In general, the reported linkage between inherited thrombophilia and adverse outcomes other than stillbirth was always more tenuous. In the case of preeclampsia, however, meta-analyses of studies done before 2000 showed a fairly strong association between thrombophilia and preeclampsia, while studies published in and after 2001 found no such association.
There are a few exceptions to the lack of association found in larger prospective cohort studies. Most notably, an Australian study published this year of nulliparous women was suggestive of a weak association between the PGM and a composite index of adverse pregnancy outcomes (Obstet. Gynecol. 2010;115:5-13).
However, when investigators analyzed individual outcomes, they found that the only statistically significant associations were between the PGM and placental abruption, and between FVL and stillbirth. These associations, moreover, were based on very small sample size (nine and six patients, respectively). The investigators concluded that “the majority of asymptomatic women who carry an inherited thrombophilia polymorphism have a successful pregnancy outcome.”
There also is, at best, conflicting evidence in the literature of any benefit to heparin therapy for recurrent fetal loss.
A New Outlook on Screening
Given the evolving body of literature, it now seems wholly unjustified to screen low-risk populations. Knowing whether or not the patient has inherited thrombophilia, particularly in the nulliparous state, does not appear to be important for predicting outcomes.
There are questions that remain, however—most notably the question of whether women who have repetitive fetal losses or repetitive preeclampsia or abruptions should be screened and treated for inherited thrombophilia. Certainly, the failure of large prospective cohort studies to demonstrate any consistent association dampens our enthusiasm for the idea that inherited thrombophilia are to blame.
My opinion on this topic has evolved considerably over the last 10 years. I now believe that while screening for antiphospholipid syndrome is still warranted, screening for inherited thrombophilia in women having recurrent adverse pregnancy outcomes should occur only in the setting of an institutional review board–approved study in which ascertainment is done before a subsequent pregnancy and the patient's thrombophilia status is correlated with subsequent outcome (i.e., live birth, miscarriage, stillbirth, fetal growth restriction, preeclampsia, or abruption).
Furthermore, until we have established a definitive link between inherited thrombophilia and adverse pregnancy outcomes, we shouldn't even begin to think about clinical trials of thromboprophylaxis for affected women.
A particularly thorny question that has been raised concerns the issue of early fetal loss. Some have argued that the latest prospective cohort studies involved blood collection at or after 10 weeks' gestation and, therefore, are not relevant to conclusions drawn about the association (or lack thereof) between inherited thrombophilia and embryonic fetal loss.
However, I believe there are several reasons why we can conclude that thrombophilia and embryonic fetal losses are not linked. For one, there are enough data available from negative retrospective studies in which blood was obtained right after the pregnancy was completed. Secondly, there is no correlation between inherited thrombophilia and subsequent in vitro fertilization (IVF) failures in almost a dozen published studies. In fact, there is actually some evidence that FVL is associated with IVF success.
Lastly, we now know there is very little blood flow to the placenta before 10 weeks' gestation. There is some evidence, in fact, that hypoxia is the normal state of the embryo and may even be the preferred condition for culturing embryos in IVF.
Again, this issue requires prospective studies amongst patients with recurrent loss in which ascertainment occurs before the pregnancy commences.
Maternal Thrombotic Risk
While it's fair to say that, in general, inherited thrombophilia modestly increases the risk of maternal venous thrombotic events (VTE), it is critical to appreciate the role that a personal or strong family history of thrombosis (i.e., an affected first-degree relative) plays in determining a mother's risk.
Most women (greater than 93%) without a personal or strong family history of VTE will have uneventful pregnancies even when highly thrombogenic mutations are present. Once a personal or family history is factored in, however, the risk of VTE increases dramatically.
In the absence of a personal history of VTE or such an episode in a first-degree relative, heterozygosity for FVL or PGM is associated with a risk of thrombosis in pregnancy of well under 1% (0.2% and 0.5%, respectively). Similarly, protein C and protein S deficiencies are associated with a VTE risk under 1% in the absence of a personal or close family history.
In contrast, with a positive personal or family history, the risk of VTE in pregnancy increases to 10% in women who have heterozygosity for FVL, greater than 10% for women who have heterozygosity for PGM, 4%-17% in cases of protein C deficiency, and potentially up to 22% in cases of protein S deficiency.