Parity and Subfertility Effects of Continuous Oral Contraceptives on Fertility Are Important

18 06 2009

To the Editor:

In recent articles, Barnhart and colleagues present data on time to conception following discontinuation of continuous oral contraception (OC) (1). They compare these and other data and conclude that “the return of fertility in former OC users … is comparable to … other contraceptive methods” (2). While we are pleased to see the addition of empirical evidence to this debate, we have some concerns about the role of parity in the time to conception, and are concerned that an uncritical acceptance of this conclusion may cause harm.

The authors have focused on a 12-month endpoint as the official timeframe for infertility. However, women often approach their physicians with questions about fertility before a year has passed, and, particularly for women in their 30s and 40s, clinicians must weigh the relative likelihood of infertility and decide on intervention vs. watchful waiting. In this context, Gnoth’s observations that most truly fertile couples will conceive within six months are an important clinical guideline (3), and it would be reasonable to start investigating possible causes of infertility (e.g., male factor, daily diary and ovulation monitoring) after six months for a couple discontinuing other methods of contraception. Women and the clinicians they consult need to know that a transient delay in conception is to be expected following discontinuation of oral contraceptives. This will reduce anxiety and forestall unnecessary infertility workups and assisted reproduction interventions.

We also remain concerned about the implications of widespread elective use of continous oral contraceptives for menstrual suppression, particularly for young women during development and prior to first pregnancy. A closer examination of the data by parity (1) shows a lower rate of conception for nulliparous women (Figure 1) particularly after 3 months when the majority (73% or 8/11) of parous women, but only 30% (3/10) of nulliparous women had conceived. It should also be noted that many women did not complete the one-year study before seeking pregnancy, and that the study only included women age 18 or older. Conception rates following a longer duration of use, or use during reproductive development remain unclear.

Finally, we wish to draw attention to the conflicts of interest. Both the review and the original article were written under contract to the pharamaceutical company, which also performed the statistical analysis. An example of this bias is in the extension of reporting from 12 to 13 months, presumably to include one more pregnancy.

Figure 1

Figure 1

Christine L Hitchcock, PhD
Jerilynn C Prior, BA, MD
Centre for Menstrual Cycle and Ovulation Research (CeMCOR)
Division of Endocrinology
Department of Medicine
University of British Columbia
Vancouver, British Columbia, Canada

References
1. Barnhart K et al. Return to fertility after cessation of a continuous oral contraceptive. Fertil Steril 2009;91:1654-6.

2. Barnhart KT, Schreiber CA. Return to fertility following discontinuation of oral contraceptives. Fertil Steril 2009, 91:659-63.

3. Gnoth C et al. Definition and prevalence of subfertility and infertility. Hum Reprod 2005; 20:1144-7.

Published online in Fertility and Sterility doi:10.1016/j.fertnstert.2009.06.036

The Authors Respond:

I would like to thank Dr. Hitchcock and colleagues for their insightful letter. Critical review of the scientific literature is necessary, and the discussions that such letters generate are always beneficial. The main point of their letter was the important distinction between return to fertility and the definition of subfertility (or infertility). It is widely recognized and appreciated that the definition of infertility is the inability to achieve a pregnancy in one year in the absence of family planning or the use of contraception. It is also recognized that there are limitations to this definition. The American Society for Reproductive Medicine clearly recommends that there are circumstances when evaluation for subfertility should be initiated prior to one year (1). Examples include a suspicion of anatomic or physiologic disorder as well as the woman’s age greater than 35 years. Clarification of the natural history of return to fertility after stopping oral contraception, and therefore assisting astute clinicians in the decision to reassure a couple or initiate a workup for subfertility, was one the goals of this series of publications (2,3). The decision about when to initiate a work-up for subfertility must be individualized based upon the age of the woman and the context of the couple’s lives, comorbidities, and their goals and desires. Given the small and certainly transient contribution that prior oral contraceptive pill (OCP) use appears to contribute, this is unlikely to play a substantial role in the decision of when to intervene.

Dr. Hitchcock raises an interesting point regarding the potential confounding effect of parity on return to fertility. I agree that the data suggest there may be a lower rate of fertility for nulliparous women at 3 months, which attenuates at 6 months and disappears by 12 months. One must be cautious, however, in overinterpreting the clinical and statistical significance of findings based on a small sample size in a single trial. In this trial, the relative risk for a nulliparous women achieving a pregnancy within three months compared to parous women was 0.41 (95% CI 0.15 – 1.14), a non-statistically significant finding. I hope that Dr. Hitchcock and others will conduct the further research needed to verify or refute this finding.

Finally, I wish to address the concern regarding conflict of interest. The study of return to fertility after continuous oral contraception was part of a pharmaceutically sponsored clinical trial, of their own product, for the purposes of obtaining FDA approval. This is clearly stated in the manuscript (2). I was one of the many investigators who participated in the pivotal multicenter trial (4). I had full editorial control and received no compensation for preparation of this manuscript. In order to guard against the unfortunate implicit suggestion that all data collected and analyzed with pharmaceutical support are biased, I elected to present all the data (return to fertility at 3 months, 12 months, and 13 months) to be transparent and complete. An educated reader can draw their own conclusion from objective data.

Unintended pregnancy, with a 49% prevalence in the United States, is a major public health problem. It is our responsibility to understand the relative risks and benefits of the contraceptive technologies available so that we can responsibly counsel our patients and maximize healthy pregnancy outcomes.

Kurt Barnhart, M.D., M.S.C.E.
Director, Women’s Health Clinical Research Center
Assistant Dean, Clinical Trial Operations
Penn Fertility Care
Philadelphia Pennsylvania

References
1. Practice Committee of the American Society for Reproductive Medicine. Definitions of infertility and recurrent pregnancy loss. Fertil Steril 2008;90(5 Suppl):S60.

2. Barnhart K et al. Return to fertility after cessation of a continuous oral contraceptive. Fertil Steril 2009;91:1654-6.

3. Barnhart KT, Schreiber CA. Return to fertility following discontinuation of oral contraceptives. Fertil Steril 2009; 91:659-63.

4. Archer DF, Jensen JT, Johnson JV, Borisute H, Grubb GS, Constantine GD. Evaluation of a continuous regimen of levonorgestrel/ethinylestradiol: Phase 3 study results. Contraceptive 2006;74:439-45.

Published online in Fertility and Sterility doi:10.1016/j.fertnstert.2009.06.037

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