Hypertension in Pregnancy and Women of Childbearing Age

REVIEW

Hypertension in Pregnancy and Women of Childbearing Age Scott R. Yoder, MD,a Loralei L. Thornburg, MD,b John D. Bisognano, MD, PhDa a

Department of Internal Medicine, Cardiology Division; bDepartment of Obstetrics and Gynecology, University of Rochester Medical Center, Rochester, New York.

ABSTRACT Hypertension in women of childbearing age is a challenging medical problem with increasing prevalence. Essential hypertension remains the most common diagnosis in young women. Reproductive goals and possible teratogenic effects must be considered when initiating therapy. Hypertensive disorders of pregnancy are frequent causes of maternal/fetal morbidity and mortality, the most common being preeclampsia/ eclampsia. Pregnant patients should be screened routinely. Early recognition and prompt care from a multidisciplinary service, including obstetrics, cardiology, and intensive medicine, are required to prevent deleterious outcomes. Hypertensive disorders of pregnancy reflect endometrial endothelial dysfunction/ abnormalities and systemic endothelial dysfunction, which might predict future cardiovascular disease in these young women, prompting early preventive measures. © 2009 Elsevier Inc. All rights reserved. • The American Journal of Medicine (2009) 122, 890-895 KEYWORDS: Hypertension; Preeclampsia; Pregnancy; Women

Women of childbearing age with hypertension represent an interesting and challenging population. As a general rule, women tend to have lower blood pressure than men. There is an age delay in the development of hypertension such that most women do not require hypertensive therapy during their childbearing years. However, the increasing prevalence of obesity and metabolic syndrome can herald increased numbers of younger women presenting with hypertension.1 The Joint National Committee 7 classification of hypertension and treatment goals remain the same regardless of age or gender.1 Significant hypertension in young patients should prompt consideration of secondary causes of hypertension. One of the particular challenges in evaluation and treatment of hypertension in women of childbearing age is the selection of medications because many have potential Funding: None. Conflict of Interest: None of the authors have any conflicts of interest associated with the work presented in this manuscript. Authorship: All authors had access to the data and played a role in writing this manuscript. Reprint requests should be addressed to John D. Bisognano, MD, PhD, Associate Professor of Medicine, University of Rochester, Department of Internal Medicine, Cardiology Division, 601 Elmwood Avenue, Box 679-7, Rochester, NY 14642-8679. E-mail address: [email protected]

0002-9343/$ -see front matter © 2009 Elsevier Inc. All rights reserved. doi:10.1016/j.amjmed.2009.03.036

teratogenicity necessitating counseling and discussion of reproductive goals. Several well-defined clinical hypertensive disorders are associated with pregnancy.2,3 All are thought to be associated with abnormal placentation leading to aberrant autonomic control and inappropriate release of vasoactive substances causing maternal or fetal morbidity and mortality. Appropriate diagnosis of these disorders and timely intervention (eg, medications, early delivery) are significant challenges necessitating close interdisciplinary management with the obstetric, cardiac, and general medical services.

TREATMENT OF ESSENTIAL HYPERTENSION IN WOMEN OF CHILDBEARING AGE The Joint National Committee 7 definition of hypertension and the treatment goals do not vary by age or gender (Table 1). Medications should be considered carefully before prescribing in women who may be or who are planning to become pregnant. Many common antihypertensive medications have teratogenic potential. The Food and Drug Administration has developed guidelines and recommendations for use of these medications during pregnancy. Medications with significant risk for fetal effects are identified as class D or have a black box recommendation and should be avoided. Angiotensin-converting enzyme inhibi-

