1. Choice of antihypertensive Peter von Dadelszen BMedSc, MBChB, DipObst, DPhil, FRANZCOG, FRCSC, FRCOG Associate Professor of Obstetrics & Gynaecology, UBC Consultant in Maternal-Fetal Medicine, BC Women’s Co-Director, CFRI Reproduction & Healthy Pregnancy Cluster

2. Christchurch

3. PRE-EMPT (PRE-eclampsia-Eclampsia Monitoring, Prevention & Treatment) Five objective, LMIC community intervention- focussed, pre-eclampsia project Funding: –Bill & Melinda Gates Foundation

4. Why use antihypertensives? Maternal stroke risk associated with both severe systolic and/or diastolic hypertension –sBP >160mmHg –dBP >110mmHg CEMACH 2007 Severe hypertension associated with placental abruption and attendant maternal and perinatal risks Severe hypertension is included in most definitions of ‘severe’ pre-eclampsia, although such classification systems are flawed Menzies et al. Hypertens Pregnancy 2007

5. Why use antihypertensives? In non-severe pregnancy hypertension –No clear evidence of benefit other than to reduce the frequency of episodes of severe hypertension –May adversely effect fetal growth velocity von Dadelszen et al. Lancet 2000 Therefore, my focus will be on the pharmacological management of severe hypertension

6. The ‘ideal’ agent in rural & remote settings Oral administration Reliable reduction in BP Smooth reduction in BP Rapid onset of action Minimal overshoot –BP in target range sBP 130-160mmHg dBP 80-110mmHg

7. From what can we choose? Hydralazine Beta-blockers (& alpha-/beta-blockers) –Atenolol –Labetalol Calcium channel blockers –Nifedipine Alpha-methyldopa Angiotensin converting enzyme inhibitors Angiotensin-II receptor blockers

8. From what can we choose? Hydralazine Beta-blockers (& alpha-/beta-blockers) –Atenolol –Labetalol Calcium channel blockers –Nifedipine Alpha-methyldopa Angiotensin converting enzyme inhibitors Angiotensin-II receptor blockers –Risks of fetal renal toxicity and IUFD

9. From what can we choose? MgSO 4 is NOT an antihypertensive

10. The ‘ideal’ agent in rural & remote settings Oral administration Reliable reduction in BP Smooth reduction in BP Rapid onset of action Minimal overshoot –BP in target range sBP 130-160mmHg dBP 80-110mmHg

11. Oral administration Atenolol –No adverse effects on fetal growth when used acutely Labetalol Methyldopa Nifedipine capsules Nifedipine intermediate acting –PA/Retard Hydralazine Modified from: Magee & Abdullah. Expert Opin Drug Saf 2004

12. The ‘ideal’ agent in rural & remote settings Oral administration Reliable reduction in BP Smooth reduction in BP Rapid onset of action Minimal overshoot –BP in target range sBP 130-160mmHg dBP 80-110mmHg

13. Reliable reduction in BP severe hypertension CCBs are more reliable than hydralazine in lowering BP in pregnant women with severe hypertension Magee et al. BMJ 2004 Duley et al. CDSR 2006 Hydralazine appears more reliable than labetalol Magee et al. BMJ 2004 Methyldopa may be an agent of choice for severe hypertension

14. Duley et al. CDSR 2006

15. Reliable reduction in BP severe hypertension CCBs are more reliable than hydralazine in lowering BP in pregnant women with severe hypertension Magee et al. BMJ 2004 Duley et al. CDSR 2006 Hydralazine appears more reliable than labetalol Magee et al. BMJ 2004 Methyldopa may be an agent of choice for severe hypertension

16. Magee et al. BMJ 2004

17. Reliable reduction in BP severe hypertension CCBs are more reliable than hydralazine in lowering BP in pregnant women with severe hypertension Magee et al. BMJ 2004 Duley et al. CDSR 2006 Hydralazine appears more reliable than labetalol Magee et al. BMJ 2004 Methyldopa may be an agent of choice for severe hypertension –Widely used – routinely on EMLs

18. The ‘ideal’ agent in rural & remote settings Oral administration Reliable reduction in BP Smooth reduction in BP Rapid onset of action Minimal overshoot –BP in target range sBP 130-160mmHg dBP 80-110mmHg

19. Smooth reduction in BP The ideal agent will reduce BP effectively and over a relatively short period of time –<60min –Stabilise and reduce MAP by 10% per hour BP fall will not be precipitous –Adverse maternal CNS effects –Adverse fetal effects

20. Normal Pregnancy Early-onset pre-eclampsia

21. The ‘ideal’ agent in rural & remote settings Oral administration Reliable reduction in BP Smooth reduction in BP Rapid onset of action Minimal overshoot –BP in target range sBP 130-160mmHg dBP 80-110mmHg

22. ‘Rapid’ onset of action Modified from: Magee & Abdullah. Expert Opin Drug Saf 2004

23. The ‘ideal’ agent in rural & remote settings Oral administration Reliable reduction in BP Smooth reduction in BP Rapid onset of action Minimal overshoot –BP in target range sBP 130-160mmHg dBP 80-110mmHg

24. Minimal overshoot CCBs less likely to cause overshoot than hydralazine Magee et al. BMJ 2004 Beta-blockers less likely to cause overshoot than hydralazine Magee et al. BMJ 2004 Nifedipine PA/Retard less likely to cause overshoot than capsules? Brown et al. AJOG 2002 –Small RCT –End-point (‘in range BP’) measured at time PA approaching maximal effect

25. On balance An intervention package should include 1 - 3 oral antihypertensive agent(s) The choice for a single antihypertensive lies between methyldopa, nifedipine, and another beta-blocker, probably atenolol –labetalol is not on EMLs Theoretical and practical reasons to have all available –Combined CNS control, beta-blockade and vasodilatation –Second effective agent for women whose BP is resistant to another agent Reserve i.v. hydralazine for obtunded/comatose women

26. PRE-EMPT Objective 3 CLIP (Community-Level Interventions for Pre-eclampsia) –Cluster randomised controlled trial of community level interventions for women with pre-eclampsia –Aims Can –identification, –early risk stratification, and –initiation of life-saving treatment at the community level decrease pre-eclampsia-related maternal and perinatal mortality in LMIC?

27. CLIP Intervention –CLIP package of care Case recognition & triage Treatment of severe hypertension (sBP ≥160mmHg) –Oral antihypertensive ? Atenolol; ? Nifedipine, ? Methyldopa –Intramuscular MgSO 4 (5g each buttock) Treatment of eclampsia –Intramuscular MgSO 4 (5g each buttock) Transfer into facilities offering evidence-based care –Setting Community – community health workers Primary health units (not repeated)

28. The ‘ideal’ agent in rural & remote settings Oral administration Reliable reduction in BP Smooth reduction in BP Rapid onset of action Minimal overshoot –BP in target range sBP 130-160mmHg dBP 80-110mmHg