Subfertility - Investigations and Management

Infertility is the inability to conceive.

Classification

• Primary infertility describes the condition in which the couple have not conceived before.
• Secondary infertility describes the situation where there has been previous conception, whether or not the outcome was a live child.

Couples should be having regular and satisfactory intercourse about 3 times a week with failure to conceive for a year or two before they are investigated.
Preliminary investigations in primary care may be undertaken at the end of 1 year, and referral may be made sooner if problems are anticipated such as if the woman is over 35.¹

Subfertility may be due to problems with one or both partners.
Natural female fertility seems to decline quite rapidly after the age of 35, but this is just an average and the actual point of decline for any individual may vary significantly.² Increasing maternal age occurs with increased obstetric risks and risk of miscarriage. This should be noted by women who choose to delay their family.

Infertility statistics show considerable variation. When couples try to conceive:

• 16% will still be unsuccessful at the end of 1 year
• 8% after 2 years
• 7% at the end of 3 years

This means that of those who were unsuccessful at the end of the first year, half will conceive in the second year but only an eighth of the remainder in the third year. Therefore 2 years is an appropriate time to delay intervention.
The cause of infertility is never found in around 30%. Other factors include:

• Failure of ovulation in 27%
• Male factors in 19%
• Tubal factors in 14%
• Endometriosis in 5%
• Problems with both partners in 39%

• Ask how long they have been trying to conceive?
  • This means how long have they been having intercourse without contraception.
  • There is no significant difference between the time taken to conceive after stopping the various forms of contraception except that depot contraception (Depo Provera) may take slightly longer from the time of expiry of the last injection but it does not seem to have a long term adverse effect.³
• How often do they have sexual intercourse?
  • If you ask them both you will probably get a different answer with the man estimating a greater frequency than the woman although they presumably do it together.
  • There may be problems such as the man working away on oil rigs or abroad for much of the time.
• Are there any problems with intercourse?
  • Satisfactory intercourse is important as conjugal problems such as erectile dysfunction, retrograde ejaculation and dyspareunia will reduce the chance of conception.
  • Deep dyspareunia or dysmenorrhoea may indicate endometriosis or pelvic inflammatory disease.
• Has there ever been conception even if the outcome was miscarriage?
  • Ask as delicately as possible if there has ever been conception with a different partner.
  • Couples may well have hidden such facts from their partners, including not disclosing about a past termination of pregnancy.
• General health:
  • Systemic or debilitating diseases including thyroid disease, diabetes, inflammatory bowel disease, and anorexia nervosa will have an adverse effect on fertility.
  • Diabetes in pregnancy requires immaculate control of the disease even before conception.
• Drugs may impair fertility:
  • NSAIDs may impair ovulation, especially indomethacin.⁴
• Is there a normal menstrual cycle?
  • It does not have to be 28 days but the further it is from that, the less likely is ovulation and it is extremely unlikely if the cycle exceeds 42 days.
  • If there is amenorrhoea this requires investigation in its own right.
• Some tact may be needed in asking both parties about any previous sexually transmitted diseases including pelvic inflammatory disease.
• Past medical history in both parties.
  • In the woman there is special attention to appendicitis or pelvic surgery.
  • In the man, testicular trauma, undescended or maldescended testes, torsion of testis, mumps after puberty and varicocele are important.
• Health promotion:
  • It is an excellent time to check that cervical smear is up to date and rubella immunity may be confirmed with immunisation if negative.
  • Take opportunity to offer pre-conceptual advice.

• Note height, weight and BMI.
• It may be of significance in the man and of great significance in the woman.
• A BMI below 20 may suggest anovulation as in anorexia nervosa.
• A BMI above 29 is associated with decreased fertility.
• There may be polycystic ovary disease.

