To the Editor:
We read with respect the article by Ruopp et al. (1) that has questioned the methodological approach of our previously published review (2) on the use of aspirin in in vitro fertilization cycles. We disagree with the authors in that random-effects models should only be used in the absence of inter-study heterogeneity. With fixed-effects models, it is assumed that there is a sole common effect estimates for all studies, i.e., the true effect of treatment, in both magnitude and direction, is the same value in every study. This assumption implies that the observed differences among study results are due exclusively to chance, with no statistical heterogeneity. With the range of data available in most meta-analyses, failure to reject the null hypothesis of homogeneity does not prove homogeneity. In the presence of any between-study heterogeneity, fixed-effects give tighter confidence intervals compared with random-effects. This leads to spurious lower levels of statistical significance for the summary effects (3). In contrast, the random-effects model makes an adjustment to the study weights according to the extent of variation among the treatment effects. In our analysis, where I2 ranges from 27% to 62%, we do not anticipate that the weights are so unfair to the big trials. The main concern with the re-analysis by Ruopp et al. is that the use of fixed-effects model in the presence of heterogeneity shrinks the confidence interval of the summary estimate leading to an erroneous statistically significant result (4). Indeed, using the random effects model, Ruopp et al. did not find any significant differences between the aspirin and no aspirin groups.
We made a concerted effort to minimize the combination of data from different clinical groups. In contrast with Ruopp et al, we excluded studies that were not randomized and those that investigated the use of low-dose aspirin only in a specific subgroup of patients such as poor responders, recipients of donated oocyte and subjects who had frozen embryo transfer. We also excluded two conference abstracts as we failed to get a positive response by the authors to retrieve missing data.
In the current climate of good and safe medical practice, there is no such a thing as ‘premature meta-analysis.’ It is unethical and scientifically unsound to ignore the best available evidence that comes from meta-analysis, even if the evidence may not be seen as conclusive. Further, issues surrounding the safety of aspirin administration in the very early stages of pregnancy have to be borne in mind, especially as more information is needed. A published meta-analysis (5) demonstrated that the use of aspirin in the first trimester of pregnancy was associated with a significantly increased risk of gastroschisis (odds ratio, 2.37; 95% CI, 1.44–3.88).
In agreement with the available literature, our meta-analysis is well placed to inform fertility professionals that aspirin supplementation should not be routinely recommended to women undergoing assisted conception treatments and should only be offered within the context of clinical trials. Indeed, our views are different from those expressed by Ruopp and collaborators.Tarek A.Gelbaya, MD Luciano G.Nardo, MD Department of Reproductive Medicine St Mary’s Hospital, CMMC University Hospitals Manchester, United Kingdom
1. Ruopp MD, Collins TC, Whitcomb BW, Schisterman EF. Evidence of absence or absence of evidence? A reanalysis of the effects of low-dose aspirin in in vitro fertilization. Fertil Steril 2008; 90:71.
2. Gelbaya TA, Kyrgiou M, Li TC, Stern C, Nardo LG. Low-dose aspirin for in vitro fertilization: a systematic review and meta-analysis. Hum Reprod Update 2007; 13:357–64.
3. Ntzani EE, Rizos EC, Ioannidis JP. Genetic effects versus bias for candidate polymorphisms in myocardial infarction: case study and overview of large-scale evidence. Am J Epidemiol 2007; 165:973–84.
4. Schmidt FL, Oh IS, Hayes TL. Fixed- versus random-effects models in meta-analysis: Model properties and an empirical comparison of differences in results. Br J Math Stat Psychol 2007; 13 (Epub ahead of print).
5. Kozer E, Nikfar S, Costei A, Boskovic R, Nulman I, Koren G. Aspirin consumption during the first trimester of pregnancy and congenital anomalies: a meta-analysis. Am J Obstet Gynecol 2002; 187:1623-30.
Published online in Fertility and Sterility DOI: 10.1016/j.fertnstert.2008.12.069
The Authors Respond:
Gelbaya and Nardo (1) raise no new objections, instead repeating previous statistical misperceptions and of meta-analysis techniques in particular. Regarding the question of fixed versus random-effect models, the issues they raise have been addressed by us (2) and experts in the field (3). Fixed effect models are the appropriate choice to estimate a weighted average effect of existing studies. The presence of inter-study variance alone is not sufficient justification for use of random-effect models. In addition to the assumptions required by these models, their confidence intervals are based on large number theories, and yield estimates that apply only to a hypothetical population and are of questionable utility (4).
The assertion that “there is no such thing as a ‘premature meta-analysis'” is not necessarily true. Viewed as a synthesis of knowledge, meta-analysis offers a systematic approach to describe the state of the science; however, as an approach to hypothesis testing, meta-analysis is as prone to inadequate sample size as individual-level studies. In the current context, the absence of evidence for or against a benefit of aspirin in IVF provides no basis for answering this question.
Since no conclusion can be drawn regarding benefits, the recommendations of Gelbaya and Nardo have as their premise evidence of the risk related to aspirin use in IVF, as per a previously published report (5). Given firm evidence of a strong risk, we would agree (and noted so in our paper) that aspirin should not be recommended clinically; however, as we have described, this is not the case. The risk of gastroschisis related to aspirin use is not well established (6).
Thus, we are left with substantial uncertainty regarding both benefits and risks related to aspirin in IVF. We reiterate previous conclusions regarding the inadequacy of data to warrant recommendations. More studies regarding the effectiveness of aspirin on IVF are needed to provide conclusive evidence.Enrique F. Schisterman, PhD Brian W. Whitcomb, PhD Marcus Ruopp, BS
Eunice Kennedy Shriver National Institute of Child Health and Human Development Bethesda, MD
1. Gelbaya TA, Kyrgiou M, Li TC, Stern C, Nardo LG. Low-dose aspirin for in vitro fertilization: a systematic review and meta-analysis. Hum Reprod Update 2007; 13:357–64.
2. Ruopp MD, Collins TC, Whitcomb BW, Schisterman EF. Evidence of absence or absence of evidence? A reanalysis of the effects of low-dose aspirin in in vitro fertilization. Fertil Steril 2008; 90:71.
3. Peto R. Why do we need systematic overviews of randomized trials? Stat Med 1987;6:233–40.
4. Greenland S, O’Rourke K. Meta-analysis. In: Rothman KJ, Greenland S and Lash TL, eds. Modern Epidemiology, 3rd Edition. Philadelphia (PA): Lippincott Williams & Wilkins, 2008: 675–7.
5. Kozer E, Nikfar S, Costei A, Boskovic R, Nulman I, Koren G. Aspirin consumption during the first trimester of pregnancy and congenital anomalies: a meta-analysis. Am J Obstet Gynecol 2002; 187:1623–30.
6. Hertz-Picciotto I. Effects of aspirin on female reproductive function and on in utero development. In: Feinman SE, ed. Beneficial and toxic effects of aspirin. Boca Raton (FL): CRC Press, 1993:73–88.
Published online in Fertility and Sterility DOI: 10.1016/j.fertnstert.2008.12.070