Postgraduate Training Course in Reproductive Health/Chronic Disease

Current evidence on infertility treatment

Review prepared for the 12th Postgraduate Course in Reproductive Medicine and Biology, Geneva, Switzerland

M.A.M. Abdel-Aleem
Assistant Lecturer, OB&GYN Dept
Assiut University Hospital
Assiut, Egypt

See also presentation

Abstract

Infertility is a problem for many couples wishing to conceive. It is estimated that one in 6-7 couples seeks medical advice for an infertility problem. The increased demand for treatment may be due to the increased public awareness of and greater expectations about new treatments. Different treatments in use may not have been evaluated thoroughly (e.g. in randomized clinical trials). The aim of this review is to assess the evidence of different infertility treatments. Medline was searched for randomized controlled trials (RCTs) and systematic reviews between 1997-2003. Also, the Cochrane library issue 1, 2003 was searched. The effectiveness of various treatments is reported. Conclusion: few lines of infertility treatments have been evaluated in either systematic reviews or in well-designed RCTs . For the rest of the treatment options the evidence is unclear.

Introduction

Infertility is generally defined as the state in which a couple cannot conceive after 12 month of unprotected intercourse (1,2) . This is taken as being abnormal as 90% of couples will conceive during that time (3). The cause of infertility is either primary (no pregnancy has ever occurred), or secondary (there has been a pregnancy, regardless of the outcome (2). Primary infertility represents nearly two thirds of the cases while the remaining one third constitutes patients with secondary infertility (4). Idiopathic or unexplained infertility means there has been no definite cause of infertility identified. This ranges between 8%–28% of the infertile population, depending on the strictness of the criteria used for the definition (5,6). Delay in childbearing and the adverse effect of increasing age on women's fertility have increased referrals for fertility investigations and treatments (7). One in six to seven couples require referral for investigation or treatment for sub-fertility (8,9). In general, the exact incidence of the various factors causing infertility varies among different populations and cannot be precisely determined. The main causes of female infertility are ovulation disorders (32%) and tubal damage (26%), and of male infertility oligo-terato-asthenozoospermia (21%), asthenozoospermia (17%), teratozoospermia (10%) and azoospermia (9%). Infertility may be caused by disorders in both male and female partners together in 39% of cases. Female infertility accounts for one-third of all cases and man infertility for one-fifth (4).
Treatments for subfertility have evolved from a plethora of largely unsubstantiated diagnostic tests and empirical treatments into an advanced set of clinical diagnostic tests, allowing identification of subsets of subfertility and their treatments. Appropriate effective therapies are available, but many of them deserve further scientific evaluation (10). There has been no general increase in the prevalence of infertility and the increase in the demand for treatment appears to have been generated by greater expectations (4,11). This in turn has been partly generated by the increased media focus on the new medical procedures and technologies available (12). Natural human fertility is low compared with most other species. The average monthly fecundity rate is only 20% and it is unrealistic to expect a higher chance of pregnancy than this from any fertility treatment (13). The role of the physician is to provide the couple with accurate information leading either to effective therapy or at least a situation that permits the great majority of couples to define an end to a given approach. Armed with accurate information, the physician together wit the couple should be able to establish the goals and probabilities of success of any treatment, the period of time during which pregnancy should occur and the end points when conception is no longer likely to occur (14).
There are four cornerstones to provide patients the accurate information about their problem and the available treatments and have to be discussed with the couple before starting any treatment (14) :

• The factor causing infertility must occur more frequently in an infertile than a fertile population.
• Intervention treatment must produce more pregnancies than expectant treatment.
• The probabilities of success should be known.
• The realistic maximum treatment to conception interval must be known.

Methods

This review aims at assessing the evidence of different methods of infertility treatment by looking for systematic reviews and randomized controlled trials (RCTs) involving any aspect of infertility treatment. These were obtained by searching :

1. The Cochrane library , issue 1,2003.
2. The Medline electronic database was searched using Ovid software (1997 to 2003)

The following search strategy was used :

1. Infertility treatment.
2. Subfertility treatment.
3. Randomized controlled trial (RCT).
4. Controlled clinical trial
5. Randomized controlled trials (RCTs).
6. Meta-analysis.

