Sage Journals: Discover world-class research

Abstract

The role of anticoagulants in the prevention of pregnancy complications, including recurrent miscarriage, late fetal loss, and preeclampsia, continues to be an area of active research and debate. Although prophylactic anticoagulation with heparin and aspirin is considered the standard of care in some conditions, such as obstetric antiphospholipid antibody syndrome, the optimal management of pregnant women with factor V Leiden mutation, prothrombin G20210A mutation, and other inherited thrombophilias without a history of thrombosis remains unknown. Some studies suggest a benefit of heparins in preventing late-term losses but not earlier miscarriages in the inherited thrombophilias. In the following review, we will discuss the recent literature regarding anticoagulation and pregnancy complications and conclude with our suggested approach to the management of these challenging patients.

Keywords

recurrent miscarriage late fetal loss preeclampsia antiphospholipid antibody syndrome inherited thrombophilia anticoagulation

Introduction

Pregnancy complications including recurrent miscarriage, late fetal loss, and preeclampsia/hemolysis, elevated liver function tests, low platelets (HELLP) syndrome have widespread psychological and economic repercussions, affecting not only women and their communities but also the health care system at large.¹ Physicians often prescribe anticoagulants such as heparins and aspirin in an attempt to prevent recurrent pregnancy complications; however, it is not clear that such interventions are always beneficial. Over the last few decades, efforts have been made to recognize predictors of recurrent pregnancy complications, identify those women at increased risk, and determine who might benefit from antenatal treatment.

Thrombophilias, both inherited and acquired, are a major risk factor for venous thromboembolic event (VTE) before and after delivery.² The odds ratio (OR) for the development of VTE during pregnancy is 15.8,³ 34.4, and 26.36⁴ in women with antiphospholipid antibody syndrome (APS), homozygous factor V Leiden mutation (FVL), and homozygous prothrombin gene mutation (PGM), respectively. However, the data regarding the association between thrombophilia and recurrent pregnancy loss are less conclusive. Although some acquired thrombophilic disorders such as APS have a recognized association with recurrent pregnancy loss,⁵ the impact of FVL and PGM on nonthrombotic complications of pregnancy is less certain.⁶ These inherited disorders likely have little impact on miscarriage or placental-mediated complications such as preeclampsia, with only modest effect on late-term loss. Multiple studies have attempted to determine whether recurrent pregnancy loss may be mitigated with prophylactic anticoagulation^7

–13; however, these trials are often plagued by small numbers, heterogeneous patient populations, and differing definitions of early versus late loss and prior pregnancy complications.¹⁴

Hemostatic Changes in Pregnancy

Pregnancy is characterized by physical and physiologic changes that contribute to a tendency to clot. Congestion within the pelvic veins from a gravid uterus leads to decreased blood flow to the lower extremities, and compression of the left iliac vein by the right iliac artery is a well-known phenomenon.² Yet, aside from the physical transformations of pregnancy, physiologic and hormonal changes within the placenta itself are key to the pathogenesis of many adverse pregnancy outcomes.^15,16 The placenta is a highly vascular organ composed of low-resistance vessels, and it is reasonable to infer that clot formation within the placental vasculature might result in placental insufficiency, intrauterine growth restriction, and other complications of gestation. During pregnancy, there is an increase in clotting factors VII, VIII, and X as well as a rise in the levels of von Willebrand factor and fibrinogen.² There is also a marked decrease in the activity of protein S as well as acquired resistance to activated protein C (Table 1).¹⁷ Of note, there is little change in protein C activity during pregnancy,¹⁸ and antithrombin levels remain constant.¹⁹

Table 1.

Physiologic Changes During Pregnancy.^a

Procoagulant	Anticoagulant
Factor VII ↑	Annexin V ↑
Factor VIII ↑	Tissue factor inhibitor 1 ↑
Factor X ↑	Tissue factor inhibitor 2 ↑
von Willebrand ↑	Thrombomodulin ↑
Fibrinogen ↑	Prostacyclin ↑
Protein S ↓	Antithrombin III ↔

^aChanges in procoagulant and anticoagulant hematologic parameters during pregnancy.^17

–21

The placental circulation is shifted toward the procoagulant state, likely to counterbalance the risk of hemorrhage during placental implantation and as maternal blood flows through the intervillous space.²⁰ Trophoblasts, which line the spiral arteries of the uterus and eventually develop into the placenta, have a decreased capacity to lyse fibrin as compared with other endothelial cells. This is thought to be due to high levels of plasminogen activator inhibitors (PAI-1 and PAI-2), which lay down a framework of fibrin on the placental bed and impair the action of the anticoagulant tissue-type plasminogen activator.^19,22,23 Trophoblasts also express large amounts of tissue factor and phosphatidylserine, thus tipping the balance further toward hemostasis.²⁰ Microparticles—extracellular vesicles shed during cell signaling and apoptosis²⁴—have also been implicated in the development of thrombotic pregnancy complications.²⁵ In a case–control analysis of 74 women with a history of pregnancy loss, 41 had increased levels of procoagulant circulating microparticles.²⁶

However, as in any biologic model, compensatory mechanisms exist within the placental milieu to offset the prothrombotic state, and these include annexin V, which is critical to preventing intervillous thrombosis, tissue factor pathway inhibitors (TFP-1 and TFP-2), thrombomodulin, and prostacyclin.^20,21,27 Yet, when the procoagulant factors overwhelm the anticoagulant ones, the risk of placental thrombosis rises.²² Might not maternal thrombophilia disrupt this delicate equilibrium, potentiating clotting and potentially fetal loss? Although a hypercoagulable state is often invoked as the cause of adverse placenta-mediated events, this theory is not supported by therapeutic trials of anticoagulation. Excessive thrombosis may be only one of the several mechanisms contributing to the overall pathophysiology of adverse pregnancy outcomes.

