To the Editor:
Ata et al. (1) published a systematic review of randomized controlled trials (RCTs) testing intravenous immunoglobulin (IvIg) treatment of unexplained recurrent miscarriage (RM). They concluded that IvIg was beneficial neither in patients with primary nor secondary RM.
A significant limitation of the conclusions is that only 6 of a total of 8 relevant RCTs were included in the review comprising 272 patients. Two trials from our group (2,3) comprising 92 patients were excluded since, as stated in the article, “they also recruited women with antiphospholipid antibodies, and RM was defined as pregnancy loss before 28 weeks’ and 26 weeks’ gestation.”
We are surprised of the arguments for the elimination of our trials. The statement that we included patients with antiphospholipid (APL) antibodies is only correct to a minor degree. In our first RCT article (2) it is clearly stated that all patients had normal APPT (as a screening for lupus anticoagulant) and were negative for anticardiolipin antibody of IgG and IgM type at the time of inclusion. In the second trial (3), 38% of the patients were positive for anticardiolipin or lupus anticoagulant at the time of inclusion. However, as indicated in the article, the cut off values in the anticardiolipin tests were > 7 MPL and > 22 GPL for IgM and IgG anticardiolipin, respectively, defined as > 95% percentile. Now the international anticardiolipin-related criteria for the APL syndrome are either anticardiolipin titres > 99% percentile or > 40 MPL or > 40 GPL (4). Applying these updated cut-off values in our second trial, only three patients would remain APL positive and thus only 3.2% of the patients in both our RCTs should be excluded in the review by Ata et al.
The other argument for the elimination of our RCTs, that trials with RM patients with a pregnancy loss between gestational weeks 20 and 28 should be excluded, is also a matter for discussion. In Denmark and other countries, a pregnancy loss < 27 + 6 weeks was until April 1, 2004, legally and medically defined as a miscarriage. The RCOG Guidelines about RM still define RM as 3 or more pregnancy losses without any more specification. We think that it is methodologically incorrect to discharge whole RCTs conducted at a time when the definition of miscarriage was < 27 + 6 weeks and comprising only a minority of RM patients with a pregnancy loss between weeks 20 and 28 – in our RCTs only 14% of 92 patients.
If Ata et al. systematically want to adhere to updated criteria they should certainly adhere both to the updated criteria for APL positivity and miscarriage. To accomplish this, they should have contacted the authors of the RCTs and obtained relevant original data. Subsequently, they could exclude individual patients who had APL and exclusively miscarriages according to the updated criteria. We realize the huge task to collect these data but it has been done successfully in a previous meta-analysis (5) and, if done, the credibility of the systematic review would improve considerably.
Ole B. Christiansen, Professor, M.D.
Elisabeth C. Larsen, M.D.
Merete Husth, M.D.
Bjørn Pedersen, M.D.
The Fertility Clinics
1. Ata B, Tan SL, Shehata F, Holzer H, Buckett W. A systematic review of intravenous immunoglobulin for treatment of unexplained recurrent miscarriage. Fertil Steril 2011; 95: 1080-5.
2. Christiansen OB, Mathiesen O, Husth M, Rasmussen KL, Ingerslev HJ, Lauritsen JG. et al. Placebo-controlled trial of treatment of unexplained secondary recurrent spontaneous abortions and recurrent late spontaneous abortions with iv. immunoglobulin. Hum Reprod 1995; 10: 2690-5.
3. Christiansen OB, Pedersen B, Rosgaard A, Husth M. A randomized, double-blind, placebo-controlled trial of intravenous immunoglobulin in the prevention of recurrent miscarriage – evidence for a therapeutic effect in women with secondary recurrent miscarriage. Hum Reprod 2002; 17: 809-16.
4. Myakis S, Lockshin MD, Atsumi T, Branch DW, Brey PL, Cervera R, Derksen RHWM, de Groot PG, Koike T et al. International consensus statement on an update of the classification criteria for the definite antiphospholipid syndrome (APS). J Tromb Haemost 2006; 4: 295-306.
5. Recurrent Miscarriage Trialists Group. Worldwide collaborative observational study and meta-analysis on allogeneic leukocyte immunotherapy for recurrent spontaneous abortion. Am J Reprod Immunol 1994; 32: 55-72.
Published online in Fertility and Sterility doi:10.1016/j.fertnstert.2011.03.040
The Authors Respond:
We appreciate the interest of Dr. Christiansen and colleagues in our work.
They correctly point out that the definition of recurrent miscarriage (RM) varies. Indeed, in their own two trials, Christiansen et al. used different definitions of RM [≥3 miscarriages before 28th gestational week (1) and ≥4 miscarriages before 26th gestational week (2)] and of secondary miscarriage [at least one pregnancy proceeding after the 14th gestational week was required for secondary RM (1) and at least one pregnancy proceeding after the 26th gestational week was required for secondary RM (2)]. In order to ensure generalizability of the conclusions, we wanted to standardize inclusion criteria and therefore excluded these two trials from our main analyses (3).
Regarding lupus anticoagulant (LA) screening with activated partial prothrombin time (aPTT) assay, unless an LA-sensitive reagent is used, it is possible that women with LA can have aPTT within the normal range (4). Therefore, we do not know whether all women in the mentioned study (1) can be considered LA negative. On this basis the data was also excluded from our primary analyses.
However, we did not disregard these trials completely and presented an auxiliary analysis that included data from these two trials and yielded the same conclusion, that IVIG does not increase live birth rate in women with secondary RM defined as ≥3 pregnancy losses before the 20th gestational week after a previous live birth (odds ratio for live birth 1.89, with a 95% confidence interval between 0.93 and 3.85). This was discussed in the text and presented in our supplemental figure 1 (3).
We acknowledge Dr. Christiansen`s expertise and work on RM and we are looking forward to the results from their ongoing trial (5).
Baris Ata, M.D., M.C.T.
William Buckett, M.D.
Reproductive Endocrinology and Infertility
Department of Obstetrics and Gynecology
Montreal, Quebec, Canada
1. Christiansen OB, Mathiesen O, Husth M, Rasmussen KL, Ingerslev HJ, Lauritsen JG et al. Placebo-controlled trial of treatment of unexplained secondary recurrent spontaneous abortions and recurrent late spontaneous abortions with iv immunoglobulin. Human Reproduction 1995;10:2690-5.
2. Christiansen OB, Pedersen B, Rosgaard A, Husth M. A randomized, double-blind, placebo-controlled trial of intravenous immunoglobulin in the prevention of recurrent miscarriage: evidence for a therapeutic effect in women with secondary recurrent miscarriage. Human Reproduction 2002;17:809-16.
3. Ata B, Tan SL, Shehata F, Holzer H, Buckett W. A systematic review of intravenous immunoglobulin for treatment of unexplained recurrent miscarriage. Fertil Steril 2011;95:1080-5 e2.
4. Dembitzer FR, Ledford Kraemer MR, Meijer P, Peerschke EI. Lupus anticoagulant testing: performance and practices by north american clinical laboratories. Am J Clin Pathol 2010;134:764-73.
5. Christiansen OB. http://www.clinicaltrials.gov/ct2/show/NCT00722475?term=recurrent+miscarriage&rank=1 ongoing.
Published online in Fertility and Sterility doi:10.1016/j.fertnstert.2011.03.041