The PEARLS Trial (Preventing pre-eclampsia: Evaluating AspiRin Low-dose regimens following risk Screening) A multi-country, multi-centre, two-arm, parallel, double-blind, randomised trial of low-dose aspirin for women at increased risk of pre-eclampsia in Ghana, Kenya, South Africa, and India to prevent pre-eclampsia and improve maternal and newborn outcomes. EXECUTIVE SUMMARY Funder: Gates Foundation, USA Sponsor: Concept Foundation, Geneva International Sites: India, Ghana, Kenya & South Africa Participating institutions in India: Karnataka · Gadag Institute of Medical Sciences, Gadag · District Hospital, Vijayapura · District Hospital, Bagalkot Maharashtra · Government Medical College, Nagpur · Daga Memorial Hospital, Nagpur · District Hospital, Wardha Rajasthan · Sawai Man Singh Medical College, Jaipur
Background: Pre-eclampsia is a leading cause of maternal and neonatal mortality worldwide (about 4–5% of pregnancies). Early antenatal risk screening is essential to identify high-risk women and start preventive measures (low-dose aspirin and calcium) as early as possible. However, in many Low- and Middle-Income Countries (LMICs) (including India) screening has relied on clinical checklists, which have low predictive value. The Fetal Medicine Foundation (FMF) developed a multivariable screening algorithm (combining maternal factors, blood pressure, biomarkers, and uterine Doppler) that outperforms history-based approaches. Evidence from ASPRE trial shows prophylactic aspirin in screened high-risk women markedly reduces preterm pre-eclampsia. WHO acknowledged that a daily dose of 75mg up to 150mg may be more beneficial than less than 75mg but were concerned about the possible risk of postpartum haemorrhage (PPH), which might be greater with higher doses of aspirin. PEARLS (Preventing pre-eclampsia: Evaluating Aspirin Low-dose regimens following risk Screening) Trial is a two-stage research study designed to (Stage 1) Adapt and validate pre-eclampsia risk screening in India and (Stage 2) Conduct a multi-country randomised trial of aspirin dosing in high-risk pregnancies. By combining formative implementation research with a rigorous clinical trial, PEARLS study aims to generate robust, context-specific evidence to guide policy and practice.
Knowledge gaps in pre-eclampsia risk screening Currently, pre-eclampsia risk screening using the Fetal Medicine Foundation (FMF) algorithm has not reached routine clinical practice in most LMICs. The reasons for this are multifactorial: · Using the ‘full’ FMF algorithm requires the use of special investigations (PLGF, PAPP-A testing, UTPI measurement with Doppler ultrasound) which are expensive and rarely available in limited-resource contexts. · The coverage of early antenatal care (prior to 20 weeks’ gestation) is consistently lower in many LMICs, meaning many high-risk women are not identified until late in pregnancy, if at all. · A high-quality risk assessment requires an accurate estimation of gestational age; however, many pregnant women in LMICs do not have access to dating ultrasound, or may have an uncertain or unknown last menstrual period (LMP). · FMF is a relatively new tool and is still being rolled out in high-income country settings where they have been developed for use. These tools have not been developed for, or tailored to, other contexts such as sub-Saharan Africa or South Asia. The FMF algorithm has been validated in pregnant women across multiple European countries. However, there is no published primary study that has evaluated its diagnostic/prognostic performance in routine practice across south-Asian populations and settings. Stage 1: Formative Research – Screening Algorithm and Feasibility Overview Stage 1 component of the trial focusses on adapting and validating the FMF risk algorithm for the Indian population and preparing sites for the trial. The formative research objectives are: Objective 1: Implement and optimise pre-eclampsia risk screening using FMF algorithm with restricted variables in study sites. · Objective 1A: Tailor Tommy’s Tool for pre-eclampsia risk screening to India context, and train research staff on its use. · Objective 1B: Evaluate performance of the pre-eclampsia risk screening tool (restricted-variable FMF algorithm) and estimate the proportion of women identified as high risk in India · Objective 1C: Conduct qualitative research to optimize pre-eclampsia risk screening. · Objective 2: Assess and harmonize current clinical practices related to pre-eclampsia screening, prevention and management in study sites. · Objective 3: Assess women’s and care providers’ willingness and possible barriers to participating in the main trial. Study Activities - Algorithm adaptation and validation: A restricted-variable version of the FMF model (omitting complex laboratory inputs) will be used via an adapted web-based tool (Tommy’s National Centre tool). A cohort of about 5,000 pregnant women will be screened in early pregnancy to calibrate the algorithm to the local population and rates of those identified a high risk. Past validation work in South Asia showed the FMF model “performed satisfactorily but could still be improved to ensure markers are correctly adjusted for indigenous women”; our data will allow us to refine centiles and risk thresholds accordingly. This cohort will also establish the baseline prevalence of preterm pre-eclampsia in Indian sites.
