Hypertension is the most common medical disorder encountered during pregnancy. Hypertensive disorders are one of the major causes of pregnancy-related maternal deaths in the United States. We will present a comprehensive update of the literature pertinent to hypertension in pregnancy. The paper begins by defining and classifying hypertensive disorders in pregnancy. The normal vascular and renal physiological changes which occur during pregnancy are detailed. We will summarize the intriguing aspects of pathophysiology of preeclampsia, emphasizing on recent advances in this field. The existing diagnostic tools and the tests which have been proposed for screening preeclampsia are comprehensively described. We also highlight the short- and long-term implications of preeclampsia. Finally, we review the current management guidelines, goals of treatment and describe the potential risks and benefits associated with various antihypertensive drug classes. Preeclampsia still remains an enigma, and the present management focuses on monitoring and treatment of its manifestations. We are hopeful that this in depth critique will stimulate the blossoming research in the field and assist practitioners to identify women at risk and more effectively treat affected individuals.
Hypertension is the most common medical disorder of pregnancy and is reported to complicate up to 1 in 10 gestations and affects an estimated 240,000 women in the United States every year [
The National High Blood Pressure Education Program of the NHLBI classifies hypertensive disorders of pregnancy into following categories: gestational hypertension, chronic hypertension, preeclampsia, and preeclampsia superimposed on preexisting hypertension [
Classification of hypertension in pregnancy.
Chronic hypertension | (i) increased BP before week 20 (or known to exist prior to pregnancy) |
Preeclampsia-eclampsia | (i) de novo appearance of hypertension after mid-pregnancy |
Preeclampsia superimposed upon existing hypertension | (i) new onset proteinuria |
Gestational hypertension | (i) transient hypertension appearing after mid-pregnancy |
Hypertension in pregnancy is defined as a systolic of 140 mm Hg or greater or a diastolic of 90 mm Hg or greater. Blood pressure should be taken in the upper arm with the patient seated using an appropriately sized cuff. The patient should be at rest for at least several minutes. The blood pressure should be confirmed with another reading at least at a twenty-minute interval or even on a separate occasion. The diastolic reading is determined by the disappearance of sound and
Dramatic physiologic changes occur in systemic hemodynamics during pregnancy. It is essential that these differences from the nonpregnant state be appreciated when one attempts to assess blood pressure during pregnancy. In uncomplicated pregnancy, mean arterial pressure drops, reaching its nadir between the 16th and 20th weeks of gestation (Figure
Relative changes in renal hemodynamics during normal human pregnancy. Dramatic changes occur in systemic hemodynamics during physiologic pregnancy. In uncomplicated pregnancy, mean arterial pressure drops, reaching its nadir between the 16th and 20th weeks of gestation. After the 20th week, mean arterial blood pressure slowly returns to close to pre-pregnancy levels at about 40-week gestation. Changes in systemic blood pressure are paralleled by a change in cardiac output which increases dramatically. The apex is reached between the 16th and 20th weeks of gestation. Plasma volume increases substantially as well but lags behinds the increased cardiac output. MAP: mean arterial pressure. CO: cardiac output.
Changes in systemic blood pressure are paralleled by a change in cardiac output, which increases dramatically. The apex is reached between the 16th and 20th weeks of gestation, and at its apogee the increment is typically at least 40% greater than the baseline. Both stroke volume and heart rate increase to achieve this profound rise in the quantity of blood pumped into the pulmonary and systemic circulations [
The circulating levels of the hormones that help regulate blood volume, specifically all components of the renin-angiotensin aldosterone system as well as catecholamines, are paradoxically increased during gestation. The usual physiologic stimuli for the release of these hormones are a reduction in plasma volume or diminished renal perfusion. Nonetheless, enhanced activity of the renin-angiotensin axis is a hallmark of the volume-expanded state of gestation. This has led to the description of pregnancy as a state of “decreased effective plasma volume.” Increases in both arterial compliance and venous capacitance appear to underlie this unique physiologic phenomenon [
The alterations in vascular reactivity are not limited to the responses to endogenous hormones. The vasoconstrictive effect of infused pressor compounds is also substantially diminished. During gestation, pregnant women were demonstrated to be resistant to the pressor effect of angiotensin II and norepinephrine more than 40 years ago [
The amount of angiotensin required to raise blood pressure by 20 mm Hg. This figure demonstrates two important findings obtained from serial observations in primiparas. Women undergoing physiologic pregnancy (■) become resistant to the pressor effect of infused angiotensin II by 14 weeks of gestation. They require significantly higher dose of angiotensin II to increase blood pressure by 20 mm of Hg. In contrast, women destined to develop preeclampsia (♦) regain their sensitivity to angiotensin II between 22–26 weeks of gestation, well before any other clinical manifestations of preeclampsia are appreciated [
Healthy pregnant women show marked glomerular hyperfiltration. The rapid developing rise in renal blood flow and glomerular filtration rate were documented in careful studies undertaken in humans [
Laboratory tests of renal function during pregnancy.
