Obstetrics and Gynecology

Unexplained Infertility

Unexplained Infertility

1. What every clinician should know

Infertility is commonly defined by the inability to conceive a pregnancy after 1 year of unprotected intercourse and affects one in seven couples. The standard evaluation of infertility includes some assessment of fallopian tube patency, sperm count and motility, and ovulation. When these tests are normal, the couple is diagnosed with unexplained infertility. About 25% of couples with infertility are diagnosed with unexplained infertility after testing is completed. Unexplained infertility is sometimes referred to as "subfertility," since many of these couples will eventually conceive a pregnancy even without treatment.

Women who are of older reproductive age are more often diagnosed with unexplained infertility than are younger women. This is because the infertility is not truly unexplained in older women, it is due to either reduced egg number or reduced egg quality. Specifically, more of an older woman's eggs are chromosomally abnormal, which leads to a failure of embryo development and implantation.

2. Diagnosis and differential diagnosis

Diagnostic Criteria

The initial evaluation of the infertile couple should include tests to determine fallopian tube patency, ovulation, normal sperm parameters, and, in some women, tests for ovarian reserve. Each of these tests is described below. If all tests are normal, then the couple is diagnosed with unexplained infertility.

Tests of Ovulation

A woman is likely ovulating if she has regular menstrual cycles, particularly if she also has moliminal symptoms including breast tenderness and bloating before the onset of her period. However, tests for ovulation should be ordered to confirm this impression. Two tests are commonly considered to confirm ovulation: use of the urinary ovulation predictor kit; or use of a luteal phase progesterone level.

The ovulation predictor kit can be purchased in a local drug store and there are many brands to choose from. Basically, the woman tests a urine sample daily, usually beginning with day 11 or 12 of her cycle with day 1 being the first day of bleeding. These tests assay for LH concentration in the urine; when elevated, this signals the onset of ovulation. These tests are reasonably accurate, although there is approximately a 7% false positive rate in which ovulation is presumed but, in fact, did not occur.

The second commonly used test is a serum progesterone level, generally obtained on approximately day 21 of the normal menstrual cycle. If a woman has irregular cycles, the test is best performed approximately 7 days after the presumed day of ovulation. Any value greater than 3 ng/mL in most laboratories signifies ovulation. Values greater than 10 ng/mL have been linked to higher pregnancy rates in ovarian cycles in women treated with Clomid. Therefore, it may be preferable to have progesterone levels above this level of 10 ng/mL to signify optimal fertility.

Tests of Tubal Patency

The most common test ordered to confirm patency of the fallopian tubes is the hysterosalpingogram (HSG). This is a radiologic test performed under fluoroscopy in which contrast is injected via a cannula into the uterus. Under fluoroscopy, this contrast is visualized until it exits the uterus into the fallopian tube and ultimately spills into the peritoneal cavity. The HSG is normal when there are no filling defects in the uterine cavity and contrast spills from both fallopian tubes. Filling defects in the uterine cavity are often caused by either endometrial polyps or fibroids which should be further evaluated by a transvaginal ultrasound exam.

Care must be taken not to introduce air during the injection of contrast because bubbles can also displace contrast in the uterine cavity and give the false impression of a structural lesion. In some women, either one or both tubes will not fill at all with contrast, indicating a proximally-obstructed fallopian tube. This can be due either to a true obstruction or to uterine muscular spasm leading to a false appearance of obstruction.

The presence of unilateral proximal obstruction has been shown to have little prognostic significance, meaning that couples conceive at a similar rate to patients with bilateral tubal patency. If bilateral proximal obstruction is seen, this will require further evaluation to confirm that it is a true finding either by repeating the HSG at another time or performing surgical evaluation of tubal function by laparoscopy and hysteroscopy.

True bilateral proximal obstruction will ultimately require either surgical correction or, more commonly, in vitro fertilization (IVF) to bypass the fallopian tubes. The presence of distal obstruction indicates fallopian tube damage and this is likely the cause of the couple's infertility. Distally blocked tubes will need to be surgically opened or, more commonly, the patients are treated by IVF. Common causes of blocked fallopian tubes include prior pelvic inflammatory disease, pelvic surgery or ectopic (tubal) pregnancies (see Figure 1).

Figure 1.

