EB Research: Effects of Aspirin in Gestation and Reproduction (EAGeR) Study

Study Objective

EAGeR logoThe EAGeR Trial is a multisite, prospective, double-blind, block-randomized, placebo-controlled clinical trial designed to evaluate the effect of daily low-dose aspirin (LDA) on live-birth rates.

Background

Maximally fertile couples have only an approximately 30% chance of conception in each menstrual cycle, and average monthly fecundity is 20%. Estimates of pregnancy loss range from about 15% to 30%. Available data suggest that LDA has the potential to favorably impact several aspects of reproduction, including conception, implantation, early pregnancy loss, late fetal death, low birth weight, placental insufficiency, and preterm birth. LDA is widely available, inexpensive, and has few maternal side effects.

Prior studies focused on narrow aspects of the effects of LDA, such as in vitro fertilization outcomes or the development of preeclampsia; such studies also have generally begun therapy mid- or late-gestation. Because each stage of reproduction is inextricably linked, better blood flow at the time of conception and implantation may ultimately lead to improved placental function and a reduced risk of preeclampsia, small-for-gestational-age infants, and preterm birth, and increased probabilities of pregnancy and live birth.

Study Design and Progress

EAGeR Trial researchers enrolled 1,228 regularly menstruating women, between 18 and 40 years of age, who had experienced one or two prior miscarriages and who were attempting pregnancy again. Participants were randomized to receive treatment (81 milligrams (mg) of aspirin plus 0.4 mg of folic acid daily) or placebo (0.4 mg of folic acid only), beginning before conception and continuing for up to six menstrual cycles while trying to become pregnant or until week 36 of pregnancy for women who became pregnant. Participants used fertility monitors to time intercourse and home digital pregnancy testing kits to confirm pregnancy. Daily urine samples were also collected to monitor very early pregnancy and pregnancy loss.

The primary outcomes of the EAGeR Trial were published in 2014, with additional secondary outcomes and investigations of potential biological mechanisms published between 2015 and 2020. Overall, this research found that daily LDA did not prevent subsequent pregnancy loss among women with a history of one or two prior pregnancy losses. However, among women who had experienced a single recent pregnancy loss, LDA increased the likelihood of becoming pregnant and having a live birth and decreased the risk of preterm birth.

These findings led to recent studies into the biological mechanisms of aspirin’s effects on reproductive outcomes. Notably, low-grade inflammation was associated with fewer pregnancies and reduced secondary sex ratio, and treatment with LDA restored both these decrements. EB researchers determined that LDA was most effective in increasing pregnancy and birth rate in women who had no or few components of the metabolic syndrome.

Other potential mechanisms of LDA impact could include platelet function. A pre-pregnancy measurement marker of platelet function was associated with subsequent risk of placenta-mediated adverse pregnancy outcomes in women randomized to placebo, whereas this finding was attenuated in women receiving LDA. Notably, opioid exposure, pre-pregnancy cannabis use, and a common class of antidepressants, Selective Serotonin Reuptake Inhibitors, were all associated with longer time to pregnancy.

Following a pregnancy loss, highest live birth rates were observed among couples who did not wait before trying to conceive again. In addition, this research found that nausea and vomiting were common very early in pregnancy and were associated with a strongly reduced risk for pregnancy loss. Accounting for nausea and bleeding symptoms, taking LDA at least 4 of 7 days per week while trying to conceive significantly improved the live birth rate by 15 births per 100 women.

The team intends to build upon existing findings from the EAGeR Trial to fill gaps in reproductive epidemiology, including continuing to understand the role of chronic inflammation in reproductive processes; investigating links between commonly used medications, fecundability, and pregnancy loss; and adjusting for compliance with treatment.

EAGeR Publications (PDF 261 KB)

Principal Investigators

Enrique F. Schisterman, Ph.D., and Sunni L. Mumford, Ph.D.