Yoder et al

Hypertension in Pregnancy

891

tors are associated with renal agenesis, especially in the first tive to the pre-pregnancy state. This likely facilitates placentrimester of pregnancy. Angiotensin receptor blockers have tal perfusion, which is a low pressure system but requires high teratogenic effects similar to those of angiotensin-convertflux to maintain fetal growth. Maternal heart rate increases by ing enzyme inhibitors. approximately 10 beats/min, and cardiac output/index inMany medications fall into an ambiguous category with creases by 30% at 32 weeks gestation. The uterus and placenta no clinical evidence of harm but consume more than 20% of the carno controlled studies demonstratdiac output (equivalent to the kiding safety. The American Heart ney and brain at rest). Oxygen conCLINICAL SIGNIFICANCE Association, American College of sumption increases by 30%. By 20 Cardiology, and American Colweeks gestation, the uterus might ● Hypertension goals for women of childlege of Obstetrics and Gynecology impinge on the inferior vena cava bearing age are the same as for other have developed recommendations when supine, causing position-degroups. based on limited data sets and hispendent decreased cardiac pre-load● Physicians should consider reproductive torical data. There are many oping. These changes lead to increased goals when selecting medications. tions for hypertension managestress on the cardiovascular system ment that seem to carry minimal and can have profound effects on ● Hypertension during pregnancy is often risk in pregnancy and represent maternal blood pressure control. a symptom of an underlying syndrome good options for treatment.1,4-6 Several disorders result in a hywith significant maternal and fetal morWomen of childbearing age pertensive state during pregnancy. bidity and mortality. with class I hypertension likely Pre-gravid maternal medical illneed no medical therapy. They are nesses (eg, diabetes, hypertension, ● Early recognition and prompt treatment ideal candidates for lifestyle modobesity) increase the likelihood of of hypertensive disorders during pregification and exercise therapy. the developing these disorders and nancy are necessary to avoid deleteriThis is an ideal opportunity to incan increase the severity associous outcomes. tervene early with preventive ated with these disorders. Abnor● Hypertensive disorders of pregnancy likely measures to avoid future morbidmal placentation is thought to be ity. Available evidence demonkey to the development of these portend future cardiovascular disease. strates better blood pressure condisorders, which causes aberrant trol in patients who are able to maternal–fetal interaction and plaappropriately change their lifestyle. cental hypoperfusion. NeurohorOf note, hormonal contraceptive use remains a common cause monal feedback induces or exacerbates maternal hypertenof hypertension, and all women with new hypertension should sion in an attempt to maintain placental perfusion and fetal be asked about contraceptive use.1,7-10 growth. End-organ damage is caused directly by elevated blood pressure and by complicated multisystem disorders (eg, preeclampsia/eclampsia, hemolysis-elevated liver enNormal Hemodynamic Changes in Pregnancy zymes, and low-platelet syndrome). The most common disA detailed discussion of physiologic changes during pregorders of pregnancy are reviewed next. nancy can be reviewed from an obstetric text. The most Blood pressure in many patients with chronic hypertenimportant changes from cardiac/hemodynamic perspectives sion will decrease to appropriate levels in early pregnancy are reviewed in this article. Within the first 20 weeks of because of normal physiologic changes of pregnancy. Espregnancy, the total intravascular volume increases by 30% sential hypertension is independently associated with preto 40%. Red cell mass increases by approximately 20%, but eclampsia, although blood pressure therapy does not prewith the increased volume there is a relative decrease in the vent the development of preeclampsia/eclampsia. Treatment hematocrit (dilutional anemia). Increased intravascular volof maternal hypertension is primarily for the prevention of ume and neurohormonal changes lead to vasodilation relahypertension-related maternal sequelae. At this time, there are no compelling interventions to reduce the risk of developing preeclampsia.11-13 Table 1 Joint National Committee 7 Classification of Hypertension BP Classification

BP Measurement

Normal Pre-hypertension Hypertension Stage I Stage II

⬍120/80 120-139/80-89 ⬎140/90 140-159/90-99 ⬍160/100

BP ⫽ blood pressure.

Approach to Hypertension during Pregnancy Blood pressure in pregnant women should be screened regularly. The American College of Obstetricians and Gynecologists definitions of hypertension are broken into 2 subgroups: mild (140 to 159/90 to 109 mm Hg) and severe (⬎160/110 mm Hg), rather than the Joint National Committee 7 stages. International obstetric groups have varied recommendations regarding initiation of hypertensive therapy.1,5,14,15 There is little evidence in the obstetric literature to support aggressive med-

892

The American Journal of Medicine, Vol 122, No 10, October 2009

ical interventions for blood pressures ⬍160/110 mm Hg. The decision to treat hypertension must be individualized to a patient’s condition. Women with chronic hypertension tolerate higher blood pressures without complication; however, a marked increase in the risk of arterial hemorrhagic events occurs with blood pressures ⬎160/110 mm Hg associated with mortality rates of 50%. In many ways, the evaluation and treatment of pregnant women with severe hypertension do not differ from treatment of hypertensive urgency/emergency. In the presence of severe end-organ damage or neurologic compromise, rapid and aggressive parenteral interventions are necessary. The safety of the mother must come first, and early delivery of the fetus should be considered, especially in the setting of eclampsia. Immediate goals of therapy are a 25% reduction of mean arterial pressure within 2 hours of presentation and a goal of 160/110 over the next several hours. Abrupt reductions of ⬎25% mean arterial pressure might lead to maternal end-organ hypoperfusion (eg, cerebrovascular accident, myocardial infarction) or fetal compromise due to placental ischemia. Associated syndromes should be considered as causes of hypertension, such as preeclampsia, gestational hypertension, and acute fatty liver.

