It has been brought to my attention from the pathologist in our system who was asked to review data on a 28-year-old woman who had one viable pregnancy, one blighted ovum, and one first trimester missed abortion. There was no prior history of DVT (deep vein thrombosis) or VTE (venous thromboembolism). There is no family history of such. The patient had significant testing done. The pertinent findings are a homozygous MTHFR C677T mutation with a normal homocysteine and the fact that she was heterozygous for a prothrombin mutation. The pathologist has referenced an article by Altomare from the Thrombosis Journal, 2007;5:17. There is a suggestion in this article of patients with early fetal demise who have the MTHFR mutation. The prevailing thought is that the MTHFR mutation is not thrombogenic; however, this patient, as well as this article, does raise some questions. Therefore, I would appreciate if you would forward this note to experts in your foundation for their opinion regarding: Is MTHFR mutation thrombogenic and is it worthwhile doing the test? Is there a role for the MTHFR mutation in fetal demise? If such, what are the recommendations if any for anticoagulation? Is the prothrombin mutation in the patient referenced above the real culprit here instead of the MTHFR mutation? I appreciate your help and insight in this matter. I will be looking forward to your review and discussion.

Kenneth Krupp, MD
Promedica Cancer Center Sylvania, OH

Dear Dr. Krupp:

Thank-you for your question.

I'm not sure why this patient was tested for an underlying thrombophilia after a single early pregnancy loss. This would not have been my practice. Although these events are very sad; they are very common and do not necessarily indicate any underlying pathology. Most affected women go on to have a subsequent normal pregnancy without any intervention.

The data regarding the role of hereditary thrombophilia in pregnancy loss (even recurrent or late loss) is by no means definitive. This is very much the case with respect to the two thrombophilias you mention. Available data are inconsistent. Even when positive associations have been reported, they are weak - e.g., odds ratios of less than two in case control studies. Case control studies almost always exaggerate the strength of association so that when methodologically stronger cohort studies are conducted, the association invariably becomes weaker or even disappears. The available data have not
convinced me that that either of the MTHFR or the prothrombin gene mutation is associated with an increased risk of pregnancy loss. There are no good studies demonstrating benefit to intervention with low molecular weight heparin (LMWH) in women with a single early loss, regardless of the presence of absence of thrombophilia.

As you have mentioned, homozygosity for the MTHFR mutation is not considered thrombophilic (in the absence of elevated homocysteine levels). We no longer offer routine testing for this thrombophilia at our centre.

In the absence of a personal or family history of VTE, there is no role for either antepartum or postpartum prophylaxis in asymptomatic women with thrombophilias other than those considered high risk (e.g., homozzygosity for factor V Leiden).  I would not consider this patient's thrombophilia to be high risk.

Therefore, unless I have missed something, I do not see any role for antepartum or postpartum LMWH in this setting. This patient should ensure that she is taking appropriate folate supplementation during any subsequent pregnancy. As for any pregnant woman, she should be vigilant for signs and symptoms of venous thromboembolism and seek medical attention urgently should they occur. Her need for thrombosis prophylaxis should be re-evaluated if intervening risk factors develop.

I hope that is of some help.

Best regards,


Shannon M. Bates, MDCM, MSc, FRCP(C)
Associate Professor, Department of Medicine
McMaster University
Director, Division of Hematology & Thromboembolism
Discipline Director for Hematology in Laboratory Medicine
Telephone: 905-521-2100, ext. 73928
Fax: 905-521-4997