The Effects of Aspirin in Gestation and Reproduction (EAGeR) Trial: A Story of Discovery

Abstract

Human reproduction is an inefficient process. There are several drivers of complications along the path to and during pregnancy, one of which is inflammation. Treatments to mitigate the deleterious effects of aberrant inflammation with something inexpensive and widely available like aspirin could have dramatic global impact. The Effects of Aspirin in Gestation and Reproduction (EAGeR) trial enrolled women aged 18 to 40 years with one to two prior pregnancy losses and no diagnosis of infertility. Patients were randomized to either low-dose aspirin or placebo. Here, we review the collective findings of the EAGeR trial to date and discuss several important lessons learned from the unique data resulting from this groundbreaking trial. Findings reported from this trial provide significant advances in the understanding of aspirin's potential mechanisms in modulating reproductive processes and the role of inflammation in these processes. This review describes the collective findings of the EAGeR trial in the context of the existing literature regarding aspirin and inflammation in reproduction to inform relevant next steps in fertility and obstetric research, as well as potential implications for clinical care.

Keywords

aspirin - inflammation - implantation

Trial Registration

ClinicalTrials.gov, NCT00467363.

Funding

This study was funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD (contract nos. HHSN267200603423, HHSN267200603424, and HHSN 267200603426) and by the National Institutes of Health (NIH) Medical Research Scholars Program, a public–private partnership supported jointly by the NIH and generous contributions to the Foundation for the NIH from the Doris Duke Charitable Foundation, the American Association for Dental Research, the Colgate-Palmolive Company, Genentech, and alumni of student research programs and other individual supporters via contributions to the Foundation for the National Institutes of Health.

