Preeclampsia Etiologies and Management Dr Mahmoud A Ismail

Preeclampsia: Etiologies and Management Dr. Mahmoud A. Ismail Professor and Chief of Maternal Fetal Medicine

Classification of the Hypertensive Disorders Complicating Pregnancy Chronic Hypertension (Primary and Secondary) Preeclampsia/eclampsia Superimposed preeclampsia Gestational hypertension (re-designated “transient” when pressure normalizes postpartum).

Causes of hypertension in pregnancy superimposed pre-eclampsia preeclampsia secondary hypertension essential hypertension gestational hypertension (Brown, Buddle 1997)

Cardiovascular Adaptation in Normal Pregnancy Early systemic vasodilation with increased CO Modest decrements in BP despite large increases in ECV Early and marked increase in arterial compliance Marked stimulation of the renin-aldosterone systems Refractoriness to infused vasopressors (eg, AII) Early renal vasodilation and hyperfiltration – no increase in PGC – renal vasodilation appears mediated by relaxin, via the endothelin B receptor-NO by increasing vascular MMP-9 & 2 activity (rat MMP-2 m. RNA increased) Significant Na (volume) retention; sensed as normal BP may rise towards nonpregnant level near term

BP throughout gestation in 6000 normal pregnancies (white women, 25 -34) Christianson et al 1976

DEFINITIONS Hypertension: BP > 140 systolic and/or 90 diastolic (Severe: BP > 170 systolic and/or 110 diastolic) probably too high Protienuria: >300 mg/24 h, spot Cr/Protein = 0. 3, Dipstick 1+ (high false + & -) Preeclampsia: De Novo hypertension and proteinuria after midpregnancy

Many women with mild to moderate hypertension can discontinue their medications in early pregnancy due to physiological gestational vasodilation Failure of this physiological decrease in BP may predict poorer outcome Monitor pregnancy closely re: high risk of superimposed preeclampsia (> 20%) and likely need for antihypertensives later in pregnancy

Why should we treat hypertension during pregnancy? Will BP control prevent preeclampsia? Will BP control improve neonatal outcome? Will BP control decrease maternal morbidity?

Not just dangerous for the fetus * BP of 170 systolic or 110 diastolic can lead to cerebrovascular catastrophe in pregnancy Uncontrolled hypertension often leads to hospital admission and early delivery to preserve maternal safety Retrospective studies suggest increased cerebral accidents when systolic levels >150 mm Hg *

Prevent: No (definitive trial needed) Improve neonatal outcome: Probably…Maybe (definitive trial needed Decrease maternal morbidity: Yes Morbidity in 2 & 3 primarily severe hypertension

Regardless of drug class, BP control does not prevent proteinuria or preeclampsia Abalos et al, Cochrane 2002

• Pregnancy-specific multi-organ syndrome • Hypertension + proteinuria • Over 60, 000 maternal deaths worldwide per year • 30% of premature deliveries are consequence of PE • Two-fold increased risk of CVD later in life

Preeclampsia: Definition, Diagnosis and Impact De novo hypertension and proteinuria presenting after mid-pregnancy (exceptions exist) Accounts for most, but not all, of the morbidity of hypertension in pregnancy May be superimposed on chronic hypertension or renal disease, (such scenarios often severe) Unique to human gestation, resolves with delivery A systemic disease with multiorgan involvement May progress to convulsive phase: eclampsia A leading cause of maternal mortality A leading cause of of preterm births (~15%)

Why are preeclamptic women hypertensive? AII sensitivity increases even before overt preeclampsia, and despite decreased AII, PRA and aldosterone levels (Role of Ang I receptor autoantibodies? ) Invasive hemodynamic studies in preeclamptic women reveal high SVRs and decreased COs Renal vasoconstriction with greater fall in GFR than in ERPF, suggesting afferent vasoconstriction Sympathetic activity is increased, in parallel with BP; whether causal or compensatory unknown Endothelial dysfunction related (enormous literature) Pathogenetic roles for increased AII action and impaired VEGF signaling perhaps secondary to s. Flt-1 & s. Endoglin