. Normal HSG showing bilateral spill of dye

Semen Analysis

Males should be evaluated through a seminal fluid analysis. It is generally preferred that males have between 2 and 7 days of abstinence from ejaculation prior to collecting a sample for evaluation. The WHO criteria for normal seminal fluid analyses have recently changed and normal values are listed below (see Table I). The newer parameters are less stringent and are based on results from normal fertile males from around the world. There is still debate about which guidelines are the most appropriate to use.

table 1.

WHO Reference Guidelines

When evaluating the semen analysis, it is important to remember that there is great overlap in semen analysis results when comparing fertile with infertile populations. For example, some men with quite low sperm concentrations or sperm motility can still father a pregnancy naturally. In addition, semen analyses can be highly variable from sample to sample so an abnormal or borderline result generally should be repeated. However, if sperm counts are repetitively abnormal, this indicates a male factor infertility requiring further evaluation and treatment

Ovarian Reserve Testing

A newly appreciated cause of infertility has been described as reduced or diminished ovarian reserve (DOR). The term ovarian reserve refers to the number of eggs left in the ovaries. Some women with otherwise unexplained infertility will have regular menstrual cycles and yet be discovered to have DOR which has been linked to reduced ovarian responsiveness during infertility treatments and also to somewhat reduced pregnancy rates.

Although there is some link between egg number and egg quality, the two do not necessarily go hand-in-hand. Egg quality is reduced due to aneuploidy of eggs which is increased as women get older. Some younger women with DOR will still have good quality eggs and will still be able to conceive pregnancies at reasonable rates either spontaneously or with treatment.

A number of ovarian reserve tests have been discovered in recent years, including a cycle day 3 FSH and estradiol level, ovarian antral follicle count by ultrasound and an anti-mullerian hormone (AMH) level . In general, these tests predict egg number and response to ovarian stimulation better than they predict whether or not a pregnancy will occur either naturally or with treatment.

Day 3 FSH and Estradiol level

On day 3 of the menstrual cycle (the 3rd day after bleeding begins) FSH levels are usually low due to hormonal feedback inhibition from the ovary. An FSH value above 10 mIU/mL suggests some DOR and values above 15 mIU/mL are very concerning. Occasionally the FSH value on day 3 can be falsely suppressed due to a high estradiol level. Therefore, along with the FSH value, an estradiol is also measured and this value should be below 50 pg/mL. If the estradiol level is higher than that, the FSH reading is not as reliable and should probably be repeated.

Antral follicle count by ultrasound

A transvaginal ultrasound can be performed in an infertile woman to assess the number of small antral follicles between 2 and 10 mm in diameter in each ovary. The number of antral follicles on each ovary are summed and this value has been shown to correlate with the total number of follicles left in the ovaries. The cutoff to indicate DOR is still debated but some have proposed that less than 10 antral follicles indicates possible DOR. Of course, the lower the number, the more severe the reduction in oocyte number is likely to be and some centers use values below 4. Using lower numbers will improve the specificity of the test (see Figure 2).

Figure 2.

Transvaginal ultrasound reveals high normal ovarian volume (3.6 x 1.9 x 2.6 x/6 = 9.3 cc) and multiple antral follicles

AMH levels

AMH is made by granulosa cells of early developing and pre-antral follicles. Therefore, serum AMH levels reflect the number of eggs left in the ovaries. AMH levels decline steadily with increasing female age. In an individual, AMH levels are stable across the menstrual cycle. Therefore, blood levels can be drawn at any time of the cycle and will be accurate. Values below 1 ng/mL suggest reduced ovarian reserve. Once again, the lower the value that is obtained, the more likely it is that the woman has DOR as a cause of her inability to conceive.

Tests of ovarian reserve are surrogate markers for the actual number of eggs remaining in the ovary. Like any test, there are false positives and false negative rates. AMH levels and antral follicle counts are considered to be the best tests available. The prevalence of DOR increases as women get older, so generally these tests should be performed in somewhat older populations to have good positive and negative predictive value. Most experts recommend testing for diminished ovarian reserve in women who are 35 years of age and older as well as testing women who are at increased risk for DOR, including women who are smokers, women who have had ovarian surgeries performed, and women with a family history of early menopause.

Diagnostic Laparoscopy

In addition to the testing above, some women undergo diagnostic laparoscopy to further evaluate infertility. Although laparoscopy used to be a standard part of the infertility evaluation, it is being performed with less and less frequency today for this indication. The purpose of performing the laparoscopy is to diagnose endometriosis or pelvic adhesive disease that was not discovered by HSG testing. Laparoscopy has fallen out of favor since treatment of endometriosis is not very effective at improving pregnancy rates. It has been estimated that up to 16 women would have to undergo laparoscopy for every additional pregnancy that might result from surgical treatment of mild endometriosis. Given the cost of laparoscopy versus IVF, the cost-effective approach is often to forego the laparoscopy and proceed with infertility treatments including IVF.

