Assessment of Point of CaRe creatinine testing In pregnancy: a feasibilty Cohort sTudy in Sierra Leone (APRICOT-SL)

Background: Every day, approximately 800 women die in pregnancy or childbirth. 99% of all of these deaths occur in the developing world. Women with limited access to healthcare are at the greatest risk. Many women die in pregnancy because problems are recognised too late. We have experience using a simple, accurate, handheld device (CRADLE VSA) to measure blood pressure and pulse with minimal skill. It uses a 'traffic light' system; the device tells the user if the blood pressure and pulse measurements are normal (green), worrying (amber) or severely abnormal (red) thus highlighting those who are unwell; however, further work is needed to identify women at greatest risk of death.

Our previous work in Africa showed that women with raised creatinine (a marker of kidney function) indicating acute kidney injury (AKI) were more likely to die. AKI is the sudden loss of kidney function and many cases are preventable. AKI leads to an increase in number of all pregnancy complications. Costs of AKI are high due to longer length of stay and extra treatment costs, especially if life-saving dialysis is needed. Longer term problems for the mother after AKI including chronic kidney disease, heart disease and pre-eclampsia (high blood pressure and urine protein) in future pregnancies. Early delivery of the baby, if the mother has AKI, also may lead to infant death and short and long term health problems including future chronic kidney disease.

Point of care testing of creatinine (POC-Cr) on finger prick blood is ideal for low income settings as blood taking and laboratory processing are not required. But POC-Cr testing in pregnancy to identify AKI at early stages, when treatments are likely to be successful, has not been performed. In the future we think that preventing AKI in pregnancy using POC-Cr in low income settings could lead to a reduction in death of mother and baby.

The aim of this study is to work out:
-How easy it is to do POC-Cr testing in pregnant or postpartum women: we will measure number of test failures, time taken for training and time taken for testing
-How accurate POC-Cr testing is compared to routine blood creatinine concentration testing
-Whether POC-Cr testing is acceptable to health care providers and women
-How many women are at risk of AKI and how many develop AKI
-How long it takes to complete a POC-Cr study in pregnancy and analyse the findings
-What increase in POC-Cr testing value from study entry and at 6-8 hours indicates the likely development of AKI at 24 hours?
-An estimate of the reduction in AKI rate if repeat POC-Cr testing and training to treat AKI is used

Method: We will recruit 2000 pregnant women with abnormal CRADLE VSA readings. All women will have:
i) POC-Cr at admission/at time of AKI event and again after 6-8 hours
ii) Blood creatinine test at admission/ at time of AKI event again at 24 hours

Run-in period (6 months): 1000 women - POC-Cr results will not be seen by the clinical team. We will compare POC-Cr results with blood laboratory tests. We will calculate the number of women who develop AKI from blood creatinine changes at 24 hours and work out what increase in POC-Cr measured at 6-8 hours is best at predicting which women get AKI at 24 hours.
Intervention period (6 months): 1000 pregnant women - POC-Cr results will be seen by the clinical team. The clinical team will also have training in AKI care and it will be recommended that this is given to women who have a rise POC-Cr measured at 6-8 hours which predicts that they might develop AKI at 24 hours.
We will compare how many women get AKI in the run-in period and in the intervention period.

Next steps: The results of this study will be used to design a large international study which will work out if POC-Cr testing can reduce the number of cases of AKI, maternal and neonatal death in low income countries.

The CRADLE VSA device 'traffic light' system identifies unwell pregnant women but more work is needed to prioritise care for those with highest mortality risk. Raised creatinine is an excellent predictor of maternal death. Point of care (POC) finger prick creatinine testing (POC-Cr) is ideal for low income settings but serial POC-Cr with CRADLE VSA to identify early AKI in high risk women in a low-income setting has not been studied.
Study design: Prospective feasibility study in 2000 pregnant women with CRADLE VSA Amber or Red readings
Primary Outcome: Feasibility of POC-Cr testing in pregnant or postpartum women (testing strip failure rate, time taken for training and testing)
Secondary Outcomes: - Accuracy and precision of POC-Cr testing compared to venous creatinine concentration
-Acceptability of POC-Cr testing to health care providers and women / -Number of eligible women, baseline rate of AKI according to Kidney Disease Improving Global Outcomes criteria (KDIGO) and time needed for study and analysis / -Threshold change in POC-Cr testing between baseline and 6-8 hours predictive of AKI at 24 hours / -Estimated mean and standard deviation of AKI rate using serial POC-Cr testing and AKI supportive care
Method: Women will have i) POC-Cr at admission/AKI associated event and at 6-8 hours after baseline
ii) Venous serum creatinine at admission/AKI associated event and at 24 hours after baseline.
Run-in period: 1000 women - POC-Cr will be unrevealed to clinical team, background rate of AKI determined and threshold changes at 6-8 hours predictive of AKI established / Intervention period: 1000 women - Serial POC-Cr will be revealed to clinical team. AKI supportive care (after training) will be recommended to be given to those with predictive threshold for AKI.
Significance: Findings will be used to inform design of a large randomised cluster step-wedge study of maternal POC-Cr screening and CRADLE VSA for AKI in low income countries.

Important areas of impact from these study findings include:

1. Future study design: We will be able to provide an estimate of incidence of AKI and impact of POC-Cr with CRADLE VSA on maternal outcomes to inform sample size calculation for a future larger stepped-wedge randomised cluster intervention study testing the impact of POC-Cr and Kidney Disease education for maternity health care professionals in different low income settings .

2. Women and their families: We anticipate that future work with POC-Cr testing with CRADLE VSA will be associated with improved overall maternal and neonatal outcomes and long term health for mother and baby.

3. Society - women who are alive and healthy will continue to be able to work and contribute to economic growth and be able to care for and support their families and communities.

4. Local workforce: The POC-Cr intervention and AKI care training will enhance the knowledge base of healthcare providers at all levels which will improve health care delivery, and be of benefit to local and national stakeholders and policy makers. The study will also provide valuable training in the rigors of clinical research for the staff in Harare and Parirenyatwa Hospitals, and build research capacity locally.

5. Local health care providers: POC-Cr with CRADLE VSA will improve targeted health care, reduction in complication rates including dialysis requirements which will reduce immediate and long term health costs and health care interventions

6. Government: reductions in maternal mortality and morbidity would contribute to meeting Sustainable Development Goal 2.3 by 2030