• References

• 1 Zinaman MJ, Clegg ED, Brown CC, O'Connor J, Selevan SG. Estimates of human fertility and pregnancy loss. Fertil Steril 1996; 65 (03) 503-509
• 2 Wilcox AJ, Weinberg CR, O'Connor JF. , et al. Incidence of early loss of pregnancy. N Engl J Med 1988; 319 (04) 189-194
• 3 Guttmacher AF. Factors affecting normal expectancy of conception. J Am Med Assoc 1956; 161 (09) 855-860
• 4 Wilcox AJ, Baird DD, Weinberg CR. Time of implantation of the conceptus and loss of pregnancy. N Engl J Med 1999; 340 (23) 1796-1799
• 5 Risch HA, Weiss NS, Clarke EA, Miller AB. Risk factors for spontaneous abortion and its recurrence. Am J Epidemiol 1988; 128 (02) 420-430
• 6 Eiben B, Bartels I, Bähr-Porsch S. , et al. Cytogenetic analysis of 750 spontaneous abortions with the direct-preparation method of chorionic villi and its implications for studying genetic causes of pregnancy wastage. Am J Hum Genet 1990; 47 (04) 656-663
• 7 Acién P. Reproductive performance of women with uterine malformations. Hum Reprod 1993; 8 (01) 122-126
• 8 Committee on Practice Bulletins—Obstetrics, American College of Obstetricians and Gynecologists. Practice Bulletin No. 132: Antiphospholipid syndrome. Obstet Gynecol 2012; 120 (06) 1514-1521
• 9 Abalovich M, Gutierrez S, Alcaraz G, Maccallini G, Garcia A, Levalle O. Overt and subclinical hypothyroidism complicating pregnancy. Thyroid 2002; 12 (01) 63-68
• 10 Greene MF. Spontaneous abortions and major malformations in women with diabetes mellitus. Semin Reprod Endocrinol 1999; 17 (02) 127-136
• 11 Silver RM, Branch DW. Sporadic and recurrent pregnancy loss. In: Reece EA, Hobbins JC. , eds. Medicine of the Fetus and Mother. 2nd ed. Philadelphia, PA: JB Lippincott Company; 1999: 195-216
• 12 Mor G, Cardenas I, Abrahams V, Guller S. Inflammation and pregnancy: the role of the immune system at the implantation site. Ann N Y Acad Sci 2011; 1221: 80-87
• 13 Romero R, Dey SK, Fisher SJ. Preterm labor: one syndrome, many causes. Science 2014; 345 (6198): 760-765
• 14 Kalagiri RR, Carder T, Choudhury S. , et al. Inflammation in complicated pregnancy and its outcome. Am J Perinatol 2016; 33 (14) 1337-1356
• 15 Bossick AS, Peters RM, Burmeister C, Kakumanu N, Shill JE, Cassidy-Bushrow AE. Antenatal inflammation and gestational diabetes mellitus risk among pregnant African-American women. J Reprod Immunol 2016; 115: 1-5
• 16 Thilaganathan B, Wormald B, Zanardini C, Sheldon J, Ralph E, Papageorghiou AT. Early-pregnancy multiple serum markers and second-trimester uterine artery Doppler in predicting preeclampsia. Obstet Gynecol 2010; 115 (06) 1233-1238
• 17 Boots CE, Jungheim ES. Inflammation and human ovarian follicular dynamics. Semin Reprod Med 2015; 33 (04) 270-275
• 18 Reljic M, Gorisek B. C-reactive protein and the treatment of pelvic inflammatory disease. Int J Gynaecol Obstet 1998; 60 (02) 143-150
• 19 Escobar-Morreale HF, Luque-Ramírez M, González F. Circulating inflammatory markers in polycystic ovary syndrome: a systematic review and metaanalysis. Fertil Steril 2011; 95 (03) 1048-58.e1 , 2
• 20 Agic A, Xu H, Finas D, Banz C, Diedrich K, Hornung D. Is endometriosis associated with systemic subclinical inflammation?. Gynecol Obstet Invest 2006; 62 (03) 139-147
• 21 Vane JR, Botting RM. The mechanism of action of aspirin. Thromb Res 2003; 110 (5-6): 255-258
• 22 Rubinstein M, Marazzi A, Polak de Fried E. Low-dose aspirin treatment improves ovarian responsiveness, uterine and ovarian blood flow velocity, implantation, and pregnancy rates in patients undergoing in vitro fertilization: a prospective, randomized, double-blind placebo-controlled assay. Fertil Steril 1999; 71 (05) 825-829
