1. HYPERTENSION IN PREGNANCY (Summary of the CHS guidelines) February, 2004 Nicolas Szecket (From New Zealand)

2. Objectives 1.Classification of HTN in pregnancy 2.When to initiate treatment and when to admit 3.Pharmacologic and non-pharmacologic management of HTN in pregnancy 4.Management of severe HTN in pregnancy 5.Overview of Pre-eclampsia

3. References 1.Canadian Hypertension Society Consensus Conference, CMAJ, Sept. 15, 1997; 157 (6). 2.Fortnightly review: management of hypertension in pregnancy, Magee, LA et al. BMJ 1999; 318:1332. 3.Fall in mean arterial pressure and fetal growth restriction in pregnancy hypertension: a meta-analysis, Von Dadelszen, P et al. Lancet 2000; 355:87. 4.UpToDate – various modules 5.The Magpie Trial, Lancet 2002 Jun 1;359(9321):1877- 90.

4. Introduction Hypertension in Pregnancy: Major cause of maternal and perinatal morbidity and mortality Complicates up to 10% of pregnancies Second leading cause of maternal mortality in the developed world (after VTE) ~1/3 of all maternal deaths are from HTN’sive disorders

5. Severe complications MATERNAL CVA DIC End-organ failure Placental abruption FETAL IUGR Prematurity Intra-uterine death

6. The Case 34 year old G2P1 at 28 weeks gestation Sent to you for a BP of 160/98 mm Hg in GP’s office the previous day No previous medical problems No smoking and on no meds Review of antenatal record shows her BP was 145/90 at 14 and 18 weeks gestation

7. From this information alone you conclude: A) She has pre-eclampsia B) She likely has pre-existing hypertension C) She needs immediate delivery D) She has underlying renal disease

8. BP Weeks ~20 wks 0 wks 15 mm Hg

9. Grading of Recommendations Grade A – Very strong evidence Grade B – Fair evidence Grade C – Poor studies Grade D – Expert opinion

10. A word about technique (all Grade B evidence) Use a mercury sphygmomanometer Cuff size 1.5 X the patient’s upper arm circumference Patient should be at rest for 10 mins prior to measurement Patient in sitting position Cuff at level of heart Use phase IV Korotkoff (ie, muffling)

11. Back to the Case She remains asymptomatic and states there are good fetal movements Exam shows her to be overweight BP is 155/98 No pitting edema, reflexes are brisk, but no clonus There is no evidence of any secondary cause of HTN Urinary dipstick is negative for protein

12. Appropriate measures at this point include: A) Laboratory investigations B) 24 hour urine collection for protein C) Admission to hospital D) All of the above E) A and B

13. Definitions HTN defined as DBP > 90 mm Hg (D) Severe HTN is > 110 mm Hg (D) All reading > 90 mm Hg must be confirmed 4 hours later with 2 nd reading (D) –Except when > 110 mm Hg Significant proteinuria defined as > 0.3 g/day using a 24 hr urine collection (increased from 0.15 g/day in non-pregnancy) (A) Severe proteinuria is > 3 g/day Edema and weight gain no longer used to diagnosis of PET

15. CHS classificationInterpretation Pre-existing HTN Essential hypertension Secondary Pre-existing HTN Essential hypertension Secondary causes Gestational HTN without proteinuria“Pregnancy-Induced” HTN Gestational HTN with proteinuriaPre-eclampsia Pre-existing HTN + superimposed gestational HTN with proteinuria Pre-existing HTN with superimposed pre-eclampsia Unclassifiable Classification of Hypertensive Disorders in Pregnancy

16. When do you initiate therapy? (Grade D) Immediately: SBP > 169 or DBP > 109 symptomatic After 1-2 hrs: SBP > 169 or DBP >109 asymptomatic After few days observation: SBP > 139 or DBP > 89 if PET/underlying problems SBP > 149 or DBP > 94 if otherwise

17. When do you admit to hospital? Mandatory: SBP > 169, DBP > 109 symptomatic Strongly recommended: –Pre-eclampsia –anyone with DBP > 99 –anyone you can’t monitor closely as outpatient Recommended : –anyone with DBP 90-99 that you want to follow closely –to assess fetal well-being Note: for purposes of RC exam, it is never wrong to admit for a few days of monitoring

18. Back to the Case... This woman likely had pre-existing hypertension given that she had a diastolic blood pressure of 90 mm Hg prior to 20 weeks’ gestation (answer B). HTN at 28 weeks gestation raises the possibility of PET Should have appropriate initial investigations Admission is debatable, but most prudent thing to do Allows for fetal assessment, collection of urine to rule out PET, and monitoring of blood pressure (answer D) Note: Some centres have “Obstetric Day Units”, an acceptable option

19. Which investigations would be appropriate on admission? (mostly Grade C + D) CBC, blood film Lytes, BUN, Creat Uric acid (Grade B) – may reflect severity Liver enzymes Coags 24 hr urine for protein Urinalysis (Grade A) OB to see + BPP/NST/FMC/doppler flow…

20. Back to the case Our patient is admitted to hospital and monitored closely Fetal ultrasound is normal Bloodwork is normal 24 urinary protein excretion is 0.20 g/day Her DBP remains 95-105 You would like to begin treatment. What would you prescribe?

