Aspirin In The Prevention Of Pre-Eclampsia: Where Are We Now?

Khalid A, Byrne B M.
RCSI Dept of Obstetrics and Gynaecology, Coombe Women and Infants University Hospital, Dublin 8

Pre-eclampsia is a pregnancy specific multi-systemic disorder that causes maternal and perinatal morbidity and mortality worldwide. It is estimated to complicate between three to five percent of pregnancies and contributes to 8 to 10% of all preterm births1,2. Aspirin inhibits cyclooxygenase in platelets and endothelium in a fashion that alters the balance between the vasoconstrictor thromboxane and the vasodilator prostacyclin. This potentiates vasodilatation and reduces platelet aggregation, contributors to the endothelial dysfunction seen in preeclampsia. Over 100 clinical trials have examined whether or not Aspirin, when prescribed from early pregnancy, can prevent pre-eclampsia, and the consensus is that it reduces the incidence by approximately 10 to 24 % in women that are deemed to be at risk3,4.

There is broad consensus that pre-eclampsia in a previous pregnancy is a risk factor for pre-eclampsia in a subsequent pregnancy, particularly if the disease prompted delivery prior to 34 weeks gestation, or there was an adverse outcome for mother or fetus. The risk of recurrence of pre-eclampsia in a future pregnancy is estimated at one in two (55%) if delivery occurred prior to 28 weeks, and one in four (25%) if delivery occurred before 34 weeks2. Following the work of the Task Force on Hypertension in Pregnancy in 2013, the American College of Obstetrics and Gynaecology (ACOG) recommended low dose aspirin from the late first trimester for those with a history of early onset pre-eclampsia or, more than one previous pregnancy with pre-eclampsia5. They later expanded recommendations to include multiple gestation, chronic hypertension, diabetes, renal disease and autoimmune diseases such as SLE or APLS. The National Institute for Health and Care Excellence (NICE) and the World Health Organisation (WHO) have similar recommendations but criteria vary slightly6. The limitations of this history based risk assessment has prompted research into alternative markers for the disease.

Maternal mean arterial blood pressure (MAP) and uterine artery pulsatility index (PI) are higher and the placental biomarkers [(serum pregnancy associated plasma protein A (PAPP-A) and placental-like growth factor (PLGF)] are lower in the first trimester in women who subsequently develop pre-eclampsia. The Fetal Medicine Foundation has explored whether or not a combination of maternal history, maternal biophysical characteristics and placental biomarkers can better predict pre-eclampsia. At a false positive rate of 10%, detection rates for early onset pre-eclampsia increase from 50% using maternal factors alone to 75% when all modalities are combined. Of note, PAPP-A did not increase detection when PLGF-1 was incorporated into the model7. External validation on independent data from different sources is required to support these findings.

The Fetal Medicine Foundation algorithm was applied to define high risk in the Combined Multimarker Screening and Randomised Patient Treatment with Aspirin for Evidence Based Preeclampsia Prevention (ASPRE) trial that has recently been published8. Twenty-six thousand, nine hundred and forty-one women with singleton pregnancies were screened in this fashion at a routine antenatal visit between 11 and 14 weeks gestation. Two thousand, nine hundred and seventy-one (11%) were deemed to be at high risk and were randomised to receive Aspirin 150 mgs or placebo until 36 weeks gestation. The primary outcome was delivery before 37 weeks for pre-eclampsia and this was less likely to occur in the group that received aspirin 13/700 (1.6%) compared to placebo 35/700 (4.3%): OR = 0.38 (95% CI = 0.2 – 0.74). There was no significant difference in term pre-eclampsia. Adverse outcomes for the fetus or neonate were not different but the study was not powered to detect these. There was also no significant difference in adverse or serious adverse events in either group8.

This study is a well-designed multicentre, randomised, placebo controlled trial with rigorous methodology and adds to the considerable amount of research work in this area. Despite this, more questions than answers remain. Two recent meta-analyses report conflicting evidence for whether or not aspirin prevents preeclampsia when commenced before or after 16 weeks gestation9. The optimum dose is controversial with issues such as compliance, bioavailability, target effect, and ‘aspirin resistance’ needing clarification. In the ASPRE trial, however, we can clearly say that aspirin commenced before 14 weeks gestation at a dose of 150 mgs appears to reduce the incidence of delivery for pre-eclampsia before 37 weeks in women deemed to be at high risk as determined by the Fetal Medicine Foundation Algorithm.

There is robust evidence dating back to the CLASP trial confirming the safety of aspirin in pregnancy. There has been no evidence of increased risk of maternal or fetal bleeding, no evidence of teratogenicity and no association with adverse outcome when regional anaesthesia is used10. More recently, a systematic review by the US Preventative Services Task Force also confirmed normal follow-up of these children at 18 years5.

How does this trial influence clinical practice? It provides more evidence to support the use of aspirin for the prevention of pre-eclampsia in high risk women. Unfortunately the screening tools used for prediction are complex, not externally validated, costly and not necessarily applicable to all health care systems. The aspiration is to invert the ‘pyramid of care’ delivered routinely. A recent report from US Preventative Services Task Force concluded that ‘ Current screening practices are considered routine and represent relatively minor burdens to patients, clinicians and health care systems, but evidence is limited for determining the benefits and harm of preeclampsia screening5. An alternative strategy would be to prescribe low dose aspirin universally, regardless of risk, a concept that is pragmatic and not without merit, considering the overwhelming evidence for its safety in pregnancy10.

Correspondence
Bridgette Byrne MD, FRCPI, FRCOG, Senior Lecturer in Obstetrics and Gynaecology, RCSI Dept of Obstetrics and Gynaecology, Coombe Women and Infants University Hospital, Dublin 8.
Email: BByrne3@rcsi.ie

References
1. Hutcheon JA, Lisonkova S, Joseph KS. Epidemiology of pre-eclampsia and the other hypertensive disorders of pregnancy. Best Practice & Research Clinical Obstetrics & Gynaecology. 2011; 25 (4): 391-40
2. The National Institute for Health and Clinical Excellence. The management of hypertensive disorders during pregnancy. Clinical Guideline 107; August 2010.
3. Bujold E, Roberge S, Lacasse Y, Bureau M, Audibert F, Marcoux S, Forest JC, Giguere Y. Prevention of preeclampsia and intrauterine growth restriction with aspirin started in early pregnancy. Obstetrics & Gynecology 2010; 116: 402–12
4. Duley L Pre-eclampsia, eclampsia, and hypertension. Clinical Evidence 2011; 2: 1402
5. Henderson JT, Thompson JH, Burda BU, Cantor A, Beil T, Whitlock EP, Rockville MD. Screening for pre-eclampsia: A systematic evidence review for the US Preventive Services Task Force. Agency for Healthcare Research and Quality (US); 2017 Apr Report No: 14-05211-EF-1.
6. Practice Advisory on Low – Dose Aspirin and Prevention of Preeclampsia: Updated Recommendations. ACOG July 11, 2016.
7. O’Gorman N, Wright D, Syngelaki A, Akolekar R, Wright A, Poon LC, Nicolaides KH. Competing risks model in screening for preeclampsia by maternal factors and biomarkers at 11-13 weeks gestation. Am JOG 2016; 214(1): 103 e 1-12.
8. Rolnik DL, Wright D, Poon LC, O’Gorman N, Syngelaki A, De Paco Matallana C, Akolekar R, Cicero S, Janga D, Singh M, Molina FS, Persico N, Jani JC, Plasencia W, Papaioannou G, Tenenbaum-Gavish K, Meiri H, Gizurarson S, MacLagan K, Nicolaides KH. Aspirin versus Placebo in Pregnancies at High Risk for Preterm Preeclampsia. N Engl J Med 2017; 377:613-622
9. Tong S, Mol BW, Walker SP. Preventing preeclampsia with aspirin: does dose or timing matter? AJOG Feb 2017: 95-97.
10. Mone F, Mulcahy C, McParland P, McAuliffe F. Should we recommend universal aspirin for all pregnant women? AJOG 2017: 141-144

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