Increased Male‐to‐Female Ratio Among Children Born to Women With Systemic Lupus Erythematosus: Comment on the Article by Lockshin et al

Abstract

New experimental evidence suggests that a subset of anti-DNA antibodies cross-reacting with the N-methyl-D-aspartate (NMDA) receptor can bind brainstem neuronal receptors, induce apoptosis, and result in a marked preferential loss of female fetuses in murine models of systemic lupus erythematosus (SLE) (1). Observational studies assessing the sex of offspring born to women with SLE are scant and limited by their sample size (2). In a recent study of 281 liveborn children of mothers with SLE, Lockshin et al did not observe an increased male-to-female ratio in offspring of antiphospholipid antibody-negative mothers with SLE compared with the general population (2). Thus, in a large population-based study, we aimed to determine the sex ratio of children born to women with SLE compared with children born to women without SLE.We identified all women with at least 1 hospitalization for a delivery (either for a stillbirth or a live birth) after SLE diagnosis, using Quebec's physician billing and hospitalization databases (from January 1, 1989 to December 31, 2009). These administrative databases capture all fee-for-service outpatient and hospital medical visits in a universal health care system within the province of Quebec, Canada (population ϳ7.5 million). Women were defined as having SLE if they had either been hospitalized at least once with an SLE diagnosis recorded prior to or at the time of delivery, or if they had at least 2 physician visits with a diagnosis of SLE, occurring 2 months to 2 years apart, up to the time of delivery. This way of defining cases of SLE has been previously shown to have high specificity (99.9%) (3). We randomly selected a general population control group, composed of women matched at least 4:1 for age and year of delivery, who had not been diagnosed as having SLE prior to or at the time of delivery.Quebec's administrative databases contain valid data on the sex of newborns (4), which we used to calculate the male-to-female ratios for all births occurring in SLE patients and in non-SLE subjects. We performed multivariate logistic regression analysis, with the offspring's sex as the dependent variable, adjusting for the potential effect of preeclampsia (previously shown to increase the male-to-female ratio in the general population [5]) and race/ethnicity. As administrative databases do not provide data on antibody profiles (i.e., anti-DNA antibodies) and as anti-NMDA receptor antibodies are not commercially available, we could not assess the independent effect of autoantibodies on the sex of the offspring.Among this population, 512 women with SLE had 729 births after diagnosis, while 5,836 matched control women had 8,541 births. In unadjusted estimates, the male-to-female ratio was higher among children born to women with SLE (odds ratio [OR] 1.26, 95% confidence interval [95% CI] 1.09-1.46) versus controls (OR 1.06, 95% CI 1.02-1.11), resulting in an unadjusted OR of 1.18 (95% CI 1.01-1.38). In multivariate analysis with adjustment for the effect of preeclampsia and race/ethnicity, wo...

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

“…In this large study, we did not confirm previous findings of male dominance among offspring born to women with SLE , which was predicted by mouse models . On the contrary, we observed a slightly lower proportion of male offspring born to women with RA or SLE compared with the general population.…”

“…Reports of the sex ratio among offspring born to women with SLE are inconsistent and have generally not supported this finding. Several studies showed an increased male‐to‐female ratio , one showed no difference compared with the general population , and one study showed a higher proportion of female offspring .…”

Brief Report: Causes of Stillbirths in Women With Systemic Lupus Erythematosus

“…We also noted a trend toward an increase in female stillbirths in mothers with SLE compared to controls. This is consistent with our previous analysis of OSLER data showing a substantially greater male‐to‐female ratio among live offspring of mothers with SLE as compared to controls (OR 1.18 [95% CI 1.01, 1.38]) , although this has not yet been confirmed in a large population‐based study. Our findings are supported by recent experimental evidence suggesting that a subset of anti‐DNA antibodies cross‐reacting with the N ‐methyl‐ d ‐aspartate receptors can bind brainstem neuronal receptors and induce apoptosis, resulting in a marked preferential loss of female fetuses in murine models of SLE .…”

Antibodies as Mediators of Brain Pathology

“…GluN2A is expressed earlier in female compared with male midbrain and mice lacking GluN2A exhibited no fetal loss in this model [116]. Interestingly, it was recently confirmed that mothers with SLE are more likely to have a male child [117]. This finding further supports the hypothesis that maternal antibodies may have gender-specific effects on brain development.…”