This article describes these three elements and provides guidance on the factors to consider during decision making. In particular, it discusses why delaying referral on the basis of normal initial tests is not good practice, and why the advice to ‘keep trying’ may be inappropriate for many patient groups.

 

Fertility services

Fertility services in the UK are delivered at 3 distinct levels. The couple typically presents to the GP with a history of trying for pregnancy (Level 1). The GP may initiate testing and consider referral to a specialist fertility clinic in secondary care (Level 2).

At Level 2, fertility investigations are completed and certain treatments, such as ovulation induction or fertility-enhancing surgery, are performed. If assisted conception treatment (IVF) is required, the couple is referred to a dedicated fertility treatment centre (Level 3).

Depending on local resources, the specialist team providing Level 2 services may also deliver the Level 3 services. However, it is not uncommon for private providers to deliver IVF and other assisted conception treatment for couples entitled to NHS funding.

 

Optimising the chances of a successful pregnancy

A couple can take steps to optimise their chances of achieving natural conception.

For otherwise fit and healthy individuals, optimising lifestyle may help. This includes smoking cessation, aiming for a healthy BMI, and moderating alcohol excess, all of which have been reported to improve fecundity.1

For women with irregular periods, achieving a normal BMI is likely to improve the frequency of ovulation and, subsequently, natural fertility.

Chlamydia testing for the woman is desirable, as this is a common and treatable infection and also a risk factor for tubal infertility.2 Partners of chlamydia-positive women should also be treated according to current guidelines.3 Some over-the-counter medication often used by women, such as NSAIDs, are known to interfere with ovulation and should be avoided if possible.

However, it is not just about improving the chances of conception, but also of a healthy term pregnancy. While most couples do not routinely see a healthcare professional unless pregnant, subfertile couples will present before pregnancy and can benefit from pre-pregnancy counselling.

 

Delaying referral on the basis of normal initial tests is not good practice

 

Improving pregnancy outcomes

In addition to the above lifestyle advice, which can also help to improve pregnancy outcomes, it is important to address any avoidable conditions that could harm a pregnancy.

Women should be up-to-date with their cervical cancer screening. Immunity to rubella should be checked.  In contrast to pregnant women – where routine rubella screening has been abandoned – subfertile women can benefit more from screening; if susceptible, they can receive immediate vaccination before getting pregnant.4 Rubella immunity can be assumed if there is documented evidence of full vaccination. However, in the few cases where the rubella vaccination history cannot be confirmed, the detection of specific serum IgG antibodies is still the recommended test for demonstrating immunity.1

Folic acid supplementation (400mcg daily) in preparation and during pregnancy reduces the risk of neural tube defects (anencephaly and spina bifida). Certain groups, such as women on anti-epileptics, diabetic women, obese women (BMI≥30) and women with a previous pregnancy affected by a neural tube defect, should aim to use high-dose folic acid (5mg daily) (Table 1).5

 

It is important to consider couples from certain ethnic groups who may be at risk of certain genetic conditions, such as thalassaemia or sickle cell anaemia. Identification of the ‘trait’ in one partner should prompt testing of the other partner.

Women with confirmed or suspected polycystic ovary syndrome (PCOS) may benefit from being tested for diabetes if they are overweight or have a family history of diabetes.6 It is well established that getting pregnant with uncontrolled diabetes increases the risk of serious congenital anomalies.7

Nowadays, it is not uncommon to see women with a chronic medical condition express a desire to become pregnant. While in the earlier days, many of these women would have been discouraged from falling pregnant, advances in medicine have allowed many of them to have a successful – even though still high-risk – pregnancy. Ideally, these women will have already received pre-pregnancy advice by their specialists; if not, it is worth referring them to do so.

One needs to consider whether the chronic condition can adversely affect the course of pregnancy or, vice versa, if pregnancy can exacerbate this condition.

The safety of regularly used medication also needs to be considered in the context of future pregnancy. Often, it is a balance between presumed benefits – keeping the condition under remission – and risks to the pregnancy. Before stopping any medication, consideration should be given to how likely it is for the original condition to worsen. For example, discontinuing a SSRI may be associated with relapse of depression, which could prove harmful during pregnancy or post-partum.8 This should be balanced against the potential teratogenicity of this particular drug, in accordance with reliable sources such as the British National Formulary (BNF). Minimising the number and dose of necessary medication is a sensible practice, as in the case of anti-epileptic medication.9 Fertility specialists are required to look at potential risks to the unborn baby before offering fertility treatment (so called ‘welfare of the child’ assessment).10 This formal assessment includes investigating the impact of known physical, mental or hereditary conditions on the health of the pregnancy and how this risk can be moderated. Only if the specialist is satisfied that no serious risk to the future child welfare is present, can fertility treatment be offered.

