November 30, 2016

Driving Transformative Innovation to Better Detect and Treat Pre-eclampsia/Eclampsia

Pre-eclampsia and eclampsia are among the leading causes of maternal death and disability worldwide. The risk of a pregnant woman dying from it in a developing country is approximately 300 times greater than in developed countries. The World Health Organization (WHO) estimates that 14 percent of maternal deaths in low-resource settings can be attributed to pre-eclampsia and eclampsia. These stark statistics drive PATH’s work to develop new technologies for detection and treatment, and ultimately improving maternal and newborn health outcomes in developing countries.

Because proteinuria remains a key diagnostic indicator for pre-eclampsia screening, along with other criteria such as high blood pressure, PATH, in collaboration with LifeAssay Diagnostics (Cape Town, South Africa) and clinical partners, is advancing an affordable protein/creatinine (Pr/Cr) dipstick spot urine test. The current standard of proteinuria measurement—24-hour urine collection—is often limited to tertiary centers of care due to expense and technical complexity. Conversely, the protein-only dipstick, which is widely used at the secondary and primary care levels, has poor sensitivity—between 51 and 68 percent—due to daily fluctuations in body hydration levels (Gangaram et al. 117–123). To address this gap, our new Pr/Cr provides ratiometric measurement of protein to creatinine, which adjusts for fluctuations due to urine dilution thereby improving accuracy. Using a threshold Pr/Cr ratio of 0.2, the results of this test have been shown to correlate well with results of 24-hour collection for detecting significant proteinuria (Morris et al. 345).

Our urine dipstick test will undergo extensive laboratory validation through 2017, including samples from an ongoing clinical study in Fort Hare, South Africa, led by Dr. Justus Hofmeyr of the University of Witwatersrand. In parallel, PATH will conduct environmental stability testing and usability evaluations of the refined prototype to ensure our simple, point-of-care dipstick has appropriate characteristics for widespread use in low-resource settings. Field use in clinical and operational studies could begin in 2018, pending funding, in order to facilitate commercial availability and public-sector procurement in 2020. The Pr/Cr strip test could serve as a near-term improvement over the commonly used protein-only dipstick in providing increased accuracy for proteinuria evaluation while maintaining a comparable low cost and simplicity to enable widespread use.

Making the diagnosis is only a part of the solution to preventing poor outcomes from pre-eclampsia and eclampsia in low resource settings. So, on the treatment front, PATH is workingto ensure the sustainable introduction of innovative solutions to increase access to magnesium sulfate (MgSO4).

The WHO recommends MgSO4 as the most effective anticonvulsant for the treatment of severe pre-eclampsia and eclampsia, yet this intervention is widely underused. The current regimen for MgSO4—requiring intravenous and/or intramuscular administration and complex calculation of dilution and dosing—is a key barrier to widespread use. Based on this knowledge, we identified four promising technology solutions that offer more user-friendly options for intravenous treatment: dilution bottle; dosing and dilution mobile application; ready-to-use MgSO4 loading- and maintenance-dose packs; and a reusable, electricity-free, and low-cost infusion [RELI] delivery system. In addition, we assessed a new drug delivery platform—rectally administered gel.

During product development, PATH rigorously assessed market viability, acceptability, and health system fit and made a no-go/go decision at each milestone to make sure we are advancing technology solutions that achieve great value in terms of money and health impact. Based on these considerations, development of three of the five technology solutions has been discontinued. User feedback about the dilution bottle from Ugandan and Ethiopian providers showed it did not significantly reduce steps currently required for dilution. Stakeholders from Uganda and Ethiopia, however, concurred about the convenience of having all necessary items in a single loading-dose or maintenance-dose pack; but their desire for just a 20percent MgSO4 solution was stronger. Global experts thought rectal formulations of MgSO4 to manage pre-eclampsia and eclampsia might make drug administration easier, but animal studies did not show significant bioavailability to warrant further studies.
A low-cost delivery system and a dosing and dilution mobile application could make it easier for health care professionals at lower-level facilities to administer MgSO4, thereby increasing proper use of this life-saving product. Positive user feedback from Kenyan providers suggested that the mobile app was easy to use and a valuable tool to support training and drug administration. Target use cases for the delivery of MgSO4 for obstetric emergencies using the RELI infusion pump delivery system are being explored. In addition, our health impact modeling suggests that much greater investment will be necessary to achieve an impact by implementing a more holistic approach. This includes creating better access to more accurate and user-friendly diagnostic tests to detect pre-eclampsia during pregnancy and strengthening referral systems to provide better-timed delivery of infants by skilled medical professionals. In this way, we will be able to save a greater number of women and newborns currently dying from this very treatable condition.

We look forward to continued development of these new technologies as an integral piece of the journey toward ending preventable deaths from pre-eclampsia and eclampsia around the world.

Works cited

1.) Gangaram R, Ojwang PJ, Moodley J, Maharaj D. The accuracy of urine dipsticks as a
screening test for proteinuria in hypertensive disorders of pregnancy. Hypertension in Pregnancy. 2005;24(2):117–123.
2.) Morris RK, Riley RD, Doug M, Deeks JJ, Kilby MD. Diagnostic accuracy of spot urinary
protein and albumin to creatinine ratios for detection of significant proteinuria or adverse pregnancy outcome in patients with suspected preeclampsia: systematic review and meta-analysis. British Medical Journal. 2012;345:e4342.


Patricia S. Coffey, Ph.D., MPH, Leader of Health Technologies for Women and Children Group at PATH