gynecology journals. Obstet Gynecol 2009;114:1284–6. 3. Mayo NE, Goldberg MS. When is a case-control study a case-control study? J Rehabil Med 2009;41:209–16.
In Reply: We appreciate the comments from Dr. Wald concerning appropriate study design and labeling in the clinical and scientific literature and agree that careful characterization is paramount to investigators and readers alike. The statement, “all information and indicated biopsies were completed at the time of entry”1 refers to information and biopsies regarding anal evaluation only. Patients were screened for anal intraepithelial neoplasia according to our protocol only after the diagnosis of genital intraepithelial neoplasia, not concurrently. Additional review by Dr. Thomas Riggs, Statistical Editor of Obstetrics & Gynecology, confirms there was a sequence to ascertainment. We make no claim to a description of either the natural history of anal intraepithelial neoplasia or its temporal relationship to genital intraepithelial neoplasia. In light of this, the validity of our results should be reiterated. Both Drs. Wald and Riggs note the correct use of logistic regression and prevalence reporting for this data set. The statement that our patients were collected from a prospective cohort is true. Dr. Wald’s conclusion that our data were analyzed in a cross-sectional manner is also true. The future plan for this cohort remains prospective in nature, following to evaluate the efficacy of treatment for anal intraepithelial neoplasia. Financial Disclosure: The author did not report any potential conflicts of interest.
Adam C. ElNaggar, MD Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, The Ohio State University Wexner Medical Center, Columbus, Ohio
REFERENCE 1. ElNaggar AC, Santoso JT. Risk factors for anal intraepithelial neoplasia in women with genital dysplasia. Obstet Gynecol 2013;122:218–23.
184
Letters to the Editor
Antiphospholipid Antibodies in Stillbirth To the Editor: I read with great interest the article by Silver et al regarding antiphospholipid antibody testing in stillbirth.1 Extensive evaluations were performed in an attempt to assign a cause for the fetal death, and antiphospholipid testing was performed routinely. The findings included the presence of one or more antiphospholipid antibodies in almost 10% of patients with stillbirth, but also in 6% of control patients with live births. The adjusted odds ratio for both immunoglobulin (Ig)G anticardiolipin and anti-b2-glycoprotein-1 antibodies was approximately 3. Abnormal antiphospholipid antibody test results were present in a similar proportion of patients with stillbirths with and without complications. The authors conclude that testing for antiphospholipid antibodies in patients with unexplained stillbirth is reasonable, and that testing for all four antibodies is warranted. I would like to suggest other ways to interpret some of the data. In reviewing the details of the 56 cases of stillbirth, it is noted that only seven had antiphospholipid syndrome listed as a probable or possible cause of fetal death, and all were positive for either anticardiolipin IgG or IgM. Stated differently, in the entire study of 582 stillbirths, not a single case of stillbirth thought to be related to antiphospholipid antibodies was identified based on anti-b2-glycoprotein-1 antibody testing. Further, almost 90% of antiphospholipid antibody– positive patients were deemed to have stillbirth unrelated to these antibodies. The similarly elevated odds ratios for antiphospholipid antibodies in patients with and without complications goes against prior findings that the antibodies are not acute actors in adverse pregnancy outcomes, but rather act through longstanding vascular and placental pathophysiology. These findings are more consistent with stillbirths and possibly other pregnancy events causing cell damage with subsequent release of antiphospholipid antibodies into the systemic circulation. It may be more prudent to use the data from the current study to recommend that antiphospholipid testing is
not yet indicated in stillbirths without preeclampsia, growth restriction, or abruption and that testing need not include anti-b2-glycoprotein-1 antibodies. At this point, testing for antiphospholipid antibodies could lead to treatment without benefit in situations where an argument for causation is lacking. Financial Disclosure: The author did not report any potential conflicts of interest.
Alan M. Peaceman, MD Division of Maternal-Fetal Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois
REFERENCE 1. Silver RM, Parker CB, Reddy UM, Goldenberg R, Coustan D, Dudley DJ, et al. Antiphospholipid antibodies in stillbirth. Obstet Gynecol 2013;122:641–57.
