Around one in seven couples in the UK is affected by infertility and a small proportion of these need treatment with assisted conception. The National Institute for Health and Care Excellence (NICE) guidelines currently do not have a definition for infertility, although previous versions defined it as failure to conceive despite regular unprotected sexual intercourse for two years. Current guidance recommends offering investigation after one year. Over 80% of couples should conceive within a year if the woman is aged under 40 and they are having regular unprotected sexual intercourse. Of those who do not conceive within a year, half will conceive within the next year (so 90% over two years).
Causes of infertility
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 be involved.
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. Couples often conceive whilst awaiting further investigation, as half of those who have not conceived within a year will do so during the second year. The stress of trying to conceive can adversely affect relationships, further contributing to fertility issues.
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.
- Folic acid: 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 in those receiving anti-epileptic medication or who have diabetes.
- Frequency of sexual intercourse: couples may be advised that regular intercourse every two to three days optimises the chances of conception occurring.
- Alcohol: in men, excessive consumption may affect semen quality but there is no evidence that drinking within recommended safe limits has an adverse effect. Women should be advised that when pregnant, drinking alcohol is not advised due to the potential risk to the developing fetus.
- Smoking: advise women that smoking can harm a developing baby; offer those who smoke support and referral to help them quit. Advise men that smoking affects semen quality (although it is not known if this adversely affects fertility) and discuss the benefits of quitting smoking to their general health and discuss risks of passive smoking to partner and potential baby.
- Weight: advise women that having a body mass index (BMI) ≥30 may be a cause of taking longer to conceive. Being overweight may reduce fertility in men also. Being underweight with a BMI <19 may also have an adverse effect on fertility.
- Alternative therapies: 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.
- Timed intercourse: there are insufficient data to draw conclusions about effectiveness of methods to predict ovulation so that intercourse can be concentrated in the right time of the cycle.Methods used include measuring basal temperature and urinary hormones, monitoring cervical mucus and using ultrasound scans. There may be a slight improvement in pregnancy rates but concerns remain about the side-effects of stress and the detrimental effect on relationships and sexual spontaneity.
Treatments for disorders of the male genital tract and spermatogenesis
Management of abnormal sperm counts
- 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.
- Persistent azoospermia is incompatible with fertility. The couple may wish to consider donor sperm.
- Treatments not recommended:
- 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.
Management of disorders of the male genital tract
- Men with hypogonadotrophic hypogonadism should be offered gonadotrophins as these have been shown to improve fertility.
- In men with cryptorchidism and azoospermia, orchidopexy may result in spermatozoa being present in the ejaculate.It is uncertain to what extent age at orchidopexy affects future fertility.
- 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.
- There are many causes of non-obstructive azoospermia. In some cases testicular biopsy and testicular sperm extraction may be indicated.
Ovulation disorder treatment
World Health Organization (WHO) Group I ovulation disorder
This 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
This is due to hypothalamic-pituitary-ovarian dysfunction, predominately due to polycystic ovary syndrome (PCOS). 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 using CC treatment should be monitored by ultrasound and should not have treatment for more than six months.
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).
- Combined treatment with CC and metformin.
WHO Group III ovulation disorder
This is due to ovarian failure or hypergonadotrophic hypogonadism.
Women with ovulatory disorders due to hyperprolactinaemia should be offered treatment with dopamine agonists such as bromocriptine.
Treatments for other female factors in infertility
A number of other treatments may be appropriate in certain cases. These include:
- Tubal and uterine surgery: for women with blockages or adhesions.
- Medical or surgical treatment of endometriosis. See the separate Endometriosis article for more detail.
- Ovarian hyperstimulation. Agents used are CC, anastrozole and letrozole. This is not advised in women with unexplained infertility.
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, widely known as IVF).
- Intracytoplasmic sperm injection (ICSI).
In certain cases donor sperm or eggs may be required for these procedures.
The Human Fertilisation and Embryology Authority (HFEA) has published data showing that there are variations in the success rates of fertility clinics. Success depends upon numerous factors, including the woman's age, BMI, previous pregnancy history and lifestyle factors, as well as differences between clinic treatment populations, etc.
Intrauterine insemination (IUI)
IUI involves the introduction of prepared sperm into the uterine cavity around the time of ovulation (spontaneous or induced).
NICE guidelines advise that unstimulated 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)
NICE guidelines state 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.
In vitro fertilisation (IVF)
Around 25% of IVF treatments result in a live birth according to HFEA statistics. Around two thirds of women treated are aged 37 or under and only 2% are aged over 45. The chances of success reduce with increasing age of the woman. There is a trend of increasing demand for IVF in same-sex female couples. Ovarian stimulation is advised prior to IVF with ultrasound monitoring of the ovarian response. Progesterone is used after embryo transfer for luteal phase support.
