Chapter 43 PREGNANCY-RELATED HYPERTENSION James M. Roberts, MD © CLASSIFICATION AND DEFINITIONS The hypertensive disorders of pregnancy challenge the medical and obstetric skills of the health care team. Decisions ws 0 the possible use and appropriate choice of pharmaco- logic agents require not only an understanding of the patho- physiology of the hypertensive disorders and a recognition of the pharmacokinetic changes occurring during pregnancy but also an appreciation of the possible fetal effects of such ther- apeutic agents. Obstetric management demands meticulous maternal observation and use of tests of fetal-placental fune- tion and fetal maturity in order to weigh maternal risks and the risks to the infant of intrauterine versus extra existence. ‘The management of elevated blood pressure (BP) and the impact of the disorder on the mother and fetus depend on whether hypertension antedated the pregnancy or appeared as the marker of pregaancy-specific vasospastic syndrome. An. attempt to distinguish between the two has led to several systems of nomenclature and classification. The hypertensive disorders of pregnancy were for many years mregnancy, a verm that originally included even hyperemesis gravidarum and acute yellow atrophy of the liver. This term reflected the opinion that these disorders had, as a common etiology, circulating toxins, Failure to identify these toxins did riot lead to a revision of this terminology, a circumstance which is indicative of the continuing confusion that has plagued the taxonomy of these disorders, This archaic rermi- nology, which neither describes the disorders nor clarifies t etiology, has rightly been abandoned. (One of the difficulties in interpreting studies of the hyper- tensive disorders of pregnancy is the inconsistency of termi- nology (Rippman, 1969). Several systems of nomenclature are in use around the world. The system prepared by the National Institutes of Health (NIH) working group on hypertension in pregnancy (Gifford et al., 2000a) although as imperfect as all such systems, has the advantage of clarity and is available in published form to investigators throughout the world. This classification is as follows led toxemias of & Chronic hypertension m Preeclampsia-eclampsia Preeclampsia superimposed upon chronic hypertension 1 Gestational hypertension The various classifications are explained in the following discussion, Chronic Hypertension Chronic hypertension is defined as hypertension that is present and observable prior to pregnancy or that is diagnosed before the 20th week of gestation. Hypertension is defined as a blood pressure greater than 140/90 mm Hg. Hypertension for which a diagnosis is confirmed for the first time during preg nancy, and which persists beyond the 84th day postpartum, is also classified as chronic hypertension, Preeclampsia and Eclampsia The diagnosis of preeclampsia is determined by increased blood pressure accompanied by proteinuria... Diagnostic blood pressure increases are either a systolic blood pressure of greater than of equal to 140 mm Hy or a diastolic blood pressure of seater than or equal to 90 mm Hg, Diastolic blood pressure is determined as Krotkoff V (disappearance of sounds), Ie is ec ommended that gestational blood pressure elevation be defined on the basis of at least two determinations. The repeat blood pressure should be performed in a manner that will reduce the likelihood of artifact and/or patient anxiety (Gifford et al., 2000b), Absent from the diagnostic criteria ts the former inclusion of an increment of 30 man Hg systolic or 15 mm Hg diastolic blood pressure, even when absolute values are below 140/90 mm Hg. This definition was excluded because the only available evidence shows that women in this group are not likely to suffer increased adverse outcomes (North et al,, 1999; Zhang et al., 2001). Nonetheless, women who have a rise of 30 mm He systolic or 15 mm Hg diastolic blood pressure warrant close observation, especially if pro- teinuria and hyperuricemia (uric acid [UA] greater than or equal t0 6 mg/dL) are also present (Gifford et al., 2000). Proteinuria is defined as the urinary excretion of 03 protein or greater in a 24-hour specimen. This will usually correlate with 30 myjdL ("I+ dipstick”) or greater in a random: urine determination. Because of the discrepancy between random protein determinations and 24-hour urine protein in preeclampsia (which can be either higher or lower) (Abuelo, 1992; Kua et al, 1992; Meyer et al., 1994), itis recommended that the diagnosis be hased on a 24-hour urine specimen if at all possible of, if this is not feasible, it should be based fon a timed collection corrected for creatinine excretion Gifford et al., 2000b). Preeclampsia occurs as a spectrum but is arbitrarily divided into mild and severe forms. This terminology is useful for clescriprive purposes but does not indicate specific diseases, not 859860 43/Pregnancy-Related Hypertension should it indicate arbitrary cutoff points for therapy. The diag: nosis of severe preeclampsia is confirmed when the following ctiteria are present: Systolic blood pressure of 160 mm Hg or greater, or diastolic pressure of 110 mm Hg or greater 2, Proteinuria of 2 g or more in 24 hours (2- or 3-plus on qual- itative examination) 3. Increased serum creatinine (greater than 1.2 mgldL. unless known to be previously elevated) Persistent