Antiphospholipid Antibody Syndrome

Antiphospholipid antibody syndrome, an acquired thrombophilia defined by certain clinical and laboratory characteristics (Table 2), has been linked to myriad pregnancy complications, including VTE, preeclampsia, eclampsia, small for gestation age (SGA), preterm delivery, and fetal loss at all stages of gestation. Antiphospholipid antibody syndrome can present with thrombosis or manifest as “pure” obstetric APS. Obstetric APS refers specifically to a syndrome of recurrent early loss or sporadic late loss with positive antiphospholipid antibodies—lupus anticoagulant, anti–β2-glycoprotein 1, and anticardiolipin antibodies—without concurrent VTE.

Table 2.

Revised Criteria for APS.^a

Clinical criteria
Vascular thrombosis One or more clinical episodes of arterial, venous, or small vessel thrombosis in any tissue or organ. Thrombosis must be confirmed by objective validated criteria. For histopathologic confirmation, thrombosis should be present without significant evidence of inflammation in the vessel wall Pregnancy morbidity One or more unexplained deaths of a morphologically normal fetus at or beyond the 10th week of gestation, with normal fetal morphology documented by ultrasound or by direct examination of the fetus or One or more premature births of a morphologically normal neonate before the 34th week of gestation because of eclampsia or severe preeclampsia defined according to standard definitions or recognized features of placental insufficiency (including a birth weight <10th percentile for gestational weight) or Three or more unexplained consecutive spontaneous abortions before the 10th week of gestation, with maternal anatomic or hormonal abnormalities and paternal and maternal chromosomal causes excluded
In studies of populations of patients who have more than one type of pregnancy morbidity, investigators are strongly encouraged to stratify groups of participants according to a, b, or c mentioned previously
Laboratory criteria
LA present in plasma on 2 or more occasions at least 12 weeks apart or aCL antibody of IgG and/or IgM isotype in serum or plasma, present in medium or high titer (ie, >40 GPL or MPL or >the 99th percentile), on 2 or more occasions, at least 12 weeks apart or Anti-β2-glycoprotein 1 antibody of IgG and/or IgM isotype in serum or plasma (in titer >the 99th percentile), present on 2 or more occasions, at least 12 weeks apart

Abbreviations: aCL, anticardiolipin; APS, antiphospholipid antibody syndrome; GPL, IgG phospholipid units; Ig, immunoglobulin; LA, lupus anticoagulant; MPL, IgM phospholipid units.

^aAPS is present if at least one of the clinical criteria and one of the laboratory criteria mentioned previously are met. All data derived from Miyakis et al.²⁸

Antiphospholipid antibody syndrome is a complex disorder characterized by abnormalities of coagulation, complement dysfunction, and other autoimmune phenomena. Antiphospholipid antibodies are known to increase the risk of maternal thrombosis during pregnancy³ and are also thought to impair trophoblast growth and development, ultimately leading to placental insufficiency.²⁹ In 1997, a randomized control trial of 90 women with recurrent miscarriage and persistently positive antiphospholipid antibodies found a beneficial effect on live birth rate in women treated with antepartum low-molecular-weight heparin (LMWH) and aspirin (71% live birth rate) versus aspirin alone (42% live birth rate).⁵ However, this study has been critiqued for a heterogeneous study population, a lower than expected birth rate in the aspirin-alone group, and for the inclusion of women with very low titers of anticardiolipin antibodies.³⁰ And although some trials evaluating LMWH plus aspirin in women with antiphospholipid antibodies and recurrent loss have failed to show such positive results,^31
–33 antepartum treatment with LMWH and aspirin is endorsed by the American College of Chest Physicians³⁴ and The American College of Obstetricians and Gynecologists³⁵ in women with obstetric APS. However, it should be noted that there are no data to support the use of aspirin alone in the prevention of recurrent miscarriage in patients with APS. Three placebo-controlled trials and one meta-analysis found no difference in outcome in women treated with and without aspirin.^33,36

Data indicate a stronger association between pregnancy complications and APS depending on the type of antibody present.^37
–39 Of the 3 most prevalent antiphospholipid antibodies, the lupus anticoagulant is thought to be the most predictive of adverse pregnancy outcomes.⁴⁰ Moreover, a recent retrospective analysis concluded that patients with APS having thrombosis and “triple” antibody positivity (ie, lupus anticoagulant, anti–β2-glycoprotein 1, and anticardiolipin antibodies) are at highest risk of pregnancy complications and benefit most from combined antepartum anticoagulation.³⁸ These women had a live birth rate of 58.3% when treated with just heparin or low-dose aspirin alone, but the birth rate increased to 92.9% when at least 2 medical therapies were used (ie, aspirin plus heparin).

