Monday, 27 April 2020

Vol. 9 April 2020: UNEXPLAINED SUBFERTILITY: Definition, Investigations & Management

Unexplained Subfertility: Definition, Investigations & Management
     Author: J. Adeghe PhD, FRCOG.

In about 15% of couples experiencing difficulty in conceiving, investigations do not reveal any abnormality, therefore this diagnosis is labelled as unexplained. Many couples find this label frustrating and often questions it and say, “if there is no underlying cause, why am I not getting pregnant?”.

What the term ‘unexplained infertility’ really means is that basic assessment of the three pillars of fertility – ovaries/ovulation, fallopian tubes and sperm – have not shown any obvious abnormality. It does not mean that there are no problems with other bodily systems that must function well for pregnancy to occur. For example, the endocrine organs (e.g. thyroid gland), immune system, nutritional status, must function optimally for pregnancy to occur and develop normally. In fact, these other organs are generally not tested as part of first line investigation into subfertility. In essence the so-called unexplained subfertility is really ‘subfertility of no obvious cause’, because the couple have not been investigated well enough. The obvious causes being tubal, sperm factor or ovulatory dysfunction.

Treatment options that are often offered to couples with Subfertility of no obvious cause usually  include:

a 1)  ‘Wait and See’ approach (expectant management), especially if the couple have been trying for less than 2 years and the woman is less than 30 years old. The couple is advised to keep ‘practising’ and hope for a pregnancy.

S2) Simple ovarian stimulation with Clomifene or Letrozole tablets, with ultrasound follicle tracking.

c 3)  Intrauterine insemination (IUI) with mild ovarian stimulation.

I 4) IVF treatment, especially if the woman is over 35 years age, or have been trying for 3 years or more.

The management dilemma arises, when one or more or the above treatment modalities are unsuccessful. What to do? How to proceed?

Further tests should be carried out to diagnose the underlying cause of subfertility of no obvious cause. Investigations should be structured and directed by the couple’s medical history and other relevant findings.

The following investigations should be considered.

In many cases tubal patency test as part of first line fertility investigations is assessed by hysterosalpingography (HSG) or Hysterosalpingo-Contrast-Sonography (HyCoSy). While both methods are effective in checking whether or not fallopian tubes are patent, they give no indication of any background pelvic conditions often referred to as peritoneal factors - peritubal or tubo-ovarian adhesions, or endometriosis, conditions that can impair fertility. In addition to being diagnostic, laparoscopy provides an opportunity to carry out therapeutic procedures e.g. division of adhesions to restore normal pelvic anatomy, or diathermy to endometriotic deposits.

·        Hysteroscopy
Hysteroscopy is a minor endoscopic procedure to visualise the uterine cavity in order to identify and treat any endometrial lesions present. This is a simply procedure that can be done on an outpatient basis. It is often overlooked in discussions and publications on investigations of subfertility of uncertain cause. Clearly, it should be in the forefront of investigations because endometrial lesions can impact on implantation. Conditions such as polyps, adhesions, inflammatory changes, can impair implantation. In my clinic, endometrial factors (polyps, adhesions, septum, inflammatory changes) are found in about 14% of women with recurrent implantation failure.
Hysteroscopy should be performed in women with recurrent unsuccessful assisted conception treatment cycles.

 Infection screen 
Various infections can impair fertility at every level of the reproductive pathway including fertilisation, implantation, and embryo viability. Infections are causal to many cases of miscarriage. It is therefore important to conduct a thorough screening for infections in cases of subfertility of no obvious cause. A recent research publication suggests that sperm cells carrying human papilloma virus have increased DNA fragmentation which can impair the ability of sperm to fertilize. Infection screen can be carried out on first urine catch using polymerase chain reaction (PCR) technique. This identifies exposure to chlamydia trachomatis, gonorrhoea, herpes virus I & II, gardnerella, trichomonas, and ureaplasma urealyticum, mycoplasma hominis. Other pathogens include cytomegalovirus and toxoplasmosis. If this methodology is not available a simple high vaginal swab for microscopy, culture and sensitivity is also good and effective. Tuberculosis is becoming resurgent in many communities, therefore a thorough medical history to identify possible exposure should be taken. Previous tuberculous infection may have caused damage to the
fallopian tubes or caused granulomatous endometritis, and remain asymptomatic.
It goes without saying that infection screening should be carried out in both women and men. In my practice, testing of the man is carried out on a first urine catch in the morning.

