Dr. Rana Choudhary
(MBBS, DNB, DGO, DFP, DCR, FCPS, FICMCH, FICOG, MNAMS)
Masters in Reproductive Medicine & IVF (UK)
Consultant Obstetrician & Gynaecologist
Reproductive Medicine (Fertility) Specialist
Certified Personal Counsellor
It has been observed over the last few decades that the overall incidence of infertility is constant. However the success rates in terms of achieving pregnancy has markedly increased because of the advent and use of assisted reproductive technologies like intra uterine insemination (IUI), in vitro fertilitisation (IVF) and intra cytoplasmic sperm injection (ICSI). (1) In approximately 15% to 30% of couples no cause can be found (2). Unexplained Infertility (UI) remains a puzzle till date and is basically a diagnosis of exclusion. If the standard investigations like semen analysis, ovulation detection tests and tubal patency were normal, the couple is labelled as suffering from unexplained infertility. (3)
However some authors have questioned the use of the term UI. They have argued that women having mild endometriosis, premature ovarian ageing and immunological infertility can be misdiagnosed as UI. It is interesting to note that with the current management options, further investigations and more ‘accurate’ diagnosis is unlikely to change course of action in these couples.
Diagnosis of Unexplained Infertility: The Basic Infertility Evaluation
Infertility is defined as the failure to conceive after 1 year of unprotected intercourse. The NICE guidelines have categorized infertility into the following types (4):
- Male factor,
- Tubal disease,
- Endometriosis and
- Unexplained infertility (UI) (4).
The American Society for Reproductive Medicine (ASRM) has also published guidelines for a standard evaluation in fertility seeking couples.(5) These investigations include :
- Semen analysis,
- Assessment of ovulation,
- Tubal patency tests using a hysterosalpingogram
They have stated that, further tests in the form of ovarian reserve testing and diagnostic laparoscopy may be added.
Study of literature shows that conception rate is strongly inﬂuenced by female age and infertility duration, and treatment independent cumulative live birth rates have been around 33 and 60% at the end of 3 years. It is interesting to note that pregnancy rate does not change neither does the management in this group of patients. As there is unavailability of precise diagnostic methods many times UI is over diagnosed.
Following conditions may be the underlying cause in these couples with unexplained infertility:
WHO has laid down guidelines stating parameters for normal semen report. But even then there is an overlap between ‘normal’ and ‘abnormal’ values. Use of intracytoplasmic sperm injection (ICSI) has revolunised the treatment for male infertility which would include UI due to immunological origin. Sometimes there is an increase in sperm DNA fragmentation index which could be the cause of UI. This is more common in men with diabetes and can be improved by maintaining tight blood sugar levels and use of antioxidants.
Upto 20% of couples having infertility may have underlying autoimmune disease. Various tests like antiphospholipid, antinuclear, antithyroid and antisperm antibodies have been used for a long time. Preliminary studies reported an association between early reproductive failure / miscarriage and abnormal immune function. However recent studies have failed to conﬁrm a causal effect. Matsubayashi et al reported elevated peripheral NK activity in patients with UI (Matsubayashi et al., 2001). This has led to confusion in the therapy for these patients. Therapies like intravenous immunoglobulin has not shown consistent results in improvement of live birth rates in couples with IUI and repeated unexplained IVF failures (Stephenson and Fluker, 2000). Hence use of this therapy routinely is thus questionable.
Mild tubal disease:
Assessment of the uterine contour and tubal patency is an integral part of basic infertility evaluation. This may be achieved by hysterosalpingography (HSG). Mol et al. (1999) reported a sensitivity of 0.81 and a speciﬁcity of 0.75 for HSG in identifying tubal occlusion as compared to laparoscopy However, patent fallopian tubes on HSG do not confirm ideal tubal functioning. For example, women with severe endometriosis may have adherent ovaries in the cul de sac with normal fallopian tubes.
Laparoscopy direct visual examination of the pelvic reproductive anatomy, and is the test of choice to identify otherwise unrecognized peritoneal factors, specifically endometriosis and pelvic adhesions. Laparoscopy is more reliable in predicting pregnancy, (fecundity rate ratios of 0.38 and 0.19 when a one- and two-sided occlusion appeared, respectively) compared with HSG (expressed by a kappa statistic of 0.42). However, even this has some limitations in terms of accuracy in assessing tubal patency and function.
