Understanding the Evidence:Preventing, Detecting &

ManagingPre-Eclampsia & Eclampsia

Objectives

1. Present evidence on pre-eclampsia and eclampsia (PE/E) interventions available for PE/E prevention, detection and management

2. Share emerging evidence and innovations on PE/E

Hypertensive Disorders among Global Maternal Mortality Causes

Eclampsia

Source: Khan et al., 2006; POPPHI, 2009

Declines in Maternal Deaths and Global MMR, 1990–2008

526,300

~440,000

342,900

422

~320

251

0

100

200

300

400

500

0

100000

200000

300000

400000

500000

600000

1980 1990 2008

Glo

bal M

MR

# m

ate

rnal death

s

# maternal deaths Global MMR

Source: Hogan et al., 2010

Declining MMR & Changing Causes of Maternal Deaths: Indonesia

Source: Indonesia Maternal Health Assessment, 2010

Hypertension in Pregnancy

Source: American Society of Hypertension, 2009

Hypertension complicates 5–7% of all pregnancies

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 hypertensionwomen 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 hypertensionTransient 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

69 (60 - 77)

0 20 40 60 80 100

Doppler combinations of FVWDoppler resistance indexDoppler pulsatility indexDoppler other ratiosDoppler bilateral notchingDoppler any/unilateral notchingSDS Page proteinuria 100 (88 - 100)KallikreinuriaMicroalbumin/creatinine ratioMicroalbuminuriaTotal albuminuriaTotal proteinuriaUrinary calcium/creatinine ratioUrinary calcium excretionSerum uric acidOestriolHCGFoetal DNAFibronectin totalFibronectin cellularAFPBMI<19.8BMI>24.2BMI>29

0 20 40 60 80 100

BMI>34

2529882119111224645316332127982

2289679821469726192933114345153307142219088

22281345705514

2681172732351373135

13709715272044021441082316200

11 (8 - 16)41 (29 - 53)23 (15 - 33)18 (15 - 21)

64 (54 - 74)66 (54 - 76)48 (29 - 69)55 (37 - 72)48 (34 - 62)63 (51 - 74)

19 (12 - 28)62 (23 - 90)70 (45 - 87)35 (13 - 68)50 (36 - 64)57 (24 - 84)36 (22 - 53)26 (9 - 56)24 (16 - 35)50 (31 - 69)65 (42 - 83)50 (30 - 70)9 (5 - 16)

83 (52 - 98)

80 (73 - 86) 75 (62 - 84)88 (80 - 93)93 (87 - 97)

86 (82 - 90)80 (74 - 85)87 (75 - 94)80 (73 - 86)92 (87 - 95)82 (74 - 87)

75 (73 - 77)68 (57 - 77)89 (79 - 94)89 (79 - 94)80 (66 - 89)74 (69 - 79)83 (73 - 90)82 (61 - 93)89 (86 - 92)88 (80 - 93)94 (86 - 98)96 (79 - 99)96 (94 - 98)

98 (98 - 100)

Sensitivity Specificity

Sn (95% CI)Test No of studies No of women Sp (95% CI)

Poor ability to Predict Pre-Eclampsia

Source: Meads CA, 2008.

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.

Levels of PE/E Prevention

LEVEL STRATEGY DEFINITION

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. Management2. Detection

1. Prevention

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 mortalitySource: Steegers EA et al., Lancet. 2010

3. Management2. Detection

1. Prevention

Taking Evidence to Scale

Seeking simple,

inexpensive and effective solutions that

reach all pregnant women

Photo credit: D

aniel Antonaccio

3. Management2. Detection

1. Prevention

Preventing Pre-Eclampsia

x x x

Almost 100 interventions tested in randomized trials

1. Prevention

Primary Prevention

Source: Prevention and management of pre-eclampsia and eclampsia reference manual, MCHIP, 2011

Intervention Pregnancy outcome Recommended?

Prevention of IUGRTheoretically contributes to primary prevention of PE (and IUGR) in the next generation

Yes

Family planning Potential to reduce pregnancies at risk for PE Yes

Pre-conceptual prevention and/or treatment of obesity

Potential to reduce PE Yes

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 reductionInsufficient evidence to

recommend*

Fish oil supplementation and other sources of fatty acids

No effect on low- or high-risk populationsInsufficient evidence to

recommend*

Heparin or low-molecular weight heparin 

Reduces PE in women with renal disease and thrombophilia

Insufficient evidence to recommend*

Anti-oxidant vitamins (C, E)  Reduced PE in one trial, but not all trials Insufficient evidence to recommend*

Protein or salt restriction No effect No

1. Prevention

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

1

4

4

43

19

4

2

1

2

1

3

1

12

7

2

1

2

1

0

128

170

1391

33439

2402

1683

474

100

284

782

512

136

15206

6082

631

32

45

228

0

Relative Risk (95% Confidence Interval)

