How common is pregnancy loss? What are the causes?
Pregnancy loss (= miscarriage) in the general population is common. Most losses occur in the first trimester. As many as 5 % of women have 2 or more early losses; 1-2 % have 3 or more early losses [ref 1]. Well established risk factors for pregnancy loss are: (a) advanced age of the mother, (b) anatomic abnormalities of the uterus (such as fibroids), (c) chromosome abnormalities of fetus, the mother or the father, (d) underlying diseases of the mother (endocrine, immunologic), (e) maternal hormonal unbalances. The acquired clotting disorder called “antiphospholipid antibody syndrome” is also a risk factor for pregnancy loss. The role of inherited clotting disorders (= thrombophilias) contributing to pregnancy loss is less clear.
Are clotting disorders risk factors for pregnancy loss?
a) Acquired Clotting Disorders: Repeatedly and clearly positive antiphospholipid antibodies (= APLA) are associated with pregnancy loss [ref 2]. APLA are proteins that are made by the body’s immune system. Often it is not clear why certain people make them. A person can make a variety of different APLA and there are a number of tests that can be done to test for them:
- Lupus anticoagulant
- anticardiolipin antibodies
- anti-beta-2-glycoprotein-I antibodies
- anti-phosphatidyl-serine antibodies
- anti-phosphatidyl-inositol antibodies
- anti-phosphatidyl-ethanolamine antibodies.
However, only the first three in the list above are well established risk factors for pregnancy loss [ref 2,3]. APLA have to be clearly elevated and repeatedly positive (preferably 3 or more months apart) before they are considered to be relevant / significant.
b) Inherited Clotting Disorders
A number of inherited clotting disorders exist that put people at risk for blood clots, most commonly clots in the legs (deep vein thrombosis = DVT) and lung (pulmonary embolism = PE). In theory, these clotting disorders may also lead to blood clots in the placenta and, thus, decreased oxygen delivery to the unborn, and miscarriages. Investigators have, therefore, looked whether these clotting disorders are associated with pregnancy loss. And, indeed, some of them are: (a) Factor V Leiden and the prothrombin 20210 mutation are slight risk factors for pregnancy loss [ref 2]; (b) The 3 clotting disorders “Protein C, S, and antithrombin deficiency” are uncommon and, therefore, not enough data exist as to whether they increase the risk for pregnancy loss; (c) Some genetic variants in a gene called MTHFR (methylene-tetrahydrofolate reductase) was, in the past, thought to be a risk factor for blood clots and pregnancy loss. However, in recent years they have been found to neither cause clots nor pregnancy loss, and, therefore, should not be considered any more a clotting disorder [ref 4].
It is important to keep in mind that the risk for pregnancy loss in women with thrombophilia is low: the majority of women with thrombophilia will have a successful pregnancy [ref 5]. To summarize, the potentially relevant inherited clotting disorders to be considered in pregnancy loss, are:
- Factor V Leiden
- Prothrombin 20210 mutation (also referred to as factor II mutation)
- Protein C deficiency
- Protein S deficiency
- Antithrombin deficiency
In women with pregnancy loss and thrombophilia, do “blood thinners” prevent future pregnancy losses?
a) APLA: Treatment with heparin plus aspirin in women with a history of pregnancy losses who have APLA leads to a higher live birth rate in a subsequent pregnancy compared to no treatment. Therefore, heparin plus aspirin treatment is recommended in women with pregnancy loss associated with APLA [ref 2,6].
b) Inherited Clotting Disorders: At present it is not known whether treatment with heparin and/or aspirin in women with a history of pregnancy losses and inherited thrombophilia leads to an increase in live birth rate in a subsequent pregnancy [ref 2]. The potential benefit of therapy – i.e. higher live birth rate – needs to be weighed against the potential downsides of treatment – i.e. cost, inconvenience, discomfort, risk for bleeding, skin reactions, the complication called “heparin induced thrombocytopenia” or HIT, withholding of epidural anesthesia, induction of labor. An individual decision needs to be made in discussion with the woman.
c) Women with pregnancy loss and no detectable thrombophilia:Data to this date show that there is no benefit of giving heparin and/or aspirin therapy to women with unexplained pregnancy loss who do not have a detectable clotting disorder.
What should the woman WITH pregnancy loss know?
- One or more pregnancy losses are common in the general population.
- The majority of women with 1, 2 or 3 pregnancy losses have a successful subsequent pregnancy WITHOUT any treatment.
- The majority of pregnancy losses is not explained by clotting disorders, but is due to other causes.
- The woman with 3 or more 1st trimester pregnancy losses or 1 or more losses after week 10 should be worked up for a variety of causes (chromosomal abnormalities, anatomic uterus abnormalities, endocrine disorders, hormonal abnormalities) before being defined as having “unexplained” pregnancy losses.
- If the woman truly has recurrent early or one or more later UNEXPLAINED losses, thrombophilia work-up can be considered. Appropriate testing should/could are:
- Lupus anticoagulant
- anticardiolipin IgG and IgM antibodies
- anti-beta-2-glycoprotein-I IgG and IgM antibodies
- factor V Leiden
- prothrombin 20210 mutation
- protein C activity (also called functional protein C)
- protein S activity (also called functional protein S)
- antithrombin activity (also called functional antithrombin).
- If one of these clotting disorders is clearly / unequivocally found, then discussion of heparin therapy with or without aspirin can be discussed, weighing all the risks and benefits of treatment.
What should the woman with a known thrombophilia, but WITHOUT a history of pregnancy loss know if she plans to get pregnant?
- The majority of women who have a thrombophilia have uneventful pregnancies
- Thrombophilias are only very mild risk factors for pregnancy loss.
- A discussion should be held with the woman’s physician whether heparin therapy might be needed to prevent blood clots in the legs (deep vein thrombosis = DVT) or lung (pulmonary embolism = PE).
- Barely ever is there an indication for therapy with “blood thinners” purely to prevent pregnancy loss.
- Rai R et al. Recurrent miscarriage. Lancet. 2006;368:601-611.
- Bates SM. Consultative hematology: the pregnant patient pregnancy loss. Am Soc Hematol Educ Program. 2010;2010:166-172.
- Alijotas-Reig J et al. Anti-β2-glycoprotein-I and anti-phosphatidylserine antibodies in women with spontaneous pregnancy loss. Fertility and Sterility 2010;93:2330-2336.
- Rey E et al. Thrombophilic disorders and fetal loss: a meta-analysis. Lancet 2003 Mar 15;361(9361):901-8.
- Rodger MA et al. The association of factor V Leiden and prothrombin gene mutation and placenta-mediated pregnancy complications: a systematic review and meta-analysis of prospective cohort studies. PLoS Med. 2010 Jun 15;7(6):e1000292.
- Bates SM et al. Venous thromboembolism, thrombophilia, antithrombotic therapy, and pregnancy: Amercian College of Chest Physicians evidence-based clinical practice guideline (8th edition).Chest. 2008 Jun;133(6 Suppl):844S-886S.