Sex ratio following preconception low-dose aspirin in women with prior pregnancy loss

Abstract

Background: Several lines of evidence suggest that male embryos may have greater vulnerability than female embryos to disordered inflammation; therefore, antiinflammatory drugs, such as low-dose aspirin (LDA), may alter the sex ratio. Here, we assessed the effect of LDA on male live birth and male offspring, incorporating pregnancy losses (n = 56) via genetic assessment, as part of a parallel-design, block-randomized, placebo-controlled trial of preconception LDA.

Methods: Participants (615 treated with LDA, 613 treated with placebo) ranged in age from 18 to 40 years of age, with 1 to 2 prior pregnancy losses. We estimated the intention-to-treat (ITT) risk ratio (RR) and 95% CI and assessed interaction with baseline high-sensitivity C-reactive protein (hsCRP) serum concentration - a marker of systemic inflammation.

Results: Among the 1,078 women who completed follow-up (535 treated with LDA, 543 treated with placebo), the male live birth ITT RR equaled 1.31 (95% CI: 1.07-1.59). With increasing tertile of hsCRP, the proportion of males at birth decreased in the placebo group, and the effect of LDA on male live birth increased (first tertile: 48% male in LDA vs. 52% in placebo, ITT RR = 0.97, 95% CI: 0.70-1.35; second tertile: 57% male in LDA vs. 43% in placebo, ITT RR = 1.36, 95% CI: 0.98-1.90; third tertile: 53% male in LDA vs. 35% in placebo, ITT RR = 1.70, 95% CI: 1.13-2.57; P interaction = 0.03). Analysis of pregnancy with male offspring yielded similar results.

Conclusion: Initiation of LDA prior to conception restored numbers of male live births and pregnancy with male offspring among women with 1 to 2 prior pregnancy losses. Moreover, our data suggest that LDA modulates inflammation that would otherwise reduce the conception or survival of male embryos.

Trial registration: ClinicalTrials.gov NCT00467363.

Funding: Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health.

Figures

Figure 2. EAGeR trial flow diagram.

The total numbers of male and female offspring are shown in parentheses, reflecting 8 twin gestations.

Figure 1. LDA and pregnancy with male offspring among 775 women with a pregnancy detected by a urine hCG test.

Colors depict the P values from the χ2 test of independence between LDA and male offspring, calculated in each of the 10,201 data sets containing imputed outcomes for 126 women who had a pregnancy with undetermined offspring sex. Each data set represents one possible scenario for the percentage male among missing data in the LDA and placebo groups, respectively. The central triangle comprises the data sets that met assumptions for plausible values of percentage male in the respective groups, i.e., 44%–56%, with the percentage male in LDA group greater than or equal to that of the placebo group. The analysis excluded 453 women who did not become pregnant. Each woman contributed one observation, with inverse probability weighting to adjust for selection of pregnant women.