Female

• Look for signs of hirsutism:
  • Facial hair may be more profuse than normal, although this should be interpreted in the light of racial norms.
  • Acne may also indicate high androgen levels.
  • There may be a hint of male pattern alopecia with slight bitemporal recession.
  • The pubic hairline may extend up towards the umbilicus in a typical male pattern.
• Examination of the cardiovascular or respiratory system is unlikely to be rewarding as is examining the breasts for galactorrhoea unless indicated by history.
• Abdominal examination should be performed and it must precede bimanual pelvic examination or it is very easy to miss a large mass like a big ovarian cyst.
• Gynaecological examination, especially vaginal examination, may indicate undisclosed sexual difficulties.
  • For example her response may suggest vaginismus and you may even find an intact hymen.
• An unusually large clitoris would suggest excessive androgen activity, but this is more likely to be a long standing condition such as congenital adrenal hyperplasia. This will probably be in a mild form, as it is presenting so late.
• Bimanual examination:
  • May find an adnexal mass from an ovary of tubo-ovarian mass or tenderness suggesting PID or endometriosis.
  • Uterine fibroids can distort the uterus and interfere with implantation.

Male

• Is there any gynaecomastia?
• Does the penis appear normal?
  • If there is hypospadias it will deposit semen away from the cervix in the acid vagina where the spermatozoa are immobilised
• Check that both testes are down and that they feel normal in size and consistency.
  • Check for inguinal hernia and varicocele.

In the woman

• Mid-luteal progesterone level to assess ovulation.
  • If low it may need repeating as ovulation does not occur every month.
  • The blood test is taken 7 days before the anticipated period, that is on day 21 of a 28 days cycle but this day will need to be adjusted for different lengths of cycle.
• Basal body temperature charts are not recommended as they are unreliable
• FSH and LH should be measured, especially if there is menstrual irregularity.
  • High levels may suggest poor ovarian function.
  • A comparatively high LH relative to FSH is typical of polycystic ovary disease.
• Clinical Knowledge Summaries advise that thyroid function tests a should only be undertaken if there are grounds for suspicion as infertile women are no more likely to have thyroid disease than the rest of the population.
• Similarly, prolactin (PRL) should only be measured where there is clinical suspicion.
• Chlamydia screening is recommended.
  • Not only may it be a cause of infertility but instrumentation of the genital tract in subsequent investigations may produce PID.

In the man

Semen analysis should be performed:

• The specimen should be produced by masturbation and not into a condom as they contain spermatocides, after 3 days abstinence from sexual activity.
• The specimen should be kept warm and sent to the laboratory for examination, ideally within an hour from production although in practice this is difficult to achieve.
  Prior arrangement with laboratory may be necessary to ensure that they are able to deal with the specimen on the day collection.

Referral should be made to a specialist team for further investigation and treatment of subfertility if:

• There is no success after trying for 18 months
• The woman is under 35 and all previous investigations are normal
• Older women and abnormal preliminary investigations require earlier referral

Each clinic may well have its own protocol for the investigation of couples in whom no problem has been identified, and even after extensive investigation no problem is found in 30%.

Tubal patency

Tubal damage is estimated to account for 14% of infertility in women.⁵If the test has not been performed in primary care, a test for chlamydia will be performed before using instruments that may induce a chlamydial salpingitis.

