Royal College of Obstetrics and Gynaecologists. Clinical Guideline no 4. The management of infertility in tertiary care


Introduction

Guidelines are ‘systematically developed statements to assist decisions about appropriate care for specific clinical circumstances’[1]. Guidelines have been shown to improve the process of care and improve outcomes for patients [2]. The Royal College of Obstetrics and Gynaecologists (RCOG) have produced two previous guidelines in this series, both of which were published in an abridged form in the BJU Int[3]. The purpose of the present guideline summary is to provide recommendations to help clinicians and other staff in the tertiary care setting in managing infertile couples, particularly those undergoing in vitro fertilization (IVF) and donor insemination.

Infertility affects one in seven couples in the UK [4,5]; it appears there has been no major change in prevalence but many more couples are seeking help than previously [5]. A typical District Health Authority may see ≈ 230 new consultant referrals each year [6]. There is a wide variation in management among centres [7–9] and patient dissatisfaction with clinical services has been highlighted [10,11]. Infertility can cause considerable psychological distress to couples [12,13]. The United Nations states that reproductive health is ‘a state of complete physical, mental and social well-being and not merely the absence of disease or infirmity in all matters relating to the reproductive system and its functions and processes’[14]. Infertility should therefore be considered to be a disease process worthy of investigation and treatment

This guideline represents best medical practice based on the available evidence, but it is not intended to be a fully comprehensive textbook on infertility. The methodology used in developing the guideline is made explicit and the recommendations are graded according to the strength of evidence on which they are based. Areas lacking evidence are highlighted and may form the basis of future research. Guidelines are not intended to restrict clinical freedom but practitioners are expected to use the recommendations as a basis for their practice. Local resources, and the circumstances and preferences of the individual patients, will need to be considered.

The Guideline includes 42 recommendations, each specifically concerned with the provision of assisted reproduction or of donor gametes. The Guideline assumes that the initial investigation and management of the infertile couple has been carried out as described in the first Guideline and that the management in secondary care has followed the recommendation laid out in the second Guideline [3]. Many of the issues covered in the first two Guidelines are relevant to the provision of care in the tertiary setting, in particular; (a) the principles of full patient participation and decision making; (b) access to appropriate facilities and trained staff; and (c) the need for close monitoring to avoid unnecessary complications, including multiple pregnancy. As in previous Guidelines the importance of counselling is emphasized, including several situations not covered by the human fertilization and embryology act.

The Guideline addresses the treatment of male infertility in two respects; first, recognizing the importance of the provision of intracytoplasmic sperm injection (ICSI); and second, the provision of donor insemination treatment. However, it is important to recognize that a rational discussion about the relevant merits of these two treatments can only take place in the context of the equal availability of both options. For ICSI, the current effectiveness is accepted but there is a need for appropriate genetic advice and further information from follow-up studies. Donor insemination can be a highly effective treatment but again the need to avoid the risk of multiple pregnancy if gonadotrophin drugs are used is underlined.

Men undergoing medical treatment likely to make them infertile should have access to semen cryostorage facilities and if this is to be effective, local protocols will have to be in place to deal with the situation quickly, effectively and sensitively.

Local protocols and audit

It is anticipated that this National Guideline will be used as the basis for developing local protocols which will take into account local service provision, and the needs and preferences of the local population. Such local adaptation should take place in the similar multidisciplinary group with collaboration between all interested parties likely to be affected by the Guideline. It is essential that Commissioners of Health Care as well as GPs and specialists take part in such a process. Furthermore, the individual recommendations can be translated into standards for use in the local audit of infertility management and practitioners are encouraged in this respect.

Most of the procedures considered in this Guideline are already embedded in clinical practice and where new ethical issues arise these are addressed in the text of the full Guideline.

Forming the recommendations

Recommendations were derived using informal consensus methods and where there were areas with no evidence consensus was again used. The recommendations were then graded according to the level of evidence on which they were based. The grading used was formed by the Clinical Outcomes Group (COG) and recommended by the NHS Executive [15].

  • Grade A: based on randomized controlled trials.

  • Grade B: based on other robust experimental or observational studies.

  • Grade C: based on more limited evidence but the advice relied on expert opinion and was endorsed by respected authorities.

The strength of evidence is shown after each recommendation.

Recommendations

Counselling and support

 1. All infertility clinics in the UK that are licensed by the Human Fertilization and Embryology Authority (HFEA) to provide licensed treatment services (in vitro fertilization or treatment using donated gametes, or the use or storage of embryos or the donation and storage of gametes), must provide the opportunity for counselling before consent to treatment is given. [C]

 2. Infertility and its investigation and treatment can cause significant psychological stress. Counselling decreases stress and may also alter the outcome of treatment though this is not yet proven. [B] Counselling should be offered to all patients. [C]

 3. Counselling should be made available throughout all stages of infertility investigations and treatment, and after the treatment process is complete. Counselling will help some people come to terms with ending treatment and adjusting to childlessness. Where a pregnancy occurs as a result of treatment, the offer of further counselling should also be considered. [C]

 4. Whenever any genetic tests are proposed, written and oral information should be provided and counselling should be offered by an appropriately trained person [C].

