CORRESPONDENCE Need for a prospective treatment trial To the Editors: On the basis of data presented by Lockshin and colleagues (Lockshin MD, Druzin ML, Qamar T. Prednisone does not prevent recurrent fetal death in women with anti phospholipid antibody. AM J OBSTET GYNECOL 1989; 160:439-43), it would be wrong to conclude that "Prednisone does not prevent recurrent fetal death in women with antiphospholipid antibody." It was equally wrong to conclude from previous reports'" that prednisone is efficacious in the prevention of fetal death in these women. The promise of treatment represents the most persuasive reason for identification of women with lupus anticoagulant or anticardiolipinrelated recurrent fetal loss. On the basis of our very limited knowledge of the relationship of these antibodies to fetal loss, logical approaches to treatment have been either suppression of the (possibly) offending antibodies by steroids or immunosuppressive agents, or prevention of the (presumed) abnormal placental clotting process by subcutaneous administration of heparin, aspirin alone, or aspirin and dipyridamole. It should be stated that Professor Lubbe and coworkers and Dr. Branch and coworkers have extended their series well beyond the numbers originally reported'" and both groups continue to find (in series each exceeding 25 treated women) that pregnancy outcome is improved with the use of relatively high doses of pred-' nisone and aspirin. A careful review of the data published by Dr. Lockshin and colleagues suggests that only three of their patients with histories of recurrent fetal loss received high doses of prednisone for> 10 weeks, and two of these had live births. They also happened to be two in this series who received prednisone for the longest period of time-36 weeks (patient 8) and 27 weeks (patient 10). Whether these two patients would have done equally as well on aspirin alone, as did other patients in this series, is a matter of speculation. Rather than continue the controversy about the efficacy' or lack thereof, of prednisone, it would be better that some objective means be used to answer this question. After the Third International Workshop on Antiphospholipid Antibodies,' >40 clinical centers in 12 countries have prepared a carefully designed plan for a prospective, multicenter treatment trial of women with anti phospholipid antibody-related recurrent fetal loss.' This study will compare prednisone (40 mg/day) plus low-dose aspirin (60 to 80 mg/day) versus high doses of subcutaneous administration of heparin (sufficient to prolong the partial thromboplastin time to 1.5 to 2.0 times normal). In affected women pregnant for the first time, a second study will compare low-dose aspirin with a placebo. To achieve statistically significant results it is estimated that >350 women will need to be recruited. However, the enthusiasm with which investigators worldwide have greeted plans for this study makes recruitment of this seemingly large number of patients a distinct reality. Efficacy and toxicity will be equally important con-

cerns of this study, and an external Advisory-Review and Data Monitoring Committee (made up of experts in relevant biomedical fields, biostatistics, and medical ethics) has been appointed and will be empowered to recommend cessation of the study if one form of treatment is found unacceptable because of complications. Only with the conduct of a study such as this one can some of the troubling issues raised by Lockshin and colleagues be answered satisfactorily. E. Nigel Harris, MD Department of Medicine University of Louisville Louisville, KY 40292 REFERENCES 1. Lubbe WF, Palmer SJ, Butler WS, Liggins GC. Fetal survival after prednisone suppression of maternal lupus anticoagulant. Lancet 1983; I : 1361-3. 2. Branch DW, Scott JR, Kochenour NK, Hershgold E. Obstetric complications associated with the lupus anticoagulant. N EnglJ Med 1985;313:1322-6. 3. Harris EN. Solid phase anticardiolipin test revisited. Am J Med 1988;85:599-601.

Journal article appraisal To the Editors: The article by Seifer et al. (Seifer DB, Adelson MD, Abdul-Karim RW, Baggish MS. Appraising a clinical journal article in obstetrics and gynecology. AM J OBSTET GYNECOL 1989;160:198-201) should be mandatory reading for every resident before discussion of articles in a journal club. By using their guidelines a reader can more easily assess the validity and importance of the article. In addition to these guidelines, another important piece of information can be found in the lower lefthand corner of the title page of each article. While I was a resident at Northwestern University, Dr. Albert Gerbie, the director of our journal club, pointed out that it was helpful to note who funded the study that was being reported. Because it is very rare to find a study that is sponsored by a pharmaceutical company and is critical of its own product, I believe it is necessary to examine such articles with additional scrutiny. In regard to ideas for further research, the authors of this article may wish to consider writing an article appraising clinical journals in obstetrics and gynecology. Joseph C. Capecchi, MD Parkview Women's Center 360 Sherman St., Suite 400 St. Paul, MN 55102 Oral contraceptives and infection rates To the Editors: Louv et al. (Louv WC, Austin H, Perlman J, Alexander WJ. Oral contraceptive use and the risk of chlamydial and gonococcal infections. AM J OBSTET Gy-