The identified studies were then evaluated according to the guidelines adapted from "How to use an article about therapy or prevention" for the following criteria (15) :

1. Appropriateness of the study question and study design to answer this question.
2. Duration, timing and location of the study.
3. Randomization procedure.
4. Presence or absence of blinding to treatment allocation.
5. The presence of a statistical power calculation.
6. Number of participants randomized, excluded or lost to follow-  up.
7. Were the participants in all groups followed up and data collected in the same way ?
8. How the results are presented and what is the main result.
9. How the precise results are presented; is the confidence interval is reported?
10. Importance and application of the results.

Results

The search retrieved 70 Cochrane reviews and 109 systematic reviews; meta-analysis and RCTs through the Medline search.
For the Cochrane reviews ; 34 reviews were found to be related to this overview.
The Medline search resulted in 109 articles. Only 14 trials were eligible. Seven studies could not be retrieved. The results are presented in table 1.
Cochrane reviews : the 34 reviews are presented in table 1.

Table 1: Characteristics of relevant studies.

Male infertility

Varicocele is the most frequent physical finding in infertile men (16). It may lead to testicular and epididymal damage via hypoxia and stasis, increased testicular pressure, elevated spermatic vein catecholamines and increased testicular temperature (17,18). Despite the common practice of varicocelectomy for many years, evidence of treatment efficacy was based mainly one non-randomized uncontrolled trial (19). There is no evidence that treatment of varicocele (by either surgery or embolisation) in men from couples with otherwise unexplained infertility will improve the couples’ spontaneous pregnancy chances (20). If varicocelectomy is indicated, the subinguinal approach disclosed a more prominent improvement in both semen concentration and motility in the 6- and 12-month follow-up evaluation when compared to either retroperitoneal, inguinal or percutaneous venous embolisation approaches. Furthermore, due to its simplicity and avoidance of opening the external oblique fascia, it may represent the more plausible approach (21).
Total normal sperm count increases after combined zinc sulfate and folic acid treatment in both subfertile and fertile men. Although the beneficial effect on fertility remains to be established, this finding opens avenues of future fertility research and treatment and may affect public health (22).

Female infertility

Polycystic Ovarian Syndrome (PCOS)

It is a syndrome characterized by chronic anovulation and hyperandrogenism and affects approximately 5% to 10% of women of reproductive age (23). It is probably the most prevalent endocrinopathy in women and by far the most common cause of anovulatory infertility being associated with 75% of cases with anovulatory infertility (24). The development of various types of ovulation induction agents; clomiphene citrate (CC), human menopausal gonadotrophins (hMG), follicle stimulating hormone (FSH) whether urinary or recombinant together with laparoscopic ovarian drilling over the last several decades have been a major advantage in the management of PCOS induced infertility. Treatment options and their outcomes are summarized in table 2.

Table 2 : Evidence of treatments for PCOS.

Endometriosis

It is one of the most frequently encountered benign diseases in gynecology. It is the cause for pelvic pain and infertility in more than 35% of women of reproductive age (32). Complete resolution of endometriosis is not yet possible, but therapy has essentially three main objectives (33) : to reduce pain, to increase the possibility of pregnancy and to delay recurrence for as long as possible. Both medical and surgical treatments are available for this disease. The following points address the evidence of effectiveness of each of these treatments :

• Laparoscopic surgery : the use of laparoscopic surgery in the treatment of minimal and mild endometriosis may improve the success rates. This conclusion is cautiously taken because of methodological problems in the design of the 2 RCTs included in the systematic review (34).
• Ovulation suppression : using danazol, MPA, gestrinone, combined oral contraceptives (CoCs), gonadotrophin releasing hormone analogues (GnRHa). This treatment should not be the standard treatment because of lack of evidence of benefit and the presence of side effects (35).
• Prolonged use of GnRH agonists before in-vitro fertilization- embryo transfer (IVF-ET) in patients with endometriosis resulted in significantly higher ongoing pregnancy rates than did standard controlled ovarian hyperstimulation regimens. No deleterious effect on ovarian response was observed (36).