3. Management

Expectant management can certainly be considered for couples with unexplained infertility. Factors that have been shown to affect the odds of conceiving a pregnancy naturally without treatment include the woman's age, the duration of infertility and sperm parameters. Couples in which the semen analysis is normal, the female partner is relatively young (under the age of 35), and with a short duration of infertility will have up to a 4-5% chance of spontaneous conception each month. With increasing duration of infertility and increasing age, these percentages go down. The average couple with unexplained infertility presenting to a practice will have about a 2% pregnancy rate per month without treatment.

Some couples are looking for advice about how to best conceive naturally. Proper timing of intercourse can be helpful, with the optimal time being 2-3 days leading up to and including the day of ovulation. Use of ovulation predictor kits can be helpful and I advise couples to have intercourse on the day the kit demonstrates the LH surge (actual ovulation will generally occur 24 hours later) and on the following day as well. Lifestyle changes that may be helpful are to avoid smoking and heavy alcohol consumption. Optimal fertility rates for women are seen with a BMI between 20-25.

For unexplained infertility, ovulation induction alone has been shown to be of little use. In a woman who is already ovulating, the addition of ovulation-inducing agents does not add significantly to the chances of conception.

Whether or not intrauterine insemination (IUI) adds to the pregnancy rate for unexplained infertility is controversial. IUI is performed by isolating the motile sperm from the rest of the ejaculate through laboratory processing. The motile sperm are then concentrated into a small volume and injected through the cervix and into the uterus, resulting in greater numbers of motile sperm reaching the upper reproductive track where fertilization occurs. IUI has been shown to improve pregnancy rates in couples with cervical factor or male factor infertility,

For cervical factor infertility, it is likely that IUI improves pregnancy rates over natural conception since "hostile" cervical mucus is bypassed. However, cervical factor infertility is difficult to diagnose because there is no reliable test to make this determination. If a woman has a history of a previous surgery to the cervix (e.g. cone biopsy or treatment for cervical dysplasia), then a cervical factor is more likely to be present and IUI alone may benefit this couple. Likewise, if the semen analysis has abnormal sperm concentration or motility, then IUI is indicated. However, in the absence of male factor or presumed cervical factor, IUI alone does not dramatically increase the pregnancy rate for couples with unexplained infertility (see Figure 3).

Figure 3.

Illustration of IUI with sperm transfer high in reproductive tract

For unexplained infertility, a common strategy is to treat the couple with a combination of both ovulation induction plus IUI. Usually this is done with an oral agent like Clomiphene Citrate (CC) or Letrozole with IUI occurring with ovulation. Pregnancy rates with this type of treatment are typically about 8% per cycle, a higher pregnancy rate than is seen with expectant management of infertile couples. Multiple pregnancy rates are approximately 10% and most of these are twins if only oral drugs are used to stimulate the ovary. If several cycles of oral ovulation induction and IUI are unsuccessful, it is reasonable to try more aggressive ovulation induction using injectable gonadotropins (hMG) and IUI for a few cycles.

With this treatment, pregnancy rates are typically about 12-14% per cycle and multiple pregnancy rates are in the 15-20% range. Use of hMG therapy for ovarian stimulation can be quite challenging and can result in high order (triplets and more) multiple gestations. For these reasons, some couples elect to have IVF rather than hMG-IUI. A recent trial randomized couples with unexplained infertility who had failed to concieve with three cycles of CC-IUI to either hMG-IUI for three cycles followed by IVF for three cycles or directly to three cycles of IVF. Couples treated by early IVF conceived pregnancies more quickly and at equal or possibly less cost than couples who were randomized to hMG-IUI.

4. Complications

Complications of unexplained infertility mainly involve emotional upset over not having a child.This can be quite devastating to couples who view child-bearing as an important aspect of their life that is missing.

