1. Hypertensive Disorders in Pregnancy Aleksandra Rajewska PhD Chair and Department of Obstetrics and Gynecology

2. Hypertensive disorders (HD) in pregnancy Affects 7 – 10% pregnancies Affects 7 – 10% pregnancies Increased perinatal morbidity & mortality Increased perinatal morbidity & mortality Mild hypertension in pregnancy: Mild hypertension in pregnancy: 33% preterm delivery; 11% SGA neonates Severe hypertension in pregnancy: Severe hypertension in pregnancy: 62 – 70% preterm delivery; 40% SGA neonates

3. Hypertensive disorders in pregnancy: classification 1. Pregnancy Induced Hypertension (PIH) or Gestational Hypertension (GH) or Transient Hypertension 2. Preeclampsia 3. Eclampsia 4. Chronic hypertension 5. Preeclampsia superimposed on chronic hypertension

4. Maternal & fetal consequences of HD Maternal  DIC  Cerebral hemorrhage  Retinal hemorrhage  Liver insufficiency  Acute renal failure  Cardiac insufficiency  Pulmonary edema  Placental abruption Fetal  IUGR  Low birth weight  Oligohydramnios  Preterm delivery  Neonatal prematurity  Intrauterine hypoxia  Intrauterine fetal death  Placental abruption

5. Ethiology Incomplete trophoblastic invasion of uterine vessels: Incomplete trophoblastic invasion of uterine vessels: Uteroplacental blood flow impairment Uteroplacental blood flow impairment Diminished placental perfusion Diminished placental perfusion Immunological factors: Immunological factors: Microscopic changes: acute graft rejection Microscopic changes: acute graft rejection Impairment of blocking antibodies formation Impairment of blocking antibodies formation Th 1 /Th 2 imbalance Th 1 /Th 2 imbalance Anticardiolipin antibodies Anticardiolipin antibodies

6. Spiral arteries modification

7. Ethiology Vasculopathy & inflammatory changes Vasculopathy & inflammatory changes Placental ischemia: released factors provoke endothelial injury Placental ischemia: released factors provoke endothelial injury Oxidative stress: formation of self-propagating lipid peroxides Oxidative stress: formation of self-propagating lipid peroxides Nutritional factors Nutritional factors Antioxidants deficiency Antioxidants deficiency Obesity & atherosclerosis Obesity & atherosclerosis Genetic factors: primipaternity? Genetic factors: primipaternity?

8. Pathogenesis Vasospasm Vasospasm Endothelial cell activation Endothelial cell activation Increase pressor response Increase pressor response Coagulation promotion Coagulation promotion

9. Pregnancy Induced Hypertension (PIH) 6 – 17% of primiparas 6 – 17% of primiparas 2 – 4% of multiparas 2 – 4% of multiparas Blood pressure ≥ 140/90 mmHg occurring for first time during pregnancy Blood pressure ≥ 140/90 mmHg occurring for first time during pregnancy Blood pressure returns to normal < 12 weeks postpartum Blood pressure returns to normal < 12 weeks postpartum No proteinuria No proteinuria Edema is not a PIH criterion any more! Edema is not a PIH criterion any more! Final diagnosis – postpartum Final diagnosis – postpartum

10. Preeclampsia (PE) 2 – 7% of primiparas 2 – 7% of primiparas 14% of twin pregnancies 14% of twin pregnancies 18% with PE in previous pregnancy 18% with PE in previous pregnancy Minimum criteria BP ≥ 140/90 mmHg after 20 weeks’ gestation BP ≥ 140/90 mmHg after 20 weeks’ gestation Proteinuria ≥ 300 mg/24 hours or ≥ 1+ dipstick Proteinuria ≥ 300 mg/24 hours or ≥ 1+ dipstick Increased certainty BP ≥ 160/110 mmHg BP ≥ 160/110 mmHg Proteinuria ≥ 2.0 g/24 hours or ≥ 2+ dipstick Proteinuria ≥ 2.0 g/24 hours or ≥ 2+ dipstick Serum creatinine >1,2 mg/dL Serum creatinine >1,2 mg/dL Persistent headache or other cerebral or visual disturbances Persistent headache or other cerebral or visual disturbances Persistent epigastric pain Persistent epigastric pain

11. Preeclampsia (PE) Pregnancy-specific syndrome of reduced organ perfusion secondary to placental hypoperfusion, vasospasm and endothelial activation Pregnancy-specific syndrome of reduced organ perfusion secondary to placental hypoperfusion, vasospasm and endothelial activation Risk factors: nulliparity, multifetal gestation, maternal age >35 years, obesity, ethnicity Risk factors: nulliparity, multifetal gestation, maternal age >35 years, obesity, ethnicity

12. Preeclampsia (PE) Preventive factors: placenta previa, smoking Preventive factors: placenta previa, smoking Histopathology: glomerular lesion Histopathology: glomerular lesion In severe cases proteinuria may fluctuate over any 24-hours period In severe cases proteinuria may fluctuate over any 24-hours period

13. Eclampsia Generalized tonic-clonic convulsions (beginning about facial muscles) with subsequent coma in a woman with preeclampsia