21. Management of Mild-Moderate HTN in pregnancy First line drug: Methyldopa (grade A) Second line drugs: –Labetalol/Pindolol/Oxprenolol/Nifedipine(grade A/B) Third line drugs: –Hydralazine + clonidine (A) –Hydralazine + metoprolol (A) –Clonidine (B) Diuretics - only in specific situations DRUGS TO AVOID: ACE- inhibitors Angiotensin II receptor antagonists Goal of therapy: DBP 80-90 mm Hg (grade D)

22. Beyond the guidelines... Lancet, January 2000 –meta-analysis –45 trials including 3773 women Aggressive lowering of BP can cause LOW BIRTH WEIGHT (100-200 grams!) Guidelines will likely be modified soon Most experts now aim to keep HTN’sive pregnant women at BP 150-160/90-100

23. Outcomes of treatment Perinatal death Methydopa - in women with pre-existing HTN

24. Outcomes of treatment Prevention of severe HTN Methydopa in women with pre-existing HTN Beta-blockers/Nifedipine/combination therapy with hydralazine

25. Outcomes of treatment Superimposed PET NO known pharmacologic prevention

26. Outcomes of treatment Preterm delivery No good data

27. Outcomes of treatment IUGR Poor evidence ?Maybe Beta blockers cause IUGR? ?Maybe Diuretics cause IUGR?

28. What about Non-Parmacologic Treatment and Prevention?  Indicated for SBP> 140mmHg or DBP > 90mmHg  “Non-pharmacologic Rx alone is recommended for women with SBP of 140- 150 mmHg or DBP 90-99mmHg in the absence of maternal or fetal risk factors (Grade D)”

29. Possibly Promising therapies  ASA  no role for routine use (Grade B)  BUT…low dose ASA reduces incidence of pre-term delivery and early onset PET in women at risk (Grade A)  Calcium  primary prevention of PET  does not prevent development of more severe GESTATIONAL HTN (Grade B) (NEJM 1991, NEJM 1997)

30. Others...  Bedrest  no evidence for efficacy  in fact, Grade B evidence that it is not advisable  Exercise  no evidence  Stress control  no evidence  Increased energy and protein intake  Grade B evidence that they are NOT beneficial  Weight reduction  not recommended (Grade C)

31.  Na restriction  not recommended (Grade C)  Alcohol restriction  no evidence  Magnesium  not justified (Grade B)  Zinc/iron/folate  not beneficial (Grade B)

32. Back to the Case Methyldopa, 250 mg BID is started BP drops to 140/88 Pt. Discharged home 2 weeks later - presents to ER with epigastric pain, headache and blurred vision BP 190/115 3+ protein on dipstick

33. Each of the following would be appropriate initial therapy except: A) Labetalol 5-10 mg IV B) Nifedipine 5 mg PO C) Metoprolol 50 mg PO D) Hydralazine 5-10 mg IV

34. Management of Severe Hypertension in Pregnancy (DBP> 110 mm Hg) First line drugs: –Hydralazine (grade B) –Labetalol (grade B) –Nifedipine (grade B) Second line drugs: if refractory to above –Diazoxide (grade D) –Sodium nitroprusside (grade D) Note: need continuous fetal monitoring Treatment goal: 90-100 mm Hg

35. Back to the case... This patient has severe hypertension in the setting of pre-eclampsia, and is symptomatic Her blood pressure needs to be lowered acutely, and so oral metoprolol is NOT an appropriate initial choice (Answer C)

36. Pre-eclampsia Multi organ disorder Diagnosis after 20 wks gestation –HTN –significant proteinuria

37. Burden of disease Affects 3-14 % of all pregnancies worldwide in 2nd pregnancy: –1 % if Normal 1st preg –5-7 % if mild PET in 1st preg –60-80 % if early severe PET in 1st preg

38. Other Risk Factors HTN at start of preg FHx Multiple pregnancies Chronic maternal HTN DM APLAS CTD Increased maternal age New partner Note: smoking reduces the risk of PET

39. Pre-eclampsia: Presentation Clinical headache vision disturbances RUQ pain nausea and vomiting elevated blood pressure edema convulsions stroke cerebral edema pulmonary edema retinal detachment Laboratory proteinuria >0.3 g/24 hr high uric acid (indicates severity) HELLP syndrome - hemolysis, high liver enzymes, low platelets increased hematocrit elevated PTT, d-Dimers, low fibrinogen (markers of DIC)

40. Back to the Case She is treated with labetalol 10 mg IV BP drops to 160/97 Fetal heart tracing is reassuring Lab tests are as follows: AST 520, ALT 480, platelets 200, creatinine 100, uric acid 500 She is transferred to labour and delivery, and has a tonic-clonic seizure

41. Which of the following is the MOST EFFECTIVE in preventing further seizures? A) Dilantin B) Diazepam C) Magnesium sulfate D) Control of blood pressure

42. Eclampsia Complicates about 1% of patients with PET Magnesium sulfate is the treatment of choice: more effective than dilantin or diazepam in the prevention of further seizures/status eclampticus Role of MgSO4 in the primary prevention of PET is controversial, and not yet proven Typical loading is 4-6 g IV bolus followed by 1-2 g/hour should be continued 12-24 hrs postpartum

43. Recent NEJM article comparing MgSO 4 to Calcium Channel blocker MgSO 4 better

44. Should MgSO 4 have been initiated before the seizure? Probably… MAGPIE trial Primary prevention of eclampsia for all degrees of PET NNT = 63 in severe PET NNT = 109 in mild-moderate PET

45. Back to the Case patient is treated with MgSO 4 BP controlled with labetalol IV She undergoes a STAT caesarean section and delivers a healthy baby boy (taken to NICU…doing well) After 24 hrs of monitoring, she is transferred to the ward, and discharged 6 days later

46. Summary and Editorial comments Hypertension in pregnancy is a common medical problem Guidelines exist to assist in decision-making, however, most are based mostly on expert opinion Some recommendations are certainly “murky” (ie, when to admit, when to start therapy) bottom line: never wrong to admit a patient for a few days until pre-eclampsia is safely ruled out Don’t forget to ask for OB help from the beginning

47. THE END