Volume 4, Issue 2, Pages 48-51 (October 2006)

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ABSTRACT

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Effective empiric treatment of infertility

Infertility is a common problem that can be addressed through advanced treatments, which are becoming increasingly commonplace. However, the efficacy of many of these is still largely in question. Empiric evidence reveals several promising solutions.

Article Outline

• Abstract

• Infertility evaluations

• Evidence-based therapies

• The risk–benefit analysis

• Alternative therapies

• Conclusion

• References

• Copyright

Key Points

▪Basic infertility examinations are generally performed after the couple has been trying to conceive for one year.

▪The accumulation of clinical data has shown that some combination therapies are particularly effective in the treatment of infertility.

▪Alternative medical practices have not produced enough high quality data regarding their safety and efficacy.

For pregnancy to occur, a mature egg must be released from the ovary, picked up by the fallopian tube, and fertilized by a motile sperm. The embryo must be transported to the uterus, implant in the endometrium, and successfully complete its development. Infertility results when a problem develops in one or more of these steps. Numerous conditions can cause infertility, but effective treatments are available to increase the chances for conception in infertile patients.1

Infertility evaluations

Because 85% of couples practicing regular unprotected intercourse conceive during the first twelve months, evaluation and treatment for infertility is usually recommended after one year of trying. Earlier evaluation is indicated if oligoanovulation, sperm dysfunction, tubal disease or endometriosis is suspected, or if the woman's age is over 35 years.2 To determine the fertility status in couples, a basic initial evaluation is conducted, which includes a careful history and physical examination, as well as evaluation of ovulation, sperm production, and tubal patency. Tests of ovarian reserve, ancillary hormonal tests, and laparoscopy to detect or to treat pelvic adhesions or endometriosis are sometimes included, depending on the clinical situation. This evaluation fails to reveal an obvious abnormality in up to 30% of infertile couples, who are diagnosed as having unexplained infertility. Couples in this category may represent the lower extreme of the normal distribution of fertility, or may have defects in fecundity not detected by the basic evaluation.3

Empiric treatment is infertility therapy performed without identification of underlying causes. In the case of unexplained infertility, treatment is, by definition, empiric. Furthermore, during the past decade the increased efficacy and availability of in vitro fertilization for treatment of infertility has resulted in its being used in selected patients rather than having them undergo a laparoscopy for diagnosis and treatment of potential pelvic adhesions or endometriosis. Laparoscopy to identify and to treat surgically these common pelvic abnormalities is often also omitted prior to less invasive treatments, such as intrauterine insemination or superovulation. These omissions of laparoscopy for diagnosis of these conditions is an expanded use of empiric treatment.

It is important to remember that conception may occur without therapy. Among 562 couples having unexplained infertility without treatment observed over 9520 total months, the 36-month cumulative live birth rate was 33% (95% CI=28 to 39). Young female age and short duration of infertility were associated with higher likelihood of pregnancy. The prognosis is significantly worse when the duration of infertility exceeds three years or the female is >35 years of age.4

Evidence-based therapies

The demand for infertility therapy has often led to treatment approaches that become accepted without the benefit of clinical trials demonstrating their efficacy. Randomized controlled trials (RCTs) provide the most reliable evidence of effectiveness, but require considerable expense, skill, and time.5, 6 Measured differences in the likelihood of pregnancy are often reported as a statistically significant difference in relative risk. However, clinical significance depends on the absolute magnitude of the rates.7 Clinically useful measures of effect include the absolute difference in rates between alternative treatments, and the inverse of that rate difference, which is the number needed to treat (NNT). Simply put, this number estimates how many times the intervention would be used before there were a single additional event with treatment as compared with control.8

Valid evidence from randomized clinical trials of empiric treatment is now accumulating. Table 1 summarizes efficacy estimates in an analysis of available RCTs published by the Practice Committee of the American Society for Reproductive Medicine.9 Proposed treatment regimens for unexplained infertility include intrauterine insemination (IUI), superovulation with oral or injectable medications, combinations of IUI with superovulation, and assisted reproductive technologies (ARTs). Assessment of clomiphene citrate (CC) therapy is based on three RCTs with 1471 enrolled women, and shows that on average one additional pregnancy will occur in 40 cycles of CC as compared with placebo treatment.10, 11, 12 A similar, low efficacy is seen with intrauterine insemination treatment based on two randomized controlled trials involving 1691 cycles.13, 14 A single RCT of crossover design involving 51 women for 298 cycles shows the estimated need to treat for CC + IUI to be 16 cycles.15 There is no published high quality data evaluating treatment beyond six cycles. Based on these limited data, Collins points out that three-to-six cycles of CC + IUI are a reasonable initial approach to treating unexplained infertility, but it will be effective for only a minority of couples.7

TABLE 1.

