1. The Effect of Continuous Combination Oral Contraceptive use on Subsequent Fertility The Effect of Continuous Combination Oral Contraceptive use on Subsequent Fertility Won Bahng Hwee, PA-S Pacific University School of Physician Assistant Studies, Hillsboro, OR USA Background Combination oral contraceptive (COC) is the most common method of contraception utilized in the United States. Currently, the traditional 28-day cyclic COC is the mainstay. In the 21 st century, continuous COC, a pill taken daily without a pill-free or placebo period, was developed. Continuous COC shows multiple advantages over the traditional cyclic COC, both in reducing the frequency of menses and the severity of associated symptoms, as well as providing lifestyle benefits and convenience for women. Recently, a large phase 3 contraceptive trial has demonstrated a good safety and efficacy profile for continuous COC comparable to the traditional cyclic COC. This systematic review evaluates the effect of continuous COC use on subsequent fertility in healthy women of child- bearing age. Method An extensive electronic search of MEDLINE, CINAHL, and Evidence Based Medicine Review Multifile was conducted using fertility and oral contraceptives as key words. Articles were included if they evaluated the effect of continuous COC use on subsequent fertility in healthy women of child-bearing age. The exclusion criteria entailed articles assessing the traditional cyclic COC or the use of COC for therapeutic purposes. The search was restricted to reports written in English language between 1990 and the present with human subjects. For the included articles, the GRADE system was utilized to assess the validity and quality. Results Two studies were included in this systematic review. Both studies were follow-up studies of a phase 3 contraceptive trial evaluating the safety and efficacy of continuous COC containing 90 mcg of Levonorgestrel (LNG) and 20 mcg of Ethinyl estradiol (EE). Barnhart et al: For 21 women who had discontinued continuous COC for pregnancy intent, the pregnancy rate at 12 months post treatment was 81%, comparable to the 84% pregnancy rate of women with previous traditional cyclic COC use. 1 Davis et al: For 187 women who had at least 6 months of continuous COC treatment, 185 (98.9%) had spontaneous return of menses or pregnancy within 3 months of treatment discontinuation. The median time to return of spontaneous menses after cessation of continuous COC use was 1 month. The amenorrhea induced by continuous COC use appears to be readily reversible regardless of the duration of amenorrhea. 2 References 1.Barnhart K, Mirkin S, Grubb G, Constantine G. Return to fertility after cessation of a continuous oral contraceptive. Fertil Steril. 2009;91(5):1654-1656. 2.Davis AR, Kroll R, Soltes B, Zhang N, Grubb GS, Constantine GD. Occurrence of menses or pregnancy after cessation of a continuous oral contraceptive. Fertil Steril. 2008;89(5):1059-1063. Acknowledgements: I would like to thank Mark Hwee, Elinor Hwee, Chul and Sunhee Bahng, Num-Kock and Kim-Ping Hwee, my classmates, my professors and staff at Pacific University! Table 1. Characteristics and Quality Assessment of Reviewed Studies Table 2. Summary of Findings Conclusion COC is the leading contraceptive method in the United States. The traditional 28-day cyclic COC has been the mainstay due to its naturalness and acceptance by women. Yet, the newly developed continuous COC may provide superior benefits for women by reducing the frequency of menses and severity of related symptoms and offering lifestyle benefits and convenience. Based on a large phase 3 contraceptive trial, continuous COC has a good safety and efficacy profile. And recent studies point towards lack of delay in return to fertility; however, more high quality research is necessary to ascertain the effect of continuous COC use on subsequent fertility. At this time, women should be educated about the limitations of current research to make their own decisions in choosing continuous COC as a contraceptive method. Discussion The two included studies suggest that continuous COC use does not delay the return to fertility. However, the quality of evidence in both studies are very low. The major flaws are listed: 1.Lack of control group in both studies. This limited their methodologies making it likely to result in biased assessment of the treatment effect and also made it impossible to determine if the results were consistent. 2.Time to fertility was evaluated for women who may not have necessarily wanted to become pregnant. Davis et al 2 included women with at least 6 months of previous continuous COC treatment, who then were using non-hormonal contraceptives. This degraded the methodology. 3.Indirectness of evidence in Davis et al. 2 The occurrence of first spontaneous menses was used as a measure of return to fertility; yet, the bleeding could have resulted from the withdrawal of COC hormones. 4.Short mean duration of continuous COC treatment in both studies. It is difficult to postulate the effect of long-term continuous COC use on return to fertility. 5.Small sample sizes in both studies. This induced some imprecision overall. 6.Possible publication bias. Wyeth Research, the manufacturer of Lydrel, the drug utilized in both studies, also sponsored both studies. Future Study Idea: A prospective, cohort study  Population: healthy women of child-bearing age desiring pregnancy in the future with no previous history of COC use  Intervention: continuous COC treatment for at least 6 months  Control: no method of contraception  Outcome: time to pregnancy o Control – measure from study initiation o Experimental – measure from treatment cessation Clinical Recommendation: For healthy women seeking to try continuous COC as a contraceptive method, the clinicians need to inform them about the limitations of the current research. Continuous COC does induce amenorrhea in most women and this could be advantageous for some desiring to have less frequent menses and related symptoms, as well as lifestyle benefits and convenience. While continuous COC does have a good safety and efficacy profile comparable to the traditional cyclic COC, its effect on subsequent fertility needs further research.