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
Hypertension complicates 5–7% of all pregnancies
Sources: American Society of Hypertension, 2009;
Source: American Society of Hypertension, 2009

7. TYPICAL SIGNS AND SYMPTOMS
PROBABLE DIAGNOSIS
TYPICAL 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
Eclampsia
Pre-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
69 ( ) 20 40 60 80
100
Doppler combinations of FVW
Doppler resistance index
Doppler pulsatility index
Doppler other ratios
Doppler bilateral notching
Doppler any/unilateral notching
SDS Page proteinuria
100 ( )
Kallikreinuria
Microalbumin/creatinine ratio
Microalbuminuria
Total albuminuria
Total proteinuria
Urinary calcium/creatinine ratio
Urinary calcium excretion
Serum uric acid
Oestriol
HCG
Foetal DNA
Fibronectin total
Fibronectin cellular
AFP
BMI<19.8
BMI>24.2
BMI>29
BMI>34 25 29 8 21 19 1 2 4 6 5 3 16 12 7 9
22896
7982
14697
2619
29331
14345
153
307
1422
190 88
2228
1345
705
514
26811
72732
351
373
135
137097
152720
440214
410823
16200
11 (8 - 16)
41 ( )
23 ( )
18 ( )
64 ( )
66 ( )
48 ( )
55 ( )
48 ( )
63 ( )
19 ( )
62 ( )
70 ( )
35 ( )
50 ( )
57 ( )
36 ( )
26 (9 - 56)
24 ( )
50 ( )
65 ( )
50 ( )
9 (5 - 16)
83 ( )
80 ( )
75 ( )
88 ( )
93 ( )
86 ( )
80 ( )
87 ( )
92 ( )
82 ( )
75 ( )
68 ( )
89 ( )
80 ( )
74 ( )
83 ( )
82 ( )
89 ( )
94 ( )
96 ( )
96 ( )
98 ( )
Sensitivity
Specificity
Sn (95% CI)
Test
No of studies
No of women
Sp (95% CI)
Source: Meads CA et al. Methods of prediction and prevention of pre-eclampsia: systematic reviews of accuracy and effectiveness literature with economic modelling. Health Technology Assessment 2008; Vol. 12: No. 6.
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.
Risk factors not very useful:
Primigravida are now about 50% of obstetric population
A significant proportion of PE occurs postpartum
No effective or affordable biochemical or biophysical predictor available

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

11. PE/E Prevention Prevention and prediction are difficult because:
3. Management
2. Detection
1. 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

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

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

14. Primary Prevention 1. Prevention Intervention Pregnancy outcome
Recommended?
Prevention of IUGR
Theoretically contributes to primary prevention of PE (and IUGR) in the next generation
Yes
Family planning
Potential to reduce pregnancies at risk for PE
Pre-conceptual prevention and/or treatment of obesity
Potential to reduce PE
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
Heparin or low-molecular weight heparin 
Reduces PE in women with renal disease and thrombophilia
Anti-oxidant vitamins (C, E) 
Reduced PE in one trial, but not all trials
Protein or salt restriction
No effect No
Source: Prevention and management of pre-eclampsia and eclampsia reference manual, MCHIP, 2011

15. Primary Prevention of PE
0.01
0.1
0.2
0.5 1 2 5 10
Progesterone
0.21 (0.03, 1.77)
Nitric oxide donors and precursors
0.83 (0.49, 1.41)
Diuretics
0.68 (0.45, 1.03)
Antiplatelets
0.81 (0.75, 0.88)
Antihypertensives v none
0.99 (0.84, 1.18)
Marine oils
0.86 (0.59, 1.27)
Magnesium
0.87 (0.57, 1.32)
Garlic
0.78 (0.31, 1.93)
Energy/protein restriction
1.13 (0.59, 2.18)
Isocaloric balanced protein supplementation
1.00 (0.57, 1.75)
Balanced protein/energy intake
1.20 (0.77, 1.89)
Nutritional advice
0.98 (0.42, 1.88)
Calcium
0.48 (0.33, 0.69)
Antioxidants
0.61 (0.50, 0.75)
Altered dietary salt
1.11 (0.46, 2.66)
Rest alone for normal BP
0.05 (0.00, 0.83)
Exercise
0.31 (0.01, 7.09)
Bed rest for high BP
0.98 (0.80, 1.20)
Ambulatory BP 4 43 19 3 12 7
128
170
1391
33439
2402
1683
474
100
284
782
512
136
15206
6082
631 32 45
228
Relative Risk (95% Confidence Interval)
RR (95% CI)
Intervention
No of RCTs
No of women

