Presentation on theme: "Hypertensive Disorders in Pregnancy (I)"— Presentation transcript:
1 Hypertensive Disorders in Pregnancy (I) Williams Obstetrics 22nd Edition Chapter 34부산백병원 산부인과조인호
2 Index Diagnosis Etiology Pathogenesis Pathophysiology Prediction and PreventionManagementLong-term consequences
3 Gestational Hypertension – 3.7% in 150,000 (National Center for Health Statics, 2001)Pregnancy-related hypertension :Pregnancy-related deaths(3201명 in US, )의 16% 차지Black women are 3.1 times to die as white womenHypertensive disorders remain among the most significant and intriguing unsolved problems in obstetricsIncidence에 관한 내용, 선진국으로 갈 수록 mortality가 떨어짐.
4 Diagnosis Gestational hypertension Preeclamsia Eclamsia Superimposed preeclamsia (on chronic hypertension)Chronic hypertension21판부터 정립된 내용
5 Gestational hypertension BP≥ 140/90mmHg for first time during pregnancyNo proteinuriaBP returns to normal < 12 weeks’ postpartumFinal diagnosis made only postpartumMay have other signs or symptoms of preeclampsia, for example, epigastric discomfort or thrombocytopeniaEclampsia seizure의 10%는 proteinuria가 발견되기 이전에 나타남. 그러므로 BP가 상승하면 모체와 태아 모두에게서 위험성이 높아진다.
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 elevated - Platelets <100000/mm3 - Microangiopathic hemolysis (Increased LDH) - Elevated ALT or AST - Persistent headache or other cerebral or visual disturbance - Persistent epigastric painTable 34-1의 내용Proteinuria 양은 wide하게 fluctuation을 보임. 연속해서 측정해야 함.Renal Bx.에서 특징적인 조직학적 변화(glomerular histologic alteration)를 동반
7 Preeclampsia Diastolic hypertension ≥95mmHg Worsening proteinuria Fetal death rate : 3배이상 증가Worsening proteinuriapreterm labor 증가Neonatal survival 변화없음Epigastric or RUQ painHepatocellur necrosis, ischemia, edema that stretches the Glisson capsureAST/ALT상승 : 임신종결의 signHepatic rupture : rareThrombocytopeniasevere vasospasm -> microangiopathic hemolysis -> Platelet activation, aggregationProteinuria만 있는 경우는 benign으로 봄.Thrombocytopenia가 심해 gross hemolysis (hemoglobineia, hemoglobinuria, hyperbilirubinemia)가 있는 경우 질병의 심각성을 보여줌이전 chapter에서는 diastolic BP와 proteinuria와의 상관관계에 따른 fetal death를 표로써 보여주었음.
8 Severity of Preeclampsia Differentiation between mild & severe preeclampsia can be misleading-because apparently mild disease may progress rapidly to severe diseaseRapid increase in BP followed by convulsions is usually preceded by unrelenting severe headache or visual disturbances.
9 Table 34-2BP단독으로는 severity indicator 아님.BP보다는 proteinuria의 양이 severity를 결정하는데 큰 영향을 미침. (130/ > seizure, 180/ : no seizure)
10 Eclampsia preeclampsia+convulsion Seizures that cannot be attributed to other causes in woman with preeclampsiaSeizures are generalized and may appear before, during, of after labor10%는 단백뇨가 발생되지 않는 상태이므로 임신 후반기에 BP가 상승하면 설사 단백뇨가 없다고 해도 함부로 생각해서는 안됨.
11 Chronic hypertensionBP ≥140/90 mmHg before pregnancy or diagnosed before 20weeks’ gestation (not attributable to gestational trophoblastic disease)orHypertension first diagnosed after 20weeks’ gestation and persistent after 12weeks’ postpartum진단기준에 관한 내용임
12 Chronic Hypertension Chronic hypertension은 임신후반기까지 진단하기 어려움. 이유: BP decreases during the second and early third trimesters in both normotensive and chronically hypertensive womenUnderlying hypertension의 원인Essential familial hypertension (90%)예) 원래 chronic vascular disease를 가지고 있는 여성이 임신 20주에 처음 혈압을 검사했을 경우엔 정상 수치를 나타내다가 3rd trimester동안에는 이전상태로 고혈압소견을 나타내게 된다. 이로 인하여 HBP가 chronic인지 gestational hypertension, preeclampsia 인지 진단하기가 어렵게 된다.
