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Hypertensive Disorders in Pregnancy (I)

Williams Obstetrics 22nd Edition Chapter 34

부산백병원 산부인과조인호

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Index

Diagnosis Etiology Pathogenesis Pathophysiology Prediction and Prevention Management Long-term consequences

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Gestational Hypertension – 3.7% in 150,000 (National Center for Health Statics, 2001)

Pregnancy-related hypertension : Pregnancy-related deaths(3201 명 in US, 1991-

1997) 의 16% 차지 Black women are 3.1 times to die as white w

omen

Hypertensive disorders remain among the most significant and intriguing unsolved problems in obstetrics

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Diagnosis Gestational hypertension

Preeclamsia

Eclamsia

Superimposed preeclamsia (on chronic hypertension)

Chronic hypertension

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Gestational hypertension BP≥ 140/90mmHg for first time during pregnancy

No proteinuria

BP returns to normal < 12 weeks’ postpartum

Final diagnosis made only postpartum

May have other signs or symptoms of preeclampsia, for example, epigastric discomfort or thrombocytopenia

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Preeclampsia ￭ Minimum Criteria

  - BP≥140/90mmHg after 20weeks' gestation   - Proteinuria ≥300mg/24hrs or ≥1+dipstick

￭ Increased certainty of preeclampsia   - BP≥160/110mmHg   - Proteinuria 2.0g/24hrs or ≥2+dipstick   - Serum creatinine >1.2mg/dl unless known to be previously ele

vated   - Platelets <100000/mm3   - Microangiopathic hemolysis (Increased LDH)   - Elevated ALT or AST   - Persistent headache or other cerebral or visual disturbance   - Persistent epigastric pain

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Preeclampsia Diastolic hypertension ≥95mmHg

Fetal death rate : 3 배이상 증가 Worsening proteinuria

preterm labor 증가 Neonatal survival 변화없음

Epigastric or RUQ pain Hepatocellur necrosis, ischemia, edema that stretch

es the Glisson capsure AST/ALT 상승 : 임신종결의 sign Hepatic rupture : rare

Thrombocytopenia severe vasospasm -> microangiopathic hemolysis ->

Platelet activation, aggregation

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Severity of Preeclampsia

Rapid increase in BP followed by convulsions is usually preceded by unrelenting severe headache or visual disturbances.

Differentiation between mild & severe preeclampsia can be misleading

-because apparently mild disease may progress rapidly to severe disease

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Eclampsia preeclampsia+convulsion

Seizures that cannot be attributed to other causes in woman with preeclampsia

Seizures are generalized and may appear before, during, of after labor

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Chronic hypertension

BP ≥140/90 mmHg before pregnancy or diagnosed before 20weeks’ gestation (not attributable to gestational trophoblastic disease)

or Hypertension first diagnosed after 20week

s’ gestation and persistent after 12weeks’ postpartum

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Chronic Hypertension

Chronic hypertension 은 임신후반기까지 진단하기 어려움 . 이유 : BP decreases during the second and ea

rly third trimesters in both normotensive and chronically hypertensive women

Underlying hypertension 의 원인 Essential familial hypertension (90%)

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Underlying Causes of Chronic hypertensive Disorder

Essential familial hypertension (hypertensive vascular disease)ObesityAtrterial abnormalities

Renovascular hypertensionCoarctation of the aorta

Endocrine diordersDiabetes mellitusCushing syndromePrimary aldosteronismPheochromocytomaThyrotoxicosis

Glomerulonephritis (acute and chronic)Renoprival hypertension

Chronic glomerulonephritisChronic renal insufficiencyDiabetic nephropathy

Connetive tissue diseaseLupus erythematosusSystemic sclorosisPeriarteritis nodosa

Polycystic kidney diseaseAcute renal failure

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Chronic Hypertension

Chronic HT → ventricular hypertrophy, cardiac decompe

nsation, cerebrovascular accidents, renal damage

임신 때 superimposed preeclampsia 가 생기는 경우 ( 최고 25% 까지 보고됨 , 1998,

Sibai) 위의 합병증들이 더욱 호발함 .

