March 27, 2023

Modeling the Cumulative Effectiveness of Fertility Treatments: A Review

By Katelyn Rennyson

Executive Director’s Note: Despite a high prevalence of subfertility in the general population, the cause is often multifaceted, and the diversity of treatment options leaves many couples confused and overwhelmed. Through her summary of a research article titled, “Cumulative pregnancy probabilities among couples with subfertility: effects of varying treatments,” fourth-year medical student Katelyn Rennyson lends insight into the diagnosis of subfertility and discusses the data on a couple’s ability to conceive over a 3-year period depending on the treatment plan. She also highlights how fertility awareness-based methods (FABMs) offer couples hope when combined with restorative reproductive treatment options, information she gained while on the FACTS elective.

Introduction

Infertility is usually defined as a failure to conceive after twelve months of regular unprotected intercourse.[1] According to Gnoth et al, subfertility should be considered as early as six cycles without conception with fertility-focused intercourse regardless of the woman’s age.[2] Although subfertility is estimated to affect 15% of couples in their reproductive years, only about half of them seek medical attention for subfertility, since most couples will succeed in having children on their own without intervention.[3] When couples do seek advice from a medical professional, an infertility workup is typically initiated to identify and differentiate between reversible or treatable causes and those which are not. Yet, after thorough assessments, many couples fall under a category of “subfertility of unknown etiology” without a specific diagnosis. These couples may become frustrated in a difficult situation as they consider whether to pursue treatment.

“Although subfertility is estimated to affect 15% of couples in their reproductive years, only about half of them seek medical attention for subfertility, since most couples will succeed in having children on their own without intervention.”

Although various treatment options are available, such as ovulation induction and in vitro fertilization (IVF), extended data analyzing patterns of treatment success over months to years is lacking to clarify whether pursuing these routes is superior to continuing their efforts to conceive naturally without treatment. Most studies seeking these answers have been randomized controlled trials (RCTs), but many are conducted and analyzed within a short time frame due to high rates of study attrition. As a result, these studies lack the foresight into which methods offer the best long-term success rates, which is important considering that even with treatment, it may take months to achieve pregnancy. Furthermore, many fertility studies analyze treatment effectiveness on a per-cycle basis rather than per couple, which often fails to answer the question of how many couples were able to conceive per treatment method over time. [3] [4]

Cumulative calculations over the course of consecutive cycles also allow natural variations in success over time to be considered, since more fecund couples will often conceive in earlier cycles than less fecund couples; in a per-cycle model, this would inflate the success rates of earlier cycles. [3] Given the importance of considering cumulative effects over time when comparing subfertility treatment options, the study by Stanford et al summarized below sought to model the cumulative effectiveness of previously studied fertility treatments over a 3-year period. [3]

Methodology

Stanford et al designed a simulation model on hypothetical subfertile patients, defined as patients who had attempted to conceive naturally for two years without success and who were evaluated to exclude identifiable causes of infertility, including anovulation, tubal obstruction, and severe male factor infertility. A hypothetical sample population of one million couples and their associated fertility was first generated using statistical methods to create a distribution that mirrored prior studies of natural fertility. Subsequently, this sample was run through a model built with five different treatment scenarios: (1) Frequent intercourse (i.e., continuing the same efforts as the previous two years), (2) Infrequent intercourse, (3) Conservative treatment (modeled on a Cochrane review of clomiphene-induced ovulation), (4) IVF treatment for up to three cycles followed by less frequent intercourse (IVF + infrequent intercourse), and (5) 20 cycles of conservative treatment followed by IVF for up to three cycles (conservative + IVF).

The model was built by extrapolating data from prior studies or reviews in the literature that published about success rates of these different methods. The time required for each IVF cycle was set to be equal to the time required for three conservative cycles in scenario 3, and IVF cycles were assumed to be conducted without delay between each treatment cycle. This model was then simulated for three years (39 cycles) on this hypothetical population of subfertile couples who had failed to conceive for the prior two years. The model also accounted for a proportion of patients within this subfertile population who are truly sterile, which was set at 5% for the model.

Results

This model found that, initially, IVF + infrequent intercourse has the highest cumulative probability of conception — offering the highest probability within the shortest amount of time — with approximately 30% of couples becoming pregnant within six consecutive cycles. However, at around the 1-year mark, the cumulative effectiveness of the conservative treatment method caught up to the IVF + infrequent intercourse method and eventually surpassed it. Additionally, after less than 30 cycles of unprotected, frequent intercourse alone (i.e., no treatment), couples pursuing this method achieved the same outcomes as those who pursued IVF + infrequent intercourse. Furthermore, these couples without treatment, when compared to IVF + infrequent intercourse, ended up with a higher probability of pregnancy at the end point of 39 cycles (about 3 years), with a 60% cumulative probability of conception. Finally, the study compared the conservative + IVF method against the other scenarios and found that conservative treatment for 20 cycles followed by IVF offered the highest probability of success in becoming pregnant at around the 2-year mark (26 cycles), with a nearly 70% cumulative success probability.

