Clinical Review - Subfertility in women

Contributed by Mr David Walker, consultant obstetrician and gynaecologist at the Royal United Hospital, Bath.

Section 1: Epidemiology and aetiology

Infertility is defined as failure to conceive after regular unprotected sexual intercourse for two years, in the absence of known reproductive pathology. One in seven couples will have fertility problems.1 With referral rates of 3.2 in 1,000 females between the ages of 20 and 44, fertility is not an uncommon problem in primary care.

Management
An understanding of the aetiology and management of this condition will help GPs make timely and appropriate referrals and support patients through what can often be a long and painful journey.

Although the prevalence of infertility is not increasing, more women now seek help. The overwhelming factor that has affected fertility in the last decade is the increasing age at which women plan their first pregnancy. This has consequences for clinical practice, as the number of couples with an absolute factor stopping conception - the infertile - is decreasing, in favour of the subfertile couple, who with time often have a reasonable chance of spontaneous conception.

Fertility: rapide decline after 40

Reduction in male fertility
Concerns about the apparent reduction in male fertility and increased knowledge and expectation of treatments (managing sometimes unrealistic expectations can be a major challenge all clinicians will face) contribute to the increased prevalence.

Often, simple reassurance and time is required. Knowledge of cumulative conception rates is useful: 84 per cent of couples will conceive naturally after 12 months, 92 per cent after 24 months.

These figures reduce to 60 and 85 per cent in women aged 35-9. Fertility declines rapidly after the age of 40, with fertility clinics having little to offer, apart from oocyte donation, in women asking for help over the age of 44.

Investigations should be offered for couples who have not conceived after one year of unprotected sexual intercourse but earlier investigations are indicated in couples with a history of predisposing factors; where the woman is >35 years old; people with HIV, hepatitis B or C; or in patients who have had prior treatment for cancer.

Causes of subfertility
Male factor30%
Ovulatory problems25%
Tubal factor20%
Unexplained25%
Endometriosis5%
Sexual dysfunction5%
Cervical problems (mucus)3%
Uterine anomalies<1%

Section 2: Diagnosis

Prior to investigation, there should be a general discussion about lifestyle advice. There is conflicting advice about the amount of alcohol women trying to conceive should drink.

NICE recommends no more than one or two units per week, whereas the DoH recommends no alcohol. After months or years of trying to conceive, I suggest that limited alcohol can be very healthy and can help relieve some of the stress couples experience.

Smoking should be actively discouraged, and smoking cessation programmes offered. Most PCTs will refuse NHS funding for assisted conception to couples who smoke.

The optimal BMI is between 19 and 29. Reducing weight improves pregnancy outcomes and reduces pregnancy complications. Optimal weight reduces risk of miscarriage, hypertension, pulmonary embolus and diabetes mellitus.2

Pre-conceptual advice regarding folate supplements, rubella susceptibility and cervical screening should be discussed.

Sexual activity should be discussed; the optimal frequency of sexual intercourse is every two to three days throughout the cycle, not concentrating solely on fertile times. Raising this subject can prompt couples to mention sexual difficulties they may be having. The stress of trying to conceive commonly results in erectile problems or premature ejaculation.

History and examination
Clinical history and examination may highlight possible causes of subfertility. Frequency and regularity of menstrual cycles may suggest a possible ovulatory problem.

The presence of acne and hirsutism would suggest a likely diagnosis of polycystic ovarian syndrome (PCOS) - the commonest cause of anovulation. Relevant investigations are a menstrual FSH and LH and serum progesterone taken seven days before menses. Measurement of sex hormone binding globulin, testosterone and insulin levels do not contribute to the management.

Painful periods accompanied by deep dyspareunia may suggest endometriosis. Examination may reveal thickening of the uterosacral ligaments and a tender, fixed retroverted uterus.

A previous history of sexually transmitted diseases suggests a tubal factor. Some 10-30 per cent of women will have significant tubal disease after a single episode of proven pelvic inflammatory disease (PID), rising to 50-90 per cent after three episodes.3

Chlamydia is the commonest pathogen resulting in PID. Most women, however, are usually completely unaware of any history of chlamydia and their first awareness of possible disease is during screening for subfertility. Screening for chlamydia antibodies is recommended. A titre of >512 suggests tubal disease and both partners should receive a 1g dose of azithromycin.

Investigations
All patients attending the clinic at Bath receive a baseline vaginal ultrasound scan. This non-invasive investigation is a useful screening tool.

Ovarian pathologies include polycystic ovaries and ovarian endometriomas.

In the older woman, an antral follicle count can be used in conjunction with a menstrual FSH to predict ovarian reserve. Hydrosalpinges can be clearly seen - removal of these is recommended prior to an IVF cycle because of the potential adverse effects of tubal fluid on the developing embryo.

Uterine anomalies will also be seen - fibroids, uterine septae and polyps may be contributing to the subfertility.

A vaginal scan may also raise the possibility of a psychosexual problem if insertion of the vaginal probe causes significant distress.

Seminal fluid analysis (SFA) is mandatory prior to any testing for tubal occlusion. When interpreting the results, check volume (>2ml), count (>20 million/ml), motility (>60 per cent) and morphology (varies from lab to lab - check reference range).

Measurement of FSH and testosterone level is useful in identifying an underlying cause. In borderline abnormalities, repeat semen analysis in three months, and I recommend a course of vitamin C (50mg) and zinc (15mg) to aid spermatogenesis.