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Preeclampsia superimposed on Chronic Hypertension

New-onset proteinuria≥ 300mg/24hours in hypertensive women but no proteinuria before 20 weeks’ gestation

A sudden increase in proteinuria or blood pressure or platelet count <100,000/mm3 in women with hypertension and proteinuria before 20weeks’ gestation

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Superimposed preeclampsia Placental abruption, growth restriction, pr

eterm delivery, death 의 위험성이 증가

일반적으로 “ Pure” preeclampsia 에 비해 증상이 훨씬 severe 하고 종종 fetal growth restriction 이 동반된다 .

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Incidence and Risk Factor Nulliparous women 에게 흔함 . Incidence : 5% (wide variation) Influence by

Parity, race, ethnicity, genetic predisposition Nulliparous

Total :7.6% / severe : 3.3% (Hauth, 2000) Risk factor

Chronic hypertension, multifetal gestation, maternal old age(>35 yrs), obesity, African-American ethnicity

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Incidence and Risk Factor Maternal weight and the risk of preeclampsia is progressi

ve.

Smoking during pregnancy reduced risk of hypertension during pregnancy (Bainbridge,2005 ; Zhang, 1999)

Placenta previa also reduced the risk of hypertension

BMI (Kg/m2) Morbidity (%)

<19.8 4.3

>35 13.3

Gestation

twin 13

single 5 (Sibai, 2000)

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Incidence and Risk Factor(Eclampsia)

Eclampsia Somewhat preventable

Receive adquate prenatal care 1976 (williams Obstetrics 15th edition)

1/700 deliveries (Parkland Hospitial) 1983-1986

1/1150 deliveries 1999

1/1750 deliveries 2000, National Vital Statistics Report, in US

1/3250 1994, Douglas and Redman in UK

1/2000

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Etiology Basic concepts

Exposed to chorionic villi for the first time

Exposed to a superabundance of chorionic villi, as with twins or hydatidiform mole

Have preexisting vascular disease

Genetically predisposed to hypertension developing during pregnancy

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Vascular endothelial damage with vasospasm, transudation of plasma, and ischemic and thrombotic sequelae.

Currently plausible potential cause (2003, Sibai) Abnormal trophoblastic invasion of Uterine vessels Immunological intolerance between maternal and fet

oplacental tissues Maternal maladaptation to cardiovascular or inflamm

atory changes of normal pregnancy Diatary deficiencies Genetic influences

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Abnormal Trophoblastic Invasion

In normal implantation, endovascular trophoblasts invade the uterine spiral arteries

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In preeclampsia Incomplete trophoblastic invasion The magnitude of defective trophoblastic invasion of

the spiral arteries correlated with the severity of the hypertensive disorder (2000, Madazli)

Using electron micorscopy Endothelial damage Insudation of plasma constituents into vessel walls Proliferation of myointimal cells Medial necrosis Lipid and macrophage accumulates in myointimal cel

ls

Abnormal Trophoblastic Invasion

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Lipid-laden cells -> atherosis (Hertig, 1945)

Obstruction of the spiral arteriolar lumen by atherosis may impair placental blood flow

Placental perfusion -> diminished

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Immunological Factors Theory

Formation of blocking antibodies of placental antigenic sites might be impaired.

Number of antigenic sites provided by the placenta is unusually great compared with the amount of antibody, as with multiple fetuses. (Beer, 1978)

Effective immunization by a previous pregnancy is lacking, as in first pregnancies.

The immunization concept was supported by their observations that preeclampsia developed less

often in multiparas who had a prior term pregnancy (Mostello, 2002; Trupin, 1996)

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Early second timester - Develop preeclampsia women Lower proportion of helper T cells (Th1) Th2 dominance, mediated by adenosine, whi

ch is found in higher serum level in preeclamptic compared with normotensive women (Yoneyama, 2002)

These helper T lymphocytes secrete specific cytokines that promote implantation, and their dysfunction may favor preeclampsia (Hayashi, 2004; Whitecar, 2001)

Immunological Factors

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The Vasculopathy and the Inflammatory Changes

The decidua contains an abundance of cells that, when activated, can release noxious agents. (Staff, 1999) -> mediators to provoke endothelial cell injury

Preeclamsia due to an extreme state of activated leukocytes in the maternal circulation (Faas, 2000) Cytokines : TNF-a, interleukin → oxidative stress (hi

ghly toxic radicals)

Potential benefit of antioxidants to prevent preeclampsia (Chappell, 1999; Zhang, 2002)

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Nutritional Factors Dietary deficiencies and Excesses over the cent

uries have been blamed as the cause of eclampsia.