headache or cerebral or visual disturbances . Persistent epigastric pair Platelet count ess then 100,000/mm: and/or evidence of microangiopathic hemolytic anemia (with increased lactic acid dehydeogenase) oat Eclampsia is the occurrence of seizures in a proeclampric patient that cannot be attributed to other causes, Edlema occurs in too many normal pregnant women to be discriminant and has been abandoned as a marker in preeclampsia by the National High Blood Pressure Education, Program (NHBPEP) and by other classification schemes (Brown et al, 2001; Helewa et al., 1997; Practice, 2002). Preeclampsia Superimposed on Chronic Hypertension There is ample evidence that preeclampsia can occur in women who ate already hypertensive and that the prognosis for mother and fetus is much worse for these women than with, either condition alone. Distinguishing superimposed preeclampsia from worsening chronic hypertension tests the skills of the clinician. For clinical management, the principles of high sensitivity and unavoidable overdiagnosis are appropri- ate. The suspicion of superimposed preeclampsia mandates close observation, with delivery indicared by the overall assess- ‘ment of maternal-fetal well being rather than by any fixed end- point. The diagnosis of superimposed preeclampsia is highly likely with the following findings: 1. In women with hypertension and no proteinuria early in Pregnancy (prior to 20 weeks’ gestation) and new-onset proteinuria, defined as the urinary excretion of 0.3 g protein ‘or more in a 24-hour specimen 2. In women with hypertension and proteinuria prior to 20 weeks’ gestation: a. A sudden increase in proteinuria—urinary excretion of 0.3 g protein or more in a 24-hour specimen, or ewo dlipstick-test results of 2+ (100 mg/dL), with the values recorded at least 4 hours apart, with no evidence of urinary tract infection b. A sudden increase in blood pressure in a woman whose blood pressure has previously heen well controlled «. Thrombocytopenia (platelet count lower 100,000/mm:) An inctease in ALT or AST to abnormal levels (Gifford cet al., 2000b) than Gestational Hypertension The woman who has blood pressure elevation detected for the first time during pregnancy, without proteinuria, is classified as having gestational hypertension. This nonspecific term includes women with preeclampsia syndrome who have not yet manifested proteinuria as well as women who do not have the syndrome. The hypertension may be accompanied by other signs of the syndrome, which will influence manage- ment. The final differentiation chat the woman does not have preeclampsia syndrome is made only postpartum. If preeclamp- sia has not developed and blood pressure has returned to normal by 12 weeks postpartum, the diagnosis of mansient hypertension of pregnancy can be assigned. If blood pressure ele vation persists, the woman is diagnosed as having chronic hypertension. Note that the diagnosis of gestational hypetten- sion is used during pregnancy only until a more specific din ‘nosis can be assigned postpartum (Gifford et al, 2000b). Problems with Classification The degree of blood pressure elevation that constitutes ges- tational hypertension is controversial. Because average blood pressure in women in their teens to 208 is 120/60 mim Hy, the stanclatd definition of hypertension—blood pressure greater than 140/90 mm Hg—is judged by some investigators to be too high (Vartran, 1966). This has resulted in the suggestion in the NHBPEP report that women with increased BP greater than 30 mm Hg systolic or 25 mm He diastolic be observed closely even if absolute blood pressure has not exceeded 140/90. There are also problems inherent in the use of blood pres- sures measured in early pregnancy to diagnose chronte hyper tension. Blood pressure usually decreases early in pregnat reaching its nadir at about the stage of pregnancy at which women usually present for obstetric care (Fig. 43-1). The decrease averages 7 mm Hyg for diastolic and systolic readings. In some women, obviously, blood pressure decreases more tha 7 mm Het in others, the early decline and subsequent return of blood pressure to prepregnant levels in late gestation are sufficient for a diagnosis of preeclampsia. Women who have hypertension prior to pregnancy actually experience a greater decrease in blood pressure in early pregnancy than do nor- motensive women (Chesley and Annitto, 1947) and thus are sm Hg 125 Systoe PARAG nsf. 10 75| Diastolic 16 20 24 28 3296 a0 Gestational age (weeks) FIGURE 43-1 Mean blood pressure by gastational age in {8000 Caucasian women 25-24 years of age who delivered singleton term infants. (From Christianson &, Page EW. Stucies on blood pressure during pregnancy: Influence at party and age. Am J Obstet Gynecol 126:509, 1876. Courtesy of the American College of Obstetricians and Gynecologists)Mig TABLE 42-1. RENAL BIOPSY FINDINGS IN PATIENTS. 