William H. Kutteh1
(1)
Department of Obstetrics and Gynecology, Vanderbilt University, 80 Humphreys Center, Memphis, TN 38120, USA
William H. Kutteh
Email: wkutteh@fertilitymemphis.com
Keywords
PregnancyInherited thrombophiliasRecurrent pregnancy lossPreeclampsiaIntrauterine growth restrictionPlacental abruptionOB/GYN
Introduction
Three decades ago antiphospholipid antibodies (aPL) were proposed to have a causal association with recurrent pregnancy loss (RPL) , suspected due to placental clots that were observed after pregnancy loss with subsequent positive serum aPLs . Following the hypothesis-inducing investigations, an association was found between aPL and RPL. However, it was not until 1996 that Kutteh et al. found that treatment of pregnant women who have aPL syndrome with heparin and aspirin increased live birth rate to 80 % [1].
With a causal role of aPL established [2], research was driven by further hypotheses that inherited thrombophilias may cause pregnancy losses via their resulting hypercoagulability, and expanded to also include other adverse pregnancy outcomes, including effects on preeclampsia, intrauterine growth restriction (IUGR ) , placental abruption, and stillbirth. The various case control trials that resulted have yielded conflicting conclusions regarding inherited thrombophilias and adverse pregnancy outcomes, and randomized controlled trials are lacking. No causal role has been established to date [3]. Our group performed a survey of the screening and treatment patterns for thrombophilia in pregnancy among obstetricians (OBs) and reproductive endocrinologists (REIs) regarding thrombophilias in pregnancy [4]. We found that many physicians may still screen and treat for inherited thrombophilias beyond the recommendations. This chapter provides an overview of the pathophysiology of the most common inherited thrombophilias, and historical findings of their relationships to adverse pregnancy outcomes. It also summarizes the current recommendations for screening and treatment of inherited thrombophilias [5].
Overview
Inherited thrombophilia is defined as a genetic predisposition to venous thromboembolism (VTE), usually a genetic deletion or alteration of a functional protein in the coagulation cascade.
The most common inherited thrombophilias include factor V Leiden (FVL G1691A) mutation, prothrombin gene mutation (prothrombin G20210A), protein C deficiency (PCD), protein S deficiency (PSD), methyltetrahydrofolate reductase (MTHFR) mutation, and antithrombin III (AT) deficiency. Each of these has a common role in inducing a hypercoagulable state via direct or indirect augmentation of prothrombin to thrombin, its active clot-inducing form (Fig. 5.1). Since hypercoagulability with inherited thrombophilias has been well established, screening of pregnant women with a personal history of VTE has been generally well accepted in practice, with the purpose of providing thromboembolic prophylaxis if needed. This practice is supported by the most recent guidelines, and its acceptance confirmed in our survey findings of physicians’ practices [4]. Screening in the presence of a family history of VTE has also historically been accepted, but has recently been challenged as not being founded on evidence [6–9]. Subsequently, the practice is being reassessed currently, with some evidence against screening in women with a positive family history of VTE [9].
Fig. 5.1
Cascade of thrombus formation. Intrinsic pathway (left side) starts with endothelial damage. Extrinsic pathway (right side) starts with trauma
A larger controversy has existed in the recent past around the utility of screening for inherited thrombophilias in women with a history of adverse pregnancy outcome or loss. Several strong arguments exist against screening in this population. Perhaps most importantly, only weak associations have been found between hypercoagulability and pregnancy outcomes, and no causative relationship has been established [3]. Even more, many inherited thrombophilias are common in the general population, and most of these women have normal pregnancy outcomes [10]. From the standpoint of thromboembolism prevention, some argue that inherited genetic aberrations in clotting proteins are less likely to be significant in the absence of a thromboembolic event history, and that screening this population is akin to screening the general population, which has shown to be cost ineffective [11]. Due to these positions, recommendations are against screening women in this group.
Despite the above arguments and published recommendations regarding the utility of screening in pregnant women with a history of loss or adverse outcome, our findings have suggested that many physicians continue to screen this population. These convictions are not unfounded, and several historical studies support this stance. Most studies in support of this practice hypothesize microthrombi, thrombosis, and infarction of the placenta as a contributing etiology of pregnancy complications or loss [1, 11, 12]. In addition, an argument exists that women with any type of thromboembolic defect have a higher prevalence of pregnancy complications [13]. Following is a summary of the available evidence regarding each inherited thrombophilia in relation to adverse pregnancy outcomes and risk of VTE. All data reported here is assuming an absence of personal or family history of VTE.
Factor V Leiden
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
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 C and Protein S Deficiencies
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 Deficiency
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
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].
