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Need to know - infertility

Consultant gynaecologist Miss Ying Cheong answers GP Dr Pam Brown’s questions on obesity, first-line GP investigations and the treatment of PCOS and endometriosis

Consultant gynaecologist Miss Ying Cheong answers GP Dr Pam Brown's questions on obesity, first-line GP investigations and the treatment of PCOS and endometriosis

1. What is the effect of increasing maternal and paternal age on fertility and pregnancy rates?

41204313It is still unclear why human evolution has allowed the female reproductive system to age faster than other parts of the body. With the physiological aging of the ovary, the decline in female fertility is seen after age 30 and is seen most markedly after 35. By this time, a woman will take twice as long to conceive as she would have 10 years earlier. Age changes cannot be reversed, older oocytes are more susceptible to aneuploidy and pregnancies conceived by older women have poorer outcomes.

The effect of age on male fertility is less clear. But several studies have shown older men are more likely to have DNA changes in their sperm and to have poorer sperm parameters than younger men.

2. How long should couples try to conceive before referral?

In the general population, it is estimated that 84% of women would conceive within one year of regular unprotected sexual intercourse. This rises to 92% after two years and 93% after three years. According to the 2004 NICE fertility guidelines, infertility is defined as ‘failure to conceive after regular unprotected sexual intercourse for two years in the absence of any known reproductive pathology'. Couples with known pathology such as anovulation, tubal pathology or male infertility should be referred earlier.

3. What is the impact of obesity on natural and assisted conception rates and successful pregnancy outcomes?

Women with BMI over 30kg/m2 take longer to conceive naturally compared with women with lower BMI. For infertile women who are anovulatory with BMIs of over 29kg/m2, a supervised weight loss programme or a group programme including exercise, dietary advice and support appears to help reduce weight, restart ovulation and improve pregnancy rates.

Obese women also have a higher risk of miscarriage and are more at risk of pregnancy-related complications such as diabetes, hypertension and shoulder dystocia. Women who are obese prior to pregnancy are more likely to have excessive weight gain during pregnancy and are more likely to fail to lose weight after pregnancy. Excessive weight gain and failure to lose weight after pregnancy are important predictors of long-term weight change and higher BMI in later life.

Studies have shown that there is a significantly reduced number of normal-motile sperm cells and a higher DNA fragmentation rate in men who are obese compared with men of normal weight. Obesity also has a deleterious effect on erectile function in men with existing vascular risk factors such as heart disease and diabetes.

The effect of obesity on the pregnancy results of assisted conception such as IVF is less clear. However, because of the increase in maternal and fetal risks with obesity, IVF should be reserved for treatment of women with normal BMI.

4. What is the likelihood of a successful pregnancy for women with primary infertility of unknown cause and how much is that improved by different fertility treatments?

Couples with subfertility will have basic fertility investigations including:

• semen analysis

• confirmation of ovulation

• tubal patency testing.

In a third of cases these investigations find no specific cause of infertility and these patients are given a ‘diagnosis' of unexplained infertility. Treatments for these patients include:

• stimulation of ovulation using clomiphene or gonadotrophins

• intrauterine insemination with or without ovarian stimulation

• in vitro fertilisation.

A stepwise treatment strategy is often used, starting with low-risk interventions such as stimulation of ovulation and unstimulated intrauterine insemination, which are also cheaper. When such treatments fail, clinicians usually recommend more interventional treatment such as intrauterine insemination with ovarian stimulation and then in vitro fertilisation.

Earlier this month a randomised controlled trial was published which compared the use of clomiphene citrate or unstimulated intrauterine insemination (IUI) for six months with expectant management in 580 women with unexplained infertility. The authors found no significant difference in the live birth rate between the groups1. But this study did not compare stimulated IUI treatment with expectant management.

IVF has been shown to be effective in the treatment of couples with unexplained subfertility.

There is no cost-effectiveness data on these interventions in unexplained subfertility.

The choice of the precise first-line treatment for patients with unexplained subfertility should therefore be individualised according to the patient's expectations, the centre's experience, and available resources and expertise.

5. It has been suggested that high caffeine intake and smoking decrease the likelihood of conception and increase miscarriage rates. Is there evidence to support this and are there any other lifestyle factors we should address in women with infertility?

There is evidence to suggest that smoking significantly reduces fertility in females.

It has also been reported that passive smoking in women is associated with delayed conception.

There are significant associations between maternal cigarette smoking in pregnancy and increased risk of miscarriage, delayed conception, small-for-gestational-age infants, stillbirth and infant mortality.

There is also an association in men between smoking and reduced semen parameters. But the relationship between male smoking habits and fertility is uncertain.

The association between caffeine and female infertility is inconsistent.

Of course all women should be encouraged to take prophylactic folic acid while trying for pregnancy and during the first 12 weeks. Women who have a BMI over 30 should be encouraged to lose weight.

Use of recreational drugs and excessive alcohol intake has a detrimental impact on sperm parameters and should therefore be discouraged. There is inconsistent evidence about the impact of alcohol intake on female fertility but obviously excessive alcohol is harmful to the fetus.

6. What are the common causes of male infertility, and should we recommend zinc or selenium supplements for men with poor sperm motility?