A recent prospective observational study of 6318 women with pregnancy complications was undertaken at the University Hospital of Nimes, France (the Nimes Obstetricians and Hematologists Antiphospholipid Syndrome [NOH-APS] observational study).⁴¹ The authors enrolled women without a history of thrombosis who had experienced at least 3 consecutive spontaneous abortions before the 10th week of gestation or 1 fetal loss at or beyond the 10th week of gestation (late loss) and observed them during subsequent pregnancies. The control group consisted of women with prior pregnancy loss without antiphospholipid antibodies or inherited thrombophilia (N = 796).^38,42 A total of 517 women with obstetric APS were included in the study, 3.3% of whom had concurrent antiphospholipid antibodies and an inherited thrombophilia. All women with confirmed obstetric APS were treated with low-dose aspirin 100 mg/d while not pregnant, and prophylactic enoxaparin 40 mg/d was initiated at the time of positive pregnancy test through delivery.

Women with APS and prior late fetal loss were found to be at increased risk of subsequent fetal loss, preeclampsia, premature birth, and other placenta-mediated pregnancy complications when compared to women with APS and recurrent early losses. Patients with obstetric APS and previous spontaneous abortions had similar rates of early loss as women in the control group; however, women with obstetric APS experienced more late losses. Moreover, despite treatment with LMWH and aspirin, the incidence of pregnancy complications in all women with obstetric APS was higher than that of the controls.⁴¹ Thus, although the data are somewhat mixed, and despite the fact that women with APS treated with LMWH and aspirin still have higher rates of pregnancy complications, we recommend the combination of these agents in obstetric APS. However, there is an urgent need for further randomized trials exploring additional treatment options in these patients.

Recommendation

In women with obstetric APS, we recommend prophylactic LMWH combined with aspirin 81 mg/d once pregnancy is confirmed.

Inherited Thrombophilias: FVL and PGM

There are no sufficiently powered trials to adequately determine the effect of inherited thrombophilias on recurrent pregnancy loss, preeclampsia, SGA, or other placenta-mediated complications.^6,43,44 An observational study assessed the effect of LMWH with or without aspirin on miscarriages in 1011 pregnancies amongst 416 women with FVL or PGM.⁶ After adjusting for multiple variables, the authors concluded that LMWH had a protective effect on late pregnancy loss with an OR of 0.52 (95% confidence interval [CI]: 0.01-0.21). Aspirin appeared to have no effect on recurrent miscarriage.⁶ However, this observational study was fraught with heterogeneity, and it is difficult to draw definitive conclusions from the data. In another trial, the HABENOX (Habitual abortion and enoxaparin) group randomized 207 women with at least 3 consecutive first trimester miscarriages, 2 or more second trimester miscarriages, or 1 third trimester loss combined with 1 first trimester miscarriage to enoxaparin 40 mg and placebo once daily (n = 68), enoxaparin 40 mg and aspirin 100 mg (n = 63), or aspirin 100 mg alone (n = 76). About 25% of patients in each arm had a history of thrombophilia. There was no difference in live birth rate among all 3 arms, with an overall live birth rate of 65% (95% CI: 58.66-71.74).⁸

Some data suggest that inherited thrombophilias contribute more to late losses than to earlier miscarriages.^45
–47 The NOH-APS study enrolled a third cohort of women (n = 279) with FVL and PGM, no prior thrombosis, and a history of 3 consecutive spontaneous abortions before 10 weeks’ gestation or 1 fetal death (considered a late loss) after 10 weeks.⁴² Only women with a history of late loss were given prophylactic LMWH at a dose of 40 mg/d. The incidence of fetal death, premature live birth, early and late onset preeclampsia, and other placenta-mediated complications was recorded.

The authors found that women receiving LMWH for a history of late fetal loss had lower rates of fetal death (10.3% vs 23.2%) and premature birth (12.3% vs 25%). Moreover, treated women with prior late pregnancy loss were more likely to give birth to a live infant than their untreated counterparts (70.3% vs 50.2%). The difference in the rate of recurrent miscarriage between thrombophilic women with prior early losses and nonthrombophilic women was similar. Although there was a trend toward higher rates of fetal death (8.8% vs 2.3%), preeclampsia (6.6% vs 2.9%), preterm live birth rates (16.4% vs 9.2%), and neonatal mortality (2.7% vs 0.5%) in the untreated thrombophilic group, there was no statistically significant difference.⁴² These data suggest the benefit of prophylactic LMWH in women with FVL or PGM and late loss and question recommendations not to use LMWH in thrombophilic women with early loss or other complications.³⁴

In the Thrombophilia in Pregnancy Prophylaxis Study (TIPPS), investigators enrolled 292 pregnant women with a history of thrombophilia and VTE or placenta-related adverse event and randomized them to receive either dalteparin or no drug.^48,49 Women with FVL and PGM were included in the study, and aspirin use was not controlled. There were many primary composite outcome measures including symptomatic VTE, preeclampsia, birth of SGA infant, or pregnancy loss. A total of 17.1% of women receiving antepartum dalteparin experienced one of the primary outcomes, as compared with 18.9% of patients in the untreated group, revealing no statistical difference. However, when compared to the Nimes Obstetricians and Hematologists (NOH) study, the number of women with FVL and PGM was smaller in the TIPPS study, and patients were not stratified according to early or late loss or thrombophilic risk factor. In another negative study, the Scottish Pregnancy Intervention (SPIN) trial, 294 women with a history of 2 or more fetal losses at <24 weeks were randomized to treatment with enoxaparin 40 mg once daily and aspirin 75 mg daily or surveillance alone. There was no difference in the rate of recurrent miscarriage, although very few thrombophilic women were included.⁷ A recent Cochrane review of 9 studies with a total of 1228 women concluded that there are no definitive data to recommend the use of anticoagulation in women with recurrent miscarriages who have inherited thrombophilias.⁵⁰ An ongoing trial, Anticoagulants for Living Fetuses in Women with Recurrent Miscarriages and Inherited Thrombophilia study (ALIFE2), hopes to shed further light on this subject. Women who are actively trying to conceive, and with a history of thrombophilia and 2 or more prior miscarriages, will be randomized to prophylactic LMWH once daily or no intervention. We anxiously anticipate these results.

