Low-dose Aspirin to Prevent Preeclampsia
Abstract & Commentary
By John C. Hobbins, MD, Professor, Department of Obstetrics and Gynecology, University of Colorado Health Sciences Center, Denver, is Associate Editor for OB/GYN Clinical Alert.
Dr. Hobbins reports no financial relationship to this field of study.
Synopsis: Low-dose aspirin, given before 17 weeks, significantly decreases the risk of preeclampsia, severe preeclampsia, IUGR, and preterm birth, compared with its effect when given after that time.
Source: Bujold E, et al. Prevention of preeclampsia and intrauterine growth restriction with aspirin started in early pregnancy: A meta-analysis. Obstet Gynecol 2010;116:402-414.
Many clinicians are reluctant to give low-dose aspirin (ldasa) to pregnant women for the prevention of preeclampsia. This reluctance is not based on a fear of potential risk, but on inconsistent study results regarding the efficacy of ASA. Generally, the normal two-stage trophoblastic invasion of the placental spiral arteries is complete by 18-20 weeks of gestation. However, in preeclampsia this trophoblastic remodeling does not happen. The rationale for using LDASA is anchored in the concept that the use of ASA can encourage placental remodeling by altering the relationship between thromboxane and prostacyclin. However, initially, results from randomized clinical trials (RCTs) evaluating patients at risk for preeclampsia or intrauterine growth restriction (IUGR) had not uniformly shown benefit.
Bujold et al, invoking the adage "the earlier the better," reviewed the recent literature and found 12 studies where there was information regarding patients who were randomized to LDASA or placebo at or before 16 weeks and another 22 studies where randomization occurred after 16 weeks. The analysis involved 11,348 women at risk for preeclampsia (a previous history of preeclampsia, IUGR, hypertensive disease, and/or those with abnormal uterine artery waveforms).
Those getting LDASA at or before 16 weeks had a reduction in preeclampsia by half (odds ratio [OR], 0.47; 95% confidence interval [CI], 0.34-0.65) compared with those who received LDASA after 16 weeks of gestation (OR, 0.81; 95% CI, 0.63-1.03). An impressive difference was noted for severe preeclampsia in those getting LDASA at or before 16 weeks (relative risk [RR], 0.09; 95% CI, 0.02-0.37), compared with those who received LDASA after 16 weeks (RR, 0.26; 95% CI, 0.05-1.26). Also, there were significant and dramatic reductions in the incidence of preterm birth and IUGR when LDASA was given at or before 16 weeks, compared with after 16 weeks.
Commentary
The concept of heading preeclampsia off at the pass with LDASA has been around for many years, and was the subject of two large NICHD perinatal network RCTs, one in low-risk patients1 and the other in high-risk patients.2 The results were inconclusive, but when data from the second study were pooled with those from later studies,2 benefit was demonstrated, especially in preventing severe preeclampsia. The featured study above from Bujold et al strongly suggests that the early administration of LDASA is the best approach to preventing adverse pregnancy outcome.
So who would benefit most from LDASA?
1. Patients at historical risk for adverse pregnancy outcome would include those with a history of preeclampsia, pregnancy-induced hypertension, abruption, and IUGR, where the bulk of "high-risk" studies and the meta-analyses by Coomarasamy3 and Bujold have shown benefit, especially if used early.
2. Patients with abnormal uterine artery wave forms. Interestingly, although initial study results have been inconsistent regarding the ability of using uterine arteries to predict preeclampsia, recent data have shown its use in high-risk patients to have very reasonable efficacy in predicting preeclampsia and IUGR.4-6 Coomarasamy et al published a meta-analysis of RCTs involving the use of LDASA in patients with abnormal second trimester uterine artery waveforms and found a statistically significant halving of preeclampsia and, although not significant, it added, on average, 84 g to birth weights.7 They estimated that one patient would be prevented from having preeclampsia for every 16 patients treated. Bujold et al, in another publication, added more studies to the above meta-analysis and found a distinct benefit from LDASA in patients with abnormal uterine artery waveforms, particularly in the two studies that included patients who were given the medication at or before 16 weeks.8 Specifically in this group, significant reductions were noted, with an RR for preeclampsia and severe preeclampsia of 0.48 and 0.38, respectively, in those given LDASA before 16 weeks. In patients with abnormal uterine arteries, five patients would need to be treated for every patient in whom preeclampsia was prevented.