13 Underlying Causes of Chronic hypertensive Disorder Essential familial hypertension (hypertensive vascular disease)ObesityAtrterial abnormalitiesRenovascular hypertensionCoarctation of the aortaEndocrine diordersDiabetes mellitusCushing syndromePrimary aldosteronismPheochromocytomaThyrotoxicosisGlomerulonephritis (acute and chronic)Renoprival hypertensionChronic glomerulonephritisChronic renal insufficiencyDiabetic nephropathyConnetive tissue diseaseLupus erythematosusSystemic sclorosisPeriarteritis nodosaPolycystic kidney diseaseAcute renal failureTable 34-3
14 Chronic Hypertension Chronic HT → ventricular hypertrophy, cardiac decompensation, cerebrovascular accidents, renal damage임신 때 superimposed preeclampsia가 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’ gestationA 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, preterm delivery, death 의 위험성이 증가일반적으로 “Pure” preeclampsia에 비해 증상이 훨씬 severe하고 종종 fetal growth restriction이 동반된다.
18 Incidence and Risk Factor Maternal weight and the risk of preeclampsia is progressive.Smoking during pregnancy reduced risk of hypertension during pregnancy (Bainbridge,2005 ; Zhang, 1999)Placenta previa also reduced the risk of hypertensionBMI (Kg/m2)Morbidity (%)<19.84.3>3513.3Gestationtwin13single5(Sibai, 2000)
19 Incidence and Risk Factor (Eclampsia) Somewhat preventableReceive adquate prenatal care1976 (williams Obstetrics 15th edition)1/700 deliveries (Parkland Hospitial)1/1150 deliveries19991/1750 deliveries2000, National Vital Statistics Report, in US1/32501994, Douglas and Redman in UK1/2000
20 Etiology Basic concepts Exposed to chorionic villi for the first time Exposed to a superabundance of chorionic villi, as with twins or hydatidiform moleHave preexisting vascular diseaseGenetically predisposed to hypertension developing during pregnancy
21 Currently plausible potential cause (2003, Sibai) Vascular endothelial damage with vasospasm, transudation of plasma, and ischemic and thrombotic sequelae.Currently plausible potential cause (2003, Sibai)Abnormal trophoblastic invasion of Uterine vesselsImmunological intolerance between maternal and fetoplacental tissuesMaternal maladaptation to cardiovascular or inflammatory changes of normal pregnancyDiatary deficienciesGenetic influences
22 Abnormal Trophoblastic Invasion In normal implantation, endovascular trophoblasts invade the uterine spiral arteries
24 Abnormal Trophoblastic Invasion In preeclampsiaIncomplete trophoblastic invasionThe magnitude of defective trophoblastic invasion of the spiral arteries correlated with the severity of the hypertensive disorder (2000, Madazli)Using electron micorscopyEndothelial damageInsudation of plasma constituents into vessel wallsProliferation of myointimal cellsMedial necrosisLipid and macrophage accumulates in myointimal cells
25 Lipid-laden cells -> atherosis (Hertig, 1945) Obstruction of the spiral arteriolar lumen by atherosis may impair placental blood flowPlacental perfusion -> diminished
26 Immunological Factors TheoryFormation 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 bytheir observations that preeclampsia developed less often in multiparas who had a prior term pregnancy (Mostello, 2002; Trupin, 1996)
27 Immunological Factors Early second timester - Develop preeclampsia womenLower proportion of helper T cells (Th1)Th2 dominance, mediated by adenosine, which 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)
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 injuryPreeclamsia due to an extreme state of activated leukocytes in the maternal circulation (Faas, 2000)Cytokines : TNF-a, interleukin → oxidative stress (highly toxic radicals)Potential benefit of antioxidants to prevent preeclampsia (Chappell, 1999; Zhang, 2002)Antioxidants283 (high risk women) 주 사이에 vit E, C복용 / 대조군은 placebo복용결과는 significant reduction : 11% / 17% (Chappell, 1999) – page 780
