Appraise screening for and aspirin prophylaxis of pre-eclampsia

In one line

Pre-eclampsia prevention is a screen-then-treat problem: identify the woman at risk early, start aspirin 150 mg at night before 16 weeks, and continue to 36 weeks — the single intervention with a real, dose- and timing-dependent effect on preterm pre-eclampsia. The pathophysiology and acute management are in pre-eclampsia basics; this chapter covers getting the prophylaxis right, why the regimen is the regimen, and the arguments on dose, timing, screening method and the calcium controversy.

Why this is a prevention problem at all

This chapter assumes the two-stage placental model from pre-eclampsia & HELLP basics and the early-vs-late phenotype split developed in pre-eclampsia-early-onset-severe. The idea that unifies everything below is this: aspirin acts on Stage 1 (placentation), not Stage 2 (the maternal syndrome) — which is why it works only when given before spiral-artery remodelling is complete (the <16-week window), why it prevents the placental phenotype (preterm pre-eclampsia and its travelling companion, FGR) and not the maternal-constitutional term phenotype, and why it is useless once the disease is established. Every dose, timing and screening argument that follows is downstream of that one mechanistic commitment.

Aetiology / mechanism — why aspirin, why 150 mg, why at night

The prostacyclin–thromboxane story is assumed here. What matters is the pharmacology that justifies the exact regimen, because that is where the guideline disagreements live.

The COX-1 / thromboxane mechanism, at the level that explains the dose. Low-dose aspirin (<300 mg) irreversibly acetylates serine-529 of cyclo-oxygenase-1 (COX-1) in the anucleate platelet. Because the platelet cannot resynthesise the enzyme, its thromboxane-A₂ output is suppressed for the platelet's whole ~10-day lifespan; the vascular endothelium, being nucleated, regenerates COX and keeps making the vasodilator/antiaggregant prostacyclin (PGI₂). The pre-eclamptic placenta sits on the wrong side of a thromboxane-dominant imbalance, so selectively crippling platelet thromboxane while sparing endothelial prostacyclin restores the vasodilator-to-vasoconstrictor balance and, more importantly, improves the deep placentation that is failing in Stage 1. This is why the effect is antiplatelet, not analgesic — and why the relevant dose is the antiplatelet dose, not the anti-inflammatory one. Aspirin must be on board while trophoblast is still invading, which is the entire basis of the <16-week rule.

Why 150 mg and not 75–81 mg — the pharmacodynamic argument. The dose question is not arbitrary tablet-counting; it is about incomplete platelet COX-1 inhibition at the low end. A meaningful minority of pregnant women — disproportionately those with raised BMI and accelerated platelet turnover — show non-optimal platelet inhibition on 75–81 mg, with residual thromboxane production ("biochemical aspirin non-response"). Higher mg and a circadian-aligned dose both push more women across the threshold of full platelet inhibition. The 150-vs-81 mg difference is therefore not "the Americans use a smaller pill" but a pharmacodynamic dose-response one: 150 mg captures responders that 81 mg misses, which is why the trials favour it.

Why at night — chronotherapy, not folklore. Platelet reactivity and the thromboxane:prostacyclin ratio follow a circadian rhythm, and the maternal blood-pressure and angiogenic milieu vary across the 24 hours. Aspirin taken in the evening more completely suppresses the overnight/early-morning thromboxane surge and the nocturnal blood-pressure profile than the same dose taken on waking. The bedtime instruction in the SA NDoH and FIGO regimens is therefore a deliberate chronotherapeutic choice with a mechanistic rationale — worth stating as such rather than as a quirk.

Why it cannot rescue established disease. Once Stage 1 is over and the anti-angiogenic Stage-2 cascade (sFlt-1 scavenging PlGF/VEGF → endothelial dysfunction) is running, an antiplatelet agent acting upstream on placentation has nothing left to modify. This is the mechanistic reason aspirin is prophylaxis, never treatment, and the reason it does little for term (maternal-phenotype) disease where placentation was relatively normal to begin with.

Assessment — who screens positive, and how

Two screening philosophies compete, and they are best contrasted by where each one fails and how the method matches the resource setting, not by the checklists themselves.

1. Risk-factor (checklist) screening — the SA and NICE default. Treat any woman with one high-risk factor OR two or more moderate-risk factors (NICE NG133).

