Precision is the adherence intervention .

01 / ParadoxA proven drug. A rising disease.

Low-dose aspirin initiated before 16 weeks of gestation is one of the few prevention strategies in modern obstetrics supported by a Level-1 randomised trial. In the ASPRE trial of 1,776 high-risk women identified by first-trimester multi-marker screening, aspirin reduced preterm preeclampsia by 62% (adjusted odds ratio 0.38; 95% CI 0.20–0.74).¹ The U.S. Preventive Services Task Force has issued a Grade B recommendation for aspirin prophylaxis since 2014, reaffirmed in 2021.⁵ The American College of Obstetricians and Gynecologists and the Society for Maternal-Fetal Medicine concur.⁶

And yet. Across the decade in which this prevention strategy was endorsed, ratified, and reinforced, the prevalence of preeclampsia in U.S. delivery hospitalisations has risen — not fallen — from approximately 3.4% in 2005 to 5.2% in 2014, with severe preeclampsia discharge rates increasing by 41% between 2004 and 2014 alone.^3,4 By 2025, a large prospective U.S. cohort study reported a preeclampsia incidence of 12.6%.⁷ The economic burden — $2.18 billion in incremental costs to the U.S. health care system in the first year after delivery alone, with infant costs ranging from $1,311 at 36 weeks to $150,000 at 26 weeks — climbs in lockstep.²³

This is not a story about pharmacology. The drug works. It is a story about how the U.S. system identifies which women need it — and what that identification does, or fails to do, to the women themselves.

02 / The Checklist ProblemWhen the risk label captures everyone, it identifies no one.

The current U.S. approach to preeclampsia prevention rests on a maternal risk-factor checklist. The USPSTF recommends aspirin for individuals with one or more high-risk factors (prior preeclampsia, chronic hypertension, type 1 or 2 diabetes, renal disease, autoimmune disease, multifetal gestation) or more than one moderate-risk factor (nulliparity, obesity, family history, Black race, age ≥35, lower income, certain personal-history factors, in-vitro conception).⁵

The arithmetic of this list is unforgiving. In a 2025 prospective cohort of 5,684 U.S. pregnancies analysed against the USPSTF criteria, 88.8% of all participants qualified as at increased risk — 70.3% as moderate-risk, 18.5% as high-risk.⁷ A clinical signal that flags nine of ten patients is no longer a signal; it is noise. And the downstream uptake numbers reflect exactly that.

These figures describe a system in which the gap between guideline and practice is so wide that even the 2021 USPSTF reinforcement did not bend the curve. In the Mass General Brigham series — perhaps the highest-resource obstetric setting in the United States — aspirin documentation rose from 4% in 2013 to only 24% by 2023.⁹ When near-universal labelling collapses prescriber attention, the patient never receives the conversation that would lead to adherence in the first place.

03 / What Precision DoesWhen risk is personal and quantitative, women act.

First-trimester multi-marker screening, established by the Fetal Medicine Foundation, combines maternal characteristics with mean arterial pressure, uterine artery pulsatility index, and placental growth factor to produce a quantitative, individualised probability of preterm preeclampsia. In the SPREE study of 16,747 singleton pregnancies, this approach identified a screen-positive group of approximately 10% with a detection rate of 77% for preterm preeclampsia at a 10% false-positive rate — far outperforming the NICE risk-factor checklist (detection rate 41%).¹¹

The clinical performance is well-established. What is less widely appreciated — and what matters for the prevention gap — is what precision does to adherence. The numbers are striking.

The contrast with the U.S. real-world data is severalfold. In FORECAST, adherence among screen-positive women reaches 93%; in the U.S. moderate-risk USPSTF category, aspirin uptake under 25% is the modal observation.^2,8 The mechanism is direct: women who receive a personalised, quantitative risk estimate — “your individual probability of developing preterm preeclampsia is 8%” — respond differently than women who receive a categorical label drawn from a list that nearly everyone qualifies for.

Patient-reported data confirm the mechanism. In a 2024 U.S. survey of 1,022 pregnant and recently delivered individuals, 88% indicated they would be more motivated to follow medication recommendations following a positive predictive test, including 83% of those self-identifying as medication-hesitant.¹³ Risk identification, made personal, becomes a behavioural intervention in its own right.

04 / The Folic Acid ComparatorIf even folic acid fails on adherence, aspirin needs all the help precision can offer.

To appreciate the size of the obstacle aspirin faces, consider folic acid — the most widely accepted, longest-recommended, and best-publicised preventive intervention in pregnancy. Folic acid has every structural advantage aspirin lacks: classification as a supplement rather than a drug; decades of safety data; near-universal awareness of the recommendation; low cost; over-the-counter availability; and, in many countries, mandatory food fortification programmes.

It still fails on adherence.

The French national registry datum is the most arresting: among 186,061 pregnancies, only 14.3% had folic acid dispensed during the recommended periconceptional window between 2006 and 2016, with the preconception rate rising from 3.8% to just 8.3% over a full decade of guideline reinforcement.¹⁵ A March of Dimes survey reported that while 97% of U.S. women take prenatal vitamins during pregnancy, only 34% begin them before knowing they are pregnant — i.e., during the periconceptional window when neural-tube-defect prevention actually works.¹⁶

Aspirin starts from a substantially more disadvantaged baseline than folic acid. Pregnant women systematically overestimate teratogenic risk and avoid medications even when explicit safety data are available.¹⁸ Qualitative studies of high-risk pregnancies specifically describe aspirin in pregnancy as “not yet trusted” by women — and in many cases by their clinicians — because its prophylactic indication conflicts with the heuristic that medications in pregnancy should be reserved for active problems.¹⁹

This is the a fortiori argument the field has not yet absorbed: if the most trusted preventive in pregnancy fails on adherence absent personal necessity, an off-label–perceived prophylactic drug recommended to nine-in-ten pregnancies under a checklist will fail more profoundly. Exactly as the U.S. data show.