29 Nutritional FactorsDietary deficiencies and Excesses over the centuries 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 preeclampsiaC-reactive protein, an inflammatory marker, was shown to be increase in obesity, which in turn was associated with preeclampsia (Wolf, 2001)
30 Genetic FactorsHereditary hypertension is linked to preeclampsia (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-DR4와 preeclampsia와의 연관성(kilpatrick,1989)Nilsson, swedish, 1,2 million birth : genetic component for gestational hypertension as well as preeclampsia
31 Pathogenesis Vasospasm Vascular constriction →resistance and subsequent hypertensionMaldistribution, ischemia of the surrounding tissues → blood flow 의 감소→ necrosis, hemorrhage, and other end-organ disturbancesSubsequent : 차후의
32 Pathogenesis Endothelial cell activation Unknown factors (from placenta) are secreted into the maternal circulation→ activation and dysfunction of the vascular endothelium.Damaged or activated endothelial cells secrete substances→ promote coagulation and increase the sensitivity to vasopressors→changes in glomerular capillary endothelial morphology→increasd capillary permeability→elevated blood concentrations
33 Fig 34-3, (Friedman and Lindheimer, 1999) Pathophysiological considerations in the development of hypertensive disorder due to pregnancy
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 Y축 : angiotensin II를 infusion하여 vessel을 contraction시킬 수 있는 최소한의 농도 검은색 실선은 정상 산모, 파란색 실선은 preeclampsia산모
36 Increased Pressor Responses Prostaglandins In preeclampsiaEndothelial prostacyclin (PGI2) production is decreasedThromboxane A2 (TXA2) secretion by platelets is increased→ Increased sensitivity to infused angiotensin II→ vasoconstrictionMembrane phospholipidPhospholipaseA2Arachidonic acidCOX1,2Prostaglandin이 pressor response를 blunt시키는 역할을 할 것으로 예상.PGI2, PGE2TXA2Platelet
37 Increased Pressor Responses Nitric oxide 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)
38 Increased Pressor Responses Endothelins Endothelin-1 (ET-1) :potent vasoconstrictorsProduced by human endotheliumPlasma ET-1 is increased in normotensive pregnant women, but women with preeclampsia have even higher levels (Ajne, 2003 ; Clark, 1992)
39 Increased Pressor Responses Angiogenic factors Vascular endothelial growth factor (VEGF), Placental growth factor (PIGF),which secretion increases in normal pregnancyPromote angiogenesisInduce nitric oxideVasodilatory prostaglandinsParadoxically, VEGF is increased in serum from women with preeclampsia, but its bioavailability is decreased (Baker, 1995 ; Simmons, 2000)sFlt 1 (soluble fms-like tyrosine kinase-1) : VEGF antagonist -> preeclampsia때 증가함.
40 Pathophysiology Cardiovascular System Increased cardiac afterload caused by hypertensionCardiac preload in preeclampsiaPathologically diminished hypervolemia of pregnancyIatrogenically increased by iv crystalloid or oncotic solutionExtravasion into the extracellular space, especially the lung
41 Cardiovascular System Hemodynamic Changes PreeclampsiaCardiac output elevated before hypertension developed than normal pregnancy.With clinical onset of preeclampsiaMarked reduction in cardiac output.Increased peripheral resistance.By contrast, Gestational hypertensionElevated cardiac outputs with development of hypertension.
43 (Hankin, 1984) Before therapy : G (Y축 : LVSWI) Fluid restriction : B, H AVolume expansion : R, P B(Hankin, 1984)
44 Cardiovascular System Blood volume Blood volume in termNormal pregnancy : 5000mlNot pregnancy : 3500mlEclampsia : 3500mlHemoconcentration in preeclampsiaVasoconstriction and Endothelial dysfunction with vascular permeability.Sevirity 와 연관되어 있지 않음.Whereas, gestational hypertension have a normal blood volume (Silver, 1998)
46 Cardiovascular System Blood volume With severe hemoconcentration, an acute fall in hematocrit suggested resolution of preeclampsiaIntravascular 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.