Estimated number of cycles needed to achieve one additional pregnancy (NNT) compared to control cycles without treatment among couples with unexplained infertility9


	Therapy	NNT (95% CI)
	CC	40 (20 – 202)
	IUI	37 (23 – 101)
	CC + IUI	16 (9 – 165)
	FSH + IUI	15 (11 – 23)

CC = clomiphene citrate; IUI = intrauterine insemination; FSH = follicle stimulating hormone; NNT = number needed to treat; CI = confidence interval

Randomized clinical trials have revealed that one treatment—gonadotropin therapy—is particularly effective in the treatment of unexplained infertility, especially when combined with IUI.9, 16 The Guzick et al randomized multicenter trial studied 932 couples with unexplained infertility, including some women who had undergone treatment of stage I or II endometriosis more than six months prior to the trial. Up to four cycles of FSH + IUI produced higher cumulative pregnancy rates (33%) than FSH alone (19%), IUI alone (18%) and intracervical insemination (10%).14 Data from this trial show that on average, one additional pregnancy will occur in 15 cycles of FSH + IUI as compared with intracervical insemination cycles. In Table I the NNTs estimated for CC + IUI and FSH + IUI are similar, but are derived from heterogenous trials. The only RCT of couples with unexplained infertility directly comparing CC + IUI to gonadotropin + IUI showed pregnancy rates of 1/17 CC + IUI cycles versus 3/15 gonadotropin + IUI cycles, but lacked the power to demonstrate that the latter combination is superior to CC + IUI.17

Assisted reproductive technologies—primarily IVF—are often recommended to treat unexplained infertility based on cohort and uncontrolled trials reporting live birth rates above 20% per cycle.16 Two randomized clinical trials directly compare FSH + IUI and IVF in couples with unexplained infertility.18, 19 The more recent Goverde et al trial involving 122 couples showed live birth rates in 6% of IUI cycles, 9% of FSH + IUI cycles, and 13% of IVF cycles. This Dutch trial provided up to six cycles of treatment at no cost, but more couples withdrew from IVF cycles (42%) than from FSH + IUI cycles (16%) so that the cumulative pregnancy rates for both treatments were similar. The Goverde et al trial included treatment cost data showing that the cost of an IVF cycle was about 3½ times the cost of an FSH + IUI cycle. The increased effectiveness of IVF over FSH + IUI treatment occurs at considerable incremental cost.7

The risk–benefit analysis

Common serious risks of superovulation and IVF are multiple pregnancy and ovarian hyperstimulation. Controlled ovarian stimulation (superovulation), a common empiric treatment that results in multiple follicles, is shown in the ultrasound image in Figure 1. Follicle stimulating hormone therapy with standard monitoring during the Guzick et al multicenter trial resulted in 24 of 86 live births (28%) being multiple, including three quadruplet, four triplet, and 17 twin pregnancies that were delivered as five triplet and 19 twin births. Six of 465 FSH-treated women (1.3%) were hospitalized because of ovarian hyperstimulation.14 The ASRM/SART year 2000 registry shows that among all deliveries from ART procedures, 31% were twins, 4% were triplets, and 0.2% were higher order multiples.20 Ovarian hyperstimulation has been reported in up to 5% of ART cycles.21

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Figure 1. Ultrasound of multiple follicles. Ovarian stimulation results in the development of multiple mature ovarian follicles, shown here. Mature follicles are approximately 18 mm or greater in average diameter. However, not all follicles this size contain oocytes and many follicles that are 12–18 mm in average diameter contain mature oocytes. The desired outcome from ovarian stimulation is a single, healthy baby—not a multiple pregnancy.

Alternative therapies

The occurrence of treatment-independent pregnancies and the relatively low effectiveness of conventional empiric treatments have prompted interest in alternative medical practices in the hope that they might confer some effect at lower cost, risk, and discomfort. Psychological interventions, relaxation techniques, yoga, spiritual practices, dietary changes, herbal treatments, and acupuncture are some of the approaches that have been proposed.22, 23, 24, 25, 26 Such practices are sometimes introduced as complementary interventions, helping some couples persist in using conventional therapy. Although alternative treatments are commonly practiced at considerable expense, there is very little high quality data on the efficacy and safety of these approaches. For example, acupuncture as an adjunct to IVF has recently received attention because two small RCTs suggested it might increase clinical pregnancy rates.27, 28 Careful critiques of the studies highlight deficiencies in a priori hypothesis formulation, procedure methodology, control treatment, blinding, and primary outcome selection, all of which are crucial to obtain evidence of efficacy.29, 30 As stated by Stener-Victorin et al: “There is only medicine that has been adequately tested and medicine that has not, medicine that works and medicine that may or may not work… All methods of treatment referred to as alternative treatments should be subjected to scientific tests of efficacy no less rigorous than those required for conventional treatments.”31