Complications of Treatment

The complications of treatment largely revolve around ovarian stimulation, which can cause ovarian discomfort due to cyst formation and rarely due to ovarian hyperstimulation syndrome (OHSS). OHSS is a rare (less than 5%) complication of stimulating the ovary with gonadotropin injections. It is seldom seen unless human chorionic gonadotropin (hCG) is used to stimulate ovulation. OHSS results when multiple follicles develop within the ovary. Ovarian production of VEGF is thought to lead to increased vascular permeability which, in turn, can cause ascites to develop. In addition, the ovaries can become quite large leading to pain and discomfort. OHSS is usually self-limited and generally resolves in 1-2 weeks.

The other major risk of ovarian stimulation is of multiple gestation. Multiple pregnancy rates with oral ovulation-inducing medications are approximately 10%, with most being twins. When gonadotropin injections are used to stimulate the ovary and IUI is performed, multiple pregnancy rates are approximately15-20% per pregnancy. Again, most of these are twins but triplets and even higher order multiple gestations are possible. With in vitro fertilization the multiple birth rate depends largely on the number of embryos transferred but, in most IVF clinics in the United States, multiple birth rates are currently around 30% of pregnancies.

5. Prognosis and outcome

The expected pregnancy rates for treatment are listed above. There are no known long-term affects of infertility treatment on a woman's health. Likewise, the health of infants born after infertility treatment is generally quite favorable. There are some reports of a slight increased risk of birth defects in children conceived after infertility treatments. It would appear from the literature that this increase in birth defect rate is small, on the order of 6-7% of infants conceived after infertility treatment versus 4-5% rate in naturally conceived controls.

Furthermore, the birth defects seem to be related to the underlying infertility rather than the treatment given. Although there is also a slightly higher risk of pregnancy complications in pregnancies conceived with infertility treatment, much of this increased risk is due to multiple gestations. Multiple gestations will frequently lead to premature delivery, which can have long-term consequences for the offspring. Nevertheless, a large majority of infants conceived after infertility treatment are healthy and not compromised in any way.

6. What is the evidence for specific management and treatment recommendations

Reindollar, RH, Regan, MM, Neumann, PJ, Levine, BS, Thornton, KL. "A randomized clinical trial to evaluate optimal treatment for unexplained infertility: the fast track and standard treatment (FASTT) trial". Fertil Steril. vol. 94. 2010. pp. 888-99.

(This study is a prospective randomized trial about advanced treatment for unexplained infertility.)

Guzick, DS, Sullivan, MW, Adamson, GD, Cedars, MI, Falk, RJ. "Efficacy of treatment for unexplained infertility". Fertil Steril. vol. 70. 1998. pp. 207-13.

(This is a nice review of standard treatments by a panel of experts.)

Verhulst, SM, Cohlen, BJ, Hughes, E, Heineman, MJ, TeVelde, E. "Intra-uterine inseminatioin for unexplained subfertility (Review)". Cochrane Database Systematic Reviews. vol. 18. 2006 Oct. pp. CD001838. http://www.thecochranelibrary.com.

(This is an analysis of the evidence for IUI for unexplained infertility.)

Cantineau, AEP, Janssen, JM, Cohlen, BJ. "Synchronised approach for intrauterine insemination in subfertile couples (Review)". Cochrane Database of Systematic Reviews. vol. 14;. 2010 April. pp. CD006942. http://www.thecochranelibrary.com.

(This is a nice summary of IUI for unexplained infertility.)

Quaas, A, Dokras, A. "Diagnosis and treatment of unexplained infertility". Rev Obstet Gynecol. vol. 1. 2008. pp. 69-76.

(This is a well-written summary of the diagnostic work-up for infertility.)

Jacobson, TZ, Duffy, JMN, Barlow, D, Farquhar, C, Koninckx, PR, Olive, D. "Laparascopic surgery for subfertility associated with endometriosis (Review)". Cochrane Database of Systematic Reviews. 2010. pp. CD001398.

(This study reviews the evidence for laparoscopy in the evaluation of infertility.)

Bhattacharya, S, Porter, M, Amalraj, E, Templeton, A, Hamilton, M. "The epidemiology of infertility in the North East of Scotland". Hum Reprod. vol. 24. 2009. pp. 2096-3107.

(This is an up to date study of the epidemiology of infertility.)

Bhattacharya, S, Harrild, K, Mollison, J, Wordsworth, S, Tay, C. "Clomifene citrate or unstimulated intrauterine insemination compared with expectant management for unexplained infertility: a pragmatic randomised controlled trial". BMJ. vol. 337. 2008. pp. a716.

(This is a prospective randomized trial of some common infertility treatments for unexplained infertility as compared to a no treatment arm.)
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