Recommendation

We do not routinely recommend prophylactic anticoagulation for women heterozygous for FVL or PGM with a history of recurrent early miscarriage or late loss. However, anticoagulation may be prescribed depending on VTE risk.

Protein C, S, and Antithrombin Deficiency

The data supporting the use of prophylactic anticoagulation for the prevention of miscarriage and late-term losses in women with inherited deficiencies of the endogenous anticoagulants protein C, S, and antithrombin III are fraught with heterogeneity. The European Prospective Cohort on Thrombophilia (EPCOT), a large retrospective case–control study, enrolled 843 women with thrombophilia, 571 of whom had 1524 pregnancies, and compared them with a control group of 541 women, of whom 395 had 1019 pregnancies. The overall risk for late loss was higher than for early loss in women with thrombophilia: OR 3.6 (95% CI: 1.4-9.4) versus 1.27 (95% CI: 0.94-1.71). The OR for fetal loss after 28 weeks was 2.3 for women with protein C deficiency (95% CI: 0.6-8.3), 3.3 with protein S deficiency (95% CI: 1.0-11.3), and 5.2 with antithrombin deficiency (95% CI: 1.5-18.1). The OR for late loss in women with combined thrombophilias was 14.3 (95% CI: 2.4-86.0). Antithrombin deficiency was the only defect statistically associated with loss less than 28 weeks.¹⁰

A prior study from the Nimes group evaluated 232 women with a history of late fetal loss and compared them with 464 matched controls. The OR of a woman with protein C deficiency sustaining a late loss was 1.00 (95% CI: 0.09-10.9), whereas the OR of late loss in a woman with protein S deficiency was 22.0 (95% CI: 2.8-170).⁵¹ A case–control study by Many et al evaluated 40 women with late unexplained intrauterine fetal deaths and compared them with a reference group of 80 healthy women with at least 1 normal pregnancy. Although there was a trend toward late loss in women with protein S deficiency, it was not statistically significant.⁵² Alfirevic et al found increased numbers of late pregnancy losses in women with antithrombin deficiency, but this did not reach statistical significance likely given the small sample size.⁵³ A meta-analysis of 31 cohort, case–control, and cross-sectional studies concluded that protein S deficiency portended an OR of 7.39 for late nonrecurrent fetal loss (95% CI: 1.28-42.63). Although the protein C and antithrombin deficiency were not associated with fetal loss, the numbers were too small to determine.¹¹

Recommendation

We do not recommend anticoagulation in women with protein C, protein S, and antithrombin III deficiency for the prevention of placenta-medicated complications. However, anticoagulation may be prescribed depending on VTE risk.

Anticoagulation in Preeclampsia, HELLP Syndrome, and Placental Abruption

Women with a history of preeclampsia have a 25% to 65% risk of recurrent preeclampsia, and those with a history of HELLP syndrome have about a 19% to 27% chance of recurrence.^54
–56 Women with previous preeclampsia also have about a 3% risk of placental abruption and a 10% risk of having an SGA child.^54,57

A meta-analysis of 32 217 women at risk of preeclampsia, randomized to receive either aspirin or dipyridamole versus placebo, concluded that for women who received an antiplatelet agent, the relative risk of developing preeclampsia was 0.90 (95% CI: 0.83-0.98).⁵⁸ As such, aspirin has been touted as providing a small but important advantage in reducing the risk of preeclampsia. However, it is thought to be most advantageous when given prior to 16 weeks’ gestation and in the prevention of severe and early-onset preeclampsia.^59,60

In a prospective randomized controlled trial (RCT) conducted by the HAPPY (Adverse Pregnancy outcome to improve the rate of successful PregnancY) study group, 135 women with a history of preeclampsia, HELLP syndrome, and other placental-mediated complications received either medical surveillance or 3800 IU of nadroparin daily. The primary outcome was late pregnancy complications. A total of 13 (21%) of 63 women in the observation arm and 12 (18%) of 65 in the treatment arm reached the primary outcome, with an absolute risk difference of 2.2 (95% CI: 11.6-16.0) that was not statistically significant.⁶¹ However, in the HAPPY study, prophylaxis with nadroparin only began after the 13th week of gestation, and it is possible that earlier institution of anticoagulation would have resulted in a different outcome. In a multicenter retrospective study, 58 women with a history of preeclampsia and thrombophilia were evaluated for recurrent preeclampsia during subsequent pregnancies. Twenty-six women received LMWH plus aspirin, 22 received aspirin alone, and 10 received no intervention. No benefit was seen with the addition of LMWH.⁶²

