Screening and early detection of Preeclampsia

1. Screening and early detection of Preeclampsia Harshad Sanghvi Vice-President & Medical Director Jhpiego Africa meeting: Interventions For Impact in EONC Addis Ababa, 22 February 2011

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

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 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

5. Test No of studies No of women Sn (95% CI) Sp (95% CI) 2 16200 18 (15 - 21) 93 (87 - 97) BMI>34 23 (15 - 33) 88 (80 - 93) 8 410823 BMI>29 41 (29 - 53) 75 (62 - 84) 9 440214 BMI>24.2 11 (8 - 16) 80 (73 - 86) 7 152720 BMI<19.8 9 (5 - 16) 96 (94 - 98) 12 137097 AFP 2 135 50 (30 - 70) 96 (79 - 99) Fibronectin cellular 3 373 65 (42 - 83) 94 (86 - 98) Fibronectin total 50 (31 - 69) 88 (80 - 93) 3 351 Foetal DNA 24 (16 - 35) 89 (86 - 92) 16 72732 HCG 26 (9 - 56) 82 (61 - 93) 3 26811 Oestriol 36 (22 - 53) 83 (73 - 90) 5 514 Serum uric acid 4 705 Urinary calcium excretion 57 (24 - 84) 74 (69 - 79) 6 1345 Urinary calcium/creatinine ratio 50 (36 - 64) 80 (66 - 89) 35 (13 - 68) 89 (79 - 94) 4 2228 Total proteinuria 70 (45 - 87) 89 (79 - 94) 2 88 Total albuminuria 62 (23 - 90) 68 (57 - 77) 2 190 Microalbuminuria 19 (12 - 28) 75 (73 - 77) 1 1422 Microalbumin/creatinine ratio 83 (52 - 98) 98 (98 - 100) 1 307 Kallikreinuria 1 153 SDS Page proteinuria 100 (88 - 100) 69 (60 - 77) 63 (51 - 74) 82 (74 - 87) 19 14345 Doppler any/unilateral notching 48 (34 - 62) 92 (87 - 95) 21 29331 Doppler bilateral notching 55 (37 - 72) 80 (73 - 86) 8 2619 Doppler other ratios 48 (29 - 69) 87 (75 - 94) 8 14697 Doppler pulsatility index 66 (54 - 76) 80 (74 - 85) 29 7982 Doppler resistance index 64 (54 - 74) 86 (82 - 90) 25 22896 Doppler combinations of FVW Prediction of preeclampsia 0 20 40 60 80 100 0 20 40 60 80 100 Sensitivity Specificity Methods of prediction and prevention of pre-eclampsia: systematic reviews of accuracy and effectiveness literature with economic modelling CA Meads, et al 2008

6. Intervention No of RCTs No of women RR (95% CI) Ambulatory BP 0 0 Bed rest for high BP 1 228 0.98 (0.80, 1.20) Exercise 2 45 0.31 (0.01, 7.09) Rest alone for normal BP 1 32 0.05 (0.00, 0.83) Altered dietary salt 2 631 1.11 (0.46, 2.66) Antioxidants 7 6082 0.61 (0.50, 0.75) Calcium 12 15206 0.48 (0.33, 0.69) Nutritional advice 1 136 0.98 (0.42, 1.88) Balanced protein/energy intake 3 512 1.20 (0.77, 1.89) Isocaloric balanced protein supplementation 1 782 1.00 (0.57, 1.75) Energy/protein restriction 2 284 1.13 (0.59, 2.18) Garlic 1 100 0.78 (0.31, 1.93) Magnesium 2 474 0.87 (0.57, 1.32) Marine oils 4 1683 0.86 (0.59, 1.27) Antihypertensives v none 19 2402 0.99 (0.84, 1.18) Antiplatelets 43 33439 0.81 (0.75, 0.88) Diuretics 4 1391 0.68 (0.45, 1.03) Nitric oxide donors and precursors 4 170 0.83 (0.49, 1.41) Progesterone 1 128 0.21 (0.03, 1.77) Primary Prevention Of PE 0.01 0.1 0.2 0.5 1 2 5 10 Relative Risk (95% Confidence Interval)

7. Comparing Cost and Effectiveness of Interventions for Preventing PE 500 450 400 350 300 Cost per woman ( UK £ 2005) 250 200 150 100 No test, calcium to all 50 0 0.94 0.95 0.96 0.97 0.98 0.99 Effectiveness (proportion free of pre - eclampsia) Good Question: Are calcium supplements out of reach for low resource settings

8. Coverage of prenatal care: selected countries* *Macro International, 2011. Measure DHS. Data representative of women who gave birth in the 5 years prior to the survey.

9. Massive unmet need for early detection of PE Source DHS

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

11. 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.

12. 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.

13. 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 Sanghvi, Lee, Jayaram, Trachtenberg, Acharya

14. 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

17. Diagnostic Platform 17

18. 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 Sanghvi, Crocker, Mongale

19. Performance standards: Severe PE/E Example of Verification criteria: Administer 4 gm of Magnesium Sulphate IV over 5 minutes ( 20 ml of 20% Magnesium Sulphate)

20. 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

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