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EB Research - Reproductive Epidemiology
Effects of Aspirin in Gestation and Reproduction (EAGeR) Study
The EAGeR Trial is a multisite, block-randomized placebo-controlled clinical trial designed to evaluate the effect of daily low-dose aspirin (LDA) on live-birth rates.
Maximally fertile couples have only an approximately 30-percent chance of conception in a given menstrual cycle, and average monthly fecundity is 20 percent. Estimates of miscarriages and early pregnancy loss vary, ranging from about 15 percent to 30 percent. 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 outcome or development of preeclampsia; such studies have also generally begun therapy mid or late gestation. Reproduction is unique in that each stage is inextricably linked. Therefore, 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.
Study Design & Progress
The EAGeR trial is a multisite, prospective, double-blind, block-randomized trial designed to assess the effects of low-dose aspirin on implantation and pregnancy outcomes. A total of 1,228 regularly menstruating women age 18 to 40 years with up to two recent miscarriages and who planned to become pregnant again were randomized for this trial. Each woman was randomly assigned to the treatment group with 81 mg aspirin plus 0.4 mg folic acid daily, or to the placebo group with 0.4 mg folic acid only. Treatment/placebo administration began prior to conception and continued during pregnancy. Fertility monitors were used to assist with timing of intercourse; home digital pregnancy testing kits were used to indicate pregnancy; and daily urine samples were collected to monitor very early pregnancy and pregnancy loss. Women were followed for up to six menstrual cycles while trying to become pregnant and, if they became pregnant, throughout pregnancy.
The primary outcomes of the EAGeR trial were published in 2014, with additional findings regarding secondary outcomes published in 2015 and 2016. Overall, we found that a daily LDA did not appear to prevent subsequent pregnancy loss among women with a history of one or two prior pregnancy losses. However, in a smaller group of 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. LDA was also associated with increased pregnancy rates, and the sex ratio, among women with high inflammation.
The EAGeR team has also been active evaluating other hypotheses. Importantly, we found that nausea and vomiting were common very early in pregnancy and were associated with a reduced risk for pregnancy loss.
These findings overcome prior analytic and design limitations and represent the most definitive data available to date about the protective association of nausea and vomiting in early pregnancy and the risk for pregnancy loss. Moreover, our data also suggest that the current recommendations for delaying pregnancy attempt after an early loss may be unwarranted. The team intends to build upon its current findings from the EAGeR Trial to fill critical research gaps in its quest to answer important public health questions for women of reproductive age.
Biomarker Ancillary Study
Stored biospecimens from the EAGeR Trial have been used to measure several important metabolic, inflammatory, and dietary biomarkers to address other pressing questions for women of reproductive age. Specifically, we have evaluated the utility of routine anti-Mullerian hormone (AMH) testing for prediction of pregnancy loss and preconception counseling in young, fecund women. This work found that AMH levels were not associated with pregnancy loss; thus, our data do not support routine AMH testing in fertile women.
We also evaluated the role of subclinical hypothyroidism and antithyroid antibodies and found no associations with time-to-pregnancy or pregnancy loss. Lipids also offer the potential for identifying pregnancies at risk for adverse outcomes. We found that abnormal baseline serum lipoprotein cholesterol levels were associated with reduced fecundability. Because lipid levels are modifiable, future work is needed to investigate whether they may offer a simple and inexpensive target to improve female fecundability. Ongoing work includes evaluating lipids in relation to other pregnancy outcomes, as well as understanding the role of dietary biomarkers on fecundability and pregnancy.
Enrique F. Schisterman, Ph.D.
Matthew Connell, D.O.
Tiffany Holland, B.A.
Katherine Laughon Grantz, M.D., M.S.
Keewan Kim, Ph.D.
Pauline Mendola, Ph.D.
- Carrie Nobles, Ph.D.
Sunni L. Mumford, Ph.D.
Neil Perkins, Ph.D.
Lindsey Sjaarda, Ph.D.
Edwina Yeung, Ph.D.
Cuilin Zhang, M.D., M.P.H., Ph.D.
- Schisterman EF, Silver RM, Lesher LL, Faraggi D, Wactawski-Wende J, Townsend JM, Lynch AM, Perkins NJ, Mumford SL, Galai N. Preconception Low-Dose Aspirin and Pregnancy Outcomes: Results from the EAGeR Randomised Trial. Lancet. 2014 Jul 5;384(9937):29-36. PMCID:
- Schisterman EF, Mumford SL, Schliep KC, Sjaarda LA, Stanford JB, Lesher LL, Wactawski-Wende J, Lynch AM, Townsend JM, Perkins NJ, Zarek SM, Tsai MY, Chen Z, Faraggi D, Galai N, Silver RM. Preconception low dose aspirin and time to pregnancy: Findings from the effects of aspirin in gestation and reproduction randomized trial. The Journal of Clinical Endocrinology and Metabolism. 2015 May;100(5):1785-91. PMCID:
- Radin RG, Mumford SL, Silver RM, Lesher LL, Galai N, Faraggi D, Wactawski-Wende J, Townsend JM, Lynch AM, Simhan HN, Sjaarda LA, Perkins NJ, Zarek SM, Schliep KC, Schisterman EF. Sex ratio following preconception low-dose aspirin in women with prior pregnancy loss. The Journal of Clinical Investigation. 2015 Sep;125(9):3619-26. PMCID:
- Hinkle SN, Mumford SL, Grantz KL, Silver RM, Mitchell EM, Sjaarda LA, Radin RG, Perkins NJ, Galai N, Schisterman EF. Association of Nausea and Vomiting During Pregnancy with Pregnancy Loss: A Secondary Analysis of a Randomized Clinical Trial. JAMA Internal Medicine. 2016 Nov;176(11):1621-7. PMID:
- Pugh SJ, Schisterman EF, Browne RW, Lynch AM, Mumford SL, Perkins NJ, Silver R, Sjaarda L, Stanford JB, Wactawski-Wende J, Wilcox B, Grantz KL. Preconception maternal lipoprotein levels in relation to fecundability. Human Reproduction. 2017 May 1;32(5):1055-63. PMID:
- Sjaarda LA, Radin RG, Silver RM, Mitchell E, Mumford SL, Wilcox B, Galai N, Perkins NJ, Wactawski-Wende J, Stanford JB, Schisterman EF. 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. 2017 May 1;102(5):1495-504. PMCID:
PMC5443323 [Available 2018-05-01]. PMID: