Subfertility – when to investigate and what to do

Infertility affects up to one in six couples in the UK. If a woman is under 40 years old there is an 80% chance she will conceive within a year, and half of the remaining 20% will conceive if they continue trying for a further year. A woman of reproductive age who has not conceived after one year of unprotected vaginal sexual intercourse, in the absence of any known cause of infertility, should be offered further clinical assessment and investigation along with her partner.

Most couples with concerns about their fertility will initially consult their GP. Although they may be registered with different practices, the couple should understand they both require investigation.

The main reasons for subfertility are male factor (30%), tubal damage (20%), anovulation (25%), endometriosis (5%) and unexplained subfertility (25%).

Increasingly, local protocols are being developed between primary and secondary care based on NICE guidelines (CG 156 published February 2013) to ensure consistency in investigations and to eliminate duplication.

The initial consultation provides an opportunity for general pre-pregnancy advice.

Initial consultation

At initial consultation, a detailed history should be taken. It should be established that the couple have intercourse at least two-three times a week and that they are aware of the likely time of ovulation and thereby their fertile time.

GPs should investigate a couple after 12 months, but earlier investigations and referral are justified if there are significant risk factors such as previous pelvic inflammatory disease or irregular menstrual cycles. When and how aggressively a couple should be investigated depends on their particular circumstances, but as female age is an important determinant of outcome of fertility treatment older women (aged 35 years or above) should be referred without delay.

Pre-pregnancy advice

The initial consultation provides an opportunity for general pre-pregnancy advice:

• Smoking: both partners should be advised and supported to give up with referral for smoking cessation
• Folic acid: supplements (0.4mg daily) should be taken by women to reduce the risk of fetal neural tube defects. A higher dose of 5mg daily is advised if the patient has had a previous child with a neural tube defect or if the woman herself is epileptic, diabetic or is obese
• Caffeine: although there is no consistent evidence on the impact of caffeinated drinks, it is advisable to reduce intake
• Alcohol: intake should be no more than 2 units per week for women and men should not drink to excess
• Weight: women with a body mass index >30 should attempt to lose weight whether they have regular menstrual cycle or not. In anovulatory women with PCOS, a modest reduction in weight through a programme of calorie restriction and regular exercise may help in restoring spontaneous ovulation or permit easier induction of ovulation with clomifene. Women with a BMI >30, whether associated or not, are likely to take longer to conceive and obese men are likely to have impaired fertility. Obesity has implications for pregnancy, including gestational diabetes, and for delivery, should an obese woman conceives naturally.

Investigations in primary care for female partner

Rubella

Immunity should be tested. If the woman is found to have no immunity – or low immunity – a vaccination should be offered. Conception should be avoided for one month after the vaccination as it is a live attenuated vaccine. If she has had a child within the last few years she will have had this checked as part of her booking investigations.

Ovulation

The majority of women with regular periods (range 25-35 days) are likely to be ovulating. Thyroid function and prolactin should not be measured in women with regular cycles, unless a clinical feature of thyroid disorder or hyperprolactinaemia exists.

Recognition of thinning cervical mucus, detectable as a discharge, is an excellent physiological sign of ovulation and it is worth asking the patient about as it helps guide the timing of intercourse for the couple.

Progesterone

A mid-luteal phase serum sampled seven days prior to the next anticipated period – e.g. day 21 in a 28-day cycle; day 23 in a 30-day cycle and day 28 in a 35-day cycle – should be =30nmol/l. This is taken as evidence of ovulation.

Oligomenorrhoea (>42 day cycle) is associated with inconsistent ovulation and a reduced prospect of conception. As the mid-luteal point is difficult to predict, progesterone levels should be performed from day 28 and then weekly until the period begins. Basal body temperature charts are not recommended.

Amenorhorea (absent periods) could be due to PCOS, hyperprolactinaemia, premature ovarian failure (early menopause) or hypothalamic causes (such as low BMI). A serum LH, FSH, prolactin, testosterone and sex hormone binding globulin (SHBG) is useful in differentiating theses causes.

It is advisable to check a urinary pregnancy test and if negative prescribe a progestagen such as norethisterone 5mg tds for seven days to induce a withdrawal bleed. If the patient menstruates it indicates she has endogenous oestrogen and would be suitable for ovulation induction with clomifene.

Women with hyperprolactinaemia, premature ovarian failure or hypothalamic amenorrhoea will not menstruate as they have very low circulating oestrogen levels, hence their endometrial lining will be thin. After checking the endocrine profile, and excluding a high FSH or prolactin, the GP could undertake a progestogen challenge.