Conclusion

In conclusion, high quality data indicate that the combinations of CC + IUI, gonadotropin + IUI, as well as ART provide relatively small but clinically significant improvements in cycle fecundity for couples with unexplained infertility. Given the efficacy, cost, risks, and tolerance of the various alternatives, it is reasonable to consider several cycles of CC + IUI before proceeding to gonadotropin + IUI or ART, especially if the woman is young. Ultimately, treatment may simply shorten the time to conception in couples who would eventually conceive anyway.

References

1. 1 Adamson GD , Baker VL . Subfertility: causes, treatment and outcome . Best Practice and Research Clinical Obstetrics and Gynecology . 2003;17:169–185 .

2. 2 The Practice Committee of the American Society for Reproductive Medicine . Optimal evaluation of the infertile female . Fertil Steril . 2004;82:S169–S172 . Full Text | Full-Text PDF (21 KB) | CrossRef

3. 3 Silverberg KM . Ovulation induction in the ovulatory woman . Semin Reprod Endocrinol . 1996;14:339–344 . MEDLINE

4. 4 Collins JA , Burrows EA , Wilan AR . The prognosis for live birth among untreated infertile couples . Fertil Steril . 1995;64:22–28 . MEDLINE

5. 5 Vail A , Gardener E . Common statistical errors in the design and analysis of subfertility trials . Hum Reprod . 2003;18:1000–1004 . MEDLINE | CrossRef

6. 6 Arce JC , Andersen AN , Collins J . Resolving methodological and clinical issues in the design of efficacy trials in assisted reproductive technologies: a mini-review . Hum Reprod . 2005;20:1757–1771 . MEDLINE | CrossRef

7. 7 Collins J . Current best evidence for the advanced treatment of unexplained subfertility . Hum Reprod . 2003;18:907–914 . MEDLINE | CrossRef

8. 8 Cook RJ , Sackett DL . The number needed to treat: a clinically useful measure of treatment effect . BMJ . 1995;310:452–454 .

9. 9 The Practice Committee of the American Society for Reproductive Medicine . Effectiveness and treatment for unexplained infertility . Fertil Steril . 2004;82:S160–S163 . Full Text | Full-Text PDF (40 KB) | CrossRef

10. 10 Fisch P , Casper RF , Brown SE , Wrixon W , Collins JA , Ried RL , et al. Unexplained infertility: evaluation of treatment with clomiphene citrate and human chorionic gonadotropin . Fertil Steril . 1989;51:828–833 . MEDLINE

11. 11 Glazener CM , Coulson C , Lambert PA , Watt EM , Hinton RA , Kelly NG , et al. Clomiphene treatment for women with unexplained infertility: placebo controlled study of hormonal responses and conception rates . Gynecol Endocrinol . 1990;4:75–83 . MEDLINE | CrossRef

12. 12 Harrison RF , O'Moore RR . The use of clomiphene citrate with and without human chorionic gonadotropin . Ir Med J . 1983;76:273–274 . MEDLINE

13. 13 Kirby CA , Flaherty SP , Godfrey BM , Warnes GM , Matthews CD . A prospective trial of intrauterine insemination of motile spermatozoa versus timed intercourse . Fertil Steril . 1991;56:102–107 . MEDLINE

14. 14 Guzick DS , Carson SA , Coutifaris C , Overstreet JW , Factor-Litvak P , Steinkampf MP , et al. Efficacy of superovulation and intrauterine insemination in the treatment of infertility . N Engl J Med . 1999;340:177–183 . MEDLINE | CrossRef

15. 15 Deaton JL , Gibson M , Blackmer KM , Nakajima ST , Badger GJ , Brumsted JR . A randomized, controlled trial of clomiphene citrate and intrauterine insemination in couples with unexplained infertility or surgically corrected endometriosis . Fertil Steril . 1990;54:1083–1088 . MEDLINE

16. 16 Guzick DS , Sullivan MW , Adamson GD , Cedars MI , Falk RJ , Peterson EP , et al. Efficacy of treatment for unexplained infertility . Fertil Steril . 1998;70:207–213 . Abstract | Full Text | Full-Text PDF (80 KB) | CrossRef

