Screening and early detection of Preeclampsia

Harshad SanghviVice-President & Medical Director

Jhpiego

Africa meeting: Interventions For Impact in EONCAddis Ababa, 22 February 2011

Definitions

Preeclampsia: Hypertension, proteinuria in pregnancy Mild: Diastolic 90-100, proteinuria1-2g/l Severe: diastolic 110+, proteinuria 3g/l Eclampsia: +convulsions

2

3

Why an additional Focus on PE/E

Mortality associated with PE/E shows little decline in more than 75% of low resource countries

Between 7-15% of pregnant women develop preeclampsia (high BP and proteinuria)

Approximately 1-2% develop Eclampsia

Contribute between 8-25% of maternal mortality

Increased risk of perinatal mortality: PE : RR 1.7-3.7 E : RR 2.9-13.7

Nepal Maternal Mortality Study 1998 & 2009

1998 2009

MMR 539 247

PPH 37% 19%

Eclampsia 14% 21%

Source: Nepal maternal mortality study 2008-9

4

Prediction of Preeclampsia

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

Implication: All pregnant women potentially at risk need prevention or early detection of PE

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)

Prediction of preeclampsiaMethods of prediction and prevention of pre-eclampsia: systematic reviews ofaccuracy and effectiveness literature with economic modelling CA Meads, et al 2008

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

7

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)

Co

st p

er w

om

an(

UK

£ 2

005)

No test, calcium to all

Comparing Cost and Effectiveness of Interventions for Preventing PE

Good Question: Are calcium supplements out of reach for low resource settings

Coverage of prenatal care: selected countries*

At least 1 visit (%) 4+ visits (%)

Kenya (2008-09) 91 47

Tanzania (2004-05) 97 62

Uganda (2006) 95 47

Zambia (2007) 97 60

Zimbabwe (2005-06) 94 71

Malawi (2004) 95 58

Nigeria (2008) 55 45

Ethiopia (2005) 28 12

Mozambique (2003) 84 53

Ghana (2008) 94 78

Rwanda (2007-08) 96 24

Senegal (2005) 91 40

8

*Macro International, 2011. Measure DHS. Data representative of women who gave birth in the 5 years prior to the survey.

Massive unmet need for early detection of PE Source DHS

Country % Unmet need for BP Check

% Unmet need for Proteinuria Check

Bangladesh 53.1% 70.5%

Bolivia 24.5% 50.9%

DRC 38.8% 57.8%

India 52.5% 56.8%

Indonesia 13.9% 63.0%

Kenya 22.8% 38.9%

Malawi 28.6% 81.3%

Mozambique 48.7% 73.9%

Nepal 43.8% 77.7%

Zimbabwe 14.0% 39.8%

9

10

Detecting Preeclampsia

Measuring BP: Significant training needed to do BP well Robust and maintained equipment

• Aneroid BP machines require frequent recalibration

Currently completely missing about 50% women who do not receive antenatal care,

Also missing an additional 15-30% who attend ANC but do not have BP taken

Assessment of BP technology

The absence of accurate, easily-obtainable, inexpensive devices for blood pressure measurement;

The frequent marketing of non-validated blood pressure measuring devices;

The relatively high cost of blood pressure devices given the limited resources available;

Limited awareness of the problems associated with conventional blood pressure measurement techniques;

A general lack of trained manpower and limited training of personnel.

11

How can we detect all the Preeclampsia before it becomes life threatening

One approach: Take testing for hypertension and proteinuria to women in their homes rather than only depending on them reaching facilities

Seeking simple, inexpensive and effective solutions that reach all pregnant women

• Reliably detect diastolic BP > 90mmHg• Low cost, low power, easy to manufacture ($5)• For use by semi literate community workers• Culturally compatible e.g. women in deeply conservative

societies will not expose their upper arm for a typical blood pressure cuff.

• Robust in wide temperature ranges and in extreme dry and wet areas.

Solution

Modular Components• Manual inflatable pressure cuff applied to the wrist to

restrict blood flow. • Self deflating cuff with digital pressure sensor to

provide feedback to a microcontroller. This automates hypertension diagnosis set at 90 diastolic for community use devices

• Hand Cranked generator with a super capacitor for power as well as batteries.

• Binary LED panel to indicate sufficient power, inflation, and color codes for semi-literate volunteer to interpret.

Procedure:Apply Cuff, Crank till Green LED light, inflate till LED yellow LED, wait as cuff automatically deflates, Red light and audible signal indicates hypertension

13

Sanghvi, Lee, Jayaram, Trachtenberg, Acharya

Current Prototype

15

Secondary Prevention: Detecting Pre-eclampsia

Measuring Urine Protein Urine dipstick tests quite pricy:

Test reagent is not what makes it pricy.

Boiling not feasible in high-volume sites, not suitable for home testing

Alternatives e.g., PATHstrips developed for clinic/lab

setting dependant on central manufacture of

test strips

16

Extremely Affordable Point of Care Diagnostics:Prototype Protein Test

Sanghvi, Crocker, Mongale

Diagnostic Platform

Reagent Solution

Purpose Chemical

Protein Indicator Tetrabromophenol Blue

Acid Buffer Citric Acid, Sodium Citrate

Liquid Vehicle Isopropyl Alcohol, DI H2O

17

Solution

Reagent modified to yield sharp color change when there is 0.7g/l protein:

The test strip prepared by marking an end of a piece of filter paper with the reagent.

Use: Pregnant woman who is instructed to void urine on the test area of the strip and report if a color change from yellow to blue occurs.

Blue Color indicates pathological proteinuria

18

Sanghvi, Crocker, Mongale

Performance standards: Severe PE/E

Performance standard Verification n criteria

The provider correctly describes signs and symptoms of Severe PE and E

7

The provider describes correct management of Severe PE and E

12

The provider correctly describes follow up actions 12

19

Example of Verification criteria: Administer 4 gm of Magnesium Sulphate IV over 5 minutes ( 20 ml of 20% Magnesium Sulphate)

SBMR: Nepal Experience in improving quality of PEE care

Intervention: 1 day on site whole facility orientation by NESOG

Review of standards, practice of skills Baseline assessment, gap analysis, action plan Re-assess at 2, 4 months

20

Baseline

2 months

4 months

% facilities meeting standards

14% 36% 59%

% facilities where no standard met

27% 0% 0%

Average score 26% 60% 63%

facility % reaching standard

SBA training sites

87%

Govt Hosp

50%

Private hospitals

17%

Med school

38%

PHCC 33%

Achieving maximum impact of reducing mortality from PE: From Household to Hospital

Predict preeclampsia

•Risk factors not very useful: Primigravida are now about 50% of obstetric population and a significant proportion of PE occurs postpartum•No effective or affordable biochemical or biophysical predictor available

Primary prevention √

Calcium, √Aspirin

Secondary Prevention•Detect Hypertension•Detect Proteinuria•Timely delivery

•BP: Not available for women not reaching prenatal care (50%) : Missing an additional 15-30% who attend ANC but do not have BP taken•Protein test offered to less than 20%( SPA, 6 countries)

Tertiary Prevention√

Magnesium Sulphate, AntihypertensivesUrgent delivery 21