PREECLAMPSIA SYNDROME in pregnancy .pptx

Pre eclampsia

1. PREECLAMPSIA SYNDROME PART 1 ETIOPATHOGENESIS PREDICTION PREVENTION Dr. Jishnu MS 1

2. TERMINOLOGY AND DIAGNOSIS Hypertensive disorders include - Preeclampsia - Gestational hypertension - Chronic hypertension Complicates up to 10 % of pregnancies. Along with haemorrhage and infection – form deadly triad – contributes greatly to maternal morbidity. Dr. Jishnu MS 2

3. ACOG (2020) describes four types of hypertensive diseases. Preeclampsia and Eclampsia Syndrome. Chronic hypertension of any eitiology Preeclampsia superimposed on chronic hypertension Gestational hypertension -in which definitive evidence of the preeclampsia syndrome does not develop and hypertension resolves by 12 weeks postpartum. Dr. Jishnu MS 3

4. Diagnosis of hypertensive disorders. Diagnosed empirically when systolic and diastolic blood pressure exceeds 140mmhg and 90mmhg respectively. Korotkoff phase V is used to define diastolic pressure. Previously, increase of 30 mmhg systolic or 15 mmhg diastolic above blood pressure values taken at mid pregnancy was used as diagnostic criteria even if the blood pressure is less than 140/90mmhg . Dr. Jishnu MS 4

5. Surveillance of these patients is reasonable – eclamptic seizures can develop in some even when blood pressure is less than 140/90 mmhg In some cases – MAP suddenly rise but remain in normal range – delta hypertension – may signify preeclampsia. Dr. Jishnu MS 5

6. Gestational hypertension. Blood pressure that reach 140/90mmhg or greater, detected for first time after mid pregnancy (20 weeks) but lack proteinuria. Almost half of the affected women subsequently develop preeclampsia. Appreciable rise in blood pressure even in the absence of proteinuria is significant – 10 % of eclamptic seizure develop before overt proteinuria can be detected. Transient hypertension – when preeclampsia does not develop and BP returns to normal by 12 weeks post partum. Dr. Jishnu MS 6

7. Severe gestational hypertension – BP >/= 160/100 mm Hg in the absence of proteinuria. These women sooner or later develops proteinuria or other features of [re eclampsia – Pre eclampsia with severe features. Dr. Jishnu MS 7

8. Preeclampsia syndrome Pregnancy specific syndrome that can affect virtually every organ system. It is more than simply gestational hypertension with proteinuria – appearance of protein remains a primary diagnostic criterion. It is an objective marker and reflects system wide endothelial leak. Preeclampsia can be divided into - Early onset < 34 weeks - Late onset >/= 34 weeks - Preterm onset < 37 weeks - Term onset >/= 37 weeks Dr. Jishnu MS 8

9. In some women with preeclampsia, neither overt proteinuria nor fetal growth restriction are features. ACOG task force suggested other diagnostic criteria. Dr. Jishnu MS 9 CONDITION CRITERIA REQURIED Gestational hypertension BP > 140/90mmhg after 20 weeks in previously normotensive women on 2 occasions, 4 hours apart. Preeclampsia: Gest Hypertension plus Proteinuria Thrombocytopenia Renal insufficiency Liver involvement Cerebral symptoms Pulmonary edema >/= 300mg/24 hr or urine protein creatinine ratio >/= 0.3 or Dipstick 1+ persistent. PLC <100000/ mcL Creatinine > 1.1 mg or doubling of baseline Serum transaminase levels twice normal Headache, visual disturbances, convulsion. Basal creps

10. ACOG (2020) categorize preeclampsia into SEVERE and NON SEVERE. ABNORMALITY NON SEVERE SEVERE Diastolic BP Systolic BP Proteinuria Headache Visual disturbances Upper abdominal pain Oliguria Convulsion Serum creatinine Thrombocytopenia Serum transaminase elevation Fetal growth restriction Pulmonary edema Gestational age <110 mmhg < 160 mmhg None to positive Absent Absent Absent Absent Absent Normal Absent Minimal Absent Absent Late >/= 110 mmhg >/= 160 mmhg None to positive Present Present Present Present Present Elevated Present Marked Present Present Early Dr. Jishnu MS 10

11. Some symptoms are considered omnious . Headache and visual disturbance can precede eclampsia – which is convulsion in a woman with preeclampsia that is not attributed to another cause. Seizures are generalized and may appear before, during or after labor . Approximately 10 % patients develops seizures after 48 hours postpartum. Photophobia, cortical blindness, scotomata – due to retinal vasospasm and changes in optic fundus Epigastric or right upper quadrant pain – accompanies hepatocellular necrosis, ischemia and hepatic edema causing stretching of liver capsule Dr. Jishnu MS 11

12. Elevated serum hepatic transaminase levels can be one marker – Liver ischemia Thrombocytopenia – signifies worsening of preeclampsia – represents platelet aggregation and microangiopathic hemolysis . Other factors indicative of severe preeclampsia – renal or cardiac involvement - Serum creatinine > 1.1 mg/dL or doubling of s.creatinine - Pulmonary edema – LVF and extravasation of fluid into interstitial space Dr. Jishnu MS 12

