazoxide is a direct vasodilator which appears to be safe and effective in pregnancy for intravenous use to treat severe hypertension [119]. Because it inhibits insulin secretion, diazoxide should be avoided in type 2 diabetics .

Antihypertensive Drugs in Breastfeeding

There are few well-designed studies of the safety of antihypertensive medications in breastfeeding. In general, agents that are considered safe during pregnancy remain so in breastfeeding. Methyldopa , if effective and well tolerated during pregnancy, may be continued. Beta-blockers with high protein binding, such as labetalol and propranolol, are preferred over atenolol and metoprolol, which are concentrated in breast milk [107]. Diuretics may decrease milk production and should be avoided [107]. ACE inhibitors, particularly enalapril and captopril, are poorly excreted in breast milk and generally considered safe in lactating women [120]. Hence, in women with diabetes or proteinuric chronic kidney disease, initiation of ACE inhibitors should be considered immediately after delivery. Specific data on the pharmacokinetics of each medication should be used to guide mothers to time breastfeeding intervals before or well after peak breast milk excretion to avoid significant exposure to the baby. LactMed, a free online database maintained by the National Library of Medicine and the National Institutes of Health, is a useful clinical tool for assessing the safety of specific medications in breastfeeding [121].