Inherited thrombophilias in pregnancy

INTRODUCTION — Inherited (hereditary) thrombophilias are genetic conditions that increase the risk for thromboembolic disease. During pregnancy, the thrombogenic potential of these hereditary disorders is enhanced because of the hypercoagulable state produced by normal pregnancy-associated physiologic changes in several coagulation factors. (See "Maternal adaptations to pregnancy: Hematologic changes", section on 'Coagulation and fibrinolysis'.)

The best documented potential sequelae of the hypercoagulable state are maternal deep venous thrombosis and pulmonary embolism; arterial thrombosis is rare [1]. A modest association with some adverse pregnancy outcomes (eg, recurrent and nonrecurrent pregnancy loss) has been suggested, but this is controversial and the body of evidence suggests treatment with an anticoagulant does not improve subsequent pregnancy outcome.

This topic will discuss issues related to inherited thrombophilias in pregnant patients. Issues related to inherited thrombophilias in other settings are reviewed elsewhere.

●Nonpregnant patients – (See "Overview of the causes of venous thrombosis", section on 'Inherited thrombophilia' and "Screening for inherited thrombophilia in asymptomatic adults".)

●Nonpregnant patients undergoing fertility therapy – (See "In vitro fertilization: Procedure", section on 'Preparation'.)

INHERITED THROMBOPHILIAS — The most common inherited thrombophilias are:

●Factor V Leiden (FVL) variant – (See "Factor V Leiden and activated protein C resistance".)

●Prothrombin G20210A variant – (See "Prothrombin G20210A".)

●Protein S deficiency – (See "Protein S deficiency".)

●Protein C deficiency – (See "Protein C deficiency".)

●Antithrombin (AT) deficiency – (See "Antithrombin deficiency".)

The FVL and prothrombin G20210A variants (also called the prothrombin gene mutation [PGM]) together account for 50 to 60 percent of cases of an inherited (primary) hypercoagulable state in White populations. Deficiencies in protein S, protein C, and AT account for most of the remaining cases. Although collectively prevalent in approximately 10 percent of White populations, these disorders appear to be responsible, at least in part, for up to one-half of maternal venous thromboembolism (VTE) [2]. Of note, the prevalence of an inherited thrombophilia in White populations can vary by ethnicity [3].

High-risk types — Individuals with the following inherited thrombophilias are at higher risk for VTE:

●AT deficiency

●FVL homozygote

●Prothrombin G20210A homozygote

●Heterozygosity for both FVL and prothrombin G20210A

Low-risk types — Individuals with the following inherited thrombophilias are at lower risk for VTE:

●FVL heterozygote

●Prothrombin G20210A heterozygote

●Protein C deficiency

●Protein S deficiency

KNOWN AND POSSIBLE COMPLICATIONS — Inherited thrombophilias increase the risk of maternal venous thromboembolism (VTE).

It has been hypothesized that they also increase the risk of thrombosis at the low flow maternal-placental interface, resulting in placenta-mediated complications, such as pregnancy loss, preeclampsia, fetal growth impairment, and abruption; however, data do not clearly support an increase in these adverse pregnancy outcomes.

Maternal VTE risk — In all pregnant patients, the risk of VTE increases because of physiologic changes in the coagulation system; predisposing physical changes, such as stasis in the large veins of the lower extremities from uterine compression and compression of the left iliac vein by the right iliac artery; and decreased mobility and vascular injury accruing from the delivery process (especially cesarean birth). The risk is augmented in the presence of traditional risk factors for VTE, such as recent surgery, age over 35 years, obesity, smoking, and immobilization [4]. Nevertheless, the overall absolute risk of VTE is low at approximately 0.1 percent. (See "Deep vein thrombosis in pregnancy: Epidemiology, pathogenesis, and diagnosis".)

In pregnant patients with an inherited (or acquired) thrombophilia, the risk of VTE is increased above the risk associated with pregnancy alone [5-10]. Data suggest that up to 50 percent of White patients with VTE during pregnancy have an inherited or acquired thrombophilia [11].

There are two major factors that affect the magnitude of risk of VTE in pregnant patients with an inherited thrombophilia:

●Patients with high-risk inherited thrombophilias are at higher risk than those with low-risk inherited thrombophilias (table 1)

●Patients with a personal history of VTE or VTE in a first-degree relative are at higher risk of VTE than those with a negative history [12]

Evidence — The reported risks of VTE vary among studies because of differences in study design.

