THROMBOPHILIA

Key points:

• Studies have found an association with Factor V Leiden, prothrombin G20210A and recurrent pregnancy loss
• Early pregnancy loss (less than 10 weeks gestation) may not be related to thrombophilias
• Thrombophilia screening for recurrent pregnancy loss remains controversial but should be considered

The question:
You follow a 30 year old female and her husband in your clinic.  She has had 3 late first trimester miscarriages in the last year and is anxious to become pregnant.  She is otherwise healthy.  Her mother also had difficulties with conception but did not have any documented pregnancy loss.  The rest of her family history is non-contributory. 

Do you think thrombophilia testing is indicated in this patient?

Which of the following tests would you order assuming the patient has given her consent?  (please check all that apply)

On a scale from -1 (less likely to screen) to +1 (more likely to screen), how does the following information affect your choice to screen?                                

 Issues addressed:

• Infertility
• Recurrent pregnancy loss

Infertility:

Infertility as caused by VTE and/or thrombophilia tends to present as recurrent pregnancy loss rather than failure to conceive.  As such, it is important to distinguish between these two etiologies on history and physical exam, as the work up and implications are different.  It is likely that some other factor such as an ovulatory disorder or anatomic abnormality was present in the patient’s mother and therefore is unrelated to a potential thrombophilia in the patient. back to issues

Recurrent pregnancy loss:

Recurrent pregnancy loss, as defined by the loss of 3 or more consecutive pregnancies prior to 20 weeks gestation, has been linked with inherited and acquired thrombophilias.  The pathogenesis is thought to relate to thrombosis of spiral arteries and the intervillous space causing impaired placental perfusion.  As discussed above, there are several physiologic changes that occur in the clotting cascade and maternal anatomy making pregnancy a particularly high-risk time for VTE (see pre-pregnancy counseling under scenario 3).  Therefore, a certain percentage of patients with thrombophilias will present for the first time during pregnancy.  The highest risk yet identified is Antithrombin deficiency with an associated 3 to 7.2% probability of VTE during peripartum in the absence of both personal and family history of VTE.1    However, in general such risk for other thrombophilias including compound FVL and prothrombin G20210A heterozygotes is quite low (i.e. less than 5%).   

A meta-analysis published in 2004 looked at the risk of recurrent pregnancy loss, which they defined as two or more pregnancy losses in the first two trimesters and found that carriers of FVL or prothrombin G20210A were twice as likely to experience recurrent pregnancy loss compared to non-carriers.2  Similar findings were published in 2005, which found a correlation between second trimester pregnancy losses and FVL, as well as high homocysteine levels and antiphospholipid antibodies.  There was no relation between protein C or S deficiency, Antithrombin deficiency or prothrombin G20210A and recurrent pregnancy loss.3  This may relate to the infrequency of these thrombophilias with underpowered studies. 

At least one study refuted a connection between thrombophilias and early pregnancy loss (less than 10 weeks gestation).  Roque et al performed thrombophilia testing in 491 patients with a least one previous adverse pregnany outcome.  The presence of at least 1 thrombophilic state significantly lowered the probability of a pregnancy loss earlier than 10 weeks gestation with an odds ration of 0.55.4  Results after 10 weeks gestation were similar to other studies. 

Gris et al. prospectively assessed the use of enoxaparin compared to low-dose aspirin in thrombophilic patients with at least one pregnancy loss beyond 10 weeks amenorrhea.  Use of enoxaparin significantly increased the odds of a healthy live birth with an odds ration of 15.5.  Neonate weight was also higher in the enoxaparin group.5

Because our patient has had several late first trimester pregnancy losses, thrombophilia testing should be considered after consultation with a fertility expert as there is now evidence for low molecular weight improving parity in such patients. back to issues