One of the largest RCTs to evaluate the effect of LMWH on preeclampsia and the HELLP syndrome was the FRUIT (FRactionated heparin in pregnant women with a history of Utero-placental Insufficiency and Thromophilia) study.⁶³ Inclusion criteria for the study were (1) history of thrombophilia, (2) prior delivery at less than 34 weeks’ gestation, and (3) previous pregnancy complicated by preeclampsia, eclampsia, HELLP, or SGA. In this study, 139 women were randomly assigned to receive aspirin 80 mg once daily with or without dalteparin 5000 IU daily beginning at less than 12 weeks’ gestation. The primary outcomes were recurrence of preeclampsia, eclampsia, or HELLP at any gestational age or at <34 weeks’ gestation. There was no statistically significant difference in the development of these disorders irrespective of gestational age: 18.6% of women randomized to LMWH and ASA (n = 13 of 70) developed preeclampsia, eclampsia, or HELLP as compared with 21.7% (n = 15 of 69) of those taking aspirin alone (95% CI: 10.5-16.7). However, of the women who developed hypertensive disorders at <34 weeks’ gestation, 0 were in the dalteparin and ASA arm and 6 (8.7%) were in the ASA-alone group.

The data regarding the association between maternal thrombophilia and risk for placental abruption are mixed. In a single-center pilot study, Gris et al randomized 160 women with a history of placental abruption to either prophylactic enoxaparin or no enoxaparin beginning at the time of positive pregnancy test. Women with antiphospholipid antibodies were excluded, but those with FVL or PGM comprised a small percentage of the study population. The primary outcome included placental abruption, preeclampsia, low birth weight, or fetal loss after 20 weeks. The investigators found that enoxaparin reduced the composite outcome from 31.3% to 12.5% (hazard ratio: 0.37, 95% CI: 0.18-0.77). However, other studies have failed to yield such positive results.⁶⁴

A recent meta-analysis by Rodger et al sought to determine the utility of LMWH in the prevention of recurrent placenta-mediated pregnancy complications such as preeclampsia.⁴⁵ Six RCTs with a total of 848 pregnant women at risk for recurrent preeclampsia, SGA, placental abruption, or pregnancy loss >20 weeks were included. Overall, 67 (18.7%) of 358 women administered prophylactic LMWH had recurrent placental-mediated pregnancy complications as compared with 127 (42.9%) of 296 women receiving no intervention. The number of women with recurrent preeclampsia in the LMWH group was 34 (8.6%) of 391 versus 75 (21.6%) of 348 women who were not treated with anticoagulation.⁴⁵ The FRUIT study was the only trial that specifically included women with a history of thrombophilia. The authors emphasize that LMWH may be effective only in the most severe cases of placenta-mediated pregnancy complications, and call for more sophisticated multicenter trials help elucidate this issue.

Recommendation

We recommend antepartum aspirin 81 mg once daily in women with a history of preeclampsia. There is currently insufficient data to recommend LMWH for the secondary prevention of preeclampsia or other placenta-mediated pregnancy complications.

Anticoagulation for Recurrent Miscarriage Without Thrombophilia

We believe that the data do not support the use of anticoagulation (either with LMWH or aspirin) for the prevention of recurrent miscarriage in women without thrombophilia. This has been clearly demonstrated in the Anticoagulants for Living Fetuses (ALIFE1) trial,⁹ TIPPS, and SPIN⁷ among others. Pasquier et al recently published a randomized placebo-controlled trial of enoxaparin 40 mg once daily versus placebo in 258 pregnant women with a history of recurrent miscarriage without acquired or inherited thrombophilia. The primary end point was live birth rate. In an intention-to-treat analysis, 66.6% of women in the enoxaparin group and 72.9% of women in the placebo group had a live birth.¹³ There was no statistically significant improvement in the primary or secondary end points with the addition of LMWH. Schleussner et al randomized 449 women with at least 2 consecutive early miscarriages or 1 late miscarriage to prophylactic dalteparin plus multivitamin or multivitamin alone. The majority of patients did not have inherited thrombophilia, and those with APS were excluded. Low-molecular-weight heparin did not improve ongoing pregnancy or live birth rates among participants.⁶⁵ Yet, despite what we feel are conclusive results, clinicians continue to prescribe anticoagulation for the prevention of recurrent miscarriage in women without thrombophilia, subjecting their patients to increased risk of bleeding, withholding of epidural anesthesia, and financial burden.

Recommendation

We do not recommend LMWH or aspirin to patients with 2 or more unexplained pregnancy losses without thrombophilia.

If Choosing to Anticoagulate, What to Use?

Heparins—LMWH, unfractionated heparin (UFH), and danaparoid—are the most commonly used anticoagulants during pregnancy as they do not cross the placenta.⁶⁶ Low-molecular-weight heparin is preferred over UFH, as LMWH is easier to administer, has more predictable pharmacokinetics, does not require monitoring, and is less likely to cause osteoporosis and heparin-induced thrombocytopenia than UFH. However, in the final weeks of pregnancy, women are often transitioned from LMWH to UFH given the shorter half-life of the latter, allowing for rapid epidural placement or cesarean section if needed. Warfarin is not recommended except in certain circumstances (such as in women with mechanical heart valves), and there is little data regarding the use of novel anticoagulants (including factor Xa inhibitors) in pregnancy.^34,67,68

For prophylactic anticoagulation dosing, we recommend enoxaparin 40 mg once daily, UFH 5000 U twice daily, or dalteparin 5000 U daily. However, as pregnancy progresses, women require higher doses of anticoagulation to achieve the same peak plasma concentrations.⁶⁹ For instance, the American College of Obstetricians and Gynecologists recommends UFH 5000 to 7500 U twice daily in the first trimester, UFH 7500 to 10 000 U twice daily in the second trimester, and UFH 10 000 U twice daily in the third trimester.⁷⁰ Although we do not routinely monitor anti-Xa levels, we target a goal of 0.1 to 0.3 four hours after the administration of LMWH.