●Females with high-risk thrombophilias – Females with a high-risk thrombophilia have a high absolute risk of pregnancy-associated VTE. In one study, the absolute risks of thrombosis during pregnancy and the puerperium were as follows, and the risk was independent of a positive family history of thrombosis [13]:

•Antithrombin (AT) deficiency (<60 percent activity)

-6.1 percent at age <35 years

-9.0 percent at age ≥35 years

•Factor V Leiden (FVL) homozygote

-2.2 percent at age <35 years

-3.4 percent at age ≥35 years

•Heterozygosity for both FVL and prothrombin G20210A

-5.5 percent at age <35 years

-8.2 percent at age ≥35 years

●Females with low-risk thrombophilias – In contrast to females with high-risk thrombophilias, studies suggest that the risk of pregnancy-associated VTE in asymptomatic patients with FVL, prothrombin G20210A, or deficiencies of protein S or protein C is low. In the absence of other major risk factors for VTE, one study reported the following risks of thromboembolism in such patients [13]:

•FVL heterozygote

-0.5 percent at age <35 years

-0.7 percent at age ≥35 years

•Prothrombin G20210A heterozygote

-0.4 percent at age <35 years

-0.6 percent at age ≥35 years

•Protein C deficiency

-0.7 percent at age <35 years

-1.1 percent at age ≥35 years

•Protein S deficiency

-0.7 percent at age <35 years

-1.0 percent at age ≥35 years

●Females with an inherited thrombophilia plus a positive personal or family history of thrombosis have a high absolute risk of VTE during pregnancy.

•An observational study of 23 female carriers of thrombophilic variants with a personal history of thrombosis reported that the overall risk of recurrent VTE related to pregnancy was 26 percent per patient-year of observation [14]. VTE occurred in 7 of 28 (25 percent) pregnancies managed without prophylactic anticoagulation and in 1 of 12 (8 percent) pregnancies of women treated with anticoagulants. The types and numbers of thrombophilias included FVL heterozygote (8), AT deficiency (6), protein S or C deficiency (7), prothrombin G20210A heterozygote (2).

•In another series of 25 females with thrombophilia and a personal history of one previous unprovoked or idiopathic VTE, VTE recurred in four (16 percent; two antepartum and two postpartum), despite postpartum anticoagulation [15]. The thrombophilias included FVL and prothrombin G20210A heterozygotes and deficiencies of protein S, C, or AT.

•Results from the Thrombophilia in Pregnancy Prophylaxis Study (TIPPS) randomized trial also showed an increased frequency of VTE in females with an inherited thrombophilia plus a positive personal or family history of thrombosis, but the absolute rate was lower: 1.4 percent (without treatment) [16]. The 292 patients in this trial had either thrombophilia associated with an increased risk of VTE or previous placenta-mediated pregnancy complications, and, importantly, 40 percent also had a first-degree family member with a VTE or a personal history of VTE. The types and approximate proportions of thrombophilias were FVL (61 percent), prothrombin G20210A (22 percent), antiphospholipid syndrome (8 percent), protein S or C deficiency (14 percent), and AT deficiency (1 percent).

●By contrast, females with low-risk inherited thrombophilias and no personal or family history of VTE appear to have a low absolute risk of VTE [17-20]. Although both of the following studies were underpowered to rule out a modest association between FVL and VTE, they underscore the low risk of thrombosis in asymptomatic (no prior VTE) carriers of these variants.

•In a prospective study of patients with low-risk pregnancies and no history of thromboembolism, 0 of the 134 those heterozygous for FVL had a VTE during pregnancy or up to six weeks postpartum [17].

•In a prospective study of 1707 nulliparous Australian patients with no prior history of adverse pregnancy outcome or personal or family history of VTE, 0 of 92 pregnant patients heterozygous for FVL and 0 of 41 pregnant patients heterozygous for prothrombin G20210A developed VTE [18].

Adverse pregnancy outcome risk — It is unlikely that inherited thrombophilia is a major risk factor for most adverse pregnancy outcomes, including miscarriage, fetal demise, fetal growth restriction, and placental abruption. If there is any association between inherited thrombophilia and these adverse pregnancy outcomes, it is likely modest and limited to high-risk populations.

Most prospective studies have found no significant association [17-22] whereas several retrospective studies suggested a modest link between FVL heterozygosity (and possibly prothrombin G20210A heterozygosity and protein C or S deficiency) and fetal loss after 10 weeks of gestation, and particularly for nonrecurrent loss after 20 weeks [23-26]. The discordancy between prospective studies and small case-control or retrospective cohort studies involving heterogeneous populations is likely due to the influence of various confounders that are often not analyzed appropriately [27,28]. Publication bias likely also plays a role.

Fetal/neonatal risk in those with an inherited thrombophilia — Fetal demise, growth restriction, preterm birth, perinatal stroke, and cerebral palsy have been reported in offspring with inherited thrombophilic variants, but there were only a few affected patients [29-34]. The proposed mechanism is thrombosis on the fetal side of the placenta.

