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Am Fam Physician. 2006;73(1):63-65

Clinical Scenario

A 32-year-old woman has been trying to conceive for the past 12 months without success. Medical history, physical examination, hysterosalpingography, and laboratory testing provide no explanation.

Clinical Question

How does in vitro fertilization (IVF) compare with other available therapies for unexplained infertility?

Evidence-Based Answer

Although IVF is used routinely for the treatment of unexplained infertility, there is limited evidence to show that it is more effective than expectant management, and there is insufficient evidence to recommend it as an alternative to other therapies such as clomiphene citrate (Serophene), intrauterine insemination, or gamete intrafallopian transfer.1 Risks of IVF include psychological stress, multiple gestations, operative risks, and ovarian hyperstimulation syndrome. Another issue is its high cost. More research is needed to clearly establish the efficacy of IVF compared with other therapies.1

Practice Pointers

Unexplained infertility, also called subfertility, is defined as failure to conceive after one year in couples with normal semen samples and no abnormality found during an infertility work-up. In 1995, of women between 15 and 44 years of age, 15 percent received an infertility service—an increase of 3 percent over the previous decade.2 IVF is becoming increasingly common as a treatment for unexplained infertility.

In IVF, the patient’s ovaries are stimulated with gonadotropins, after which eggs are retrieved surgically from the ovaries, fertilized with sperm in a laboratory, and transferred to the patient’s uterus. IVF is widely used and accepted because it can overcome many of the factors considered to be causes of unexplained infertility, such as ovarian dysfunction, cervical factors, and problems with sperm-egg interaction and fertilization. Pregnancy rates with IVF can approach 30 percent, making it a favorable option when compared with expectant management; however, at least one study has shown a live-birth rate of 33 percent during 36 months in couples using expectant management.1

Despite the routine use of IVF therapy in the United States and other developed countries, it has not been rigorously evaluated in comparison with other fertility treatments; thus, evidence-based decision making is difficult. This Cochrane review1 examined six studies that variously compared IVF with expectant management, intrauterine insemination with or without ovarian stimulation, gamete intrafallopian transfer, and clomiphene citrate, using live-birth rate per woman as the primary outcome. There was considerable variation among individual studies with regard to outcomes reported as well as to the therapies compared. IVF was found to be significantly better than expectant management in the two studies that have been performed to answer this question. There were no significant differences found between IVF and intrauterine insemination with or without ovarian stimulation. Although a single study did find a significant advantage of IVF compared with gamete intrafallopian transfer, the authors recommend caution in interpreting these results given significant differences in the trial designs. None of the trials directly compared IVF with clomiphene citrate. Therefore, this Cochrane review provides insufficient evidence to compare IVF with other methods of infertility treatment. Larger randomized trials are needed.

Cochrane Abstract

Background. In vitro fertilization (IVF) is now a widely accepted treatment for unexplained infertility. However, with estimated live-birth rates per cycle varying between 13 and 28 percent, its effectiveness has not been rigorously evaluated in comparison with other treatments. With increasing awareness of the role of expectant management and less invasive procedures such as intrauterine insemination, as well as concerns about multiple complications and costs associated with IVF, it is extremely important to evaluate the effectiveness of IVF against other treatment options in couples with unexplained infertility.

Objectives. The aim of this review is to determine, in the context of unexplained infertility, whether IVF improves the probability of live birth compared with (1) expectant management, (2) clomiphene citrate, (3) intrauterine insemination alone, (4) intrauterine insemination with controlled ovarian stimulation, and (5) gamete intrafallopian transfer.

Search Strategy. The authors1 searched the Cochrane Menstrual Disorders and Subfertility Group Trials Register (searched March 2004), the Cochrane Central Register of Controlled Trials (Cochrane Library Issue 3, 2004), MEDLINE (1970 to August 2004), EMBASE (1985 to August 2004), and reference lists of articles. They also hand-searched relevant conference proceedings and contacted researchers in the field.

Selection Criteria. Only randomized controlled trials (RCTs) were included. Live-birth rate per woman was the primary outcome of interest.

Data Collection and Analysis. Two reviewers independently assessed eligibility and quality of trials.