Nonpregnant | Pregnant | |
---|---|---|
BUN | ||
Creatinine | ||
Creatinine clearance | 80–120 | 125 |
Serum uric acid | Greater than 4 | Less than 4 |
Urinalysis | Normal | Normal |
Changes in renal function during pregnancy. Kidney function also dramatically increases during pregnancy. The rapid developing rise in renal blood flow and glomerular filtration rate were documented in careful studies undertaken in humans. These increments average between 40 and 50%. Dr. Davison and his associates found that these improvements in renal hemodynamics occurred even prior to the changes in cardiac output and plasma volume. GFR: glomerular filtration rate. ERPF: effective renal plasma flow [
Throughout pregnancy the average women will retain about 1000 mEq of sodium as she experiences the fairly steady increase in extracellular and plasma volume. Nonetheless women experiencing physiologic pregnancy will respond appropriately to sodium restriction or sodium infusion [
It is difficult to study totally untreated preeclampsia, and often preeclampsia is diagnosed in patients with underlying chronic medical conditions. Data generated from treated preeclamptic patients or those patients with preexisting renal disease, diabetes, or hypertension might not accurately reflect those of the uncomplicated preeclamptic patient. These concerns aside, the available data suggests that the systemic hemodynamic preeclamptics vary substantially from those of women with uncomplicated pregnancy.
Visser and Wallenburg undertook detailed hemodynamic assessments of untreated primiparous preeclamptics. Using Swan-Ganz catheters, they consistently found cardiac outputs and intravascular volumes lower and systemic vascular resistance and cardiac afterload higher in these carefully selected group of women with pregnancy-induced hypertension as compared to normal control pregnant subjects [
If one focuses on the properties of the arterial system in preeclampsia using impedance techniques, compliance of the large conduit arteries is reduced. This suggests that the reservoir properties of the arterial system are compromised. The left ventricle muscle mass and cardiac wall diastolic pressure in late gestation is similar between preeclamptic and controlled subjects. Limited data suggests, however, that left ventricular contractility in preeclamptics is inappropriately low given the high afterload [
Some changes in the systemic hemodynamics of pregnant women destined to become preeclamptic may develop prior to overt clinical manifestations of the disease. Ambulatory blood pressure readings suggest that a reduction or obliteration in the usual decrease in nocturnal blood pressure may be present in many patients who eventually become preeclamptic. Such changes usually manifest at 18 to 26 weeks of gestation. The resistance to pressor substances appears to be altered well before the systemic hypertension and proteinuria are noted. Figure
Renin levels actually decrease in preeclamptic patients, but remain well above those of nonpregnant individuals. Similar changes are also seen in the circulating levels of aldosterone and angiotensin II. Maintaining relatively high levels of these hormones may be critically important because most often preeclamptic patients have a relatively diminished plasma volume.
The dramatic improvement in renal function experienced by women undergoing a physiologic pregnancy is abrogated in women who develop preeclampsia. The GFR and renal blood flow decline. The severity of the reduction is quite variable and correlates with the overall severity of the illness. If proteinuria develops, as is most common, and a kidney biopsy were to be undertaken, it would typically show glomerular endotheliosis. This lesion, although not limited to pregnancy, is characteristic in preeclamptic women. This endothelial abnormality is quite consistent with the notion of endothelial injury playing a key role in the pathophysiology of this systemic condition with the kidney not being spared. These hemodynamic and endothelial changes also appear to make the kidneys more vulnerable for the development of acute renal failure (acute tubular necrosis) and uncommonly a particular form of acute, often irreversible renal failure known as renal cortical necrosis. Cortical necrosis is seen almost exclusively in severe preeclamptics and rarely occurs in settings outside of pregnancy [
The pathophysiology of de novo hypertension and proteinuria in pregnancy known as preeclampsia remains largely undiscovered. More than 30 years ago Dr. Leon Chesley, a champion in the field of hypertension in pregnancy divided the most likely causative factor into four major categories: dietary, renal, immunologic, and placental [
Delivery of the placenta usually initiates the resolution of the acute clinical symptoms of preeclampsia, suggesting that the placenta plays a central role in preeclampsia pathogenesis. During normal pregnancy, the placenta undergoes dramatic vascularization to enable circulation between fetus and mother. Placental vascularization involves vasculogenesis, angiogenesis, and pseudovasculogenesis or maternal spiral artery remodeling. These processes require a delicate balance of proangiogenic and antiangiogenic factors. The imbalance of proangiogenic and antiangiogenic factors in preeclampsia is thought to trigger abnormal placental vascularization and disease onset.