Access criteria for IVF:
- 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. This is to minimise the numbers and associated risks of a multiple pregnancy. HFEA has produced criteria for single/multiple embryo transfers and a strategy to reduce the numbers of multiple births. Reports show this has been effective, with numbers of multiple births declining.
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).
Conditions where donor insemination may be considered include:
- Azoospermia (obstructive or non-obstructive not amenable to treatment).
- Severe deficits in semen quality in couples who do not wish to undergo ICSI.
- Where there is a high risk of transmitting a genetic disorder to the offspring.
- Where there is a high risk of transmitting infectious disease to the offspring or woman from the man.
- Severe rhesus isoimmunisation.
Conditions where oocyte donation may sometimes be appropriate include:
- Premature ovarian failure.
- Gonadal dysgenesis (eg, Turner syndrome).
- Bilateral oophorectomy.
- Ovarian failure following chemotherapy or radiotherapy.
- Some cases of IVF treatment failure.
- Some cases where there is a high risk of transmitting a genetic disorder to the offspring.
Guidelines exist for the screening of sperm and egg (and embryo) donations.
Complications of assisted conception
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.
The most serious complication is ovarian hyperstimulation syndrome (OHSS) which may occur when ovarian stimulation techniques are used.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.
- 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.Cochrane systematic reviews found the use of cabergoline may be of benefit but found no convincing evidence for "coasting" (the term used for stopping the gonadotrophin stimulation and continuing the agonist suppression until oestrogen levels decline to acceptable values before proceeding to egg collection).[13, 14]
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.
Further reading and references
Santos EP, Lopez-Costa S, Chenlo P, et al; Impact of spontaneous smoking cessation on sperm quality: case report. Andrologia. 2011 Dec43(6):431-5. doi: 10.1111/j.1439-0272.2010.01089.x. Epub
Maggi M, Buvat J, Corona G, et al; Hormonal causes of male sexual dysfunctions and their management (hyperprolactinemia, thyroid disorders, GH disorders, and DHEA). J Sex Med. 2012 Apr 23. doi: 10.1111/j.1743-6109.2012.02735.x.
Fertility - Assessment and treatment for people with fertility problems; NICE Guidance (February 2013, updated Aug 2016)
Manders M, McLindon L, Schulze B, et al; Timed intercourse for couples trying to conceive. Cochrane Database Syst Rev. 2015 Mar 173:CD011345. doi: 10.1002/14651858.CD011345.pub2.
Guidelines on Male Infertility; European Association of Urology (2015)
Farquhar C, Brown J, Marjoribanks J; Laparoscopic drilling by diathermy or laser for ovulation induction in anovulatory polycystic ovary syndrome. Cochrane Database Syst Rev. 2012 Jun 136:CD001122. doi: 10.1002/14651858.CD001122.pub4.
Understand fertility clinic success rates; Human Fertilisation and Embryology Authority (HFEA)
Fields E, Chard J, James D, et al; Fertility (update): summary of NICE guidance. BMJ. 2013 Feb 20346:f650. doi: 10.1136/bmj.f650.
Fertility treatment in 2013 - trends and figures; Human Fertilisation and Embryology Authority (HFEA)
Limits on egg and embryo transfer; Human Fertilisation and Embryology Authority (HFEA)
Tomlinson M, Pacey A, Morroll D, et al; UK guidelines for the medical and laboratory screening of sperm, egg and embryo donors (2008). Hum Fertil (Camb). 2008 Dec11(4):201-10. doi: 10.1080/14647270802563816.s
Grady R, Alavi N, Vale R, et al; Elective single embryo transfer and perinatal outcomes: a systematic review and meta-analysis. Fertil Steril. 2012 Feb97(2):324-31. doi: 10.1016/j.fertnstert.2011.11.033. Epub 2011 Dec 15.
Fiedler K, Ezcurra D; Predicting and preventing ovarian hyperstimulation syndrome (OHSS): the need for individualized not standardized treatment. Reprod Biol Endocrinol. 2012 Apr 2410:32. doi: 10.1186/1477-7827-10-32.
Marzal A, Holzer H, Tulandi T; Future developments to minimize ART risks. Semin Reprod Med. 2012 Apr30(2):152-60. doi: 10.1055/s-0032-1307423. Epub 2012 Apr 27.
Tang H, Hunter T, Hu Y, et al; Cabergoline for preventing ovarian hyperstimulation syndrome. Cochrane Database Syst Rev. 2012 Feb 152:CD008605. doi: 10.1002/14651858.CD008605.pub2.
D'Angelo A, Brown J, Amso NN; Coasting (withholding gonadotrophins) for preventing ovarian hyperstimulation syndrome. Cochrane Database Syst Rev. 2011 Jun 15(6):CD002811. doi: 10.1002/14651858.CD002811.pub3.
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