Tests for tubal occlusion will depend on the results of SFA. A hysterosalingogram is recommended if there is no history of co-morbidity, being simple, safe and cost-effective. If there is co-morbidity, a laparoscopy is the investigation of choice.

Summary of investigations
Chlamydia serologyTreat both partners if titre >512
Rubella statusMMR vaccine and retest if not immune
Menstrual FSHEarly referral if >9.5
Mid luteal progesteroneRepeat and refer if sub-optimal or consider clomifene
Semen analysisCheck local lab reference ranges and refer if abnormal
Vaginal ultrasound scanRefer if pathology
TSH and prolactinOnly if symptomatic

Section 3: Management

Management will depend on the results of initial investigations, the age of the woman and their wishes. Managing expectations can be one of the most difficult tasks.

With normal investigations and age, assisted conception should be deferred for up to three years because of the reasonable chance of natural conception during this time.

Ovulatory problems
Ovulatory problems are often the simplest to manage. With shared-care protocols, treatment may be commenced in primary care with clomifene. Women should be warned about the risks of multiple pregnancy (up to 10 per cent twin pregnancies) and the common vasomotor side-effects.

Treatment should be monitored with serum progesterone levels as the minimum and ideally with follicle tracking on day 12 of the first cycle.

Metformin was thought to be the wonder drug in anovulatory women and would replace clomifene. The response is very variable and now I recommend its use only in obese anovulatory women, some of whom lose weight, which may in itself help obese women to ovulate. Due to GI side-effects, I start at 500mg daily for one week and increase at weekly intervals up to 1,500mg daily. Women should be advised that it is not licensed for this indication and that they should discontinue once pregnant (although there is good evidence suggesting that metformin may reduce the higher rates of miscarriage in women with PCOS).

In women who fail to respond, ovarian drilling or ovulation induction with gonadotrophins is offered in secondary care. Women who have hypothalamic pituitary failure (low FSH often secondary to weight loss) will not respond to clomifene and need referral for gonadotrophin therapy.

Ovarian drilling is an option after failure to respond to clomifene

Tubal disease
Management of tubal disease will depend on the age of the woman, the duration of subfertility and the severity of the disease. Proximal obstruction may be treated with selective salpingography. Mild-to-moderate distal disease may be helped with tubal surgery. The decision for surgery will be dependent on the local skills available and the local NHS contract to fund such surgery.

Hydrosalpinges should be removed prior to IVF; studies have demonstrated higher implantation rates after treatment.

Male factor infertility
Mild male factor infertility may be managed with lifestyle changes, intra-uterine insemination or IVF. The treatment of severe male factor infertility changed with the introduction of intra-cytoplasmic sperm injection (ICSI) with IVF in 1992. Used for all major forms of sperm dysfunction and after previous poor fertilisation rates, ICSI is also used in men with obstructive azoospermia. Sperm may be retrieved directly from the epididymis (PESA) or from the testis (TESE) under local anaesthesia or conscious sedation.

Unexplained subfertility
The management of unexplained subfertility will again depend on the
age of the woman, the duration of subfertility and their wishes. Treatments include watchful waiting, a six-month trial of clomifene, stimulated intra-uterine insemination or IVF.

IVF has the advantage of being a diagnostic as well as a therapeutic procedure.

Section 4: Prognosis

Obesity, advancing maternal age and smoking are the three main factors affecting the chances of successful treatment. While there have been some great advances in the field of reproductive medicine over the past 30 years, lifestyle modification is becoming important.

Success rates
The success rates of IVF/ICSI with maternal age are shown in the figure.

Units should not offer treatment to women over the age of 44 unless donor oocytes are acceptable. However, they should offer supportive advice and counselling to such patients, treating them sensitively and sympathetically and providing them with evidence on which the decision not to treat is based.

The option of oocyte cryopreservation has been offered as a possible solution for women wishing to delay starting a family. Technically possible, the success of treatment remains low and costs high.

The demand for oocyte donation is increasing and supply in the UK is very limited, forcing women to seek treatment overseas where supply of donor oocytes is higher and donation remains anonymous.

For too long, success of treatment has been measured solely in terms of live birth rates. 25-30 per cent of pregnancies after assisted conception are multiple. The rising numbers of multiple pregnancies and resultant increased numbers of premature babies has put an increased burden on neonatal intensive care facilities across the UK.

The HFEA stipulate the maximum number of embryos replaced is two in women under the age of 40, with strong recommendations that a single embryo be replaced.

With improved identification of optimal embryos and prolonged in vitro culture, pregnancy rates from a single embryo transfer have not fallen, with the benefit of a massive reduction in rates of multiple pregnancies.

Conclusion
GPs are in a prime position to support and direct their patients in the management of their fertility problems.

They should be aware of investigations they can undertake in primary care and of the treatment options available.

Their local fertility clinic should provide an investigation pro forma for them to follow.

RESOURCES
References
1. NICE Clinical Guidelines on Fertility 2004.

2. Yu C, Teoh T, Robinson S. Obesity in pregnancy. BJOG 2006; 113: 1,117-25.

3. Svensson L, Mardh P A, Westrom L. Infertility after acute salpingitis with special reference to Chlamydia trachomatis. Fertil Steril 1983; 40: 322-9.

4. Human Fertilisation and Embryology Authority. Contains details of treatments available, all UK Licensed clinics and pregnancy rates. www.hfea.gov.uk

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