1. Understanding the Evidence: Preventing, Detecting & Managing Pre-Eclampsia & Eclampsia

2. Objectives  Present evidence on pre-eclampsia and eclampsia (PE/E) interventions available for PE/E prevention, detection and management  Share emerging evidence and innovations on PE/E

3. Hypertensive Disorders among Global Maternal Mortality Causes Eclampsia Source: Khan et al., 2006; POPPHI, 2009

4. Declines in Maternal Deaths and Global MMR, 1990–2008 Source: Hogan et al., 2010

5. Declining MMR & Changing Causes of Maternal Deaths: Indonesia Source: Indonesia Maternal Health Assessment, 2010

6. Hypertension in Pregnancy Source: American Society of Hypertension, 2009 Hypertension complicates 5–7% of all pregnancies

7. PROBABLE DIAGNOSISTYPICAL SIGNS AND SYMPTOMS Chronic hypertension Diastolic BP 90 mm Hg or more prior to first 20 weeks of gestation Pre-eclampsia superimposed on chronic hypertension women with hypertension and no proteinuria early in pregnancy (<20 weeks’ gestation) In women with hypertension and proteinuria before 20 weeks gestation any of the following are seen:  New-onset or worsening proteinuria, or  Sudden increase in blood pressure in a woman whose hypertension has previously been well controlled Gestational hypertension Transient hypertension of pregnancy if PE is not present at the time of delivery and blood pressure returns to normal by 12 weeks postpartum (a retrospective diagnosis)  Two readings of diastolic BP 90 mm Hg or more but below 110 mm Hg 4 hours apart after 20 weeks gestation  No proteinuria Mild pre-eclampsia  Two readings of diastolic BP 90 mm Hg or more but below 110 mm Hg 4 hours apart  Proteinuria up to 2+ Severe pre-eclampsia Diagnosis of pre-eclampsia PLUS one or more of the following diagnostic criteria:  Diastolic BP 110 mm Hg or more  Proteinuria 3+ or more  Hyperreflexia  Headache (increasing frequency, unrelieved by regular analgesics)  Blurred vision  Oliguria (passing less than 400mL of urine in 24 hours)  Upper abdominal pain (epigastric or right upper quadrant pain)  Pulmonary oedema EclampsiaPre-eclampsia with:  Convulsions  Coma (unconscious) Source: Prevention and management of pre-eclampsia and eclampsia Reference Manual for Healthcare Providers, MCHIP, 2011

8. Poor ability to Predict Pre-Eclampsia Source: Meads CA, 2008.

9. Who is at Increased Risk for PE?  A personal or family history of PE/E  Pre-existing medical condition including obesity, chronic hypertension, or diabetes  Age: ≤19; >35 years  Primigravida  IUGR, abruption placenta or fetal death in previous pregnancy  First pregnancy with a new partner All pregnant women potentially at risk. All need prevention and early detection of PE.

10. Levels of PE/E Prevention LEVELSTRATEGYDEFINITION 1. Primary Prevention Prevention  Avoiding the development of the disease  Avoiding pregnancy and conditions favorable to PE development 2. Secondary Prevention Detection, Screening Detecting the disease before clinical PE symptoms appear 3. Tertiary Prevention Treatment, Management Treating the disease early to prevent complications 3. Management 2. Detection 1. Prevention

11. PE/E Prevention  Prevention and prediction are difficult because:  The cause is not well understood  The associated factors are difficult to influence  Focus on symptomatic clinical management to prevent maternal morbidity (e.g., eclampsia) and mortality Source: Steegers EA et al., Lancet. 2010 3. Management 2. Detection 1. Prevention

12. Taking Evidence to Scale Seeking simple, inexpensive and effective solutions that reach all pregnant women Photo credit: Daniel Antonaccio 3. Management 2. Detection 1. Prevention