Goravic et al, AJOG, April, 07: Preeclampsia is also a podocyte disorder (podocyturia present)

Longitudinal changes in cardiac output and SVR in normal pregnancy and in women with preeclampsia or gestational hypertension Bosio et al, 1999 (Vascular compliance decreased in superimposed preeclampsia independent of increase in blood pressures) Hibbard et al 2005

Endoglin - overview Endoglin or CD 105 is a TGF -b 1 and b 3 co-receptor on endothelial cells and syncytotrophoblasts of the placenta • Endoglin mutations underlie Hereditary Hemorrhagic Telangiectasia-1, characterized by AV malformations and focal loss of capillaries • Endoglin null mice die at mid-gestation due to defective angiogenesis and cardiovascular development • Endoglin may be involved in the regulation of endothelial nitric oxide synthase (e. NOS) activity and the local regulation of vascular tone

An Animal Model for “severe” Preeclampsia The simultaneous introduction of adenoviruses encoding both s. Flt 1 and soluble endoglin produced severe hypertension, heavy proteinuria, elevated liver enzymes, and circulating schistocytes, in essence creating a powerful model that simulates most of the protean manifestations of preeclampsia in humans and has obvious implications for the study of mechanisms or therapy of the disease.

Preeclampsia: Maternal Factors: Diagnosis, Risk, Recurrence Increased in women with hypertension, diabetes mellitus, renal disease, multiple fetuses, obesity, previous preeclampsia, insulin resistance, hyperhomocysteinemia, or Thrombophilias Difficult to diagnose with underlying hypertension, renal disease, collagen vascular disease… err in favor of diagnosis Considerably less common in parous women unless they have underlying risk factors Recurrent preeclampsia predicts later cardiovascular disease By contrast, cardiovascular risk is lowest in women who have been pregnant, but never preeclamptic

WHO systematic review of screening to predict preeclampsia Conde-Agudelo A, et al Obstet and Gynecol 2004; 104: 1367 -1391 87 of 7, 191 articles (211, 369) women met criteria. CRITERIA Population adequately described (by age, parity, risk) Cut off levels; clear definitions of + or - test Adequate blinding + results from >90% of participants RESULTS No clinically useful screening test to predict PE Promising and being investigated: Combinations of tests: e. g. , Anti and pro-angiogenic factors (s. Flt-1, s. Eng, Pl. GF) (see Obstet Gynecol 109: 168. 07)

Levine et al N Engl J Med 9/06

Levine et al N Engl J Med 9/06

Preterm Preeclampsia Levine et al N Engl J Med 9/06 Preeclampsia >37 weeks

Preeclampsia prevention/intervention trials Aspirin: Initially very effective in small trials, but little effect in large subsequent trials. Meta analyses galore ! Latest (Paris collaboration) suggests small effect. Calcium supplementation: Minimal (if any) effect on preeclampsia, but decreases disease severity in populations with low Ca intake (<600 mg/d). Blood pressure control, per se: no decrease in preeclampsia regardless of agent (diuretic, β blocker, other) more definitive trials needed. Fish oil, Mg supplementation appear without benefit, Vitamin C+E: Major trials negative to-date and possibly harmful.

Remember the Objectives of Treating Preeclampsia Prevent convulsions Deliver a surviving child Prevent mortality and residual pathology in mother and child

“Conservative Management” in Severe Preeclampsia While there are studies suggesting prolongation of pregnancy, fetal outcome is improved minimally, if at all, while maternal morbidity increases substantially. Temporize only as long as BP control is acceptable, and in the absence of ominous symptoms and signs (i. e. , headache, visual disturbance, epigastric pain, coagulopathy or thrombocytopenia, microangiopathy, abnormal LFTs, renal dysfunction, or fetal jeopardy) and preferably in a tertiary care setting.

