Antihypertensive therapy in pregnancy

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    InHymweocthRethtensinprancastamgrawhfolsivstugreffstrspthAntihypertensive Therapy in PregnancyJason G. Umans, MD, PhD, FACP*, and Marshall D. Lindheimer, MD, FACP

    dressivision of Nephrology and Hypertension, Georgetown University dical Center, 6PHC, 3800 Reservoir Road, NW, Washington, DC 007, USA.

    ail: jgu@georgetown.edu

    rrent Hypertension Reports 2001, 3:392399rrent Science Inc. ISSN 1522-6417pyright 2001 by Current Science Inc.

    troductionpertension in pregnancy remains a major cause of

    orbidity and mortality in the mother and fetus in bothstern and developing nations. Much of this morbiditycurs in women with chronic hypertension, especially inose who develop superimposed pre-eclampsia. In 1976dman et al. [1] published a landmark report describingeir randomized trial of methyldopa to treat chronic hyper-

    sion in pregnant women. There have been other trialsce then, some of excellent quality, and considerable

    ogress has been made towards understanding the etiologyd pathophysiology of the hypertensive disorders compli-ting gestation, particularly pre-eclampsia [2]. Yet, as wert this millennium, there are few guidelines on how to

    anage the most challenging of pregnant patients, thevida with pre-existing essential hypertension, includingen and how to treat with antihypertensive drugs. In thelowing sections we review evidence guiding antihyperten-e therapy in pregnant women; assess the contributions ofdies that shed light on the mechanisms of hypertension in

    avidas; direct the reader to several recent and ongoingorts that use the tools of meta-analysis to provide auctured review of this inadequate literature; highlightecific treatment recommendations of the expert panelsat have recently opined on this subject [35]; and

    present recommendations for critically needed research inthe area. Not discussed here are current recommendationsfor clinical surveillance of hypertensive gravidas, treatment ofeclamptic seizures, risk factors for pre-eclampsia or strategiesfor its prevention, or guidelines for counseling these patients;these have all been recently reviewed elsewhere [2,6,7].

    Maternal and Fetal Risks of Hypertension in PregnancyRegarding risk, we first must ask the following: 1) what arethe short-term risks of hypertension during pregnancy, 2)do available treatment trials allow us to advocateantihypertensive use for their control, 3) can we adequatelyjassess the comparative safety and efficacy of available anti-hypertensives, and 4) can we define appropriate therapeuticgoals and treatment protocols?

    The major maternal risk associated with underlyinghypertension that might justify pharmacotherapy is super-imposed pre-eclampsia, whose complications account formost, but not all, of the morbidity ascribed to chronichypertension during pregnancy [8]. Other risks that couldconceivably be modified by treatment include placentalabruption, accelerated hypertension leading to hospital-ization or to target organ damage, and cerebral vascularcatastrophes [9]. It is also conceivable that treatmentmight avert the fetal risks that include death, growthretardation, neonatal morbidity, and early delivery, thelatter occurring in many cases due to concerns regardingmaternal safety. Unfortunately, we have little data tosupport most of the above assumptions, and we needunequivocal answers to these questions for the followingreasons: First, although the diagnosis of superimposedpre-eclampsia is often difficult in the setting of chronichypertension (the careful clinician should always err infavor of cautious overdiagnosis), several well-conductedstudies suggest that superimposed pre-eclampsia willcomplicate at least 15% to 20% of pregnancies in womenwith blood pressures greater than 140/90 mm Hg, withincreased r i sk a t h igher va lues [9 ,10] . Second,hypertension doubles the incidence of placental abrup-tion [9,11], and in one large prospective study the riskwa s f u r t h e r i n c r e a s e d t h r e e f o l d w h e n c h r o n i chypertension was complicated by superimposed pre-eclampsia [9]. Finally, chronic hypertension is associated,with remarkable consistency, with a threefold increase inperinatal mortality [11], along with impaired fetalgrowth and neonatal outcome; early delivery, perinatal

    Human pregnancy, normally characterized by systemic vasodilation and modest hypotension, can be complicated by underlying maternal hypertension and several unique hypertensive disorders, including pre-eclampsia. Although well-designed and adequately powered clinical trials are critically needed, there have been several recent meta-analyses of this large literature, along with consensus statements and treatment guidelines from three distinct multidisciplinary groups of clinicians and investigators. In this paper we review recent analyses and guidelines, advising on our current approach to antihypertensive therapy in pregnant women.

  • Antihypertensive Therapy in Pregnancy Umans and Lindheimer 393

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    perfusion pressure. However, despite the accord between

    women with either superimposed pre-eclampsia orth target organ damage as evidenced by proteinuria atseline [9].Currently, it appears that treatment of underlying hyper-

    nsion does not prevent superimposed pre-lampsia, abruptio placenta, or reliably decrease perinatalortality; however, these conclusions are based on the results several small trials whose results vary considerably [11]. The major apparent benefit of antihypertensive therapypears to be decreased occurrence of severe hypertensiond hypertension necessitating hospital admission later inegnancy [1214]. This more limited outcome remainsnically important since blood pressures as low as 170/110m Hg are clearly associated with cerebrovascular hemor-age in pregnant women, leading experienced clinicians toat such values as a medical emergency; improved bloodessure control also provides the reassurance required to per-it safer prolongation of the pregnancy, with its attendantnefit to the neonate. Importantly, since the relative risks ofard" morbid endpoints are low in mild hypertension, andne of the available trials are either comprehensive or ade-ately powered, our ability to advocate specific guidelinespends more on considerable clinical experience [35]combination with a critical evaluation of an unfortunatelydequate literature [2,6,1116], than on clear data.Enthusiasm for aggressive control of underlying mild

    pertension is further tempered by relatively unknownal and remote childhood risks of antihypertensive drugposure in utero. In this respect, while several recent smalldies have assessed some measures of fetal and neonatal

    owth, development, and function [1719], thentinued preference of many workers for methyldopa ase first-line agent for blood pressure control in pregnancyates to its apparent safety, demonstrated, albeit in smallmbers, through 7.5 years follow-up of children exposed