 

Initiating fertility testing

In order to achieve pregnancy, three elements must be present: healthy sperm, healthy egg and access to the fallopian tube.

Accordingly, the basic fertility tests consist of:

  1. The semen analysis (SA)
  2. Serum progesterone levels for confirming ovulation
  3. Imaging of the anatomy of the uterus and fallopian tubes after dye instillation.

The first 2 tests are typically performed by the GP, while the latter is undertaken at Level 2.

 

In order to achieve pregnancy, three elements must be present: healthy sperm, healthy egg and access to the fallopian tube

 

Semen analysis

The SA requires the production of a fresh sperm sample after a short period of abstinence (3-7 days). A standard SA report includes various semen parameters with reference values (Table 2).

The current reference values have been set by WHO in 2010. In order to identify the cut-off values for defining male subfertility, WHO analysed the semen parameters of a large multinational cohort of men who had achieved natural pregnancy within 12 months (recent ‘fathers’). The 5th centile of sperm values in this cohort (lower 5% of the distribution) was arbitrarily chosen as the reference values for clinical use.11

There is no single best way of ‘reading’ a SA report. As a rule of thumb, there are 3 semen characteristics which are clinically relevant:

  1. The amount (as expressed by the total count in the ejaculate or concentration per ml)
  2. Motility (as expressed by the proportion of total motile or progressively motile sperm)
  3. Morphology (as expressed by the proportion of normal forms).

A ‘normal’ SA requires all 3 characteristics within the reference range. If 1 of 3 characteristics is low, the odds of male infertility increase 2-3 fold. If 2 of 3 are low, the odds increase 5-7 fold. If all 3 characteristics are low, the odds of infertility increase 15 fold.12 Consequently, the more abnormal a semen analysis is, the higher the chance of male subfertility.

 

Physiological variation in individuals

There is physiological variation in sperm numbers within the same individual. About 15-20% of men attending fertility clinics will have a low result in their first SA, followed by a normal result in the second SA.13 If the initial SA is not normal, a second abnormal sample 3 months later is required before diagnosing male infertility. If the initial SA is normal, NICE does not recommend repeating the SA.1

The limitations of semen assessment must be kept in mind when counselling couples, particularly when the results indicate a potential male problem.

The SA compares the man’s sperm to the sperm of ‘recent fathers’, but it does not confirm or refute the ability to achieve natural pregnancy; by definition, 5% of ‘recent fathers’ will have numbers lower than the reference values.

An abnormal SA is informative that male factor likely contributes to the couple’s subfertility. This finding may warrant further testing of the male partner (physical examination, hormonal or genetic testing). On the basis of weak evidence, oral supplements, such as vitamins and anti-oxidants, can also be recommended. It should be noted though that head-to-head comparisons between male supplements have not been performed and, therefore, no single type is preferable over another.

 

The limitations of semen assessment must be kept in mind when counselling couples, particularly when the results indicate a potential male problem

 

Progesterone levels

After ovulation, the corpus luteum produces progesterone with a view to supporting implantation and early pregnancy. Checking serum progesterone levels is thus a sensible method for confirming that ovulation has taken place.

Progesterone testing is not required for every subfertile woman. If the cycles are obviously irregular (longer than 35 days or shorter than 21 days), it is unlikely that regular ovulation occurs, obviating the need for checking progesterone levels.

For women who have regular cycles, progesterone levels are useful for confirming ovulation. The best time to perform the test is when the levels are expected to be highest; this is about 7 days before an expected period. For a woman with a 28-day cycle, this is around day 21 of the cycle. Since the luteal phase of the cycle remains constant, the rule of ‘7 days before the period’ stands, even for women with rather longer or shorter - but still regular – cycles (Table 3).

Although progesterone levels above 30nmol/L are generally thought to confirm ovulation, intermediate levels between 16-29nmol/L could still indicate recent ovulation.14 A possible explanation for obtaining these intermediate levels lies in the timing of the test in relation to the following period. If the next period comes a few days after or before the 7-day mark, then progesterone levels will have been captured while rising or declining respectively.

