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 2

3. 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 19982009 MMR 539247 PPH 37%19% Eclampsia14%21% Source: Nepal maternal mortality study 2008-9

4. 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. 69 (60 - 77) 020406080100 Doppler combinations of FVW Doppler resistance index Doppler pulsatility index Doppler other ratios Doppler bilateral notching Doppler any/unilateral notching SDS Page proteinuria100 (88 - 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 020406080100 BMI>34 25 29 8 8 21 19 1 1 1 2 2 4 6 4 5 3 16 3 3 2 12 7 9 8 2 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 (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) 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) SensitivitySpecificity Sn (95% CI)TestNo of studiesNo of womenSp (95% CI) Prediction of preeclampsia Methods of prediction and prevention of pre-eclampsia: systematic reviews of accuracy and effectiveness literature with economic modelling CA Meads, et al 2008

6. 0.010.10.20.512510 Progesterone0.21 (0.03, 1.77) Nitric oxide donors and precursors0.83 (0.49, 1.41) Diuretics0.68 (0.45, 1.03) Antiplatelets0.81 (0.75, 0.88) Antihypertensives v none0.99 (0.84, 1.18) Marine oils0.86 (0.59, 1.27) Magnesium0.87 (0.57, 1.32) Garlic0.78 (0.31, 1.93) Energy/protein restriction1.13 (0.59, 2.18) Isocaloric balanced protein supplementation1.00 (0.57, 1.75) Balanced protein/energy intake1.20 (0.77, 1.89) Nutritional advice0.98 (0.42, 1.88) Calcium0.48 (0.33, 0.69) Antioxidants0.61 (0.50, 0.75) Altered dietary salt1.11 (0.46, 2.66) Rest alone for normal BP0.05 (0.00, 0.83) Exercise0.31 (0.01, 7.09) Bed rest for high BP0.98 (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)InterventionNo of RCTsNo of women Primary Prevention Of PE

7. 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) Cost per woman ( UK £ 2005) 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

8. Coverage of prenatal care: selected countries* At least 1 visit (%) 4+ visits (%) Kenya (2008-09) 9147 Tanzania (2004-05) 9762 Uganda (2006) 9547 Zambia (2007) 9760 Zimbabwe (2005-06) 9471 Malawi (2004) 9558 Nigeria (2008) 5545 Ethiopia (2005) 2812 Mozambique (2003) 8453 Ghana (2008) 9478 Rwanda (2007-08) 9624 Senegal (2005) 9140 8 *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 Country% Unmet need for BP Check % Unmet need for Proteinuria Check Bangladesh53.1%70.5% Bolivia24.5%50.9% DRC38.8%57.8% India52.5%56.8% Indonesia13.9%63.0% Kenya22.8%38.9% Malawi28.6%81.3% Mozambique48.7%73.9% Nepal43.8%77.7% Zimbabwe14.0%39.8% 9

10. 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. 11

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 13 Sanghvi, Lee, Jayaram, Trachtenberg, Acharya

14. Current Prototype

15. 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. 16 Extremely Affordable Point of Care Diagnostics: Prototype Protein Test Sanghvi, Crocker, Mongale

17. Diagnostic Platform Reagent Solution PurposeChemical Protein IndicatorTetrabromophenol Blue Acid BufferCitric Acid, Sodium Citrate Liquid VehicleIsopropyl Alcohol, DI H 2 O 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 18 Sanghvi, Crocker, Mongale

19. Performance standards: Severe PE/E Performance standardVerification 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 actions12 19 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 20 Baseline2 months 4 months % facilities meeting standards 14%36%59% % facilities where no standard met 27%0% Average score26%60%63% facility% reaching standard SBA training sites 87% Govt Hosp 50% Private hospitals 17% Med school 38% PHCC33%

21. Achieving maximum impact of reducing mortality from PE: From Household to Hospital Predict preeclampsiaRisk 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, Antihypertensives Urgent delivery 21