13. HELLP SYNDROME Hemolysis, elevated liver enzymes and low platelet – occurs in pre eclampsia and represents a severe form. May also develop as separate disorder – 15 to 20 % of women with HELLP syndrome do not have hypertension or proteinuria. Develops in 0. 1 % to 1% of all pregnancies. Develops between 28 and 36 weeks of gestation and more common in multiparous women. Diagnosis - Schistocytes in PS - Serum bilirubin >/= 1.2 mg/ dL - Low serum hemoglobin - Low platelet - >100000/ micro liter - AST/ALT twice the upper limit of normal - LDH > 600 IU/mL Dr. Jishnu MS 13

14. CHRONIC HYPERTENSION Chronic hypertension is diagnosed – BP >/= 140/90 mm Hg before pregnancy or before 20 weeks of gestation or both or that continues beyond 12 weeks postpartum. May be primary or secondary to renal or vascular disease. Blood pressure usually decreases during 2 nd trimester – a woman with chronic hypertension may have normal BP during this period and rise to pre pregnant levels in third trimester. This may be misdiagnosed as new onset hypertension – pre existing end organ damage and other systemic signs can differentiate the two Dr. Jishnu MS 14

15. Preeclampsia superimposed on chronic hypertension. Any chronic hypertensive disorder predisposes a woman to develop superimposed preeclampsia syndrome. In 20 – 30% of women with chronic hypertension – blood pressure rises to abnormal levels typically after 24 weeks gestation. If new onset or worsening baseline hypertension is accompanied by new onset proteinuria or worsening and features of multi organ failure – superimposed preeclampsia is diagnosed. Dr. Jishnu MS 15

16. Compared to pure preeclampsia – superimposed preeclampsia commonly develops earlier in pregnancy. Tend to be more severe and often accompanied by fetal growth restriction . OTHER HYPERTENSIVE DISORDERS White collar hypertension – elevated BP at clinic but normal BP at home. Associated with increased risk of preeclampsia Masked hypertension – normal BP in the clinic but elevated BP other times. Dr. Jishnu MS 16

17. Incidence and risk factors. Preeclampsia is identified in 5 to 8 % of all pregnancies globally and 7 – 8 % in India. Young and nulliparous women are particularly vulnerable. Older women are at greater risk for chronic hypertension with superimposed preeclampsia. Global incidence of preeclampsia in nulliparas ranges from 3 – 10 % and in multiparas it is 2 – 5 % Eclampsia occurs in 1 % of all pregnancies in India. Dr. Jishnu MS 17

18. RISK FACTORS POOLED UNADJUSTED RELATIVE RISK Prior preeclampsia ( HELLP syndrome) Chronic hypertension Diabetes Multifetal gestation BMI > 30 ( Metabolic syndrome) APA SLE Prior still birth Nulliparity Prior abruption CKD ART Age > 35 8.4 5.1 3.7 2.9 2.8 2.8 2.5 2.4 2.1 2.0 1.8 1.8 1.2 Dr. Jishnu MS 18

19. Of lesser factors – HIV seropositivity, sleep disordered breathing and male fetus pose slightly higher risk. Preeclampsia frequently complicates – “ mirror syndrome” or Ballantyne syndrome or triple edema. Smoking ironically lowers the risk of hypertension in pregnancy- CO inhibit placental production of anti angiogenic proteins and inhibit placental apoptosis and necrosis. Dr. Jishnu MS 19

20. Etiopathogenesis The mechanism by which pregnancy incites or aggrevates hypertension remain unsolved. Hypertensive disorders are more likely to develop in women with the following characteristics: - Exposure to chorionic villi for the first time. - Exposure to a superabundance of chorionic villi as with twins or hydatidiform mole. - Pre existing conditions associated with endothelial cell activation and inflammation. - Genetic predisposition to hypertension developing during pregnancy. Dr. Jishnu MS 20

21. A fetus is not a requisite for preeclampsia to develop. Chorionic villi are essential and they need not to be intrauterine. Regardless of precipitating etiology , the cascade of promoting events leads to systemic vascular endothelial damage, vasospasm, plasma transudation and ischemic and thrombotic sequelae. Dr. Jishnu MS 21

22. ETIOLOGY Suggested mechanisms include Placental implantation with abnormal trophoblastic invasion of the uterine vessels. Dysfunctional immunological tolerance between maternal, paternal and fetal tissues. Maternal maladaptation to cardiovascular or inflammatory changes of normal pregnancy. Genetic factors that include predisposing genes and epigenetic influences. Dr. Jishnu MS 22

23. Redman and et al (2015) described “ two stage disorder” theory of preeclampsia. Stage 1 – PLACENTAL SYNDROME Normal placental implantation is characterised by extensive remodelling of the spiral arterioles within the decidua basalis. In this placental bed endovascular trophoblasts replace the vascular endothelial and muscular lining – enlarging arteriole diameter. Veins are invaded superficially only. Stage 1 – Invasion of the decidual segment of the spiral arterioles at 10 – 12 weeks Stage 2 – Invasion of the myometrial segment of the spiral arterioles at 16 – 18 weeks. In some cases of preeclampsia – this trophoblastic invasion is incomplete. Dr. Jishnu MS 23