SELECTION OF PATIENTS FOR TESTING

Our approach — Routinely testing for inherited thrombophilias in unselected populations is not recommended because of the low frequency of the condition becoming symptomatic and the lack of a safe, cost-effective, long-term method of prophylaxis against thromboembolism [4,35]. Furthermore, there is no strong evidence on which to base recommendations regarding whom to test or the optimal panel of tests. (See "Screening for inherited thrombophilia in asymptomatic adults" and "Venous thromboembolism in pregnancy: Prevention".)

We believe testing is appropriate in the following nonpregnant patients who are planning to become pregnant:

●History of venous thromboembolism (VTE) associated with a transient nonhormonal provoking factor – Testing is appropriate in females of childbearing potential with history of VTE associated with transient nonhormonal provoking factors, such as femoral fracture, surgery, or prolonged immobilization. Testing results are useful because:

•Those with no hereditary thrombophilic defect are at low risk for recurrent thrombosis and do not require antepartum thromboprophylaxis. They should, however, receive postpartum anticoagulant prophylaxis. (See 'Overview of antepartum and postpartum anticoagulation' below.)

•Those with a thrombophilic defect are at higher risk of VTE both during pregnancy and the postpartum period [15]. The magnitude of this risk and management of these patients, however, may depend upon the defect. (See 'Prevention of VTE' below and 'Prevention of pregnancy complications' below.)

●History of idiopathic (unprovoked) VTE, recurrent VTE, or VTE in association with estrogen-progestin contraceptive use or pregnancy – These females are at relatively high risk of recurrent thrombosis and should receive prophylactic anticoagulation antepartum regardless of thrombophilia status. (See 'Prevention of VTE' below.)

However, we believe testing is still useful in this population because the presence and type of thrombophilia affect the anticoagulant dose.

•In patients with this history and no laboratory evidence of an inherited thrombophilia, we prescribe low-dose anticoagulation.

•In patients with this history and an inherited thrombophilia, we prescribe either low-, intermediate-, or therapeutic-dose anticoagulation, depending on patient-specific factors. (See 'Our approach to patients with high-risk thrombophilias' below and 'Our approach to patients with lower risk thrombophilias' below.)

●No prior VTE but a first-degree relative with a history of a high-risk thrombophilia – We believe testing is reasonable in asymptomatic (no prior VTE) females planning a pregnancy who have a first-degree relative with a history of a high-risk thrombophilia. Identification of a heritable thrombophilic defect in the relative can narrow the laboratory evaluation to determine whether or not the patient carries the specific defect.

The rationale for such testing is that antepartum and postpartum prophylaxis are indicated if the asymptomatic patient is a carrier of one of the more highly thrombogenic defects (eg, antithrombin deficiency, double heterozygosity or homozygosity for factor V Leiden [FVL] and/or prothrombin gene mutation). (See 'Our approach to patients with high-risk thrombophilias' below.)

If the asymptomatic patient is heterozygous for one of the less thrombogenic defects (eg, heterozygous FVL), thromboprophylaxis may be indicated in the presence of other risk factors for VTE (eg, prolonged immobilization, cesarean birth, or a first-degree relative with unprovoked VTE before age 50 years) [36-38].

We would not test the following patients:

●Females with a history of recurrent or nonrecurrent pregnancy loss, abruption, fetal growth restriction, or preeclampsia – There is a lack of evidence of a causal association between inherited thrombophilia and these conditions and a lack of evidence that administration of anticoagulant drugs to such patients is effective in improving pregnancy outcomes [37,39,40]. We have tested patients with a history of fetal loss associated with substantial maternal decidual vasculopathy and thrombi with placental infarction; however, these cases are rare.

●Couples with in vitro fertilization failure – Inherited thrombophilia is not associated with failure to conceive or implantation failure. FVL heterozygosity is associated with a significantly shorter median time to conception (11 weeks) compared with noncarriers (23 weeks; hazard ratio 1.94, 95% CI 1.03-3.65), suggesting improved implantation rates [41]. Inherited thrombophilias have been associated with higher live birth rates following assisted reproductive technologies, further evidence of thrombophilia-associated enhanced implantation [42].

Recommendations of others

●The American College of Obstetricians and Gynecologists (ACOG) suggests testing for thrombophilia when the results will affect pregnancy/postpartum management, including either of the following [39]:

•Patients with a personal history of VTE, with or without a recurrent risk factor, and no prior thrombophilia testing

•Patients with a first-degree relative (eg, parent or sibling) with a high-risk inherited thrombophilia

ACOG recommends not testing mothers of stillborns for inherited thrombophilias (but does recommend testing for antiphospholipid syndrome) [43].

●The American Society of Hematology 2023 guidelines for thrombophilia testing made conditional recommendations for thrombophilia testing, which included the below scenarios [44]. The term "conditional" was used when the guideline panel "suggested" a recommendation as opposed to making a "strong" recommendation.