Underlying genetic explanations for the overproduction of anti-angiogenic factors in preeclampsia are still being proposed [
Altered uteroplacental blood flow has long been the focus of the pathophysiology of preeclampsia. Clinicians and research scientists have garnered a wealth of data to support the hypothesis that a reduction in uterine blood flow is the overriding factor in the etiopathogenesis of this condition (Table
Observations supporting uteroplacental ischemia as a key factor in preeclampsia.
(i) predominantly occurs in primagravidas with immature uterine vasculature |
(ii) consistent abnormalities of the placentae and uteroplacental vascular interface |
(iii) increased risk with more fetuses and placentas (twins) |
(iv) disease occurs late in gestation |
(v) labor aggravates |
(vi) high incidence with large, rapidly growing hydatidiform moles |
(vii) increase incidence in patients with underlying vascular disease (diabetes, hypertension and lupus (SLE)) |
(viii) findings in animals subjected to uteroplacental ischemia mimic those of preeclampsia |
Finally, there is a wealth of data derived from experiments in various pregnant mammals spanning the spectrum from rats to primates supporting this hypothesis. When subjected to reduced uteroplacental blood flow, these animals develop findings that mimic those seen in preeclamptic women. Sustained hypertension, proteinuria, and glomerular endotheliosis, the renal lesion that characterizes preeclampsia, have all been reported in these laboratory animals following uterine constriction of blood flow [
Although preeclampsia appears to originate in the placenta, the tissue affected most is the maternal endothelium. The clinical manifestations of preeclampsia reflect widespread endothelial dysfunction, with vasoconstriction and end organ ischemia. Systemic hypertension, renal, hepatic, and cerebral vascular pathology are hallmarks of severe preeclampsia. Taylor, Davidge and Roberts explore in great depth the evidence placing endothelial dysfunction as the focal point of the disease [
There is a published body of work that has grown almost logarithmically since 2003 suggesting that circulating angiogenic factors play a key role in the pathogenesis of preeclampsia. Increased expression of soluble fms-like tyrosine kinase (sFlt1), together with decreased placental growth factor (PGF) and vascular endothelial growth factor (VEGF) signaling, were the first abnormalities described [
Several investigators spearheaded by Karumanchi have seized on the finding that pregnant women may produce a soluble variant of vascular endothelial growth factor receptor. This kinase has been designated sFlt1. sFlt1 consists of the extracellular ligand-binding domain of Flt1, but lacks the transmembrane and intracellular signaling domain. Hence, it is secreted into the circulation where it binds and antagonizes both vascular endothelial growth factor (VEGF) and placenta growth factor (PGF) [
More recent studies have identified a second sFlt1 splice form expressed in cytotrophoblasts, which differs in its c-terminus and also appears to be upregulated in preeclampsia [
Proponents of the vascular endothelial growth factor-receptor antagonist hypothesis or so-called anti-angiogenic theory recognize that blocking the action of these growth factors alone was insufficient to explain all the clinical manifestations seen in severe eclampsia. Another factor, soluble endoglin (sEng), has now been also found to be upregulated in preeclampsia in a pattern similar to sFlt1. sEng is a truncated form of endoglin (CD 105), a cell surface receptor for transforming growth factor B (TGF-B), which binds and antagonizes TGF-B [
As with sFlt1, circulating sEng levels are increased weeks before preeclampsia onset, and increased sEng levels are observed in the reduced uterine perfusion pressure rat model of preeclampsia [
Endoglin excess has now been incorporated into the anti-angiogenic theory. Collectively, this is an appealing hypothesis. Skeptics could say, however, we may not as yet have reached the root cause level.