    utero [20].The Australasian Society for the Study of Hypertension

    Pregnancy has advocated drug therapy to maintainaternal pressures of less than 140/90 mm Hg [4], aal shared by the Canadian Hypertension Society forme groups of women at perceived excess risk [5]. Weefer the recommendations of the National High Bloodessure Education Program (NHBPEP) Working Group Hypertension in Pregnancy [3], with somewhat

    gher threshold pressures for (re)instituting treatment50160/100110 mm Hg), and somewhat less stringentgets for blood pressure control (but would treat at lowerels in select patients, such as those with underlying renal

    sease). This preference is in accord with a recent meta-ression analysis of results from 14 trials that suggested

    at tighter control of maternal mean arterial pressureight contribute to fetal growth restriction, irrespective ofe specific agents used [21]. This conclusion gains physio-gic plausibility from the presumed inability of intervil-us placental blood flow to autoregulate with reduced

    this metaregression analysis and the NHBPEP WorkingGroup guidelines, we believe that a definitive prospectivetrial specifically focused on the maternal and fetal effects ofdiffering levels of targeted (and achieved) blood pressurecontrol has yet to be performed and is critically needed.

    Maternal Hemodynamics During Normal and Hypertensive PregnancyNormal pregnancy is marked by early systemic vasodila-tion; decrements in systemic vascular resistance are so largethat mean arterial pressure falls by approximately 10 mmHg despite 40% to 50% increases in blood volume andcardiac output [2]. Blood pressure is maximallydecreased by midpregnancy, increasing gradually towardsterm. Women with underlying essential hypertension mayexhibit an even greater early gestational fall in bloodpressure, by as much as 15 to 20 mm Hg [2,22], so as toeither obscure recognition of their underlying condition orto make continued treatment unnecessary.

    The hypertension in pre-eclampsia is characterized byprimary intense systemic vasoconstriction, as determinedby invasive hemodynamic measurements [2,23]. Thevasoconstriction is associated with modest decrements ofcardiac output, but with normal left ventricular fillingpressures. Curiously, there is now evidence that somewomen destined to develop pre-eclampsia exhibit evengreater than normal increments in cardiac output prior tothe onset of hypertension, their cardiac outputs fallingwith onset of the systemic vasoconstriction and hyperten-sion that characterize overt disease [24]. Women whodevelop (nonproteinuric) gestational hypertension sharethis early exaggerated increase in cardiac output butmaintain their hyperdynamic circulation, with lowperipheral resistance, throughout pregnancy. Easterling etal. [25] hypothesized that treatment of this early excessivecardiac output with atenolol would prevent subsequentpre-eclampsia; this prediction was supported by a pilotstudy of 56 hemodynamically selected and initiallynormotensive gravidas [25]. However intriguing, thispreliminary report neither offers guidance on thetreatment of already hypertensive women, nor allows us tobalance the fetal risks of more widespread -blocker useagainst possible maternal benefit. Pre-eclampsia is furthercharacterized by markedly increased sympathetic outflow[26], which, although not a likely cause of the hyperten-sion, has been taken by many as a mechanistic justificationfor the initial selection of agents such as methyldopa.

    The renin-angiotensin system is activated in normalhuman pregnancy [27]. Even in pre-eclampsia, whereangiotensin II levels are lower than in normal gestation,there may be simultaneous upregulation of AT1 receptors,accompanied by mechanistically fascinating evidence forthe production of AT1 receptor agonistic autoantibodies[28]. Thus, angiotensin converting enzyme (ACE)

  • 394 Antihypertensive Therapy: Patient Selection and Special Problems

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    Methyldopa decreases the subsequent incidence of severe1tractive antihypertensive agents for use in pregnantmen. Unfortunately, ACE inhibition not only increasedal wastage in animal studies, but it has been associatedth a specific fetopathy in humans (including renalsgenesis and calvarial hypoplasia), oligohydramnioskely a result of fetal oliguria), intrauterine growthardation, and often-fatal neonatal anuric renal failure

    9,30]. AT1 blockers also lead to fetal and neonatal renallure in the rat, leading us to similarly reject their use inegnancy [31]. In spite of these concerns, noted by the USod and Drug Administration and each of the recentnsensus panels [35], there have been several reports ACE inhibition during pregnancy. A case report [33]ted eventually reversible neonatal renal failure, while aall series, whose authors suggested low-dose captopril as

    alvage therapy" for refractory hypertension, notedrprisingly good neonatal outcome [34]. We remainconvinced, and do not believe that there are clinicalcumstances that would currently warrant the use of theseugs late in human pregnancy. We note that many womenrisk for hypertension during pregnancy, particularly thoseth underlying diabetes mellitus, may benefit from use ofE inhibitors prior to conception. Since all cases of ACE

    hibitor-associated fetopathy or renal failure occurred withug use in the latter two trimesters, it seems reasonable toe these drugs when appropriate, counseling women thatey should either change to alternate agents whentempting to conceive, or discontinue them early inegnancy, not resuming these agents until they areished nursing their infants.

    nsiderations in the Selection of Specific tihypertensive Agents in Pregnancy

    noted above, early pregnancy is profoundly vasodilatord hypotensive in most women with stage 1 or 2 hyper-sion (140179/90109 mm Hg); indeed most women

    th such mild to moderate hypertension will be able toarkedly decrease or eliminate their need for antihyper-

    sives early in gestation. Conversely, many cliniciansnsider failure of this early hemodynamic adaptation toegnancy to be an ominous prognostic factor. We willxt focus our discussion on agents used for nonemergentood pressure control during pregnancy, turningerward to drugs used for urgent control of higher or

    ore refractory elevations of blood pressure, usuallyarer to delivery.

    al agents for initial blood pressure controlethyldopa remains the preferred agent for initial bloodessure control [3], since no modern antihyperten-e has proven superior, or shares its history of clinical

    fety, bolstered by prospective long-term follow-up. It hasen assessed in both prospective placebo-controlled andmparative trials in pregnant women [24,1114].

    hypertension, while being well tolerated by the motherand without apparent adverse effects on uteroplacental orfetal hemodynamics [34] or on fetal well being. A recentmeta-analysis, which found no effect of antihypertensivetherapy on perinatal mortality (23 trials, RR, 0.71 [0.461.09]), suggested that other drugs might be superior tomethyldopa in preventing this outcome [14]. The markedheterogeneity in these mostly small trials tempers our will-ingness to abandon consensus recommendations favoringmethyldopa based on an ongoing meta-analysis in theabsence of an adequately powered randomized trial. (Inaddition, these poorer perinatal outcome results may beconfounded by the fact that many of the methyldopastudies were performed earlier when neonatal salvage wasless developed.) Most important to us are data, albeit froma small number of patients, that birthweight, neonatalcomplications, and development during the first year weresimilar in children exposed to methyldopa or placebo, andboth intelligence and neurocognitive development wereunimpaired at 7 years of age [20].