24. Only decidual vessels gets lined with endovascular trophoblasts. Deeper myometrial arterioles thus do not lose their endothelial lining and musculoelastic tissue. The mean external diameter of myometrial arterioles – only half that of corresponding vessels in placenta. This mechanism is more prevalent in women with early onset preeclampsia. Evidence suggests involvement of soluble anti angiogenic growth factors in this faulty endovascular remodelling. Dr. Jishnu MS 24

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26. Electron microscopic study of placenta in preeclampsia. - Endothelial damage. - Insudation of plasma constituents into vessel wall. - Myointimal cell proliferation. - Medial necrosis – lipid accumulation in myointimal cells and macrophages – Atherosis. These findings are more common in placentas from women diagnosed with preeclampsia before 34 weeks. Acute placental vascular atherosis – higher risk for developing atherosclerosis and cardiovascular diseases. Dr. Jishnu MS 26

27. Abnormally narrow spiral arteriole lumen – impair placental blood flow, reduces perfusion and create a hypoxic environment. Placental perfusion declines progressively – resultant ischemia and hypoxia lead to release of syncytiotrophoblast debris and microparticles – production of cytokines, interleukins and TNF alpha to induce oxidative stress. These changes incite a systemic inflammatory response leading to maternal vascular endothelial inflammation, damage and dysfunction – STAGE II OR MATERNAL SYNDROME. Defective placentation predispose to gestational hypertension, preeclampsia syndrome, preterm delivery, fetal growth restriction and placental abruption . Dr. Jishnu MS 27

28. IMMUNOLOGICAL FACTORS Loss of immune tolerance to paternally derived placental and fetal antigens is another theory proposed for preeclampsia. Histological changes at maternal – placental interface suggests in preeclampsia suggests acute graft rejection. Tolerance dysregulation also explain the elevated risk when paternal antigenic load is increased – complete molar pregnancy – diploid complement of chromosomes is solely from the father. Dr. Jishnu MS 28

29. Women with a trisomy 13 fetus also have a 30 – 40 % incidence of preeclampsia – gene for one preeclampsia linked factor, soluble fms like tyrosine kinase 1 , is on chromosome 13. These women have elevated levels of antiangiogenic factors which can affect placenta. Women previously exposed to paternal antigens – prior pregnancy with the same partner – may be immunized against preeclampsia. Multiparous woman impregnated by a new partner have a greater risk of preeclampsia. Dr. Jishnu MS 29

30. In women destined to have preeclampsia – extravillous trophoblasts early in pregnancy express reduced amounts of immunosuppressive non classic human leukocyte antigen G ( HLA G) In normal pregnancy – T helper cells are produced so that type 2 activity is increased in relation to type 1 – type 2 bias - Th 1 cells promote humoral immunity – In early second trimester in women who develop preeclampsia, Th1 action increased. - Th 2 cells stimulate inflammatory cytokine secretion. These immune maladaptation – contributes to the defective placental vascularization seen with preeclampsia. Dr. Jishnu MS 30

31. Genetic factors Preeclampsia is multifactorial and polygenic disorder. Hereditary predisposition for preeclampsia stems from interactions of hundreds of genes – both maternal and paternal – that control many enzymatic and metabolic functions throughout every organ system. Plasma derived factors may also induce some of these genes in preeclampsia. The clinical manifestations of preeclampsia syndrome will reflect a spectrum. The phenotypic expression will differ among similar genotypes depending on interactions with environmental components. Dr. Jishnu MS 31

32. Stage II – MATERNAL SYNDROME ENDOTHELIAL CELL ACTIVATION . Inflammatory changes are believed to be the continuation of placental syndrome. In response to ischemia or other inciting causes, placental factors are released and initiates a series of events. Anti angiogenic factors, metabolic factors and other inflammatory leukocyte mediators provoke the systemic endotheliopathy – endothelial cell activation. Injury to systemic endothelial cells – centrepiece of preeclampsia pathogenesis Dr. Jishnu MS 32

33. Extreme activated state of leukocytes in maternal circulation – Cellular dysfunction. Cytokines ( TNF alpha) and interleukins – systemic oxidative stress associated with preeclampsia – generation of highly toxic radicals. These injure systemic vascular endothelial cells, lower nitric oxide production by these cells and interfere with prostaglandin balance. Other changes - Production of lipid laden macrophages – foam cells in placental atherosis. - Activation of systemic microvascular coagulation - thrombocytopeina - Increased systemic capillary permeability – edema and proteinuria. Dr. Jishnu MS 33

34. Injured endothelial cells produce less nitric oxide and secrete substances that promote coagulation and vasopressor sensitivity. Further evidence of endothelial activation includes - Changes in glomerular capillary endothelial morphology. - Greater capillary permeability. - Elevated blood concentration of substances associated with endothelial activation . Dr. Jishnu MS 34

35. VASOSPASM AND HYPERTENSION. Systemic endothelial activation causes vasospasm – increase in resistance – produce hypertension. Concurrently, systemic endothelial cell damage promotes interstitial leakage and platelet and fibrinogen are deposited in subendothelial space. Endothelial junctional proteins are disrupted and the subendothelial region of resistance arteries undergoes ultrastructural changes. Much larger venous circuit is also involved. Dr. Jishnu MS 35

36. With diminished blood flow because of maldistribution from vasospasm and interstitial leakage – ischemia of the surrounding tissue can cause necrosis, hemorrhage and other end organ damages. Dr. Jishnu MS 36