Combined Defects
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.
Acquired Thrombophilias
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].
Treatment of Inherited Thrombophilias
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.
Table 5.1
Recommended thromboprophylaxis for pregnancies complicated by inherited thrombophilias
|
Clinical scenario |
Antepartum management |
Postpartum management |
|
Low-risk thrombophiliaa without previous VTE |
Surveillance only or prophylactic heparin |
Surveillance only if no risk factors; postpartum anticoagulation if risk factorsb |
|
Low-risk thrombophiliaa with a single previous episode of VTE—not receiving long-term anticoagulation therapy |
Surveillance only or prophylactic heparin |
Postpartum anticoagulation therapeutic or intermediate-dose heparin |
|
High-risk thrombophiliac without previous VTE |
Prophylactic heparin |
Postpartum anticoagulation therapy |
|
High-risk thrombophiliac with a single previous episode of VTE—not receiving long-term anticoagulation therapy |
Prophylactic, intermediate-dose, or adjusted-dose heparin |
Postpartum anticoagulation therapy or intermediate or adjusted-dose heparin |
|
Thrombophilia or no thrombophilia with two or more episodes of VTE—not receiving long-term anticoagulation therapy |
Prophylactic or therapeutic-dose heparin |
Postpartum anticoagulation therapy or Therapeutic-dose heparin for 6 weeks |
|
Thrombophilia or no thrombophilia with two or more episodes of VTE—receiving long-term anticoagulation therapy |
Therapeutic-dose heparin |
Resumption of long-term anticoagulation therapy |
Based on data from Ref. [47]
aLow-risk thrombophilia: factor V Leiden heterozygous; prothrombin G20210A heterozygous; protein C or protein S deficiency
bFirst-degree relative with a history of a thrombotic episode before age 50 years, or other major thrombotic risk factors (e.g., obesity, prolonged immobility)
cHigh-risk thrombophilia: antithrombin deficiency; double heterozygous for prothrombin G20210A mutation and factor V Leiden; factor V Leiden homozygous or prothrombin G20210A mutation homozygous
Discussion
The most recent ACOG recommendations indicate that evidence is insufficient to screen for thrombophilias based on previous adverse pregnancy outcomes (intrauterine growth restriction, stillbirth, abruption, or pregnancy loss) alone in the absence of additional risk factors for thrombosis [5]. However, around 40 % of physicians treated these women, suggesting that many are still following older literature, which suggests that inherited thrombophilias are associated with adverse pregnancy outcomes [4]. Nevertheless, the authors agree that evidence is not adequate to make a definitive association between these pregnancy outcomes and inherited thrombophilias.
For those who meet appropriate criteria for inherited thrombophilia screening, ACOG recommends that the following tests be ordered: factor V Leiden, prothrombin G20210A, protein C and S, and antithrombin III [5]. Most physicians currently order all of the above, but greater than 40 % of physicians reported also ordering MTHFR and homocysteine levels in their thrombophilia screen, both of which are not considered part of the recommended thrombophilia evaluation according to ACOG. However, some of these decisions may have been based on the well-supported association of MTHFR polymorphisms with neural tube defects [36–38].
Concerning treatment, ACOG recommends that only acquired thrombophilias (antiphospholipid antibody syndrome) be treated for RPL, and then with heparin and aspirin [5, 49]. While over half of physicians appropriately treat these antibodies, a large percentage still only use heparin or aspirin, which has been shown to be inferior to combination therapy [1, 2]. The majority of physicians who treat inherited thrombophilias appropriately use heparin with or without aspirin [4].
Summary of Current State of Research and Future Direction
Overall, discrepancies in the literature do still exist concerning appropriate screening and management of those with prior adverse pregnancy outcomes. Large prospective, multicentered trials and evaluation of national databases, which are currently being conducted, will be required to clearly determine the risks associated with inherited thrombophilias in this regard. Until these data are available, physicians should compare their current practice patterns for thrombophilia screening to the guidelines in the ACOG Practice Bulletin, with an emphasis on individualizing their management where data is not sufficient.
References
1.
Kutteh WH. Antiphospholipid antibody-associated recurrent pregnancy loss: treatment with heparin and low-dose aspirin is superior to low-dose aspirin alone. Am J Obstet Gynecol. 1996;174(5):1584–9.PubMedCrossRef
2.
Rai R et al. Randomised controlled trial of aspirin and aspirin plus heparin in pregnant women with recurrent miscarriage associated with phospholipid antibodies (or antiphospholipid antibodies). BMJ. 1997;314(7076):253–7.PubMedPubMedCentralCrossRef
3.