    Studies of clonidine have been more limited. One third-t r imester comparat ive t r ia l o f c lonidine versusmethyldopa showed similar efficacy and tolerability, wherasa small controlled follow-up study of 22 neonates reportedan excess of sleep disturbance in clonidine-exposed infants[17]. Clonidine should be avoided in early pregnancy due tosuspected embryopathy. Although the Australasian group[4] recognizes it as an acceptable agent, we find littlejustification for its use in place of methyldopa.

    -Blockers have been used extensively in pregnancy andhave been the subject of several randomized trials [25,1114] and of an ongoing meta-analysis [15].Animal studies and clinical observations led to concernsthat these agents could cause intrauterine growthrestriction, impair uteroplacental blood flow, and exertdetrimental cardiovascular and metabolic effects on thefetus. However, most prospective studies, focusing on drugadministration in the third trimester and including a mix ofhypertensive disorders, have shown effective bloodpressure control in the absence of significant adverse effects.By contrast, atenolol, started between 12 and 24 weeks ges-tation, was associated with striking growth retardation alongwith decreased placental weight [35]; this observation wassupported by a review comparing atenolol with alternativetherapies [36], and was extended to -blockers as a class intwo recent meta-analyses [14,15]. Likewise, several studieshave noted fetal and neonatal bradycardia, adverse influ-ences on uteroplacental and fetal circulations, or evidence ofother fetal insults following nonselective -blockade. Partialagonists, such as pindolol or oxprenolol (not available inthe United States) [37], appear not to share these shortcom-ings, leading the Australasian Society to advocate their use[4]. Labetalol, a nonselective and 1 receptor blocker, isadvocated as an alternative to methyldopa by the NHBPEPWorking Group [3]. It appears safe and equi-effective with

  • Antihypertensive Therapy in Pregnancy Umans and Lindheimer 395

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    poglycemia and it has been associated with fetal growthardation or neonatal difficulties in several studies. In sum,lockers, like other agents, decrease the incidence of severe

    aternal hypertension, apparently with an acceptableofile of risks [12,14,15] and without evidence ofvelopmental abnormality at 1-year follow-up [18]. Recenteta-analysis of several small trials suggested that -ockers might decrease (and calcium entry blockerscrease) the incidence of proteinuria or superimposed pre-lampsia; however, given the limited and heterogeneousta available, we remain circumspect in according toouch credence to this suggestion, and, along with thethors of that analysis, await further results from moreequately powered trials [14].

    Although the Australasian consensus group [4]ognizes the peripheral 1 blocker prazosin as an accept-le agent in pregnancy, we note that -blockers, even thoseth improved time-action profiles, have lost favor as first-e antihypertensives in nonpregnant patients. Therefore, do not advocate their use during pregnancy other than

    the rare setting of suspected pheochromocytoma.Prospective trials of diuretics or dietary salt restriction in

    egnancy have focused more on prevention of pre-lampsia than on treatment of hypertension. A meta-alysis (nine trials, more than 7000 women [38]) showed decrease in the incidence of proteinuric hypertension.uretics can prevent most of the physiologic volumepansion that normally accompanies pregnancy [2].hile the resulting volume contraction might be expected limit fetal growth, such concerns have not been bornet in trials [38]. A more subtle concern is that diuretic-duced hyperuricemia may limit the utility of thisboratory test, used by many to support the alreadyfficult clinical diagnosis of superimposed pre-eclampsia.ally, observations of volume depletion and primary sys-ic vasoconstriction in pre-eclampsia [2,23] make

    uretics physiologically irrational agents in this disorder. contrast, diuretics are commonly prescribed in essentialpertension prior to conception and, given their apparentfety, there is general agreement that they may bentinued through gestation or used in combination withher agents, especially for women maintained on theseents prior to pregnancy whose clinical course is notmplicated by pre-eclampsia or intrauterine growthtriction [3].Calcium entry blockers are widely used, albeit

    adequately studied, in pregnancy. They appear not to beportant teratogens [3]. Most studies have focused on

    fedipine [3,13,14], including one small study with months infant follow-up [19]. However, there aredies of several other dihydropyridine and nondihydro-

    ridine calcium channel blockers as well. In spite of theirll-known tocolytic activity, there are no data to suggest

    at use of calcium channel blockers as antihypertensivesmpromises the progression of labor or leads to

    data remain sorely lacking, these agents, especiallynifedipine, are reasonably recognized as acceptablealternatives to methyldopa or -blockers for use duringpregnancy [3]. Table 1 lists those oral agents, available inthe United States, which we recommend for initial bloodpressure control in gravidas with chronic hypertension orpre-eclampsia.

    Although not yet available in the United States, therehave been several recent reports, and considerableattention, focused on the use of ketanserin, an antihyper-tensive S2 serotonin receptor antagonist, during pregnancy[39,40]. While there may be a mechanistic basis for its usein pre-eclamptic hypertension, and it is likely a relativelysafe agent, data are currently too limited to advocate its usein the place of the drugs discussed above.

