1106 Leiters May 1998 Am J Obstet Gynecol
Vandenbroucke's proposal to explain earlier epidemi-ologic study findings biepidemi-ologically is based on the small observational study by Rosing et al. with serious limita-tions in its design and based on a new test ("acquired ac-tivated protein C resistance"), which has been not vali-dated against venous thrombosis in vivo. The results could not be reproduced with clinically validated acti-vated protein C resistance tests by the Maastricht group themselves nor by another much larger population-based study.2 Furthermore, the mismatch between the labora-tory results of the Maastricht group and the latest epi-demiologic data that failed to show a differential risk of venous thromboembolism of third-generation pills add further question marks to the rash conclusions by Vandenbroucke et al.
It is unfortunate that Vandenbroucke et al. do not rec-ognize that, irrespective of their Interpretation of the earlier studies in 1995, studies in seven European coun-tries could not show significant associations aniong rising third-generation market share and differences in venous thromboembolism mortality over a period of 11 years. This is the bottom line. The authors obviously also disre-gard the published potential benefits of newer pills with regard to arterial diseases. The debate over the safety of newer oral contraceptives is not enhanced by scientific tunnel vision.
Lothar A.J. Heinemann, MD, DSc Centre for Epidemiology and Health Research Berlin, 16341 Zepernick, Germany
Walter O. Spitzer, MD, PhD Department of Epidemiology, McGill Umversity Montreal, Montreal,
Quebec, Canada H3A 1A2
Ulrich H. Winkler, MD, PhD Centre for Gynaecology, Unwersity Clinics Essen, 45122 Essen, Germany
REFERENCES
1. Spitzer WO. The 1995 pill scare revisited- anatomy of a non-epi-demic. Hum Reprod 1997;12:2347-57.
2. Schramm W, Heinemann LAJ. Oral contraceptives and venous thromboembolism. acquired APC resistance' Br J Haematol 1997;98:491-2.
6/8/90139
Reply
To the Editors: The letter by Heinemann et al. contains no new data, or new arguments, except for the allegations of "epidemiologic esotericism" and "scientific tunnel vi-sion." In his 1983 PhD Thesis, Vandenbroucke quoted Corrigan, an Irish physician living in the first half of the previous Century1 who did not shy away from contro-versy: "Whether my observations and opinions be dis-proved or supported, I shall be equally satisfied. Truth is the prize aimed for; and, in the contest, there is at least this consolation, that all the competitors may share equally the good attained."
Given that the current controversy has now exacer-bated to the level of personal allegations, the wisest move for all parties might be to invoke outside expertise. This has been done by the responsible scientists at the World Health Organization who have called for a "Scientific Group Meeting on Cardiovascular Disease and Steroid Hormone Contraceptives."2 Several independent U.S. sci-entists took part in this meeting in which all papers, even the unpublished ones, were brought in by all parties and were taken together to come to a carefully weighted over-alljudgement of benefits and risks. Thus all Information from more recent studies, which were already largely cov-ered in our review by taking published abstracts into con-sideration, will even be more fully covered in the World Health Organization report. The preliminary summary of this report states: "Combined oral contraceptive prepara-tions containing desogestrel and gestodene probably carry a small risk of venous thromboembolism beyond that attributable to combined oral contraceptives contain-ing levonorgestrel The Suggestion that gestodene or desogestrel-containing Iow-dose oral contraceptives may carry a lower risk of myocardial infarction compared with Iow-dose formulations containing levonorgestrel remains to be substantiated."2 Although the füll report is not yet available, it was already commented on by Spitzer,3 with two factual misquotations and a number of misgivings about its independence. A reply about the misquotations and the unfoundedness of these misgivings has been pub-lished.4
Regarding the "third generation controversy," new co-agulation findings about acquired "activated protein C resistance" have been found, which for the first time in 30 years offer a glimmer of hope that we might finally un-derstand why oral contraceptives may cause venous thrombosis—and which also show the strong interaction with the factor V Leiden mutation. Several investigators had already reported that the original (by now classic) test for activated protein C resistance showed an effect for women using steroid hormones,4^6 thereby giving cre-dence to the concept of hormonally acquired activated protein C resistance. These data have already been sented at several meetings at which all parties were pre-sent. We are really intrigued by die reluctance to discuss these biochemical findings.
We urge all interested parties to stop the discussion until the füll World Health Organization report is avail-able. Physicians in the United States will only be able to make up their minds after they have read this report and discussed it with responsible epidemiologists and coagu-lation researchers. We expect that it will be available by the time that this correspondence appears in print.