HELLP Syndrome Hemolysis Elevated Liver-Enzymes Low Platelet Count

Eclampsia: Pathophysiology and Prevention in 2006 Noninvasive techniques suggest elevated CPP in eclampsia, lowered by magnesium or labetalol. Possible role for drug effects on autoregulation in addition to systemic BP Magnesium is drug of choice to prevent recurrent seizures (RCTs: Mg vs diazepam or phenytoin) 24 h of Magnesium prevents seizures (without monitoring!) in Magpie trial (>15, 000 women) Magnesium prevents seizures better than selective cerebral vasodilator Can occur days to weeks postpartum (Hirshfeld-Cytron et al Obstet Gynecol Survey 61: 471, 2006)

Principles of management of hypertension in pregnancy Most do not treat mild to moderate hypertension < BP 150 -160/100 -110 (except if underlying disease or target organ damage present). All should treat BP >150 -160/100 -110, 170/110 is a medical emergency We have no randomized trials to guide BP targets! Aim for vaginal delivery close to term if possible Monitor maternal and fetal welfare closely in these very high risk pregnancies renal, hepatic, coagulation status fluid balance fetal growth, activity, cardiac reactivity

Drugs for Chronic Hypertension in Pregnancy Methyldopa-B: 0. 5 -3 g/d 2 -4 divided doses (preferred drug of NHBPEP Working Group) Labetalol-C: 200 -1200 mg/d 2 -3 divided doses Hydralazine-C: 50 -300 mg/d 2 -4 divided doses (useful only with sympatholytic agent) β receptor blockers-C: (dose depends on agent); those with ISA preferred by Australasian group Nifedipine-C: 30 -120 mg/d of sustained release preparation, other CCBs seem similarly effective Thiazide Diuretics-C: (dose depends on agent) can cause volume depletion and electrolyte disorders, but effective in chronic hypertensives (? salt sensitive? ) as adjunct therapy.

Drugs for Urgent Control of Severe Hypertension Hydralazine-C: 5 mg iv/im, then 5 -10 mg q 15 -40 min (or infusion of 0. 5 -10 mg/h) Labetalol-C: 20 mg iv, then 20 -80 mg q 20 -40 min up to max of 300 mg (or infusion of 1 -2 mg/min) Nifedipine-C: 5 -10 mg po, repeat in 30 min prn, then 10 -20 mg q 2 -4 h (noted by NHBEP working group, but not approved by FDA for treatment of hypertension) Nitroprusside-C: 10 µg/kg/min, agent of last resort due to possible toxicity Some newer (designer) ones: untested in gravid women

Antihypertensive Selection in Nursing Mothers Key pharmacokinetic principles governing drug transfer to milk include: small maternal Vd, low plasma protein binding, high lipid solubility. Of additional importance are neonatal oral bioavailability and safety. Well-designed studies are pitifully few, if at all. Atenolol and metoprolol are concentrated in milk Diuretics can decrease milk production CCBs and methyldopa transfer to milk, apparently with no adverse effects Few data on ACE inhibitors or ARBs except for captopril which appears safe in nursing

Key Issues in Antihypertensive Selection In spite of recent small series, there remains NO justification for use of ACE inhibitors or ARBs due to possible congenital malformations and definitive fetal toxicity Data remain inadequate and contradictory to choose between drug classes for maternal/fetal risk/benefit – (controversy re: early β blockers vs methlydopa) Choose the drugs you know best from among those commonly used in pregnancy

Summary Pregnancy is normally a vasodilated state which can be complicated by several hypertensive disorders, potentially threatening mother and fetus Specific diagnosis may matter Goals of antihypertensive therapy differ from those in nonpregnant women Choice of drugs depends more on established clinical experience than on well-designed and adequately-powered trials in pregnant women, which remain shamefully lacking

Hypertension in Pregnancy: Reviews, Guidelines, Consensus NHBEP Working Group on Hypertension in Pregnancy: AJOG 183: S 1 S 22, 2000 AHRQ Evidence Report on Management of Mild Chronic Hypertension in Pregnancy: Obstet Gynecol 96: 849 -60, 2000 Cochrane Pregnancy and Childbirth Group: Cochrane Database of Systematic Reviews New Developments in Preeclampsia. Semin Nephrol 24: 537 -625 , 2004 (issue edited by Davison JM & Lindheimer MD) Karumanchi S et al. Kidney Itl 67: 12001 -13, 2005 Redman CW, Sargent Il: Science 308: 1592 -4, 2004 Karumanchi SA, Lindheimer MD. Advances in the understanding of eclampsia. Curr Hypertens Rep; 10: 305 -12, 2008. Lindheimer MD, Taler SJ, Cunningham FG. Hypertension in pregnancy (invited Am Soc Hypertension position paper) Journal of the American Society of Hypertension, (in press Nov-Dec 2008)