Rodger MA et al. Inherited thrombophilia and pregnancy complications revisited. Obstet Gynecol. 2008;112(2 Pt 1):320–4.PubMedCrossRef
4.
Davenport WB, Kutteh WH. Inherited thrombophilias and adverse pregnancy outcomes: a review of screening patterns and recommendations. Obstet Gynecol Clin N Am. 2014;41:133–44.
5.
Lockwood C, Wendel G. Practice bulletin no. 124: inherited thrombophilias in pregnancy. Obstet Gynecol. 2011;118(3):730–40.PubMedCrossRef
6.
Wichers IM et al. Assessment of coagulation and fibrinolysis in families with unexplained thrombophilia. Thromb Haemost. 2009;101(3):465–70.PubMed
7.
Villani M et al. Risk of obstetric and thromboembolic complications in family members of women with previous adverse obstetric outcomes carrying common inherited thombophilias. J Thromb Haemost. 2012;10(2):223–8.PubMedCrossRef
8.
Lussana F et al. Pregnancy-related venous thromboembolism: risk and the effect of thromboprophylaxis. Thromb Res. 2012;129(6):673–80.PubMedCrossRef
9.
Horton AL et al. Family history of venous thromboembolism and identifying factor V Leiden carriers during pregnancy. Obstet Gynecol. 2010;115(3):521–5.PubMedPubMedCentralCrossRef
10.
Branch DW. The truth about inherited thrombophilias and pregnancy. Obstet Gynecol. 2010;115(1):2–4.PubMedCrossRef
11.
Bates SM et al. Venous thromboembolism, thrombophilia, antithrombotic therapy, and pregnancy: American College of Chest Physicians evidence-based clinical practice guidelines (8th edn). Chest. 2008;133(6 Suppl):844S–86.PubMedCrossRef
12.
Dizon-Townson DS et al. Fetal carriers of the factor V Leiden mutation are prone to miscarriage and placental infarction. Am J Obstet Gynecol. 1997;177(2):402–5.PubMedCrossRef
13.
Rey E et al. Thrombophilic disorders and fetal loss: a meta-analysis. Lancet. 2003;361(9361):901–8.PubMedCrossRef
14.
Bradley LA et al. Can factor V Leiden and prothrombin G20210A testing in women with recurrent pregnancy loss result in improved pregnancy outcomes? Results from a targeted evidence-based review. Genet Med. 2012;14(1):39–50.PubMedCrossRef
15.
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;7(6), e1000292.PubMedPubMedCentralCrossRef
16.
Howley HE, Walker M, Rodger MA. A systematic review of the association between factor V Leiden or prothrombin gene variant and intrauterine growth restriction. Am J Obstet Gynecol. 2005;192(3):694–708.PubMedCrossRef
17.
Dizon-Townson D et al. The relationship of the factor V Leiden mutation and pregnancy outcomes for mother and fetus. Obstet Gynecol. 2005;106(3):517–24.PubMedCrossRef
18.
Jaaskelainen E et al. M385T polymorphism in the factor V gene, but not Leiden mutation, is associated with placental abruption in Finnish women. Placenta. 2004;25(8-9):730–4.PubMedCrossRef
19.
Prochazka M et al. Factor V Leiden in pregnancies complicated by placental abruption. BJOG. 2003;110(5):462–6.PubMedCrossRef
20.
Rogers BB et al. Avascular villi, increased syncytial knots, and hypervascular villi are associated with pregnancies complicated by factor V Leiden mutation. Pediatr Dev Pathol. 2010;13(5):341–7.PubMedPubMedCentralCrossRef
21.
Silver RM et al. Prothrombin gene G20210A mutation and obstetric complications. Obstet Gynecol. 2010;115(1):14–20.PubMedPubMedCentralCrossRef
22.
Infante-Rivard C et al. Absence of association of thrombophilia polymorphisms with intrauterine growth restriction. N Engl J Med. 2002;347(1):19–25.PubMedCrossRef
23.
Alfirevic Z, Roberts D, Martlew V. How strong is the association between maternal thrombophilia and adverse pregnancy outcome? A systematic review. Eur J Obstet Gynecol Reprod Biol. 2002;101(1):6–14.PubMedCrossRef
24.
Di Nisio M, Middeldorp S, Buller HR. Direct thrombin inhibitors. N Engl J Med. 2005;353(10):1028–40.PubMedCrossRef
25.
Blumenfeld Z, Brenner B. Thrombophilia-associated pregnancy wastage. Fertil Steril. 1999;72(5):765–74.PubMedCrossRef
26.