Conclusion

Despite current available evidence, real-world decisions regarding anticoagulation for pregnancy complications are often difficult to make. Robust RCTs are lacking, and much has yet to be learned about the pathophysiology of recurrent pregnancy loss and placenta-mediated complications. Table 3 summarizes our approach to most patients. Of course, as each patient has unique risk factors, preferences, and values, recommendations must be tailored to the specific individual.

Table 3.

Recommendations for the Prevention of Recurrent Loss or Placenta-Mediated Complications.^a

Clinical Scenario	Our Recommendations^b
Obstetric APS	Aspirin 81 mg once daily preconceptionally and prophylactic LMWH (with uptitration during the third trimester) after pregnancy is confirmed
Recurrent miscarriage and inherited thrombophilia	No antepartum anticoagulation
History of single late pregnancy loss and inherited thrombophilia	No antepartum anticoagulation
Severe preeclampsia/HELLP	Aspirin 81 mg once daily once pregnancy is confirmed
Two or more unexplained miscarriages	No antepartum anticoagulation

Abbreviations: APS, antiphospholipid antibody syndrome; HELLP, hemolytic anemia with elevated liver enzymes and low platelets; LMWH, low-molecular-weight heparin.

^aThis table does not include recommendations for VTE prevention or treatment. Please see text for further details. These are general recommendations, and each case has its own nuances.

^bFor dosing options, see text.

Footnotes

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

References

Brigham

Conlon

Farquharson

. A longitudinal study of pregnancy outcome following idiopathic recurrent miscarriage. Hum Reprod. 1999;14(11):2868–2871.

Battinelli

Marshall

Connors

. The role of thrombophilia in pregnancy. Thrombosis. 2013;2013:516420.

James

Jamison

Brancazio

Myers

. Venous thromboembolism during pregnancy and the postpartum period: incidence, risk factors, and mortality. Am J Obstet Gynecol. 2006;194(5):1311–1315.

Robertson

Langhorne

. Thrombophilia in pregnancy: a systematic review. Br J Haematol. 2006;132(2):171–196.

Rai

Cohen

Dave

Regan

. 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):253–257.

Tormene

Grandone

De Stefano

. Obstetric complications and pregnancy-related venous thromboembolism: the effect of low-molecular-weight heparin on their prevention in carriers of factor V Leiden or prothrombin G20210A mutation. Thromb Haemost. 2012;107(3):477–484.

Clark

Walker

Langhorne

. SPIN (Scottish Pregnancy Intervention) study: a multicenter, randomized controlled trial of low-molecular-weight heparin and low-dose aspirin in women with recurrent miscarriage. Blood. 2010;115(21):4162–4167.

Visser

Ulander

Helmerhorst

. Thromboprophylaxis for recurrent miscarriage in women with or without thrombophilia. HABENOX: a randomised multicentre trial. Thromb Haemost. 2011;105(2):295–301.

Kaandorp

Goddijn

van der Post

. Aspirin plus heparin or aspirin alone in women with recurrent miscarriage. N Engl J Med. 2010;362(17):1586–1596.

10.

Preston

Rosendaal

Walker

. Increased fetal loss in women with heritable thrombophilia. Lancet. 1996;348(9032):913–916.

11.

Rey

Kahn

David

Shrier

. Thrombophilic disorders and fetal loss: a meta-analysis. Lancet. 2003;361(9361):901–908.

12.

Robertson

Twaddle

. Screening for thrombophilia in high-risk situations: systematic review and cost-effectiveness analysis. The Thrombosis: Risk and Economic Assessment of Thrombophilia Screening (TREATS) study. Health Technol Assess. 2006;10(11):1–110.

13.

Pasquier

de Saint Martin

Bohec

. Enoxaparin for prevention of unexplained recurrent miscarriage: a multicenter randomized double-blind placebo-controlled trial. Blood. 2015;125(14):2200–2205.

14.

Kist

Janssen

Kalk

Hague

Dekker

de Vries

. Thrombophilias and adverse pregnancy outcome—a confounded problem! Thromb Haemost. 2008;99(1):77–85.

15.

Waitara

Bordas

. Heparin rescues factor V Leiden-associated placental failure independent of anticoagulation in a murine high-risk pregnancy model. Blood. 2013;121(11):2127–2134.

16.

Pabinger

. Thrombophilia and its impact on pregnancy. Hamostaseologie. 2008;28(3):130–134.

17.

Brenner

. Haemostatic changes in pregnancy. Thromb Res. 2004;114(5-6):409–414.

18.

Kjellberg

Andersson

Rosen

Tengborn

Hellgren

. APC resistance and other haemostatic variables during pregnancy and puerperium. Thromb Haemost. 1999;81(4):527–531.

19.

Greer

. Thrombophilia: implications for pregnancy outcome. Thromb Res. 2003;109(2-3):73–81.

20.

Lanir

Aharon

Brenner

. Haemostatic mechanisms in human placenta. Best Pract Res Clin Haematol. 2003;16(2):183–195.

21.

Roberts

Schwartz

. Clotting and hemorrhage in the placenta—a delicate balance. N Engl J Med. 2002;347(1):57–59.

