Reply of the authors

Reply of the Authors: We thank Dr. Jones and colleagues for the crucial comments on our article and would like to address the question of whether decrease in factor XII (FXII) in patients with a history of recurrent first-trimester miscarriages is inherited or acquired. Regarding FXII, decrease is associated with both thrombosis and miscarriages. Recently, a common genetic polymorphism (46 C to T substitution) and an association between the T allele and low plasma levels of FXII was reported (1). Levels of FXII activity are strongly linked with this polymorphism, and therefore we are presently examining its association with recurrent miscarriages. We excluded patients with a history of second- or thirdtrimester fetal loss in our previous study because we wished to examine the significance of each parameter in the first trimester, before placental structure. Decrease in FXII may not only be related to inhibition of the intrinsic pathway but also to reduced fibrinolysis, because it can contribute to this process as a plasminogen activator (PA) (2). Concerning in vivo function of the plasminogen and plasmin system, plasminogen-deficient mice survive embryonic development but develop spontaneous fibrin deposition due to impaired thrombolysis and suffer retarded growth and reduced fertility and survival (3). The data suggest that fibrinolysis may play a crucial role during early stages of placentation or reproduction. Jones and colleagues have presented evidence that the presence of antibodies to FXII leads to reduced levels of the factor associated with recurrent fetal loss. However, a conclusion that antibodies to FXII prove to be better predictors of fetal loss than levels of FXII cannot be drawn because their study was retrospective and cross-sectional, and the subsequent pregnancy outcome of recurrent aborters with antibodies to FXII was not examined prospectively. We have shown that patients with reduced FXII activity have a significantly higher likelihood of miscarriage in their subsequent pregnancy. Patients with recurrent miscarriages may exhibit many different kinds of antibodies. The prevalence of antinuclear antibodies in recurrent aborters is higher than that of controls, but again this is not a predictor because no subsequent miscarriage rates were found between patients with and without antibodies (4). Further investigations are needed to elucidate the significance of antibodies to FXII and FXII activity in patients with a history of recurrent miscarriages. Mayumi Sugiura Ogasawara, M.D. Department of Obstetrics and Gynecology Nagoya City University Medical School Nagoya, Japan August 9, 2001

References 1. Kanaji T, Okamura T, Osaki K, Kuroiwa M, Shimoda K, Hamasaki N, et al. A common genetic polymorphism (46 C to T substitution) in the

FERTILITY & STERILITY威

5⬘-untranslated region of the coagulation factor XII gene is associated with low translation efficiency and decrease in plasma factor XII level. Blood 1998;91:2010 – 4. 2. Braat EA, Dooijewaard G, Rijken DC. Fibrinolytic properties of activated FXII. Eur J Biochem 1999;263:904 –11. 3. Ploplis VA, Carmeliet P, Vazirzadeh S, Van Vlaenderen I, Moons L, Plow EF, et al. Effects of disruption of the plasminogen gene on thrombosis, growth, and health in mice. Circulation 1995;92:2585–93. 4. Ogasawara M, Aoki K, Kajiura S, Yagami Y. Are antinuclear antibodies predictive of recurrent miscarriage? Lancet 1996;347:1183– 4.

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Recombinant FSH vs. urinary FSH—retrospective study of matched pairs for type of treatment (IVF or ICSI) To the Editor: I have read with great interest the article by Ravhon and colleagues (1) in anticipation of reaching an answer to the frequently raised question, “Is the recombinant FSH (rFSH) clinically better than the urinary FSH (uFSH)?” However, despite the conclusion of this article (1), the answer is still in debate. Whereas meta-analysis of 12 randomized studies (2) concluded that rFSH is superior to the uFSH in terms of clinical pregnancy rate for IVF cycles, and a more recent doubleblind, randomized study (3) comparing rFSH with uFSH concluded the first preparation to be more effective than the latter, others (4, 5) reached opposite conclusions, preferring the urinary preparations to the recombinant FSH because of the presence of LH in the uFSH and its role in supplying androgens as substrate to the granulosa cell aromatase according to the two-cell, two-gonadotropin theory. The investigators emphasize that their study “represents clinical experience with a very large number of patients in a single clinical center. None of the prospective randomized multicenter studies have included such a large number of patients . . . we included almost 700 patients in each arm of treatment.” However, the above-quoted citation may be somewhat misleading. The investigators did not prospective include 700 patients, neither did they prospectively randomize between the two arms of treatment; rather, they retrospectively compared one treatment with another. As the investigators were aware of the possible biases in comparing retrospective treatments occuring over successive years, they tried to minimize biases due to older patients in the later period of treatment, 1997–1998, as compared with in 1996, when they retrospectively “randomized matched pairs of patients who were similar in age and treatment modality.” However, an overlooked problem still remains—is it correct to compare the results from two periods of times differing by 16 months from each other? The uFSH group was treated between January and December 1996, whereas the 1289