EB Collaborators

Selected Publications

Theilen, L. H., Campbell, H. D., Mumford, S. L., Purdue-Smithe, A. C., Sjaarda, L. A., Perkins, N. J., Radoc, J. G., Silver, R. M., & Schisterman, E. F. (2020). Platelet activation and placenta-mediated adverse pregnancy outcomes: an ancillary study to the Effects of Aspirin in Gestation and Reproduction trial. American Journal of Obstetrics and Gynecology, 223(5), 741.e1–741.e12. PMID: 32434001. PMCID: PMC7609468 (available on November 1, 2021)

Flannagan, K. S., Mumford, S. L., Sjaarda, L. A., Radoc, J. G., Perkins, N. J., Andriessen, V. C., Zolton, J. R., Silver, R. M., & Schisterman, E. F. (2020). Is opioid use safe in women trying to conceive?. Epidemiology (Cambridge, Mass.), 31(6), 844–851. PMID: 33311959. PMCID: PMC7725439 (available on November 1, 2021)

Sjaarda, L. A., Radoc, J. G., Flannagan, K. S., Mumford, S. L., Kim, K., Perkins, N. J., Silver, R. M., & Schisterman, E. F. (2020). Urinary selective serotonin reuptake inhibitors across critical windows of pregnancy establishment: a prospective cohort study of fecundability and pregnancy loss. Fertility and Sterility, 114(6), 1278–1287. PMID: 33066974.

Mumford, S. L., Garbose, R. A., Kim, K., Kissell, K., Kuhr, D. L., Omosigho, U. R., Perkins, N. J., Galai, N., Silver, R. M., Sjaarda, L. A., Plowden, T. C., & Schisterman, E. F. (2018). Association of preconception serum 25-hydroxyvitamin D concentrations with livebirth and pregnancy loss: a prospective cohort study. The Lancet. Diabetes & Endocrinology, 6(9), 725–732. PMID: 29859909. PMCID: PMC6109429

Sjaarda, L. A., Radin, R. G., Silver, R. M., Mitchell, E., Mumford, S. L., Wilcox, B., Galai, N., Perkins, N. J., Wactawski-Wende, J., Stanford, J. B., & Schisterman, E. F. (2017). Preconception low-dose aspirin restores diminished pregnancy and live birth rates in women with low-grade inflammation: a secondary analysis of a randomized trial. The Journal of Clinical Endocrinology and Metabolism, 102(5), 1495–1504. PMID: 28323989. PMCID: PMC5443323

Hinkle, S. N., Mumford, S. L., Grantz, K. L., Silver, R. M., Mitchell, E. M., Sjaarda, L. A., Radin, R. G., Perkins, N. J., Galai, N., & Schisterman, E. F. (2016). Association of nausea and vomiting during pregnancy with pregnancy loss: a secondary analysis of a randomized clinical trial. JAMA Internal Medicine, 176(11), 1621–1627. PMID: 27669539. PMCID: PMC6191846

Radin, R. G., Mumford, S. L., Silver, R. M., Lesher, L. L., Galai, N., Faraggi, D., Wactawski-Wende, J., Townsend, J. M., Lynch, A. M., Simhan, H. N., Sjaarda, L. A., Perkins, N. J., Zarek, S. M., Schliep, K. C., & Schisterman, E. F. (2015). Sex ratio following preconception low-dose aspirin in women with prior pregnancy loss. The Journal of Clinical Investigation, 125(9), 3619–3626. PMID: 26280577. PMCID: PMC4588294

Schisterman, E. F., Silver, R. M., Lesher, L. L., Faraggi, D., Wactawski-Wende, J., Townsend, J. M., Lynch, A. M., Perkins, N. J., Mumford, S. L., & Galai, N. (2014). Preconception low-dose aspirin and pregnancy outcomes: results from the EAGeR randomised trial. Lancet (London, England), 384(9937), 29–36. PMID: 24702835. PMCID: PMC4181666

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