13. Preventing Pre-Eclampsia xx x Almost 100 interventions tested in randomized trials 1. Prevention

14. Primary Prevention Source: Prevention and management of pre-eclampsia and eclampsia reference manual, MCHIP, 2011 InterventionPregnancy outcomeRecommended? Prevention of IUGR Theoretically contributes to primary prevention of PE (and IUGR) in the next generation Yes Family planningPotential to reduce pregnancies at risk for PEYes Pre-conceptual prevention and/or treatment of obesity Potential to reduce PEYes Calcium supplementation  Reduces PE in those at high risk and with low baseline dietary calcium intake  No effect on perinatal outcome High risk of gestational hypertension; low dietary calcium intake Low-dose aspirin  Reduces PE  Reduces fetal or neonatal deaths Populations at increased risk Magnesium or zinc supplementation No PE reduction Insufficient evidence to recommend* Fish oil supplementation and other sources of fatty acids No effect on low- or high-risk populations Insufficient evidence to recommend* Heparin or low-molecular weight heparin Reduces PE in women with renal disease and thrombophiliaInsufficient evidence to recommend* Anti-oxidant vitamins (C, E) Reduced PE in one trial, but not all trialsInsufficient evidence to recommend* Protein or salt restrictionNo effectNo 1. Prevention

15. Primary Prevention of PE 1. Prevention

16. Potential Impact of Calcium  Calcium reduces PE by 48%  Potential of universal calcium supplementation:  Prevent 21,500 maternal deaths  Reduce DALYs by 620,000 Source: Bhutta et al., Lancet, 2008 1. Prevention

17. Preventing PE: Calcium StudyHofmeyr et al., 2010 (Cochrane) Design13 studies, most used 1.5–2g of calcium/day Majority included: low-risk (n=15,143); low dietary calcium intake (n=10,678) ResultsReduced risk of:  High blood pressure (35%)—greater for high-risk, low baseline calcium  PE (31–65%)—greater for high-risk and low baseline calcium  Preterm births (24%)—greater for high-risk (55%)  Composite outcome maternal death or serious morbidity (20%) No overall effect on stillbirth or neonatal death before hospital discharge  Supplementation (≥1g/day) halves the risk ratio of PE  Greatest among women who are high risk or have low dietary calcium intake  No side effects reported 1. Prevention

18. Cochrane 2009: Calcium & PE Source: Hofmeyr GJ, Lawrie TA, Atallah AN, Duley L, Cochrane Database Syst Rev. 2010 1. Prevention

19. Preventing PE: Calcium, WHO Reproductive Health Library, 2010  Useful in low-resource settings  Women with low habitual calcium intake appeared to benefit more  No adverse effects, relatively safe  Supports Cochrane findings calcium supplementation (>1 g/day) during pregnancy reduced risk, but interpret results with caution:  High BP  Half as likely to get PE  No evidence of significant difference for:  Maternal outcomes (proteinuria, severe PE, eclampsia, maternal death)  Perinatal/neonatal (preterm birth, LBW, SGA, stillbirth or death before discharge from hospital greatest for women at high risk for PE; low baseline dietary calcium Source: RHL Commentary by Palacios C and Pena-Rosas JP, 2010 1. Prevention

20. Daily Calcium Intake Minimum daily calcium intake, Adult WRA (1000−1200 mg/day) Minimum daily calcium intake, Pregnant Women (1300−1500 mg/day) Source: Calcium and Prevention of Pre-Eclampsia: Summary of Current Evidence, Monitoring, Evaluation and Research Task Force of the PE/E working group 2010 1. Prevention

21. Calcium & Iron Evidence (2005)  Added calcium reduced the initial uptake of heme iron by 20%  Reduced total iron absorbed by 25%  Nonheme iron absorption not significantly affected  “the long-term use of dietary calcium supplements… may further increase the risk of iron deficiency in women who are having difficulty in meeting their iron requirements.” Implications (2010)  Consider bioavailability of calcium from supplements:  Solubility, size of the dose  Interacts with iron, zinc, magnesium and phosphorus  Inhibits iron absorption in a dose- dependent and dose-saturable fashion  separate time during the day from daily iron+folic acid supplementation Sources: Roughead, Z; Zito CA, Hunt JR 2005; RHL Commentary by Palacios C and Pena- Rosas JP, 2010 Photo credit: Paul Geor, www.sxc.hu 1. Prevention