Supplementation with various elements such as zinc, calcium, and magnesium to prevent preeclampsia (John, 2002)

Obesity, is a potent risk factor for preeclampsia

C-reactive protein, an inflammatory marker, was shown to be increase in obesity, which in turn was associated with preeclampsia (Wolf, 2001)

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Genetic Factors Hereditary hypertension is linked to preeclampsi

a (Ness, 2003)

Preeclampsia- eclampsia is highly heritable in sisters, daughters, granddaughters, and daughters-in-law. (Chesley and Cooper, 1986)

60% concordance in monozygotic female twin pairs (Nilsson, 2004)

HLA-DR4 와 preeclampsia 와의 연관성 (kilpatrick,1989)

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PathogenesisVasospasm

Vascular constriction →resistance and subsequent hypertension

Maldistribution, ischemia of the surrounding tissues → blood flow → 의 감소 necrosis, hemorrhage, and other end-organ disturbances

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PathogenesisEndothelial cell activation

Unknown factors (from placenta) are secreted into the maternal circulation → activation and dysfunction of the vascular endotheliu

m.

Damaged or activated endothelial cells secrete substances → promote coagulation and increase the sensitivity to v

asopressors→changes in glomerular capillary endothelial morpholog

y→increasd capillary permeability→elevated blood concentrations

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Increased Pressor Responses

Normally, pregnant women develop refractoriness to infused vasopressors (Abdul-Karim an Assali, 1961)

But, early preeclampsia women have increased vascular reactivity to infused norepinephrine and angiotensin II (Raab, 1956)

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Increased Pressor Responses Prostaglandins

In preeclampsia Endothelial prosta

cyclin (PGI2) production is decreased

Thromboxane A2 (TXA2) secretion by platelets is increased

→ Increased sensitivity to infused angiotensin II

→ vasoconstriction

Membrane phospholipid

Arachidonic acid

COX1,2

TXA2 PGI2, PGE2

Phospholipase A2

Platelet

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Synthesized from L-arginine by endothelial cells. (potent vasodilator)

Nitric oxide maintains the normal low-pressure vasodilated state characteristic of fetoplacental perfusion (Myatt, 1992)

Preeclampsia is associated with decreased endothelial nitric oxide synthase expression, which increases cell permeability (Wang, 2004)

Increased Pressor Responses Nitric oxide

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Endothelin-1 (ET-1) : potent vasoconstrictors Produced by human endothelium

Plasma ET-1 is increased in normotensive pregnant women, but women with preeclampsia have even higher levels (Ajne, 2003 ; Clark, 1992)

Increased Pressor Responses Endothelins

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Vascular endothelial growth factor (VEGF), Placental growth factor (PIGF), which secretion increases in normal pregnancy Promote angiogenesis Induce nitric oxide Vasodilatory prostaglandins

Paradoxically, VEGF is increased in serum from women with preeclampsia, but its bioavailability is decreased (Baker, 1995 ; Simmons, 2000)

Increased Pressor Responses Angiogenic factors

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PathophysiologyCardiovascular System

Increased cardiac afterload caused by hypertension

Cardiac preload in preeclampsia Pathologically diminished hypervolemia of pregnancy Iatrogenically increased by iv crystalloid or oncotic s

olution

Extravasion into the extracellular space, especially the lung

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Cardiovascular System Hemodynamic Changes Preeclampsia

Cardiac output elevated before hypertension developed than normal pregnancy.

With clinical onset of preeclampsia Marked reduction in cardiac output. Increased peripheral resistance.

By contrast, Gestational hypertension Elevated cardiac outputs with development of hypert

ension.