Table 2

Whenever possible, hypertensive therapy with lifestyle modification (diet and exercise) should be initiated and continued in pregnancy. Exercise has been associated with reductions in gestational hypertension and lower risk of eclampsia/preeclampsia.7-10 Most pregnant women can tolerate some degree of dietary restriction and exercise. Care must be taken in making these recommendations for pregnant women to maintain appropriate caloric intake and prevent injury, and obstetric evaluation is recommended to rule out any pregnancy-related hypertension syndromes. Table 2 lists common antihypertensive medications used during pregnancy, as well as pregnancy class, class of action, and common side effects. First-line medical agents include L-methyldopa, labetalol, and nifedipine. The largest literature base exists for methyldopa, which is often the first medication attempted in pregnant patients. It is the only Food and Drug Administration class B medication for hypertension. Labetalol also has a long history of safety and is increasingly used because of its efficacy and tolerability, although some studies have associated it with fetal growth restriction.5 Angiotensin-converting enzymes/angiotensin receptor blockers are effective medications for chronic hypertension but should be avoided in women who are pregnant or might become preg-

Hypertensive Medications for Use during Pregnancy

Drug First-line agent Methyldopa (B) Second-line agent Labetalol (C)

Route

Dose

Activity Time

Action

Side Effects

PO

0.25-1.5 g twice per day

3-5 d

False neurotransmitter

Orthostasis, sleepiness

PO/IV

200-1200 mg/d 2 or 3 times per day in divided doses 20-40 mg IV every 30 min as needed 30-120 mg/d

2-4 h/5 min

Nonselective ß-blockade Tremulousness, headache

30 min

Calcium channel blocker

50-300 mg/d 2 or 3 times per day 10 mg IV every 2 h as needed 12.5-25 mg daily Variable

1-2 h/20-30 min

Direct vasodilator

3-5 d 1-2 wk

Diuretic Selective ß-blocker

25-150 mg daily

3-5 d

Selective ß-blocker

Generally safe, bradycardia, may decrease uteroplacental perfusion, neonatal hypoglycemia at higher doses Bradycardia

30-50 mg IV every 5-15 min 0.25-5 ␮g/kg/min

2-4 min

Direct vasodilator

Hypotension, hypoglycemia

1-2 min

Direct vasodilator

Hypotension, cyanide toxicity if used ⬎ 4 h

Nifedipine (C)

PO

Hydralazine (C)

PO/IV

HCTZ (C) Selective ß-blockers (C)

PO PO

Metoprolol (C) PO/IV Emergency Medications IV labetalol as noted above IV hydralazine as noted above Nifedipine (C) as noted above Diazoxide (C) IV Nitroprusside (C or D)

IV

IV ⫽ intravenously; PO ⫽ by mouth; HCTZ ⫽ hydrochlorothiazide.

Edema, orthostasis, dizziness Lupus-like syndrome with chronic use

Yoder et al

Hypertension in Pregnancy

nant. These medications are associated with renal agenesis and fetal demise. If a woman becomes pregnant while taking angiotensin-converting enzymes/angiotensin receptor blockers, the medications should be stopped immediately. If these medications are thought to be necessary for hypertensive control in the non-pregnant patient, careful counseling and contraception discussion are required. Diuretics are probably safe in pregnancy, although there are theoretic concerns regarding decreased uteroplacental perfusion. These problems are less likely in women treated chronically with thiazide diuretics before conception; however, in general these would not be first-choice agents during pregnancy.16 Calcium channel blockers are likely safe during pregnancy. The majority of evidence has been accumulated in nifedipine, but case reports demonstrating efficacy and safety have been published regarding nicardipine, isradipine, verapamil, and felodipine. Theoretic concerns exist regarding calcium channel blocker use early in pregnancy because many processes of embryogenesis are calcium-dependent. Pregnancy outcome data in humans after exposure to calcium channel blockers are not adequate to assess risk,17 but the largest randomized trial to date demonstrated no significant risk.18 Because of the increased renal and hepatic clearance, starting doses and administration frequency often require adjustment.17 Case reports have been published of concomitant magnesium sulfate and nicardipine administration causing neuromuscular blockade or circulatory compromise. Magnesium is used for seizure prevention in preeclampsia, and this interaction is of concern for the obstetrician. Beta-blockers, especially labetalol, compare favorably with other antihypertensives for use during pregnancy.5,19 Selective beta-blockade agents are considered safe, but because they have less vasodilatory activity there is a higher risk of bradycardia. At higher doses, beta-blockers are associated with transient neonatal hypoglycemia, and atenolol has been associated with fetal growth restriction.