47 Blood and Coagulation Platelet Thrombocytopenia → life threateningSevere disease : < 100,000/uLPlatelet count 감소 -> indication of delivery -> 분만 후 3-5 days, 정상수준으로 회복Platelet activation, aggregation, consumption -> “exhausion” -> thrombocytopenia (Harlow, 2002)HELLP syndrome : hemolysis (H) , elevated liver enzymes (EL), and low platelets (LP) (Weinstein, 982)Neonatal thrombocytopeniaMaternal thrombocytopenia와 연관이 없음. (Prichard, 1987)
48 Blood and Coagulation Coagulation PT, aPTT, fibrinogen level (routine lab assessment of coagulation) -> preeclampsia 의 management에 필요하지 않음.FDP의 증가 : unknown (but, hepatic derangements 때문일 것으로 추정(Leduc, 1992) )Thrombophilias :clotting factor deficiencies -> early onset preeclampsiaAntithrombin 을 투약하면 대조군에 비해 preeclampsia의 발생빈도를 낮출 수 있음(Chang, 1992)FibronectinGlycoprotein-vascular endothelial cell basement membranePreeclampsia의 예측인자로 활용Derangement : 장애
49 Blood and Coagulation Fragmentation Hemolysis Severe preeclampsia 때 LDH의 증가 – hemolysis의 증거Peripheral blood change :Schizocytosis, spherocytosis, reticulocytosis
50 Volume Homeostasis Endocrine changes Renin, angiotensin, aldosterone정상 임신에서는 증가But, preeclampsia에서는 비임신의 정상 level로 감소기전 : Na + retension, hypertension 에 의해Juxtaglomerular apparatus에서 renin분비가 감소Angiotensinogen이 angiotensin I 으로 conversion (renin의 작용) 이 감소Angiotensin II의 감소 -> aldosterone의 감소이런 상황에도 불구하고 preeclampsia 산모에서 Na retension이 계속 된다. (Brown, 1988)Aldosterone의 역할 : kidney에서 Na 재 흡수에 관여
51 Volume Homeostasis Endocrine changes Deoxycorticosterone (DOC)Another potent mineralocorticoid3rd trimester에 매우 증가Maternal adrenal gland에서 분비가 증가된 것이 아니라 plasma progesterone의 전환임.그러므로 Na retension이나 hypertension이 있어도 감소하지 않음-> preeclampsia의 발병과 지속에 중요한 역할을 담당할 것으로 기대.
52 Volume Homeostasis Endocrine changes Atrial Natriuretic peptide (ANP)Blood vol. expansion에 의한 atrial wall streching에 의해서 분비됨Vasoactive한 물질, aldosterone, renin activity, angiotension II, vasopressin의 action을 억제하여 sodium과 water excretion을 조장함.정상 임신에서도 증가하지만 preeclampsia때는 더욱 증가
53 Volume Homeostasis Fluid and Electrolyte Changes Preclampsia산모ECF vol. 이 정상산모보다 더욱 많이 증가.Pathologic retension : endothelial injuryElectrolyte concentration do not differ.Electrolyte unbalance가 생기는 경우Vigorous diuretic therapySodium restrictionAdministration of water with sufficient oxytocin to produce antidiuretisis.Following eclamptic convertion -> lower HCO3
54 Kidney Renal perfusion and glomerular filtration 감소 (in preeclampsia) Due to vasospasmBut, Cr. Level의 감소는 일반적으로 심하지 않음 -> severe한 경우는 2-3배 올라가기도 함. (Pritchard, 1984)Oligouria가 있는 preeclampsia산모에게서 intensive iv fluid therapy는 indication이 아님.
56 LiverPeriportal hemorrhagic necrosis in the periphery of the liver lobuleSerum liver enzyme 상승의 원인Nonfatal case에서는 잘 보이지 않음Autopsy에서 주로 확인Hepatic rupture(more rare), subcapsular hematoma(more common)을 일으킬 수 있음.TreatmentSurgical intervention이 기본, life saving가능Blood T/F이 도움.Liver transplantation도 시행가능Spontaneous hepatic rupture 의 mortality :30%
62 Brain Cerebral Blood Flow Eclampsia : loss of autoregulation of cerebral blood flow (Apollon, 2000)Hyperperfusion – similar in hypertensive encephalopathy.Increased cerebral perfusion –> headache유발Cerebral vasospasm을 밝혀내지 못함.