In principle, most women with regular cycles tend to ovulate. A notable exception is women with a mild hormonal imbalance, usually mild PCOS, but these constitute the minority of regularly cycling women. One should therefore not rush to declare anovulation on the basis of a single unsatisfactory progesterone test in a woman with regular cycles, particularly in the presence of mid-cycle pain, PMS-related symptoms (breast tenderness, mood swings etc.) or dysmenorrhea, all of which tend to occur in ovulatory women. On the other hand, it should be remembered that a ‘positive’ progesterone test has proven ovulation only for that tested cycle and, only as long as the cycle remains regular, it can be assumed that ovulation occurs regularly.

Testing for other female hormones – such as serum FSH, Prolactin or TSH levels – can be useful in managing the subfertile couple. Early follicular FSH levels can be informative in 2 ways; in regularly menstruating women, elevated FSH levels (more than 9 IU/L) may indicate diminishing ovarian reserve (low egg stores); in women with anovulation, FSH and Prolactin levels are helpful in investigating the cause of anovulation. Obvious thyroid dysfunction can interfere with menstrual function. Moreover, there is accumulating evidence that subclinical hypothyroidism may be associated with pregnancy loss, as well as adverse pregnancy outcomes.15 It has been recommended that even TSH levels in the high side of normal (2.6–4mIU/L) should prompt further testing for anti-peroxidase (anti-TPO) antibodies; if these are present, thyroxine supplementation should take place, aiming to reduce TSH levels to no more than 2.5mIU/L.15

If not performed in primary care, hormone testing other than progesterone levels can be picked up at Level 2 and beyond.

Table 4 summarises the required checks before proceeding with Level 2 referral.

 

Referral to the next level

Approximately 8 out of 10 couples will achieve natural conception within 1 year of trying. Of the remaining, 50% will do so during the second year. Taking these basic statistics into account, NICE recommends referring to secondary care (Level 2) any couple that has not achieved pregnancy after 1 year of trying.1

Attention should be paid to what constitutes ‘trying’ for each couple.

The duration of subfertility is simply defined by how long they have been having regular (twice weekly) unprotected intercourse.1 Often couples erroneously believe that ‘trying’ involves having intercourse at very high frequency, thereby underestimating the duration of their subfertility.

In certain cases, 6 months of trying is enough to consider referral. This relates to women over 35 years old, where natural fertility and the success of assisted conception are reduced. Early referral is also justified if there is a known factor contributing to subfertility (PCOS, endometriosis, previous PID or extensive pelvic surgery etc.).

 

Even if all fertility investigations are normal (unexplained subfertility), the chances of natural conception are also dependent on other factors

 

Delayed referral

Delaying referral on the basis of normal initial tests is not good practice. Firstly, subsequent testing undertaken at Level 2 could reveal tubal blockage, endometriosis or other relevant pathology. Even if all fertility investigations are normal (unexplained subfertility), the chances of natural conception are also dependent on other factors, such as the age of the woman, the duration of infertility and the history of previous pregnancy (or not as the case may be).16

Consequently, older women who have never been pregnant may have overall low chances of natural conception. It is also the same group where delay in initiating fertility treatment could be detrimental to its success.

Diminishing ovarian reserve, as demonstrated by low anti-Mullerian hormone (AMH) levels, low antral follicle count (AFC) on pelvic scan or high FSH levels, is not uncommon in older women and tends to have a negative effect on performance during IVF. AMH is more accurate than FSH in predicting low ovarian response (80% versus 66% accuracy).17 It won’t be surprising if AMH eventually replaces FSH as a referral criterion for IVF treatment.

Even when there is a place for lifestyle improvement in the older age group, this should not cause significant delay in accessing fertility treatment. This is because, overall, the detrimental effect of advancing age on success of assisted conception outweighs the potential benefit from addressing lifestyle.

 

Conflict of interest: None declared.

References available online at www.bjfm.co.uk


Thanos Papathanasiou Regional Lead Clinician, Bourn Hall Clinic

Nausheen Mawal Consultant Gynaecologist and IVF Specialist, Bourn Hall Clinic

Mohammed Edris General Practitioner and Fertility Specialist, Bourn Hall Clinic