•Pregnant individuals with a family history of high-risk thrombophilia types.

In patients with a family history of VTE and known homozygous FVL, combination of FVL and PGM, or antithrombin deficiency in the family, testing is suggested for the known familial thrombophilia. For those with the same familial thrombophilia, antepartum and postpartum thromboprophylaxis is suggested. For those without the same familial thrombophilia, no antepartum or postpartum prophylaxis is suggested.

In patients with a family history of VTE and known protein C or protein S deficiency in the family, either testing for the known familial thrombophilia or not testing for thrombophilia is suggested to guide prophylaxis.

•Patients with VTE associated with nonsurgical major transient or hormonal risk factors

•Patients with cerebral or splanchnic venous thrombosis, in settings where anticoagulation would otherwise be discontinued

•Patients with a family history of antithrombin, protein C or protein S deficiency when considering thromboprophylaxis for minor provoking risk factors, and for guidance to avoid hormonal contraceptives or menopausal hormone therapy

•Patients with cancer at low or intermediate risk of thrombosis and with a family history of VTE

Testing nonpregnant people with and without VTE for thrombophilias is discussed in detail separately. (See "Screening for inherited thrombophilia in asymptomatic adults", section on 'General screening issues' and "Evaluating adult patients with established venous thromboembolism for acquired and inherited risk factors".)

LABORATORY TESTING

Test panel — We recommend testing for the following inherited thrombophilias:

●Antithrombin deficiency – (See "Antithrombin deficiency", section on 'Diagnostic evaluation'.)

●Factor V Leiden – (See "Factor V Leiden and activated protein C resistance", section on 'Diagnostic tests'.)

●Protein S deficiency – (See "Protein S deficiency", section on 'Diagnosis'.)

●Protein C deficiency – (See "Protein C deficiency", section on 'Diagnostic evaluation'.)

●Prothrombin G20210A – (See "Prothrombin G20210A", section on 'Diagnosis'.)

In addition, patients with indications for evaluation for a thrombophilia should undergo evaluation for antiphospholipid syndrome (APS), which is an acquired thrombophilia. The diagnosis of APS is based upon a combination of clinical features and laboratory findings (table 2). (See "Diagnosis of antiphospholipid syndrome".)

When to test

●Molecular analysis for genetic variants can be performed anytime.

●Non-molecular laboratory testing (eg, activated protein C resistance ratio, functional assay for protein C, free protein S antigen assay, antithrombin-heparin cofactor assay):

•For patients who are pregnant or were recently pregnant, the ideal time is to wait until at least three months following delivery and after terminating breastfeeding to exclude pregnancy-related effects [4,45]. Normalization of coagulation parameters and factor levels postpartum varies depending upon the factor, but all should return to baseline by six to eight weeks after delivery, as long as the patient is not using hormonal contraception [46]. It is also preferable to perform testing when the patient is off anticoagulation [4].

Tests to avoid — We recommend not performing the following tests as part of thrombophilia testing: homocysteine level, methylenetetrahydrofolate reductase (MTHFR) polymorphism (C677T, A1298C) testing, plasminogen activator inhibitor-1 (PAI-1) polymorphism testing, or factor VIII level.

●Homocysteine level – We do not check homocysteine levels for several reasons.

•In the United States population, homocysteine levels have decreased since folic acid fortification of flour and enriched grain products was mandated; thus, fewer patients with venous thromboembolism (VTE) are found to have high homocysteine levels.

•Pregnant patients are routinely prescribed multivitamins containing folic acid to reduce the risk of neural tube defects.

•High homocysteine levels are a weaker risk factor for VTE or arterial thrombosis than reported in early studies (odds ratio 1.2-1.6 versus 2.0) [47] and may not be an independent risk factor at all [48]. Furthermore, intervention studies with B vitamin supplementation, albeit in nonpregnant patients, do not show a reduction in arterial or venous thrombotic events [49-51]. (See "Overview of homocysteine" and "Evaluating adult patients with established venous thromboembolism for acquired and inherited risk factors".)

●MTHFR and PAI-1 polymorphisms – In our opinion, the available studies linking MTHFR and PAI-1 polymorphisms with preeclampsia and other adverse pregnancy outcomes have many limitations and do not provide any evidence for testing patients with an adverse pregnancy outcome or using the results of prior testing to influence patient management.

Homozygosity for MTHFR polymorphisms (C677T, A1298C) is a relatively common cause of mildly elevated plasma homocysteine levels in the general population, often occurring in association with serum folate levels in the low normal range. High-quality epidemiologic studies (eg, Leiden Thrombophilia Study, Physicians' Health Study) found no significant increase in VTE risk among individuals homozygous for MTHFR polymorphisms [52-55]. Data that MTHFR polymorphisms carry no additional risk in pregnancy are less definitive but clearly trend that way [56].