63 Brain Blindness Visual disturbance Rare 4hr to 8days 정도까지 지속되지만 결국 완전히 회복된다.Visual disturbanceMore commonRetinal detachementTotal loss를 초래 하지는 않음주로 one side를 involve수술적치료는 필요없음.일반적으로 prognosis는 good, 1주일이내에 정상으로 돌아옴
64 Brain Cerebral Edema Electroencephalopgraphy Sx Letharge, confusion, blurred vision, comaMental change정도와 brain involvement정도는 어느정도 비례한다. (CT, MRI상 변화)Sudden severe blood pressure elevatoin광범위한 vasogenic edema로 급격하게 악화Blood pressure control이 중요함.ElectroencephalopgraphyEclampsia환자의 75%에서 abnormal finding이 나타남. (48hr 이내)50%이상은 1주일이상 지속하지만 , 3개월 이내에 대부분 좋아진다.
65 Uteroplacental perfusion Vasospasm ->placental perfusion저하 -> perinatal mortality and morbidity 증가의 중요한 요소MeasurementSpiral a. : 500μm (정상), 200 μm (preeclampsia)Placental blood flowInaccesibility, complexity, unsuitablityDHAS sulfate-> estradiol-17B (in placenta)의 clearance rate로 간접측정 (Everett, 1980)
66 Uteroplacental perfusion DopplerDoppler measurement of blood velocity through uterine artery.-> estimate uteroplacental blood flowS/D ratio in preeclampsia : 증가Abnormal wave form -> fetal indication으로 c/sec필요함.HELLP synd.의 18-36% : abnormal wave form을 보임.Preeclampsia 산모는 정상산모에 비해 mean resistance가 높음.
67 Prediction and Prevention Lots of attemption to predict preeclampsia in early pregnancy -> poor sensitivity, poor positive predictive value
68 Roll over test28-32wksLt. lat. Recumbent position -> supine positionHypertension유발되면 abnormal이 경우, angiotension II infusion에도 abnormal반응을 보임.Positive predictive value (true positive) : 33% (Dekker, 1990 ; Friedman and Lindhemier, 1999)
69 Uric acidDecreased renal uric acid excretion -> elevated serum uric acid levelJacobson (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 the detection of hypertension
72 Cytokines Released by vascular endothelium and leukocytes 50개 이상의 cytokine이 preeclampsia때 증가Interleukin, TNF – aCRP증가Not sufficiently predictive (Savvidou, 2002)
73 Placental peptidesCorticotropin releasing hormone, chorionic gonadotropin, activin A, inhibin ABut, variation이 심해 investigator마다 결과가 다양하게 나타남.Angiogenic factor :VEGF, PlGFFirst trimester때 PlGF, sFlt1 의 serum level증가임상적으로 유용하나 의견이 분분.
74 Fetal DNAIdentification of Fetal DNA in marternal serum -> prediction of preeclampsia (Zhong, 2001)이유: endothelial activation and inflammation이 발생하면 fetal cells and cellular material이 maternal circulation에 분비됨.
75 Uterine Artery Doppler Velocimetry Second trimester – uteroplacental vacular resistance측정 (by doppler of uterine artery)Basic conceptsImpaired trophoblastic invasion of the spiral arteries -> uteroplacental blood flow의 감소Bower (1993)Sensitivity : 78%Positive predictive value :28%
76 Prevention Dietary Manipulation Salt restriction -> ineffective (Knuist, 1998)Prenatal Ca supplementation -> significant reduction in BP and incidence of preeclampsia (Brucher, 1996)But, Levin, (1997) 4600 nulliparas -> calcium and placebo섭취 -> preeclampsia와 gestational hypertension의 incidence는 두 그룹간의 차이가 없음.
77 Low dose aspirin60mg aspirin -> reduce the incidence of preeclampsia ; selective TXA2억제, dominence of endothelial prostacyclin (Hauth, 1998, Wallenburg, 1986)Caritis, 1998; CLASP Collaborative Group, 1994; Hauth, 1993, 1998; Rotchell, 1998; Sibai, 1993aLow-dose aspirin was ineffective in preventing preeclampsia
78 Antioxidants Davidge, 1992 Chappel, 1999 Markedly reduced antioxidant activity in preeclampsia women.Chappel, 1999283 high risk women18-22wks , vit C & E versus placeboSignificant reduction in preeclampsia (11% / 17%)
79 진단 질병 양성 음성 a b c d Sensitivity : a/ a+c Specificity : d/b+d Positive predictive value : a/a+bNegative predictive value : d/c+d