RR (95% CI)Intervention No of RCTs No of women

Primary Prevention of PE

1. Prevention

Potential Impact ofCalcium

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

Preventing PE: Calcium

Study Hofmeyr et al., 2010 (Cochrane)

Design 13 studies, most used 1.5–2g of calcium/dayMajority 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 calciumPE (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

Cochrane 2009: Calcium & PE

Source: Hofmeyr GJ, Lawrie TA, Atallah AN, Duley L, Cochrane Database Syst Rev. 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

1. Prevention

Daily Calcium Intake

472

346 363

499 498

352

860

0

500

1000

1500

World DevelopedCountries

Developingcountries

Africa Latin America Near East Far East

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

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

cred

it: Paul G

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1. Prevention

0 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

Cos

t per

wom

an(

UK

£ 2

005)

No test, calcium to all

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 £

Preventing PE: Low-Dose Aspirin

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

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

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 deathsSource: Villar J et al., BJOG 2009

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 BMISource: Haugen M et al., Epidemiology 2009; Mulligan et al., Am J Obstet Gynecol. 2010

1. Prevention

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

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

cred

it: Sheena C

urrie

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

cred

it: Danie

l A

nto

naccio

Source: Thornton CE et al., Clin Exp Pharmacol Physiol 2010; Thangaratinam S et al., BMC Med. 2009

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

Source: Steegers EA et al., Lancet. 2010; Gangaram R, Ojwang PJ, Moodley J, Maharaj D. Hypertens Pregnancy. 2005

Photo credit: D

aniel Antonaccio

2. Detection

Components of ANC in Africa: BP Measurement and Urine Analysis

0

10

20

30

40

50

60

70

80

90

100

Blood pressure measured Urine sample taken Burkina Faso-2003 Ethiopia 2005 Ghana 2003 Kenya 2003 Liberia 2007Malawi 2004 Nigeria 2003 Rwanda 2005 Senegal 2005 Tanzania 2004Uganda 2006 Zambia 2007 Egypt 2005

Source: DHS, years as noted above

2. Detection

ANC: PE Screening Opportunity

64%

80%

0%

20%

40%

60%

80%

100%

1990 2008

At least 1 ANC Visit 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

Managing PE/E

Anticonvulsants—magnesium sulfate Antihypertensives Timed delivery Clinical monitoring and vigilance

Diazepam Lytic Cocktail Rectal Avertinx x x

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

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

3. Management

Magnesium Sulfate & ReducedMaternal Mortality from PE/E

19%

11%

8%

8% 8%

0%

20%

40%

60%

80%

100%

2002 2003 2004 2005 2006

% o

f M

agnesi

um

Sulfate

Use

d

0%

5%

10%

15%

20%

25%

Case

fata

lity

rate

% MgSO4 use Case fatality rate

Magnesium Sulfate Use in Purulia, West Bengal, India, 2002–2006

3. Management

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

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

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

5%

18%

77%

0

50

100

150

200

<6 hours 6-12 hours >12 hours

# m

ate

rnal death

s

0%

20%

40%

60%

80%

100%

% m

ort

alit

y

# maternal deaths % mortality

Source: Rashida et al., 2004

Seizure to Treatment Interval

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.

3. Management

Standard Magnesium Sulfate Regimens

1. IV: 4 g loading dose over 10 to 15 minutes followed by infusion of 1g/hour over 24 hours

2. IM: 4 g IV and 10 g IM as loading dose followed by5g IM every four hours for 24 hours

Source: Duley L, Matar HE, Almerie MQ, Hall DR. Cochrane Database Syst Rev. 2010

3. Management

Innovations for Low-resource Settings

1. Springfusor pump2. Pre-packaged kits3. 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

Single Dose for Treatment ofEclampsia: 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

Magnesium Sulfate: Challenges

1. No policies to promote use: Lack of guidelines mandating the use Not on national essential drugs list

2. No information: if in national guidelines, not widely disseminated or mandatory

3. Available only at highest-level facilities because of perceived need for close monitoring

4. Health workers are commonly not trained or authorized to administer magnesium sulfate; lack confidence and knowledge

5. Rare and inexpensive=no incentive for drug companies6. Inconvenient packs of 500–1000 mL; only 250 mL needed

Source: Reducing eclampsia-related deaths—a call to action, the Lancet, 2008

3. Management

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

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 cureSources: Steegers EA et al., Lancet. 2010; Sibai BM, Barton JR Am J Obstet Gynecol. 2007

3. Management

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 eclampsiaSource: Tsu and Coffey, BJOG, 2009

3. Management2. Detection

1. Prevention