22. Source: Meads et al., Health Technol Assess. 2008 1. Prevention Cost-effectiveness to Predict and Prevent PE: Test & Treatment  Second most cost-effective 'test-treatment' combination=Calcium supplementation to all women without any initial testing  Cost of an average case of PE approximately 9000 UK £

23. Preventing PE: Low-Dose Aspirin StudyDuley L et al., 2007 (Cochrane)Bujold et al., 2010 Design59 trials, n = 37,560 women, antiplatelet agents use 34 trials of women “at risk”: 12 at ≤16 weeks gestation; 22 after ResultsReduced risk of:  PE (17%)  SGA births  Fetal, neonatal & infant deaths (14%) Higher doses >75 mg of aspirin per day) <16 weeks significant decrease:  PE  Severe PE  IUGR  Preterm birth  Daily prevents PE and IUGR for women at moderate or high-risk for PE  Greater benefits if started earlier in pregnancy (<16 weeks) 1. Prevention

24. Preventing PE: Vitamins C & E  Oxidative stress = Underlying mechanism for PE/E?  Vitamins C & E for pregnant women at high-risk for PE  Communities at risk of poor nutritional status in developing countries  14–22 weeks gestation, daily supplements of vitamin C (1000mg) & E (400 iu), n = 1365  Did not prevent PE, eclampsia, gestational hypertension, LBW, SGA or perinatal deaths Source: Villar J et al., BJOG 2009 1. Prevention

25. Preventing PE: Vitamin D  Deficiency in pregnancy:  Associated with adverse maternal and fetal outcomes  Worldwide epidemic (18–84%)  Linkage to calcium absorption which increases during pregnancy, peaking in the third trimester  Recent studies found:  Vitamin D deficiency <22 weeks is an independent predictor of PE  Vitamin D plus calcium supplementation started at 20–24 weeks significantly reduced BP but not PE  Daily vitamin D intake (10–15 g/day) in Norway reduced the adjusted risk for PE by 29% when adjusting for maternal BMI Source: Haugen M et al., Epidemiology 2009; Mulligan et al., Am J Obstet Gynecol. 2010 1. Prevention

26. Detecting Pre-Eclampsia  No clinically-useful screening test to predict PE in either high- risk or low-risk groups (2004)  Doppler ultrasonography  24-hour ambulatory blood pressure  Placental and fetal peptides  Renal dysfunction-related tests  Endothelial and oxidant stress dysfunction-related tests  Ideal predictive test:  Simple, innocuous, rapid, inexpensive, reproducible, and noninvasive  Easy to perform early in pregnancy Source: Conde-Agudelo A, Villar J, Lindheimer M. Obstet Gynecol. 2004 2. Detection

27. Detecting Pre-Eclampsia: Measuring BP  Hypertension  10% of pregnancies, >20 weeks  Diastolic BP 90 mm Hg  Most common: high BP before proteinuria  WHO ANC Guidelines  4 ANC visits/pregnancy  BP history and measurement at each visit  Accuracy  Significant training needed to do BP well  Robust and maintained equipment Photo credit: Sheena Currie 2. Detection

28. Detecting Pre-Eclampsia: Proteinuria  Hypertension with proteinuria associated with poorer maternal and perinatal outcomes  Proteinuria among women with:  Higher antenatal BP  Deliver earlier  More often require operative delivery  Magnitude of proteinuria is a poor predictor of the major maternal and fetal complications  Available tests:  Urine dipstick test: Rapid, simple  Boiling: Not feasible in high volume sites  Esbach: time-consuming, inpatient Photo credit: Daniel Antonaccio Source: Thornton CE et al., Clin Exp Pharmacol Physiol 2010; Thangaratinam S et al., BMC Med. 2009 2. Detection

