1Pregnancy induced hypertension ( PIH ) & Eclampsia Speaker- Dr Ajisha AravindanModerator – Dr Anjan Trikha
2HypertensionIn US, 28.7% adults, or ~58.4 million individuals, have hypertension.National Health and Nutrition Examination Survey (NHANES)Incidence in pregnancy : 3-5 %India – PIH incidence 5 %PIH is the 3rd leading cause of mortality during pregnancy ( 1-thromboembolism , 2-hemorrhage )India – 4th ( Bleeding, Sepsis, Unsafe abortions)
3Pregnancy induced HTN PIH : 2- 8 % of pregnancies. Eclampsia : 1 in 1000–1700 pregnancies- developing world.1 in 2000 pregnancies - developed countries.In UK, 1/5 of antenatal admissions, 2/3 of referrals to day care units, and ¼ of obstetric admissions to ICU.Maternal and neonatal outcome depend on gestational age at onset, severity of the disease and presence of preexisting medical conditions.
4Its not so uncommon … Laura Bush Angelina Jolie (with the twins) Britney Spears (rumored)Julia Roberts (rumored with her twins)Jennifer LopezLisa Marie PresleyJenna Jameson
5Classification of Hypertension in Pregnancy 1) P.I.HPreeclampsia(6-8%)Eclampsia (0.05% )Gestational Hypertension(6-7%)2) Chronic Hypertension(3-5%)3) Chronic Hypertension with superimposed P.I.HDavid H. Chestnut, Obstetric anaesthesia
71) Preeclampsia Hypertension Proteinuria A sustained systolic BP of at least 140 mm Hg, or a sustained diastolic BP of at least 90 mm Hg, that occurs after 20 weeks' gestation in a woman with previously normal BP.Proteinuria≥300 mg protein in a 24-hour urine collectionDavid H. Chestnut, Obstetric anaesthesia
8Severe PreeclampsiaBlood pressure : ≥ 160 mm Hg systolic or ≥ 110 mm Hg diastolic BP on two occasions at least 6 hours apart while the patient is on bed rest.Proteinuria : ≥5 g in a 24-hour urine specimen (or ≥3+ on two random urine samples at least 4 hours apart).Oliguria : Urine output < 500 ml in 24 hours.Cerebral or visual disturbances: Headache, blurred vision, or altered consciousness.David H. Chestnut, Obstetric anaesthesia
9Severe Preeclampsia Thrombocytopenia Impaired liver function Epigastric or right upper quadrant pain: stretching of Glisson's capsule by hepatic edemaHepatic rupture: a rare complicationPulmonary edemaFetal growth restriction, oligohydramniosDavid H. Chestnut, Obstetric anaesthesia
102) Chronic Hypertension BP 140/90 mm Hg before pregnancy or diagnosed before20 weeks' gestation not attributable to gestation. orHypertension first diagnosed after 20 weeks' gestation andpersistent after 12 weeks' postpartumIncidence- 5 %David H. Chestnut, Obstetric anaesthesia
113) Chronic hypertension with Superimposed Preeclampsia New-onset proteinuria > 300 mg/24 hours in hypertensive womenbut no proteinuria before 20 weeks' gestation.orA sudden increase in proteinuria or blood pressure or platelet count< 100,000/mm3 in women with hypertension and proteinuria before20 weeks' gestation David H. Chestnut, Obstetric anaesthesia
13Preconceptional &/or Chronic risk factors for PIH 1) History of previous preeclampsia 2) Age 3) Interval between pregnancies 4) Family historyDavid H. Chestnut, Obstetric anaesthesia
14Preconceptional &/or Chronic risk factors for PIH 5) Presence of underlying diseases• Chronic HTN, renal disease • Obesity, insulin resistance• GDM, type I DM • Ac protein C resistance (factor V mutation), protein S deficiency • Antiphospholipid antibodies• Hyperhomocysteinemia David H. Chestnut, Obstetric anaesthesia
17Preconceptional &/or Chronic risk factors for PIH Partner related risk factors• Limited sperm exposure, donor insemination, oocyte donation • Partner who fathered a preeclamptic pregnancy in another womanDavid H. Chestnut, Obstetric anaesthesia
18Pathogenesis of Preeclampsia PlateletEndothelialImmunologicalPathogenesis of PreeclampsiaCalciumGeneticFatty acid metabolismCoagulation
19Historical TheoriesThe Immunity Model describes it in terms of self versus non-self, with loss of immunity control leading to a disease state.The Danger Model suggests that stress or abnormal cell death in pregnancy-related tissues causes expression of specific danger signals and potential activation of anti-fetal immunity.The Genetics Model, including factor V Leiden mutation, TNF-α, Angiotensinogen , AR II etc have also been implicated.American Journal of Therapeutics 16, 284–288 (2009)
20Pathogenesis of Preeclampsia DysfunctionEndothelialIschemiaPlacental
21Normal PlacentaCytotrophoblasts of fetal origin invade the uterine spiral arteries of the decidua and myometrium and replace the endothelial layer of the maternal spiral arteries, transforming them from small, high-resistance vessels to high-caliber capacitance vessels.Alice Wang et al. Physiology 24: , 2009.