37. INCREASED PRESSOR RESPONSES . Pregnant women normally develop refractiveness to infused vasopressors. In early preeclampsia – there is enhanced reactivity to infused norepinephrine and angiotensin II. Increased sensitivity to angiotensin II precedes the onset of gestational hypertension. Paradoxically women who develop preterm eclampsia have lower circulating levels of angiotensin II Dr. Jishnu MS 37

38. Numerous PGs are central to preeclampsia syndrome pathophysiology. Decreased pressor response in normal pregnancy – partially due to diminished vascular responsiveness mediated by endothelial PG synthesis. Endothelial prostacyclin (PGI2) production is lower in preeclampsia. - This is mediated by phospholipase A2. Thromboxane A2 secretion by platelets is increased and Prostacyclin: Thromboxane A2 ratio declines. The net result favours greater sensitivity to infused angiotensin II and results in vasoconstriction. These changes appears as early as 22 weeks in women who later develop preeclampsia. Dr. Jishnu MS 38

39. Nitric oxide is a potent vasodilator – synthesized from 1- arginine by endothelial cells. Inhibition of nitric oxide synthesis increases mean arterial pressure, lowers heart rate and reverses pregnancy induced refractiveness to vasopressors. Nitric oxide is likely the compound which maintains the low pressure vasodilated state characteristic of normal fetoplacental perfusion. It mediates the effects of placental growth factor and vascular endothelial growth factor in vitro. In preeclampsia - Decreased nitric oxide synthase expression in endothelial cells causing lower nitric oxide activity. Dr. Jishnu MS 39

40. ANGIOGENIC AND ANTI ANGIOGENIC FACTORS. Placental vasculogenesis is evident by 21 days after conception. The list of pro and anti angiogenic factors involved is extensive – VEGF and angiopoietin families are most significant. Trophoblast of the women destined to develop preeclampsia overproduce at least two anti angiogenic peptides that enter the maternal circulation. Dr. Jishnu MS 40

41. Soluble fms like tyrosine kinase – 1 - Soluble variant of the membrane bound receptor for VEGF. - Elevated maternal sFlt - 1 – inactivates and reduces the concentration of placental growth factor and VEGF. - This leads to endothelial dysfunction. - Levels begins to rise months before preeclampsia develops. - These factors are also involved in pregnancies complicated by fetal growth restriction. Dr. Jishnu MS 41

42. 2 . Solube endoglin ( sEng ) - Inhibits various transforming growth factor beta isoforms from binding to endothelial receptors. - Endoglin is one of these receptors. - Decreased binding to endoglin diminishes endothelial nitric oxide dependent vasodilatation. - Levels of sEng also begin to rise months before clinical preeclampsia develops. Dr. Jishnu MS 42

43. Simultaneously elevated levels of sFlt -1 and sEng are associated with more severe form of eclampsia. The cause of placental over production of soluble factors remains an enigma. The levels are not higher in fetal circulation or amniotic fluid of preeclamptic women. Levels in maternal blood dissipate after delivery. Dr. Jishnu MS 43

44. PATHOPHYSIOLOGY CARDIOVASCULAR SYSTEM Disturbances in the CVS are related to - Greater cardiac afterload imposed by hypertension. - Cardiac preload - which is reduced by pathophysiologically diminished volume expansion. - increased by administration of IV crystalloid or oncotic solutions. - Endothelial activation leading to leakage of intravascular fluid into the extravascular space. Dr. Jishnu MS 44

45. HEMODYNAMIC CHANGES AND CARDIAC FUNCTION. Cardiovascular aberrations of pregnancy related hypertensive disorders varies. Modifying factors - Severity of pre eclampsia - Degree of hypertension - Presence of underlying chronic hypertension - Point in the clinical spectrum in which these are studied. Sometimes the cardiovascular changes precedes hypertension. With clinical onset of preeclampisa – cardiac output declines – due to increase in the peripheral resistance. Dr. Jishnu MS 45

46. MYOCARDIAL FUNCTION. There will be diastolic dysfunction in at least 45 % patients with preeclampsia – end diastolic volume decreases. In some cases functional difference persists up to 4 years after delivery. Diastolic dysfunction is due to ventricular remodelling – maladaptive response to increased afterload. High level of antiangiogenic factors are also contributory. If there is underlying ventricular dysfunction – as in ventricular hypertrophy in chronic hypertension – diastolic dysfunction results in cardiogenic pulmonary edema. Dr. Jishnu MS 46

47. VENTRICULAR FUNCTION. Even if the frequency of ventricular dysfunction with preeclampsia is high – clinical cardiac function remains appropriate in most patients. In some patients with preeclampsia – high sensitivity cardiac troponin levels remains slightly elevated. In severe preeclampsia – amino terminal pro brain natriuretic peptide ( NT – pro BNP) levels are increased. In preeclampsia syndrome – there will be slightly hyperdynamic ventricular function. DrJishnu MS 47

48. Both in normotensive and preeclampsia – cardiac output is appropriate to the left sided filling pressure. Aggressive hydration results in overtly hyperdynamic ventricular function – increase in pulmonary capillary wedge pressure – pulmonary edema – even in case of normotensive patients . Pulmonary edema - partially due to alveolar endothelial – epithelial leak and decreased oncotic pressure from a low serum albumin . Dr. Jishnu MS 48

