Thrombophilia, heparin and aspirin in IVF: what the evidence shows

It is not uncommon for a patient to arrive with a three-page coagulation report, an MTHFR mutation highlighted in red, and a prescription for heparin for the entire pregnancy. This concern is understandable. But the medical reality is more nuanced, and it is useful to distinguish between what constitutes treatment and what is merely a precaution without evidence.

What is thrombophilia?

Thrombophilia is an increased tendency to form clots. A distinction is made between:

• Hereditary thrombophilias: Factor V Leiden mutation, prothrombin gene mutation, and deficiencies in antithrombin, protein C or protein S.
• Antiphospholipid syndrome (APS): an acquired autoimmune disorder characterised by specific antibodies (lupus anticoagulant, anticardiolipin, anti-beta-2-glycoprotein I) associated with thrombosis or obstetric complications.

The case of APS: a treatment that has proven its worth

In women with confirmed obstetric APS (persistent antibodies at 12-week intervals and a history of recurrent miscarriages or pregnancy complications), the combination of low-dose aspirin and low-molecular-weight heparin during pregnancy is recommended. This is the situation where the benefit is best established. Testing for antiphospholipid antibodies is therefore part of the assessment following recurrent miscarriages.

Hereditary thrombophilia: increased risk of thrombosis, no proven risk of implantation failure

A woman who is a carrier of Factor V Leiden has a higher risk of venous thrombosis, particularly during pregnancy and in cases of significant ovarian stimulation. This justifies thrombosis prevention based on her personal and family history, to be decided in consultation with a haematologist.

However, the link between hereditary thrombophilia and implantation failure or miscarriage is weak and uncertain. The large randomised ALIFE2 trial, published in The Lancet in 2023, compared heparin with no treatment in women with hereditary thrombophilia who had experienced at least two miscarriages: no difference in birth rates. The ESHRE therefore does not recommend routine screening for these thrombophilias to explain miscarriages or IVF failures, unless there is a history of thrombosis.

The MTHFR mutation

It is very common in the general population; a large proportion of people carry at least one copy of the C677T variant. It is no longer considered a thrombophilia, and professional bodies advise against screening for it. If your test results mention it, simply bear in mind that standard-dose folic acid supplementation is sufficient in the vast majority of cases.

‘Empirical’ heparin following IVF failures

Administering heparin without a diagnosis, to ‘improve implantation’, has not shown any clear benefit in trials. The ESHRE, in its 2023 guidelines on recurrent implantation failure, does not recommend it. Heparin is not without risks: bruising, rare allergic reactions, bleeding, cost, and daily injections.

Low-dose aspirin, on the other hand, has been shown to be beneficial in preventing pre-eclampsia in at-risk women, from around the second trimester onwards. It is not a treatment for implantation.

Stimulation, pregnancy and thrombosis

The risk of thrombosis increases during ovarian hyperstimulation and during pregnancy, particularly in the first trimester following IVF. Women with a personal history of thrombosis or high-risk thrombophilia receive appropriate preventive treatment. For others: stay active, stay hydrated, and report any pain or swelling in a calf, especially during a flight.

My advice

If you are offered anticoagulant treatment, ask: what diagnosis justifies it? Is it to prevent thrombosis, or to improve implantation? For how long? A haematologist can resolve complex situations, and your Greek clinic can liaise with the doctor who is treating you at home.

Frequently asked questions