“After less than 30 cycles of unprotected, frequent intercourse alone (i.e., no treatment), couples … achieved the same outcomes as those who pursued IVF + infrequent intercourse.”

Discussion

This model-based, hypothetical study on a sample of couples with subfertility contributed multiple novel findings over a larger theoretical follow-up period than previous studies. By estimating cumulative probabilities of conception over this period, the study displayed a broad overview of the success of these treatments, making the differences between options easier to understand and apply when treating couples experiencing subfertility. The model demonstrated that IVF may offer an initial benefit of higher probabilities of success for couples early on in treatment, and thus may offer the quickest option to conception for some couples. However, after this initial 6-month period, its cumulative effectiveness diminishes, and other methods become comparable and eventually superior to IVF.

After about one year, continuous conservative treatment prevailed as the best option, with the highest probability of pregnancy among the modeled scenarios. After a little over two years, frequent intercourse matched the cumulative pregnancy probabilities of IVF, and proved to be better than IVF by the end of the 3-year study period. After 20 cycles, IVF in addition to conservative treatment was shown to further accelerate the cumulative pregnancy probability for couples, amounting to the highest success over all methods within a 2-year period. Predictably, infrequent intercourse alone was the only method inferior to IVF that maintained a low cumulative probability of achieving pregnancy over the course of the model.

This study offers couples experiencing subfertility greater insight into different treatment options available to them. Specifically, it provides a broader timeline for patients to understand when most couples are successful with each of these methods. This knowledge enables couples to make more informed decisions based on their individual goals, such as their desired time frame and level of intervention. As these goals vary from couple to couple, there is no clear superior choice for all couples when considering the study outcomes. In fact, the findings suggest each couple must weigh the advantages and disadvantages of each approach, with the largest tradeoff factors being time and cost.

“The findings suggest each couple must weigh the advantages and disadvantages of each approach, with the largest tradeoff factors being time and cost.”

A major limitation of this research is the inherent study design as a statistical model rather than one conducted on actual patients or couples experiencing subfertility via a randomized controlled trial. Furthermore, the studies the model was based on offer their own limitations; for two of the scenarios, this may have underestimated the cumulative effectiveness of these methods. For the IVF group, the estimated probability of success was based on an IVF trial conducted in the Netherlands, where couples without absolute IVF indications must undergo other treatment prior to IVF, thus potentially underestimating the effect of IVF applied to populations without prior treatment. The cumulative effectiveness estimations for the conservative treatment scenario were based on a Cochrane review that suggested a 2-3-fold increase in fecundity with clomiphene; yet, the researchers decided to build this model on a factor of a 1.5-fold increase, thus potentially underestimating the effectiveness of this treatment scenario as well. Concerns also exist regarding the feasibility of patients continuing each of these treatments for as long as the model suggests (up to 2-3 years), which may diminish the applicability of the study to the general population.

As this model demonstrated, more randomized controlled trials with actual couples are needed to gain a better understanding of the long-term outcomes for each of these methods. RCTs with longer follow-up periods comparing any two or more of these methods would allow further validation of the conclusions made through this model-based study. Furthermore, other treatment options were not included in this model and would be interesting to incorporate in a model such as the one designed for this study or to compare in a future trial. Additional analysis could include a comparison of couples continuing frequent intercourse while using fertility awareness-based methods (FABMs) such as the Creighton Model or Sympto-Thermal Method, which would allow timing of intercourse to the fertile window in women. Given the long-term success of both the conservative (clomiphene) treatment group and the group without treatment that continued frequent intercourse, these options, in tandem with FABMs, may ultimately be found to be the best solution in future trials, as an FABM may expedite the success of these methods through the ability to identify the fertile window.

Sources

[1] World Health Organization. Infertility. www.who.int. Published September 14, 2020. https://www.who.int/news-room/fact-sheets/detail/infertility.

[2] Gnoth C, Godehardt E, Frank-Herrmann P, Friol K, Tigges J, Freundl G. Definition and prevalence of subfertility and infertility. Hum Reprod. 2005;20(5):1144-1147. doi:10.1093/humrep/deh870.

[3] Stanford JB, Mikolajczyk RT, Lynch CD, Simonsen SE. Cumulative pregnancy probabilities among couples with subfertility: effects of varying treatments. Fertil Steril. 2010;93(7):2175-2181. doi:10.1016/j.fertnstert.2009.01.080.

[4] Daya S. Pitfalls in the design and analysis of efficacy trials in subfertility. Hum Reprod. 2003;18(5):1005-1009. doi:10.1093/humrep/deg238.

About the Author

Katelyn Rennyson

Katelyn Rennyson is a fourth-year medical student at Georgetown University School of Medicine in Washington, DC. She completed her undergraduate education at William & Mary in Williamsburg, VA and plans to pursue residency in internal medicine. Her interests include health education and leadership and serving underserved populations in healthcare. She enrolled in the FACTS elective to better understand fertility awareness-based methods and their role in medicine to have another tool to help future patients meet their health goals.