29. Dipstick Urine Testing for Protein  Limited in reliability, sensitivity, specificity, and predictive value  False negative rate of 48.6% during ANC screening in South Africa— missed a significant number of patients with proteinuria  Widely used  Only test available in low-income and middle-income countries Source: Steegers EA et al., Lancet. 2010; Gangaram R, Ojwang PJ, Moodley J, Maharaj D. Hypertens Pregnancy. 2005 Photo credit: Daniel Antonaccio 2. Detection

30. Components of ANC in Africa: BP Measurement and Urine Analysis Source: DHS, years as noted above 2. Detection

31. ANC: PE Screening Opportunity  Identify and act on known risk factors at booking  Risk of PE with raised BP at ANC booking warrants better risk assessment during ANC  Recognize and respond to signs and symptoms from 20 weeks’ gestation  Screening during ANC in Tanzania, 95% coverage for BP screening; 33% for proteinuria testing  <50% who developed eclampsia had been referred from ANC clinic  <10% were admitted to the antenatal ward before onset of eclamptic fits Source: Trends in maternal mortality: 1990 – 2008, WHO, UNICEF, UNFPA, World Bank; Milne F et al., BMJ 2005; Urassa DP et al., Acta obstet gynecol scand. 2006 2. Detection

32. Managing PE/E  Anticonvulsants—magnesium sulfate  Antihypertensives  Timed delivery  Clinical monitoring and vigilance Diazepam Lytic Cocktail Rectal Avertin x xx 3. Management

33. Magnesium Sulfate: Treat Eclampsia  Collaborative Eclampsia Trial,1991–1992, 27 centers in 9 countries, n =1680  Compared 3 most popular treatments  Magnesium sulfate  Diazepam  Phenytoin  Magnesium sulfate had a 52% and 67% lower recurrence of convulsions than diazepam and phenytoin respectively Source: The Eclampsia Trial Collaborative Group Lancet 1995 3. Management

34. Magnesium Sulfate: Treat Severe PE & Prevent Eclampsia  Magpie Trial, 2002, 10,000 women, 33 countries  Reduced the occurrence of eclampsia by 58%  Reduced maternal deaths by 46% (not significant)  No evidence of substantive harmful effects in the short-term  Increased flushing (side effect) by 19%  Increased risk of Cesarean section by 5% Sources: Magpie Trial Collaboration Group Lancet. 2002 3. Management

35. Magnesium Sulfate & Reduced Maternal Mortality from PE/E Magnesium Sulfate Use in Purulia, West Bengal, India, 2002–2006 3. Management

36. Preventing Recurrent Convulsions  Compared magnesium sulphate and diazepam  7 trials, 1441 women  Reduced:  Recurrence of convulsions  Maternal mortality  Apgar scores <7 at 1 and 5 minutes  Other reviews confirm magnesium sulfate better than phenytoin or lytic cocktail Source: Duley L, Henderson-Smart D. Cochrane Database Syst Rev. 2003 Magnesium sulfate saves more mothers’ lives than diazepam when given for eclamptic fits. For every 7 women treated with magnesium sulfate (vs diazepam), 1 case of recurrent convulsions prevented 3. Management

37. Magnesium Sulfate and the Neonate  Better outcomes for babies of mothers who received magnesium sulfate for eclampsia (than diazepam or phenytoin)  Greater vigor of the babies (5 minutes after birth)  Lower chances of a long hospital stay in an intensive care unit  Fewer neonatal admissions to a special care unit  Shorter duration of stay (in days) in the neonatal care unit  Fewer neonatal deaths Source: Duley et al., 2003a 3. Management

38. Immediate Treatment: Severe PE/E  Severe PE/E patients who received the loading dose before referral:  Reduced number of convulsions  Controlled convulsions  Shortened time to full consciousness  Reduced maternal mortality and stillbirths  Loading dose useful at home births and peripheral facilities Source: Rashida et al., 2004 Seizure to Treatment Interval 3. Management

