Causes of infertility^[1]

The main causes of infertility in the UK are:

• Unexplained infertility (no identified male or female cause) (25%)
• Ovulatory disorders (25%)
• Tubal damage (20%)
• Factors in the male causing infertility (30%)
• Uterine or peritoneal disorders (10%)

In about 40% of cases disorders are found in both the man and the woman. Uterine or endometrial factors, gamete or embryo defects, and pelvic conditions such as endometriosis may also play a role.^[2]

For further information on aetiology, prevalence and investigation see the separate articles Infertility - Male and Infertility - Female.

Disorders of the testis and spermatogenesis^[1] 

• Whilst a low sperm count is a poor prognostic feature, and the lower the count the worse the prognosis, it is not totally incompatible with fertility.
• Men should be informed that there is an association between elevated scrotal temperature and reduced semen quality, but that it is uncertain whether wearing loose-fitting underwear actually improves fertility.
• Where appropriate expertise is available, men with obstructive azoospermia should be offered surgical correction of epididymal blockage because it is likely to restore patency of the duct and improve fertility.
• Men should not be offered surgery for varicoceles as a form of fertility treatment because it does not improve pregnancy rates.
• Men with idiopathic semen abnormalities should not be offered anti-oestrogens, gonadotrophins, androgens, bromocriptine or kinin-enhancing drugs because they have not been shown to be effective.
• Men should be informed that the significance of antisperm antibodies is unclear and the effectiveness of systemic corticosteroids is uncertain.
• Men with leukocytes in their semen should not be offered antibiotic treatment unless there is an identified infection, as there is no evidence that this improves pregnancy rates.

Persistent azoospermia is incompatible with fertility. The couple may wish to consider donor sperm.

Disorders of the male genital tract

• Failure of adequate differentiation of the embryonic testis can cause failure of proper development of the spermatic ducts.
• Primary or secondary hypogonadism should be treated with testosterone substitution therapy. This has been shown to achieve fertility in men with hypogonadotrophic hypogonadism.
• In men with unilateral cryptorchidism, fertility is almost equal to that of men without cryptorchidism. However, bilateral cryptorchidism means the likelihood of achieving a pregnancy is significantly reduced.^[3] 
• Obstructive lesions of the seminal tract should be suspected in azoospermic or severely oligo-azoospermic patients with normal-sized testes and normal endocrine results. Results of reconstructive microsurgery depend on the cause and location of the obstruction and the expertise of the surgeon.

Assisted conception

Assisted conception broadly refers to procedures whereby treated or manipulated sperm are brought into proximity with oocytes. It includes:

• Intrauterine insemination (IUI) with partner or donor sperm (in natural or stimulated cycles)
• Gamete intrafallopian transfer (GIFT)
• In vitro fertilisation and embryo transfer (IVF-ET)
• Intracytoplasmic sperm injection (ICSI)

The Human Fertilisation and Embryology Authority (HFEA) has published data showing that there are wide variations in the success rates of IVF clinics.^[4] Success depends upon numerous factors, including the woman's age, BMI, previous pregnancy history and lifestyle factors. Around 25% of IVF treatments using a woman's own fresh eggs result in a live birth.

Intrauterine insemination (IUI)^[1] 

IUI involves the introduction of prepared sperm into the uterine cavity around the time of ovulation (spontaneous or induced).

IUI can be considered as a treatment option in the following groups:

• People who are unable to, or would find it very difficult to, have vaginal intercourse because of a clinically diagnosed physical disability or psychosexual problem, who are using partner or donor sperm.
• People with conditions that require specific consideration in relation to methods of conception (for example, after sperm washing where the man is HIV-positive).
• People in same-sex relationships.

People with unexplained infertility, mild endometriosis or 'mild male factor infertility', who are having regular unprotected sexual intercourse should no longer routinely be offered IUI, either with or without ovarian stimulation. They should be considered for IVF if they have not conceived after trying for two years.

Gamete intrafallopian transfer (GIFT)

There is insufficient evidence to recommend the use of GIFT or zygote intrafallopian transfer in preference to IVF in couples with unexplained fertility problems or male factor fertility problems.^[1]

In vitro fertilisation and embryo transfer (IVF-ET)^[5]

When IVF-ET is used:

• Women aged under 40 years should be offered three cycles.
• Those women who reach 40 years during treatment should not be offered further cycles.
• Women aged over 40 years should be offered one cycle of IVF as long as these women:
  • Have never had IVF in the past.
  • Have no evidence of low ovarian reserve.
  • Have had a discussion of the additional implications of IVF and pregnancy at this age.