• A hysterosalpingogram (HSG) is recommended by NICE for women who are not known to have had pelvic inflammatory disease, ectopic pregnancy or endometriosis. The test is reliable and less invasive than laparoscopy. This test is more useful than laparoscopy at demonstrating the cavity of the uterus that may be distorted by fibroids or septate. However, this test merely demonstrates the patency of one or both tubes whilst what really matters is the function of fine cilia within the tubes.
  • The procedure does not require general anaesthesia although some sedation may be used as it can be uncomfortable.
  • With the patient in the lithotomy position a Vulsellum forceps is attached to the cervix and the tip of a syringe is pushed into the cervix.
  • A radio-opaque medium is injected and the picture viewed on x-ray screening.
  • If there is no occlusion then little pressure should be required to inject the contrast material and screening should show free spill of medium from both tubes.
  • If it is available, hystero-salpingo-contrast-ultrasonography may be used.
• Laparoscopy is recommended by NICE if there are known problem such as PID, endometriosis or previous ectopic pregnancy.
  • Laparoscopy is usually performed under general anaesthetic.
  • The abdomen in insufflated with carbon dioxide and a trocar is inserted through an incision in the lower curve of the umbilicus.
  • Under direct vision a smaller trocar is inserted through the lower abdomen and this allows forceps to be introduced to move the pelvic organs to inspect them.
  • Simple inspection is the first task. The surgeon checks if the pelvic organs look normal. He looks for endometriosis and sign of inflammation and adhesions. Do the ovaries look normal and active or is there the shiny sclerocystic appearance of polycystic ovary disease? The pelvic organs should be freely mobile.
  • Another operator injects a blue dye into the cervix and he sees if there is free spill of dye from both fallopian tubes.
  • Through the lower abdominal portal it is possible to introduce scissors or diathermy to cut any minor adhesions that may be found.
  In a study of 256 infertile women who underwent tubal patency tests by laparoscopy and dye, the tubes were classified as normal, patent with macroscopic tubal adhesions, patent with one tortuosity, and patent with multiple tortuosities. Only in the last group did the procedure seem to have any effect on outcome with 66% pregnant within a year and 81% pregnant within 2 years.⁶
• Post coital tests: NICE recommend that the test has no predictive value and so should not be offered.

See Subfertility treatment article.

General care

• The couple need support and reassurance. It can be a very difficult time for them, especially if there is pressure from parents or in-laws, that may be more prominent in some cultures, but can occur in all.
• Ovulation predictor kits should be discouraged. Not only do they appear to be ineffective, but making love should be a spontaneous and amorous act, not dictated by a calendar or a kit.
• Pregnancy probably will occur even without intervention but they must not feel neglected or that nothing can be done. There are many stories of couples who conceive after giving up hope.
• There can also be considerable feeling of guilt or lack of worth.
  • Perhaps she should not have deferred the family to further her career.
  • Perhaps some injudicious act in their youth has cost their fertility.
  • There may be guilt about a previous TOP.
  • Others can have babies, why can't they?

By now it is possible to assess:

• If the man appears to be making sperm of satisfactory quality
• If the woman is ovulating
• If the fallopian tubes are patent

Anovulatory subfertility

• Clomiphene: Clomiphene citrate (CC) is the best initial treatment for the majority of women with anovulatory problems.⁷ Treatment should be limited to the minimum effective dose (50-100 mg for first 5 days of the cycle) and to no more than six ovulatory cycles. Failure to conceive after successful CC-induced ovulation is indication for further evaluation to exclude other contributing causes of infertility. The principle side-effect of CC is multiple pregnancy, which occurs in <10%.
• Surgical therapy with laparoscopic ovarian 'drilling' (LOD): This may avoid or reduce the need for gonadotrophins, or improve their usefulness. The procedure can be done on an outpatient basis with less trauma and fewer postoperative adhesions than with traditional surgical approaches e.g. wedge resection.
  A Cochrane review found no evidence of a difference in the live birth rate and miscarriage rate in women with clomiphene-resistant PCOS undergoing LOD compared to gonadotrophin treatment.⁸ There was a reduction in multiple pregnancy rates for women having LOD. However, there are concerns about long-term effects of LOD on ovarian function.

The record on subfertility treatments and the publications from NICE, listed under the Internet section at the end give greater detail of what is available and the chance of success.

• Despite the advances in the management of infertility there are still a significant number of couples who are not able to have children of their own for reasons known or unknown.
• If they are still eager for a family they may wish to consider adoption.
• Babies for adoption are far less plentiful than once they were. This is partly due to the increased rate of termination of pregnancy and partly due to the reduced likelihood of even young and unsupported mothers surrendering their babies for adoption.
• Hence potential adoptive parents are more likely to be offered an older child who has possibly been through traumas that have resulted in behavioural disorders.
• Furthermore, before being approved for adoption they will have to submit to substantial checks of their suitability whilst those who conceive their own children have no checks at all.
• They should be discouraged from looking abroad to adopt children from Eastern Europe of South-East Asia as the whole issue is fraught with enormous difficulties.