Tuboplasty and adhesiolysis

There is a high risk of pelvic adhesions after surgery. Any uterine , tubal or ovarian surgery can lead to the formation of adhesions , ovarian failure and tubal dysfunction with subsequent infertility (37). Adhesions may be due to ischemia associated with suturing (38). Adhesion reformation continues to be of concern and appears to be related more to the disease or the patient than to the technique used (37). Four systematic reviews in the Cochrane library were found dealing with this issue :

• Use of fluid agents for preventing adhesions : there is no evidence of benefit if used (39). Further trials are needed to justify the use of steroids.
• Use of barrier agents to prevent postoperative adhesions : although there is evidence that barrier agents reduce the incidence of adhesion formation, there is no evidence to support its use to improve pregnancy rates. Goretex® is superior to Interceed® but it needs suturing and later removal. There is no evidence of effectiveness of Seprafilm® in preventing adhesion formation (40).
• During adhesiolysis, whether by laparoscopy or laparotomy, the following conclusions were made :
  • From randomized controlled trials :
    • No benefit of using operating microscope over loupe.
    • No benefit of using laser in terms of better pregnancy rate.
  • From non-randomized trials :
    • The treatment of adhesions by adhesiolysis appears to improve the possibility of conception.
    • The results are better with magnification rather than without.
    • Laparoscopic salpingostomy appears to be less effective compared to open surgery.
    • Laparoscopic adhesiolysis may be as effective as microsurgical adhesiolysis.

• No evidence on the  use of hydrotubation as a routine following pelvic reconstructive surgery (42).

Unexplained infertility

• Use of clomiphene citrate appears to be a sensible first choice in these cases despite the small treatment effect. This is due to the low cost and the ease of administration (43).

• Use of danazol: there is not enough evidence to support its use in addition to the special precautions regarding its use : cost, side effects and the need for contraception (44).

• Use of bromocriptine : there is no evidence to support its use in unexplained infertility however, it may be used in women with galactorrhea (45).

• There is insufficient evidence of injectable ovulation induction agents being superior to oral drugs. The sample sizes of the included studies addressing this problem are too small (46).

• IVF as a line : although 9 RCTs were found and included in the systematic review, without  reaching  sufficient power to allow firm conclusions. Future studies should  also address adverse effects and costs of the treatments (47).

Intrauterine insemination (IUI)

This is often used for treatment of infertility with various etiologic factors.

• CC is an effective alternative to hMG before intrauterine insemination (48).
• There is a definite advantage for IUI over timed intercourse, both in natural cycles and in cycles with COH (49).
• There is no increase in pregnancy rate per couple if double intrauterine insemination is used instead of single insemination using the partner’s semen (50).
• A 10-minute interval of bed rest after IUI has a positive effect on the pregnancy rate (51).
• A meta-analysis of randomized controlled trials in patients with unexplained infertility showed a significant improvement in pregnancy rates with fallopian sperm perfusion (odds ratio 1.9; 95% confidence interval 1.2-3). It is stated that Fallopian sperm perfusion does not improve the chances of pregnancy in patients with infertility other than those with unexplained infertility. Fallopian sperm perfusion does significantly improve the pregnancy rates of patients with unexplained infertility undergoing controlled ovarian stimulation with gonadotrophin /insemination protocols (52).
• Intrauterine insemination appears to be beneficial when cervical insemination using cryopreserved donor sperm was less successful. However, it is of little benefit where high pregnancy rates have been achieved with cervical insemination. There is no benefit from intrauterine insemination when fresh sperm is used for donor insemination (53).

Assisted reproductive technologies (ART)

The methods of gamete manipulation used in assisted reproductive technology (ART) are rapidly proliferating. The perceived safety and success of ART have led to an increasing demand for its use. Common to all methods of ART are procedures for egg and sperm collection, fertilization in vitro and embryo transfer. Intra-cytoplasmic sperm injection (ICSI) was developed to circumvent the inability of sperm to fertilize an egg. The following tables represent the IVF-ET steps with the corresponding evidences (tables 3, 4, 5, 6).

Table 3 : ART : Controlled Ovarian Hyperstimulation.

Table 4 : ART : Sperm manipulations.

Table 5 : ART : Embryo transfer.

Table 6 : ART: Luteal phase support.