3. Other patients possibly benefiting from LDASA. Space constraints will not allow discussion of all of the screening tests for preeclampsia and IUGR, but the ones that have shown most promise are: first trimester uterine artery waveforms, first trimester placental volume, plasma protein-13 (PP13), second trimester inhibin-A, or combinations of the above.
Who have not yet been shown to benefit from LDASA? Women at low risk for adverse pregnancy outcome or those who have been started on LDASA after 20 weeks.
Is there any danger in giving LDASA? In the second NICHD trial, the incidence of placental abruption was higher in the LDASA group than controls,2 and this triggered concern about using it for preeclampsia prophylaxis. However, lost in the details of the study was the fact that the difference between abruption in the LDASA group and controls was largely due to an incredibly low rate of abruption in the control group. All subsequent meta-analyses, including the recent Bujold study above, have found no differences between groups in the incidence of abruption or any other complication that might be attributed to the medication.
What seems to be the most efficacious dosage of LDASA? For a while I started prescribing two tablets of 84 mg a day based on a study showing a greater benefit in preventing strokes in adults using a double dose of "baby" aspirin vs a single dose per day. However, I soon backed off, realizing this was a simplistic attempt to equate preeclampsia in pregnant women to strokes in non-pregnant older adults, and no study has yet pitted a single dose against a double dose for preeclampsia. Interestingly, the Bujold benefit analysis included studies where the dosage varied from 50 mg to 150 mg per day. I suggest staying with a single 84 mg tablet a day.
When should the medication be stopped? This is not going to be answered based on evidence, because none exists. However, in the absence of other factors, we have been stopping LDASA after 34 weeks, simply because some anesthesiologists have been reluctant to give epidurals to patients on LDASA.
What about thrombophilia and LDASA? This represents a separate topic, which was covered in the June 2009 issue of OB/GYN Clinical Alert, but, because there seems to be little consensus on whom to treat with LDASA and/or anticoagulation (except in true anti-phospholipid antibody syndrome), thrombophilia will be revisited in the near future when the data are clearer.
References
- Sibai BM, et al. Prevention of preeclampsia with low-dose aspirin in healthy, nulliparous women. The National Institute of Child Health and Human Development Network of Maternal-Fetal Medicine Units. N Engl J Med 1993;329:1213-1218.
- Caritis S, et al. Low-dose aspirin to prevent preeclampsia in women at high risk. National Institute of Child Health and Human Development Network of Maternal-Fetal Medicine Units. N Engl J Med 1998;338:701-705.
- Coomarasamy A, et al. Aspirin for prevention of preeclampsia in women with historical risk factors: A systematic review. Obstet Gynecol 2003;101:1319-1332.
- Albaiges G, et al. One-stage screening for pregnancy complications by color Doppler assessment of the uterine arteries at 23 weeks' gestation. Obstet Gynecol 2000;96:559-564.
- Onwudiwe N, et al. Prediction of pre-eclampsia by a combination of maternal history, uterine artery Doppler and mean arterial pressure. Ultrasound Obstet Gynecol 2008;32:877-883.
- Plasencia W, et al. Uterine artery Doppler at 11 + 0 to 13 + 6 and 21 + 0 to 24 + 6 weeks in the prediction of pre-eclampsia. Ultrasound Obstet Gynecol 2008;32:138-146.
- Coomarasamy A, et al. Aspirin for prevention of preeclampsia in women with abnormal uterine artery Doppler: A meta-analysis. Obstet Gynecol2001;98:861-866.
- Bujold E, et al. Acetylsalicylic acid for the prevention of preeclampsia and intra-uterine growth restriction in women with abnormal uterine artery Doppler: A systematic review and meta-analysis. J Obstet Gynaecol Can 2009;31:818-826.
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