PROTECT-Africa: Biomarker Validation for Preeclampsia Triage

PROgnostic Testing to Enhance Clinical Triage of Preeclampsia in Africa (PROTECT-Africa): Biomarker Validation for Timely Intervention in Hypertensive Disorders of Pregnancy

Preeclampsia is a serious high blood pressure condition that can develop during pregnancy. It is one of the leading causes of death and illness for mothers and babies in Africa. Doctors find it hard to tell which women with high blood pressure in pregnancy will go on to become seriously ill, because the tests available today are not accurate enough and are often not available in local clinics.

Two proteins in the blood, called sFlt-1 and PlGF, may help predict who is at risk. The balance between them (the sFlt-1/PlGF ratio) has been useful in other parts of the world, but it has not been properly tested in African women. New rapid tests can measure these proteins at the clinic in minutes, using a small blood or urine sample, without a large laboratory.

This study will look at how well these tests work in African women. Researchers will do two things. First, they will work out the result levels that best predict whether a woman will or will not develop severe preeclampsia in the following weeks, using a well-established laboratory test as the standard for comparison. Second, they will check how closely the rapid clinic tests match that laboratory standard. The study will also look at what these tests cost and whether using them could save money for families and health services.

The study will include about 1,106 pregnant women at large maternity hospitals in Zimbabwe, Rwanda and Tanzania. Women may join if they are between 23 and 37 weeks pregnant with one baby and their care team suspects preeclampsia, for example because of raised blood pressure, protein in the urine, or symptoms such as headache, swelling or vision changes.

Taking part does not change a woman's medical care in any way. Women will attend their usual pregnancy visits, plus study visits at 1 week, 2 weeks and 4 weeks, at delivery, and about 4 weeks after birth. At these visits the study team will record health information and collect blood and urine samples. About 15 ml of blood (around one tablespoon) is collected at each visit.

The test results are not used to make any decisions about a woman's treatment. Doctors and nurses caring for her will not see them, and neither will she. All treatment decisions stay with her own healthcare team. Routine tests such as blood counts and liver tests are shared with her care team as usual.

The results of this study may help clinics in Africa spot dangerous preeclampsia earlier, so mothers and babies can be treated in time.

Hypertensive disorders of pregnancy account for approximately 16 to 22 percent of maternal deaths in Africa, and the incidence of preeclampsia is estimated to be several times higher in low- and middle-income countries than in high-income settings. Angiogenic biomarkers, particularly the ratio of soluble fms-like tyrosine kinase-1 (sFlt-1) to placental growth factor (PlGF), have demonstrated strong negative predictive value for short-term progression to preeclampsia in European and Asian cohorts, where a ratio cut-off of 38 has been validated. These cohorts did not include African populations. Differences in baseline angiogenic profiles and in the prevalence of comorbidities such as anaemia and infection may affect biomarker performance, so population-specific thresholds are required before these tools can be relied upon locally.

The study is organised in two parts using a single enrolled population. Part A establishes and then confirms sFlt-1/PlGF ratio thresholds on the Roche Elecsys reference platform, using a derivation cohort of 553 participants followed by an independent validation cohort of 553 participants. Part B evaluates rapid point-of-care platforms against those confirmed reference thresholds in the same 1,106 participants. The platforms under evaluation include quantitative serum or plasma immunoassays and a qualitative urine-based test that detects misfolded proteins. Stored samples may be used for additional platforms as they become commercially available.

Blinding is maintained at all sites: neither participants nor investigators receive biomarker results. Serum samples are batch-processed after collection, and urine tests requiring immediate analysis are performed without results being released to clinical teams. Because the reference and investigational results cannot influence management, the diagnostic accuracy estimates reflect the natural course of disease under routine care. Routine safety laboratory results, including full blood count and liver function tests, are returned to treating clinicians, since these are inconsistently available at the participating sites and support standard care.

Participants are grouped for analysis by the timing of diagnosis relative to the baseline visit: within one week, more than one week to four weeks, and beyond four weeks through two weeks postpartum. Those who develop none of the study conditions through four weeks postpartum form the comparator group. A within-trial economic evaluation runs alongside the clinical analysis. It uses a decision-analytic model from a societal perspective, capturing both health system and household costs, with short-term and five-year time horizons. Cost and volume data are collected from between three and seven purposively sampled health workers at participating facilities, who are not part of the trial population.

Inclusion Criteria:

• Gestational age between 23 weeks 0 days and 36 weeks 6 days, established by ultrasound performed at 22 weeks of gestation or earlier Singleton pregnancy Suspicion of a clinical diagnosis of preeclampsia based on one or more of the following: new onset of elevated blood pressure (systolic ≥130 mmHg or diastolic ≥80 mmHg); aggravation of pre-existing hypertension; new onset of protein in urine; aggravation of pre-existing proteinuria; or one or more other reasons for clinical suspicion of preeclampsia Other reasons for clinical suspicion include preeclampsia-related symptoms (epigastric pain, excessive oedema or severe swelling of the face, hands or feet, headache, visual disturbances, or sudden weight gain greater than 1 kg per week in the third trimester) or preeclampsia-related findings (low platelets, elevated liver transaminases, suspected intrauterine growth restriction, or abnormal uterine perfusion on Doppler sonography with mean pulsatility index above the 95th percentile in the second trimester and/or bilateral uterine artery notching, where available) Not currently enrolled in any other study or receiving an investigational medicinal product Able to provide informed consent

Exclusion Criteria:

• Multiple pregnancy (for example twins or triplets) Proteinuria 2+ or greater on dipstick AND elevated blood pressure (systolic ≥140 mmHg and/or diastolic ≥90 mmHg, reproducible on two occasions) Proteinuria 2+ or greater on dipstick and current antihypertensive treatment Confirmed diagnosis of HELLP syndrome No verified or documented ultrasound scan performed prior to 22 weeks of gestation to establish gestational age