Surgical treatment for tubal disease prior to IVF is an important issue because the presence of hydrosalpinx has been shown to lower the pregnancy rates in IVF cycles. Out of 3 eligible RCTs , it is strongly evident that laparoscopic salpingectomy should be considered for all women with hydrosalpinges prior to IVF treatment. There are 2 issues that need further research : assessment of other surgical options for patients with tubal diseases and the role of surgery in non-hydrosalpinx tubal diseases (73). A meta-analysis performed on 5592 patients (1004 with hydrosalpinx and 4588 with tubal infertility without hydrosalpinx) supports clearly that existing hydrosalpinx during IVF-embryo transfer has negative consequences on the rates of pregnancy, implantation, live delivery and has higher rates of early pregnancy loss. It would be premature, nonetheless, to conclude that routine salpingectomy should be performed on all patients with hydrosalpinx (74).

Discussion

Infertility is a problem for many couples wishing to conceive; for most couples, it means ''failure''. The infertility rate among females has increased over the last 3 decades because of the increasing incidence of PID and STDs. Damaged fallopian tubes are the major causes of infertility and the two organisms ; N. gonorrhea and C. trachomatis are responsible for the majority of cases (1). Also cigarette smoking is becoming more prevalent amongst teenage girls and young adult women: smoking has been shown to be associated with increased risk of infertility due to both an effect on the tubes and on the cervix (12). This could mean that infertility is a semi-preventive health problem.
In the last 60 years, there has been a major advance in the management of infertility but most of the methods used are not based on well-designed studies. The role of the clinician is not only to help to define the couple's problem, but also to be sympathetic and considerate to their emotional state at this most difficult time (12). The results of this overview can be summarized into 3 groups depending on the evidence: Interventions with a good evidence of effectiveness , those with a good evidence of ineffectiveness (that means that they should be abandoned) and a third group with neither (that means that these should be the area of future research).

1. Interventions with good evidence of effectiveness :
   1. Use of clomiphene citrate in PCOS patients.
   2. Use of GnRH antagonists in pituitary desensitization in ART programs.
   3. Use of r-hCG in the final maturation of the oocyte.
   4. Use of intravenous albumin to prevent severe OHS.
   5. Use of ICSI in cases with borderline semen.
   6. Luteal phase support by progesterone.
   7. Use of GnRH in patients with endometriosis before IVF-ET.
2. Interventions with good evidence of ineffectiveness :
   1. Routine varicocelectomy in infertile male patient with varicocele
   2. Use of uFSH or  GnRH in patients with PCOS patients
   3. Use of depot GnRH in pituitary desensitization in ART programmes
   4. Use of growth hormone in ovarian hyperstimulation
   5. Use of ICSI for men with normal semen
   6. Use of danazol or bromocriptine in patients with unexplained infertility
   7. Use of ovulation suppression drugs in women with endometriosis
3. The major group is the third one that includes for example use of GnRH analogues, pulsatile GnRH,  gonadotrophins, metformin and ovarian drilling in the induction of ovulation in patients with PCOS. In addition, in ART programmes, the use of rFSH versus hMG in controlled ovarian hyperstimulation, the prevention of OHS by either coasting or embryo freezing. Also, the following issues deserve exploration: management of  idiopathic abnormal semen parameters and cervical factor infertility.

This overview has disclosed many facts. Firstly, very few treatments have been described either effective or ineffective , while the majority is still in the gray zone. This means that the way is still long in searching the evidence in this particular field. Secondly, poor methodological quality was the major criterion for criticizing the articles, this means that the forthcoming trials should have sound methodology with sufficient sample sizes (e.g. multi-center trials) so not to miss any -even small- differences. Thirdly, the outcome of the ARTs should not be just the clinical pregnancy rate but the rate of single live birth per cycle.
In addition of the importance of the clinical evidence, cost is becoming a more important factor for couples faced with the plethora of therapeutic choices. Therefore infertility treatment options may be dictated by economical considerations rather by the medical effectiveness of the treatments being offered. For example, the evidence in unexplained infertility indicates that IVF as a first -line is not cost effective compared with ovarian stimulation and IUI (75). In order to establish cost-effective care, clinical outcomes under various cost conditions need to be examined. Such a process cannot be static since it has to consider ever evolving treatments and outcome results (76). Infertile couples would probably increase their uptake of IVF services if they are more economic (77).
The emotional aspect isn't to be overlooked but instead, should be an integral part in the management of those patients. An enormous effort is still needed to provide the infertile couples with the best evidence.

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Edited by Aldo Campana,