In secondary care, early follicular phase LH, FSH and oestradiol (a single sample measured on days two-four of the menstrual cycle) is an important assessment. This tends to be reserved for couples undergoing IVF/ICSI. Normal FSH concentrations should be less than 9 IU/L. If higher, reduced ovarian reserve is likely and is associated with poorer outcomes at IVF. It is essential the blood sample is taken during the menstrual phase of the cycle, as at any other stage it becomes uninterpretable. Ovarian reserve can also be assessed by ultrasound scan assessment of the number of antral follicles (antral follicle count) or by testing serum anti-mullerian hormone (AMH), which can be assayed at any stage of the menstrual cycle. This is more relevant to IVF practice.

Investigations in Primary care for male partner

Seminal fluid analysis (SFA)

A semen analysis, if abnormal, should be repeated ideally after three months to allow for a complete cycle of spermatogenesis. It is recommended these be carried out in the laboratory used by the infertility clinic to which the patients will be referred.

Laboratories should belong to an external quality control scheme to ensure consistent reporting and adhere to recognised WHO methodology.

IVF/ICSI referral

If history and investigations indicate IVF or ICSI are necessary then an awareness of the local CCG Assisted conception policy is useful. The number of fresh IVF/ICSI cycles recommended by NICE remains at three, but there is significant variation between different CCG’s with most offering one fresh cycle of IVF or ICSI.

Additional frozen embryo replacements may be NHS funded, but this again varies and it is advisable for the GP or patient to check before raising expectations unnecessarily.

CCGs have eligibility criteria and most exclude couples who have a child, where either partner smokes, where the female’s BMI is >30 and where either partner has been sterilised (vasectomy in male). Treatment is usually only available to women 39 years or less. The NICE guidance does recommend a single cycle for women aged 40-42 years who have a normal ovarian reserve, but this has not been adopted uniformly.

In the referral letter to the infertility centre, the GP should include the results of initial screening tests and mention the past obstetric, medical and surgical as well as personal history of the woman along with details of pregnancies fathered by the male partner.

The GP should also support or mention any concerns about suitability of the couple for treatment with details on past history of sexual or physical abuse. The Human Fertilisation and Embryology Authority (HFEA) requires a statement on potential problems that might affect the ‘welfare of the unborn child’ before any assisted conception treatment is provided.

Secondary/tertiary care

Investigations in secondary care: females

Endocrine profile, if done by the GP, is not repeated unless abnormal. An elevated prolactin is repeated to ensure it was not due to stress, and if over 1000mIU/l then a MRI of the pituitary fossa is performed, along with examination of the visual fields.

A transvaginal scan is performed to look at the size and position of the uterus, presence of fibroids, if any, and their location, ovarian morphology and presence and size of cysts, if any Tubal patency is assessed by one of the following:

hysterosalpingography, laparoscopy and dye test (if patient has co-morbidities such as previous PID, previous ectopic pregnancy or history of a sexually transmitted infection) or hysterocontrastsonography (HyCoSy)

If uterine anomaly or presence of fibroids is suspected, a hysteroscopy can be carried out to assess the uterine cavity

Consideration is given to screening for pelvic infection prior to uterine instrumentation with a high vaginal swab and endocervical swab (specifically for chlamydia trachomatis). Active infection should be treated appropriately to minimise the risk of causing a flare up of PID.

Male investigations

If an SFA result is normal, then no further tests are performed

If SFA is abnormal, clinical examination is then carried out for secondary sexual characteristics, testicular size or varicocele

Karyotype, microdeletion of the Y chromosome, cystic fibrosis screen and hormonal profile including gonadotropins, testosterone and prolactin is performed

If the ejaculate shows recurrent infection, it is sent for microbiological assessment and the man with his partner is referred to genitourinary medicine clinic for further screening and treatment

If testicular examination is abnormal, a scrotal ultrasound is performed to identify masses and varicoceles.

Management in secondary care: females

First line ovulation induction is with clomifene (with ultrasound follicle tracking to ensure the dose is effective) +/-metformin. Clomifene should be used for a maximum of six cycles and the multiple pregnancy rate is between 5-10% of conceptions, which is higher than spontaneous multiples of 1-2%

If this is unsuccessful then second line treatment is either daily gonadotropin injections or laparoscopic ovarian drilling, which are equally effective

Surgical treatment of endometriosis and fibroids

Tubal reconstruction surgery, although the success rates for pregnancy are poor.