In Reply: We appreciate the interest and comments by Dr. Peaceman regarding our article.1 We agree with many of his comments and believe that he highlights several important issues. First, although a higher proportion of women with stillbirth have positive tests for antiphospholipid antibodies compared with those with live births, it is not clear that these women have antiphospholipid syndrome. To be considered to have antiphospholipid syndrome, it is necessary to have confirmatory repeat testing 12 weeks after initial testing.2 Most of the women in our study did not have repeat testing documented in our database, a fact that was stressed in the article. Thus, it is not clear whether these women would benefit from treatment in subsequent pregnancies. A second point raised by Dr. Peaceman is that the antibodies may be a marker of tissue damage in the setting of pregnancy loss rather than an antecedent cause of the events. Thus, he has raised the proverbial “chicken or egg” question, and our data do not exclude the possibility that antiphospholipid antibodies are epiphenomenal and the result of tissue damage. On the other hand, positive antiphospholipid antibodies (often persistently positive) are associated with a risk for subsequent adverse pregnancy outcomes, including fetal death.3 Also, the antibodies are directly pathogenic in animal models.4
OBSTETRICS & GYNECOLOGY
In Reply: We appreciate the comments from Dr. Wald concerning appropriate study design and labeling in the clinical and scientific literature and agree that careful characterization is paramount to investigators and readers alike. The statement, “all information and indicated biopsies were completed at the time of entry”1 refers to information and biopsies regarding anal evaluation only. Patients were screened for anal intraepithelial neoplasia according to our protocol only after the diagnosis of genital intraepithelial neoplasia, not concurrently. Additional review by Dr. Thomas Riggs, Statistical Editor of Obstetrics & Gynecology, confirms there was a sequence to ascertainment. We make no claim to a description of either the natural history of anal intraepithelial neoplasia or its temporal relationship to genital intraepithelial neoplasia. In light of this, the validity of our results should be reiterated. Both Drs. Wald and Riggs note the correct use of logistic regression and prevalence reporting for this data set. The statement that our patients were collected from a prospective cohort is true. Dr. Wald’s conclusion that our data were analyzed in a cross-sectional manner is also true. The future plan for this cohort remains prospective in nature, following to evaluate the efficacy of treatment for anal intraepithelial neoplasia. Financial Disclosure: The author did not report any potential conflicts of interest.
Adam C. ElNaggar, MD Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, The Ohio State University Wexner Medical Center, Columbus, Ohio
REFERENCE 1. ElNaggar AC, Santoso JT. Risk factors for anal intraepithelial neoplasia in women with genital dysplasia. Obstet Gynecol 2013;122:218–23.
184
Letters to the Editor
Antiphospholipid Antibodies in Stillbirth To the Editor: I read with great interest the article by Silver et al regarding antiphospholipid antibody testing in stillbirth.1 Extensive evaluations were performed in an attempt to assign a cause for the fetal death, and antiphospholipid testing was performed routinely. The findings included the presence of one or more antiphospholipid antibodies in almost 10% of patients with stillbirth, but also in 6% of control patients with live births. The adjusted odds ratio for both immunoglobulin (Ig)G anticardiolipin and anti-b2-glycoprotein-1 antibodies was approximately 3. Abnormal antiphospholipid antibody test results were present in a similar proportion of patients with stillbirths with and without complications. The authors conclude that testing for antiphospholipid antibodies in patients with unexplained stillbirth is reasonable, and that testing for all four antibodies is warranted. I would like to suggest other ways to interpret some of the data. In reviewing the details of the 56 cases of stillbirth, it is noted that only seven had antiphospholipid syndrome listed as a probable or possible cause of fetal death, and all were positive for either anticardiolipin IgG or IgM. Stated differently, in the entire study of 582 stillbirths, not a single case of stillbirth thought to be related to antiphospholipid antibodies was identified based on anti-b2-glycoprotein-1 antibody testing. Further, almost 90% of antiphospholipid antibody– positive patients were deemed to have stillbirth unrelated to these antibodies. The similarly elevated odds ratios for antiphospholipid antibodies in patients with and without complications goes against prior findings that the antibodies are not acute actors in adverse pregnancy outcomes, but rather act through longstanding vascular and placental pathophysiology. These findings are more consistent with stillbirths and possibly other pregnancy events causing cell damage with subsequent release of antiphospholipid antibodies into the systemic circulation. It may be more prudent to use the data from the current study to recommend that antiphospholipid testing is
not yet indicated in stillbirths without preeclampsia, growth restriction, or abruption and that testing need not include anti-b2-glycoprotein-1 antibodies. At this point, testing for antiphospholipid antibodies could lead to treatment without benefit in situations where an argument for causation is lacking. Financial Disclosure: The author did not report any potential conflicts of interest.
Alan M. Peaceman, MD Division of Maternal-Fetal Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois
REFERENCE 1. Silver RM, Parker CB, Reddy UM, Goldenberg R, Coustan D, Dudley DJ, et al. Antiphospholipid antibodies in stillbirth. Obstet Gynecol 2013;122:641–57.
In Reply: We appreciate the interest and comments by Dr. Peaceman regarding our article.1 We agree with many of his comments and believe that he highlights several important issues. First, although a higher proportion of women with stillbirth have positive tests for antiphospholipid antibodies compared with those with live births, it is not clear that these women have antiphospholipid syndrome. To be considered to have antiphospholipid syndrome, it is necessary to have confirmatory repeat testing 12 weeks after initial testing.2 Most of the women in our study did not have repeat testing documented in our database, a fact that was stressed in the article. Thus, it is not clear whether these women would benefit from treatment in subsequent pregnancies. A second point raised by Dr. Peaceman is that the antibodies may be a marker of tissue damage in the setting of pregnancy loss rather than an antecedent cause of the events. Thus, he has raised the proverbial “chicken or egg” question, and our data do not exclude the possibility that antiphospholipid antibodies are epiphenomenal and the result of tissue damage. On the other hand, positive antiphospholipid antibodies (often persistently positive) are associated with a risk for subsequent adverse pregnancy outcomes, including fetal death.3 Also, the antibodies are directly pathogenic in animal models.4
OBSTETRICS & GYNECOLOGY