- Care pathway mapping and harmonization: We will conduct surveys and interviews with obstetricians, midwives and community health workers to document current antenatal practices, resource constraints, and referral workflows. This mixed-methods work (in-depth interviews and focus groups) will identify logistic and cultural barriers (e.g. late antenatal registrations, limited ultrasound access) and facilitators (e.g. strong community health networks) to trial activities. Using these insights, we will standardize local care pathways: for example, all high-risk women identified by screening will be referred to a predefined management protocol (including prophylactic aspirin and calcium). Training materials and consent procedures will be tailored to local languages and literacy, and early engagement with hospital administrators will help align trial processes with routine services.
- Feasibility and acceptability: At the first phase, Stage 1, will test the logistics such as data collection on tablets and participant follow up. We will assess health workers’ and women’s willingness to participate in research, and attitudes toward daily aspirin during pregnancy. These qualitative findings will guide further refinements: for instance, we will allocate research midwives at each site, set up reminders for appointments, and planned community sensitization. By proactively addressing issues (equipment needs, transport, follow-up), Stage 1 ensured that “critical pre-conditions for trial implementation are met before randomization begins”.
The output of Stage 1 will be a calibrated FMF-based screening tool for Indian settings, plus operational protocols for screening, referral and follow-up. These will be shared with all sites and will form the eligibility criteria for Stage 2. In summary, Stage 1 will validate the risk algorithm locally, mapped care pathways, and confirmed the trial is feasible and acceptable. Eligibility criteria · - Pregnant women presenting for an antenatal visit from 11 weeks and 0 days to <20 weeks’ gestation at participating facilities with confirmed gestational age by USG. · - Woman must be at least 18 years old and intend to give birth at a participating facility. · - Woman should be able and consent to a follow-up cohort study. Sample size requirements The sample size calculation is based on the primary calibration objective. To estimate precisely the risk threshold for a screen-positive rate of 10%, a cohort of 5,000 pregnant women offers a precision of near 0.85%. The corresponding precision for a screen positive rate of 15% is nearly 1%, and for a 20% screen-positive rate it is nearly 1.12%. For the secondary objective (prognostic performance), a sample size of 5,000 and a preterm pre-eclampsia incidence rate of 1.6%, we expect to observe about 80 preterm pre-eclampsia events. With 80 such women with preterm pre-eclampsia, we have a precision of around 9 % for an assumed sensitivity of 75%. Study Outcomes: The primary endpoint for the calibration objective is the pre-eclampsia risk threshold (e.g. 1 in 20, 1 in 30, etc) that equates to a screen positive rate of 10%. The endpoints for the prognostic objectives for this study is: • Birth with pre-eclampsia prior to 37 weeks’ gestation • Birth with pre-eclampsia prior to 32 weeks’ gestation • Birth with pre-eclampsia prior to 34 weeks’ gestation • Birth with pre-eclampsia at or beyond 37 weeks’ gestation. The endpoint for the health care utilisation objective is: · - Characteristics of participants interaction with the health system as measured by: - Number of antenatal visits - Referral to higher-level care · - Self-reported use of aspirin · - Self-reported use of calcium supplementation - Women who have not developed pre-eclampsia by time of discharge after birth will form the group with ‘no pre-eclampsia’ outcome. The diagnosis of pre-eclampsia will not be concealed from women or clinicians. Maternal secondary outcomes: · Maternal death during enrolment/follow up period · Eclampsia · Placental abruption · Severe maternal morbidity - any one or more of: Eclampsia; cerebrovascular accident (stroke); Retinal detachment; Cortical blindness; Pulmonary oedema; Acute kidney injury; Liver capsule hematoma or rupture; Renal failure; liver failure; HELLP syndrome · Intensive care unit (ICU) admission: Any; for more than 24 hours; duration of ICU admission · Intubation and mechanical ventilation (not for childbirth) · Severe hypertension · Composite outcome on use of additional interventions for management of primary PPH (regardless of mode of birth) up until the end of the study Fetal/newborn secondary outcomes: · Pregnancy loss prior to 22 weeks’ gestation (either