The Aspirin Story in Reducing the Incidence of Preeclampsia
February 1, 2002
The Aspirin Story in Reducing the Incidence of Preeclampsia
Abstract & Commentary
Synopsis: This study evaluates the ability of aspirin to lessen the incidence of preeclampsia in patients who had abnormal uterine artery Dopplers in the second trimester.
Source: Coomarasamy A, et al. Obstet Gynecol. 2001; 98:861-866.
Coomarasamy and colleagues recently published a meta-analysis evaluating the ability of aspirin (ASA) to lessen the incidence of preeclampsia in patients who had abnormal uterine artery (UtA) Dopplers in the second trimester. The group applied stringent criteria to articles in the literature surfacing after 1990 that were met by 5 randomized clinical trials (RCTs). Each study involved patients with at least 1 abnormal UtA waveform at 18-24 weeks of gestation who were then randomized to having 50-100 mg of aspirin, no treatment, or a placebo. Coomarasamy et al were interested in 2 main outcomes: the presence or absence of preeclampsia and the birthweight.
The pooled data showed a significant benefit of ASA in preventing preeclampsia (OR, 0.55, 95% CI, 0.32-0.95). Although infants born to mothers on ASA were on average 84 g larger, this difference did not attain statistical significance.
Comment by John C. Hobbins, MD
Original work by Brosens and, later, others indicates that the spiral arteries, the end tributaries of the UtAs, are invaded in 2 phases by the adjacent trophoblast in the first and second trimester. This creates open conduits for maternal blood to freely enter the intravillous space. In preeclampsia, this trophoblastic invasion simply does not occur.
Years ago, Campbell postulated that this critical event could be monitored with UtA Dopplers since the opening of the spiral arteries would create a decrease in resistance that would be reflected upstream. The original work from the King’s College Hospital group, showing a strong relationship between abnormal UtA waveform and preeclampsia has been confirmed by many recent investigations, the last of which involving 8300 patients, emerged in November. The strongest correlation with abnormal UtA waveform occurs in patients with severe preeclampsia requiring delivery prior to 33 weeks of gestation. Here the sensitivity of abnormal UtA waveforms exceeds 90%.
Unfortunately, there are 2 facets of this type of screening that have generated confusion. First, some patients who have abnormal UtA waveform at 18 weeks will convert to a normal waveform by 24 weeks and these patients will have normal outcomes. These "late bloomers" confused the interpretation of the original investigations that were aimed at screening only at 18 weeks. However, if screening were to be accomplished at 24 weeks, the sensitivity and positive predictive values are enhanced appreciably.
The second problem has to do with the definition of abnormality. When increased resistance (impedence) is encountered downstream, the UtA will reflect this in 1 of 2 ways: 1) a low-end diastolic flow (S/D ratio of > 2.9); or 2) a notch in the diastolic component of the waveform. Many of the studies in the literature have defined any of the above in either UtA as being abnormal. However, it is clear that patients with bilateral notches and low-end diastolic flows have a far higher risk of preeclampsia and/or intrauterine growth retardation (IUGR) than a patient who, for example, has only low-end diastolic flow in 1 artery.
Boiling down the literature to numbers that can be used clinically, at 24 weeks the chance of a patient developing some form of preeclampsia and/or IUGR with a unilateral UtA abnormality is about 20%, while bilateral abnormalities increase the chance to about 70%.
Now to this, many might legitimately say "So what! What can one do preemptively, except to watch these patients carefully for signs of preeclampsia?"
This is where the above meta-analysis comes in. In preeclampsia, there is an imbalance between thromboxane (higher) and prostacyclin (lower). Low-dose ASA can restore this critical balance by selectively diminishing thromboxane levels.
Interestingly, 2 NICHD perinatal network RCTs did not yield results that generated much excitement about the preventative value of ASA. The first study involved relatively low-risk patients for preeclampsia (nulliparous), and the second involved "high-risk" patients. Neither showed a significant decrease in preeclampsia in those taking aspirin. However, most importantly, these studies did not include assessment of UtA waveform.
Sifting through the data generated over the last 15 years (including our own investigation), it seems that screening everyone in the second trimester with UtA Dopplers is not worthwhile. However, in patients who are at-risk for preeclampsia and/or IUGR, this type of Doppler investigation makes sense. These would include patients with a previous history of hypertension in pregnancy, a strong family history of hypertension, a history of IUGR, and elevated second trimester human chorionic gonadotropin (HCG) or maternal alpha-fetoprotein (MSAFP), or a strong suspicion by reproductive history of antiphospholipid antibody syndrome without laboratory confirmation of such.
Coomarasamy et al found that for every case of preeclampsia prevented with ASA, 16 patients would have to be treated. This may be well worth the effort, since low-dose ASA has a negligible risk of complications.
The questions that remain are "when to screen and when to treat?" By screening and treating at 18 weeks, one would be unnecessarily treating the late convertors who are destined to have normal pregnancies. However, although there are no studies available that address this, it would seem that the earlier the opportunity to get ASA on board, the better the chance of preventing a problem whose genesis starts long before the 24th week of gestation. Repeating the Doppler evaluation at 24 weeks in those with abnormal results at 18 weeks would allow the discontinuation of ASA in the later convertors, comprising about half of the treated population. In this way, only those who needed the ASA would get it throughout the remainder of pregnancy and these patients might benefit from an early start. v
Suggested Reading
1. Caritis S, et al. N Engl J Med. 1998;338(11):701-705.
2. Campbell S, et al. Lancet. 1983;1(8326 Pt 1):675-677.
3. Bower S, et al. Obstet Gynecol. 1993;82(1):78-83.
4. Papageorghiou AT, et al. Ultrasound Obstet Gynecol. 2001;18:441-449.
Dr. Hobbins is Professor and Chief of Obstetrics, University of Colorado Health Sciences Center, Denver, CO.
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