• 23 Dentali F, Ageno W, Rezoagli E. , et al. Low-dose aspirin for in vitro fertilization or intracytoplasmic sperm injection: a systematic review and a meta-analysis of the literature. J Thromb Haemost 2012; 10 (10) 2075-2085
• 24 Kaandorp SP, Goddijn M, van der Post JA. , et al. Aspirin plus heparin or aspirin alone in women with recurrent miscarriage. N Engl J Med 2010; 362 (17) 1586-1596
• 25 Kaandorp S, Di Nisio M, Goddijn M, Middeldorp S. Aspirin or anticoagulants for treating recurrent miscarriage in women without antiphospholipid syndrome. Cochrane Database Syst Rev 2009; (01) CD004734
• 26 Tulppala M, Marttunen M, Söderstrom-Anttila V. , et al. Low-dose aspirin in prevention of miscarriage in women with unexplained or autoimmune related recurrent miscarriage: effect on prostacyclin and thromboxane A2 production. Hum Reprod 1997; 12 (07) 1567-1572
• 27 Badawy AM, Khiary M, Sherif LS, Hassan M, Ragab A, Abdelall I. Low-molecular weight heparin in patients with recurrent early miscarriages of unknown aetiology. J Obstet Gynaecol 2008; 28 (03) 280-284
• 28 Clark P, Walker ID, Langhorne P. , et al; Scottish Pregnancy Intervention Study (SPIN) collaborators. SPIN (Scottish Pregnancy Intervention) study: a multicenter, randomized controlled trial of low-molecular-weight heparin and low-dose aspirin in women with recurrent miscarriage. Blood 2010; 115 (21) 4162-4167
• 29 Dolitzky M, Inbal A, Segal Y, Weiss A, Brenner B, Carp H. A randomized study of thromboprophylaxis in women with unexplained consecutive recurrent miscarriages. Fertil Steril 2006; 86 (02) 362-366
• 30 Visser J, Ulander VM, Helmerhorst FM. , et al. Thromboprophylaxis for recurrent miscarriage in women with or without thrombophilia. HABENOX: a randomised multicentre trial. Thromb Haemost 2011; 105 (02) 295-301
• 31 Dirckx K, Cabri P, Merien A. , et al. Does low-dose aspirin improve pregnancy rate in IVF/ICSI? A randomized double-blind placebo controlled trial. Hum Reprod 2009; 24 (04) 856-860
• 32 Duvan CI, Ozmen B, Satiroglu H, Atabekoglu CS, Berker B. Does addition of low-dose aspirin and/or steroid as a standard treatment in nonselected intracytoplasmic sperm injection cycles improve in vitro fertilization success? A randomized, prospective, placebo-controlled study. J Assist Reprod Genet 2006; 23 (01) 15-21
• 33 Lambers MJ, Hoozemans DA, Schats R, Homburg R, Lambalk CB, Hompes PG. Low-dose aspirin in non-tubal IVF patients with previous failed conception: a prospective randomized double-blind placebo-controlled trial. Fertil Steril 2009; 92 (03) 923-929
• 34 LeFevre ML. ; U.S. Preventive Services Task Force. Low-dose aspirin use for the prevention of morbidity and mortality from preeclampsia: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med 2014; 161 (11) 819-826
• 35 Schisterman EF, Silver RM, Lesher LL. , et al. Preconception low-dose aspirin and pregnancy outcomes: results from the EAGeR randomised trial. Lancet 2014; 384 (9937): 29-36
• 36 Mumford SL, Silver RM, Sjaarda LA. , et al. Expanded findings from a randomized controlled trial of preconception low-dose aspirin and pregnancy loss. Hum Reprod 2016; 31 (03) 657-665
• 37 Schisterman EF, Mumford SL, Schliep KC. , et al. Preconception low dose aspirin and time to pregnancy: findings from the effects of aspirin in gestation and reproduction randomized trial. J Clin Endocrinol Metab 2015; 100 (05) 1785-1791
• 38 Haiman CA, Pike MC, Bernstein L. , et al. Ethnic differences in ovulatory function in nulliparous women. Br J Cancer 2002; 86 (03) 367-371
• 39 Malcolm CE, Cumming DC. Does anovulation exist in eumenorrheic women?. Obstet Gynecol 2003; 102 (02) 317-318
• 40 Park SJ, Goldsmith LT, Skurnick JH, Wojtczuk A, Weiss G. Characteristics of the urinary luteinizing hormone surge in young ovulatory women. Fertil Steril 2007; 88 (03) 684-690
