Activated factor V is a clotting protein that works in conjunction with activated factor X to directly convert prothrombin to thrombin. A specific mutant form of this protein, factor V Leiden (F5 c.1691G>A; and p.Arg506Gln), is resistant to inactivation, leading to higher amounts of activated factor V, more thrombin formation, and thus a hypercoagulable state (Fig. 5.1). Although its heterozygous form is the most common inherited thrombophilia, its prevalence is still low in the general population [4]. Less than 0.3 % of these heterozygotes will have a VTE in pregnancy [5].

Concerning adverse fetal outcomes, two recent comprehensive reviews of the literature have determined that carriers of FVL G1691A have an increased relative risk for RPL (OR 1.52, 95 % CI: 1.06–2.19; and OR 2.02, 95 % CI: 1.60–2.55) [14, 15]. However, the maternal-fetal medicine (MFM) network also emphasized a low absolute risk (4.2 %) of pregnancy loss in women with FVL G1691A [15]. No significant association exists between FVL G1691A and preeclampsia or small gestational age [15, 16]. Associations between placental abruption and FVL G1691A are also lacking [17–19]. However, a more recent MFM network case–control study, while confirming a lack of association with placental abruption, did find an increase in fetal hypoxia-inducing factors in the placentas of mothers with FVL G1691A compared with age-matched controls [20]. Current guidelines agree that evidence is inadequate to recommend screening for factor V Leiden in women with adverse pregnancy outcomes of any kind [5, 9, 11, 14].

Prothrombin G20210A substitution mutation (F2 c.20210G>A) is the second most common inherited thrombophilia, second only to heterozygous factor V Leiden. A mutated form causes a deficiency in thrombin, with a resulting increase in concentration of prothrombin in the plasma (Fig. 5.1). VTE incidence with prothrombin G20210A is low, with one early study suggesting prothrombin G20210A heterozygotes to have an absolute risk of <0.5 %, and homozygotes to only reach 2–3 %. Concerning RPL, Bradley’s comprehensive literature review suggested that women with this mutation were overall twice as likely to have RPL as those without the prothrombin G20210A mutation (OR 2.07, 95 % CI, 1.59–2.7), but the MFM network determined no association in their case–control study and meta-analysis [14, 15, 21]. Both literature reviews stated that no definitive conclusion could be made about RPL and prothrombin G20210A due to a paucity of studies. There is consensus among all published reviews of literature that no association exists between prothrombin G20210A and preeclampsia or IUGR [15, 16, 22]. One study has suggested a correlation with placental abruption, but most have found no correlation between prothrombin G20210A and placental abruption [16, 21, 23]. Accordingly, the American Congress of Obstetricians and Gynecologists (ACOG) recommends against screening for prothrombin G20210A in women with any history of adverse pregnancy outcomes [5].

Protein S and activated protein C, in combination, are necessary for the activation of factors V and VIII, as summarized in Fig. 5.1. Therefore, a deficiency in either of these proteins can result in a hypercoagulable state. Whereas the risk of VTE during pregnancy with either protein deficiency is up to 7 % in the presence of a personal or family history of VTE, the absolute risk of VTE in the absence of such history is 0.1 % and 0.1–0.8 %, respectively [4]. Further, the prevalence of the disorders is only 0.2–0.3 % in the general population. No studies have found an association between either PCD or PSD and early pregnancy loss, IUGR, or placental abruption. A review of literature from 2002 that included only 3–5 pertinent studies found an increased risk of preeclampsia with PCD (OR 21.5, CI 4.4–414.4) and PSD (OR 12.7, CI 4–39.7), with an absolute risk of 1.4 % and 12.3 %, respectively. The same study suggested an increase in stillbirth among those with PSD (OR 16.2, CI 5–52.3), with an absolute risk of 6 % [23]. However, due to the small number of studies with relatively few participants, ACOG currently does not recommend screening for protein S or protein C deficiency in women with any history of adverse pregnancy outcomes [5].