In women with patent tubes, it would be reasonable to adopt an expectant approach (taking into account age and duration of subfertility) before considering IVF. Thus, inability to exclude a diagnosis of mild tubal defects is unlikely to change the overall plan of management.
In the absence of a detailed laparoscopic examination of the pelvis, endometriosis could often be misdiagnosed as UI. In a meta-analysis of women with endometriosis, pregnancy rates were found to be higher in women without endometriosis (Barnhart et al., 2002). The management of infertility in these women depends on the age and severity of endometriosis. The management strategies for minimal/mild endometriosis are similar to those used for UI, i.e. superovulation / IUI and IVF (NICE, 2004). This questions the justiﬁcation for diagnosing minimal and mild endometriosis separate from UI.
Management of minimal / mild endometriosis:
- Medical treatment is ineffective.
- Laparoscopic resection or ablation of lesions in minimal and mild endometriosis led to contradictory results. Also the cost of therapy increases without much increase in success rate of pregnancy.
- Expectant management OR superovulation/IUI and IVF is the accepted management.
Defect in the endometrial perfusion may also be the reason for UI. This can be diagnosed by endometrial Doppler evaluation in the follicular as well as luteal phase. Various therapies like ecospirin, nitric oxide donors, l arginine, sildenafil etc have been used to improve the perfusion and pregnancy rate in these women.
Additional investigations in UI :
Assessment of Ovarian Reserve
As age advances there is high rate of follicular atresia and poor follicular growth. This is known as ‘poor ovarian response’. Thus women with advanced age or history of prior ovarian surgery are at risk for diminished ovarian function or reserve and maybe the underlying cause of UI. Evaluation of ovarian reserve test maybe offered to women with UI. The testing includes a cycle day 3 serum follicle-stimulating hormone (FSH) and ultrasonographic ovarian antral follicle count. The results are not absolute indicators of infertility but abnormal levels correlate with decreased response to ovulation induction medications and lowered live birth rates even after IVF.
In the absence of reliable and accurate markers for ovarian reserve, older women will be offered the same treatment options, such as controlled ovarian stimulation with IUI, IVF, and ultimately oocyte donation.
Management of Unexplained Infertility
Treatment for unexplained infertility is mostly empiric because it does not address a specific defect or functional impairment. It is possible that unexplained infertility represents the lower extreme of the normal distribution of fertility with no defect present. It is possible that routine infertility evaluation misses subtle defects because of imperfect or incomplete methods. Studies of couples with unexplained infertility who are followed without any treatment report a broad variation in cumulative pregnancy rates. Although expectant management is associated with the lowest cost, it results in the lowest cycle fecundity rates, and is therefore inferior to the commonly available reproductive techniques outlined below. It may provide an option for a couple with unexplained infertility in whom the female partner is young with a good ovarian reserve.
The principal treatments for unexplained infertility include expectant observation with timed intercourse and lifestyle changes, oral ovulation induction, controlled ovarian hyperstimulation (COH) with IUI, and IVF.
- Expectant Management and Lifestyle Changes
Epidemiological studies indicate cigarette smoking, abnormal body mass index (BMI), and excessive caffeine and alcohol consumption reduce fertility. Thus weight reduction, reducing caffeine intake (2 cups of coffee/day), and alcohol intake to no more than 4 standardized drinks per week may benefit in these women.(6)
Whether operative laparoscopy improves pregnancy outcomes in a subject with unexplained or minimal/mild endometriosis is of debate. A Cochrane review on the topic (2002) said that laparoscopic surgery in the treatment for mild endometriosis and may improve pregnancy success rates, but further research is needed. However, current literature does not support performing a diagnostic laparoscopy in all patients.
