Jess Mandel, MD
William H Gaasch, MD
Kenneth A Bauer, MD
Lawrence LK Leung, MD
Charles J Lockwood, MD
Stephen A Landaw, MD, PhD
Kevin C Wilson, MD
INTRODUCTION — Clinicians are occasionally faced with the dilemma of managing pregnant patients who require ongoing anticoagulation for the prophylaxis or treatment of thrombotic complications. Examples include women with mechanical heart valves, venous thromboembolism (VTE) immediately prior to or during pregnancy, heart failure, and symptomatic antiphospholipid antibody syndrome (see appropriate topic reviews).
Strategies to maintain therapeutic anticoagulation while avoiding maternal or fetal harm due to antithrombotic agents are based largely upon retrospective data because ethical and legal considerations make large prospective trials among pregnant women difficult to conduct.
This topic review will describe the experience with major antithrombotic agents among pregnant women and discuss the management of several common conditions that require anticoagulation during pregnancy. General issues related to the clinical use of warfarin and heparin are discussed separately. (See “Therapeutic use of warfarin” and “Therapeutic use of heparin and low molecular weight heparin”.)
Due to the unique nature of managing pregnant women with mechanical prosthetic valves, anticoagulation in this setting is discussed in detail separately. (See “Management of pregnant women with prosthetic heart valves”.)
COMMON ANTITHROMBOTIC AGENTS — Unfractionated heparin (UFH) and low-molecular-weight heparin (LMWH) are the antithrombotic agents most commonly considered for use in pregnant women. Oral anticoagulants (OACs), usually warfarin, are generally not used during pregnancy for the reasons outlined below.
Warfarin — The anticoagulant effect of warfarin is mediated by interference with the vitamin K-dependent gamma-carboxylation of coagulation factors II, VII, IX, and X . This results in the synthesis of immunologically detectable but biologically inactive forms of these coagulation proteins. (See “Therapeutic use of warfarin”.)
The anticoagulant effect of warfarin is delayed until the normal clotting factors are cleared from the circulation . During the first few days of warfarin therapy, the prolongation of the prothrombin time (PT) mainly reflects the depression of factor VII, which has a half-life of five to seven hours. This does not represent adequate anticoagulation, because the intrinsic and common clotting pathways remain intact until factors II, IX, and X are sufficiently reduced, which takes about five days with adequate dosing (figure 1).
Warfarin is the long-term anticoagulant of choice in nonpregnant patients, but its great disadvantage in pregnancy is that it freely crosses the placental barrier because of its low molecular weight and can harm the fetus [3,4]. For this reason, the drug is classified by the United States Food and Drug Administration (FDA) as pregnancy category X (table 1). However, nursing mothers can safely take the drug because there is no convincing evidence that warfarin exerts an anticoagulant effect on the breast-fed infant .
Adverse fetal effects from warfarin may result from the teratogenicity of the drug and its propensity to cause bleeding in the fetus.
Teratogenic effects — There is convincing evidence that warfarin administration is potentially teratogenic. Embryopathy is most likely with exposure during the sixth to ninth weeks of gestation, but toxicity after this period is still possible [6-9]. Exposure is also associated with higher rates of spontaneous abortion and stillbirth [10,11]. The teratogenic effect appears to be dose related, with doses less than 5 mg/day providing the highest margin of safety [12,13].
The most common developmental abnormalities affect bone and cartilage; these simulate chondromalacia punctata, with stippled epiphyses and nasal and limb hypoplasia . The mechanism of this type of warfarin teratogenicity has not been established, but may be related to the drug’s interference with the post-translational modification of calcium-binding proteins that are important for the normal growth and development of bony structures . As an example, osteocalcin carboxylation in human subjects is a vitamin K-dependent process, and circulating osteocalcin is structurally altered by warfarin . (See “Vitamin K and the synthesis of gamma carboxyglutamic acid”.)
Less well-documented are reports of central nervous system (CNS) abnormalities (including optic atrophy, microcephaly, mental retardation, spasticity, and hypotonia) associated with warfarin use at any stage during pregnancy [3,17-20]. This complication may be related to fetal anticoagulation leading to CNS hemorrhage. Fetal or neonatal hemorrhage is a concern when warfarin is administered in the second and third trimesters; however, this complication has rarely been observed [12,21-24]. The risk is thought to be greatest during and immediately after delivery [19,20].
The precise risk of warfarin embryopathy is unknown. While different series have reported widely ranging incidences among fetuses exposed to warfarin between the sixth and twelfth weeks of gestation , the best overall estimate of the risk is less than 10 percent . (See “Management of pregnant women with prosthetic heart valves”.)
One study, for example, found no congenital abnormalities in 46 women with prosthetic valves who took warfarin during the first trimester . However, other reports have not found such a benign outcome, primarily in patients taking warfarin between the six and twelfth weeks of pregnancy. As an example, the following findings were noted in report of 72 pregnancies in women with valve prostheses :
- