1. Pregnancy induced hypertension ( PIH ) & Eclampsia
Speaker- Dr Ajisha Aravindan
Moderator – Dr Anjan Trikha

2. Hypertension
In 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)

3. Pregnancy 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.

4. Its not so uncommon … Laura Bush Angelina Jolie (with the twins)
Britney Spears (rumored)
Julia Roberts (rumored with her twins)
Jennifer Lopez
Lisa Marie Presley
Jenna Jameson

5. Classification of Hypertension in Pregnancy
1) P.I.H
Preeclampsia(6-8%)
Eclampsia (0.05% )
Gestational Hypertension(6-7%)
2) Chronic Hypertension(3-5%)
3) Chronic Hypertension with superimposed P.I.H
David H. Chestnut, Obstetric anaesthesia

6. Classification

7. 1) 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 collection
David H. Chestnut, Obstetric anaesthesia

8. Severe Preeclampsia
Blood 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

9. Severe Preeclampsia Thrombocytopenia Impaired liver function
Epigastric or right upper quadrant pain: stretching of Glisson's capsule by hepatic edema
Hepatic rupture: a rare complication
Pulmonary edema
Fetal growth restriction, oligohydramnios
David H. Chestnut, Obstetric anaesthesia

10. 2) Chronic Hypertension
 BP 140/90 mm Hg before pregnancy or diagnosed before
20 weeks' gestation not attributable to gestation.
 or
    
Hypertension first diagnosed after 20 weeks' gestation and
persistent after 12 weeks' postpartum
Incidence- 5 %
David H. Chestnut, Obstetric anaesthesia

11. 3) Chronic hypertension with Superimposed Preeclampsia
New-onset proteinuria > 300 mg/24 hours in hypertensive women
but no proteinuria before 20 weeks' gestation. or
A sudden increase in proteinuria or blood pressure or platelet count
< 100,000/mm3 in women with hypertension and proteinuria before
20 weeks' gestation  
David H. Chestnut, Obstetric anaesthesia

12. Pregnancy associated risk factors for PIH
•   Multiple pregnancy   
• Hydatidiform mole
•    Structural congenital anomalies  
  •    Hydrops fetalis   
•    Chromosomal anomalies (trisomy 13, triploidy)     
•    Urinary tract infection
David H. Chestnut, Obstetric anaesthesia

13. Preconceptional &/or Chronic risk factors for PIH
1) History of previous preeclampsia 2) Age 3) Interval between pregnancies 4) Family history
David H. Chestnut, Obstetric anaesthesia

14. Preconceptional &/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

15. Preconceptional &/or Chronic risk factors for PIH
6) Exogenous Factors
•    Smoking ( % risk reduction)   
•    Stress, work-related psychosocial strain   
•    In- utero diethylstilbestrol exposure ( 50 % )
David H. Chestnut, Obstetric anaesthesia

16. ACOG Technical Bulletin # 219, 1996

17. Preconceptional &/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 woman
David H. Chestnut, Obstetric anaesthesia

18. Pathogenesis of Preeclampsia
Platelet
Endothelial
Immunological
Pathogenesis of Preeclampsia
Calcium
Genetic
Fatty acid metabolism
Coagulation

19. Historical Theories
The 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)

20. Pathogenesis of Preeclampsia
Dysfunction
Endothelial
Ischemia
Placental

21. Normal Placenta
Cytotrophoblasts 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.

22. Preeclamptic 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

23. Platelet & Endothelial function
David H. Chestnut, Obstetric anaesthesia

24. Endothelial Dysfunction
Placental ischemia leads to release of circulating factors – profound systemic effects .
prostacyclin (PGI2) , nitric oxide
thromboxane (TXA2) , endothelin
Exaggerated sensitivity to vasopressors such as angiotensin II and norepinephrine.
Compromised uteroplacental circulation.
Alice Wang et al. Physiology 24: , 2009

25. Platelet Dysfunction
Surface-mediated activation , microvascular consumption .
sensitivity to PGI2, release of TXA2 & serotonin causing further platelet aggregation.
Hypercoagulability
Thrombocytopenia
Platelet lifespan reduced – 2-3 days

26. Anti-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 receptors
Alice Wang et al. Physiology 24: , 2009

27. Role of sFlt1 and sEng
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 receptors
This results in endothelial cell dysfunction, including decreased prostacyclin, nitric oxide production, and release of procoagulant proteins
Excess 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 endoglin
Alice Wang et al. Physiology 24: , 2009

28. sFlt 1
sFlt1 antagonizes both VEGF and PlGF by binding them in the circulation and preventing interaction with their endogenous receptors
Increase 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

29. Renin 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 autoantibodies
These 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:

30. Angiotensin II Normal Pregnancy Preeclampsia Endothelial cell mass
Endothelial dysfunction
PgI2 produced in response to
angiotensin II
PgI2 production
Vasodilatation
Vasoconstriction
Minimal effect of angiotensin
Exaggerated effect of angiotensin
David H. Chestnut, Obstetric Anesthesia

31. Immunological 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 preeclampsia
Preeclampsia 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

32. Fatty Acid Metabolism Endothelial triglyceride accumulation
Hyperoestrogenaemia of pregnancy
Hepatic biosynthesis of triglycerides
Endothelial triglyceride accumulation
Inhibit PgI2 release
Vasoconstriction
Indian Journal of Clinical Biochemistry, 2006 / 21 (2)

33. Fatty Acid Metabolism
David H. Chestnut, Obstetric Anesthesia

34. Calcium Lipid peroxidation of cell membranes (oxidative stress)
cell permeability to calcium
Calcium 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.

35. Pathophysiology of Preeclampsia
CVS
CNS
HEPATIC
RENAL
RESPI

36. Cardio-vascular system
High systemic vascular resistance (SVR) - vasospasm.
Heart rate and blood pressure variability is increased.
sensitivity to endogenous pressors.
Sympathetic over activity
Intravascular volume depletion.
Normal CVP , PCWP.
Plasma COP reduced (low albumin )

37. Hematology Hypercoagulable state
Anti-thrombin III , fibrinolytic activity
D-dimer, fibrinopeptide A
Lipoprotein(a)- competes with plasminogen for binding to fibrin & endothelium
Thrombocytopenia – %
Platelet lifespan : 2-3 days

38. HELLP Syndrome
Elevated LFT
Low Platelet
Hemolysis

39. HELLP 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/mm3
Partial HELLP Syn – 1 or 2 of above
Higher risk of DIC, Stroke, ARF, Abruption, Pulmonary edema

40. HELLP Syndrome Incidence : 4- 12 % Maternal mortality – 24 %.
80% - Preterm , 20%- postpartum, peak at hrs post-partum
Malaise , 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

41. HELLP Syndrome
Most 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.

42. Renal system Generalized swelling and vacuolization of the endothelial
cells and loss of the capillary space - endotheliosis
Proteinuria > 300 mg/day
Urate , Na clearance reduced . S. uric acid > 5.5 mg/dl
Oliguria
Renal failure – rare , recovers
mild 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.

43. Respiratory System Pharyngolaryngeal edema - Difficult intubation
Leaky capillaries , low COP
Pulmonary edema - 3% of severe PIH, 2-3 days post-partum

44. Hepatic System Serum transaminase levels increase
Epigastric or subcostal pain (edema or subcapsular or parenchymal bleeding)
Periportal fibrin deposition and endothelial damage
Intraperitoneal rupture - catastrophic

45. Endocrine & Metabolic System
Suppression of RAAS
plasma renin concentration (PRC) and activity (PRA).
Increased vascular response to angiotensin II.
Deficient production of PGI2 and NO .

46. Central Nervous System
Headache
Visual disturbance
Hyperexcitablity
Hyperreflexia
Seizures

47. Utero-Placental System
Decreased perfusion
Doppler – ( IUGR )
Downstream resistance increases
Diastolic velocity decreases
The systolic/diastolic ratio increases

48. Pathophysiology of Preeclampsia
David H. Chestnut, Obstetric anaesthesia

49. Eclampsia “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.

50. Eclampsia
The 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

51. Risk factors for Eclampsia
Nulliparity,
Multiple gestation,
Molar pregnancy,
Preexisting hypertension or renal disease,
Previous severe preeclampsia or eclampsia,
Nonimmune hydrops fetalis,
Systemic lupus erythematosus.

52. THANK YOU