Relaxin, a peptide hormone secreted by the corpus luteum, circulates during pregnancy in human beings, nonhuman primates, rats, and mice [
There is an increase in almost all the components of renin-angiotensin system during an uncomplicated pregnancy, but renin activity, angiotensin II, and aldosterone decrease in preeclampsia for reasons that are unclear. Numerous studies report the presence of angiotensin II type 1 receptor agonistic antibody (AT1-AA) found circulating in preeclamptic women [
Over the last 30 years, significant progress has been made in understanding the role of immune mechanisms in the development of preeclampsia. It remains unexplained why primiparous women are more susceptible to this condition and also why the high preeclampsia attack rate (5–7%) noted in primiparous is unchanged in women who are having a first pregnancy with a second partner. This has fostered the suspicion that the immunologic difference between the partners, embedded in the fetus triggers an immune response in pregnant women. Redman et al. have postulated that preeclampsia is the continuum of the immune-mediated inflammatory changes seen in normal pregnancy. Most investigators believe that endothelial injury, perhaps caused by cytokine release induced by inflammation is a basic mechanism underlying the pathogenesis of preeclampsia [
It has also been postulated that immune accommodation to the fetus needs to be learned, and this adaptation may be relatively defective in the first pregnancy leading to the higher preeclampsia attack rate which declines in but less so in subsequent pregnancies. Such conditioning might be acquired from previous pregnancy, abortion, and exposure to paternal semen and seminal plasma. Maternal exposure to fetoplacental tissues varies with gestational age, and two interfaces have been described. Interface 1, which is predominant in the first half of pregnancy, exists between maternal immune cells and invasive, extravillous HLA expressing trophoblasts in decidua. Interface 2, which predominates during the second half of pregnancy, comprises syncytiotrophoblasts that are in contact with maternal blood-borne immune cells. Syncytiotrophoblasts are HLA negative, and thus the paternal alloantigens are only expressed at interface 1, which is most active in first half of pregnancy [
It is tempting to suggest that those women who respond vigorously to these foreign antigens are more susceptible to develop endothelial injury that precedes preeclampsia. Women indeed often develop persistent antibodies to the fetal HLA antigens of paternal origin. The presence of these antibodies substantially increases the rate of graft rejection post transplant. It is of note that the endothelium is the major attack site of antibody-mediated rejection that develops not uncommonly in this setting.
Although the risk factors for preeclampsia are both genetic and environmental, the presence of preeclampsia in first degree relatives increases a woman’s risk of preeclampsia by 2 to 4 fold [
There is some evidence to suggest that in addition to maternal genotype, paternal (or fetal) genotype may also contribute to risk of preeclampsia. The risk of fathering a preeclamptic pregnancy is increased among males who fathered a preeclamptic pregnancy with a different partner [
The diagnosis of preeclampsia is largely based upon meeting the characteristic clinical features outlined above which define preeclampsia. In this section, we explore various tools proposed to predict the development and/or accurately diagnose preeclampsia.
The hallmark features in preeclampsia include developing systolic blood pressure (SBP) ≥140, or diastolic blood pressure (DBP) ≥90, and proteinuria of 0.3 grams or greater in a 24-hour urine specimen after 20 weeks of gestation in a woman who was previously normotensive. Hypertension is generally the earliest physical abnormality seen in preeclampsia and is the most important clinical clue to the presence of the disease. Since SBP and DBP readings are an essential part of the diagnosis of preeclampsia, ensuring that the optimal and appropriate ways are employed to measure BP cannot be overemphasized.
Using different indices of BP to predict preeclampsia has been comprehensively evaluated in a meta-analysis published by Cnossen et al. [
Although proteinuria is generally considered an essential characteristic of preeclampsia, preeclampsia should be suspected in any pregnant woman with hypertension and characteristic signs or symptoms, even if proteinuria is absent. Twenty percent of women who develop eclampsia have no proteinuria and 10 percent of women with other clinical and/or histological manifestations of preeclampsia have no proteinuria [
The kidney is the organ most likely to manifest endothelial injury related to preeclampsia. Although the plasma creatinine concentration is generally normal or only slightly elevated (1.0 to 1.5 mg/dL (88 to 133 mmol/L)), this could represent a decrease by 30–40% of glomerular filtration rate (GFR) for the values experienced in pregnant normotensive controls (Table
Hyperuricemia was purportedly among the earliest manifestation described in preeclampsia. Different theories were explored trying to explain this finding [
Hypocalciuria has been reported in association with preeclampsia [
Roll over test; isometric exercise test, and angiotensin II sensitivity test [
The inadequate placental perfusion has lead to the use of Doppler ultrasonography to assess the velocity of the blood flow in the uterine arteries. A persistence of an early diastolic notch after 24 weeks of gestation or abnormal flow velocity ratio’s has been associated with an inadequate trophoblast invasion. Pregnancies associated with an abnormal uterine Doppler after 24 weeks of gestation (high pulsatility index and/or presence of an early diastolic notch) are associated with a more than six-fold increase in the rate of preeclampsia [
Current data do not support the use of Doppler ultrasonography for routine screening of patients for preeclampsia [
Several markers heretofore described, might help, alone or in combination to predict and/or diagnose preeclampsia. The data, however, are derived largely from small case studies in selected population. When evaluating new screening strategies, not only sensitivity, specificity, and predictive values need to be taken into account, but costs, patient’s acceptability, and quality control also must be considered.