16. Potential Impact of Calcium
1. Prevention
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

17. Preventing PE: Calcium
1. Prevention
Preventing PE: Calcium
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
Study
Hofmeyr et al., 2010 (Cochrane)
Design
13 studies, most used 1.5–2g of calcium/day
Majority included: low-risk (n=15,143); low dietary calcium intake (n=10,678)
Results
Reduced 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
Garlic, exercise , acupunture

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

19. Preventing PE: Calcium, WHO Reproductive Health Library, 2010
1. Prevention
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

20. Daily Calcium Intake 1. Prevention
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

21. Calcium & Iron Evidence (2005) Implications (2010)
1. Prevention
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.”
Photo credit: Paul Geor,
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

22. Cost-effectiveness to Predict and Prevent PE: Test & Treatment
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 £ 50
100
150
200
250
300
350
400
450
500
0.94
0.95
0.96
0.97
0.98
0.99
Effectiveness (proportion free of pre-eclampsia
Cost per woman
( UK £ 2005)
No test, calcium to all
Source: Meads et al., Health Technol Assess. 2008

23. Preventing PE: Low-Dose Aspirin
1. Prevention
Preventing PE: Low-Dose Aspirin
Daily prevents PE and IUGR for women at moderate or high-risk for PE
Greater benefits if started earlier in pregnancy (<16 weeks)
Study
Duley L et al., 2007 (Cochrane)
Bujold et al., 2010
Design
59 trials, n = 37,560 women, antiplatelet agents use
34 trials of women “at risk”: 12 at ≤16 weeks gestation; 22 after
Results
Reduced 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
Garlic, exercise , acupunture

24. Preventing PE: Vitamins C & E
1. Prevention
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

25. Preventing PE: Vitamin D
1. Prevention
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

26. Detecting Pre-Eclampsia
2. Detection
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
Describe why tests are pricey
Source: Conde-Agudelo A, Villar J, Lindheimer M. Obstet Gynecol. 2004

27. Detecting Pre-Eclampsia: Measuring BP
2. Detection
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
Describe why tests are pricey

28. Detecting Pre-Eclampsia: Proteinuria
2. Detection
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
Describe why tests are pricey
Source: Thornton CE et al., Clin Exp Pharmacol Physiol 2010; Thangaratinam S et al., BMC Med. 2009

29. Dipstick Urine Testing for Protein
2. Detection
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
Photo credit: Daniel Antonaccio
Source: Steegers EA et al., Lancet. 2010; Gangaram R, Ojwang PJ, Moodley J, Maharaj D. Hypertens Pregnancy. 2005

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

31. ANC: PE Screening Opportunity
2. Detection
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

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

33. Magnesium Sulfate: Treat Eclampsia
3. Management
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

34. Magnesium Sulfate: Treat Severe PE & Prevent Eclampsia
3. Management
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

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

36. Preventing Recurrent Convulsions
3. Management
Preventing Recurrent Convulsions
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
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

37. Magnesium Sulfate and the Neonate
3. Management
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

38. Immediate Treatment: Severe PE/E
3. Management
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
Seizure to Treatment Interval
Source: Rashida et al., 2004

39. Immediate Treatment: Eclampsia
3. Management
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.
Implications Magnesium sulphate must be available at homebirth

40. Standard Magnesium Sulfate Regimens
3. Management
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

41. Innovations for Low-resource Settings
3. Management
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
Springfusor® syringe infusion pump
Source: Duley L, Matar HE, Almerie MQ, Hall DR. Cochrane Database Syst Rev. 2010

42. Single Dose for Treatment of Eclampsia: Bangladesh
3. Management
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

43. Magnesium Sulfate: Challenges
3. Management
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

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

45. Managing PE/E: Timed Delivery
3. Management
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

46. On the Horizon: 2003…2011?
3. Management
2. Detection
1. Prevention
“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