Detailed Semen Analysis
Semen analysis should be re-visited. Particular attention should be paid to leucocyte count in the semen which may be an indication of infection in the testis/epididymis (epididymo-orchitis), prostate (prostatitis) or seminal vesicles.
Specialist tests such as anti-sperm antibodies (IgG and IgM subtypes) should be carried out. The role of anti-sperm antibodies in subfertility is controversial but there is reasonable evidence that they can impair sperm transport through cervical mucus and antibodies directed against the sperm head can impair fertilisation. In cases where over 50% of sperm are coated with anti-sperm antibodies, assisted reproductive treatment using ICSI technique is indicated.
Sperm DNA fragmentation have been shown to impair sperm function but at present there is no consensus on what level of fragmentation is clinically significant. Testing may be carried out but management decisions should be made taking other sperm parameters and clinical picture into consideration.

 Immunological tests

Testing for immunological factors in men involves testing for antisperm antibodies coated onto sperm. This was mentioned briefly above. Historically antisperm antibodies were tested for using blood samples but numerous studies have shown that circulating antisperm antibodies correlate poorly with infertility. The only clinically relevant tests are those based on sperm surface antibodies which can impede sperm motility and fertilizing ability.

In women, testing for Natural Killer cells (NK cells) in the blood or within the endometrium may be clinically relevant to fertility. This is a controversial area and should be dealt with by clinicians who have the appropriate training and experience.

Management Plan
The findings from further investigations would determine the treatment plan. However, general measures to optimise successful outcome to treatment is of utmost importance. 

1]  Lifestyle review and advice

This is the first line approach to management. Although lifestyle review with correctional changes should be done as the pre-conception advice, it is often overlooked. At this stage when time has moved on and there is repeated treatment failure it is time to ‘crack the whip’ or ‘read the riot act’. Lifestyle review and corrective measures should focus on:

·        Cessation of smoking – both partners

·        Stops excessive alcohol consumption

·        Reduce Caffeine intake (no more than two cups of coffee a day)

·        Weight reduction through diet control and exercises. Aim for BMI of <30

·        Dietary changes to adopt the components of the Mediterranean diet – avoid red meat, eat oily fish, reduce carbohydrate intake

·        Eat green vegetables and fruits

·        Reduce stress – observe periods of ‘down time’ where you do nothing but just ‘gaze’, listen to soothing music, yoga, etc.

·        Take Folic acid tablet 5mg once a day

       2] Eliminating or correcting any abnormal findings uncovered by investigations, including:

·        Salpingectomy if there is hydrosalpinx

·        Resection of submucous fibroids

·        Endometrial polypectomy if polyps are found in the endometrial cavity

·        Correcting low levels of Vitamin D

·        Treating underactive thyroid

·        Antibiotic treatment for men with increased leucocytes in semen

·        Treatment of underlying infection in both partners

        3]   Solutions: Note that I have said ‘solutions’ rather that treatment. This is because in helping
              couples create families, we should other options that other than assisted conception

              Careful consideration should be given to treatment planning. Review of previous treatment
               cycles to see what worked or didn’t. Procedures and strategies to optimise success include:

              -Endometrial scratch

              -Blastocyst culture

              -Augmented luteal support with combination of oestrogen tablets and injectable


              -Elective freeze of embryos and subsequent frozen embryo transfer

              IVF/ICSI using donor gametes

              For women with low AMH levels where egg numbers and quality are compromised, use of

              donor egg is indicated. Similarly, if sperm quality is very poor, donor sperm may be the way

              forward. Use of donated embryos is also an option

              Surrogacy should be considered if investigations indicate a uterine/endometrial problem
              that did not respond to treatment. In this situation, host surrogacy is an option.

              When treatment has failed repeatedly and the prospect of success with further treatment is
              bleak, adoption should be considered. This may not be acceptable for some couples but is
              one way to create a family. There are many children awaiting adoption in many countries
              though it has to be said that adoption laws in the UK are tough.

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