17. 17 Karlstrom PO , Bergh T , Lundkvist O . A prospective randomized trial of artificial insemination versus intercourse in cycles stimulated with human menopausal gonadotropin or clomiphene citrate . Fertil Steril . 1993;59:554–559 . MEDLINE

18. 18 Crosignani PG , Walters DE , Soliani A . The ESHRE multicentre trial on the treatment of unexplained infertility: a preliminary report . Hum Reprod . 1991;6:953–958 . MEDLINE

19. 19 Goverde AJ , McDonnell J , Vermeiden JP , Schats R , Rutten FF , Schoemaker J . Intrauterine insemination or in-vitro fertilisation in idiopathic subfertility and male subfertility: a randomized trial and cost-effectiveness analysis . Lancet . 2000;355:13–18 . Abstract | Full Text | Full-Text PDF (81 KB) | CrossRef

20. 20 Society for Assisted Reproductive Technology and the American Society for Reproductive Medicine . Assisted reproductive technology in the United States: 2000 results generated from the American Society for Reproductive Medicine/Society for Assisted Reproductive Technology registry . Fertil Steril . 2004;81:1207–1220 . Abstract | Full Text | Full-Text PDF (135 KB) | CrossRef

21. 21 Navot D , Bergh PA , Laufer N . Ovarian hyperstimulation in novel reproductive technologies: prevention and treatment . Fertil Steril . 1992;58:249–261 . MEDLINE

22. 22 Domar AD , Clapp D , Slawsby EA , Dusek J , Kessel B , Freizinger M . Impact of group psychological interventions on pregnancy rates in infertile women . Fertil Steril . 2000;73:805–812 . Abstract | Full Text | Full-Text PDF (72 KB) | CrossRef

23. 23 Lemmens GMD , Vervaeke M , Enzlin P , Bakelants E , Vanderschueren D , D'Hooghe T , et al. Coping with infertility: a body-mind group intervention programme for infertile couples . Hum Reprod . 2004;19:1917–1923 . MEDLINE | CrossRef

24. 24 Khalsa HK . Yoga: an adjunct to infertility treatment . Sexuality Reproduction & Menopause . 2003;1:46–51 .

25. 25 Seibel MM . The role of nutrition and nutritional supplements in women's health . Fertil Steril . 1999;72:579–591 . Abstract | Full Text | Full-Text PDF (163 KB) | CrossRef

26. 26 Chang R , Chung PH , Rosenwaks Z . Role of acupuncture in the treatment of female infertility . Fertil Steril . 2002;78:1149–1153 . Abstract | Full Text | Full-Text PDF (74 KB) | CrossRef

27. 27 Westergaard LG , Mao Q , Krogslund M , Sandrini S , Lenz S , Grinsted J . Acupuncture on the day of embryo transfer significantly improves the reproductive outcome in infertile women: a prospective, randomized trial . Fertil Steril . 2006;85:1341–1346 . Abstract | Full Text | Full-Text PDF (99 KB) | CrossRef

28. 28 Dieterle S , Ying G , Hatzmann W , Neuer A . Effect of acupuncture on the outcome of in vitro fertilization and intracytoplasmic sperm injection: a randomized prospective, controlled clinical study . Fertil Steril . 2006;85:1347–1351 . Abstract | Full Text | Full-Text PDF (95 KB) | CrossRef

29. 29 Myers ER . Acupuncture as adjunctive therapy in assisted reproduction: remaining uncertainties . Fertil Steril . 2006;85:1362–1363 . Abstract | Full Text | Full-Text PDF (53 KB) | CrossRef

30. 30 Collins J . The play of chance . Fertil Steril . 2006;85:1364–1367 . Abstract | Full Text | Full-Text PDF (115 KB) | CrossRef

31. 31 Stener-Victorin E , Wikland M , Waldenstrom U , Lundeberg T . Acupuncture-a method of treatment in reproductive medicine: lack of evidence of an effect does not equal evidence of the lack of an effect . Hum Reprod . 2002;17:1942–1946 . MEDLINE | CrossRef

Fertility Physicians of Northern California, Palo Alto, CA

Fertility Physicians of Northern California, 540 University Avenue, Suite 200, Palo Alto, CA 94301

1 Disclosure

Dr Adamson has disclosed the following relationships: contractual support in Serono and investor and CEO of Advanced Reproductive Care.

PII: S1546-2501(06)00027-2

doi:10.1016/j.sram.2006.08.008

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