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
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
5
Sn (95 CI)
Test
No of studies
No of women
Sp (95 CI)
BMIgt34
2
16200
18 (15 - 21)
93 (87 - 97)
BMIgt29
8
410823
23 (15 - 33)
88 (80 - 93)
41 (29 - 53)
75 (62 - 84)
BMIgt24.2
9
440214
BMIlt19.8
7
152720
11 (8 - 16)
80 (73 - 86)
9 (5 - 16)
96 (94 - 98)
AFP
12
137097
2
135
50 (30 - 70)
96 (79 - 99)
Fibronectin cellular
Fibronectin total
3
373
65 (42 - 83)
94 (86 - 98)
Foetal DNA
3
351
50 (31 - 69)
88 (80 - 93)
HCG
16
72732
24 (16 - 35)
89 (86 - 92)
Oestriol
3
26811
26 (9 - 56)
82 (61 - 93)
36 (22 - 53)
83 (73 - 90)
Serum uric acid
5
514
4
705
Urinary calcium excretion
57 (24 - 84)
74 (69 - 79)
Urinary calcium/creatinine ratio
6
1345
50 (36 - 64)
80 (66 - 89)
Total proteinuria
4
2228
35 (13 - 68)
89 (79 - 94)
Total albuminuria
2
88
70 (45 - 87)
89 (79 - 94)
Microalbuminuria
2
190
62 (23 - 90)
68 (57 - 77)
19 (12 - 28)
75 (73 - 77)
Microalbumin/creatinine ratio
1
1422
Kallikreinuria
1
307
83 (52 - 98)
98 (98 - 100)
69 (60 - 77)
SDS Page proteinuria
100 (88 - 100)
1
153
63 (51 - 74)
82 (74 - 87)
Doppler any/unilateral notching
19
14345
48 (34 - 62)
92 (87 - 95)
Doppler bilateral notching
21
29331
55 (37 - 72)
80 (73 - 86)
Doppler other ratios
8
2619
48 (29 - 69)
87 (75 - 94)
Doppler pulsatility index
8
14697
66 (54 - 76)
80 (74 - 85)
Doppler resistance index
29
7982
64 (54 - 74)
86 (82 - 90)
Doppler combinations of FVW
25
22896
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
RR (95 CI)
Intervention
No of RCTs
No of women
Ambulatory BP
0
0
Bed rest for high BP
0.98 (0.80, 1.20)
1
228
Exercise
0.31 (0.01, 7.09)
2
45
Rest alone for normal BP
0.05 (0.00, 0.83)
1
32
Altered dietary salt
1.11 (0.46, 2.66)
2
631
Antioxidants
0.61 (0.50, 0.75)
7
6082
Calcium
0.48 (0.33, 0.69)
12
15206
Nutritional advice
0.98 (0.42, 1.88)
1
136
Balanced protein/energy intake
1.20 (0.77, 1.89)
3
512
Isocaloric balanced protein supplementation
1.00 (0.57, 1.75)
1
782
Energy/protein restriction
1.13 (0.59, 2.18)
2
284
Garlic
0.78 (0.31, 1.93)
1
100
Magnesium
0.87 (0.57, 1.32)
2
474
Marine oils
0.86 (0.59, 1.27)
4
1683
Antihypertensives v none
0.99 (0.84, 1.18)
19
2402
Antiplatelets
0.81 (0.75, 0.88)
43
33439
Diuretics
0.68 (0.45, 1.03)
4
1391
Nitric oxide donors and precursors
0.83 (0.49, 1.41)
4
170
Progesterone
0.21 (0.03, 1.77)
1
128
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
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
Macro International, 2011. Measure DHS. Data
representative of women who gave birth in the 5
years prior to the survey.
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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
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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

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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.

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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 gt 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.

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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
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Current Prototype
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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
DiagnosticsPrototype Protein Test
Sanghvi, Crocker, Mongale
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Diagnostic Platform
Reagent Solution Reagent Solution
Purpose Chemical
Protein Indicator Tetrabromophenol Blue
Acid Buffer Citric Acid, Sodium Citrate
Liquid Vehicle Isopropyl Alcohol, DI H2O
17
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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
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
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

facility reaching standard
SBA training sites 87
Govt Hosp 50
Private hospitals 17
Med school 38
PHCC 33
Baseline 2 months 4 months
facilities meeting standards 14 36 59
facilities where no standard met 27 0 0
Average score 26 60 63
21
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 v Calcium, v 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 Preventionv Magnesium Sulphate, Antihypertensives Urgent delivery