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To the Editor:

We appreciate Vinet and colleagues' interest in our article and thank them for the new data. Both our group and Vinet et al have tested a prediction made by Wang et al (Wang L, Zhou D, Lee J, Niu H, Faust TW, Frattini S, et al. Female mouse fetal loss mediated by maternal autoantibody. J Exp Med 2012;209:1083–9) based on a model in which pregnant non-SLE mice actively immunized to generate anti–NMDA receptor antibodies (similar to anti-DNA) have more male pups due to toxic effects specific to female mice. Wang and colleagues predict that women with SLE, having similar autoantibodies, will also deliver too few girls.

Vinet et al examined administrative records to identify the sex of babies of several pregnancies of women who had a hospital discharge diagnosis code of SLE. We (in the PROMISSE study [Predictors of Pregnancy Outcome: Biomarkers in Antiphospholipid Syndrome and Systemic Lupus Erythematosus study]) prospectively monitored, during a single index pregnancy, SLE patients who met American College of Rheumatology (ACR) criteria for classification of the disease (Tan EM, Cohen AS, Fries JF, Masi AT, McShane DJ, Rothfield NF, et al. The 1982 revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum 1982;25:1271–7), all of whom were tested for anti-DNA, and a subset of whom were evaluated for anti–NMDA receptors. Vinet et al did not examine autoantibodies.

The methods used and the results found in the studies by the PROMISSE group, by Vinet et al, and by Wang et al are clearly discordant (Table 1). In the anti–NMDA receptor–positive mice studied by Wang and colleagues, the male-to-female ratio was 2.23. In the PROMISSE study, male-to-female ratios were 0.87 for all SLE patients, 0.91 for SLE patients with anti–NMDA receptors, and 0.67 for SLE patients with anti-DNA. Vinet et al found a male-to-female ratio of 1.26 but did not comment on specific documentation of ACR criteria or autoantibody status during pregnancy. Although a limited sample size was used (which could lead to a Type II error), the PROMISSE study provides stronger evidence to refute Wang and colleagues' prediction regarding the consequences of female susceptibility to anti–NMDA receptors than Vinet's more indirect study does to support it.

Table 1. Comparison of the 3 studies*
 PROMISSEVinet et alWang et al
  • *

    PROMISSE = Predictors of Pregnancy Outcome: Biomarkers in Antiphospholipid Antibody Syndrome and Systemic Lupus Erythematosus; ACR = American College of Rheumatology; NMDA = N-methyl-D-aspartate.

  • Fifty-two systemic lupus erythematosus (SLE) patients with antiphospholipid antibodies were excluded. Of these, 47 had children of known sex: 21 were boys (17 live births) and 26 were girls (23 live births), with a male-to-female ratio of 0.81.

Data sourceProspective clinicalAdministrativeBALB/c mice
Entry criteriaACR criteria–verified clinical SLEHospital discharge diagnostic code of SLEMice immunized to NMDA receptor peptide (no clinical SLE or illness)
Exclusion criteriaAntiphospholipid antibody, severe maternal illness, multigestational pregnancyNot coded as SLENone
OutcomeLive birth or neonatal death by clinical studyLive birth by administrative dataDam killed at 19–21 days; uteri dissected, “viable” embryo counts presented as sex ratios
Anti–NMDA receptorTested in 41%Not testedTested in 100%
Anti-DNATested in 93%Not testedNot tested
Antiphospholipid antibodiesExcludedNot testedNot tested
No. of mothers281512Not stated
No. of fetuses28172921–85 fetuses per experiment

Michael D. Lockshin MD*, Elizabeth Cohn BA†, Aanam Aslam BA†, Jill P. Buyon MD‡, Jane E. Salmon MD§, * Hospital for Special Surgery, and Weill-Cornell Medical College, † Hospital for Special Surgery, New York, NY, ‡ New York University School of Medicine, New York, NY, § Hospital for Special Surgery, and Weill-Cornell Medical College, New York, NY.

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