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

Abstract

alter the sex ratio of pregnancies among women with a history of pregnancy loss, given the sex-dependent embryonic effects of maternal inflammation.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.

Brief Report: Sex Ratio of Offspring Born to Women With Systemic Lupus Erythematosus or Rheumatoid Arthritis

“…Most embryos are lost between the time of fertilization and clinical recognition of the pregnancy, and if chronic inflammation affects embryogenesis (perhaps through epigenetic processes), the sex ratio at birth may be skewed (19). This hypothesis is supported by a recent study showing that higher levels of high-sensitivity C-reactive protein prior to conception were associated with a lower likelihood of having a live-born male child (9).…”

“…A skewed sex ratio could be due to specific characteristics of SLE or may be a general consequence of the associated chronic inflammatory state. A recent study showed that higher levels of inflammation in women were associated with a reduced number of male offspring, and that the sex ratio was restored by treatment with low‐dose aspirin . Because this concept has not been well substantiated in the clinic, we sought to estimate the male‐to‐female ratio among deliveries to women in a large population‐based cohort, comparing women with SLE and those with rheumatoid arthritis (RA) (another systemic inflammatory disease) with women in the general population.…”

Methods for Prenatal Sex Determination and Their Importance in Understanding and Prevention of Gender-Related Birth Defects

“…Male gender as a gestational risk factor was also reported by Radin et al [21] who investigated the effect of preconception intake of low-dose aspirin (LDA) on male live birth. They followed two groups of women with prior pregnancy loss: one group was treated with daily intake of LDA, and the second group was treated with placebo.…”

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

“…Thus, in a prespecified secondary analysis of the EAGeR trial 65 to investigate the impacts of LDA therapy on offspring sex ratio, LDA was shown to increase male live births overall (RR: 1.31, 95% CI: 1.07, 1.59) and had no effect on female live birth. A further analysis found a similar positive effect of LDA on pregnancy with male offspring by including the outcome of pregnancy with a male embryo, whether the pregnancy ended in live birth or loss.…”

“…Karyotype or microarray determined the offspring sex from pregnancy losses. 65 To further evaluate the hypotheses that inflammation was hazardous to male embryos, and that LDA was subsequently protective, the analysis was stratified by hsCRP level at study entry. Congruent with the findings of the stratified analysis of LDA and live birth, the percentage male at birth decreased with increasing tertile of hsCRP among the placebo group, but the proportion of males remained at the expected level among the LDA-treated group (►Fig.…”