• High risk: prior hypertensive disease in pregnancy, chronic hypertension, chronic kidney disease, type 1/2 diabetes, autoimmune disease (SLE, antiphospholipid syndrome).
• Moderate risk: nulliparity, age ≥40, BMI ≥35 kg/m² at booking, family history of pre-eclampsia, pregnancy interval >10 years, multifetal pregnancy.

The SA national hypertension-in-pregnancy guideline frames the indication slightly differently — it triggers aspirin on any single early-onset risk factor (prior pre-eclampsia, chronic hypertension, multiple gestation, pre-gestational diabetes, BMI >33, APS/SLE, assisted reproduction), reflecting a lower threshold to treat in a high-mortality setting.

The checklist is a deliberately blunt instrument, with three failure modes. (i) It is dichotomous — a woman with one weak moderate factor and a woman with severe chronic kidney disease are treated identically, with no gradation of risk. (ii) It cannot integrate continuous biophysical data (a high MAP, an abnormal uterine-artery waveform) that materially change risk. (iii) It mostly flags the maternal-constitutional factors (age, BMI, parity) that predict term disease, while under-detecting the placental phenotype that drives the dangerous preterm disease aspirin actually prevents — so it is weakest exactly where the stakes are highest. In effect the checklist screens for the wrong half of the disease.

2. First-trimester combined (FMF) screening. At 11–13⁺⁶ weeks, combine maternal factors with mean arterial pressure (MAP), uterine artery pulsatility index (UtA-PI) and serum placental growth factor (PlGF) through a Bayesian (competing-risks) algorithm, treating those with a risk of ≥1 in 100 for preterm pre-eclampsia. This is the FIGO 2019 "best-practice" model.

The competing-risks model's logic runs as follows: it treats gestational age at delivery with pre-eclampsia as a continuously distributed survival outcome and shifts that distribution earlier as the biophysical markers worsen, so it estimates risk specifically for preterm (and early-onset) disease — which is why it outperforms the checklist precisely on the phenotype that matters. Each marker indexes a different facet of placentation: a high MAP captures the maternal cardiovascular substrate, a raised UtA-PI is the Doppler signature of unconverted high-resistance spiral arteries (failed Stage 1), and a low PlGF is the earliest circulating evidence of the anti-angiogenic shift. The decisive evidence is SPREE: at a matched 10% screen-positive rate, the NICE checklist detected only 40.8% of preterm pre-eclampsia versus 82.4% for the full combined test.

FIGO's pragmatic compromise for limited resources is contingent screening. Stage one runs maternal factors + MAP (± UtA-PI/PAPP-A) on everyone to stratify into high-, intermediate- and low-risk bands; PlGF (the expensive reflex assay) is then measured only in the intermediate band to recompute a final risk, sparing the cost of universal PlGF while retaining most of the detection of the full test. This three-tier reflex design is the model that actually fits an SA budget — universal cheap inputs, selective expensive ones. In most SA public-sector units neither PlGF assay nor reliable first-trimester UtA-PI is available, so risk-factor screening is the operative reality, accepting that it under-performs and that the contingent fallback is what would be built if PlGF were funded.

Management — immediate, ongoing, long-term

Immediate — start aspirin correctly

Three things define the regimen: dose (150 mg, not 75 mg), early start (before 16 weeks), and night-time dosing. In SA the practical formulation is half of a scored 300 mg tablet; a 28-day supply costs roughly R2.55–R5.74 at tender price — prophylaxis is not the cost barrier, timely booking is.

The subtype-specific and edge-case decisions:

• The raised-BMI / suspected non-responder. The pharmacodynamic non-response problem is real, but the evidence does not yet license routine dose escalation. ASPREO (162 vs 81 mg in obese high-risk women) found no statistically significant difference in pre-eclampsia with severe features (35% vs 40%; RR 0.88, 95% credible interval 0.64–1.22), with only a Bayesian-framed ~78% probability of some benefit. The defensible position: 150 mg is already the higher, evidence-aligned dose SA uses; going beyond it (162 mg, or split twice-daily dosing to overcome turnover) is investigational, not standard. Do not invent a "double the dose in the obese" rule.
• The woman already past 16 weeks at booking — the commonest SA scenario. Starting late forfeits much of the preterm-PE benefit, but it is not nothing: the pragmatic stance is to start anyway (some antiplatelet effect, low harm) while being honest that the window for maximal placental benefit has narrowed. The real fix is structural (start earlier next time, see below), not pharmacological.
• Twins/higher-order multiples carry a high baseline risk and qualify on a single factor; aspirin is indicated, though its relative efficacy in multiples is less well-defined than in singletons — treat, but counsel that surveillance matters more here.
• Genuine contraindications are few: true aspirin hypersensitivity (including aspirin-exacerbated respiratory disease) and active peptic ulceration/bleeding. The much-feared concerns — Reye's (not relevant at this dose/age), premature ductal closure (a third-trimester high-dose NSAID concern, not a 150 mg first-/second-trimester issue) — should not stop prophylaxis. Routine peptic prophylaxis is not required.