Special Thanks are due to: Professor Marshall Lindheimer, M. D. for guidance and help in preparing this lecture My residents and fellows for academic assistance My children for technological assistance�

Novel Therapies for Preeclampsia Antibodies to dioxin (digibind) or to marinobufogenin (endogenous ouabain) Relaxin VEGF- 121

VEGF-121 therapy in experimental preeclampsia Li et al. Hypertension 50: 686. 07 200 Systolic BP Adv-s. Flt+Vehicle Adv-s. Flt+VEGF 121 SBP (mm. Hg) 160 120 80 40 0 Naive Null Vehicle VEGF 121 Adv-s. Flt UA (ug)/Ucrea (mg) 20000 Urine Albumin/Creatinine 0. 7 0. 6 12000 8000 4000 Naive Null Vehicle VEGF 121 Adv-s. Flt Body Weight per Fetus (g/Fetus) 16000 0 Body Weight of Fetus 0. 5 0. 4 0. 3 0. 2 0. 1 0. 0 Naive Null Vehicle VEGF 121 Adv-s. Flt

Severe morbidity and mortality according to treatment group Calcium n/N Placebo n/N Risk Ratio 95% Confidenc e Interval Maternal admission to intensive care any special care unit 116/4151 138/4161 0. 85 0. 75 - 0. 95 Maternal admission ≥ 2 days 31/4151 37/4161 0. 83 0. 57 -1. 21 Maternal death 1/4151 6/4161 0. 17 0. 03 - 0. 76 Severe maternal morbidity and mortality index (*) 167/4151 209/4161 0. 80 0. 70 - 0. 91 Stillbirth 105/4181 113/4197 0. 93 0. 74 - 1. 17 Neonatal mortality 37/3953 53/3956 0. 70 0. 56 - 0. 88 (*) At least one of the following: Admission to Intensive or any special care unit, eclampsia, severe preeclampsia, , placental abruption, HELLP, renal failure or death. All risk ratios and 95% Confidence Intervals adjusted by centre effect. Maternal outcomes are also adjusted by maternal body mass index.

Cumulative risk of neonatal mortality, by treatment group Cox regression model p =0. 02* Villar et al. 2006 Adjusted for clustering on centre

Do not Forget! Blood pressure decreases early in pregnancy; thus mild chronic hypertension can be missed and then misdiagnosed as preeclampsia or gestational hypertension near term Most women with mild to moderate hypertension require little or no drug therapy until later in pregnancy As most young women are not hypertensive, we must be aggressive in searching for secondary causes, especially renovascular hypertension and pheochromocytoma

Management Continued Roles for a laboratory data base to aid in recognition of superimposed preeclampsia Role for home BP monitoring Hospitalization recommended for new and/or worsening hypertension, or suspected preeclampsia Severe hypertension may require continued hospitalization for duration of pregnancy

Preterm delivery Calcium supplementation and maternal age 95% Confidence Interval Calcium n/N Placebo n/N Risk Ratio Preterm delivery (<37 ws) 398/4038 436/4042 0. 91 0. 79 - 1. 05 Early preterm delivery (<32 ws) 106/4038 130/4042 0. 82 0. 71 - 0. 93 Preterm delivery (<37 ws) 148/1400 180/1404 0. 82 0. 67 - 1. 01 Early preterm delivery (<32 ws) 34/1400 53/1404 0. 64 0. 42 - 0. 98 Preterm delivery (<37 ws) 250/2638 256/2638 0. 97 0. 83 - 1. 15 Early preterm delivery (<32 ws) 72/2638 77/2638 0. 93 0. 68 - 1. 28 Total population Women ≤ 20 years Women >20 years All risk ratios and 95% Confidence Intervals are adjusted by centre effect. The denominators include multiple births.

Askie et al. Lancet 2007; 369: 179