Male investigations

Testicular exploration, with a view to relieving obstruction or determining presence of spermatogenesis in azoospermic men. If a few sperms are found in centrifuged sample, the couple can be referred on for ICSI treatment.

Management in tertiary care: females

Transcervical tubal cannulation for proximal cornual block

InVitro Fertilisation (IVF)

IVF donor oocytes- women who have undergone premature ovarian failure either spontaneously, surgically or as the result of sterilising radiation or chemotherapy

Surrogacy – only option other than adoption for women who have undergone hysterectomy.

Male investigations

Intracytoplasmic sperm injection (ICSI). If the azoospermia is obstructive, percutaneous epididymal sperm aspiration (PESA), or testicular sperm aspiration (TESA)if successful, yields sperm that can be used for ICSI

Vaso-vasal anastomosis, ligation of varicocele are not associated with good outcome in terms of improvement in sperm function and is rarely recommended. Vasectomy reversal is less successful if more than seven years since undertaken and these men are better served by percutaneous epididymal sperm aspiration (PESA) and ICSI

Donor insemination (DI) is a valuable option for couples with no sperm after surgical sperm recovery (SSR) or with significant genetic abnormalities carried by the male

Preimplantation genetic diagnosis (PGD) is only available in a small number of centres in the UK. It is reserved for couples where there is a high chance of the transmission of serious genetic disease to the offspring.

Commonly encountered issues

Multiple pregnancy rates in IVF/ICSI

The HFEA set a reducing target for the proportion of IVF pregnancies that are multiple. This is in acknowledgement of the increased risks associated with twin pregnancies, including miscarriage, preterm delivery and cerebral palsy. Maternal risks of pre-eclampsia and ante and post-partum haemorrhage are also significantly increased. The one at a time campaign (oneatatime.org.uk) has lead to the development of algorithims to select groups of patients who should have one embryo replaced. This is based on female age, number of previous IVF cycles and the embryo quality. It is increasingly common that only a single embryo is replaced. The proportion of elective single embryo transfer (SET) in the UK has risen from 9.4% of cycles in 2009 to 27% in 2013.

The reduction in multiple pregnancy from 26.6% of IVF pregnancies in 2008 to 16.3% in 2013 looks set to continue as better embryo selection techniques are employed and SET becomes the norm.

Subclinical hypothyroidism

There is evidence to support treating subclinical hypothyroidism and aim to have a woman’s TSH <2.5IU/l in the lead up to IVF treatment. Requests for low dose thyroxine replacement may be received for patients whose TSH levels are within the normal range.

IUI or IVF

There is a move away from IUI (intrauterine insemination) to IVF in view of the improving success rates of the latter. IUI is now generally reserved for couples with coital difficulties or where donor sperm is used (assuming tubal patency is confirmed).

Clomifene use in primary care NICE recommends at least the first cycle of treatment is monitored and that clomifene is used for a maximum of six months. Access to regular scan monitoring is usually only available in a fertility centre and not readily amenable to use in primary care.

Clomifene for unexplained infertility?

This should not be used as it does not improve conception chances but increases the risk of multiple pregnancy. Clomifene should be reserved for anovulation and be combined with ultrasound monitoring.

Fertility preservation prior to chemo or radiotherapy is possible if there is sufficient time to undertake an IVF cycle (a minimum of two-three weeks). The oncologists have to be in agreement with the delay and that it will not affect the patient’s survival chances.

Oocyte freezing success rates has improved with the new technique of vitrification, both in terms of thaw survival and subsequent pregnancy rates. Embryo freezing is a more established technique, but is not an option if the woman is single.

For men sperm freezing is easier to arrange and does not delay the commencement of their treatment.

AMH testing for ovarian reserve This is becoming established as the most sensitive test of ovarian reserve. It is usually only available on a self-funding basis and most IVF clinics are now using it. It is used to help choose the optimal stimulation for IVF and does not predict spontaneous pregnancy. There are case reports of both spontaneous and IVF pregnancies in women with undetectable levels but these are the exceptions and within each age band a lower AMH indicates a lesser chance of success with IVF.

Conclusion

Primary care plays an important role in undertaking appropriate investigations prior to referral and identifying those patients that will benefit from earlier referral, especially older women, women with absent periods or a very irregular cycle and men whose SFA shows significant abnormalities.

Support and careful explanation should not be underestimated.

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Dr Stephen Keay, Consultant Gynaecologist, Centre for Reproductive Medicine, UHCW NHS Trust Coventry

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