22.

Sheppard

Bonnar

. Uteroplacental hemostasis in intrauterine fetal growth retardation. Semin Thromb Hemost. 1999;25(5):443–446.

23.

Gris

Neveu

Mares

Biron

Hedon

Schved

. Plasma fibrinolytic activators and their inhibitors in women suffering from early recurrent abortion of unknown etiology. J Lab Clin Med. 1993;122(5):606–615.

24.

Zwicker

Trenor

III Furie

Furie

. Tissue factor-bearing microparticles and thrombus formation. Arterioscler Thromb Vasc Biol. 2011;31(4):728–733.

25.

Patil

Ghosh

Satoskar

Shetty

. Elevated procoagulant endothelial and tissue factor expressing microparticles in women with recurrent pregnancy loss. PloS One. 2013;8(11):e81407.

26.

Laude

Rongieres-Bertrand

Boyer-Neumann

. Circulating procoagulant microparticles in women with unexplained pregnancy loss: a new insight. Thromb Haemost. 2001;85(1):18–21.

27.

Bussolino

Benedetto

Massobrio

Camussi

. Maternal vascular prostacyclin activity in pre-eclampsia. Lancet. 1980;2(8196):702.

28.

Miyakis

Lockshin

Atsumi

. International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS). J Thromb Haemost. 2006;4(2):295–306.

29.

Kutteh

. Antiphospholipid antibody syndrome and reproduction. Curr Opin Obstet Gynecol. 2014;26(4):260–265.

30.

Clark

Laskin

Spitzer

. Anticardiolipin antibodies and recurrent early pregnancy loss: a century of equivocal evidence. Hum Reprod Update. 2012;18(5):474–484.

31.

Farquharson

Quenby

Greaves

. Antiphospholipid syndrome in pregnancy: a randomized, controlled trial of treatment. Obstet Gynecol. 2002;100(3):408–413.

32.

Laskin

Spitzer

Clark

. Low molecular weight heparin and aspirin for recurrent pregnancy loss: results from the randomized, controlled HepASA Trial. J Rheumatol. 2009;36(2):279–287.

33.

Empson

Lassere

Craig

Scott

. Prevention of recurrent miscarriage for women with antiphospholipid antibody or lupus anticoagulant. Cochrane Database Syst Rev. 2005(2):CD002859.

34.

Bates

Greer

Middeldorp

Veenstra

Prabulos

Vandvik

. VTE, thrombophilia, antithrombotic therapy, and pregnancy: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141(2 suppl):e691s–e736s.

35.

Committee on Practice Bulletins—Obstetrics, American College of Obstetricians and Gynecologists. Practice Bulletin No. 132: antiphospholipid syndrome. Obstet Gynecol. 2012;120(6):1514–1521.

36.

Carp

. Aspirin in recurrent miscarriage: is there an indication? Isr Med Assoc J. 2009;11(3):178–182.

37.

Opatrny

David

Kahn

Shrier

Rey

. Association between antiphospholipid antibodies and recurrent fetal loss in women without autoimmune disease: a metaanalysis. J Rheumatol. 2006;33(11):2214–2221.

38.

Ruffatti

Salvan

Del Ross

. Treatment strategies and pregnancy outcomes in antiphospholipid syndrome patients with thrombosis and triple antiphospholipid positivity. A European multicentre retrospective study. Thromb Haemost. 2014;112(4):727–735.

39.

Gebhart

Posch

Koder

. Increased mortality in patients with the lupus anticoagulant: the Vienna Lupus Anticoagulant and Thrombosis Study (LATS). Blood. 2015;125(22):3477–3483.

40.

Lockshin

Kim

Laskin

. Prediction of adverse pregnancy outcome by the presence of lupus anticoagulant, but not anticardiolipin antibody, in patients with antiphospholipid antibodies. Arthritis Rheum. 2012;64(7):2311–2318.

41.

Bouvier

Cochery-Nouvellon

Lavigne-Lissalde

. Comparative incidence of pregnancy outcomes in treated obstetric antiphospholipid syndrome: the NOH-APS observational study. Blood. 2014;123(3):404–413.

42.

Bouvier

Cochery-Nouvellon

Lavigne-Lissalde

. Comparative incidence of pregnancy outcomes in thrombophilia-positive women from the NOH-APS observational study. Blood. 2014;123(3):414–421.

43.

Bates

. Management of pregnant women with thrombophilia or a history of venous thromboembolism. Hematology Am Soc Hematol Educ Program. 2007:143–150.

44.

Meinardi

Middeldorp

de Kam

. Increased risk for fetal loss in carriers of the factor V Leiden mutation. Ann Intern Med. 1999;130(9):736–739.

45.

Rodger

Carrier

Le Gal

. Meta-analysis of low-molecular-weight heparin to prevent recurrent placenta-mediated pregnancy complications. Blood. 2014;123(6):822–828.

46.

Rodger

Betancourt

Clark

. 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.

47.

Dudding

Attia

. The association between adverse pregnancy outcomes and maternal factor V Leiden genotype: a meta-analysis. Thromb Haemost. 2004;91(4):700–711.

48.

Rodger

Hague

Kingdom

. Antepartum dalteparin versus no antepartum dalteparin for the prevention of pregnancy complications in pregnant women with thrombophilia (TIPPS): a multinational open-label randomised trial. Lancet. 2014;384(9955):1673–1683.

49.

