Viewpoint - Infertility as an early warning sign

When to suspect thrombophilias or polycystic ovary syndrome. By Dr Maz Khan

Dr Khan (above) believes in a multidisciplinary approach to investigating patients experiencing infertility
Dr Khan (above) believes in a multidisciplinary approach to investigating patients experiencing infertility

Evidence is emerging that infertility or recurrent miscarriage in an otherwise healthy patient can provide an early indication of an underlying adverse health condition.

Investigation to reveal the causes of reproductive failure can therefore assist with an earlier management strategy, providing long-term benefit to the well-being of the woman beyond that of restoring natural fertility.

Thrombophilia and polycystic ovary syndrome (PCOS) represent two potential causes of infertility and miscarriage that remain poorly understood. Following elimination of any physical causes, such as uterine polyps, fibroids, scar tissue or congenital abnormalities, assessment of the general health and medical history of the patient is an important next step.

Thrombophilias are a group of blood coagulation disorders that increase the likelihood of inappropriate clotting. This is particularly a concern during pregnancy, because pregnancy itself causes the blood to clot more easily.

Thrombophilia can be either congenital or acquired. Antiphospholipid syndrome (APS) is the most common form of acquired thrombophilia and is characterised by the presence of antibodies against phospholipids in association with either vascular thrombosis and/or recurrent pregnancy loss.1

For women with a history of recurrent miscarriages, screening for antiphospholipid antibodies is recommended.

The most significant immunoglobins involved in APS are anticardiolipin, lupus anticoagulant and anti-beta 2-glycoprotein 1 antibodies.

Treatment with a combination of aspirin and unfractionated heparin may reduce pregnancy loss in APS-positive cases by as much as 54% compared to aspirin alone.2,3

The link between inherited thrombophilia and adverse pregnancy outcome is not as clear in early pregnancy loss as it is in late pregnancy loss.4-6 The recommendation by the Royal College of Obstetricians and Gynaecologists is therefore to screen for inherited thrombophilias in selected cases, such as second trimester pregnancy loss.7

Early knowledge of thrombophilias can enable women to protect their future health through their choice of contraceptives, because estrogen-containing pills increase the risk of venous thromboembolism including DVT.

Adverse pregnancy outcomes with thrombophilia

A woman with thrombophilia may experience the following adverse pregnancy outcomes

  • Implantation failure
  • Miscarriages
  • Pre-eclampsia
  • Intrauterine growth retardation
  • Oligohydramnios (low levels of amniotic fluid)
  • Abruptio placentae
  • Premature labour (often caused by incompetent cervix syndrome)
  • Unexplained intrauterine fetal death
  • Thrombophlebitis (blood clots in veins or arteries in pregnancy)

Polycystic ovary syndrome
PCOS is associated with endocrine and metabolic disturbances. Although PCOS is the most common cause of failure to ovulate - occurring in about 80% of anovulatory infertility patients - it produces a wide spectrum of symptoms, so is difficult to diagnose.8

Once considered a problem of adult women, PCOS can have pre-menarche onset and this may be increasing in prevalence.9 It is important that symptoms such as hirsutism and menstrual disturbances are not treated in isolation, because there is increasing evidence that women with PCOS are at greater risk of serious metabolic and cardiovascular consequences later in life.

If PCOS is not addressed until a woman tries to conceive, she may already have an increased BMI, which can further reduce fertility and increase the risk of complications.8,9

Diagnosis should be made principally on clinical grounds, supported by ultrasound and biochemical investigations; these may include estimation of serum testosterone, SHBG, LH and FSH.

Crucially, PCOS is characterised by insulin resistance and high levels of insulin in the blood. In some women, raised insulin levels lead to a hormone imbalance which can affect the ovaries, preventing them from releasing mature eggs.

If diagnosed early, before any major weight gain, PCOS can be effectively managed. Anti-estrogens such as clomifene citrate remain the first choice for treatment for anovulatory infertility; however, clomifene resistance is not uncommon.

In these cases, possible therapeutic interventions include gonadotropins or laparoscopic ovarian drilling. The former must be carefully monitored to avoid ovarian hyperstimulation syndrome and multiple pregnancies.

Although unlicensed for treatment of PCOS in the UK, metformin has level A recommendation in the NICE 2004 fertility guideline for women who have not responded to clomifene citrate and who have a BMI of more than 25kg/m2.

It has been demonstrated that for obese women, a 5-10% weight loss restores fertility in 55-100% of patients within six months.10

A balanced diet with reduced refined carbohydrates, fats and alcohol consumption can benefit both men and women and help tip the balance where subfertility of both partners is affecting conception.

Encouraging this in women, particularly those with PCOS, will improve their chances of a healthy pregnancy (through natural or assisted conception) and have lasting benefits for their health.

Ideally, a multidisciplinary holistic approach should be taken at the primary care level. Referral to a tertiary centre for assisted conception should only be made after non-invasive diagnostic techniques have been used and, if necessary, the patient has achieved the ideal body weight. Referral to the appropriate specialists is a crucial part of managing reproductive health and this may include endocrinology, gynaecology, or a dietitian.

  • Dr Khan is lead clinician at Bourn Hall Clinic, Colchester

1. Miyakis S, Lockshin MD, Atsumi T et al. J Thromb Haemost 2006; 4: 295-306.

2. Empson M, Lassere M, Craig J et al. Cochrane Database Syst Rev 2005; 2: CD002859.

3. Kutteh WH. Am J Obstet Gynecol 1996; 174: 1584-9.

4. Kupferminc MJ, Eldor A, Steinman N et al. N Engl J Med 1999; 340: 9-13.

5. Roque H, Paidas MJ, Funai EF et al. Thromb Haemost 2004; 91: 290-5.

6. Rey E, Kahn SR, David M et al. Lancet 2003; 361: 901-8.

7. Royal College of Obstetricians and Gynaecologists Green-top Guideline No 17; April 2011.

8. March WA, Moore VM, Wilson KJ et al. Hum Reprod 2010; 25(2): 544-51.

9. Hassan A, Gordon CM. Curr Opin Paediatr 2007; 19: 389-97.

10. Kiddy DS, Hamilton-Fairley D, Bush A et al. Clin Endocrinol (Oxf) 1992; 36: 105-11.

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