Coagulation problems are in the spotlight in the fertility field, especially when we encounter patients who have problems with implantation failure or repeated miscarriages.
In recent years, anticoagulant and antiplatelet treatments have been used almost indiscriminately in the management of this group of patients, but more and more studies are advocating a much more conservative treatment. Before delving into this topic, we should define what we mean by implantation failure and repeat miscarriage.
What is implantation failure?
According to the Spanish Fertility Society, implantation failure is the absence of gestation after transferring, on at least 3 occasions, 3 good quality embryos in an IVF or oocyte donation cycle. However, and taking into account that currently fewer embryos are transferred in each IVF cycle, other authors1 define implantation failure as the absence of gestation after at least 3 consecutive IVF cycles with the transfer of 1 or 2 high quality embryos.
What are implantation miscarriages?
We speak of repeat miscarriages when a woman has had three or more miscarriages before the 20th week of pregnancy with the same male partner. Although, again, there is a discrepancy between the classic definition of repeat miscarriages and clinical behavior, since, in patients with fertility problems, the study of repeat miscarriages is usually performed after 2 repeated miscarriages instead of 3.
What are coagulation disorders?
The coagulation mechanism acts as a kind of “cascade” in which multiple coagulation factors are involved; alteration in the function or levels of one or more of these factors will have repercussions on coagulation function. Coagulation disorders are known as thrombophilias and can be classified as hereditary or acquired.
Hereditary thrombophilias are those that are linked to genetic alterations; the most frequent are factor V Leiden mutation, factor II mutation, antithrombin deficiency, protein C deficiency, protein S deficiency and methyltetrahydrofolate reductase (MTHFR) gene mutation.
Among the acquired thrombophilias, the most important because of their frequency and clinical implication are antiphospholipid syndrome (APS) and activated protein C resistance not associated with Factor V Leiden.
Relationship between coagulation disorders and fertility
In the last 20 years many studies have been published on the possible association of coagulation disorders with pathologies during pregnancy, mainly repeated miscarriages, placental abruption or intrauterine growth retardation. Lately, these studies have also included their possible effect on embryo implantation failure or absence of pregnancy after fertility treatments. In some cases, studies have shown significant relationships, and in others they have not.
In patients with hereditary thrombophilias, but without previous thrombotic history, and with repeated miscarriages, there are no randomized clinical studies on the efficacy of heparin treatment. This means that, to date, several scientific societies do not recommend its use in these patients.
In the case of antiphospholipid syndrome (acquired thrombophilia of autoimmune origin), defined by presenting at least one clinical and one laboratory criterion (arterial and/or venous thrombosis, unfavorable obstetric outcomes, presence of lupus anticoagulant, anticardiolipin or anti-β2glycoprotein), there is clinical evidence that treatment with anticoagulants (low molecular weight heparin) and antiaggregants (acetylsalicylic acid) improves obstetric outcomes.
In women with a diagnosed thrombophilia and 3 or more previous failed IVF some studies have observed a positive effect of heparin. This effect, however, is not significant without known thrombophilia. Although the main effect of heparin is to act as an anticoagulant, some authors2 argue that it may have an anti-inflammatory and implantation-promoting action. However, this action is difficult to quantify and, therefore, there is not enough scientific evidence to recommend it in a generalized manner.
All these reflections lead us to think that we still have a long way to go in this field, but that the indication for treatment with anticoagulants and antiplatelet agents should be carefully evaluated by hematologists who are experts in fertility and always based on the published scientific evidence. For this reason, at URH García del Real, we have the support of a hematologist specialized in fertility with many years of experience in this field.
1. Simon, A. & Laufer, N. Repeated implantation failure: clinical approach. Fertil. Steril. 97, 1039-1043 (2012).
Nelson, S. M. & Greer, I. A. The potential role of heparin in assisted conception. Hum. Reprod. Update 14, 623-645 (2008).