Ongoing — make prophylaxis actually happen, and when to stop

The recurring SA failure is structural, not pharmacological. A woman flagged at a community clinic may only reach district level after 20 weeks — too late. The 2024 NDoH Essential Medicines review therefore moved to nurse-initiated aspirin at primary-care level before referral, precisely so the <16-week window is not lost to queue time. Counsel on adherence: the preventive effect is adherence-dependent (substantially greater at ≥90% adherence in ASPRE), and aspirin does not prevent term pre-eclampsia, so it is no substitute for continued surveillance.

The "stop date" is now an evidence question, not just a convention. The standard instruction is to stop at 36 weeks (limiting peripartum bleeding while retaining benefit, since term disease is not aspirin-modifiable anyway). But StopPRE (JAMA 2023) tested earlier discontinuation: in FMF-screened high-risk women who had reassuring mid-trimester angiogenics (sFlt-1/PlGF ratio ≤38 at 24–28 weeks), stopping aspirin then was non-inferior to continuing to 36 weeks for preterm pre-eclampsia (1.73% vs 1.48%). In a unit with angiogenic testing, a normal mid-trimester ratio identifies a woman who can safely stop early (less bleeding, fewer tablets); in an SA unit without sFlt-1/PlGF that call cannot be made, so the default 36-week stop stands — a test that is unavailable does not change practice on the ground.

Long-term — adjuncts and what to abandon

• Calcium: the historical recommendation (1.5–2 g/day elemental calcium in low-intake populations; ~500 mg/day non-inferior in 2024 trials) is now contested — see the controversy below. SA reserves it for poor dietary intake plus high risk. Note the mechanistic claim is weaker than aspirin's: calcium is hypothesised to reduce parathyroid-driven smooth-muscle calcium and vascular reactivity, but it does not touch placentation, which is why even if it lowers BP it was never expected to prevent the placental phenotype.
• Things to stop offering for prevention: vitamins C and E, salt restriction, routine bed rest — none prevent pre-eclampsia. (Antioxidant vitamins were a mechanistically attractive idea — oxidative stress is part of Stage 2 — that large RCTs comprehensively failed; a useful reminder that plausible mechanism ≠ clinical benefit.)
• Heparin / LMWH is not general pre-eclampsia prophylaxis; its role is confined to specific thrombophilia/antiphospholipid-syndrome-with-prior-loss indications — do not offer it to prevent pre-eclampsia in the general high-risk woman.
• Counsel recurrence and lifelong cardiovascular/renal risk, and plan early aspirin for the next pregnancy — see contraception-in-high-risk-women and metabolic risk in polycystic-metabolic-ovarian-syndrome. Progestogen has no preventive role here despite its other obstetric uses (progesterone-in-obstetrics-gynaecology).

The evidence & the controversy

Aspirin works — but the magnitude depends entirely on dose and timing. ASPRE (NEJM 2017), which used FMF screening to enrol high-risk women and aspirin 150 mg nightly from 11–14 to 36 weeks, cut preterm pre-eclampsia by about 62% (OR 0.38, 95% CI 0.20–0.74). The absolute numbers: 13/798 (1.6%) on aspirin vs 35/822 (4.3%) on placebo gives an absolute risk reduction of 4.3% − 1.6% = 2.7%, so the NNT ≈ 1/0.027 ≈ 37 women treated to prevent one preterm pre-eclampsia — a strikingly efficient prophylaxis in a screen-enriched high-risk population. Contrast that with the older pooled evidence: the PARIS individual-patient-data meta-analysis (32,217 women, mostly low-dose/mixed-timing trials) found only RR 0.90 (95% CI 0.84–0.97), and the Cochrane review dominated by 50–75 mg trials only an 18% relative reduction (RR 0.82, 95% CI 0.77–0.88; NNT ≈ 61 across an unselected population). The reconciling signal across meta-analyses is consistent — benefit for preterm pre-eclampsia appears confined to ≥100–150 mg started ≤16 weeks (one dose-comparison meta-analysis: 150–162 mg RR 0.34, 95% CI 0.15–0.79 vs 75–81 mg, only when started in the first trimester).