    Drugs for the urgent control of more severe hypertensionHydralazine remains the drug most often added as asecond agent for hypertension uncontrolled followingmethyldopa (or a -blocker) or, more commonly, as aparenteral agent for control of severe hypertension. Its useis justified more by long clinical experience, along withtolerable side effects when used in appropriate doses[3,13], than by any compelling pharmacologicselectivity. Several studies of hydralazine (or relatedcompounds) in pre-eclamptic women monitored withpulmonary artery catheters have highlighted concernsregarding its safety, including precipitous falls in cardiacoutput and blood pressure with oliguria, although thesemight have been predicted from its known pharmacology,along with the primary vasoconstriction and relativevolume contraction that are characteristic in these patients[41]. Some have advocated use of this vasodilating drug inconjunction with intravascular volume expansion [4], atricky approach at best. We, however, oppose thoseprotocols that involve volume expansion in severely hyper-tensive patients. Effects of hydralazine on uteroplacentalblood flow are unclear, likely due to variation in the degreeof reflex sympathetic activation, though fetal distress mayresult from precipitous control of maternal pressure. Thereis a report of neonatal thrombocytopenia followingintrauterine hydralazine exposure. Many investigators havesuggested that urgent blood pressure control might bebetter achieved with less fetal risk by use of other agents,eg, labetalol or nifedipine. However, objective outcomesdata currently fail to support significant differencesbetween hydralazine (or dihydralazine) and thesealternative therapies [16].

    Some have advocated oral or sublingual (immediate-release) nifedipine as a preferred agent in severely hyper-tensive pre-eclamptic patients [42], there being nodifference in nifedipine pharmacokinetics or time-effectcurves by these two routes of administration [43]. Indeed,several small comparative studies suggest efficacy similar

  • 396 Antihypertensive Therapy: Patient Selection and Special Problems

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    hinN that of parenteral hydralazine, with a similar spectrum maternal adverse e f fec t s (most ly ascr ibed tosodilation) [3]. When treating severe hypertension,e data appear to conflict regarding the influence oflcium channel blockers on uteroplacental blood flowd fetal well being, especially compared with otherents. In two studies [41,44], one which involved mater-l hemodynamic monitoring via a pulmonary arterytheter [41], the authors claimed less fetal distress withfedipine than with hydralazine. However, in one of thesery limited trials, this observation may have been due to aeater hypotensive effect of the hydralazine doses thatre used; several other studies have failed to discern suchfferences, finding no significant fetal benefit tofedipine or alternative agents. Of interest too, is animal study where chronically instrumented pregnanteep demonstrated fetal hypoxia and acidosis followinggh-dose maternal nifedipine infusion, unexplained byanges in maternal or uteroplacental hemodynamics

    [45]. We know of no corroborative clinical data for thisworrisome observation. The NHBPEP Working Groupnoted that immediate-release nifedipine has never beenFood and Drug Administration approved for treatment ofhypertension (indeed, it is no longer available in Australia[4]), and that one of the original cases calling attentionto its risks was of a gravida who experienced a precipitousfall in blood pressure with associated fetal distress [3].Nevertheless, they recommended it as an alternative tohydralazine or parenteral labetalol.

    An additional concern with use of calcium antago-nists for urgent blood pressure control in pre-eclampsiarelates to the widespread use of magnesium sulfate, thepreferred agent for prevention of eclamptic seizures.Magnesium can interfere with calcium-dependent con-tractile signaling in excitable tissue and in muscle; com-bined use with calcium antagonists might result inincreased risk of neuromuscular blockade or circulatorycollapse. Despite isolated reports of such complications,

    ble 1. Drugs for chronic hypertension in pregnancy*

    rug (FDA risk) Dose Concerns or comments

    referred agentMethyldopa (C) 0.53.0 g/d in two divided doses Preferred by NHBPEP working group; safety after first

    trimester well documented, including long-term follow-up of offspring

    lternative agents

    Hydralazine (C) 50300 mg/d in two to four divided doses

    Few controlled trials, long experience with few adverse events documented; useful only in combination with sympatholytic agent; may cause neonatal thrombocytopenia

    Labetolol (C) 2001200 mg/d in two to three divided doses

    May be associated with impaired fetal growth and neonatal difficulties

    b-receptor blockers (C)

    Depends on specific agent May cause fetal bradycardia and decrease uteroplacental blood flow, this effect may be less for agents with partial agonist activity; may impair fetal response to hypoxic stress; impaired fetal growth, especially when started in first or second trimester

    Nifedipine (C) 30120 mg/d of a slow-release preparation

    May inhibit labor and potentiate effects of magnesium sulfate; less experience with other calcium entry blockers

    Thiazide diuretics (C) Depends on specific agent Most studies in normotensive gravidas; can cause volume depletion and electrolyte disorders; may be useful in combination with methyldopa and vasodilator to mitigate compensatory fluid retention

    ontraindicatedAngiotensin converting

    enzyme inhibitors and AT1 receptor antagonists(D)

    Depends on specific agent Leads to fetal loss in animals; human use associated with fetopathy, oligohydramnios, growth retardation, and neonatal anuric renal failure, which may be fatal

    No antihypertensive has been proven safe for use during the first trimester (ie, US Food and Drug Administration [FDA] Category A).US FDA classifies risk for most agents as C: Either studies in animals have revealed adverse effects on the fetus (teratogenic or embryocidal effects r other) and there are no controlled studies in women, or studies in women and animals are not available. Drugs should only be given if the potential enefit justifies the potential risk to the fetus. This nearly useless classification unfortunately still applies to most drugs used during pregnancy. We omit some agents (eg, clonidine, a-blockers, ketanserin) due to limited data on use for chronic hypertension in pregnancy.We would classify in category X: Studies in animals or humans have demonstrated fetal abnormalities, or there is evidence of fetal risk based on uman experience, or both, and the risk of the use of the drug in pregnant women clearly outweighs any possible benefit. The drug is contraindicated women who are or may become pregnant.HBPEPNational High Blood Pressure Education Project.

  • Antihypertensive Therapy in Pregnancy Umans and Lindheimer 397

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    tIMhers argue against the likelihood of such adverse out-mes with routine therapy [46].