spontaneous loss or termination of pregnancy) · Stillbirth (fetal death from 22 weeks onward) · Very early neonatal death (status at 24 hours) · Perinatal death (any stillbirth or very early neonatal death) · Admission to NICU/SNCU at 24 h after birth · Very early neonatal death or admission to NICU/SNCU (composite) · Gestational age at birth (weeks) · Early preterm birth (less than 34 weeks’ gestation) · Preterm birth (less than 37 weeks’ gestation) · Birthweight (g), measured in the first 24 hours after birth using a calibrated scale · Low birthweight (less than 2500g) · Small-for-gestational-age This formative cohort will utilize an adapted version of the Tommy’s pathway for pre-eclampsia risk screening, specifically modified to suit limited-resource settings among 5,000 pregnant women who were enrolled across the 7 participating facilities and will followed up until delivery. Based on the cohort analysis we will further tailor the tool to the Indian healthcare context to ensure its feasibility and effectiveness within local facilities. The study will also confirm the proportion of the population identified as high-risk, and thus eligible for trial recruitment, informing trial site selection, timelines and planning. The data generated in India in both phases will complement the data generated in Ghana, Kenya and South Africa and will inform policy and practice broadly in LMICs. Following this stage 1 we will transition into the main trial. Stage 2: Clinical Trial – Comparing doses of Aspirin for Prevention of Pre-eclampsia The main trial is a multi-country, double-blind, two-arm randomized controlled trial of aspirin dosing among high-risk pregnant women (identified by the adapted FMF tool). The details are as follows: · Research hypotheses o Superiority hypothesis: A daily dose of 150 mg aspirin is superior in terms of efficacy to 75 mg aspirin for the prevention of pre-eclampsia in women identified as being at risk of pre-eclampsia based on restricted-variable FMF screening algorithm. o Non-inferiority hypothesis: A daily dose of 150 mg aspirin is not inferior in terms of safety to 75 mg aspirin in terms of PPH-related treatment, in women identified as being at risk of pre-eclampsia based on a restricted-variable FMF screening algorithm. · Primary objectives: o To compare the effect of a regimen of daily 150mg aspirin to a regimen of 75mg aspirin on the occurrence of birth at less than 37 weeks with pre-eclampsia, when given to women at high risk of pre-eclampsia according to a screening algorithm. o To compare the effect of a regimen of daily 150mg aspirin to a regimen of 75mg aspirin on the occurrence of a composite measure of PPH-related treatment, when given to women at high risk of pre-eclampsia according to a screening algorithm. · Secondary objectives: o To compare the effect of a regimen of daily 150mg aspirin to a regimen of 75mg aspirin on the occurrence of postpartum blood loss more than 500ml after vaginal birth, where blood loss is objectively measured. o To compare the effect of a regimen of daily 150mg aspirin to a regimen of 75mg aspirin on the occurrence of other maternal and newborn health outcomes. o To evaluate the resource requirements of the screening algorithm, and cost-effectiveness of different regimens of oral aspirin. o To assess the extent to pre-eclampsia risk screening has been implemented as intended, and barriers and facilitators to risk screening and aspirin use. · Population: Pregnant women with a pregnancy at 11 weeks’ to less than 20 weeks’ gestation, who are identified via risk screening as having high risk of pre-eclampsia. · Intervention: 150 mg/day aspirin, starting from 11 to less than 20 weeks’ gestation until 36 weeks’ gestation, childbirth, fetal death or pre-eclampsia is diagnosed, whichever occurs first. · Comparator: 75 mg/day aspirin, starting from 11 to less than 20 weeks’ gestation until 36 weeks’ gestation, childbirth, fetal death or pre-eclampsia is diagnosed, whichever occurs first. Randomized women (both arms) will continue to receive the same care they would usually receive, including other prescribed medications. All randomized women will be provided with sufficient tablets for 500mg/day oral elemental calcium until delivery. Calcium supplementation is standard of care for pre-eclampsia prevention in participating countries. · Study Inclusion criteria o Pregnant women at 11 weeks and less than 20 weeks’ gestation, identified by algorithm as high risk of pre-eclampsia o Women intend to give birth in a participating study facility/care network · Study Exclusion criteria o Pregnant women aged less than 18 years o Women identified by algorithm as low risk of pre-eclampsia