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(Hankin, 1984)

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Blood volume in term Normal pregnancy : 5000ml Not pregnancy : 3500ml Eclampsia : 3500ml

Hemoconcentration in preeclampsia Vasoconstriction and Endothelial dysfunction with va

scular permeability. Sevirity 와 연관되어 있지 않음 . Whereas, gestational hypertension have a normal bl

ood volume (Silver, 1998)

Cardiovascular System Blood volume

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With severe hemoconcentration, an acute fall in hematocrit suggested resolution of preeclampsia

Intravascular compartment in eclamptic women is usually not underfilled. → vasospasm and endothelial leakage of plasma has contracted

the space to be filled.→ It persist some time after delivery when the vascular endothelium repairs.

Sensitive to vigorous fluid therapy to expand the contracted blood volume to normal pregnancy levels.

Sensitive to even normal blood loss at delivery.

Cardiovascular System Blood volume

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Blood and CoagulationPlatelet

Thrombocytopenia → life threatening Severe disease : < 100,000/uL Platelet count 감소 -> indication of delivery -> 분만 후

3-5 days, 정상수준으로 회복

Platelet activation, aggregation, consumption -> “exhausion” -> thrombocytopenia (Harlow, 2002)

HELLP syndrome : hemolysis (H) , elevated liver enzymes (EL), and low platelets (LP) (Weinstein, 982)

Neonatal thrombocytopenia Maternal thrombocytopenia 와 연관이 없음 . (Prichard, 1987)

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PT, aPTT, fibrinogen level (routine lab assessment of coagulation) -> preeclampsia 의 management 에 필요하지 않음 .

FDP 의 증가 : unknown (but, hepatic derangements 때문일 것으로 추정 (Leduc, 1992) )

Thrombophilias : clotting factor deficiencies -> early onset preeclampsi

a Antithrombin 을 투약하면 대조군에 비해 preeclamp

sia 의 발생빈도를 낮출 수 있음 (Chang, 1992) Fibronectin

Glycoprotein-vascular endothelial cell basement membrane

Preeclampsia 의 예측인자로 활용

Blood and CoagulationCoagulation

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Severe preeclampsia 때 LDH 의 증가 – hemolysis 의 증거

Peripheral blood change : Schizocytosis, spherocytosis, reticulocytosis

Blood and CoagulationFragmentation Hemolysis

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Volume HomeostasisEndocrine changes

Renin, angiotensin, aldosterone 정상 임신에서는 증가 But, preeclampsia 에서는 비임신의 정상 lev

el 로 감소 기전 : Na + retension, hypertension 에 의해

Juxtaglomerular apparatus 에서 renin 분비가 감소 Angiotensinogen 이 angiotensin I 으로 conversion (ren

in 의 작용 ) 이 감소 Angiotensin II 의 감소 -> aldosterone 의 감소

이런 상황에도 불구하고 preeclampsia 산모에서 Na retension 이 계속 된다 . (Brown, 1988)

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Deoxycorticosterone (DOC) Another potent mineralocorticoid 3rd trimester 에 매우 증가

Maternal adrenal gland 에서 분비가 증가된 것이 아니라 plasma progesterone 의 전환임 .

그러므로 Na retension 이나 hypertension 이 있어도 감소하지 않음

-> preeclampsia 의 발병과 지속에 중요한 역할을 담당할 것으로 기대 .

Volume HomeostasisEndocrine changes

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Atrial Natriuretic peptide (ANP) Blood vol. expansion 에 의한 atrial wall strec

hing 에 의해서 분비됨 Vasoactive 한 물질 , aldosterone, renin activit

y, angiotension II, vasopressin 의 action 을 억제하여 sodium 과 water excretion 을 조장함 .

정상 임신에서도 증가하지만 preeclampsia때는 더욱 증가

Volume HomeostasisEndocrine changes

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Volume HomeostasisFluid and Electrolyte Changes

Preclampsia 산모 ECF vol. 이 정상산모보다 더욱 많이 증가 .

Pathologic retension : endothelial injury Electrolyte concentration do not differ. Electrolyte unbalance 가 생기는 경우

Vigorous diuretic therapy Sodium restriction Administration of water with sufficient oxytocin to pr

oduce antidiuretisis.

Following eclamptic convertion -> lower HCO3

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Kidney

Renal perfusion and glomerular filtration 감소 (in preeclampsia) Due to vasospasm But, Cr. Level 의 감소는 일반적으로 심하지

않음 -> severe 한 경우는 2-3 배 올라가기도 함 . (Pritchard, 1984)

Oligouria 가 있는 preeclampsia 산모에게서 intensive iv fluid therapy 는 indication 이 아님 .