    Parenteral labetalol, administered either as repeatedluses or by continuous infusion, has replaced

    dralazine as a preferred agent at many centers. It appears possess similar safety and efficacy, though comparative

    dies are few. We concur with other reviewers inggesting that, with the data currently available, theoice between hydralazine, labetalol, and nifedipine forntrol of more severe hypertension near to term beverned largely by the experience of the treating physician,3,13,16].

    Diazoxide, a hyperpolarizing vasodilator, was oncecommended for urgent blood pressure control inegnancy. However, even when dosed carefully, it oftensults in excessive hypotension [16], perhaps leading uterine hypoperfusion. Additional concerns includeug-induced hyperglycemia, arrest of labor via a directect on myometrium, and possible toxic effects on pan-atic islet cells. For these reasons, along with inferiortcomes in several small comparative trials, it is nonger recommended for use in pregnancy [3].though there are sporadic reports of ketanserin forgent blood pressure control [39], its efficacy for thisdication seems less than that of hydralazine [16].ere are isolated reports suggesting utility for sublin-al nitrates [47] or the intravenous preparation of nica-ipine [48]. We are aware of no published studiesporting a significant experience with fenoldapam inegnancy. Nitroprusside has been used rarely to controle-threatening refractory hypertension in pregnancy9]. Adverse effects are mostly due to excessive vasodila-n, including a report of cardioneurogenic (ie, paradox-lly bradycardic) syncope in volume-depleted pre-

    lamptic women [50]. The risk of fetal cyanide intoxica-n remains unknown. Given the long experience withdralazine and alternative utility of calcium channel

    blockers or parenteral labetalol, nitroprussideremains anagent of last resort. Table 2 lists those agents we advocatefor treatment of severe hypertension in pregnancy.

    ConclusionsUse of antihypertensive agents in pregnancy is either forthe urgent control of severe hypertension or for controlof chronic hypertension, realizing that this latter indica-tion may include patients with a variety of hypertensivedisorders, including early pre-eclampsia. Tables 1 and 2summarize clinical data on the use of the drugs dis-cussed above, including Food and Drug Administrationrisk classification, usual doses, and special concerns.

    Currently, there is little evidence to support thenotion that blood pressure control in gravidas withchronic hypertension will prevent the subsequent occur-rence of pre-eclampsia, itself the cause for most adverseoutcomes in these patients. Indeed, given the pathophys-iologic hypotheses that ascribe this disorder to events inearly pregnancy [2], it continues to seem unreasonableto expect such a benefit. As well, there are no data to sug-gest that antihypertensive therapy will lessen the inci-dence of placental abruption. There have been fewstudies that rigorously assessed the prevention of severeor accelerated hypertension, focusing instead on avoid-ance of the perceived need for hospitalization or urgentearly delivery. Desperately needed, however, are ade-quately powered prospective clinical trials that comparedifferent classes of drugs, account for differences inmaternal hemodynamics, distinguish between womenwith essential hypertension, transient hypertension, orpre-eclampsia, and stratify treatment both by severity ofhypertension and by gestational age. Truly rational phar-macotherapy, ensuring the safety of both hypertensivewomen and their fetuses, will depend on the fruits ofsuch research.

    ble 2. Drugs for urgent control of severe hypertension in pregnancy

    rug (FDA risk*) Dose and route Concerns or comments

    ydralazine (C) 5 mg, IV or IM, then 510 mg every 2040 minutes; or constant infusion of 0.510 mg/h

    Preferred by NHBPEP working group; long experience of safety and efficacy

    abetolol (C) 20 mg IV, then 2080 mg every 2030 minutes, up to maximum of 300 mg; or constant infusion of 12 mg/min

    Experience in pregnancy less than with hydralazine; probably less risk of tachycardia and arrhythmia than with other vasodilators

    ifedipine (C) 510 mg PO, repeat in 30 minutes if needed, then 1020 mg every 26 hours

    Possible interference with labor; may interact synergistically with magnesium sulfate

    elatively contraindicatedNitroprusside (C) Constant infusion of 0.510 g/kg/min Possible cyanide toxicity; agent of last resort

    US Food and Drug Administration (FDA) Class C, as noted in footnote to Table 1.Adverse effects for all agents, except as noted, may include headache flushing, nausea, and tachycardia (primarily due to precipitous hypotension and eflex sympathetic activation).We would classify in category D: There is positive evidence of human fetal risk, but the benefits of use in pregnant women may be acceptable despite he risk (eg, if the drug is needed in a life-threatening situation or for a serious disease for which safer drugs cannot be used or are ineffective).

    intramuscularly; IVintravenously; NHBPEPNational High Blood Pressure Education Program; POorally.

  • 398 Antihypertensive Therapy: Patient Selection and Special Problems

    References and Recommended ReadingPahig

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    14. Abalos E, Duley L, Steyn DW, Henderson-Smart DJ: Antihyper-

    pers of particular interest, published recently, have been hlighted as:

    Of importance Of major importance

    . Redman CWG, Beilin LJ, Bonnar J, Ounsted MK: Fetal outcome in trial of antihypertensive treatment in pregnancy. Lancet 1976, 2:753756.

    . Lindheimer MD, Roberts JM, Cunningham FG: Chesley's Hypertensive Disorders in Pregnancy, edn 2. Stamford: Appleton & Lange; 1999.

    is 654-page, multiauthored text provides the most comprehensive iew available of cardiovascular physiology and pathophysiology in gnancy, insights to the pathogenesis of pre-eclampsia, and critical iew of strategies for the clinical management of these patients.. Report of the National High Blood Pressure Education Pro-

    gram Working Group on High Blood Pressure in Pregnancy. NIH Publication No. 00-3029, July 2000. Accessible at www.nhlbi.nih.gov/health/prof/heart/hbp_preg.htm

    is consensus statement, revised 10 years after its initial publication, vides useful guidelines for the evaluation and management of

    pertensive gravidas.. Brown MA, Hague WM, Higgins J, et al.: The detection,

    investigation and management of hypertension in preg-nancy: full consensus statement. Aust N Z J Obstet Gynecol 2000, 40:139155.

    is consensus statement of the Australasian Society for the Study of pertension in Pregnancy provides useful guidelines with minor cific differences from the NHBPEP Working Group.