The two NNTs reconcile when read together. ASPRE's NNT ≈ 37 and Cochrane's NNT ≈ 61 are not contradictory: they measure the same drug deployed differently — ASPRE concentrated a higher dose, started early, in a screen-enriched population with a high event rate, so the absolute yield per woman treated is large; Cochrane diluted a lower dose across unselected women with a lower baseline risk, so each woman treated yields less. Prophylactic efficiency is a product of dose, timing AND case-mix, and "how good is aspirin?" has no single answer divorced from how the cohort was screened and dosed. "75 mg from 12 weeks" is a regimen the data now considers under-dosed and slightly late. Note the live transatlantic discordance: USPSTF/ACOG still recommend 81 mg (a US tablet-availability artefact), while ISSHP, FIGO and SA favour 150 mg — 81 mg is pragmatic where 150 mg tablets are unavailable, but the dose-response evidence favours 150 mg, and the head-to-head ASPREO dose trial in obese women, while underpowered, did not vindicate going higher than 150 mg.

Calcium is the controversy that has actively shifted. WHO has long recommended 1.5–2 g/day in low-intake populations. But a 2025 Cochrane review restricting to higher-quality trials (excluding several earlier studies on data-integrity grounds) found calcium made little to no difference to pre-eclampsia incidence, and low-dose (500 mg) versus high-dose (1500 mg) did not differ — concluding further research is unlikely to change this. The honest position is now nuanced: aspirin is the evidence-backed pharmacological prophylactic; calcium's preventive role is weaker and contested, defensible mainly as replacement in genuinely calcium-deplete diets. The 2025 re-analysis partly turned on excluding trials for data-integrity concerns, so the shift is as much about trial quality as about biology — that distinction matters to the appraisal.

Screening is the deeper debate. Risk-factor screening is universal and free but misses the majority of preterm disease (SPREE); FMF screening more than doubles detection but needs PlGF and skilled UtA-PI Dopplers absent from most SA facilities. In a resource-limited high-burden setting, a sensitive, cheap, low-threshold risk-factor net that actually delivers aspirin before 16 weeks may save more mothers than an accurate algorithm that cannot be run — an equity-versus-accuracy trade-off that connects to how these deaths are counted in maternity-statistics-critical-appraisal. The intermediate position — contingent screening with reflex PlGF in the intermediate band — is the genuinely fundable compromise for South Africa.

The ASPRE preterm-PE odds ratio is 0.38 (95% CI 0.20–0.74; P=0.004) — 13/798 (1.6%) on aspirin vs 35/822 (4.3%) on placebo — i.e. the "~62%" figure is the absolute-incidence reduction, and the OR is the precise effect measure.

Screening test characteristics — reading the numbers without being misled

What matters is what kind of test each tool is and where it deceives.

• The checklist is a sensitivity/specificity trade run at a fixed, blunt operating point. At a ~10% screen-positive rate it detects ~40% of preterm PE (SPREE) — i.e. it misses roughly 60% of the disease aspirin best prevents. Its apparent simplicity hides a poor positive predictive value: most checklist-positive women will not develop pre-eclampsia, and most preterm pre-eclampsia arises in women the checklist never flagged.
• The combined (FMF) test is a calibrated risk, not a yes/no. Its strength is detection of preterm/early-onset disease (~80%+); its weakness is term disease, where detection falls away because term pre-eclampsia is poorly predicted by first-trimester placentation markers. A reassuring first-trimester screen therefore does not license dropping third-trimester BP/proteinuria surveillance.
• PlGF-based tests are rule-OUT tools, strongest at low values. A low PlGF (or high sFlt-1/PlGF) is mechanistically meaningful because it indexes the Stage-2 anti-angiogenic driver; the high negative predictive value of a normal ratio is what powers both PROGNOSIS (in suspected disease) and StopPRE (the safe-to-stop signal at 24–28 weeks). The misreading to avoid: treating a positive angiogenic result as diagnostic — its positive predictive value is modest, and in the prevention context its established role is the reassuring-normal that permits early aspirin cessation, not a trigger to escalate.
• Uterine-artery Doppler alone is operator-dependent and weak in isolation — its value is as one input to the multivariable model, not a standalone screen, and its first-trimester acquisition is exactly the skill most SA units lack.

Long-term, postnatal and recurrence counselling

Prevention does not end at delivery — the index pregnancy is a window into lifelong risk, and the consultant closes that loop.

• Recurrence and the next pregnancy. Counsel that a prior hypertensive disorder is itself the strongest high-risk factor for the next pregnancy, that recurrence risk is higher and earlier the earlier and more severe the index disease (cross-link the detail in pre-eclampsia-early-onset-severe), and that the single most important preventive action next time is booking early enough to start aspirin before 16 weeks — make this an explicit, written part of the discharge and contraception plan so the next pregnancy is planned around it.
• Cardiovascular and renal legacy. Pre-eclampsia is a cardiovascular risk marker: the woman carries a durably raised long-term risk of chronic hypertension, ischaemic heart disease, stroke and chronic kidney disease. The preventive intervention here is handover to primary care with a documented plan for BP, weight, glucose and lipid surveillance — not an obstetric task, but an obstetric responsibility to initiate. Persistent proteinuria or hypertension beyond the puerperium needs renal/physician referral, not reassurance.
• Interpregnancy optimisation. Weight, glycaemia and chronic-hypertension control between pregnancies are the modifiable substrate for the maternal-phenotype (term) disease that aspirin does not touch — so prevention of the next episode is part aspirin (placental phenotype) and part metabolic optimisation (maternal phenotype). Tie this to polycystic-metabolic-ovarian-syndrome and contraception choice in contraception-in-high-risk-women.

Landmark trials & key evidence

The trials below trace why the regimen moved from "60–75 mg, modest effect" to "150 mg before 16 weeks, large effect on preterm disease" — and why calcium has fallen back.

Worked viva — how to structure the answer

A stem might run: "A 33-year-old para 1 books at 11 weeks. Her first pregnancy ended in delivery at 31 weeks for pre-eclampsia with severe features. BMI 36. How would you reduce her risk this time?" A high-scoring answer runs:

1. Frame the risk — "She is high-risk on multiple counts: prior early-onset preterm pre-eclampsia is the single strongest predictor of recurrence, plus a raised BMI; she qualifies for prophylaxis on the prior episode alone."
2. Commit to the regimen and justify it mechanistically — "Aspirin 150 mg at night, started now (before 16 weeks), continued to 36 weeks. It works by irreversibly inhibiting platelet COX-1, restoring the thromboxane–prostacyclin balance and improving deep placentation — which is why it must be on board before spiral-artery remodelling finishes, prevents the preterm/placental phenotype, and is useless once disease is established."
3. Pre-empt the dose/timing challenges — "150 mg, not 81 mg, on the dose-response evidence (Ghesquiere meta-analysis); night-time on the chronotherapy rationale; the higher BMI raises the question of non-response, but ASPREO did not show 162 mg beats the standard, so I would not escalate."
4. Address screening honestly — "Ideally first-trimester combined (FMF) screening, but PlGF and first-trimester uterine-artery Doppler aren't available in most of our units, so I rely on risk-factor screening and treat — accepting it under-detects, which is why I keep her under surveillance regardless."
5. Cite the evidence — "ASPRE for the regimen and its ~62% preterm-PE reduction (NNT ≈ 37 in a screen-enriched group); SPREE for why the checklist misses disease; StopPRE for the safe-to-stop-early signal that I can't use without angiogenic testing."
6. Close the loop — "Counsel adherence (effect is adherence-dependent), that aspirin won't prevent term disease so surveillance continues, her high recurrence and lifelong cardiovascular risk, primary-care handover, and that booking early next time is the most important single thing."