Intrauterine insemination (IUI) can be performed in conjunction with natural ovulation timed with LH kit, ovulation induction using clomiphene citrate / letrozole, or injectable gonadotropins. It has been estimated that 37 cycles of IUI without additional ovarian stimulation would be needed to obtain an additional pregnancy compared with control cycles. Cochrane review on this topic confirmed that IUI with ovulation induction increased the live birth rate compared with IUI alone.(8)
- COH and IUI
Over the past decades, there has been a marked increase in the use of COH, with or without IUI, in the treatment of UI. Clomiphene citrate, Letrozole and gonadotropins have been used for COH, with or without IUI. Subtle ovulatory defects missed by standard testing may be overcome by doing COH with IUI and we get an increased number of oocytes available for fertilization. Also when washed sperms are introduced into the uterine cavity it increases the density of motile sperm available to ovulated oocytes and maximize the chance of fertilization.
Use of clomiphene citrate with timed intercourse in patients with unexplained infertility has been shown to have a small effect on pregnancy rates: combined analysis of the available evidence revealed that 40 cycles with empiric clomiphene citrate therapy were necessary to achieve 1 additional pregnancy. Gonadotropin therapy is superior to clomiphene citrate therapy, and both are most effective when combined with IUI.
A meta-analysis of 27 studies involving 2939 cycles revealed that the pregnancy rate per cycle was 8% with gonadotropin treatment alone and 18% with gonadotropin treatment combined with IUI. The cumulative pregnancy rate rises with the number of attempted COH/IUI cycles; however, there is some evidence suggesting that the number of COH/IUI cycles prior to treatment with IVF should be limited to three. IVF can be offered if they fail to conceive after 3 trials of COH and IUI.
Role of Double IUI
There are several studies addressing the effect of IUI on 2 consecutive days over single IUI. Available trials on this issue are difficult to interpret because they are not restricted to patients with unexplained infertility, but also included subjects with other types of infertility. Although some studies suggested marginal benefits of double IUI over single, the most recent randomized trial concluded that among patients undergoing COH/IUI, results of single and double IUI do not differ statistically.
IVF/ ICSI is the treatment of choice for unexplained infertility when other treatment modalities explained above have failed. Studies have shown a 40% live birth rate for women younger than 35 years of age and 38% for women 35 to 37 years of age with UI.
The optimal treatment strategy needs to be based on individual patient characteristics such as age, treatment efficacy, side-effect profile such as multiple pregnancy, and cost considerations.
Take home messages:
1. Couples should undergo a semen analysis, ovulation testing, assessment of ovarian reserve, and imaging to assess for tubal and uterine factors before a diagnosis of unexplained infertility is made.
2. The principal treatments for unexplained infertility include expectant observation with timed intercourse and lifestyle changes, Clomiphene citrate, Letrozole and intrauterine insemination (IUI), controlled ovarian hyperstimulation with Gonadotropins with IUI, and in vitro fertilization (IVF).
3. Although expectant management is associated with the lowest cost, it results in the lowest cycle fecundity rates. It may provide an option for a couple with unexplained infertility in whom the female partner is young and has good ovarian reserve (7)
4. IVF/ ICSI is the treatment of choice for UI when the less costly, but also less successful treatment modalities have failed.
- Stephen EH, Chandra A. Updated projections of infertility in the United States: 1995–2025. Fertil Steril. 1998;70:30–34.
- The Practice Committee of the American Society for Reproductive Medicine, authors. Effectiveness and treatment for unexplained infertility. Fertil Steril. 2006;86:S111–S114.
- European Society for Human Reproduction and Embryology. Guidelines to the prevalence, diagnosis, treatment and management of infertility, 1996. Hum Reprod 1996; 11:1775–1807.
- Unexplained infertility, NICE guidelines, 2004.
- The Practice Committee of the American Society for Reproductive Medicine, authors. Optimal evaluation of the infertile female. Fertil Steril. 2006;86(5 suppl):S264–S267.
- Barbieri RL. The initial fertility consultation: recommendations concerning cigarette smoking, body mass index, and alcohol and caffeine consumption. Am J Obstet Gynecol. 2001;185:1168–1173.
- Eijkemans MJ, Lintsen AM, Hunault CC, et al. Pregnancy chances on an IVF/ICSI waiting list: a national prospective cohort study. Hum Reprod. 2008;23:1627–1632.
- Verhulst SM, Cohlen BJ, Hughes E, et al. Intrauterine insemination for unexplained subfertility. Cochrane Database Syst Rev. 2006 CD001838.