Gibson

Nerenberg

. TIPPing practice away from anticoagulation in pregnancy. Lancet. 2014;384(9955):1648–1649.

50.

de Jong

Kaandorp

Di Nisio

Goddijn

Middeldorp

. Aspirin and/or heparin for women with unexplained recurrent miscarriage with or without inherited thrombophilia. Cochrane Database Syst Rev. 2014;7:CD004734.

51.

Gris

Quere

Monpeyroux

. Case-control study of the frequency of thrombophilic disorders in couples with late foetal loss and no thrombotic antecedent—the Nimes Obstetricians and Haematologists Study5 (NOHA5). Thromb Haemost. 1999;81(6):891–899.

52.

Many

Elad

Yaron

Eldor

Lessing

Kupferminc

. Third-trimester unexplained intrauterine fetal death is associated with inherited thrombophilia. Obstet Gynecol. 2002;99(5 pt 1):684–687.

53.

Alfirevic

Mousa

Martlew

Briscoe

Perez-Casal

Toh

. Postnatal screening for thrombophilia in women with severe pregnancy complications. Obstet Gynecol. 2001;97(5 pt 1):753–759.

54.

van Rijn

Hoeks

Bots

Franx

Bruinse

. Outcomes of subsequent pregnancy after first pregnancy with early-onset preeclampsia. Am J Obstet Gynecol. 2006;195(3):723–728.

55.

Sullivan

Magann

Perry

Jr Roberts

Blake

Martin

Jr . The recurrence risk of the syndrome of hemolysis, elevated liver enzymes, and low platelets (HELLP) in subsequent gestations. Am J Obstet Gynecol. 1994;171(4):940–943.

56.

Middeldorp

. Anticoagulation in pregnancy complications. Am Soc Hematol Edu Program. 2014;2014(1):393–399.

57.

Steegers

von Dadelszen

Duvekot

Pijnenborg

. Pre-eclampsia. Lancet. 2010;376(9741):631–644.

58.

Askie

Duley

Henderson-Smart

Stewart

. Antiplatelet agents for prevention of pre-eclampsia: a meta-analysis of individual patient data. Lancet. 2007;369(9575):1791–1798.

59.

Roberge

Giguere

Villa

. Early administration of low-dose aspirin for the prevention of severe and mild preeclampsia: a systematic review and meta-analysis. Am J Perinatol. 2012;29(7):551–556.

60.

Bujold

Roberge

Lacasse

. Prevention of preeclampsia and intrauterine growth restriction with aspirin started in early pregnancy: a meta-analysis. Obstet Gynecol. 2010;116(2 pt 1):402–414.

61.

Martinelli

Ruggenenti

Cetin

. Heparin in pregnant women with previous placenta-mediated pregnancy complications: a prospective, randomized, multicenter, controlled clinical trial. Blood. 2012;119(14):3269–3275.

62.

Kalk

Huisjes

de Groot

. Recurrence rate of pre-eclampsia in women with thrombophilia influenced by low-molecular-weight heparin treatment? Neth J Med. 2004;62(3):83–87.

63.

de Vries

van Pampus

Hague

Bezemer

Joosten

. Low-molecular-weight heparin added to aspirin in the prevention of recurrent early-onset pre-eclampsia in women with inheritable thrombophilia: the FRUIT-RCT. J Thromb Haemost. 2012;10(1):64–72.

64.

Dizon-Townson

Miller

Sibai

. The relationship of the factor V Leiden mutation and pregnancy outcomes for mother and fetus. Obstet Gynecol. 2005;106(3):517–524.

65.

Schleussner

Kamin

Seliger

. Low-molecular-weight heparin for women with unexplained recurrent pregnancy loss: a multicenter trial with a minimization randomization scheme. Ann Intern Med. 2015;162(9):601–609.

66.

Forestier

Daffos

Capella-Pavlovsky

. Low molecular weight heparin (PK 10169) does not cross the placenta during the second trimester of pregnancy study by direct fetal blood sampling under ultrasound. Thromb Res. 1984;34(6):557–560.

67.

Chan

Anand

Ginsberg

. Anticoagulation of pregnant women with mechanical heart valves: a systematic review of the literature. Arch Intern Med. 2000;160(2):19119–19126.

68.

Konigsbrugge

Langer

Hayde

Pabinger

. Oral anticoagulation with rivaroxaban during pregnancy: a case report. Thromb Haemost. 2014;112(6):1323–1324.

69.

Brancazio

Roperti

Stierer

Laifer

. Pharmacokinetics and pharmacodynamics of subcutaneous heparin during the early third trimester of pregnancy. Am J Obstet Gynecol. 1995;173(4):1240–1245.

70.

James

. Practice bulletin no. 123: thromboembolism in pregnancy. Obstet Gynecol. 2011;118(3):718–729.

The Role of Anticoagulants in the Prevention of Pregnancy Complications

Abstract

Keywords

Introduction

Hemostatic Changes in Pregnancy

Antiphospholipid Antibody Syndrome

Recommendation

Inherited Thrombophilias: FVL and PGM

Recommendation

Protein C, S, and Antithrombin Deficiency

Recommendation

Anticoagulation in Preeclampsia, HELLP Syndrome, and Placental Abruption

Recommendation

Anticoagulation for Recurrent Miscarriage Without Thrombophilia

Recommendation

If Choosing to Anticoagulate, What to Use?

Conclusion

Footnotes

Declaration of Conflicting Interests

Funding

References