Chronic Hypertension Chronic hypertension, present before pregnancy or before 20 weeks gestation, complicates approximately 3% of all pregnancies. Essential hypertension is most common, although some women develop hypertension during the early periods of pregnancy. Many women with essential hypertension will not experience the usual decrease in blood pressure, or despite normal physiologic response, their blood pressure will remain in a range requiring therapy. Chronic hypertension tends to be more prevalent in African Americans, women who are obese, or women of advanced maternal age (⬎35 years).

Preeclampsia/Eclampsia Preeclampsia is a syndrome of new-onset hypertension (⬎140/90) occurring after the 20th week of gestation with proteinuria (2⫹ dipstick on 2 occasions 6 hours apart or ⬎300 mg/24 hours). Preeclampsia occurs at any time during gestation or the postpartum period with up to one third of cases occurring within 6 weeks after delivery. The syn-

893 drome occurs in approximately 4% of all pregnancies2,20-22 but complicates up to 25% of pregnancies in women with chronic hypertension.23 Abnormal placental implantation causes abnormal interactions between maternal and fetal blood vessels supplying the placenta, leading to placental hypoperfusion.24-28 The resulting neurohormonal response to maintain placental perfusion causes maternal endothelial dysfunction resulting in preeclampsia: hypertension, proteinuria, central nervous system dysfunction (cerebral edema, seizures, and occipital headaches), and hepatic dysfunction (elevated liver enzymes and low platelets).26,29-33 Preeclampsia is divided into mild and severe categories. Severe preeclampsia is defined by hypertension (⬎160/ 100), proteinuria ⬎5 g/24 hours, neurologic symptoms (seizures, headache, schiomita), renal compromise (oliguria, elevated creatine), hepatic dysfunction or hemolysis, elevated liver enzymes, low platelet count syndrome, or fetal growth restriction less than the 10th percentile. The presence of severe preeclampsia, hemolysis, elevated liver enzymes, and low platelet count syndrome, in particular, constitutes a medical emergency requiring admission, a trained obstetric service, and often a multidisciplinary medical service. The ultimate therapy for preeclampsia/eclampsia is delivery of the baby, which might be necessary at significant prematurity or even before viability. Women with earlyonset, severe preeclampsia have the potential to become ill quickly and need close monitoring, often in an intensive care unit and with a multidisciplinary service. The development of hypertension is related to placental underperfusion. The downstream effects are caused by the placental response to hypoperfusion and not directly related to the blood pressure. Consequently, treatment of the blood pressure will not prevent sequelae of preeclampsia/eclampsia. However, the blood pressure may increase quickly and require therapy for hypertensive emergency. Preeclampsia complicated by maternal seizure is eclampsia. Magnesium prevents seizures by altering membrane permeability and increasing seizure threshold. Patients with severe preeclampsia should be treated with magnesium sulfate during labor and the first 24 hours after delivery, because the majority of seizures will occur during this period. Seizures have been known to occur up to 6 weeks after delivery. Magnesium also might have additional benefits on maternal blood pressure, but these are often transitory. Most women with severe preeclampsia will require postpartum blood pressure medications for at least 6 weeks. When choosing antihypertensive agents, reproductive and breastfeeding plans should be considered. Preeclampsia likely represents a spectrum of endothelial disorder leading to downstream health effects. Although the exact mechanism remains unclear, preeclampsia affects future health. Women with a history of preeclampsia are twice as likely to develop hypertension and 2 to 5 times more likely to have ischemic stroke.34,35 Studies examining links between ischemic heart disease and preeclampsia have variable results but suggest an association.36,37 Guidelines and population studies to prevent morbidity and mortality are not developed.