Male infertility can be caused by impaired sperm production and function (such as hypogonadotropic hypogonadism), mechanical obstruction secondary to trauma or surgery, coital issues, genetic causes and environmental and lifestyle factors as discussed above. There is some evidence to suggest that zinc and selenium supplements improve sperm parameters but this has not been shown to improve live birth rate. Furthermore, many of these studies were poorly conducted.

Patients should be advised that there is currently no good evidence to recommend routine use of these supplements.

7. What examinations and investigations should we do before referring couples for infertility? How long should men abstain from intercourse before semen analysis?

Useful primary care investigations are summarised in the box below.

With regard to the semen analysis, it is sufficient in general practice to note the sperm concentration and motility, and the volume of ejaculate.

It is best to use a lab service that participates in the British quality control scheme (NEQAS).

In general, men should abstain from intercourse for a minimum of two to three days for the results to be accurate. Azoospermia warrants referral to a specialist, or the test may be worth repeating if the sample was poor.

Refer to a recent Ten Top Tips article on interpreting semen analyses for more information.

8. What is the risk of ovarian hyperstimulation and multiple pregnancy with clomiphene therapy and is this increased in women with PCOS? Should women be monitored with ultrasound during therapy?

While the risk of ovarian hyperstimulation is very rare with the use of clomiphene, the risk of multiple pregnancies is as high as 10%. Women with PCOS are more likely to over-respond than under-respond to any stimulation regime.

Women undergoing treatment with clomiphene citrate should be offered ultrasound monitoring during at least the first cycle of treatment to ensure they receive a dose that minimises the risk of multiple pregnancy.

9. Is there still a role for metformin in the management of women with PCOS who want to conceive?

This area is still rather controversial with new data constantly being published.

In women with PCOS, metformin appears to lower the fasting insulin level, but there is no evidence to suggest it results in consistent significant changes in BMI or waist-to-hip ratio.

Although oligomenorrhea improves in some women with PCOS, significant numbers remain anovulatory.

So although metformin can help women re-establish their menstrual cycle, this does not translate into a higher pregnancy rate.

There is also evidence to suggest that metformin is less effective than clomiphene in inducing ovulation, but some studies have shown that metformin together with clomiphene may be useful in some patients who do not respond to clomiphene alone.

10. What is the most appropriate management plan for a woman with endometriosis and primary infertility?

Women with endometriosis should be referred to be evaluated and treated surgically in the first instance and then – depending on individual factors such as age and social factors – be referred on for assisted conception. There is no evidence that medical management helps in these patients.

11. What are the major risks of assisted conception apart from multiple pregnancies?

Ovarian hyperstimulation syndrome (OHSS) is the most common complication of assisted conception and occurs in 3-5% of treatment cycles.

The presentation of this condition is variable but it may present in a mild case as lower abdominal discomfort with some nausea or in a more severe case with:

• marked abdominal pain

• abdominal distension

• ascites

• pleural effusion

• venous thrombo-embolic episodes.

Women with OHSS should be treated in a specialist unit, and any unit offering ovulation induction or assisted conception should inform their patients of this risk and provide them with contact information during and out of office hours.

Assisted conception such as intracytoplasmic sperm injection (ICSI) may be associated with a small rise in congenital abnormalities, but this is controversial. There is a small increase in the frequency of abnormalities in sex chromosomes in babies conceived with this technique.

There is also evidence that a small proportion of men with severe sperm abnormalities may have microdeletions on their Y chromosome, and these may potentially be passed on to any male child born as a result of ICSI.

12. What is the range of successful completed pregnancy rates for different UK NHS centres? Are rates higher in the private sector?

According to the figures from the Human Fertilisation and Embryology Authority (HFEA), the average success rate in terms of live birth rate for IVF treatment is:

• 29.6% for women under 35

• 23.6% for women 35-37

• 18.2% for women 38-39

• 10% for women 40-42

• 3.2% for women 43-44

• 0.8% for women over 44

Success rates can be affected by the type of patient a clinic will treat. If the clinic specialises in treating younger women, their overall success rate is likely to be higher than a clinic that treats older and more complicated patients. Therefore although the IVF league table is useful in some ways, the data needs to be interpreted with caution and patients should also be advised to refer to the HFEA website for more details on the clinic they wish to get treatment from.

Miss Ying Cheong is senior lecturer, consultant gynaecologist and subspecialist in reproductive medicine and surgery in the division of developmental origins of health and disease at the University of Southampton

Competing interests none declared

The role of metformin in the treatment of PCOS is controversial (cystic follicles in ovary wall in PCOS pictured) The role of metformin in the treatment of PCOS is controversial (cystic follicles in ovary wall in PCOS pictured) What I will do now What I will do now

• I will inform women that it may take twice as long to get pregnant if they
are older than 35
• But I will continue my current practice of referring women with no obvious cause for infertility and regular ovulatory cycles after one year.
• I will continue to encourage women considering pregnancy to lose weight and stop smoking and will extend this advice to their partners.
• It is time-consuming to provide lifestyle advice and challenging for patients to lose weight, but these patients may be motivated. Referral to specialist smoking cessation clinics greatly increases the quit rates, so all these women (and their partners) will be encouraged to attend.
• We already carry out all of the recommended pre-referral investigations except follicular-phase LH and FSH, so we will add this.
• I will remember to recommend that men abstain from intercourse for two to three days before semen analysis

Dr Pam Brown is a GP in Swansea

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