14. Eclampsia Typically in the third trimester Typically in the third trimester Prognosis always serious Prognosis always serious Preventable! Preventable! Fatal coma without convulsions – dgn. controversial Fatal coma without convulsions – dgn. controversial

15. Eclampsia Antepartum 38 – 53% Antepartum 38 – 53% Intrapartum 18 – 36% Intrapartum 18 – 36% Postpartum 11 – 44% Postpartum 11 – 44% Life threatening for mother & fetus! Life threatening for mother & fetus! Maternal mortality: 1,8 – 14% Maternal mortality: 1,8 – 14% Fetal/neonatal mortality: the earlier in pregnancy E occurs the higher Fetal/neonatal mortality: the earlier in pregnancy E occurs the higher

16. Eclampsia: sequels Transient diaphragm fixation: respiratory arrest Transient diaphragm fixation: respiratory arrest Continuous convulsions: „status epilepticus” Continuous convulsions: „status epilepticus” Placental abruption Placental abruption DIC DIC Massive cerebral hemorrhage Massive cerebral hemorrhage Neurological deficits Neurological deficits

17. Eclampsia: sequels Aspiration pneumonia Aspiration pneumonia Pulmonary edema Pulmonary edema Cardiopulmonary arrest Cardiopulmonary arrest Acute renal failure Acute renal failure Maternal death Maternal death

18. Eclampsia: differential diagnosis Exclude: Exclude:  Epilepsy  Encephalitis  Meningitis  Cerebral tumor  Cysticercosis  Ruptured cerebral aneurysm

19. Eclampsia: treatment 1. Loading dose of magnesium sulfate i.v.* 2. Continuous infusion of magnesium sulfate i.v. or periodic i.m. injections 3. Antihypertensive medication (i.v. or oral) if diastolic pressure > 100 mmHg 4. Avoid diuretics and limitations of fluid administration! 5. DELIVERY * Magnesium sulfate in eclampsia is given as anticonvulsant, not as hypertension treatment!

20. Chronic hypertension Blood pressure ≥ 140/90 mmHg before pregnancy or diagnosed before 20 weeks’ gestation Blood pressure ≥ 140/90 mmHg before pregnancy or diagnosed before 20 weeks’ gestationor Hypertension first diagnosed after 20 weeks’ gestation Hypertension first diagnosed after 20 weeks’ gestationor Hypertension persistent after 12 weeks’ postpartum Hypertension persistent after 12 weeks’ postpartum

21. Superimposed preeclampsia New-onset proteinuria ≥ 300 mg/24 hours New-onset proteinuria ≥ 300 mg/24 hours in hypertensive woman A sudden increase in proteinuria or blood pressure in woman with hypertension and proteinuria before 20 weeks’ gestation A sudden increase in proteinuria or blood pressure in woman with hypertension and proteinuria before 20 weeks’ gestation

22. Superimposed preeclampsia Often develops earlier in pregnancy and gets more severe than „pure” preeclampsia Often develops earlier in pregnancy and gets more severe than „pure” preeclampsia All chronic hypertensive disorders predispose to development of superimposed preeclampsia and eclampsia! All chronic hypertensive disorders predispose to development of superimposed preeclampsia and eclampsia!

23. Pathophysiology: cardiovascular system Increased cardiac afterload caused by hypertension Increased cardiac afterload caused by hypertension Cardiac preload affected by hypovolemia Cardiac preload affected by hypovolemia Hemoconcentration: a consequence of general vasoconstriction and vascular permeability Hemoconcentration: a consequence of general vasoconstriction and vascular permeability Excessive reaction to even normal blood loss at delivery Excessive reaction to even normal blood loss at delivery

24. Patophysiology: blood & coagulation Acute thrombocytopenia < 100 000/µL Acute thrombocytopenia < 100 000/µL Fragmentation hemolysis (microangiopathic h.): elevated serum lactate dehydrogenase levels Fragmentation hemolysis (microangiopathic h.): elevated serum lactate dehydrogenase levels HELLP syndrome: Hemolysis, ELevated liver transaminase enzymes, Low Platelets HELLP syndrome: Hemolysis, ELevated liver transaminase enzymes, Low Platelets 0,2 – 0,6% of all pregnancies 0,2 – 0,6% of all pregnancies 4 – 12% of pregnancies complicated by PE or E 4 – 12% of pregnancies complicated by PE or E But 15% of pregnancy without hypertension or proteinuria! But 15% of pregnancy without hypertension or proteinuria!

25. Patophysiology: volume homeostasis Decrease in renin, angiotensin II & aldosterone activity Decrease in renin, angiotensin II & aldosterone activity Paradoxical sodium retention Paradoxical sodium retention Expanded volume of extracellular fluid: Expanded volume of extracellular fluid:  Endothelial injury  Reduced plasma oncotic pressure (proteinuria)

26. Pathophysiology: kidney Reduced renal perfusion Reduced renal perfusion Reduced glomerular filtration Reduced glomerular filtration Elevated plasma uric acid concentration Elevated plasma uric acid concentration Proteinuria: albumins, globulins, hemoglobin & transferrin Proteinuria: albumins, globulins, hemoglobin & transferrin

27. Pathophysiology: kidney In mild to moderate PE: elevated plasma creatinine values In mild to moderate PE: elevated plasma creatinine values Severe PE: intrarenal vasospasm & oliguria Severe PE: intrarenal vasospasm & oliguria  Intensive intravenous fluid therapy contraindicated!  Intravenous dopamine infusion recommended!