The prevalence of the PAI-1 polymorphism (4G/5G) is very high (approximately 50 percent) in the general population, and 20 to 25 percent of these individuals are homozygous for the purported 4G/4G "thrombogenic" genotype. The latter is associated with a two- to threefold increase in PAI-1 levels, and these levels can be even higher in patients with metabolic syndrome and those with the D/D genotype in the ACE gene. The available studies linking these genotypes with preeclampsia and other adverse pregnancy outcomes have many limitations and do not provide any evidence for testing patients with an adverse pregnancy outcome or using the results of prior testing to influence patient management.

●Factor VIII level – Increased levels of some procoagulant factors other than prothrombin are risk factors for VTE. For example, elevated factor VIII coagulant activity is a prothrombotic risk factor for a first unprovoked VTE; however, elevated levels should not be viewed as an inherited thrombophilia. Furthermore, assays for factor VIII levels have not been standardized, and there is no information on the interpretation of factor VIII levels in pregnancy with respect to prothrombotic risk. (See "Overview of the causes of venous thrombosis", section on 'Factor VIII'.)

PREVENTION OF VTE

Overview of antepartum and postpartum anticoagulation — In pregnant patients with inherited thrombophilias, the goal of treatment is prevention of maternal venous thromboembolism (VTE). Based on data cited in the discussion above, as well as indirect evidence from studies in nonpregnant individuals, we suggest the following approach (table 3A-B). Our anticoagulation regimens are slightly different from those of the American College of Obstetricians and Gynecologists (ACOG).

●Antepartum/intrapartum – Ideally, anticoagulation should be initiated in the first trimester since the risk of VTE increases early in pregnancy. Details regarding anticoagulation administration are discussed in the sections below.

Anticoagulation should be discontinued at onset of labor or before scheduled induction or cesarean birth to minimize risk of hemorrhagic complications, including those related to placement of neuraxial anesthesia; timing (12 or 24 hours) depends upon the type and dose of anticoagulant. (See "Neuraxial anesthesia/analgesia techniques in the patient receiving anticoagulant or antiplatelet medication".)

●Postpartum – Because postpartum risk of VTE is as high or higher than antepartum risk, postpartum treatment dosing regimens should be as, or even more, aggressive as antepartum regimens, and postpartum treatment is sometimes indicated for patients who did not receive antepartum anticoagulation [39,57,58].

Postpartum heparin can be started no sooner than 4 to 6 hours after a vaginal birth or 6 to 12 hours after a cesarean birth in patients with normal postpartum bleeding; warfarin therapy can begin immediately after delivery since it takes a few days to achieve anticoagulation [59]. However, a longer interval may be recommended after placement of a neuraxial catheter, especially if traumatic, for labor anesthesia. (See "Neuraxial anesthesia/analgesia techniques in the patient receiving anticoagulant or antiplatelet medication".)

Details regarding anticoagulation administration are discussed in the sections below.

Our approach to patients with high-risk thrombophilias — We suggest that all patients with high-risk thrombophilias receive anticoagulation antepartum and postpartum, whether or not they have a personal or family history of VTE. (See 'High-risk types' above and 'Maternal VTE risk' above.)

●For patients with high-risk thrombophilias who are on long-term anticoagulation prior to becoming pregnant, our practice is to administer therapeutic doses of low molecular weight heparin (LMWH).

If antithrombin (AT) deficiency is identified, adding treatment with AT concentrate in the peripartum period would be reasonable. These patients typically have a history of unprovoked VTE.

•For patients with hereditary AT deficiency and either a personal history of thrombosis or a compelling family history (eg, multiple family members with thrombosis, family member with unprovoked thrombosis), we suggest administering AT just prior to and at the time of delivery when anticoagulation cannot be administered (ie, from the time LMW or unfractionated heparin is discontinued in anticipation of delivery, until postpartum anticoagulation is resumed). This practice is based on the high risk of VTE during pregnancy in such patients and the efficacy of AT replacement described in case reports and our experience [60]. (See "Antithrombin deficiency", section on 'Pregnancy'.)

Anticoagulation should be resumed as soon as possible postpartum.

•Patients with no personal history of thrombosis often can be managed with a single dose of AT concentrate just prior to delivery, while women with recurrent VTE or VTE during pregnancy may need additional doses postpartum along with therapeutic anticoagulation.

•Patients with hereditary AT deficiency without a personal or family history of thromboembolism may be treated with anticoagulation alone.

●For patients with high-risk thrombophilias without a history of VTE and not on long-term anticoagulation, we administer either low- or intermediate-dose LMWH antepartum and intermediate-dose LMWH postpartum as a single daily dose (table 3A-B).

