1 hypertensive disorders in pregnancy (i) williams obstetrics 22 nd edition chapter 34...
TRANSCRIPT
1
Hypertensive Disorders in Pregnancy (I)
Williams Obstetrics 22nd Edition Chapter 34
부산백병원 산부인과조인호
2
Index
Diagnosis Etiology Pathogenesis Pathophysiology Prediction and Prevention Management Long-term consequences
3
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
4
Diagnosis Gestational hypertension
Preeclamsia
Eclamsia
Superimposed preeclamsia (on chronic hypertension)
Chronic hypertension
5
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
6
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
7
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
8
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
9
10
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
11
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
12
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%)
13
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
14
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 .
15
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
16
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 .
17
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
18
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)
19
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
20
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
21
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
22
Abnormal Trophoblastic Invasion
In normal implantation, endovascular trophoblasts invade the uterine spiral arteries
23
24
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
25
Lipid-laden cells -> atherosis (Hertig, 1945)
Obstruction of the spiral arteriolar lumen by atherosis may impair placental blood flow
Placental perfusion -> diminished
26
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)
27
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
28
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)
29
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)
30
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)
31
PathogenesisVasospasm
Vascular constriction →resistance and subsequent hypertension
Maldistribution, ischemia of the surrounding tissues → blood flow → 의 감소 necrosis, hemorrhage, and other end-organ disturbances
32
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
33
34
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)
35
36
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
37
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
38
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
39
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
40
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
41
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.
42
43
(Hankin, 1984)
44
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
45
46
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
47
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)
48
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
49
Severe preeclampsia 때 LDH 의 증가 – hemolysis 의 증거
Peripheral blood change : Schizocytosis, spherocytosis, reticulocytosis
Blood and CoagulationFragmentation Hemolysis
50
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)
51
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
52
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
53
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
54
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 .
55
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
56
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%
57
58
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
59
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
60
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 .
61
62
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 .
63
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
64
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 .
65
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)
66
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 .
67
Prediction and Prevention
Prediction Lots of attemption to predict preeclampsia in
early pregnancy -> poor sensitivity, poor positive predictive value
68
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)
69
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
70
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%
71
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)
72
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)
73
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 .
74
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 .
75
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%
76
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 .
77
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
78
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%)
79
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