Jan P. Vandenbroucke, Frits R Rosendaal, and Frans M. Heimerhorst Departments of Clmical Epidemiology, Hemostasis, and Thrombosis Research Center, Obstetrics, Gynaecology and Reproductive Medtcine, Leiden Umversity Medical School, P.O. Box 9600, 2300 RC Leiden,
The Nelherlands
Volume 178, Number 5 Am J Obstet Gynecol
REFERENCES
1. O'Brien E. Conscience and conflict; a biography of Sir Dominic Corrigan. Dublin: Glendale Press; 1983.
2. World Health Organization Scientific Group Meeting on Cardiovascular Disease and Steroid Hormone Contracepüves. Summary of conclusions. Wkly Epidemiol Rec 1997;72:361-3. 3. Spitzer WO. Balanced view of risks of oral contraceptives.
Lancet 1997;350:1566-7.
4. Meirik O. Risk of oral contraceptives. Lancet 1998;351:521. 5. 0sterud B, Robertsen R, Äsvang GB, Thijssen F. Resistance to
activated protein C is reduced in women using oral contracep-tives. Blood Coagul Fibrmolysis 1994;5:853-4.
6. Meinardi JR, Henkens CMA, Hennga MP, van der Meer J Acquired APC resistance related to oral contraceptives and pregnancy and its possible imphcations for clmical practice. Blood Coagul Fibrinolysis 1997;8:152-4.
7. Löwe GDO, Rumley A, Woodward M, Reid E. Re: Oral contra-ceptives and venous thromboembohsm. Lancet 1997;349:1623.
6/8/90140
Factor V Leiden—A novel etiology of the
long-standing thrombosis theory for recurrent
preg-nancy loss
To the Editors: I read with interest the article by
Dizon-Townson et al. (Dizon-Dizon-Townson DS, Meline L, Nelson
LM, Varner M, Ward K. Fetal carriers of the factor V
Leiden mutation are prone to miscarriage and placental
infarction. Am J Obstet Gynecol 1997;! 77:402-4)
suggest-ing an association between factor V Leiden mutation and
spontaneous abortions in women. I wonder whether the
authors of this article had performed a MEDLINE search
before concluding that dieir study is the first report to
suggest that factor V Leiden could predispose to
sponta-neous miscarriages. One group from the United
Kingdom
1and our group from Israel
2have already
pub-lished concomitant studies suggesting an association
be-tween activated protein C resistance and factor V Leiden
to recurrent fetal loss during the first and second
trimesters. In our report
2we analyzed 39 consecutive
women with recurrent fetal loss of unknown etiology for
activated protein C resistance. Seventy-two percent of
these cases showed activated protein C resistance and
49% of them had die factor V Leiden mutation,
suggest-ing an association between this new mutation and
vascu-lar placental insufficiency.
The findings of Dizon-Townson et al. that gestational
material of abortuses and infarcted placentas has a high
incidence of factor V Leiden mutation strengthens our
previous estimation.
3Our assumption was that
mi-crothrombi of the placental bed vessels could lead to
multiple placental infarctions that adversely affect the
fe-tomaternal circulatory System, leading to fetal death.
The introduction of factor V Leiden äs an etiologic
factor for hereditary thrombophilia and the finding that
it is a widespread mutation with an estimated prevalence
of 2% to 7% in different populations have actually paved
the way to coherent Interpretation of the "thrombosis
theory" of recurrent pregnancy loss. Moreover, these
findings have presented, for the first time, an objective
rationale for thrombophylaxis during gestation in
pa-tients with recurrent pregnancy loss.
3The Suggestion that this thrombophilic mutation,
ac-cording to Dizon-Townson et al., should be assessed in
women and placental tissue from spontaneous abortuses
and placentas with evidence of placental infarction
seems to be premature. The cost effectiveness of this
assay
4should be thoroughly investigated before any final
conclusions are drawn. At this stage it is our policy to
rec-ommend this investigation in patients with at least two
consecutive recurrent pregnancy losses, especially if no
other appropriate explanation is detected.
Johnny S. Younis, MD Reproducttve Mediane Umt, Department of Obstetncs and Gynecology, Ponya Hospital, Tibenas, 15208 Israel
REFERENCES
1. Rai R, Regan L, Hadley E, Dave M, Cohen H. Second trimester pregnancy loss is associated with activated protein C resistance. Br J Haematol 1996;92:489-90
2 Brenner B, Mandel H, Lanir N, Younis J, Rothbart H, Ohel G, et al. Activated protein C lesistance can be associated with recur-rent fetal loss. BrJ Haematol 1997,97-551-4.
3 Younis JS, Ohel G, Brenner B, Ben-Ami M. Familial throm-bophilia—the scientific rationale for thrombophylaxis in recur-rent pregnancy loss. Hum Reprod 1997; 12:1389-90.
4. Altes A, SoutoJC, MateoJ, Borrell M, FontucubertaJ. Activated protein C resistance assay when apphed m the general popula-tion. Am J Obstet Gynecol 1997,176-358-9.
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