Our anticoagulation regimens are slightly different from those of the American Society of Hematology (ASH) [38] and ACOG guidelines [39].

Our approach to patients with lower risk thrombophilias — The management of patients with lower risk thrombophilias depends upon their personal history of thrombotic events as well as other standard VTE risk factors. (See 'Low-risk types' above.)

Prior VTE — Patients with lower risk thrombophilias and a single prior VTE episode that was unprovoked or associated with a hormonal risk factor are at high risk of pregnancy-related thrombosis and should receive antepartum and postpartum anticoagulation (table 3A-B). (See 'Maternal VTE risk' above.)

Patients with lower risk thrombophilias and a single prior VTE episode that was associated with a nonhormonal temporary provoking risk factor and no other risk factors for VTE are not at a similar high risk of antepartum thrombosis. We do not administer antepartum anticoagulation to these patients but we do administer postpartum anticoagulation (table 3A-B).

The relative efficacy of low versus intermediate dosing for VTE prophylaxis was compared in the Highlow trial, which randomly assigned 1110 individuals who were ≤14 weeks pregnant and had a prior history of VTE to receive weight-adjusted intermediate-dose or fixed low-dose LMW heparin once daily until six weeks postpartum [61]. The risk of VTE was similar between groups (2 percent with intermediate dose versus 3 percent with low dose; relative risk [RR] 0.6, 95% CI 0.32-1.47). The trend towards increased risk in the low-dose group was due to a slightly higher number of postpartum VTE events that was not statistically significant. The risk of bleeding was also similar (4 percent in each group; RR 1.16, 95% CI 0.65-2.09). Editorialists commented on methodologic concerns, including that it took seven years to accrue 1110 patients and that there were numerous protocol deviations by clinicians, challenges with patient adherence, a low event rate, and heterogeneity in types of LMW heparin, which are not entirely interchangeable [62]. Furthermore, it should be noted that an increased dose of LMW heparin was administered per the Highlow Study protocol in the "fixed low-dose group" with a weight ≥100 kg. Prior to this trial, intermediate dosing was thought to have an efficacy advantage based on pharmacokinetic studies that suggested a greater dose requirement after 20 weeks of gestation [63]. A small retrospective study (126 pregnancies) had found a high incidence of VTE in high-risk individuals treated with low-dose LMW heparin antepartum and postpartum, suggesting that low-dose LMW heparin prophylaxis may have been insufficient in high-risk individuals [64].

Though the Highlow trial provides evidence for a "fixed low-dose" LMW heparin regimen in pregnant individuals with a prior VTE, the choice of regimen still needs to be individualized and discussed with the patient. For those with lower risk thrombophilias and a prior episode of VTE who are not chronically on anticoagulation, we generally administer a single daily low dose of LMWH (table 3A-B). We will, however, consider a "weight-adjusted intermediate dose regimen" in higher-risk patients, particularly during the postpartum period once adequate hemostasis has been achieved (table 3B).

No prior VTE

●Antepartum – Asymptomatic patients (no prior VTE) who are heterozygotes for factor V Leiden (FVL) or prothrombin G20210A or who have deficiencies of protein C or protein S do not require routine antepartum anticoagulation, but should undergo individualized risk assessment and monitoring for clinical signs and symptoms of VTE [17,36-39,65,66]. Anticoagulation may be warranted for individual patients with these thrombophilias and additional factors that place them at greater risk of thrombosis (eg, prolonged immobility, first-degree relative with unprovoked VTE at age <50 years).

For such patients, we use a once daily fixed low dose of LMWH (table 3A-B). Our anticoagulation regimens (table 3B) are slightly different from those of ACOG [39].

●Postpartum – There is no strong evidence that postpartum prophylaxis is necessary in asymptomatic patients (no prior VTE) who are heterozygotes for factor V Leiden (FVL) or prothrombin G20210A or who have deficiencies of protein C or protein S [36,38].

Because cesarean birth is a risk factor for VTE and 80 percent of fatal pulmonary emboli in postpartum patients occur after cesarean birth [67], we suggest use of a pneumatic compression device during hospitalization after cesarean birth and postpartum prophylactic anticoagulation for up to six weeks.

Recommendations of others — American Society of Hematology (ASH) 2018 guidelines for management of VTE in the context of pregnancy provide a summary of the recommendations of ASH, the American College of Chest Physicians, ACOG, the Society of Obstetricians and Gynaecologists of Canada, and the Royal College of Obstetricians and Gynaecologists [38].