05 / MechanismWhy precision drives adherence: the necessity construct.

The behavioural mechanism that links a personalised risk score to medication uptake is well-characterised. The validated Beliefs about Medication–Necessity construct, developed by Horne and colleagues and now applied across hundreds of medication-adherence studies, identifies necessity beliefs as the single strongest predictor of adherence across virtually every therapeutic area.²⁰ Patients take a medication when, and only when, they perceive it as personally necessary for them. The Necessity-Concerns Framework that emerged from this work shows that adherence rises when necessity beliefs outweigh concerns, and falls when concerns dominate.²⁰

In pregnancy, this dynamic is amplified. A multinational European study of 1,219 pregnant women with chronic disease found that medicated women scored substantially higher on BMQ-Necessity (16.6 vs 12.1; p<0.001) and lower on BMQ-Harm (9.8 vs 10.7; p<0.001) than unmedicated women with the same indications.²¹ Women perceive medication use in pregnancy as potentially harmful to the fetus even for drugs proven safe, and they reliably overestimate teratogenic risk.^18,21

A USPSTF checklist labelling 88.8% of pregnancies as “at risk” cannot generate personal necessity in this framework. The label is too diffuse, the implied prevalence too high, and the link between the woman’s specific risk factors and her actual probability of disease too abstract. An individualised first-trimester estimate — your probability is 8%, here is what we recommend, here is how aspirin reduces that probability — speaks the language the BMQ-Necessity literature predicts will move behaviour. The Cowan 2024 patient survey is the empirical confirmation of exactly this prediction: 83% of self-identified medication-hesitant women report higher motivation when given a positive predictive test.¹³

06 / CounterpointsThe serious objections, taken seriously.

Universal aspirin can dominate screen-and-treat in Bayesian modelling

Wright and colleagues have argued, using Bayesian decision theory, that universal aspirin can dominate screen-and-treat when the implicit exchange rate between women treated and cases prevented falls below approximately 200.²² The framework is rigorous; the conclusion is contingent on a critical assumption — that adherence is equal across strategies. The data above directly contradict that assumption. Once adherence becomes endogenous to the identification strategy, the modelling result inverts: precision dominates not because it is more efficient at the individual level, but because it generates the behavioural conditions under which aspirin actually gets taken.

FORECAST missed its intention-to-treat primary endpoint

The FORECAST stepped-wedge trial did not achieve its intention-to-treat primary endpoint at the population level, attributed by the authors to COVID-19-related undersampling and a confounding pandemic-era rise in preeclampsia incidence.² This is a real limitation. It is also a reason to scrutinise the per-protocol effect — which, in the women who actually received screening and treatment as designed, replicates ASPRE: a 41% reduction in preterm preeclampsia (adjusted OR 0.59; 95% CI 0.37–0.92), a 54% reduction in preeclampsia before 34 weeks, and a 66% reduction in perinatal death.² The biology is preserved; the implementation challenge is what the trial actually surfaces.

Universal aspirin protocols also drive dramatic adherence gains

Two recent U.S. implementation reports deserve serious consideration. Del Pozzo and colleagues documented aspirin adherence rising from 8.7% to 75% in a federally qualified health centre after implementing a universal protocol.²⁴ Kern-Goldberger and colleagues documented increased prescription rates following a universal-offer policy across a multi-hospital health system.²⁵ These results show what concerted implementation can achieve — but they reflect implementation intensity at the system level rather than universal-versus-targeted strategy per se. They do not address the question of whether the same intervention delivered with a precise individual risk estimate would yield further behavioural benefit. The trial designed to test that question directly (NCT04797949) was withdrawn without enrollment, leaving the empirical question unresolved.

07 / SynthesisWhat a generation of preventable disease has cost.

The U.S. prevention failure of the past decade is not because aspirin does not work. It is because the women who would benefit are inconsistently identified, inconsistently prescribed, and inconsistently adherent — and these three failure modes are causally linked. A risk-identification system that labels nine of ten women as at-risk degrades prescriber attention and prevents the patient-level personal-necessity perception that the adherence literature consistently identifies as the strongest predictor of medication uptake.²⁰

The cost, accumulated quietly across a decade, is measurable. A 41% increase in severe-preeclampsia discharges between 2004 and 2014.⁴ An incremental $2.18 billion in annual healthcare expenditure.²³ An incidence that has continued to climb past 12% in recent prospective cohorts.⁷ The maternal-mortality figures that make U.S. obstetrics an international outlier among high-income countries are not unrelated to this prevention gap.

The principle that emerges from the literature is general: precision is the adherence intervention. First-trimester multi-marker screening — whether based on the established Fetal Medicine Foundation triple test, emerging cfRNA signatures,²⁶ or next-generation molecular approaches — addresses all three failure modes simultaneously by producing a precise individual risk estimate that concentrates clinical attention, increases prescribing, and converts an abstract population-level guideline into a personal medical necessity that women act on.