    . Rey E, LeLorier J, Burgess E, et al.: Report of the Canadian Hypertension Society consensus conference. 3. Pharmaco-logic treatment of hypertensive disorders in pregnancy. Can Med Assoc J 1997, 157:12451254.

    e Canadian Hypertension Society statement, based on a tical literature review, preceded publication of references 3 and 4, ove. These three sets of clinical guidelines are in essential agree-nt, reflecting perhaps appropriate circumspection in the face of ited data.

    . Shear R, Leduc L, Rey E, Moutquin JM: Hypertension in pregnancy: new recommendations for management. Curr Hypertens Rep 1999, 1:529539.

    . Walker JJ: Pre-eclampsia. Lancet 2000, 356:12601265.

    . Sibai BM, Abdella TN, Anderson GD: Pregnancy outcome in 211 patients with mild chronic hypertension. Obstet Gynecol 1983, 61:571576.

    . Sibai BM, Lindheimer MD, Hauth J, et al.: Risk factors for preeclampsia, abruptio placentae, and adverse neonatal outcomes among women with chronic hypertension. N Engl J Med 1998, 339:667671.

    . Rey E, Couturier A: The prognosis of pregnancy in women with chronic hypertension. Am J Obstet Gynecol 1994, 171:410416.

    . Ferrer RL, Sibai BM, Mulrow CD, et al.: Management of mild chronic hypertension during pregnancy: a review. Obstet Gynecol 2000, 96:849860.

    is presents a summary of an evidence-based review conducted for US Agency for Healthcare Research and Quality; the full report is ilable from their web site at http://www.ahcpr.gov/clinic/ptfiles.htm.. Magee LA, Ornstein MP, von Dadelszen P: Management of

    hypertension in pregnancy. BMJ 1999, 318:13321336.houghtful review with meta-analysis of recent relevant trials.. Sibai BM: Treatment of hypertension in pregnant women.

    N Engl J Med 1996, 335:257265.houghtful, selective review, including specific treatment guidelines, m one of the most prolific clinical investigators in the field.

    tensive drug therapy for mild to moderate hypertension during pregnancy. Cochrane Database Syst Rev 2001, 2:CD002252.

    A new meta-analysis from the Cochrane library. First to raise the possibility of differences between classes of antihypertensive agents.15. Magee LA, Duley L: Oral beta blockers for mild to moderate

    hypertension during pregnancy. Cochrane Database Syst Rev 2000, 4:CD002863.

    Largest meta-analysis of -blocker use in pregnancy.16. Duley L, Henderson-Smart DJ: Drugs for rapid treatment of

    very high blood pressure during pregnancy. Cochrane Database Syst Rev 2000, 2:CD001449.

    Meta-analysis results are much in accord with latest guidelines from Canadian, Australasian, and US groups.17. Huisjes HJ, Hadders-Algra M, Touwen BC: Is clonidine a

    behavioural teratogen in the human? Early Hum Dev 1986, 14:4348.

    18. Reynolds B, Butters L, Evans J, et al.: First year of life after the use of atenolol in pregnancy associated hypertension. Arch Dis Child 1984, 59:10611063.

    19. Bortolus R, Ricci E, Chatenoud L, Parazzini F: Nifedipine administered in pregnancy: effect on the development of children at 18 months. Br J Obstet Gynaecol 2000, 107:792794.

    20. Cockburn J, Moar VA, Ounsted M, Redman CW: Final report of study on hypertension during pregnancy: the effects of specific treatment on the growth and development of the children. Lancet 1982, 1:647649.

    21. von Dadelszen P, Ornstein MP, Bull SB, et al.: Fall in mean arterial pressure and fetal growth restriction in pregnancy hypertension: a meta-analysis. Lancet 2000, 355:8792.

    22. August P, Lenz T, Ales KL, et al.: Longitudinal study of the renin-angiotensin-aldosterone system in hypertensive pregnant women: deviations related to development of superimposed preeclampsia. Am J Obstet Gynecol 1990, 163:16121621.

    23. Visser W, Wallenburg HCS: Central hemodynamic observa-tions in untreated preeclamptic patients. Hypertension 1991, 17:10721077.

    24. Bosio PM, McKenna PJ, Conroy R, O'Herlihy C: Maternal cen-tral hemodynamics in hypertensive disorders of pregnancy. Obstet Gynecol 1999, 94:978984.

    25. Easterling TR, Brateng D, Schmucker B, et al.: Prevention of preeclampsia: A randomized trial of atenolol in hyperdy-namic patients before onset of hypertension. Obstet Gynecol 1999, 93:725733.

    26. Schobel HP, Fischer T, Heuszer K, et al.: Preeclampsia-a state of sympathetic overactivity. N Engl J Med 1996, 335:14801485.

    27. August P, Mueller FB, Sealey JE, Edersheim TG: Role of renin-angiotensin system in blood pressure regulation in pregnancy. Lancet 1995, 345:896897.

    28. Wallukat G, Homuth V, Fischer T, et al.: Patients with preeclampsia develop agonistic autoantibodies against the angiotensin AT1 receptor. J Clin Invest 1999, 103:945952.

    29. Pryde PG, Sedman AB, Nugent CE, Barr M Jr: Angiotensin-converting enzyme inhibitor fetopathy. J Am Soc Nephrol 1993, 3:15751582.

    30. Buttar HS: An overview of the influence of ACE inhibitors on fetal-placental circulation and perinatal development. Mol Cell Biochem 1997, 176:6171.

    31. Spence SG, Zacchei AG, Lee LL, et al.: Toxicokinetic analysis of losartan during gestation and lactation in the rat. Teratology 1996, 53:245252.

    32. Tomlinson AJ, Campbell J, Walker JJ, Morgan C: Malignant primary hypertension in pregnancy treated with lisinopril. Ann Pharmacother 2000, 34:180182.

    33. Easterling TR, Carr DB, Davis C, et al.: Low-dose, short-acting, angiotensin-converting enzyme inhibitors as rescue therapy in pregnancy. Obstet Gynecol 2000, 96:956961.

