Preeclampsia is defined by new hypertension after twenty weeks of gestation together with proteinuria or other evidence of maternal organ or uteroplacental dysfunction (Brown et al., 2018). It remains a leading cause of maternal and perinatal harm, and no treatment other than delivery stops the disease once it is established. Prevention therefore carries much of the clinical weight, and the one preventive drug supported by a large body of randomised evidence is aspirin at low dose.

The evidence accumulated over three decades. The CLASP trial, which enrolled more than nine thousand women, found a smaller effect than earlier small trials had promised (CLASP Collaborative Group, 1994). Pooled analyses later confirmed a modest but consistent reduction in preeclampsia with antiplatelet agents, and the current Cochrane review reaches that conclusion (Duley et al., 2019). A later meta-analysis that separated trials by timing and dose reported larger effects when aspirin was started before sixteen weeks and given at higher doses (Roberge et al., 2017). The ASPRE trial then tested that proposition directly, giving 150 mg at night from 11 to 14 weeks until 36 weeks to women screened as high risk, and showed a substantial fall in preterm preeclampsia (Rolnik et al., 2017).

Guidelines now recommend low dose aspirin for women at increased risk, although they differ on dose and on how risk is assessed (ACOG, 2018; NICE, 2019; US Preventive Services Task Force, 2021). What none of them can ensure is that the drug is taken. This article proposes a study design for measuring aspirin adherence in high risk pregnancy within ordinary antenatal care. It reports no data. The design is offered so that units can produce adherence figures that mean the same thing from one service to the next.

A secondary analysis of ASPRE examined the effect of aspirin according to how much of the allocated medication each woman took, judged by tablet counts. The reduction in preterm preeclampsia was considerably greater among women who took at least ninety per cent of their tablets than among those who took fewer (Wright et al., 2017). The comparison is not randomised, since women who adhere differ from those who do not, but it agrees with pharmacology and with an Australian cohort in which women with poor adherence, assessed by several methods including a biochemical one, had worse outcomes than adherent women at similar baseline risk (Shanmugalingam et al., 2020).

Adherence to long-term preventive medicine is poor across medicine, and the reasons are well described: the condition being prevented is silent, the benefit is invisible to the person taking the drug, and the regimen lasts for months (Sabaté, 2003; Osterberg and Blaschke, 2005). Pregnancy adds its own features. Women are often cautious about any medicine during pregnancy, aspirin is sold over the counter in many countries so that no dispensing record may exist, nausea in the first trimester coincides with the time the drug should start, and advice from different clinicians can conflict. A service that wants to improve uptake needs to know at which point women are lost, and a single question at one visit does not show that.

The proposed design adopts the taxonomy published by Vrijens et al. (2012), which divides adherence into three phases. Initiation is the taking of the first dose. Implementation is the extent to which actual dosing matches the prescribed regimen from first dose to last. Persistence is the length of time from initiation until the patient stops. Each phase fails for different reasons and needs a different remedy, so a study that reports one summary percentage discards most of what is useful. Figure 1 sets the phases beside the record that captures each one in this design.

Two further definitions should be fixed before any data are collected. The first is the denominator: the women who were assessed as high risk under the local guideline and offered aspirin, including those who declined. The second is the threshold for adequate implementation. Ninety per cent of prescribed doses is the value used in the ASPRE analysis and is the natural primary definition (Wright et al., 2017); the conventional eighty per cent used in much adherence research can be reported alongside it so that findings can be compared with studies of other drugs.

The design is a prospective observational cohort embedded in routine antenatal care. Its elements are described below in the order in which a unit would set them up.

The design was shaped by what an ordinary unit can sustain. Pill counts and the self-report scale add a few minutes to existing visits and can be done by the midwife or pharmacist already seeing the woman. Dispensing data depend on local arrangements. Where aspirin is supplied on prescription from a hospital or linked community pharmacy the record is complete; where women are told to buy it themselves the measure is lost, and the study should say so plainly instead of reporting a figure that covers only part of the cohort. Ethical review and written consent are required, and participants should be told at the outset that tablets will be counted. Measurement of this kind is known to raise adherence for a time, which makes the study a conservative guide to what happens in unobserved care.

Units that advise different doses or stopping points can still use the design, provided each reports adherence against its own regimen and states that regimen. The design takes no position on which dose is preferable. That question belongs to the randomised evidence and to guideline bodies, and nothing in an adherence study should be read as advice to change what women are prescribed.

The procedure described here is proposed and has not been validated. A first application would need to show three things. One is feasibility: whether pill counts are completed at enough visits to be analysed and whether women accept them. A second is agreement: how closely the inexpensive measures track the biochemical one in the subsample, since a scale that classifies nearly everyone as adherent is of little use. The third is whether the three-phase description identifies a point of loss that a service could act on, for instance a large share of women who never start.

Some weaknesses are built in. Every measure other than the biochemical one can be influenced by the woman, and the biochemical one sees only recent doses. Observation changes behaviour. Results from one unit reflect its population, its prescribing arrangements and its way of explaining risk, and should not be generalised without replication. Finally, the study describes adherence and its correlates; it cannot show that improving adherence improves outcomes, which would require a trial of an adherence intervention.

Aspirin prophylaxis is among the few antenatal interventions with strong trial support, and its benefit appears to depend on adherence that services seldom measure. The design proposed here separates initiation, implementation and persistence, pairs several imperfect measures so that their errors can be compared, and fixes definitions in advance so that results from different units can be set side by side. Whether it works as intended is for a first application to show.

To be declared by the author(s) before publication.

To be declared by the author(s) before publication.