• 41 Gaskins AJ, Mumford SL, Zhang C. , et al; BioCycle Study Group. Effect of daily fiber intake on reproductive function: the BioCycle Study. Am J Clin Nutr 2009; 90 (04) 1061-1069
• 42 Marsh EE, Shaw ND, Klingman KM. , et al. Estrogen levels are higher across the menstrual cycle in African-American women compared with Caucasian women. J Clin Endocrinol Metab 2011; 96 (10) 3199-3206
• 43 Matyas RA, Mumford SL, Schliep KC. , et al. Effects of over-the-counter analgesic use on reproductive hormones and ovulation in healthy, premenopausal women. Hum Reprod 2015; 30 (07) 1714-1723
• 44 Nargund G, Wei CC. Successful planned delay of ovulation for one week with indomethacin. J Assist Reprod Genet 1996; 13 (08) 683-684
• 45 Radin RG, Sjaarda LA, Perkins NJ. , et al. Low-dose aspirin and sporadic anovulation in the EAGeR randomized trial. J Clin Endocrinol Metab 2017; 102 (01) 86-92
• 46 Sjaarda LA, Radin RG, Silver RM. , et al. Preconception low-dose aspirin restores diminished pregnancy and live birth rates in women with low grade inflammation: a secondary analysis of a randomized trial. J Clin Endocrinol Metab 2017; 102 (05) 1495-1504
• 47 Wolowczuk I. Obesity – an inflammatory state. Acta Vet Scand 2015; 57 (Suppl. 01) K5-K5
• 48 Macklon NS, Brosens JJ. The human endometrium as a sensor of embryo quality. Biol Reprod 2014; 91 (04) 98
• 49 Bermejo-Alvarez P, Rizos D, Rath D, Lonergan P, Gutierrez-Adan A. Sex determines the expression level of one third of the actively expressed genes in bovine blastocysts. Proc Natl Acad Sci U S A 2010; 107 (08) 3394-3399
• 50 Gardner DK, Larman MG, Thouas GA. Sex-related physiology of the preimplantation embryo. Mol Hum Reprod 2010; 16 (08) 539-547
• 51 Pérez-Crespo M, Ramírez MA, Fernández-González R. , et al. Differential sensitivity of male and female mouse embryos to oxidative induced heat-stress is mediated by glucose-6-phosphate dehydrogenase gene expression. Mol Reprod Dev 2005; 72 (04) 502-510
• 52 Dobbs KB, Gagné D, Fournier E. , et al. Sexual dimorphism in developmental programming of the bovine preimplantation embryo caused by colony-stimulating factor 2. Biol Reprod 2014; 91 (03) 80
• 53 Allan BB, Brant R, Seidel JE, Jarrell JF. Declining sex ratios in Canada. CMAJ 1997; 156 (01) 37-41
• 54 Mathews TJ, Hamilton BE. Trend analysis of the sex ratio at birth in the United States. Natl Vital Stat Rep 2005; 53 (20) 1-17
• 55 Davis DL, Gottlieb MB, Stampnitzky JR. Reduced ratio of male to female births in several industrial countries: a sentinel health indicator?. JAMA 1998; 279 (13) 1018-1023
• 56 Møller H. Change in male:female ratio among newborn infants in Denmark. Lancet 1996; 348 (9030): 828-829
• 57 Parazzini F, La Vecchia C, Levi F, Franceschi S. Trends in male:female ratio among newborn infants in 29 countries from five continents. Hum Reprod 1998; 13 (05) 1394-1396
• 58 Fukuda M, Fukuda K, Shimizu T, Andersen CY, Byskov AG. Parental periconceptional smoking and male: female ratio of newborn infants. Lancet 2002; 359 (9315): 1407-1408
• 59 Mocarelli P, Gerthoux PM, Ferrari E. , et al. Paternal concentrations of dioxin and sex ratio of offspring. Lancet 2000; 355 (9218): 1858-1863
• 60 Hertz-Picciotto I. The evidence that lead increases the risk for spontaneous abortion. Am J Ind Med 2000; 38 (03) 300-309
• 61 Aschengrau A, Zierler S, Cohen A. Quality of community drinking water and the occurrence of spontaneous abortion. Arch Environ Health 1989; 44 (05) 283-290
• 62 Garry VF, Harkins M, Lyubimov A, Erickson L, Long L. Reproductive outcomes in the women of the Red River Valley of the north. I. The spouses of pesticide applicators: pregnancy loss, age at menarche, and exposures to pesticides. J Toxicol Environ Health A 2002; 65 (11) 769-786