49. BLOOD VOLUME In eclampsia, haemoconcentration is a hallmark feature. Women of average size have a nonpregnant blood volume of 3000mL and during last weeks of a normal pregnancy – 4500 mL. With eclampsia – much or all of the anticipated 1500 mL excess is lost- results from generalized vaso spam and from leakage of the plasma into interstitial space. In case of severe hemoconcentration – undue sensitivity to blood loss at delivery. Dr. Jishnu MS 49

50. Vasospasm and endothelial leakage of plasma persist for a considerable amount of time after delivery –endothelium is restored to normal vasoconstriction reverses, blood volume expands, hematocrit usually falls from dilution. Dr. Jishnu MS 50

51. HEMATOLOGICAL CHANGES THROMBOCYTOPENIA Overt thrombocytopenia ( PLC < 100,000/ mcL ) – reflects severe disease. Lower the platelet count – higher the like hood of maternal and fetal mortality and morbidity – termination of pregnancy is advisable – thrombocytopenia usually worsens. After delivery the count persist to fall for day or so – reach normal levels within 3 – 5 days. Dr. Jishnu MS 51

52. In HELLP syndrome – the platelet count continues to fall after delivery. If the fall is delayed until 48 to 72 hours – preeclampsia syndrome may be incorrectly attributed to one of the thrombotic microangiopathies. Another platelet alteration is platelet activation and increased alpha degranulation – leads to release of Beta thromboglobulin and factor 4 – leads to increase clearance of platelet. Platelet aggregation is reduced compared with the normal increase that is characteristic of pregnancy – due to platelet exhaustion following in vivo activation. Dr. Jishnu MS 52

53. Levels of platelet bound and platelet bindable immunoglobulins are elevated – suggests platelet surface alterations. Abnormally low platelet count does not develop in fetuses despite severe maternal thrombocytopenia. Thrombocytopenia in a hypertensive woman is not a fetal indication for caesarean delivery. Dr. Jishnu MS 53

54. 2. HEMOLYSIS Severe preeclampsia frequently accompanied by hemolysis – manifested as increase in the serum LDH and decreased hemoglobin levels. In peripheral smear – schizocytes , spherocytes and reticulocytosis . RDW - reflects the differences in the size of circulating RBCs – higher in preeclampsia. Hemolysis is partially results from microangiopathic hemolysis – caused by endothelial disruption with platelet adherence and fibrin deposition. Partially by serum lipid alterations – substantively decreased long chain fatty acid in erythrocytes. Dr. Jishnu MS 54

55. 3. COAGULATION CHANGES Subtle changes consistent with intravascular coagulation – in preeclampsia and eclampsia, including; - Elevated factor VIII consumption. - Increased levels of fibrinopeptides A and B - Reduced concentration of regulatory proteins. - Antithrombin III, Proteins C and S. Generally mild and seldom clinically significant. Unless placental abruption is comorbid – plasma fibrinogen levels do not differ remarkably from levels found in normal pregnancy. Routine – PT, aPTT , Plasma fibrinogen levels – not recommended in management . Dr. Jishnu MS 55

56. ENDOCRINE AND HORMONAL ALTERATIONS . Atrial natriuretic peptide (ANP) – released during atrial wall stretching from blood volume expansion and it responds to cardiac contractility. Serum ANP levels enhanced in preeclampsia. Levels of Proatrial natriuretic peptide also elevated. Metabolic clearance of Vasopressin elevated in preeclampsia. Dr. Jishnu MS 56

57. FLUID AND ELECTROLYTE ALTERATIONS . In severe preeclampsia – volume of ECF manifests as edema – greater than that in normal pregnancy. Mechanism – Endothelial injury and subsequent extravasation of intravascular fluid. - Reduced plasma oncotic pressure. Electrolyte concentrations do not differ appreciably. Following eclamptic convulsions – Serum pH and bicarbonate concentration are lowered due to lactic acidosis (metabolic acidosis) and compensatory respiratory loss of carbon dioxide ( respiratory acidosis ) Dr. Jishnu MS 57

58. KIDNEY. In preeclampsia renal perfusion and GFR are slightly reduced. The decrease in the GFR is due to increased renal afferent arteriolar resistance that may be elevated up to five fold. Morphological changes are characterised by – GLOMERULAR ENDOTHELIOSIS which blocks filtration. Creatinine levels increases ( >/= 1 mg/mL) due to diminished filtration. Plasma Uric acid levels elevated – due to reduced GFR and enhanced tubular reabsorption. Diminished urinary excretion of Calcium – due to greater tubular reabsorption. Dr. Jishnu MS 58

59. PROTEINURIA Detection of proteinuria – establishes the diagnosis of preeclampsia. Abnormal protein excretion – defined by - 24 hour urinary protein excretion exceeding 300 mg. - A spot urine protein : creatinine ratio >/= 0.3 - Persistent protein values of 30 mg/ dL ( +1 dipstick) in random urine sample. Using urinary protein excretion threshold of 165 mg in a 12 hour sample shows equal efficacy. Dr. Jishnu MS 59