o Women with a known non-viable pregnancy at recruitment o Women with a known contraindication to antiplatelet therapy, such as hypersensitivity reaction to any non-steroidal anti-inflammatory drugs (NSAID), or patients with asthma who have a history of aspirin-induced acute bronchospasm o Women with known bleeding disorders (such as von Willebrand’s disease or peptic ulceration) o Long-term use of nonsteroidal anti-inflammatory medication o Women who have taken aspirin regularly in the 28 days prior to screening o A known major fetal anomaly at recruitment o Currently participating in another drug trial o Unable or unwilling to provide informed consent. · Outcomes: o Primary outcomes: § Birth with pre-eclampsia before 37 weeks of gestation (superiority hypothesis) § Composite outcome on use of additional interventions for management of primary PPH (regardless of mode of birth) (inferiority hypothesis): - Use of uterotonics for PPH treatment OR - Use of tranexamic acid for PPH treatment OR - Use of non-surgical interventions for PPH treatment (including uterine tamponade [balloon or suction] or non-pneumatic antishock garment use) OR - Use of surgical interventions for PPH treatment (including laparotomy, B-lynch suture, uterine artery ligation, or hysterectomy) OR - Use of blood transfusion o Secondary outcomes: o Maternal secondary outcomes: § Pre-eclampsia § Birth with pre-eclampsia at less than 28 weeks, 32 weeks, 34 weeks, or 37 weeks § Maternal death, from time of randomisation until end of study follow up § Eclampsia § Placental abruption § Bleeding measures § Occurrence of antepartum haemorrhage (vaginal bleeding) requiring hospital admission, occurring prior to delivery § Objectively measured postpartum blood loss after vaginal birth § Total postpartum blood loss (in mL) after vaginal birth § Postpartum blood loss above 500ml after vaginal birth § Postpartum blood loss after Caesarean section § Total postpartum blood loss (in mL) after Caesarean section § Postpartum blood loss above 500ml after Caesarean section § Severe maternal morbidity - any one or more of: Eclampsia; Cerebrovascular accident (stroke); Retinal detachment; Cortical blindness; Pulmonary oedema; Acute kidney injury; Liver capsule hematoma or rupture; Renal failure; Liver failure; HELLP syndrome § Intensive care unit (ICU) admission for more than 24 hours § Duration of ICU admission § Intubation and mechanical ventilation (not for childbirth) § Severe hypertension § Adverse effects of intervention o Fetal/newborn secondary outcomes: § Pregnancy loss prior to 22 weeks’ gestation (either spontaneous loss or termination of pregnancy) § Stillbirth (fetal death from 22 weeks onward) § Early neonatal death, defined as death in the first 7 days of life § Perinatal death (any stillbirth or early neonatal death) § Neonatal intensive care unit (NICU) or special care nursery (SCN) for more than 24 hours § Duration of admission (hours) to the NICU or SCN § Neonatal coma § Neonatal seizures § Gestational age at birth (weeks) § Early preterm birth (less than 34 weeks’ gestation) § Preterm birth (less than 37 weeks’ gestation) § Birthweight (g), measured in the first 24 hours after birth using a calibrated scale § Low birthweight (less than 2500g) § Small-for-gestational-age § Congenital anomaly including chromosomal abnormalities and fetal structural defects § Grade III or Grade IV intraventricular haemorrhage amongst newborns born less than 32 weeks’ gestation or with birthweight less than1500g (in selected facilities, where transcranial ultrasound services are routinely available) For any maternal, fetal, or newborn deaths, we will ascertain likely cause/s based on best available information, using the ICD-MM and ICD-PM classification systems. Study activities: Participants
will be randomly assigned to either control or experimental group with a 1 is
to 1 allocation as per a computer-generated randomization sequence in balanced
permuted blocks of variable size. This sequence will be generated by the trial
statistician. All sites will receive investigational medicinal product IMP
treatment packs according to the randomization sequence. Sample size: Pregnant women less than
20 weeks gestation screening as high-risk by the Stage 1 is adapted FMF model
are randomized to daily aspirin 75 mg or 150 mg until 36 weeks with follow-up
to 7 days postpartum. All participants also receive standard calcium
supplementation 500 mg daily as per WHO and ICMR guidelines. The target sample is 5144 for India site. Global sample
size 20576 women from India Ghana Kenya and South Africa. Trial sites span
primary to tertiary centres ensuring representation of diverse health systems.
Randomization is stratified by site and allocation is double-blind to women and
providers. The trial will be registered with CTRI and will meet necessary
Indian regulatory requirements. Endpoints: The primary efficacy
outcome is incidence of preterm pre-eclampsia delivery less than 37 weeks for
pre-eclampsia. The primary safety endpoint is significant postpartum
haemorrhage blood loss requiring clinical intervention. In addition, blood loss
is measured objectively using calibrated drapes for all vaginal births
following E-MOTIVE recommendations. Secondary outcomes include term pre-eclampsia severe
maternal complications such as eclampsia and stroke neonatal outcomes such as
preterm birth and NICU admission and an economic evaluation. Health economic
analysis planned from trial budgets and outcomes will assess cost-effectiveness
of systematic screening plus higher dose aspirin versus standard care. Scientific Rigor: The trial’s size
and design provide high statistical power. Both aspirin doses being tested 75
mg and 150 mg lie within current guidelines 75 to 162 mg ensuring ethical
equipoise. Concept Foundation trial sponsor and academic partners Burnet
Institute University of Melbourne University of Ghana Nairobi Cape Town etc
bring expertise in maternal health RCTs. A Data Safety Monitoring Board DSMB oversees safety. The
trial protocol was developed by obstetric and epidemiology experts and outcomes
are clinically meaningful impacting maternal mortality and morbidity rates.
Following CONSORT and ICH GCP standards all trial conduct including
randomization blinding and data capture is rigorously managed.
In essence Stage 2 tests whether 150 mg aspirin is
superior or not to 75 mg in preventing preterm pre-eclampsia while monitoring
bleeding risks. This is the largest trial of its kind worldwide involving 20576
women and results will directly inform global and national guidelines on
pre-eclampsia prevention. Integration of Stages and Implementation Impact The two stages are closely integrated. The outputs from Stage 1 will directly inform Stage 2: - Risk Stratification: The locally validated FMF algorithm from Stage 1 sets the high-risk screening criteria for Stage 2 enrolment. Thus, women randomized in Stage 2 are precisely those most likely to benefit (and in whom aspirin efficacy is best tested).
- Workflow and Training: Stage 1 will identify practical workflow elements (timing of screening visits, who performs ultrasound, data entry processes) and acceptance issues (e.g.: beliefs about aspirin). These insights will shape the Stage 2 manual of procedures, consent scripts, and staff training.
- Sample Size and Feasibility: Data from 5,000 screened women (Stage 1) will provide estimates of high-risk prevalence and attrition rates. This will validate our sample-size assumptions for Stage 2. Similarly, Stage 1’s antenatal care surveys will inform baseline aspirin use and calcium deficiency rates, informing the trial’s monitoring plan.
- Stakeholder Engagement: The mixed-methods formative evaluation (focus groups, policy interviews) will help us to identify the barriers for participation (e.g. permission requirements, transportation) and facilitators (community health workers’ advocacy). We will use this to refine the consent process and retention strategies in Stage 2. Engaging hospital leadership and women’s groups early has improved buy-in, demonstrating ethical soundness and local support for the trial.
Overall, the integrated approach ensures academic rigor and implementation viability. By co-developing the screening tool with local data, PEARLS advances evidence-based care that fits India’s context. The collaboration (public sector, academia and industry) combines innovative technology (digital risk tool) with public health priorities. The trial’s findings on aspirin dosage and screening yield will guide future implementation: we plan to disseminate results to ICMR, national obstetric societies, and policymakers for integration into guidelines. Moreover, Stage 1’s process evaluation will highlight how the interventions could be sustained – for example, maintaining risk screening at ANC visits and monitoring aspirin adherence as part of routine care. Ethics, Regulation, and Compliance Ethical oversight and regulatory compliance are central to PEARLS. The protocols adhere to ICMR’s National Ethical Guidelines and Indian law. For example, ethics approvals have already been obtained from multiple review boards abroad (University of Melbourne, Ghana Health Service ERC, etc.); we will similarly secure Indian IEC approvals and HMSC clearance before commencing Indian sites. Informed consent is obtained from all participants (with translations provided). Both aspirin doses are standard-of-care ranges, and the study poses minimal incremental risk. A DSMB will review safety data (particularly haemorrhage rates) throughout the trial. By rigorously following the ethical standards, and by building capacity (training staff, providing equipment), the PEARLS trial is expected to demonstrate responsible conduct. The two-stage design – with an extensive formative phase – further underscores ethical soundness that has been invested in understanding and minimizing risks, optimizing participant welfare, and ensuring that the intervention (aspirin) is delivered and monitored safely in real-world settings. |