Is there really no improvement in pregnancy rate with double IUI in unexplained infertility?

6 01 2011

To the Editor:

Rahman et al. (1) conclude that single, well-timed intrauterine insemination (IUI) is sufficient in patients undergoing controlled ovarian hyperstimulation (COH)-IUI for unexplained infertility. However, we question this conclusion based on the results of this randomized controlled trial (RCT).

In their article, the authors do not mention a power calculation and sample size prediction prior to the trial. We argue that the number of events (pregnancies) in both arms of the study is too small to yield any conclusion. The odds ratio (OR) of pregnancies is 0.90 (CI 95% 0.44-1.67). This confidence interval (CI), containing 1.0, is too wide to make any conclusions, which means that double IUI could still be better. Even if we compare the cited meta-analysis of Polyzos (2) (which lack sufficient numbers as well) with the trial of Rahman, neither statistical nor clinical significance is reached: OR= 0.93 (CI 95% 0.66-1.30).

Due to the additional costs and burden for the couples, we may assume at least 10% more pregnancies after double versus single IUI. This means an experimental event rate (EER) for double insemination of 0.361 versus the known and frequently reported control event rate (CER) for single insemination of 0.329. Based on an adequate power calculation, we have to rely on a large trial of 4,007 patients in both study arms.

We state that the conclusions of Rahman et al. are premature. More evidence from larger RCTs or cumulative meta-analysis is required before any definite recommendation can be made on single versus double IUI for couples with unexplained infertility.

Geert H. Page, M.D., M.Sc.
Bianca A. J. T. Visschers, M.D.
Ilse Vanderbeke, M.D.
Department of Obstetrics and Gynaecology
Jan Yperman Hospital
Ypres, Belgium

Johan A.C. Thys, M.D.
Department of Obstetrics and Gynaecology
AZ Groeninge
Courtrai, Belgium

References
1. Rahman S, Malhotra N et al. A randomized controlled trial comparing the effectiveness of single versus double intrauterine insemination in unexplained infertility. Fertil Steril 2010 (Article in Press).

2. Polyzos NP, Tzorias S, Mauri D, Tatsioni A. Double versus single intrauterine insemination for unexplained infertility: a meta-analysis of randomized trials. Fertil Steril 2009. DOI:S0015-0282(09)01426-5.

Published online in Fertility and Sterility doi:10.1016/j.fertnstert.2011.01.025

The Authors Respond:

Our study tries to explore whether double intrauterine insemination (IUI) confers any benefit in couples with unexplained infertility. The proposed sample size of 80 per group was designed to provide 80% power for the primary comparison if the pregnancy rates for single and double IUI in the unexplained infertility population being studied are 14.4% and 30.4% per patient (1), respectively. The power calculation was performed using SAS 9.1.3 (Cary, NC). The difference in these rates in the reference study is substantial, but each rate is within a range of what may be considered reasonable possibilities in the absence of data. The absence of published studies of single and double IUI in cases of unexplained infertility alone lends to our current uncertainty and necessitates studies such as this to provide preliminary estimates of their efficacy.

One of the largest studies on this debate includes patients with both male factor and unexplained infertility (1). There is no consensus in the literature on this aspect and these studies have been limited by heterogeneity of various parameters (2-4). In our study, we tried to evaluate the utility of double IUI in a fairly homogeneous group of infertile patients with unexplained infertility. The dearth of data on this specific area has also made calculation of sample size difficult to determine.

Further, for the OR of 0.90 (CI 95% 0.44-1.67 ) 6,348 patients will be needed for a sound statistical analysis in each arm, considering the prevalence of unexplained infertility in India to be around five million couple. [CEBM Statistics Calculator KT Clearinghouse,(Canada)] However, we get this odds ratio only after performing this study. So the present study, in light of its findings can be used as a pilot study to plan large multicenter trials in the future comprising 6,348 patients in each arm.

Also ,the experimental event rate (EER) for double insemination is 0.296 (considering per couple) and not 0.361 as mentioned by the Page et al. in their letter. In our published data, if “no pregnancy” is listed as an adverse outcome, the number needed to treat/harm (NNT/NNH) is 30 (Table 1). From an NNT analysis, this sample size fulfils the requirements of an intention-to-treat pilot study, although this has probably led to type II error in our study. The study is a stimulus for future trials with larger numbers, as mentioned above, and is not intended to denounce double IUI.

Table 1: NNT Analysis for Study

Neena Malhotra, M.D.
Debjyoti Karmakar, M.D., D.N.B.
Department of Obstetrics and Gynaecology
All India Institute of Medical Sciences (AIIMS)
New Delhi, India

References
1. Ragni G, Maggioni P, Guermandi E, Testa A, Baroni E, Colombo M, et al. Efficacy of double intrauterine insemination in controlled ovarian hyperstimulation cycles. Fertil Steril 1999;72:619–22.

2. Silverberg KM, Johnson JV, Olive DL, Burns WN, Schenken RS. A prospective randomized trial comparing two different intrauterine insemination regimens in controlled ovarian hyperstimulation cycles. Fertil Steril 1992;57:357–61.

3. Alborzi S,Motazedian S, ParsanezhadME, Jannati S. Comparison of the effectiveness of single intrauterine insemination (IUI) versus double IUI per cycle ininfertile patients. Fertil Steril 2003;80:595–9.

4. Liu W, Gong F, Luo K, Lu G. Comparing the pregnancy rates of one versus two intrauterine inseminations (IUIs) in male factor and idiopathic infertility. J Assist Reprod Genet 2006;23:75–9.

Published online in Fertility and Sterility doi:10.1016/j.fertnstert.2011.01.026

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