60. . Random urine protein : creatinine ratio < 130 mg/g to 150 mg/g that is 0.13 to 0.15 indicate low likelihood of proteinuria exceeding 300 mg/dL Mid range ratios – 300mg/g or 0.3 have poor sensitivity and specificity – should be repeated- if persistent – 24 hour urine collection for measurement of protein need to be done. Dipstick method – results depends on the concentration of urine- notorious for false positive and negative values. - A concentrated urine specimen may show +1 or + 2 in women who actually excrete < 300 mg/ dL Dr. Jishnu MS 60

61. . Proteinuria may develop late, some women may already delivered or have had an eclamptic convulsion before it appears. At presentation, 10 % - 15% of women with HELLP syndrome do not have proteinuria. 17 % of patients with eclampsia does not have proteinuria by the time of seizure. Dr. Jishnu MS 61

62. . ANATOMICAL CHANGES IN KIDNEY Glomeruli are enlarged to approximately 20 % - they are bloodless Capillary loops are dilated and contracted. Glomerular capillary endotheliosis – swollen endothelial cells. - completely or partially block capillary lumen. There occur homogenous subendothelial deposits of proteins and fibrin like material. Capillary endotheliosis – may result form angiogenic protein “withdrawal” - Caused by complexing of free angiogenic proteins with a compatible circulating antiangiogenic protein receptor. Dr. Jishnu MS 62

63. Inactivation of angiogenic factors leads to dysfunction of podocytes and endothelial swelling. In eclampsia – greater excretion of epithelial podocytes. Dr. Jishnu MS 63

64. ACUTE KIDNEY INJURY Acute kidney injury – In 5 % of patients with preeclampsia and 14 % of patients with HELLP syndrome. In patients with renal injury – increased chances for placenta abruption and PPH. Abnormal renal function test values become normal in 10 days or later post partum. Although mild AKI are encountered – clinically apparent renal tubular necrosis is caused most of the time by comorbid hemorrhage , subsequent hypovolaemia and hypotension. Dr. Jishnu MS 64

65. AKI etiology is clinically evaluated with urine electrolytes. In most cases with preeclampsia – elevated urine sodium concentration – reflects intrarenal causes. In prerenal causes – increase in urine osmolality - elevated urine : plasma creatinine ratio - low fractional excretion of sodium. Sodium contained crystalloids may temporarily improves urine output. Dr. Jishnu MS 65

66. Rapid infusions may cause pulmonary edema. Intensive IV fluid therapy is not indicated in women with preeclampsia and oliguria, provided oliguria is not associated with volume loss due to haemorrhage, vomiting or fever. Dr. Jishnu MS 66

67. LIVER Several gross and microscopic anatomical derangements leads to elevated serum hepatic transaminase levels. Transaminitis indicates hepatocellular injury and is a marker of severe preeclampsia. Serum concentrations of serum transaminase inversely follows platelet levels – both usually return to normal levels within 3 days after delivery. Dr. Jishnu MS 67

68. ANATOMICAL CHANGES Regions of periportal hemorrhage in the liver periphery – typify hepatic lesions of eclampsia. There may be some degree of hepatic infraction accompanied by hemorrhage . The constellation of hemolysis , hepatoecellular necrosis and thrombocytopenia – HELLP syndrome Dr. Jishnu MS 68

69. Frank infarction is unusual - it may be worsened or precipitated by hypotension from obstetrical hemorrhage. Hepatic involvement in preeclampsia have several manifestations. Pain – Considered as sign of severe disease. - Moderate to severe right upper quadrant or midepigastric pain and tenderness. - Usually associated with elevated AST and ALT. In some cases ,the amount of hepatic tissue involved with infarction may be extensive yet still clinically insignificant. Dr. Jishnu MS 69

70. HEPATIC HEMATOMA Periportal hemorrhage and infraction may extend to develop a hepatic hematoma. This in turn can extend to form a subcapsular hematoma – may rupture – causes epigastric pain or tenderness. Unruptured hematomas are more common – likely to be found in HELLP syndrome. Majority cases are managed conservatively – sometimes surgical interventions or angiographic embolism can be life saving. Dr. Jishnu MS 70

71. Acute fatty liver of pregnancy is often confused with Preeclampsia. Both has onset late in pregnancy, hypertension, elevated serum transaminase levels and thrombocytopenia. Hallmark of AFLP is markedly deranged hepatic dysfunction. Liver function overall normal in preeclampsia syndrome/ HELLP syndrome. Dr. Jishnu MS 71

72. CENTRAL NERVOUS SYSTEM Headache and visual symptoms are common with severe preeclampsia and when associated with convulsion define Ecalmpsia . NERUROANATOMICAL LESIONS Intracranial haemorrhage can occur in up to 60% and half of this is fatal. Cortical and subcortical petechial haemorrhages are other principal lesions. The classic microscopic vascular lesions consist of fibrinoid necrosis of the arterial wall and perivascular microinfracts and hemorrhage. Dr. Jishnu MS 72

73. Other lesions - Non hemorrhagic areas of softening throughout brain. - Hemorrhages in white matter. - Subcortical edema. - Hemorrhage in the basal ganglia or pons often with rupture into ventricles Dr. Jishnu MS 73

74. CEREBROVASCULAR PATHOPHYSIOLOGY . Endothelial cell dysfunction plays key role in the cerebral abnormalities in eclampsia. There are several theories. In response to acute and severe hypertension – cerebrovascular overregulation leads to vasospasm and eventual tissue infraction. 2. Acute hypertension – exceeds the normal cerebrovascular autoregulatory capacity – regions of forced vasodilation and constriction develops in the arterial boundary zones. Dr. Jishnu MS 74