  • Antihypertensive Therapy in Pregnancy Umans and Lindheimer 399

    34. Montan S, Anandakumar C, Arulkumaran S, et al.: Effects of

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    36

    37

    38

    39

    40

    41

    42

    43. van Harten J, Burggraaf K, Danhof M, et al.: Negligible sublin-

    methyldopa on uteroplacental and fetal hemodynamics in pregnancy-induced hypertension. Am J Obstet Gynecol 1993, 168:152156.

    . Butters L, Kennedy S, Rubin PC: Atenolol in essential hypertension during pregnancy. BMJ 1990, 301:587589.

    . Lip GY, Beevers M, Churchill D, et al.: Effect of atenolol on birthweight. Am J Cardiol 1997, 79:14361438.

    . Gallery EDM, Ross MR, Gyory AZ: Antihypertensive treatment in pregnancy: analysis of different responses to oxprenolol and methyldopa. BMJ 1985, 291:563566.

    . Collins R, Yusuf S, Peto R: Overview of randomised trials of diuretics in pregnancy. BMJ 1985, 290:1723.

    . Bolte AC, van Geijn HP, Dekker GA: Pharmacological treatment of severe hypertension in pregnancy: the role of serotonin 2 receptor blockers. Eur J Obstet Gynecol Reprod Biol 2001, 95:2236.

    . Steyn DW, Odendaal HJ: Serotonin antagonism and serotonin antagonists in pregnancy: role of ketanserin. Obstet Gynecol Surv 2000, 55:582589.

    . Visser W, Wallenburg HC: A comparison between the hemody-namic effects of oral nifedipine and intravenous dihydralazine in patients with severe preeclampsia. J Hypertens 1995, 13:791795.

    . Gallery ED, Gyory AZ: Sublingual nifedipine in human pregnancy. Aust N Z J Med 1997, 27:538542.

    gual absorption of nifedipine. Lancet 1987, 2:13631365.44. Fenakel K, Fenakel G, Appelman Z, et al.: Nifedipine in the

    treatment of severe preeclampsia. Obstet Gynecol 1991, 77:331337.

    45. Blea CW, Barnard JM, Magness RR, et al.: Effect of nifedipine on fetal and maternal hemodynamics and blood gases in the pregnant ewe. Am J Obstet Gynecol 1997, 176:922930.

    46. Scardo JA, Vermillion ST, Hogg BB, Newman RB: Hemody-namic effects of oral nifedipine in preeclamptic hypertensive emergencies. Am J Obstet Gynecol 1996, 175:336338.

    47. Martinez-Abundis E, Gonzalez-Ortiz M, Hernandez-Salazar F, Huerta-J-Lucas MT: Sublingual isosorbide dinitrate in the acute control of hypertension in severe preeclampsia. Gynecol Obstet Invest 2000, 50:3942.

    48. Aya AG, Mangin R, Hoffet M, Eledjam JJ: Intravenous nicar-dipine for severe hypertension in preeclampsia-effects of treatment on mother and foetus. Intensive Care Med 1999, 25:1277.

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    Antihypertensive Therapy in PregnancyAntihypertensive Therapy in PregnancyJasonJasonG.Umans,MD, PhD, FACP

    AddressAddress*Current Hypertension ReportsCurrent Hypertension Reports

    Current Science Inc. ISSNCopyright 2001 by Current Science Inc.

    Human pregnancy, normally characterized by systemic vasodilation and modest hypotension, can be c...

    IntroductionIntroductionHypertension in pregnancy remains a major cause of morbidityand mortality in the mother and fetu...

    Maternal and Fetal Risks of Hypertension in PregnancyMaternal and Fetal Risks of Hypertension in PregnancyRegarding risk, we first must ask the following: 1) what are the short-term risks of hypertension...The major maternal risk associated with underlying hypertension that might justify pharmacotherap...Currently, it appears that treatment of underlying hypertension does not prevent superimposed pre...Enthusiasm for aggressive control of underlying mild hypertension is further tempered by relative...The Australasian Society for the Study of Hypertension in Pregnancy has advocated drug therapy to...

    Maternal Hemodynamics During Normal and Hypertensive PregnancyMaternal Hemodynamics During Normal and Hypertensive PregnancyNormal pregnancy is marked by early systemic vasodilation; decrements in systemic vascular resist...The hypertension in pre-eclampsia is characterized by primary intense systemic vasoconstriction, ...The renin-angiotensin system is activated in normal human pregnancy [

    Considerations in the Selection of Specific Antihypertensive Agents in PregnancyConsiderations in the Selection of Specific Antihypertensive Agents in PregnancyAs noted above, early pregnancy is profoundly vasodilator and hypotensive in most women with stag...Oral agents for initial blood pressure controlOral agents for initial blood pressure controlMethyldopa remains the preferred agent for initial blood pressure control [Studies of clonidine have been more limited. One third- trimester comparative trial of clonidine ...bb

    Although the Australasian consensus group [Prospective trials of diuretics or dietary salt restriction in pregnancy have focused more on pre...Calcium entry blockers are widely used, albeit inadequatelystudied, in pregnancy. They appear no...Table 1. Drugs for chronic hypertension in pregnancy*Drug (FDA risk)DoseConcerns or comments

    Preferred agent

    Methyldopa (C)0.53.0 g/d in two divided dosesPreferred by NHBPEP working group; safety after first trimester well documented, including long-t...

    Alternative agents

    Hydralazine (C)50300 mg/d in two to four divided dosesFew controlled trials, long experience with few adverse events documented; useful only in combina...

    Labetolol (C)2001200 mg/d in two to three divided dosesMay be associated with impaired fetal growth and neonatal difficulties

    b-receptor blockers (C)b

    Depends on specific agentMay cause fetal bradycardia and decrease uteroplacental blood flow, this effect may be less for a...

    Nifedipine (C)30120 mg/d of a slow-release preparationMay inhibit labor and potentiate effects of magnesium sulfate; less experience with other calcium...

    Thiazide diuretics (C)Depends on specific agentMost studies in normotensive gravidas; can cause volume depletion and electrolyte disorders; may ...