Antithrombin is a small protein that inactivates both factor Xa and thrombin, and serves as a regulator of clot formation (Fig. 5.1). A rare deficiency in this protein results in severe coagulopathy, increasing the risk up to 25 times those with normal antithrombin levels. Women with antithrombin III deficiency do indeed have an increased risk of embryonic demise and fetal death compared with the general population [24–27]. However, due to the low prevalence (1/2500), screening is not recommended in those with a prior pregnancy loss. Studies observing its effects on other adverse pregnancy outcomes are lacking, also due to low prevalence.

MTHFR is one of the three enzymes that is essential for the metabolism of folic acid, and is responsible for directly converting homocysteine to methionine. A mutation in this enzyme can cause increased levels of substrate homocysteine. Hyperhomocysteinemia debatably can result in a hypercoagulable state at the endothelium, and has historically been associated with RPL [28]; but its relationship to thrombosis is only theoretical [29]. Two predominant mutations exist, MTHFR C677T and A1298C. Most recently, however, evidence has suggested that homocysteine is only a marker for thrombosis rather than a cause, and that it must be combined with other thrombophilias to present any significant risk of VTE [29–33]. Existing data suggests an absence of any correlation with preeclampsia, IUGR, or placental abruption. However, ACOG and the MFM network has determined that data is insufficient to determine the correlation [20, 22, 34]. Accordingly, ACOG does not recommend screening women for MTHFR with any history of adverse fetal outcomes or with a history of VTE [5].

MTHFR polymorphisms are also associated with an increased risk of neural tube defects (NTDs) due to low-serum folic acid [35]. Women delivering a baby with an NTD have more than twice the incidence of having an MTHFR C677T polymorphism [36]. In addition, the combination of MTHFR C677T polymorphism with MTHFR A1298C polymorphism may further increase the risk of NTD [37]. Therefore, we think it is prudent to treat these patients with amounts of folic acid similar to those used to treat patients who had a prior infant with an NTD [36–38].

Most studies have only observed VTE risks on pregnancy outcomes with individual thrombophilias. However, a few have assessed combinations of these disorders, such as FVL G1691A/prothrombin G20210A double heterozygosity, and FVL G1691A in the presence of an MTHFR mutation, concluding that an additive or a synergistic effect is present [26, 39–44]. This distinction should be made, although further exploration of this topic is beyond the scope of our review.

Due to their non-genetic preponderance, acquired thrombophilias are classified separately from inherited thrombophilias, and will be summarized only briefly for the purpose of contrast since these disorders are also beyond the scope of this review. The most common acquired thrombophilia involves the presence of aPL. The presence of these antibodies has been associated with second-trimester as well as first-trimester pregnancy loss [45, 46]. As such, it is recommended to screen for the most common of these antibodies (lupus anticoagulant, anticardiolipin, and anti-beta2 glycoprotein) in women with a history of more than two or three first-trimester losses, and in women with one or more loss after 20 weeks with no alternative explanation [5, 11]. It is also well established that treating these thrombophilias with heparin and aspirin improves pregnancy outcomes [1, 2].

Given the current lack of evidence to support an association between adverse pregnancy outcomes and inherited thrombophilias, it is currently not recommended to treat inherited thrombophilias with adverse pregnancy outcomes alone in mind [4]. However, treatment is justifiable in some patients with known thrombophilias who are at increased risk of VTE during pregnancy [47]. The ACOG treatment recommendations have been abbreviated and summarized in Table 5.1. They specifically address thresholds at which to begin anticoagulants, which can be used to treat all known inherited thrombophilias except MTHFR mutations. Guidelines do not address the treatment of known MTHFR mutations for VTE prevention, but the traditional treatment has been vitamin B and folate. However, evidence now suggests that vitamin B supplementation does not reduce VTE incidence [32, 48]. Therefore, if one decides to test for and treat these mutations, folate alone may be the best choice.