Studies have consistently reported elevated serum levels of sFlt-1 in women with preeclampsia compared with normal pregnancies [
Levine et al. found a mean serum PGF concentration in women with preeclampsia of 137 pg/mL compared with 669 pg/mL in controls [
More recently, the assessment of the sFlt-1: PGF ratio in the maternal serum has been proposed as more reliable marker of overall preeclampsia risk. Preliminary data suggests that this ratio may be more accurate than sFlt-1 or PGF alone [
Increased maternal serum levels of sEng were detected prior to preeclampsia onset in healthy, nulliparous women [
A Korean study demonstrated that the combined ratio of (sFlt-1 + soluble endoglin) : (PGF + TGF beta −1) during the second trimester had the highest odds ratio and lowest false positive rate as compared to the individual markers for prediction of preeclampsia [
The results of various studies, unfortunately, have been inconsistent, and larger studies in more heterogenous population are needed to better define the clinical utility of these tests. There is some data, however, to suggest that tests for these biomarkers may be of use when applied to selected high-risk patients such as those with underlying hypertension [
The other suggested markers for the prediction or detection of preeclampsia are placental protein 13 (PP-13); pregnancy-associated plasma protein A (PAPP A); inhibin A; P-selectin; activin A; pentraxin; cell-free fetal DNA; ADAM-12; beta-HCG; 2-Methoxyestradiol (2-ME).
Hypertension in pregnancy is a major cause of maternal morbidity and mortality in the United States. There is approximately one maternal death due to preeclampsia-eclampsia per 100,000 live births, with a case-fatality rate of 6.4 deaths per 10,000 cases [
Outcomes for pregnancy complicated by hypertension range from uneventful pregnancy in women with chronic, controlled hypertension to death in cases of preeclampsia-eclampsia. The major adverse outcomes include central nervous system (CNS) injuries such as seizures (eclampsia), hemorrhagic and ischemic strokes, hepatic damage ranging from transaminase elevation, the so-called “HELLP syndrome” (hemolysis, elevated liver enzymes, and low platelets), hepatic failure, renal dysfunction (spanning the gamut from a trivial reduction in glomerular filtration rate and minimal proteinuria to reversible acute renal failure or so-called acute tubular necrosis to even irreversible renal failure secondary to renal cortical necrosis) as well as increased frequency of cesarean delivery, preterm delivery, and abruptio placentae [
The effects of chronic, controlled hypertension in pregnancy on the fetus are minimal. However, preeclampsia-eclampsia can lead to higher frequency of induced labor, fetal growth restriction, neonatal respiratory difficulties, and increased frequency admission to neonatal intensive care unit. Hypertension in pregnancy, even in its more severe forms, causes only minimal increased risk for perinatal or fetal death [
Though hypertension in pregnancy/preeclampsia is usually thought of as a short-term problem that resolves itself with delivery, it still carries significant risk for remote complications. Those infants born small and premature may experience prolonged stays in neonatal intensive care units and often face developmental delays. Remote outcomes include the risk of preeclampsia in subsequent pregnancies and several long-term maternal health risks as described below.
The risk of recurrent preeclampsia in subsequent pregnancies varies with the severity and time of onset of the acute episode [
The association between preeclampsia and cardiovascular diseases is both well described and well documented. Women with history of preeclampsia are at significantly increased risk to develop hypertension, ischemic heart disease, stroke, type II diabetes, and venous thromboembolism in comparison with women without history of the disease [
More renal biopsies are undertaken in victims of preeclampsia than in unaffected women [
Multiple observational studies evaluated the possible association between hypertension in pregnancy and cancer risk. Overall, women with preeclampsia were found to be at reduced risk or had no excess risk of cancer when followed by extended periods postpartum [
The first principle of treatment of hypertension in pregnancy is to correctly diagnose the category (Table
The estimated prevalence of chronic hypertension in pregnancy in United states is 3% and has been increasing over time. This increase in prevalence has been attributed to the increased prevalence of obesity and delay in childbearing to ages, when chronic hypertension is more common [
Women with the following conditions are at increased risk for maternal and fetal complications and should have a lower threshold for treatment [ underlying renal disease; secondary hypertension; end-organ damage (e.g., ventricular dysfunction, retinopathy); maternal age over forty years old; microvascular disease; history of stroke; previous perinatal loss; diabetes.