Primary Results. Ten RCTs were identified. In two, the authors1 could not extract data separately for unexplained infertility cases; two were nonrandomized, and one did not report valid rates (included in the review but not in the meta-analysis), leaving four trials for analysis. One trial compared two interventions (IVF versus intrauterine insemination with or without ovarian stimulation), and one study compared three interventions (IVF versus intrauterine insemination with ovarian stimulation and gamete intrafallopian transfer). The numbers of trials assessing the effectiveness of IVF with the other treatments were as follows: IVF versus expectant management (two), IVF versus intrauterine insemination (one), IVF versus intrauterine insemination with ovarian stimulation (two), and IVF versus gamete intrafallopian transfer (three). Live-birth rate per woman was reported in three studies, and three studies determined the clinical pregnancy rate per woman. Multiple-pregnancy rate was reported in three trials. Two studies reported ovarian hyperstimulation syndrome as an outcome measure. There were no comparative data for clomiphene citrate and no comparative data on live-birth rates for gamete intrafallopian transfer. There was no evidence of a difference in live-birth rates between IVF and intrauterine insemination without (odds ratio [OR], 1.96; 95% confidence interval [CI], 0.88 to 4.4) or with (OR, 1.15; 95% CI, 0.55 to 2.4) ovarian stimulation. There were significantly higher clinical pregnancy rates with IVF in comparison with expectant management (OR, 3.24; 95% CI, 1.07 to 9.80). There was no significant difference between IVF and gamete intrafallopian transfer for the one RCT that reported live-birth rates (OR, 2.57; 95% CI, 0.93 to 7.08). However, there was a significant difference in the clinical pregnancy rates between IVF and gamete intrafallopian transfer, with pregnancy rates greater for IVF (OR, 2.14; 95% CI, 1.08 to 4.2). There was no evidence of a difference in the multiple-pregnancy rates between IVF and intrauterine insemination with ovarian stimulation (OR, 0.63; 95% CI, 0.27 to 1.5); however, IVF had a higher rate than gamete intrafallopian transfer (OR, 6.3; 95% CI, 1.7 to 23). Clinical heterogeneity was present among the studies included. However, there was no evidence of statistical heterogeneity, which allowed the studies to be combined for statistical analysis.

Reviewers’ Conclusions. Any effect of IVF relative to expectant management, clomiphene citrate, intrauterine insemination with or without ovarian stimulation, and gamete intrafallopian transfer in terms of live-birth rates for couples with unexplained subfertility remains unknown. The studies included are limited by their small sample size so that even large differences might be hidden. Live-birth rates are seldom reported. Periods of follow-up are inadequate and unequal. Adverse effects such as multiple pregnancies and ovarian hyperstimulation syndrome also have not been reported in most studies. Larger trials with adequate power are warranted to establish the effectiveness of IVF. Future trials should report rates per woman or couple and include adverse effects and costs of the treatments as outcomes. Factors that have a major effect on these outcomes, such as fertility treatment, female partner’s age, duration of infertility, and previous pregnancy history, also should be considered.

These summaries have been derived from Cochrane reviews published in the Cochrane Database of SystematicReviews in the Cochrane Library. Their content has, as far as possible, been checked with the authors of the originalreviews, but the summaries should not be regarded as an official product of the Cochrane Collaboration; minorediting changes have been made to the text (

Risks of IVF include psychological stress, multiple gestations, operative risks, and ovarian hyperstimulation syndrome. A typical IVF cycle can cost more than $10,000; the proportion covered by insurance ranges from zero to 100 percent and varies by insurance carrier and state. The significant psychological stress of infertility often causes depression or anxiety, which can be exacerbated for women by the hormonal fluctuations that fertility medications induce. Also, a couple’s relationship can be adversely affected by rigorous treatment schedules and financial concerns. Multiple gestations occur in 25 percent of IVF pregnancies and carry an increased risk of premature delivery, low birth weight, spontaneous abortion, and congenital abnormalities.3 Although complications with egg retrieval are rare, the procedure carries operative risks such as bleeding and infection as well as the risks associated with general anesthesia. Ovarian hyperstimulation syndrome is a potentially fatal effect of the use of gonadotropins and gonadotropin agonists, with an incidence of 6 to 14 percent. Hyper-stimulation with gonadotropins causes volume overload, and ovarian hyperstimulation syndrome in its most severe form may require admission to an intensive care unit.4

Any therapy with such significant risks should benefit from a rigorous evaluation of its effectiveness. However, there is insufficient evidence to perform such an analysis for IVF. Patients and their physicians will need to compare the known risks of IVF with its well-documented pregnancy rates, in the face of little evidence to recommend other, potentially safer treatments.

These are summaries of reviews from the Cochrane Library.

This series is coordinated by Corey D. Fogleman, MD, assistant medical editor.

A collection of Cochrane for Clinicians published in AFP is available at

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