28. Patophysiology: liver Most common in HELLP syndrome Most common in HELLP syndrome Periportal hemorrhage described by Virchow in 1856 Periportal hemorrhage described by Virchow in 1856 Focal hemorrhages can cause hepatic rupture or subcapsular hematoma Focal hemorrhages can cause hepatic rupture or subcapsular hematoma

29. Patophysiology: brain Gross hemorrhage due to ruptured arteries caused by severe hypertension: most common in women with underlying chronic hypertension; PE is not necessary! Gross hemorrhage due to ruptured arteries caused by severe hypertension: most common in women with underlying chronic hypertension; PE is not necessary! Hyperemia, ischemias, thrombosis & hemorrhage: common in PE, universal with eclampsia Hyperemia, ischemias, thrombosis & hemorrhage: common in PE, universal with eclampsia

30. Patophysiology: brain Doppler findings in eclampsia: cerebral hyperperfusion similar to hypertensive encephalopathy Doppler findings in eclampsia: cerebral hyperperfusion similar to hypertensive encephalopathy Cerebral edema Cerebral edema

31. Pathophysiology: placenta Uteroplacental perfusion compromised from vasospasm Uteroplacental perfusion compromised from vasospasm Most common in HELLP syndrome Most common in HELLP syndrome Doppler velocimetry! Doppler velocimetry!

32. Prediction Uric acid Uric acid Fibronectin Fibronectin Coagulation activation Coagulation activation Oxidative stress Oxidative stress Cytokines Cytokines Placental peptides Placental peptides Fetal DNA Fetal DNA Uterine artery Doppler velocimetry Uterine artery Doppler velocimetry

33. Management: prevention? Low-dose Aspirin Low-dose Aspirin Antioixdants Antioixdants No salt intake restrictions No salt intake restrictions No slimming diet! No slimming diet!

34. Management: antepartum hospitalization Detailed examination and daily scrutiny for: headache, visual disturbances, epigastric pain and rapid weight gain Detailed examination and daily scrutiny for: headache, visual disturbances, epigastric pain and rapid weight gain Everyday weight admittance Everyday weight admittance Analysis for proteinuria (every 2 days) Analysis for proteinuria (every 2 days)

35. Management: antepartum hospitalization Blood pressure readings (every 4 hours) Blood pressure readings (every 4 hours) Measurements of plasma creatinine, hematocrit, platelets, serum liver enzymes Measurements of plasma creatinine, hematocrit, platelets, serum liver enzymes Frequent evaluation of fetal size and amniotic fluid volume Frequent evaluation of fetal size and amniotic fluid volume

36. Management: conservative antihypertensive therapy Aim: to prolong pregnancy and/or modify perinatal outcomes Aim: to prolong pregnancy and/or modify perinatal outcomes α – metyldopa: central & peripheral action; no compromise of fetal hemodynamics α – metyldopa: central & peripheral action; no compromise of fetal hemodynamics Labetalol: αβ – blocker Labetalol: αβ – blocker

37. Management: conservative antihypertensive therapy Nifedipine, werapamil: Ca channel blockers Nifedipine, werapamil: Ca channel blockers  Contraindicated in I trimester!  Contraindicated if high risk of eclampsia (magnesium sulfur administration causes hypotony) Dihydralazin: in severe hypertension Dihydralazin: in severe hypertension

38. Management: termination of pregnancy Delivery is the cure for preeclampsia! Delivery is the cure for preeclampsia! Mild PE + fetal prematurity: temporizing Mild PE + fetal prematurity: temporizing Moderate to severe PE: labor preinduction & induction Moderate to severe PE: labor preinduction & induction Severe PE or unfavorable cervix: elective caesarian section Severe PE or unfavorable cervix: elective caesarian section Subarachnoid analgesia recommended Subarachnoid analgesia recommended

39. Hypertensive disorders in puerperium PIH: recovery in few days PIH: recovery in few days Hypotensive agents: 3 – 4 weeks postpartum Hypotensive agents: 3 – 4 weeks postpartum PE/E: continue magnesium sulfate administration 24 hours postpartum PE/E: continue magnesium sulfate administration 24 hours postpartum and hypotensive agents

40. Hypertensive disorders in puerperium Eclampsia in puerperium – most common in first 48 hours postpartum; incidentally up to 4 weeks postpartum Eclampsia in puerperium – most common in first 48 hours postpartum; incidentally up to 4 weeks postpartum Chronic hypertension – risk of cardiac failure, pulmonary edema, renal failure, encephalopathy Chronic hypertension – risk of cardiac failure, pulmonary edema, renal failure, encephalopathy

41. Thank you