In vitro fertilization

 5. IVF is an effective treatment whatever the cause of infertility, providing there is a reasonable likelihood that embryos can be created in vitro and then placed in the uterus with the expectation that implantation will occur. [B]. In each individual case the decision to recommend IVF treatment should be based on: (a) the likelihood that a pregnancy will occur without treatment; (b) the possibility that a less invasive form of treatment might be effective; and (c) the likely outcome of IVF treatment. [B]

 6. Before considering IVF treatment for unexplained infertility, consideration should be given to the likelihood of treatment-independent pregnancy. The likelihood of such a pregnancy will depend mainly on the woman's age, the duration of infertility and the previous pregnancy history. [B]

 7. In assessing the likelihood of a birth after IVF treatment, it is important to consider the following factors, all of which can significantly affect the outcome: female age, duration of infertility, previous pregnancy history and number of previous treatment cycles. [B]

 8. Couples should be advised clearly of their chance of a live birth after IVF treatment. This is particularly important in women aged > 40 years, where success rates are considerably reduced and there is an increased risk of miscarriage. [B]

 9. A reduction in the number of multiple pregnancies resulting from assisted reproduction is of national importance as well as having major implications for the family. Every attempt should be made to avoid multiple births, and particularly triplets, after IVF treatment. [C]

10. A maximum of two embryos should be transferred in women aged leqslant R: less-than-or-eq, slant 40 years undergoing assisted reproduction. This will reduce the multiple pregnancy rate without diminishing the expected chance of a birth. Even for women aged over 40 years, there is a significant chance of a triplet pregnancy if three embryos are transferred. [B]

11. Natural-cycle or clomiphene-stimulated IVF have poor success rates per cycle of treatment. However, they remain a treatment option for those couples who wish to minimize the risk of ovarian hyperstimulation. [C]

12. In IVF treatment, the use of GnRH agonists in addition to gonadotrophin stimulation results in higher pregnancy rates than the use of gonadotrophins alone. Therefore, the routine use of GnRH agonists in IVF stimulation protocols is recommended. [A]

13. (a) There is a small but significantly greater pregnancy rate after using urinary derived high-purity gonadotrophin preparations than with human menopausal gonadotrophin preparations. [A]. (b) Recombinant FSH produces significantly more oocytes in an IVF cycle than urinary derived high-purity gonadotrophin preparations, but pregnancy rates in fresh embryo replacement cycles are similar. [A]. (c) If fresh and frozen embryo replacements are considered, the use of recombinant FSH produces a higher pregnancy rate than urinary derived high-purity gonadotrophin preparations. [A]. (d) Because of the small differences in outcome, additional factors should be considered when choosing a gonadotrophin regimen, including patient acceptability, costs and drug availability. [C]

14. Local protocols for preventing and managing ovarian hyperstimulation syndrome should be available in all units carrying out ovulation induction and assisted conception, as well as gynaecology units to which emergencies are referred. [C]

15. Oocytes should be retrieved transvaginally under conscious sedation, which is a safe and acceptable method of providing analgesia. [B]

16. Screening for chlamydial antigen before uterine instrumentation should be considered if patients are at risk. In general, this will mean testing women aged <25 years for the presence of asymptomatic chlamydial infections. [B]

17. (a) As there is no difference in the expected pregnancy rate, cleavage stage embryos can be replaced either on day 2 or day 3. [B]. (b) Replacement of embryos into a uterine cavity with an endometrium <5 mm thick is unlikely to result in a pregnancy. [B]

18. Variations in embryo transfer (ET) technique can affect outcome. Placement of embryos in the mid-cavity of the uterus preceded by a trial with a dummy catheter is most likely to result in a pregnancy. [A]. Tubal ET and bed rest after ET have not been shown to improve outcome. [A]

19. In IVF cycles where GnRH agonists are used for pituitary down-regulation, luteal-phase support results in higher pregnancy rates. [A]. The choice of luteal-phase support is between hCG and progesterone, and while hCG may result in higher pregnancy rates, there is an increased likelihood of ovarian hyperstimulation syndrome, and for this reason the routine use of hCG is not recommended. [A]

20. Transport IVF/ICSI results in fertilization, implantation and pregnancy rates that are similar to those achieved with conventional one-centre treatment. [A]

Intracytoplasmic sperm injection

21. The recognized indications for treatment by IVF and ICSI include: (a) severe deficits in semen quality in the male partner; (b) obstructive azoospermia; and (c) unobstructive azoospermia. In addition, treatment by IVF/ICSI should be considered for couples in whom a previous IVF cycle has resulted in failed or very poor fertilization. [B]

22. Before considering treatment by ICSI, couples should undergo appropriate investigations, both to establish a diagnosis and to enable informed discussion about the implications of treatment. [C]