Preston FE et al. Increased fetal loss in women with heritable thrombophilia. Lancet. 1996;348(9032):913–6.PubMedCrossRef
27.
Sanson BJ et al. The risk of abortion and stillbirth in antithrombin-, protein C-, and protein S-deficient women. Thromb Haemost. 1996;75(3):387–8.PubMed
28.
Peng F et al. Single nucleotide polymorphisms in the methylenetetrahydrofolate reductase gene are common in US Caucasian and Hispanic American populations. Int J Mol Med. 2001;8(5):509–11.PubMed
29.
Krabbendam I, Dekker GA. Pregnancy outcome in patients with a history of recurrent spontaneous miscarriages and documented thrombophilias. Gynecol Obstet Invest. 2004;57(3):127–31.PubMedCrossRef
30.
den Heijer M et al. Hyperhomocysteinemia and venous thrombosis: a meta-analysis. Thromb Haemost. 1998;80(6):874–7.
31.
Eichinger S. Homocysteine, vitamin B6 and the risk of recurrent venous thromboembolism. Pathophysiol Haemost Thromb. 2003;33(5-6):342–4.PubMedCrossRef
32.
den Heijer M et al. Homocysteine lowering by B vitamins and the secondary prevention of deep vein thrombosis and pulmonary embolism: a randomized, placebo-controlled, double-blind trial. Blood. 2007;109(1):139–44.CrossRef
33.
Bezemer ID et al. No association between the common MTHFR 677C → T polymorphism and venous thrombosis: results from the MEGA study. Arch Intern Med. 2007;167(5):497–501.PubMedCrossRef
34.
Nurk E et al. Associations between maternal methylenetetrahydrofolate reductase polymorphisms and adverse outcomes of pregnancy: the Hordaland Homocysteine Study. Am J Med. 2004;117(1):26–31.PubMedCrossRef
35.
Molloy AM et al. Folate status and neural tube defects. Biofactors. 1999;10(2-3):291–4.PubMedCrossRef
36.
Ceyhan ST et al. Thrombophilia-associated gene mutations in women with pregnancies complicated by fetal neural tube defects. Int J Gynaecol Obstet. 2008;101(2):188–9.PubMedCrossRef
37.
Akar N et al. Spina bifida and common mutations at the homocysteine metabolism pathway. Clin Genet. 2000;57(3):230–1.PubMedCrossRef
38.
Molloy AM, Weir DG, Scott JM. Homocysteine, folate enzymes and neural tube defects. Haematologica. 1999;84(Suppl EHA-4):53–6.PubMed
39.
Coulam CB et al. Multiple thrombophilic gene mutations rather than specific gene mutations are risk factors for recurrent miscarriage. Am J Reprod Immunol. 2006;55(5):360–8.PubMedCrossRef
40.
Kutteh WH, Triplett DA. Thrombophilias and recurrent pregnancy loss. Semin Reprod Med. 2006;24(1):54–66.PubMedCrossRef
41.
Brenner B et al. Thrombophilic polymorphisms are common in women with fetal loss without apparent cause. Thromb Haemost. 1999;82(1):6–9.PubMed
42.
Sarig G et al. Thrombophilia is common in women with idiopathic pregnancy loss and is associated with late pregnancy wastage. Fertil Steril. 2002;77(2):342–7.PubMedCrossRef
43.
Kupferminc MJ et al. Increased frequency of genetic thrombophilia in women with complications of pregnancy. N Engl J Med. 1999;340(1):9–13.PubMedCrossRef
44.
Castoldi E et al. Combinations of 4 mutations (FV R506Q, FV H1299R, FV Y1702C, PT 20210G/A) affecting the prothrombinase complex in a thrombophilic family. Blood. 2000;96(4):1443–8.PubMed
45.
Infante-Rivard C et al. Lupus anticoagulants, anticardiolipin antibodies, and fetal loss. A case-control study. N Engl J Med. 1991;325(15):1063–6.PubMedCrossRef
46.
Lockshin MD. Pregnancy loss in the antiphospholipid syndrome. Thromb Haemost. 1999;82(2):641–8.PubMed
47.
Lockwood C, Wendel G, Silverman N. ACOG Practice Bulletin no. 138. Thromboembolism in Pregnancy. Obstet Gynecol 2013;122(3);706–16.
48.
Lonn E et al. Homocysteine lowering with folic acid and B vitamins in vascular disease. N Engl J Med. 2006;354(15):1567–77.PubMedCrossRef
49.
Kutteh WH. Novel strategies for the management of recurrent pregnancy loss. Semin Reprod Med. 2015;33:159–66.CrossRef