22Preeclamptic Placenta In preeclampsia, this transformation is incomplete. Cytotrophoblast invasion of the spiral arteries is limited to the superficial decidua, and the myometrial segments remain narrow.Alice Wang et al. Physiology 24: , 2009
23Platelet & Endothelial function David H. Chestnut, Obstetric anaesthesia
24Endothelial Dysfunction Placental ischemia leads to release of circulating factors – profound systemic effects .prostacyclin (PGI2) , nitric oxidethromboxane (TXA2) , endothelinExaggerated sensitivity to vasopressors such as angiotensin II and norepinephrine.Compromised uteroplacental circulation.Alice Wang et al. Physiology 24: , 2009
25Platelet DysfunctionSurface-mediated activation , microvascular consumption .sensitivity to PGI2, release of TXA2 & serotonin causing further platelet aggregation.HypercoagulabilityThrombocytopeniaPlatelet lifespan reduced – 2-3 days
26Anti-angiogenic factors VEGF stabilizes endothelial cells in mature blood vessels and helps in maintaining the endothelium.Soluble fms-like tyrosine kinase-1(sFlt1) - a circulating antagonist to both vascular endothelial growth factor (VEGF) and placental growth factor (PlGF).Soluble endoglin (sEng)- a proteolytic cleavage product of the TGF- receptor endoglin, acts synergistically with sFlt1.sFlt1 is a truncated splice variant of the membrane-bound VEGF receptor Flt1, also called VEGFR1.sFlt1 consisting of the extracellular ligand binding domain without the transmembrane and intracellular signaling domains, is secreted by syncytio -trophoblasts into the maternal circulation. sFlt1 antagonizes both VEGF and PlGF by binding them in the circulation and preventing interaction with their endogenous receptorsAlice Wang et al. Physiology 24: , 2009
27Role of sFlt1 and sEngsFlt1 consisting of the extracellular ligand binding domain without the transmembrane and intracellular signaling domains, is secreted by syncytio -trophoblasts into the maternal circulation. sFlt1 antagonizes both VEGF and PlGF by binding them in the circulation and preventing interaction with their endogenous receptorsThis results in endothelial cell dysfunction, including decreased prostacyclin, nitric oxide production, and release of procoagulant proteinsExcess placental secretion of sFlt1 and sEng ( endogenous circulating antiangiogenic proteins) inhibits VEGF and TGF-1 signaling, respectively, in the vasculature.sFlt1- soluble fms like tyrosine kinase, sEng- soluble endoglinAlice Wang et al. Physiology 24: , 2009
28sFlt 1sFlt1 antagonizes both VEGF and PlGF by binding them in the circulation and preventing interaction with their endogenous receptorsIncrease in maternal circulating sFlt1 precedes the onset of clinical disease and is correlated with disease severity.In molar gestations, levels of sFlt1 are found to be elevated.Alice Wang et al. Physiology 24: , 2009
29Renin Angiotensin System In normal pregnancy, renin,aldosterosterone, and angiotensin are increased.In preeclampsia RAAS suppressed.Increased vascular responsiveness to angiotensin II and other vasoconstrictive agents.Presence of agonistic (AT1) receptor autoantibodiesThese autoantibodies, like angiotensin II, could lead to the production of tissue factor by endothelial cells.Placental angiotensinase enz destroyes angio II- causing vascular refractoriness .Granger et al, Hypertension 2001, 38:
30Angiotensin II Normal Pregnancy Preeclampsia Endothelial cell mass Endothelial dysfunctionPgI2 produced in response toangiotensin IIPgI2 productionVasodilatationVasoconstrictionMinimal effect of angiotensinExaggerated effect of angiotensinDavid H. Chestnut, Obstetric Anesthesia
31Immunological factors Normal placentation requires the development of immune tolerance between the fetus and the mother.Abnormal maternal immune response to novel paternally derived fetal antigens.Alterations in decidual NK (natural killer)-cell signaling with disturbance in the secretion of cytokine and angiogenic factors are thought to play an important role in the pathogenesis of preeclampsiaPreeclampsia occurs more often in first pregnancies, after a change in paternity , or with long inter-pregnancy interval. Women using barrier contraceptive methods that reduce maternal exposure to sperm have increased incidence of preeclampsia.NK cells important in modulating immune tolerance required for normal placental development as well as the induction of angiogenic factors and vascular remodeling.Alice Wang et al. Physiology 24: , 2009
32Fatty Acid Metabolism Endothelial triglyceride accumulation Hyperoestrogenaemia of pregnancyHepatic biosynthesis of triglyceridesEndothelial triglyceride accumulationInhibit PgI2 releaseVasoconstrictionIndian Journal of Clinical Biochemistry, 2006 / 21 (2)
33Fatty Acid MetabolismDavid H. Chestnut, Obstetric Anesthesia
34Calcium Lipid peroxidation of cell membranes (oxidative stress) cell permeability to calciumCalcium affects smooth muscle cell contractility indirectly by influencing the production of other vasoactive agents such as nitric oxide, prostacyclins, or angiotensin.AmericanJournal of Clinical Nutrition 2000;71(suppl):1371S–4S.