894

The American Journal of Medicine, Vol 122, No 10, October 2009

Gestational Hypertension Gestational hypertension, development of hypertension after 20 weeks gestation without evidence of preeclampsia, occurs in 6% of pregnancies. Women with gestational hypertension progress to preeclampsia in 15% to 45% of cases. These patients should be evaluated to determine whether preeclampsia or other causes of gestational hypertension exist. These patients often require early delivery, and close fetal monitoring is recommended.

Conditions Mimicking Pre-eclampsia/Eclampsia Three clinical disorders present similarly to preeclampsia and deserve attention.3 Acute fatty liver of pregnancy affects approximately 1 of 10,000 pregnancies and presents in late pregnancy (27-40 weeks). It is likely due to fetal longchain 3-hydoxyacyl-coenzyme A dehydrogenase, a recessively inherited defect in mitochondrial function.23 Patients typically present with 1 to 2 weeks of progressive fatigue, malaise, anorexia, nausea, vomiting, mid-epigastric or right upper quadrant pain, and jaundice. Mental status changes, fever, hypertension, proteinuria, severe hyperglycemia, and coagulopathy due to hepatic dysfunction are common. Ultrasound, computed tomography, or magnetic resonance imaging of the abdomen may demonstrate fatty infiltration of the liver, but the best modality (computed tomography) is diagnostic in only 50% of cases.38 Definitive diagnosis by liver biopsy is rarely performed because of procedural risk and relatively high sensitivity/specificity of laboratory findings combined with imaging. Bilirubin levels are typically higher (5-10 mg/dL) in acute fatty liver of pregnancy with than preeclampsia rarely exceeding 2 mg/dL. Maternal mortality rates are 12% in tertiary centers and dependent on prompt recognition and delivery.23 Thrombotic thrombocytopenic purpura and hemolytic uremic syndrome occurs rarely but is strikingly aggressive during pregnancy. The cause involves aggregation of platelets in the renal arteriolar bed and endothelial injury causing release of thrombomodulin and large multimers of Von Willebrand factor that disseminate to other organs, causing end-organ damage. The classic pentad of thrombotic thrombocytopenic purpura and hemolytic uremic syndrome (thrombocytopenia, microangiopathic hemolytic anemia, neurologic abnormalities, fever, and renal dysfunction) has significant clinical overlap with eclampsia, making diagnosis difficult. Early-onset hypertension or hemolysis, elevated liver enzymes, and low platelet count syndrome before 20 weeks of gestation should prompt consideration of thrombotic thrombocytopenic purpura and hemolytic uremic syndrome. Plasmapheresis and early detection have reduced the mortality from 60% to single digits. Fetal/neonatal outcomes are poor with mortality rates up to 40%. Women with systemic lupus erythematosus often have underlying hypertension, proteinuria, and microscopic hematuria. Lupus flares occur in 25% to 30% of pregnant women with thrombocytopenia, worsening renal function,

Table 3

Hypertensives Compatible with Breastfeeding

Enalapril/Captopril (caution if patient is planning another pregnancy) Diltiazem Hydralazine Hydrochlorothiazide Labetalol Methyldopa Minoxidil Nadolol Nifedipine Oxprenolol Propranolol Spironolactone Timolol Verapamil

severe hypertension, fevers, and skin lesions. Although less common, lupus cerebritis does occur, causing central nervous system dysfunction mimicking severe preeclampsia symptoms. Patients with severe nephritic flares often present with symptoms and laboratory findings of preeclampsia and hemolysis, elevated liver enzymes, and low platelet count syndrome. Low complement levels, typical of a systemic lupus erythematosus and rare in preeclampsia, can assist diagnosis. Antiphospholipid antibodies are common (30%40%) in patients with lupus and cause thromboembolic events and thrombotic microangiopathy similar to hemolysis, elevated liver enzymes, and low platelet count syndrome. Thrombocytopenia is seen in approximately 50% of cases, and hemolytic anemia is seen in 25% of cases. Catastrophic antiphospholipid syndrome with diffuse, acute thrombotic microangiopathy of multiple organ systems (commonly heart, kidney, and central nervous system) rarely occurs. Diagnosis and management are further complicated because 20% of patients with lupus without renal disease, and 2 of 3 patients with lupus with baseline renal disease, will develop preeclampsia during the pregnancy.23 Fetal growth restriction is often associated with both systemic lupus erythematosus and antiphospholipid antibody syndrome. Patients with lupus should undergo baseline renal function and 24-hour urine assessment early in pregnancy to assist diagnosis should symptoms develop. Maternal medicine specialists should be closely involved in the management of these pregnancies. Patients developing early-onset (⬍32 weeks) severe preeclampsia should be tested for underlying autoimmune disorders (systemic lupus erythematosus, antiphospholipid syndrome, and inherited/acquired thrombophilia).23