When IVF is used and a top-quality blastocyst is available, a single embryo transfer is now recommended. Currently, double embryo transfer in IVF is the most commonly used strategy in the UK. The new National Institute for Health and Clinical Excellence (NICE) guidelines will change this and, in doing so, will maximise the chance of pregnancy while minimising the risk of a multiple pregnancy.

Intracytoplasmic sperm injection (ICSI)

In ICSI, a single sperm is injected directly into an oocyte. It should be considered for those with severe deficits in semen quality, obstructive azoospermia or those with non-obstructive azoospermia. In addition, treatment by ICSI should be considered for couples in whom a previous IVF treatment cycle has resulted in failed or very poor fertilisation.

Where the indication for ICSI is a severe deficit of semen quality or non-obstructive azoospermia, the man's karyotype should be established (after genetic counselling).

Ovulation disorder treatment^[1]

World Health Organization (WHO) Group I ovulation disorder is due to hypothalamic pituitary failure (hypothalamic amenorrhoea or hypogonadotrophic hypogonadism). These women should be advised that they can improve their chance of regular ovulation, conception and an uncomplicated pregnancy by increasing their body weight (for those with a BMI of <19) and/or moderating their exercise levels (if they undertake high levels of exercise). These women should be offered pulsatile administration of gonadotrophin-releasing hormone or gonadotrophins with luteinising hormone activity to induce ovulation.

WHO Group II ovulation disorder is due to hypothalamic-pituitary-ovarian dysfunction (predominately due to polycystic ovarian syndrome). Clomifene citrate (CC) - an anti-oestrogen - is an initial treatment for the majority of these. Metformin (or a combination of clomifene and metformin) can be also considered. However, those women with a BMI of >30 should be advised to lose weight before starting treatment.

Women who are known to be resistant to CC should consider one of the following second-line treatments, depending on clinical circumstances and the woman's preference:

• Laparoscopic ovarian drilling (by laser or by diathermy)^[6]
• Combined treatment with CC and metformin
• Gonadotrophins

WHO Group III ovulation disorder is due to ovarian failure - hypothalamic-pituitary failure (hypothalamic amenorrhoea or hypogonadotrophic hypogonadism). Women with ovulatory disorders due to hyperprolactinaemia should be offered treatment with dopamine agonists such as bromocriptine.

Complications

Many of the complications are related to multiple pregnancies. Elective single embryo transfer has been shown to be associated with reduced risks of preterm birth and low birth weight compared with double embryo transfer but higher risks of preterm birth compared with spontaneously conceived singletons.^[7]

The most serious complication is ovarian hyperstimulation syndrome (OHSS) which may occur when ovarian stimulation techniques are used.^[8] It usually presents with lower abdominal discomfort, nausea, vomiting, diarrhoea and abdominal distension. Signs of severe disease, indicating a need for hospital management, include:

• Presence of ascites
• Rapid weight gain
• Tachycardia
• Hypotension
• Oliguria
• U&E/other metabolic abnormalities

Its incidence may be reduced by careful tailoring of the pharmacological agents and embryo implantation techniques used. New strategies are being introduced to try to prevent OHSS from developing.^[9] However, a Cochrane systematic review found no convincing evidence for any particular strategy.^[10]

NICE recommends that women who are offered ovulation induction should be informed that:

• No direct association has been found between these treatments and invasive cancer.
• No association has been found in the short- to medium-term between these treatments and adverse outcomes (including cancer) in children born from ovulation induction.
• Information about long-term health outcomes in women and children is still awaited.

The use of ovulation induction or ovarian stimulation agents is kept at the lowest effective dose and duration of use.

Although the absolute risks of long-term adverse outcomes of IVF treatment, with or without ICSI, are low, a small increased risk of borderline ovarian tumours cannot be excluded.^[1]

General care

The couple needs 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. 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.

Couples who have fertility problems should be informed that they might find it helpful to contact a fertility support group. Counselling may be appropriate for some couples, as fertility problems can cause psychological stress.^[1]

Women intending to become pregnant should be informed that dietary supplementation with folic acid (0.4 mg a day) before conception and up to 12 weeks of gestation, reduces the risk of having a baby with neural tube defects. The dose should be 5 mg a day in those women who have previously had an infant with a neural tube defect or those receiving anti-epileptic medication or who have diabetes.

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.

Where conventional medicine offers no help, patients are often tempted by alternative therapies. However, what little evidence there is suggests that they are of no benefit and that, as they have not been properly tested, they may even be teratogenic.