Exam traps & red flags

• "75 mg from 12 weeks" as the model answer. Acceptable historically, but the current SA/ISSHP/FIGO standard is 150 mg, started before 16 weeks — know the upgrade and why (dose-response, the <16-week window).
• Starting too late. Aspirin begun after 16 weeks loses much of its effect on preterm pre-eclampsia. The clinical failure is almost always the booking/referral delay, not the drug.
• Expecting aspirin to prevent term or established disease. It prevents preterm pre-eclampsia; it does little for term disease and nothing once pre-eclampsia is diagnosed — stop it at 36 weeks (bleeding risk at delivery).
• Escalating the dose ad hoc in the obese. Tempting on the non-response mechanism, but ASPREO did not show 162 mg beats the standard; do not invent a "double-dose in obesity" rule.
• Stopping aspirin early because you heard about StopPRE — without the test. Early cessation is only licensed by a reassuring sFlt-1/PlGF at 24–28 weeks; without that assay, continue to 36 weeks. Quoting StopPRE as a reason to stop everyone early is wrong.
• Reciting WHO calcium as settled dogma without acknowledging the 2025 evidence (and the data-integrity exclusions behind it) that undercut it.
• Treating the FMF algorithm as available everywhere. Naming PlGF/UtA-PI screening as SA routine is wrong; flag the resource gap and the contingent-screening fallback.
• Treating a reassuring first-trimester screen as licence to relax third-trimester surveillance. The combined test predicts preterm disease and is weak for term disease — a normal screen never retires BP/proteinuria checks.
• Stopping aspirin for minor bleeding or before a planned caesarean — the bleeding excess is small; routine continuation to 36 weeks is standard.
• Offering heparin/LMWH as general pre-eclampsia prophylaxis — it isn't; reserve it for specific thrombophilia/APS indications.
• Forgetting the prior-preterm-pre-eclampsia woman — her recurrence risk is high and aspirin's benefit greatest; she must be flagged and started early next time.

Evidence anchors

• NICE NG133 — Hypertension in pregnancy: diagnosis and management — aspirin 75–150 mg from 12 weeks until birth; the 1-high / ≥2-moderate risk-factor rule.
• FIGO 2019 pre-eclampsia initiative — pragmatic first-trimester screening & prevention (Poon et al, IJGO) — ~150 mg nightly from 11–14⁺⁶ to 36 weeks; ≥1-in-100 combined-test threshold; contingent screening (reflex PlGF in the intermediate band) for limited resources; calcium in low-intake diets.
• ASPRE trial — screening performance (Rolnik/Wright et al, UOG 2017) — FMF combined screening + aspirin 150 mg; ~62% reduction in preterm pre-eclampsia.
• SPREE — NICE vs combined screening (Tan et al, 2018) — at 10.3% screen-positive, NICE detected 40.8% vs 82.4% of preterm PE by the combined test.
• Aspirin 75–81 mg vs 150–162 mg for preterm pre-eclampsia — meta-analysis (2023) — higher dose, first-trimester start, lower preterm-PE risk (RR 0.34, 95% CI 0.15–0.79).
• StopPRE — aspirin discontinuation at 24–28 weeks (Mendoza et al, JAMA 2023;329:542–550) — sFlt-1/PlGF ≤38 at 24–28 wk; stopping non-inferior to continuing to 36 wk for preterm PE (1.73% vs 1.48%).
• ASPREO — aspirin 162 mg vs 81 mg in high-risk obese women (Amro et al, Am J Obstet Gynecol 2025;232:315.e1–315.e8) — no significant difference in severe PE (35% vs 40%; RR 0.88, 95% CrI 0.64–1.22).
• USPSTF 2021 — low-dose aspirin for preeclampsia (Grade B) — 81 mg/day after 12 weeks (US tablet-availability dose).
• SA NDoH Essential Medicines — aspirin in pre-eclampsia, PHC review (July 2024) — 150 mg at bedtime from 6 wk (preferably <16 wk) to 36 wk; HDP = 18% of SA maternal deaths; nurse-initiated PHC aspirin; ~R2.55–R5.74/28 days; Cochrane RR 0.82, NNT 61.
• WHO recommendation on calcium supplementation in pregnancy — 1.5–2 g/day elemental calcium in low-intake populations; preventive benefit now contested by 2024–2025 high-quality trial evidence (state cautiously).
• ASPRE main trial — aspirin 150 mg vs placebo (Rolnik et al, NEJM 2017;377:613–622) — preterm PE OR 0.38 (95% CI 0.20–0.74), 1.6% vs 4.3%; no effect on term PE.
• CLASP — low-dose (60 mg) aspirin in 9364 women (Lancet 1994) — non-significant 12% reduction in proteinuric PE; the under-dosed, late-start regimen that fuelled early scepticism.
• PARIS — antiplatelet agents IPD meta-analysis (Askie et al, Lancet 2007) — 32,217 women; PE RR 0.90 (95% CI 0.84–0.97); the modest pooled effect that anchored guidelines pre-ASPRE.
• Two trials of low-dose calcium (Dwarkanath et al, NEJM 2024;390:143–153) — India + Tanzania; 500 mg non-inferior to 1500 mg for pre-eclampsia.
• Cochrane — calcium supplementation in pregnancy (Cluver et al, 2025) — 10 RCTs, 37,504 women; little to no difference in PE on higher-quality analysis; high- vs low-dose equivalent.