    Contraindicated

    Angiotensin converting enzyme inhibitors and AT1 receptor antagonists(D)Depends on specific agentLeads to fetal loss in animals; human use associated with fetopathy, oligohydramnios, growth reta...

    *No antihypertensive has been proven safe for use during the first trimester (ie, US Food and Dru...

    Although not yet available in the United States, there have been several recent reports, and cons...

    Drugs for the urgent control of more severe hypertensionDrugs for the urgent control of more severe hypertensionHydralazine remains the drug most often added as a secondagent for hypertension uncontrolled fol...Some have advocated oral or sublingual (immediate- release) nifedipine as a preferred agent in se...Table 2. Drugs for urgent control of severe hypertension in pregnancyDrug (FDA risk*)Dose and routeConcerns or comments

    Hydralazine (C)5 mg, IV or IM, then 510 mg every 2040 minutes; or constant infusion of 0.510 mg/hPreferred by NHBPEP working group; long experience of safety and efficacy

    Labetolol (C)20 mg IV, then 2080 mg every 2030 minutes, up to maximum of 300 mg; or constant infusion of 12...Experience in pregnancy less than with hydralazine; probably less risk of tachycardia and arrhyth...

    Nifedipine (C)510 mg PO, repeat in 30 minutes if needed, then 1020 mg every 26 hoursPossible interference with labor; may interact synergistically with magnesium sulfate

    Relatively contraindicated

    Nitroprusside (C)Constant infusion of 0.510 g/kg/minPossible cyanide toxicity; agent of last resort

    *US Food and Drug Administration (FDA) Class C, as noted in footnote to Table 1. Adverse effects...

    An additional concern with use of calcium antagonists for urgent blood pressure control in pre-ec...Parenteral labetalol, administered either as repeated boluses or by continuous infusion, has repl...Diazoxide, a hyperpolarizing vasodilator, was once recommendedfor urgent blood pressure control ...

    ConclusionsConclusionsUse of antihypertensive agents in pregnancy is either for the urgent control of severe hypertensi...Currently, there is little evidence to support the notion that blood pressure control in gravidas...

    References and Recommended ReadingReferences and Recommended ReadingPapers of particular interest, published recently, have been highlighted as:Papers of particular interest, published recently, have been highlighted as: Of importance Of major importance

    1. Redman1. Redman1. RedmanCWG,BeilinLJ,BonnarJ,OunstedMK:Fetal outcome in trial of antihypertensive treatment in pregnancy.Lancet1976,2:753756.

    2. Lindheimer2. Lindheimer2. LindheimerMD,RobertsJM,CunninghamFG:Chesley's Hypertensive Disorders in Pregnancy,edn 2.Stamford:Appleton & Lange;1999.

    This 654-page, multiauthored text provides the most comprehensive review available of cardiovascu...3. Report of the National High Blood Pressure Education Program Working Group on High Blood Pr...3. Report of the National High Blood Pressure Education Program Working Group on High Blood Pr...3. Report of the National High Blood Pressure Education Program Working Group on High Blood Pr...

    This consensus statement, revised 10 years after its initial publication, provides useful guideli...4. Brown4. Brown4. BrownMA,HagueWM,HigginsJ,et al.

    This consensus statement of the Australasian Society for the Study of Hypertension in Pregnancy p...5. Rey5. Rey5. ReyE,LeLorierJ,BurgessE,et al.

    The Canadian Hypertension Society statement, based on a critical literaturereview, preceded publ...6. Shear6. Shear6. ShearR,LeducL,ReyE,MoutquinJM:Hypertension in pregnancy: new recommendations for management.Curr Hypertens Rep1999,1:529539.

    7. Walker7. Walker7. WalkerJJ:Pre-eclampsia.Lancet2000,356:12601265.

    8. Sibai8. Sibai8. SibaiBM,AbdellaTN,AndersonGD:Pregnancy outcome in 211 patients with mild chronic hypertension.Obstet Gynecol1983,61:571576.

    9. Sibai9. Sibai9. SibaiBM,LindheimerMD,HauthJ,et al.

    10. Rey10. Rey10. ReyE,CouturierA:The prognosis of pregnancy in women with chronic hypertension.Am J Obstet Gynecol1994,171:410416.

    11. Ferrer11. Ferrer11. FerrerRL,SibaiBM,MulrowCD,et al.

    This presents a summary of an evidence-based review conducted for the US Agency for Healthcare Re...12. Magee12. Magee12. MageeLA,OrnsteinMP,von DadelszenP:Management of hypertension in pregnancy.BMJ1999,318:13321336.

    A thoughtful review with meta-analysis of recent relevant trials.13. Sibai13. Sibai13. SibaiBM:Treatment of hypertension in pregnant women.N Engl J Med1996,335:257265.

    A thoughtful, selective review, including specific treatment guidelines, from one of the most pro...14. Abalos14. Abalos14. AbalosE,DuleyL,SteynDW,Henderson-SmartDJ:Antihypertensive drug therapy for mild to moderate hypertension during pregnancy.Cochrane Database Syst Rev2001,2:CD002252.

    A new meta-analysis from the Cochrane library. First to raise the possibility of differences betw...15. Magee15. Magee15. MageeLA,DuleyL:Oral beta blockers for mild to moderate hypertension during pregnancy.Cochrane Database Syst Rev2000,4:CD002863.

    Largest meta-analysis of16. Duley16. Duley16. DuleyL,Henderson-SmartDJ:Drugs for rapid treatment of very high blood pressure during pregnancy.Cochrane Database Syst Rev2000,2:CD001449.

    Meta-analysis results are much in accord with latest guidelines from Canadian, Australasian, and ...17. Huisjes17. Huisjes17. HuisjesHJ,HaddersAlgraM,TouwenBC:Is clonidine a behavioural teratogen in the human?Early Hum Dev1986,14:4348.

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    30. Buttar30. Buttar30. ButtarHS:An overview of the influence of ACE inhibitors on fetal-placental circulation and perinatal devel...Mol Cell Biochem1997,176:6171.

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