PREVENTION OF PREGNANCY COMPLICATIONS

Anticoagulation — We recommend not administering anticoagulation for prevention of preeclampsia, fetal growth restriction, placental abruption, or fetal loss. As discussed above, most available evidence does not support an association between inherited thrombophilia and these adverse outcomes (see 'Adverse pregnancy outcome risk' above). Therefore, it is not surprising that the evidence does not support prophylactic anticoagulation to prevent these adverse outcomes in patients with inherited thrombophilias [36,38]. For example:

●Pregnancy loss – A 2016 meta-analysis evaluated use of low molecular weight heparin (LMWH) to prevent pregnancy loss in eight randomized trials including 483 patients with an inherited thrombophilia and a prior late loss (≥10 weeks) or recurrent early loss (≥2 losses at <10 weeks) [68]. Compared with no treatment or aspirin alone:

•For the entire cohort, overall pregnancy loss was not significantly reduced (relative risk [RR] pregnancy loss 0.81, 95% CI 0.55-1.19; live birth rate 85 percent with LMWH versus 65 percent without LMWH).

•When analyzed by type of previous pregnancy loss, pregnancy loss was also not significantly reduced in those with a prior late loss (RR pregnancy loss 0.81, 95% CI 0.38-1.72) or those with prior recurrent early loss (RR pregnancy loss 0.97, 95% CI 0.80-1.19).

Given the limitations of available data (eg, high heterogeneity, small number of participants and events, risk of bias), more research was needed to definitively exclude whether anticoagulation has any benefit. A subsequent well-designed randomized trial including 326 participants with recurrent pregnancy loss and inherited thrombophilia compared LMWH throughout pregnancy with standard care and confirmed the findings of the meta-analysis [40]. The livebirth rate was similar in both groups (72 versus 71 percent, adjusted OR 1.08, 95% CI 0.65-1.78; absolute risk difference 0.7 percent, 95% CI –9.2 to 10.6 percent). There was also no difference in any of the secondary outcomes (miscarriage, preterm birth, small for gestational age). Recurrent pregnancy loss was defined as ≥2 consecutive miscarriages, non-consecutive miscarriages, or fetal deaths irrespective of gestational age). The inherited thrombophilias were factor V Leiden heterozygote or homozygote, prothrombin gene (G20210A) heterozygote or homozygote, antithrombin deficiency, protein C deficiency, protein S deficiency, or combined thrombophilia. LMWH options included daily enoxaparin 40 mg, dalteparin 5000 units, tinzaparin 4500 units, or nadroparin 3800 units; doses were not adjusted to bodyweight.

●Hypertensive disorders of pregnancy – In the FRUIT trial, patients with an inherited thrombophilia and history of uteroplacental insufficiency and delivery <34 weeks were randomly assigned to treatment with LMWH plus aspirin or aspirin alone [69,70].

•Use of LMWH plus aspirin reduced the risk of a recurrent hypertensive disorder of pregnancy with onset <34 weeks of gestation compared with aspirin alone (0/70 versus 6/69, risk difference 8.7 percent, 95% CI 1.9-15.5 percent); however, the incidence of all recurrent hypertensive disorders of pregnancy irrespective of gestational age did not differ between the treatment groups.

•Both treatment groups had similar fetal growth rates, birth weights, and umbilical and uterine artery Doppler flow velocities.

●Placenta-mediated pregnancy complications – In the multinational TIPPS trial that randomly assigned 292 pregnant patients with thrombophilia associated with an increased risk of venous thromboembolism (VTE) or with previous placenta-mediated pregnancy complications to antepartum prophylactic dalteparin (5000 international units once daily up to 20 weeks of gestation, and twice daily thereafter until at least 37 weeks) or no dalteparin [16]:

•Use of dalteparin did not reduce the occurrence of the composite outcome, of pregnancy loss, severe/early-onset preeclampsia, birth of small for gestational age infant, major VTE (dalteparin: 17.1 percent [25 out of 146], 95% CI 11.4-24.2 versus no dalteparin: 18.9 percent [27 out of 143], 95% CI 12.8-26.3; risk difference -1.8 percent, 95% CI -10.6 to 7.1).

•Secondary analyses did not support important treatment effects for any individual outcome or in any subgroup of patients.

The authors also performed a meta-analysis and concluded that higher quality evidence suggests that LMWH does not prevent recurrent late onset and nonsevere placenta-mediated pregnancy complications, but lower quality evidence suggested that LMWH might prevent recurrent severe placenta-mediated pregnancy complications, which warrants further research.

Low-dose aspirin — Although some retrospective studies have suggested that patients with an inherited thrombophilia are at higher risk for developing preeclampsia, prospective studies have not confirmed these findings, as discussed above. (See 'Adverse pregnancy outcome risk' above.)

Therefore, we do not prescribe low-dose aspirin for prevention of preeclampsia in patients with inherited thrombophilias who have none of the standard criteria for receiving preeclampsia prophylaxis. Candidates for low-dose aspirin therapy for prevention of preeclampsia are reviewed separately. (See "Preeclampsia: Prevention", section on 'Low-dose aspirin'.)

