A recent study (1) demonstrated that maternal antibodies to the N-methyl-D-aspartate (NMDA) receptor in BALB/c mice cause death of female fetuses, leading to ratios of male to female offspring greater than the normal ratio of 1.0. Among patients with systemic lupus erythematosus (SLE), ∼40% have anti–NMDA receptor antibodies, and if the mouse model is predictive, ratios of male to female births in human SLE might exceed the normal ratio of 1.048 in the US.

Our pregnancy studies offer an opportunity to test this prediction. PROMISSE (Predictors of Pregnancy Outcome: Biomarkers in Antiphospholipid Syndrome and Systemic Lupus Erythematosus) is a multicenter, prospective study of pregnancies in women with lupus (2). The Research Registry for Neonatal Lupus (RRNL) is a registry of families in which the mother has anti-SSA/Ro and/or anti-SSB/La antibodies and at least 1 child with neonatal lupus. The RRNL includes both affected and unaffected children (3).

Table 1 shows birth ratios of male to female children in the RRNL and the PROMISSE study, stratified by maternal serology and maternal and fetal diagnosis, and compared to the control group of healthy women in the PROMISSE study. PROMISSE patients with antiphospholipid antibodies were excluded. Ratios were similar when stillborn children were counted. The ratios of male to female children were <1.0 in almost all cases; none of the differences were significant (comparisons were performed using chi-square test with Bonferroni correction). The ratio of male to female children was >1.0 in mothers who tested negative for anti–NMDA receptor antibodies and <1.0 in those who tested positive (P = 0.36). Because anti-DNA antibodies often coexist with anti–NMDA receptor antibodies, we compared male-to-female ratios in patients who were positive and those who were negative for anti-DNA and found no difference (P = 0.30). Male-to-female ratios in patients with and those without pregnancy complications also did not differ (P = 0.34). Thus, our human data do not confirm the mouse experiments.

Table 1. Male to female ratios of live births in the RRNL and PROMISSE studies*
Study/stratification, patient characteristicMaleFemaleMale to female ratio
  • *

    Inclusion of stillborn children did not change the ratios. Patients in the PROMISSE study (Predictors of Pregnancy Outcome: Biomarkers in Antiphospholipid Antibody Syndrome and Systemic Lupus Erythematosus study) had systemic lupus erythematosus (SLE), met American College of Rheumatology criteria for classification of the disease, and were negative for antiphospholipid antibodies; all subjects from the PROMISSE study had live births before June 2012. RRNL = Research Registry for Neonatal Lupus; NMDA = N-methyl-d-aspartate.

  • In the US, the ratio of male to female live births is 1.048.

  • P = 0.007 versus children with neonatal lupus.

RRNL/child diagnosis   
 Neonatal lupus2052780.74
 No neonatal lupus2382231.07
PROMISSE/mother diagnosis   
 SLE, all pregnancies1311500.87
PROMISSE/mother serology   
 Anti-NMDA receptor positive21230.91
 Anti-NMDA receptor negative38321.19
 Anti-DNA positive40600.67
 Anti-DNA negative78830.94
 Anti-Ro positive38590.64
 Anti-La positive15210.71
PROMISSE controls89791.13

Prior data on fetal sex ratios in human SLE are weak. In a national birth registry containing 68,600 women, conclusions about the sex ratio of offspring were based on 42 women who had a diagnostic code identifying them as having lupus (4). In a summary of published case series (diagnostic criteria unspecified), studies ranging in size from 14 to 249 children were reviewed; the 4 largest series, constituting half the infants, had a combined male-to-female ratio of 1.07 (5). Our prospective studies rigorously define maternal diagnosis and fetal outcome, and the results are more likely to be correct than the mouse-based hypothesis of male predominance of live births in humans. Our data reemphasize that mouse models do not invariably predict human outcomes.


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  2. Acknowledgements identifier: NCT00198068. Supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases, NIH (grant R01-AR-49772 to the PROMISSE study and grant N01-AR-2220 to the RRNL), the Mary Kirkland Center for Lupus Research, Rheuminations, Inc., and the Barbara Volcker Center for Women and Rheumatic Disease.