Gestational hypertension is elevated blood pressure, which develops after 20 weeks of gestation in a previously normotensive woman, though without proteinuria. It complicates 6% of all pregnancies. These women are at high risk for developing preeclampsia that can occur at any time including the first postpartum week and need close monitoring. Approximately 15–45% will eventually develop preeclampsia [
The general principles as outlined to guide the treatment of women with chronic hypertension are applicable to the preeclamptic patients. Close monitoring to recognize fetal distress while receiving treatment is essential. Early onset preeclampsia (less than thirty-four weeks) requires careful use of antihypertensive medications, bed rest, and in-hospital monitoring of both mother and fetus. This approach may help delay delivery and thus improve fetal outcome. Often these patients are intravascularly depleted and are more susceptible to precipitous, drug-induced drops in blood pressure. If signs of other fetal or maternal distress are noted, delivery is the definitive treatment. Concerns about hypotension and decreased uteroplacental blood flow are central to the treatment of the preeclamptic patient, since placental ischemia is the focal point of preeclampsia pathophysiology. Furthermore, lowering of BP does not reverse the primary process. The ultimate goal of antihypertensive therapy is to reduce the main risks to the mother, which include placental abruption, accelerated hypertension requiring hospitalization, and target organ-damage including cerebrovascular and cardiovascular complications. One must be cognizant of the risk for target organ damage is increased, when a sudden change in blood pressure occurs in previously normotensive women. As is true in all dynamic clinical settings, individualization of care is often the rule. In most instances, delivery of preeclamptics is indicated after 37 weeks of gestation or when fetal lung maturity has been confirmed.
Superimposed preeclampsia complicates approximately 25% of pregnancies in women with chronic hypertension [
The benefits of antihypertensive therapy for mild to moderately increased blood pressure in pregnancy (≤160/109 mm Hg), either chronic or de novo, have not been shown in clinical trials. A Cochrane meta-analysis concluded that there are insufficient data to determine the benefits and risks of antihypertensive therapy for mild-to-moderate hypertension (defined as blood pressure 140–160 mm Hg systolic or diastolic blood pressure 90–109 mm Hg) [
International guidelines for the treatment of hypertension in pregnancy vary with respect to thresholds for starting treatment and targeted BP goals. Therapy is recommended in the United states for a BP of 160/105 mm Hg or greater [
There is consensus that treatment is indicated for severe hypertension in pregnancy, defined as 160/110 mm Hg or greater, to prevent intracerebral hemorrhage and maternal death [
Patient with severe preeclampsia are managed differently as chances for maternal and fetal complications are much higher. The criteria for diagnosis of severe preeclampsia are outlined below: sustained systolic blood pressure ≥160 mm of Hg; sustained diastolic blood pressure of ≥110 mm of Hg; pulmonary edema; oliguria <500 mL/24 hours; persistent headaches or scotoma; thrombocytopenia <100,000/mm3; persistent right upper quadrant pain or epigastric pain; intrauterine growth restriction <10th percentile.
The ultimate treatment in severe preeclampsia is prompt delivery. The timing of delivery is based on both maternal and fetal indications. If gestational age is less than 34 weeks, expectant management, when possible should be attempted with the aim of improving neonatal outcome without compromising the safety of the mother. This requires close inpatient monitoring of both mother and the fetus. If possible, delivery should be 48 hours after glucocorticoid administration to maximize fetal lung maturity and improve neonatal outcome. Prior to delivery, the focus is to improve placental perfusion by enhancing cardiac output and peripheral vasodilatation. Patient should be placed in lateral or supine position, which will optimize venous return and cardiac output. These patients are often intravascularly volume-depleted and require some degree of perfusion. Magnesium sulfate seizure prophylaxis is typically initiated in severe preeclamptics. The recommended dose for magnesium sulfate is 4–6 gm iv over 20 minutes followed by continuous infusion at 2 g/hr, which will maintain most patient at therapeutic range of >4 meq/mL. Blood pressure management is same as outlined above for severe hypertension with target BP of 150/100. Rapid vasodilatation with consequent hypotension should be obviated by adequate intravascular resuscitation. An absolute fetal or maternal indication for delivery requires immediate intervention. Delivery can be induced with oxytocin and prostaglandin. If induction fails, cesarean delivery is indicated.
All antihypertensive drugs cross the placenta but to variable degrees and most are agents categorized as “Category C.” There are no data from large well-designed randomized trials strong enough to mandate the use of one drug over another. Different drugs will be discussed separately based on their pharmacological actions and summarized in Table
Antihypertensives in pregnancy.