43/Pregnancy-Related Hypertension 61 WITH CLINICAL DIAGNOSIS OF PREECLAMPSIA Biopsy Findings Primigravidas (N= 62) ‘Multigravidas (N = 152) Glomeruloendotheliosis 70% Normal histologic appearance 5 Chronic renal disease (chronic GTN, chranic pyelonephritis) 255 Asteriolar nephrosclerosis ° GN, gostatenal wophebiastie neoplasia, 1% 4436 (with or without nephrosclerosis) 3% 533% 5% 21% 12% Mociod rom McCartney CP; Pathological anatomy of acuta hypertension of oregrancy. Coulton 30Supph7, 1064, by permission ofthe Aenican Heart Associaton Ine even more likely to be misdiagnosed as preeclamptic according, co blood pressure criteria. ‘Also, the diagnosis of chronic hypertension based on the failure of blood pressure to return to normal by 84 days post- partum can be in error. In a long-range prospective study by Chesley (1956), many women who remained hypertensive 6 weeks postpartum were normotensive at long-term follow- up. Even the proteinuria and hypertension are nonspecific signs, and their presence in pregnancy could be due to condi- tions other than preeclampsia Renal biopsy specimens from women with a diagnosis of preeclampsia (blood pressure increase and proteinuria) demon: strate these diagnostic difficulties (Table 43-1) (McCartney, 1964). Of 62 women with a diagnosis of preeclampsia in their fist pregnancies, 70% had a glomerular lesion believed to be characteristic of the disorder; 24%, however, had evidence of chronic renal disease that had not been suspected previously Renal biopsy specimens of multiparous women with a clinical diagnosis of superimposed preeclampsia also demonstrates the difficulty in diagnosis. Of 152 subjects, only 3% had the char- acteristic glomerular lesion, but 43% had evidence of preexist- ing renal or vascular disease. Preeclampsia has a clinical spectrum ranging from mild to severe forms and then potentially to eclampsia. Affected patients do not “catch” eclampsia or the severe forms of preeclampsia bur rather progress through this spectrum, In most cases, progression is slow, and the disorder may never proceed beyond mild preeclampsia. In others, the disease can progress more rapidly, changing from mild to severe over days to weeks. In the most serious cases, progression can be fulmi- nant, with mild preeclampsia evolving to severe preeclampsia or eclampsia over hours to days In a series of eclampric women analyzed by Chesley (1978), 25% had evidence of only mild preeclampsia in the days pre- ceding convulsions. Thus, for purposes of clinical manage- ment, we must accept the fact that we ate overdiagnosing the condition because, as discussed lates, a major goal in managing preeclampsia is the prevention of the serious complications of preeclampsia and eclampsia, primarily through timing of deli cry [vis also evident, however, that studies of preeclampsia w' be confounded by inclusion of women who have been given a diagnosis of preeclampsia but who actually have another car-” diovascular or renal disorder. HELLP It is quite evident that the pathophysiological changes of preeclampsia can_be present in the absence of hypertension and proteinuria. This should not be surprising, as these diag- nostic criteria are of historical rather than pathophysiological relevance. Hypertension and proteinuria were the first signs recognized as predicating preeclampsia (Chesley, 1978) Understanding this historical evolution presents a challenge to clinicians and dictates a high index of suspicion in managing pregnant women with signs and symptoms that could be explained by reduced organ perfusion. One clear setting in which this occurs is the HELLP syndrome; the acronym stands for Hemolysis, Elevated liver enzymes, and Low Platelets. This seties of findings defines a reasonably consistent syndrome that has now been studied for over twenty years (Weinstein, 1982), Although for management purposes it is appropriate to con- sider HELLP as a variant of preeclampsia, there are differences in several features of preeclampsia and HELLP that suggest they could be different entities. Women with HELLP tend to be older and are more likely to be Caucasian and multiparous than preeclamptic women; in many cases, they are not hyper tensive (Egerman and Sibai, 1999). From a pathophysiological perspective, changes in the renin-angiotensin system charac- teristic of preeclampsia are not present in HELLP (Bussen et al., 1998). Nonetheless, the progression of the disease and its termination with delivery argue for an observation and management strategy similar to that for preeclampsia. The serendipitous observation that women who had received “antepartum steroids appeared ro evidence improvement in the HELLP syndrome (Magan et al., 1993) stimulated several ret~ rospective and observational studies (Magan and Marcin, 1995; Martin et al., 1997; O'Brien et al., 2000; O'Brien et al., 2002; Tompkins and Thiagarajah, 1999; Yalcin et al. 1998). These studies and a small randomized controlled trial (Magan er al., 1994) suggest improvement in laboratory findings as well as prolongation of pregnancy. The determination of appropri- ate dosing and whether the benefit of therapy exceeds risks await larger, randomized controlled trials. @ PREECLAMPSIA AND ECLAMPSIA In spite of che difficulty of making a clinical diagnosis of preeclampsia, there is no question thac a disorder exists that is unique to pregnancy, characterized by poor perfusion of many vital organs (including the fetoplacental unit), and completely reversible with the termination of pregnancy, Pathologic, pathophysiologic, and prognostic findings clearly indicate that this condition, preeclampsia, is not merely an unmasking of preexisting, underlying hypertension. Although this fact hhas been well documented for many years, problems still arise owing to approaches in the management of preeclampsia that are based solely on principles useful in- managing