Expanded findings from a randomized controlled trial of preconception low-dose aspirin and pregnancy loss

Abstract

Study question: What is the association between daily preconception-initiated low-dose aspirin (LDA) treatment and very early pregnancy losses or euploid (chromosomally normal) losses among women with one to two prior losses?

Summary answer: Daily LDA initiated preconception was not associated with the rate or type of pregnancy loss among women with a history of one to two prior pregnancy losses.

What is known already: LDA is often used to treat recurrent pregnancy loss with reductions in pregnancy loss generally only observed among women with antiphospholipid antibodies, and null associations observed among women without antiphospholipid antibodies. We previously evaluated the association between LDA and pregnancy loss overall among women with one to two prior losses in the Effects of Aspirin in Gestation and Reproduction (EAGeR) trial and found no association, though did not distinguish between potential effects at different stages of pregnancy loss, including implantation failure, or between euploid and aneuploid losses.

Study design, size, duration: The EAGeR trial was a multi-site prospective block-randomized double-blind placebo-controlled trial. In total, 1228 women were randomized to daily LDA (81 mg/day) plus folic acid (400 mcg/day), or placebo plus folic acid. Participants were assigned study drug for less than or equal to six menstrual cycles or if they conceived, throughout pregnancy with study drug discontinued at 36 weeks gestation. This analysis includes additional outcome information obtained from chart abstractions after the completion of the trial, as well as testing of stored urine for measurement of hCG and detection of very early pregnancy losses, and karyotyping of the products of conception for assessment of aneuploidy of the losses.

Participants, setting, methods: Women aged 18-40 with a history of one to two prior losses and actively trying to conceive were randomized (n = 615 LDA and n = 613 placebo) at four clinical centers in the USA (2007-2011). Log-binomial regression was used to estimate risk ratios under the intent-to-treat approach.

Main results and the role of chance: Daily LDA initiated preconception was not associated with clinically recognized pregnancy losses or implantation failures among women with proved fecundity and a history of one to two prior losses. Specifically, 1088 (88.6%) women completed the trial with 797 having an hCG detected pregnancy (64.9%). Overall there were 133 clinical losses (12.7% LDA versus 11.8% placebo, P = 0.71) and 55 implantation failures (5.2% LDA versus 4.9% placebo, P = 0.89). No differences were found in rate of euploid losses (RR 1.11, 95% confidence interval: 0.99, 1.26).

Limitations, reasons for caution: Generalizability of these findings is limited to women with a history of one to two prior losses, and may further be limited to women of white race with higher socioeconomic status as given the rigors of the study protocol participants tended to be white and have higher incomes and more education. We were also missing karyotype information on approximately one-third of the clinically recognized pregnancy losses, which may limit our power to detect effects on euploid losses, though detailed sensitivity analysis showed similar results.

Wider implications of the findings: Our data do not support the general use of LDA to decrease pregnancy loss and further demonstrate no increased risk of loss for women on LDA treatment.

Study funding/competing interests: This research was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland (Contract Nos. HHSN267200603423, HHSN267200603424, HHSN267200603426). The authors have no conflicts of interest.

Trial registration number: The trial was registered at ClinicalTrials.gov #NCT00467363.

Trial registration date: 27 April 2007.

Date of first patient's enrollment: 15 June 2007.

Keywords: conception; fertility; live birth; low-dose aspirin; pregnancy loss.

Figure 1

Participant flow for the EAGeR trial.

Figure 2

Participant outcomes for the EAGeR trial. Notes: (1) Information regarding outcomes for 10 women who originally withdrew from the study was obtained via chart abstraction and hCG testing of stored urine samples (eight implantation failures and two live births). (2) There are a total of 55 women with implantation failures: 34 from the original trial (including 3 second peri-conception losses and 31 women with a positive pregnancy test without ultrasound confirmation of which 5 withdrew following the loss) and 21 newly detected implantation failures based on hCG testing of stored urine samples. (3) There are a total of 133 women with a clinical losses (127 clinical losses, 6 ectopic pregnancies). Upon further chart review, four losses initially classified as ‘probable ectopic’ were reclassified as one ectopic, one embryonic, one pre-embryonic and one unknown; three previously unknown losses were classified as one ectopic, one embryonic, one fetal.