Drugs | Method of action (MOA) | Side effects | Fetal concerns | Indication | Dosage |
---|---|---|---|---|---|
(A) Central acting | |||||
(1) Methyldopa agent of choice | Alpha2 agonist. Onset is gradual (6–8 hrs) | Decreased mental alertness, impaired sleep, sense of fatigue and depression, xerostomia | Considered safe (Category B) | Preferred drug for non emergent BP control | 0.5–3 gm PO in 2 divided doses |
(2) Clonidine | Alpha-2 agonist | As above | Limited data (Category C). Considered safe as same MOA as methyldopa | Nonemergent BP control | to 0.3 mg q8–12 hrs |
(B) Peripheral acting | |||||
(1) Labetalol | Beta and alpha blocker | Fatigue, lethargy, exercise intolerance, sleep disturbances, and asthma | Concern for LBW infants and decrease uteroplacental blood flow though long-term data suggesting safety. Risk of neonatal hypoglycemia at higher doses (Category C) | Nonemergent and emergent Bp control | 20–1200 mg in 2-3 divided doses. 10–20 mg IV then 20–80 mg IV every 20–30 minutes, maximum of 300 mg: for infusion 1-2 mg/min |
(A) Nifedipine | Calcium channel blocker Dihydropyridine | Tachycardia, palpitations, peripheral edema, headache, and facial flushing | Does not cause decrease maternal blood flow. Concern regarding concomitant uses with magnesium though not proven in recent evaluations (Category C) | Non-emergent and emergent BP control | 30–120 mg extended release preparations |
(A) Hydralazine | Selectively relaxes arteriolar smooth muscle by an unknown mechanism | Acutely: Headache, nausea, flushing, palpitations. Chronic use: Pyridoxine-responsive polyneuropathy or immunologic reaction like drug induced lupus | Effect on uteroplacental blood flow is uncertain. Associated with more maternal and perinatal adverse events than other agents when used acutely. Neonatal thrombocytopenia and Lupus have been reported. Not proven to be teratogenic | Useful in combination with sympatholytic agents. Used for emergent and nonemergent BP control | 50–300 PO mg in 2–4 divided doses. 5 mg IV, then 5–10 mg every 20–40 min: once BP controlled repeat every 3 hours. For infusion: 0.5 to 10 mg/hr |
(B) Sodium nitroprusside | |||||
Relatively contraindicated. Considered as a last resort | Direct NO inhibitor Non-selectively relaxes arteriolar and venular vascular smooth muscles | Excessive vasodilation and cardioneurogenic syncope in volume depleted patients. Cyanide toxicity if used greater than 4 hours. Labor arrest hyperglycemia | Risk of fetal cyanide intoxication remains unknown | Only for emergent Bp control as last resort | 30–50 mg IV every 5–15 minutes Infusion at 0.25–5.0 mcg/kg/min |
(A) Hydrochlorothiazide | Thiazide diuretics. Blocks Na channels in distal-convoluted tubules | Volume contraction and electrolyte disturbances. Hyperuricemia | Volume contraction may limit fetal growth, though not proven in studies | Nonemergent BP control | 12.5–25 mg/day |
Contraindicated in pregnancy. Should be discontinued prior to conception | ACE-I: inhibits angiotensin-converting enzyme interfering with conversion of angiotensin I to angiotensin II ARB: antagonizes ATI receptor | Angioedema, hypotension, hyperkalemia, renal failure. Cough (only in ACE-I) | ACE-I: renal dysgenesis, oligohydramnios, calvarial and pulmonary hypoplasia, IUGR. Neonatal anuric renal failure, fetal death Arbs: same concerns | Not indicated | N/A |
Methyldopa is one of the most widely used drugs for the treatment of hypertension in pregnancy. It is a prodrug metabolized to alpha methylnorepinephrine, which then replaces norepinephrine in the neurosecretory vesicles of adrenergic nerve terminals. BP control is gradual, over six to eight hours, because of the indirect mechanism of action. It is not thought to be teratogenic based on limited data and forty-year clinical experience. Treatment with methyldopa has been reported to prevent subsequent progression to severe hypertension in pregnancy [
Adverse effects are based on central alpha-2 blocking effect or decreased peripheral sympathetic tone. This drug can cause decreased mental alertness and impaired sleep, leading to sense of fatigue in some or depression in others. Still other observed side effects are decreased salivation, leading to xerostomia (chronic dry mouth), elevated liver enzymes in 5%; hepatitis and hepatic necrosis have also been reported. Some patients will develop a positive antinuclear antigen or antiglobulin (Coombs’) test with chronic use, which may occasionally cause clinical hemolytic anemia.