75. - At capillary level disruption of end capillary pressure causes increased hydrostatic pressure, hyper perfusion, extravasation of plasma and red blood cells leads to vasogenic edema. The true mechanism combines the two theories. Dr. Jishnu MS 75

76. Preeclampsia associated inter- endothelial cell leak develops at blood pressure levels much lower than those that usually cause, vasogenic edema – coupled with a loss of upper limit autoregulation. These abnormalities manifests as Posterior Reversible Encephalopathy Syndrome. Lesions principally involves the occipital and parietal cortices – less often other areas are also involved. Dr. Jishnu MS 76

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78. CEREBRAL BLOOD FLOW Autoregulation is the mechanism by which the cerebral blood flow remains relatively constant despite alterations in the cerebral perfusion pressure. In non pregnant individual – the autoregulation protects brain from hyperperfusion when MAP increases up to 160 mmHg. This autoregulation is altered by pregnancy. Dr. Jishnu MS 78

79. Cerebral blood flow during first two trimesters of normal pregnancy is similar to non pregnant values. During third trimester the cerebral blood flow decreases by 20 %. In severe preeclampsia – increase in the cerebral blood flow in third trimester – cerebral hyperperfusion – leads to capillary fluid leakage due to endothelial damage – Perivascular edema. Dr. Jishnu MS 79

80. NEUROLOGICAL MANEFESTATIONS . Several neurological manifestations typify the Preeclampsia syndrome. Head ache and scotoma – arise from cerebrovascular hyperperfusion that has a predilection for occipital lobes. In women preceding eclamptic convulsion – 75 % have head aches and 20-30 % have visual changes. Typically these head aches would not respond to traditional analgesia – frequently improves after magnesium sulphate infusion. Dr. Jishnu MS 80

81. Convulsions are diagnostic for Eclampsia. Caused by abnormal, excessive or synchronous neural activities in brian . Extended seizures can cause significant brain injury and later brain dysfunction. Women with eclampsia have been shown to have some degree of cognitive dysfunction after 5 to 10 years. Dr. Jishnu MS 81

82. VISUAL CHANGES AND BLINDNESS Retinal arterial and venular calibres are decreased in preeclampsia. Along with visual cortex involvement cause – scotomata, blurred vision or diplopia, which is common with severe preeclampsia or eclampsia. Often reversible with MgSO4 therapy or lowered blood pressure. Blindness complicates up to 15 % of women with eclampsia. It can develop a week or more following delivery . Blindness is usually reversible and can originate from visual cortex, LGN and retina. Dr. Jishnu MS 82

83. Occipital ( visual cortex) blindness is also call AMAUROSIS. In MRI there will be evidence of extensive occipital vasogenic edema. In retina – there may occur ischemia, infarction or serous detachment. Retinal infraction is called PURTSCHER RETINOPATHY. Serous detachment is unilateral , seldom cause visual loss. Asymptomatic serous detachment is common with preeclampsia. In cases of retinal artery occlusion – vison may be permanently impaired. Dr. Jishnu MS 83

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85. CEREBRAL EDEMA Symptoms ranges from lethargy, confusion, blurred vision to obtundation and coma. In most cases symptoms waxes and wanes The affected patients are more susceptible to sudden and severe blood pressure elevations – which can acutely worsen the already widespread vasogenic edema. Dr. Jishnu MS 85

86. UTEROPLACENTAL PERFUSION. Compromised uteroplacental perfusion – contributes to the increased perinatal morbidity and mortality associated with preeclampsia syndrome. Failure of second stage of trophoblastic invasion – diameter of spiral arteries in the myometrium is reduced. The vessel wall undergoes necrosis and the cell wall is replaced by amorphous material. This progresses to obliteration of vessels and areas of placental infraction. Increased apoptosis, necrosis and degeneration of trophoblast especially syncytiotrophoblast. Dr. Jishnu MS 86

87. Syncytiortophoblast debris and microparticles are released into maternal circulation – inflammation of the endothelium and endothelial dysfunction. By the completion of placentation, normally the impedance to the uterine artery blood flow is markedly decreased. In preeclampsia – abnormally high resistance persists. Dr. Jishnu MS 87

88. FETAL GROWTH RESTRICTION . This potential consequence of preeclampsia can serve as one severity indicator. Pregnancies complicated by fetal – growth restriction more likely had a maternal hemodynamic indices similar to preeclampsia including - Higher mean arterial pressure - Greater systemic vascular resistance. - Lower cardiac output - Elevated uterine artery pulsatility index. Fetuses born to preeclamptic mothers have cardiac remodelling similar to growth restricted fetuses. Dr. Jishnu MS 88

89. PREDICTION Some biological markers have been identified, which would help in the prediction of preeclampsia syndrome. Most of these have been evaluated in the first half of the pregnancy. Some are evaluated in the second half as predictors of severity of the syndrome. Even so no screening tests for preeclampsia are predictable reliable, valid and economical. Dr. Jishnu MS 89