39. Immediate Treatment: Eclampsia  The sooner treatment starts, the better the survival rates  Treatment is relatively simple if instituted immediately  Magnesium sulfate  Antihypertensive  Delivery  Delayed treatment especially beyond 2 hours requires intensive care for shock:  DIC, renal shutdown, respiratory failure, electrolyte disturbance, sepsis, pneumonia, multi organ failure  Even in best centers, mortality is high Ensure magnesium sulfate loading dose IM at the most peripheral healthcare facilities— including for homebirth. It maybe all that you need for safe transfer. 3. Management

40. Standard Magnesium Sulfate Regimens  IV: 4 g loading dose over 10 to 15 minutes followed by infusion of 1g/hour over 24 hours  IM: 4 g IV and 10 g IM as loading dose followed by 5g IM every four hours for 24 hours Source: Duley L, Matar HE, Almerie MQ, Hall DR. Cochrane Database Syst Rev. 2010 3. Management

41. Innovations for Low-resource Settings  Springfusor pump  Pre-packaged kits  Simplified regimens  Minimum effective dose  Alternative routes of administration (IV or IM)  Duration of therapy Source: Duley L, Matar HE, Almerie MQ, Hall DR. Cochrane Database Syst Rev. 2010 3. Management Springfusor® syringe infusion pump

42. Single Dose for Treatment of Eclampsia: Bangladesh  A randomized trial, 401 patients  Efficacy of loading dose vs. standard regime  Recurrent convulsion rate 4% vs 3.5%  Case fatality rate 4.5% vs 5%  Better outcomes for women receiving a loading dose at the community level before referral to a hospital (compared to those who received their loading dose in the hospital)  Single loading dose sufficient  Possible to treat—even at home 3. Management

43. Magnesium Sulfate: Challenges  No policies to promote use:  Lack of guidelines mandating the use  Not on national essential drugs list  No information: if in national guidelines, not widely disseminated or mandatory  Available only at highest-level facilities because of perceived need for close monitoring  Health workers are commonly not trained or authorized to administer magnesium sulfate; lack confidence and knowledge  Rare and inexpensive=no incentive for drug companies  Inconvenient packs of 500–1000 mL; only 250 mL needed Source: Reducing eclampsia-related deaths—a call to action, the Lancet, 2008 3. Management

44. PE/E Management: Antihypertensives  Reduce maternal risk without harming the fetus  Help extend the pregnancy to improve fetal maturity and outcomes.  Indicated when the diastolic pressure is >110 mm Hg  Aim to bring it to 90–100 mm Hg to prevent cerebral hemorrhage  No clear choice of drugs  Labetolol, hydralazine, and nifedipine currently widely recommended  Once severe PE or eclampsia is diagnosed, at least the first dose of anti-hypertensive medications prior to transfer 3. Management

45. Managing PE/E: Timed Delivery  Induction of labor  Associated with improved maternal outcome: Mild gestational hypertension >37 weeks gestation  WHO Guidelines Severe PE: Deliver <24 hours Eclamptic convulsions/fits: Deliver <12 hours  Expectant management with early onset severe PE  Gained a mean of 11 days gestation with improved perinatal and neonatal survival rates  Should not preclude timely delivery—the only definitive cure Sources: Steegers EA et al., Lancet. 2010; Sibai BM, Barton JR Am J Obstet Gynecol. 2007 3. Management

46. On the Horizon: 2003…2011? “The technologies identified 5 years ago continue to be the key issues”  Nutritional supplements to prevent PE/E  Antiplatelets to prevent PE/E  Methods for early detection of PE/E or elevated risk for PE/E  Scaling up use of magnesium sulfate for both prevention and treatment of eclampsia Source: Tsu and Coffey, BJOG, 2009 3. Management 2. Detection 1. Prevention