Clonidine, a selective alpha-2 agonist, acts similarly and is comparable to methyldopa with respect to safety and efficacy [
B-blockers have been extensively used in pregnancy. Concern still remains about their safety in pregnancy based on data derived from a few small studies, which suggests an association with low birth weight infants. Atenolol, for example, in one such study started at twelve to twenty-four weeks’ gestation, resulted in clinically significant fetal growth restriction and decreased placental weight compared with placebo [
Labetolol, a nonselective beta- and alpha-blocker has gained wide acceptance in pregnancy. Oral administration is considered safe and effective as methyldopa [
Peripherally acting alpha-adrenergic antagonists are second-line antihypertensive drugs in nonpregnant adults. These are indicated during pregnancy in the management of hypertension in patients suspected to have pheochromocytoma. Both prazosin and phenoxybenzamine have been used, with b-blockers used as adjunctive agents after alpha-blockade is accomplished [
These drugs have been used to manage chronic hypertension, mild pre-eclampsia presenting late in gestation and urgent hypertension associated with preeclampsia. Both nifedipine a nondihydropyridine calcium channel blocker and verapamil are not associated with teratogenic risks to fetus exposed in first trimester [
A concern with the use of calcium antagonists for BP control in preeclampsia has been the concomitant use of magnesium sulfate to prevent seizures. Drug interactions between nifedipine and magnesium sulfate were reported to cause neuromuscular blockade, myocardial depression, or, in some cases, circulatory collapse. Despite this concern, recent evaluation showed that these medications are commonly used together without increased risk.
Diuretics are first-line agents to be used in management of essential hypertension prior to conception and, based on their apparent safety, they may be continued during pregnancy alone or in combination with other agents especially in women more likely to have salt-responsive hypertension [
In women already taking, hydrochlorothiazide may be continued during pregnancy; use of low-doses (12.5 to 25 mg daily) may minimize untoward metabolic effects, such as impaired glucose tolerance and hypokalemia [
Hydralazine: selectively relaxes arteriolar smooth muscle by an as yet unknown mechanism. The most important indication is severe hypertension or a third-line agent in control of refractory hypertension. It can be used orally, intravenously, or intramuscularly. Adverse effects are due to excessive vasodilation or sympathetic activation (headache, nausea, flushing, or palpitations). Chronic use can lead to (in rare cases) a pyridoxine-responsive polyneuropathy or to immunologic reactions, including a drug-induced lupus syndrome. Hydralazine has been used in all trimesters of pregnancy, and data have not shown an association with teratogenicity, although neonatal thrombocytopenia and lupus have been reported [
this agent has been investigated in a small study of gestational hypertensive and preeclamptic pregnant patients. It was found that cerebral perfusion pressure is unaltered by isosorbide dinitrate, despite significant changes in maternal BP, thus decreasing the risk for ischemia and infarction, when BP is lowered [
This direct nitric oxide donor, which relaxes both arteriolar and venular vascular smooth muscles. It is used only as continuous infusion and is easily titrated because of its near immediate action of onset and only three-minute duration of action. Nitroprusside metabolism releases cyanide, which can reach toxic levels when infused rapidly. Cyanide metabolizes to thiocyanate which can lead to toxicity in 24–48 hours. Adverse effects include excessive vasodilation and cardioneurogenic (i.e., paradoxical bradycardia) syncope in volume-depleted preeclamptic women [
N.B.: The risk of fetal cyanide intoxication remains unknown. Given the long experience with hydralazine and alternative use of parenteral labetalol or oral calcium channel blockers, this drug is considered as a last resort.
Serotonin-induced vasodilation is mediated by S1 receptors and subsequent release of prostacyclin and NO. Ketanserin is a selective S2 receptor-blocking agent that has been used in the nonpregnant population. Based on the data available from Australia and South Africa, it may be safe to use in pregnancy and useful in treatment of chronic hypertension in pregnancy, preeclampsia, and HELLP syndrome [
ACE-I and ARB are contraindicated in 2nd and 3rd trimesters because of severe toxicity secondary to reduced renal perfusion of the fetal kidneys. Their use has been associated with renal dysgenesis, oligohydramnios as a result of fetal oliguria, calvarial and pulmonary hypoplasia, intrauterine growth restriction, and neonatal anuric renal failure, leading to death of the fetus [
Some women experience a rise in their BP in the postpartum period, which typically reaches a maximum on the fifth postpartum day. This has been attributed to volume expansion and fluid mobilization in postpartum period. The time period, beyond which patients with gestational hypertension and preeclampsia are labeled chronic hypertensive, is not well defined. The threshold for treatment in these patients has not been uniformly established, but medication is generally recommended to be started when systolic BP exceeds 150 mm Hg or diastolic BP is greater than 100 mm of Hg [
NSAIDS may contribute to postpartum hypertension as per few case reports [
Neonatal exposure to methyldopa via nursing is likely low and is generally considered safe. Atenolol and metoprolol are concentrated in breast milk, possibly to levels that could affect the infant; by contrast, exposure to labetolol and propanolol appears low [