Editors' ChoiceReproduction

Early evidence of male sensitivity

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Science Translational Medicine  02 Sep 2015:
Vol. 7, Issue 303, pp. 303ec151
DOI: 10.1126/scitranslmed.aad1830

The differences between males and females are a socially delicate topic that is biologically fascinating. It turns out that sex differences exist in embryos even before implantation into the uterus, and one important embryonic difference between males and females is response to maternal inflammation.

Knowing that inflammation can be detrimental to successful implantation, a clinical trial (called EAGeR, Effects of Aspirin in Gestation and Reproduction) was conducted to study whether preconception low-dose aspirin (LDA, 81 mg daily) could improve pregnancy and live birth rates in women who previously had one or two miscarriages. Schisterman and his team reported in the Lancet last year that LDA did not improve these outcomes. Interestingly however, the same team now asked: Are male embryos more sensitive and vulnerable to the detrimental effects of maternal inflammation, and if yes, can this risk to male survival be ameliorated with low-dose aspirin?

Radin et al. analyzed the data from the 1086 EAGeR trial participants and found that women receiving LDA were more likely to become pregnant with, and give birth to, a male. To put some numbers on this, 31% of the women on LDA versus 23% on placebo gave birth to a male offspring, which computes to a risk ratio of 1.31 and a risk difference of 7.18 per 100 women. The probability of having a female infant was unaltered, highlighting that this response is sex-specific. Further stratification of the patients based on their high-sensitivity C-reactive protein (hsCRP, indicative of inflammation) confirmed the heightened vulnerability of male embryos to maternal inflammation with a striking association between hsCRP concentration and reduced sex ratio (fewer males) in the placebo group. The analysis also revealed that the patients with the highest hsCRP (range ~2-62 mg/L) had the strongest response to LDA in terms of male pregnancy incidence.

This study is the first to show in humans that response to maternal inflammation is sexually dimorphic. An understanding of the specific features of inflammation that are hazardous to male embryos, the mechanisms underlying the biological fragility of male embryos and/or the resistance of females to the same stressors, and whether the divergent response to stressors persists through life thus contributing to the differential risk of inflammation-associated diseases is anticipated to be of wide clinical importance.

R. G. Radin et al., Sex ratio following preconception low-dose aspirin in women with prior pregnancy loss. J. Clin. Invest. 10.1172/JCI82357 (2015). [Full Text]

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