Subfertility Treatments

One in six couples in the UK is affected by infertility and a small proportion of these need treatment with assisted conception.

Peak human fertility (the chance of pregnancy per menstrual cycle in the most fertile couples) is no higher than 33%, so it is unrealistic to expect a higher chance of pregnancy than this from any fertility treatment.¹ However prediction models for spontaneous pregnancy have been developed, which can select subfertile couples that have good prospects who can be expectantly managed.²

Assisted conception broadly refers to procedures whereby treated or manipulated sperm is 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) recently published data showing that there are wide variations in the success rates of in vitro fertilisation clinics.⁴ Some clinics are achieving a success rate as high as 46%, while the rate at others is as low as 10%. The data also show that, on the whole, success (i.e. live birth) rates for IVF are gradually improving.

IUI involves the introduction of prepared sperm into the uterine cavity around the time of ovulation (spontaneous or induced). This technique is used for couples with:

• Low semen volume
• Poor sperm parameters
• Defects of sperm-cervical mucus interaction
• Unexplained infertility

Donor insemination is also used to treat couples where the male partner is azoospermic. It may be used to help couples where the man has a transmissible genetic abnormality (providing his partner suffers no genetic problems).

GIFT involves recovery of oocytes (in stimulated or natural cycles) from the ovaries. They are then mixed with spermatozoa and transferred into one or both fallopian tubes. This technique is usually used for couples with:

• Anovulatory infertility
• Endometriosis
• Unexplained infertility
• Defects of sperm-cervical mucus interaction
• Female immunologic infertility
• Multifactorial infertility

IVF-ET involves use of exogenous gonadotrophins to induce multiple ovarian follicular development. Multiple oocytes are then recovered from the ovaries and in vitro insemination with partner's sperm conducted. Subsequently, some of the fertilised oocytes (embryos) are transferred into the uterine cavity.
The HFEA restricts the number of embryos which may be transferred to 2 for women aged <40, and to 3 for women aged >40.⁵This technique may be performed in spontaneous cycles or following stimulation with clomifene. This technique is usually used for couples with:

• Tubal infertility
• Anovulatory infertility
• Male-factor infertility
• Defects of sperm-cervical mucus interaction
• Endometriosis
• Female immunological and multifactorial infertility
• Unexplained infertility

Factors adversely affecting treatment outcome include:

• Advancing age of the woman
• Prolonged infertility
• The presence of subtle male factors
• High basal levels of follicle-stimulating hormone (FSH) and high body mass index (BMI) in the woman

ICSI is similar to IVF-ET, differing only in the method of insemination.
With ICSI, a single sperm is injected directly into an oocyte. This has revolutionised the treatment of couples with male-factor infertility, as the procedure can be carried out when the man has severe oligospermia.
Fertilisation rates of 70% have been achieved with ICSI.
This technique is usually used for:

• Men with abnormal sperm parameters (count, motility, morphology and antisperm antibodies)
• Couples who fail to conceive with conventional IVF-ET
• Couples where male is HIV-positive but partner is not. Success/complication rates are similar to general population undergoing ICSI. The technique appears to be successful in preventing HIV transmission to partner and newborn.⁶

As this procedure bypasses the physiological stages of fertilisation, concern has been raised about the possible consequences, especially when immotile or morphologically/genetically abnormal sperm are used.

Overall, more than one million children in the world have been conceived through IVF since 1978. In England and Wales, about 23,000 women were treated and about 8,000 babies were born as a result of IVF and/or ICSI in 2000-2001 (about 2,500 of these babies were born as a result of ICSI).⁷

• There is mixed evidence of increased incidence of low birth-weight, cerebral palsy and major birth defects with all forms of assisted reproduction, including ICSI.^8,7 The majority of studies on ICSI and IVF offspring have not shown significant differences between IVF and ICSI in terms of congenital abnormalities; however, compared to naturally-conceived offspring, an increased risk is seen. This risk can be attributed mainly to factors such as maternal age, potential for abnormal parental karyotypes and poor sperm quality.⁹
• By far the greatest risk to the health of babies born by assisted reproduction is due to iatrogenic multiple pregnancy; this risk has been falling as techniques to avoid this improve.
• It may be many years before powerful enough studies elucidate if there is an increased risk of transmission of rare genetic defects with ICSI.¹⁰
• The factors that affect the success rates of ICSI are becoming clearer. Where our knowledge is incomplete, it is important to be able to counsel couples appropriately about what we do and don't know about the safety and success rates of ICSI.¹¹

Clomifene citrate (CC) - an anti-oestrogen, is the best initial treatment for the majority of women with anovulatory problems.⁷ Tamoxifen is an alternative. 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%.

Women who fail to ovulate with anti-oestrogens can be offered treatment with gonadotrophins. Human menopausal gonadotrophin, urinary FSH and recombinant FSH are equally effective in achieving pregnancy, and consideration should be given to minimising cost when prescribing.

Gonadotrophin-releasing hormone (GnRH) analogues - GnRH agonists - are most often used in conjunction with gonadotrophins to achieve pituitary down-regulation and facilitate cycle control in ovarian stimulation during IVF treatment.

Surgical therapy with laparoscopic ovarian 'drilling' (LOD) 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 post-operative 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 clomifene-resistant polycystic ovarian syndrome (PCOS) undergoing LOD compared to gonadotrophin treatment.¹² 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.

There is evidence of increased rates of obstetric complications in women who require assisted reproduction.¹³
The most important complication which needs to be recognised when using ovarian stimulation techniques is the ovarian hyperstimulation syndrome. ¹⁴ 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.¹⁵ However, a Cochrane systematic review found no convincing evidence for any particular strategy.¹⁶ It appears to be closely related to the pre-treatment presence of PCOS,¹⁷ and use of ovarian stimulation should be considered carefully in patients with this condition.