FETAL SURVEILLANCE AND TIMING OF DELIVERY — For patients who have been anticoagulated, heparin should be discontinued 12 to 24 hours before scheduled delivery to reduce risk of maternal bleeding, including neuraxial hematoma in patients who choose to have neuraxial anesthesia. Patients on low molecular weight heparin are sometimes transitioned to unfractionated heparin at approximately 36 weeks of gestation to avoid potential contraindications from receiving neuraxial anesthesia for labor and delivery. Peripartum management of anticoagulation is reviewed in detail separately. (See "Use of anticoagulants during pregnancy and postpartum", section on 'Labor and delivery' and "Use of anticoagulants during pregnancy and postpartum", section on 'Postpartum and breastfeeding'.)

Despite the absence of definitive data that there is an increased risk of stillbirth in patients with inherited thrombophilias who are receiving or not receiving prophylactic anticoagulation, we suggest weekly fetal assessment with nonstress tests beginning at ≥36 weeks of gestation; decisions regarding planned delivery prior to the onset of labor or at 39 weeks of gestation in the absence of an obstetric complication necessitating earlier delivery should be individualized.

If obstetric complications (eg, preeclampsia) are present, fetal surveillance should be initiated earlier and delivery timed to optimize maternal and neonatal outcomes, as is usual for the specific complication. (Refer to specific topic reviews on obstetric complications).

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Anticoagulation in pregnancy" and "Society guideline links: Thrombotic microangiopathies (TTP, HUS, and related disorders)".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topic (see "Patient education: Factor V Leiden (The Basics)")

SUMMARY AND RECOMMENDATIONS

●Risk of VTE – Patients with inherited thrombophilias are at higher risk of thromboembolic complications during pregnancy because of pregnancy-associated changes in several coagulation factors. The probability of venous thromboembolism (VTE) depends upon the specific thrombophilia and whether they have a personal or family history of thrombosis (table 1). The risk of thromboembolism is higher in those with a personal history or strong family history of thromboembolic events. (See 'Maternal VTE risk' above.)

●Risk of adverse pregnancy outcome – Studies have reported an association between some types of thrombophilia and adverse pregnancy outcomes, but the absolute risk is small and varies considerably among reports. Most large, prospective cohort studies have failed to establish a consistent association between inherited thrombophilias and adverse pregnancy outcomes in low-risk populations. (See 'Adverse pregnancy outcome risk' above.)

●Testing

•We test for thrombophilia when the results will affect management decisions: whether to administer prophylactic anticoagulation, when to administer it (antepartum and/or postpartum), and the dose (low, intermediate, or high) (see 'Selection of patients for testing' above). Appropriate candidates include:

-Reproductive-age females with a personal history of VTE associated with a transient provoking nonhormonal risk factor (eg, femoral fracture, surgery, prolonged immobilization).

-Reproductive-age females with a personal history of idiopathic (unprovoked) VTE, recurrent VTE, or VTE associated with estrogen-progestin contraception or pregnancy.

-Asymptomatic females (no prior VTE) planning a pregnancy who have a first-degree relative with VTE before age 50 years and a high-risk thrombophilia.

•Whenever possible, laboratory testing should be performed remote from the thrombotic event and while the patient is not pregnant and not taking anticoagulation or hormonal therapy. (See 'Selection of patients for testing' above and 'Laboratory testing' above.)

•We recommend not testing for inherited thrombophilia in patients with a history of recurrent or nonrecurrent fetal loss, abruption, intrauterine growth restriction, or preeclampsia (Grade 1B). There is mounting evidence that administration of anticoagulant drugs does not improve pregnancy outcome in affected patients. (See 'Selection of patients for testing' above.)

●Prevention of pregnancy complications – We suggest not administering prophylactic anticoagulation during pregnancy for prevention of placenta-mediated pregnancy complications (Grade 2B). (See 'Prevention of pregnancy complications' above.)

●Prevention of VTE – The goal of treatment is prevention of maternal VTE. Based upon the data cited in the discussion above, as well as indirect evidence from studies in nonpregnant individuals, we suggest the approach described in the table (table 3A-B). Our anticoagulation regimens are slightly different from those of the American College of Obstetricians and Gynecologists and others. (See "Venous thromboembolism in pregnancy: Prevention" and "Use of anticoagulants during pregnancy and postpartum".)

●Obstetric monitoring – In the absence of an obstetric complication, such as preeclampsia, abruption, or fetal growth restriction, we suggest weekly assessments with nonstress tests beginning at ≥36 weeks of gestation and delivery at 39 weeks of gestation. (See 'Fetal surveillance and timing of delivery' above.)