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Kidney Proteinuria

Preeclampsia-eclampsia 진단에 중요 Late 하게 발생 . 24hr UA 가 중요

Anatomical changes Glomeruli : 20% 까지 증가 Glomerular capillary endotheliosis

Capillary endothelial swelling with subendothelial deposits of protein materials

Acute renal failure Tubular necrosis, cortical necrosis -> oligouria, anuria, rapid

ly develped azotemia 원인 : HELLP synd. , placental abruption, postpartum hemo

rrhage

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Liver Periportal hemorrhagic necrosis in the periphery

of the liver lobule Serum liver enzyme 상승의 원인 Nonfatal case 에서는 잘 보이지 않음

Autopsy 에서 주로 확인 Hepatic rupture(more rare), subcapsular hematoma

(more common) 을 일으킬 수 있음 . Treatment

Surgical intervention 이 기본 , life saving 가능 Blood T/F 이 도움 . Liver transplantation 도 시행가능

Spontaneous hepatic rupture 의 mortality :30%

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Liver

HELLP syndrome Hemolysis, Elevated Liver enzyme and Low

Platelet 20% of severe preeclampsia and eclampsia Adverse outcome : 40% Other complication

Eclampsia (6%), Placental abruption (10%), ARF (5%), pulmonary edema (10%), subcapsular liver hematoma (1.6%)

Steroid Tx. - controversial

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Brain

Common Sx. Headache, visual disturbance – associated c

onvulsion (eclampsia) Anatomical pathology

Gross hemorrhage – severe hypertension Chronic hypertension 이 있는 경우 더욱 흔함

Postmortem cerebral lesion Edema, hyperemia, focal anemia, thrombosis, he

morrhage

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Brain Neuroimaging study

CT 50% 에서 abnormal finding Hypodense cotical area – petechial hemorrhage a

nd infarction site 에 해당 (at autopsy) MRI

주로 post. Cerebral artery area 에서 remarkable change 가 발견됨 .

Convulsion 과 직접적인 연관 Convulsion 의 25% 는 cerebral infarction area

가 있음 .

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Brain

Cerebral Blood Flow Eclampsia : loss of autoregulation of cerebral

blood flow (Apollon, 2000) Hyperperfusion – similar in hypertensive encephal

opathy.

Increased cerebral perfusion –> headache유발

Cerebral vasospasm 을 밝혀내지 못함 .

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Brain Blindness

Rare 4hr to 8days 정도까지 지속되지만 결국 완전히

회복된다 . Visual disturbance

More common Retinal detachement

Total loss 를 초래 하지는 않음 주로 one side 를 involve 수술적치료는 필요없음 . 일반적으로 prognosis 는 good, 1 주일이내에 정상으로 돌아옴

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Brain Cerebral Edema

Sx Letharge, confusion, blurred vision, coma

Mental change 정도와 brain involvement 정도는 어느정도 비례한다 . (CT, MRI 상 변화 )

Sudden severe blood pressure elevatoin 광범위한 vasogenic edema 로 급격하게 악화 Blood pressure control 이 중요함 .

Electroencephalopgraphy Eclampsia 환자의 75% 에서 abnormal finding 이

나타남 . (48hr 이내 ) 50% 이상은 1 주일이상 지속하지만 , 3 개월 이내에

대부분 좋아진다 .

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Uteroplacental perfusion Vasospasm ->

placental perfusion 저하 -> perinatal mortality and morbidity 증가의 중요한 요소

Measurement Spiral a. : 500μm ( 정상 ), 200 μm (preeclampsi

a) Placental blood flow

Inaccesibility, complexity, unsuitablity DHAS sulfate-> estradiol-17B (in placenta) 의 cl

earance rate 로 간접측정 (Everett, 1980)

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Uteroplacental perfusion Doppler

Doppler measurement of blood velocity through uterine artery.

-> estimate uteroplacental blood flow S/D ratio in preeclampsia : 증가 Abnormal wave form -> fetal indication 으로 c/sec

필요함 . HELLP synd. 의 18-36% : abnormal wave form 을

보임 . Preeclampsia 산모는 정상산모에 비해 mean resista

nce 가 높음 .