1121

1122 Correspondence

1989; 160:396-402) reported that use of oral contraceptives "increased the infection rates for both chlamydia and gonorrhea." Their analysis adjusted for the potentially distorting influence of frequency of coitus, number of partners, age, number of pregnancies, and number of live births. However, their analysis did not control for the potential confounding effect of the sexual exposures of the partners of these women. A reanalysis of the Women's Health Studyl found different risks of pelvic inflammatory disease among users of intrauterine contraceptive devices with only one sex partner in the past 6 months. Compared with sexually active women using no contraception, women who were never married were at significantly increased risk of pelvic inflammatory disease; married or cohabiting women were not. The authors suggested that the increased risk among never-married women might be a result of the promiscuous behavior of their sex partners. In the study by Louv et ai., the comparison group consisted of 201 women who were sterilized or who were users of intrauterine contraceptive devices. The comparison group was older (median difference, 4 years) and of higher parity (median difference, 1). Thus it appears plausible that such women would be more likely to be in mutually monogamous relationships than oral contraceptive users and hence at lower risk of acquiring a sexually transmitted disease. Stated alternatively, the sex partners of the younger oral contraceptive users might be more likely to have other sex partners and thus be more likely to acquire a sexually transmitted disease that could be transmitted to the oral contraceptive user. In the absence of information about the sexual exposures of these men, adjustment by marital status and number of partners might be an alternative approach. Until this question is resolved, attributing a causal role for oral contraceptives in cervical infection with chlamydia or gonorrhea seems inappropriate. Louv and associates report in their abstract that the "rates of gonorrheal infection differed significantly among oral contraceptive formulations," with rates higher for those with more androgenic progestins. The 95% confidence intervals for the relative rates for three different progestins in Table V overlap widely, and these rates do not appear to differ significantly. David A. Grimes, MD Daniel R. Mishell, Jr., MD Department of Obstetrics and Gynecology University of Southern California School of Medicine Women's Hospital 1240 North Mission Road Los Angeles, CA 90033 NECOL

REFERENCE l. Lee NC, Rubin GL, Borucki R. The intrauterine device

and pelvic inflammatory disease revisited; new results from the Women's Health Study. Obstet Gynecol 1988;72:1-6.

April 1990 Am J Obstet Gynecol

Reply To the Editors: Drs. Grimes and Mishell suggest that the increased chlamydial and gonococcal infection rates among oral contraceptive users in our study is a result of increased sexual activity among their partners. They recommend that we include marital status as an additional covariate in our regression models. We did evaluate marital status as a potentially confounding factor in our preliminary analyses. However, since it was not an independent determinant of chlamydia and gonorrhea, it did not confound the oral contraceptive association and therefore was deleted from the models. Thus the contention that our results were confounded by the sexual activity of the subjects' partners requires that among women of like marital status and sexual activity, the oral contraceptive users were exposed to greater risk by their partners than were women who did not use oral contraceptives. We consider this scenario unlikely and therefore consider their explanation of our study findings implausible. The authors also question our conclusions regarding the association between the risk of gonococcal infection and the androgenicity of the progestins used in oral contraceptives. The relative rate estimates for gonococcal infection in Table V have nonusers of oral contraceptives as the referent category, and therefore these estimates are positively correlated. Because the standard errors of comparisons between the relative rates are affected by these correlations, the fact that their confidence intervals overlap does not imply that there are no differences in the rates of gonorrhea among users of the different formulations. A one degree of freedom test with equally spaced scores for the three oral contraceptive formulations indicates that there is a statistically significant trend toward higher rates of gonorrhea with more androgenic progestins (P = 0.016). This trend is caused primarily by a significantly lower rate among users of norethindrone acetate-containing oral contraceptives compared with the other two formulations (P = 0.017). William C. Louv, PhD Merrell Dow Research Institute 2110 East Galbraith Road Cincinnati, OH 45215 Harland Austin, DSc University of Alabama at Birmingham Department of Epidemiology Birmingham, AL 35294 Jeffrey Periman, MD National Institute of Child Health and Human Development Contraceptive Evaluation Branch Center for Population Research Bethesda, MD 20205 W. James Alexander, MD Beecham Laboratories Bristol, TN 37620