23. Before treatment by IVF and ICSI, particular consideration should be given to the relevant genetic issues. [B]. (a) Where a specific gene defect associated with male infertility is known or suspected (e.g. congenital bilateral absence of the vas deferens, CBAVD), appropriate genetic counselling and testing should be offered. [B]. (c) Where the indication for ICSI is a severe deficit of semen quality or unobstructive azoospermia, the male partner's karyotype should be established. [B]. (c) Testing for Y chromosome microdeletions should not be regarded as a routine investigation before ICSI. However, it is likely that a significant proportion of male infertility results from abnormalities of genes on the Y chromosome involved in the regulation of spermatogenesis and couples should be informed of this. [C]

24. Couples contemplating ICSI should be given information about the current understanding of the health of children born after ICSI. [C]. In general, the available data are broadly reassuring for the short-term health of ICSI offspring, but no information is yet available on longer term health. [B]

25. A long-term longitudinal follow-up of children born after ICSI is important and ideally should be coordinated on a national basis. [C]

26. Ejaculatory failure may be managed by a variety of techniques ranging from drug therapy to surgical recovery of sperm from the vas deferens. [B]. In ejaculatory failure it is necessary to diagnose the cause and have a range of treatment options available. It may be possible to restore fertility with no need for invasive methods of sperm retrieval or the use of assisted conception techniques. [C]

27. Sperm can be recovered surgically before ICSI using several different techniques, depending on the pathology and wishes of the patient. In all cases, facilities for cryopreservation of spermatozoa should be available. [C]

Donor insemination

28. Recognized indications for donor insemination include: (a) severe deficits in semen quality in the male partner; (b) obstructive azoospermia; (c) unobstructive azoospermia; (d) genetic or infectious disease in the male partner; and (e) severe rhesus isoimmunization. [B]

29. It is important that any discussion with a couple about the relative merits of ICSI and donor insemination takes place in a context which allows equal access to both treatment options. [C]

30. Units undertaking semen donor recruitment and the cryopreservation of spermatozoa for treatment purposes should follow the current guidelines issued by the British Andrology Society describing the selection and screening of donors. [C]

31. Before starting treatment by donor insemination it is important to confirm that the female partner is ovulating. If the female partner has a history suggestive of tubal damage, then the tubes should be assessed before treatment. In a woman with no risk history, the tubes should be assessed after six cycles of unsuccessful treatment. [C]

32. (a) Because of the risks of multiple pregnancy, a minimum of six cycles of insemination with no ovarian stimulation should be carried out in regularly ovulating women. [C]. (b) If the anticipated pregnancy rate for intracervical insemination is <6% per cycle, intrauterine insemination with or without ovarian stimulation should be considered. [A]

33. Although the measurement of urinary LH is widely used to time intracervical insemination, pregnancy rates are no better than with other methods of timing [A]. However, LH surge detection may be beneficial in terms of clinic organization and costs. [C]

34. After 12 unsuccessful cycles of donor insemination other treatment options should be considered. [C]

Oocyte donation

35. The use of donor oocytes is considered effective in treating the following conditions: (a) premature ovarian failure; (b) gonadal dysgenesis including Turner syndrome; (c) oophorectomy; (d) ovarian failure after chemotherapy or radiotherapy; and (e) certain cases of IVF treatment failure. Oocyte donation should also be considered in certain cases at high risk of transmitting a genetic disorder to the offspring. [B]

36. Oocyte donors should understand the potential risks of ovarian stimulation and oocyte collection. They should receive independent counselling about the implications of donation for both themselves and their genetic offspring. In addition, those considering participating in an egg-sharing scheme should be counselled about its particular implications. [C]

37. Oocyte donors should be screened for both infectious and genetic disease before donating. [B]

38. The use of donated oocytes to achieve pregnancy in women beyond the age of the natural menopause remains controversial. Before such treatment is offered, consideration must be given to the welfare of the potential offspring and the risks of pregnancy and labour in older women. [C]

Embryology and cryopreservation

39. Information about semen cryostorage should be made available to men undergoing medical treatment likely to make them infertile, as the effectiveness of this procedure is established [B]. Local protocols should exist to ensure that health professionals are aware of the value of semen cryostorage in these circumstances, so that they deal with the situation quickly and effectively. [C];

40. Cryopreservation of supernumerary embryos allows multiple embryo transfers from a single egg collection and improves the chances of a live birth [B]. Embryo cryopreservation should be discussed with all couples considering IVF treatment and should be offered if sufficient embryos of suitable quality for cryopreservation are available [C].

41. In women who have regular ovulatory cycles, the likelihood of a live birth after replacement of frozen/thawed embryos is similar whether natural or artificial replacement cycles are used [B].

42. Assisted hatching has not yet been shown to be an effective treatment [A]. Therefore, it should not be offered outside the context of a clinical trial [C].

The RCOG would appreciate being cited as the source of these Guidelines. A summary of the Guidelines is published on the RCOG Website (http://www.rcog.org.uk). Copies of the Full Guidelines can be obtained from: RCOG Book Shop, 27 Sussex Place, Regents Park, London NW14 4RG.(e-mail: bookshop@rcog.org.uk)

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