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Prediction and Prevention

Prediction Lots of attemption to predict preeclampsia in

early pregnancy -> poor sensitivity, poor positive predictive value

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Roll over test 28-32wks Lt. lat. Recumbent position -> supine position

Hypertension 유발되면 abnormal 이 경우 , angiotension II infusion 에도 abnormal

반응을 보임 . Positive predictive value (true positive) : 33% (De

kker, 1990 ; Friedman and Lindhemier, 1999)

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Uric acid Decreased renal uric acid excretion -> elevated s

erum uric acid level Jacobson (1990)

Uric acid level > 5.9mg/dL at 24wks ; positive predictive value : 33%

Weerasekera and Peiris (2003) Serum uric acid levels did not vary significantly before th

e detection of hypertension

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Fibronectin Endothelial cell activation -> elevated serum

cellular fibronectin level (Brubaker, 1992) Clinical study, Paarlberg (1998)

Low sensitivity : 69% Positive predictive value :12%

Clinical study, Chavarria (2003) 16wks-20wks, 378 low-risk nulliparas Positive predictive value : 29% Negative predictive value : 98%

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Oxidative Stress Lipid peroxides level 증가 – antioxidants 의 activity

감소 -> preeclampsia 의 prediction 가능 (Walsh, 1994)

Marker Lipid peroxides: malondialdehyde Pro-oxidants : iron, transferrin, ferritin, blood lipids, TG, free

fatty acid, lipoproteins, Vit C & E

Hyperhomocysteinemia Atherosclerosis 의 risk factor (non pregnant) But, midpregnancy 때 level 이 높으면 preeclampsia 의 ris

k 가 정상보다 3-4 배 증가함 . (D’Anna, 2004; Hietala, 2001)

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Cytokines Released by vascular endothelium and leuko

cytes 50 개 이상의 cytokine 이 preeclampsia 때

증가 Interleukin, TNF – a

CRP 증가 Not sufficiently predictive (Savvidou, 2002)

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Placental peptides Corticotropin releasing hormone, chorionic g

onadotropin, activin A, inhibin A But, variation 이 심해 investigator 마다 결과가

다양하게 나타남 . Angiogenic factor :VEGF, PlGF

First trimester 때 PlGF, sFlt1 의 serum level증가

임상적으로 유용하나 의견이 분분 .

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Fetal DNA Identification of Fetal DNA in marternal seru

m -> prediction of preeclampsia (Zhong, 2001)

이유 : endothelial activation and inflammation이 발생하면 fetal cells and cellular material이 maternal circulation 에 분비됨 .

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Uterine Artery Doppler Velocimetry Second trimester – uteroplacental vacular re

sistance 측정 (by doppler of uterine artery) Basic concepts

Impaired trophoblastic invasion of the spiral arteries -> uteroplacental blood flow 의 감소

Bower (1993) Sensitivity : 78% Positive predictive value :28%

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Prevention

Dietary Manipulation Salt restriction -> ineffective (Knuist, 1998) Prenatal Ca supplementation -> significant red

uction in BP and incidence of preeclampsia (Brucher, 1996)

But, Levin, (1997) 4600 nulliparas -> calcium and placebo 섭취 -> preeclampsia 와 gestational hypertension 의 incidence 는 두 그룹간의 차이가 없음 .

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Low dose aspirin 60mg aspirin -> reduce the incidence of pree

clampsia ; selective TXA2 억제 , dominence of endothelial prostacyclin (Hauth, 1998, Wallenburg, 1986)

Caritis, 1998; CLASP Collaborative Group, 1994; Hauth, 1993, 1998; Rotchell, 1998; Sibai, 1993a Low-dose aspirin was ineffective in preventing pre

eclampsia

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Antioxidants Davidge, 1992

Markedly reduced antioxidant activity in preeclampsia women.

Chappel, 1999 283 high risk women 18-22wks , vit C & E versus placebo Significant reduction in preeclampsia (11% / 17%)

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진단

질병

양성 음성

양성 a b

음성 c d

Sensitivity : a/ a+c

Specificity : d/b+d

Positive predictive value : a/a+b

Negative predictive value : d/c+d