35Pathophysiology of Preeclampsia CVSCNSHEPATICRENALRESPI
36Cardio-vascular system High systemic vascular resistance (SVR) - vasospasm.Heart rate and blood pressure variability is increased.sensitivity to endogenous pressors.Sympathetic over activityIntravascular volume depletion.Normal CVP , PCWP.Plasma COP reduced (low albumin )
37Hematology Hypercoagulable state Anti-thrombin III , fibrinolytic activityD-dimer, fibrinopeptide ALipoprotein(a)- competes with plasminogen for binding to fibrin & endotheliumThrombocytopenia – %Platelet lifespan : 2-3 days
39HELLP Syndrome(1) Hemolysis - microangiopathic hemolytic anemia & increased bilirubin (>1.2 mg/dl)(2) Elevated liver enzymes - increased SGOT (AST) of at least 70 U/L & LDH >600 U/L(3) Low platelet count <100,000/mm3Partial HELLP Syn – 1 or 2 of aboveHigher risk of DIC, Stroke, ARF, Abruption, Pulmonary edema
40HELLP Syndrome Incidence : 4- 12 % Maternal mortality – 24 %. 80% - Preterm , 20%- postpartum, peak at hrs post-partumMalaise , epigastric pain, nausea, vomiting.HTN, proteinuria may be absent.Stillbirth is frequent (10-15%). High neonatal loss due to prematurity (20- 25%).David H. Chestnut, Obstetric anaesthesia
41HELLP SyndromeMost hematologic abnormalities return to normal within 2-3 days after delivery but thrombocytopenia may persist for a week.Intrahepatic and sub capsular hemorrhage are more common.Liver function deteriorates rapidly.
42Renal system Generalized swelling and vacuolization of the endothelial cells and loss of the capillary space - endotheliosisProteinuria > 300 mg/dayUrate , Na clearance reduced . S. uric acid > 5.5 mg/dlOliguriaRenal failure – rare , recoversmild glomerular endotheliosis also occurs in pregnancy without preeclampsia, especially in a subset of subjects with gestational hypertension .This suggests that the endothelial dysfunction of preeclampsia may be an exaggeration of a normal physiological process that occurs near the end of a term pregnancy.
43Respiratory System Pharyngolaryngeal edema - Difficult intubation Leaky capillaries , low COPPulmonary edema - 3% of severe PIH, 2-3 days post-partum
44Hepatic System Serum transaminase levels increase Epigastric or subcostal pain (edema or subcapsular or parenchymal bleeding)Periportal fibrin deposition and endothelial damageIntraperitoneal rupture - catastrophic
45Endocrine & Metabolic System Suppression of RAASplasma renin concentration (PRC) and activity (PRA).Increased vascular response to angiotensin II.Deficient production of PGI2 and NO .
46Central Nervous System HeadacheVisual disturbanceHyperexcitablityHyperreflexiaSeizures
47Utero-Placental System Decreased perfusionDoppler – ( IUGR )Downstream resistance increasesDiastolic velocity decreasesThe systolic/diastolic ratio increases
48Pathophysiology of Preeclampsia David H. Chestnut, Obstetric anaesthesia
49Eclampsia “bolt from the blue” New onset of seizure activity and/or unexplained coma during pregnancy or postpartum in a woman with signs or symptoms of preeclampsia.During or after 20th wk or post-partum. 80% intrapartum or within the first 48 hours following delivery.Rare before 20 weeks' POG or as late as 23 days’ postpartum.
50EclampsiaThe classic triad of hypertension, proteinuria, and edema may be absent or only mildly abnormal in 30%. No reliable test or symptom complex predicts the development of eclampsia.Etiology - ? Hypertensive encephalopathy,Vasospasm,Microinfarctions,Punctate hemorrhages,Thrombosis,Cerebral edema
51Risk factors for Eclampsia Nulliparity,Multiple gestation,Molar pregnancy,Preexisting hypertension or renal disease,Previous severe preeclampsia or eclampsia,Nonimmune hydrops fetalis,Systemic lupus erythematosus.