90. VASCULAR RESISTENCE TESTING AND PLACENTAL PERFUSION. TESTS TO EVALUATE BLOOD PRESSURE CHANGES IN RESPONSE TO STIMULUS. ROLL OVER TEST - WOMEN AT 28 TO 32 WEEKS GESTATION, BLOOD PRESSURE IS INITIALLY MEASURSED BY PATIENT IS LEFT LATERAL POSITION AND THEN ROLL TO LIE SUPINE - RISE IN BLOOD PRESSURE SIGNIFIES A POSITIVE TEST. ISOMETRIC EXERCISE TEST - EMPLOYS SAME PRINCIPLE BY SQUEEZING A HANDBALL. Dr. Jishnu MS 90

91. 3. The angiotensin II infusion test. - Incrementally higher doses for angiotensin II administered intravenously – hypertensive response is quantified. Sensitivities are all three tests ranges from 55 to 70 % Specificity is almost 85 % Uterine artery doppler velocimetry – posited to reflect faulty trophoblastic invasion of the spiral arteries – have poor predictive value. Dr. Jishnu MS 91

92. FETAL – PLACENTAL UNIT ENDOCRINE FUNCTION . Dr. Jishnu MS 92

93. RENAL FUNCTION TESTS Serum uric acid levels : Hyperuricemia – due to reduced clearance caused by diminished glomerular filtration, increased tubular reabsorption and decreased secretion. Sensitivity of serum uric acid to detect preeclampsia ranges from 0 to 55 % and specificity from 77 to 95 %. Isolated gestational proteinuria is a risk factor for preeclamsia . As a predictive test – microalbuminuria – sensitivity 7 to 90 % and specificity 29 to 97 % Dr. Jishnu MS 93

94. ENDOTHELIAL DYSFUNCTION AND OXIDATIVE STRESS. Endothelial activation and inflammation are major contributing factors in preeclampsia pathophysiology. Levels of some compounds have been assessed as predictors Fibronectins – high molecular weight glycoproteins released from endothelial cells and extracellular matrix following endothelial injury. Thrombocytopenia and platelet dysfunction –integral features of preeclampsia. - Platelet activation causes augmented destruction and low concentration in blood. - Platelet volume increases due to immaturity – an early predictor of preeclampsia. Dr. Jishnu MS 94

95. Higher levels of lipid peroxidase coupled with decreased antioxidant activity can be seen in preeclampsia. 4. Other markers – Iron, Transferrin and Ferritin, Resistin , Hyperhomocysteinemia , Blood lipids, antioxidants such as Ascorbic acid and vitamin E None have sufficient predictive value. Dr. Jishnu MS 95

96. ANGIOGENIC AND ANTI ANGIOGENIC FACTOR IMBALANCE . Serum levels of VEGF and P1GF begins to drop before clinical preeclampsia develops. Levels of anti angiogenic factors – sF1t – 1 and sEng begin to rise. Shows good predictive performance with early onset preeclampsia. These tests helps in differentiating between preeclampsia and mimics that includes chronic hypertension, chronic kidney disease, SLE and immunological thrombocytopenia. Also helps in differentiating mild and severe diseases. Dr. Jishnu MS 96

97. OTHER MARKERS Cell free DNA ( cfDNA) of placental origin – released in preeclampsia by accelerated apoptosis of cytotrophoblasts. Other markers include – HbA1C, serum cystain and first trimester estimated placental volume. Dr. Jishnu MS 97

98. PREVENTION DIETARY AND LIFE STYLE MODIFICATIONS . Dietary restriction of salt is not effective. Regular exercise – linked to lower risk of developing preeclampsia. Bed rest – significant reduction in the risk of developing preeclampsia. But SMFM(2020) does not recommend reduced activities for women with hypertensive disorder. Sea food diet compared to western diet – protective effect against preeclampsia – due to increased iodine level, cardioprotective fatty acid levels. Dr. Jishnu MS 98

99. ANTI HYPERTENSIVE DRUGS. Diuretics can reduce edema and hypertension but not preeclampsia. There is no evidence suggesting antihypertensives helpful in prevention of superimposed preeclampsia in women with chronic hypertension. Dr. Jishnu MS 99

100. ANTIOXIDANTS Imbalance between oxidant and anti oxidant activity plays a role in preeclampsia pathogenesis. No studies suggests the use of anti oxidants for reducing the incidence of preeclampsia. Statins are proposed to prevent preeclampsia – stimulate heme oxygenease – 1 expression – inhibits sFlt -1 release. Dr. Jishnu MS 100

101. Metformin inhibits hypoxic inducible factor 1 alpha by lowering mitochondrial electron transport chain activity. It reduces sFlt – 1 and sEng activity and thus has potential to prevent preeclampsia. Dr. Jishnu MS 101

102. ANTI THROMBOYIC AGENTS Preeclampsia is characterized by vasospasm, endothelial cell dysfunction, inflammation and activation platelet and coagulation hemostasis system. Other sequelae – includes placental infraction and spiral artery thrombosis. LOW – DOSE ASPIRIN – 50 to 150 mg daily effectively inhibits platelet thromboxane A2 biosynthesis. - It has minimal effect on vascular prostacyclin synthesis. - ACOG now recommends low dose aspirin to be given between 12 and 28 weeks in high risk women. Dr. Jishnu MS 102

103. High risk group – with >/= 1 of the following - Prior preeclampsia - Chronic hypertension - Overt DM - Renal disease. - Auto immune disorders. - Multi fetal gestation Dr. Jishnu MS 103