• 63 Fukuda M, Fukuda K, Shimizu T, Møller H. Decline in sex ratio at birth after Kobe earthquake. Hum Reprod 1998; 13 (08) 2321-2322
• 64 Saadat M. Decline in sex ratio at birth after Bam (Kerman Province, Southern Iran) earthquake. J Biosoc Sci 2008; 40 (06) 935-937
• 65 Radin RG, Mumford SL, Silver RM. , et al. Sex ratio following preconception low-dose aspirin in women with prior pregnancy loss. J Clin Invest 2015; 125 (09) 3619-3626
• 66 Anderson GD, Hauser SD, McGarity KL, Bremer ME, Isakson PC, Gregory SA. Selective inhibition of cyclooxygenase (COX)-2 reverses inflammation and expression of COX-2 and interleukin 6 in rat adjuvant arthritis. J Clin Invest 1996; 97 (11) 2672-2679
• 67 ACOG Practice Bulletin No 156: Obesity in pregnancy. Obstet Gynecol 2015; 126 (06) e112-e126
• 68 Gandevani SB, Banaem LM, Mohamadi B, Moghadam NA, Asghari M. Association of high-sensitivity C-reactive protein serum levels in early pregnancy with the severity of preeclampsia and fetal birth weight. J Perinat Med 2012; 40 (06) 601-605
• 69 Mathews TJ, Menacker F, MacDorman MF. ; Centers for Disease Control and Prevention, National Center for Health Statistics. Infant mortality statistics from the 2002 period: linked birth/infant death data set. Natl Vital Stat Rep 2004; 53 (10) 1-29
• 70 Anderson RN, Smith BL. Deaths: leading causes for 2001. Natl Vital Stat Rep 2003; 52 (09) 1-85
• 71 Duley L, Henderson-Smart DJ, Meher S, King JF. Antiplatelet agents for preventing pre-eclampsia and its complications. Cochrane Database Syst Rev 2007; (02) CD004659
• 72 Silver RM, Ahrens K, Wong LF. , et al. Low-dose aspirin and preterm birth: a randomized controlled trial. Obstet Gynecol 2015; 125 (04) 876-884
• 73 van Vliet EO, Askie LA, Mol BW, Oudijk MA. Antiplatelet agents and the prevention of spontaneous preterm birth: a systematic review and meta-analysis. Obstet Gynecol 2017; 129 (02) 327-336
• 74 MacIntyre DA, Sykes L, Teoh TG, Bennett PR. Prevention of preterm labour via the modulation of inflammatory pathways. J Matern Fetal Neonatal Med 2012; 25 (Suppl. 01) 17-20
• 75 Abramovici A, Cantu J, Jenkins SM. Tocolytic therapy for acute preterm labor. Obstet Gynecol Clin North Am 2012; 39 (01) 77-87
• 76 Lewis RB, Schulman JD. Influence of acetylsalicylic acid, an inhibitor of prostaglandin synthesis, on the duration of human gestation and labour. Lancet 1973; 2 (7839): 1159-1161
• 77 Henderson JT, Whitlock EP, O'Connor E, Senger CA, Thompson JH, Rowland MG. Low-dose aspirin for prevention of morbidity and mortality from preeclampsia: a systematic evidence review for the U.S. Preventive Services Task Force. Ann Intern Med 2014; 160 (10) 695-703
• 78 American College of Obstetricians and Gynecologists; Task Force on Hypertension in Pregnancy. Hypertension in pregnancy. Report of the American College of Obstetricians and Gynecologists' Task Force on Hypertension in Pregnancy. Obstet Gynecol 2013; 122 (05) 1122-1131
• 79 Ahrens KA, Silver RM, Mumford SL. , et al. Complications and safety of preconception low-dose aspirin among women with prior pregnancy losses. Obstet Gynecol 2016; 127 (04) 689-698
• 80 Truong A, Sayago MM, Kutteh WH, Ke RW. Subchorionic hematomas are increased in early pregnancy in women taking low-dose aspirin. Fertil Steril 2016; 105 (05) 1241-1246
• 81 Nørgård B, Puhó E, Czeizel AE, Skriver MV, Sørensen HT. Aspirin use during early pregnancy and the risk of congenital abnormalities: a population-based case-control study. Am J Obstet Gynecol 2005; 192 (03) 922-923
• 82 Kozer E, Nikfar S, Costei A, Boskovic R, Nulman I, Koren G. Aspirin consumption during the first trimester of pregnancy and congenital anomalies: a meta-analysis. Am J Obstet Gynecol 2002; 187 (06) 1623-1630