Treatment of Hypertension during Breastfeeding Postpartum, hemodynamics return to normal within 3 to 5 weeks. Blood pressure should be monitored after delivery. Therapy should be continued/initiated if blood pressure re-

Yoder et al

Hypertension in Pregnancy

mains elevated 3 to 5 days after delivery. Future reproductive plans and breastfeeding should be considered in selecting medications. Table 3 lists several medications commonly prescribed during lactation. Lactation specialists, texts, and online sources are available to help guide recommendations.39,40

CONCLUSIONS Hypertension is a growing problem in women of childbearing age requiring attention to reproductive goals before therapy. Chronic hypertension during pregnancy requires reassessment of blood pressure therapy. Regular screening for hypertension during pregnancy is required because it is a harbinger of dangerous multiorgan syndromes. Therapy should be initiated for severe hypertension (⬎160/110 mm Hg) during pregnancy. Therapy is aimed at avoiding direct morbidity and mortality associated with hypertension (intracerebral hemorrhage and stroke). Postpartum patients should be monitored for hypertension and treated according to Joint National Committee 7 guidelines with attention to reproductive goals and breastfeeding. The development of preeclampsia has long-term implications for the development of hypertension, risk of stroke, and ischemic coronary disease.

References 1. Chobanian AV, Bakris GL, Black HR, et al and the National High Blood Pressure Education Program Coordinating Committee. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 report. JAMA. 2003;289:2560-2572. 2. Cunningham FG, Lindheimer MD. Hypertension in pregnancy. N Engl J Med. 1992;326:927. 3. Sibai, Baha M. Imitators of severe preeclampsia. Obstet Gynecol 2007;109:956-966. 4. Abalos E, Duley L, Steyn D, Henderson-Smart D. Antihypertensive drug therapy for mild to moderate hypertension during pregnancy. Cochrane Database Syst Rev. 2007;CD002252. 5. Podymow T, August P. Update on the use of antihypertensive drugs in pregnancy. Hypertension. 2008;51:960-969. 6. Report of the National High Blood Pressure Education Program Working Group on High Blood Pressure in Pregnancy. Am J Obstet Gynecol. 2000;183:S1-S22. 7. Gavard JA, Artal R. Effect of exercise on pregnancy outcome. Clin Obstet Gynecol. 2008;51:467-480. 8. Sorensen TK, Williams MA, Lee IM, et al. Recreational physical activity during pregnancy and risk of preeclampsia. Hypertension. 2003;41:1273-1280. 9. Saftlas AF, Logsden-Sackett N, Wang W, et al. Work, leisure-time physical activity, and risk of preeclampsia and gestational hypertension. Am J Epidemiol. 2004;160:758-765. 10. Rudra CB, Williams MA, Lee IM, et al. Perceived exertion during prepregnancy physical activity and preeclampsia risk. Med Sci Sports Exerc. 2005;37:1836-1841. 11. Hacker N, Moore G, editors. Essentials of Obstetrics and Gynecology, 3rd edition. 1998. Chapter 9. 12. Zipes D, Libby P, Bonow R, Braunwald E, editors. Braunwald’s Heart Disease: A Textbook of Cardiovascular Medicine. 7th edition. 2004. Chapters 73 and 74. 13. Murphy J, Lloyd M, editors. Mayo Clinical Cardiology: Concise Textbook. 3rd edition. 2007. Chapter 62. 14. Helewa ME, Burrows RF, Smith J, et al. Report of the Canadian Hypertension Society Consensus Conference: 1. Definitions, evaluation and classification of hypertensive disorders in pregnancy. CMAJ. 1997;157:715-725.

895 15. Brown MA, Hague WM, Higgins J, et al. The detection, investigation and management of hypertension in pregnancy: full consensus statement. Aust N Z J Obstet Gynaecol. 2000;40:139-155. 16. Briggs GG, et al. Drugs in Pregnancy and Lactation. 4th ed. Baltimore: Williams & Wilkins; 1994:161-164/c. 17. Smith P, Anthony J, Johanson R. Nifedipine in pregnancy. Br J Obstet Gynaecol. 2000;107:299-307. 18. Bortolus R, Ricci E, Chatenoud L, Parazzini F. Nifedipine administered in pregnancy: effect on the development of children at 18 months. BJOG. 2000;107:792-794. 19. Magee LA, Elran E, Bull SB, et al. Risks and benefits of beta-receptor blockers for pregnancy hypertension: overview of the randomized trials. Eur J Obstet Gynecol Reprod Biol. 2000;88:15-26. 20. Walker JJ. Preeclampsia. Lancet. 2000;356:1260-1265. 21. Roberts JM, Cooper DW. Pathogenesis and genetics of preeclampsia. Lancet. 2001;357:53-56. 22. Duley L, Shireen M, Edgardo A. Management of pre-eclampsia. Br Med J. 2006;332:463-468. 23. Creasy RK, Resnik R, Iams JD, editors. Creasy and Resnick’s Maternal-Fetal Medicine: Principles and Practice Sixth Edition. Philadelphia, PA: Saunders Elsevier; 2009. 24. Brosens IA. Morphological changes in the utero-placental bed in pregnancy hypertension. Clin Obstet Gynaecol. 1977;4:573-593. 25. Roberts JM, Redman CW. Pre-eclampsia: more than pregnancy-induced hypertension. Lancet. 1993;341:1447. 26. Roberts JM, Taylor RN, Musci TJ, et al. Preeclampsia: an endothelial cell disorder. Am J Obstet Gynecol. 1989;161:1200-1204. 27. Granger JP, Alexander BT, Llinas MT, et al. Pathophysiology of preeclampsia: linking placental ischemia/hypoxia with microvascular dysfunction. Microcirculation. 2002;9:147-160. 28. Huppertz B. Placental origins of preeclampsia: challenging the current hypothesis. Hypertension. 2008;51:970-975. 29. Visser N, van Rijn BB, Rijkers GT, et al. Inflammatory changes in preeclampsia: current understanding of the maternal innate and adaptive immune response. Obstet Gynecol Surv. 2007;62:191-201. 30. Yang X, Ramin SM, Kellems RE. Potential roles of angiotensin receptor-activating autoantibody in the pathophysiology of preeclampsia. Hypertension. 2007;50:269-275. 31. Wallukat G, Homuth V, Fischer T, et al. Patients with preeclampsia develop agonistic autoantibodies against the angiotensin AT1 receptor. J Clin Invest. 1999;103:945-952. 32. de Jong CL, Dekker GA, Sibai BM. The renin-angiotensin-aldosterone system in preeclampsia. A review. Clin Perinatol. 1991;18:683-711. 33. Alhenc-Gelas F, Tache A, Saint-Andre JP, et al. The renin-angiotensin system in pregnancy and parturition. Adv Nephrol Necker Hosp. 1986; 15:25-33. 34. Adams EM, MacGillivray I. Long-term effect of preeclampsia on blood-pressure. Lancet. 1961;2:1373-1375. 35. Sibai BM, Mercer B, Sarinoglu C. Severe preeclampsia in the second trimester: recurrence risk and long-term prognosis. Am J Obstet Gynecol. 1991;165:1408-1412. 36. Harskaqmp RE, Zeeman GG. Preeclampsia: at risk for remote cardiovascular disease. Am J Med Sci. 2007;334:291-295. 37. Wilson BJ, Watson MS, Prescott GJ, et al. Hypertensive diseases of pregnancy and risk of hypertension and stroke in later life: results from cohort study. Br Med J. 2003;326:845-851. 38. Castro MA, Fasset MJ, Reynolds TB, et al. Reversible peripartum liver failure: a new perspective on diagnosis, treatment and cause of acute fatty liver of pregnancy based on 28 cases. Am J Obstet Gynecol. 2000;181:389-395. 39. Briggs GG, Freeman RK, Yaffe SJ. Drugs in Pregnancy and Lactation: A Reference Guide to Fetal and Neonatal Risk. 8th ed. Baltimore: Lippincott Williams & Wilkins; 2008. 40. Schaefer C, Peters PWJ. Drugs During Pregnancy and Lactation. 2nd edition. Academic Press; 2007.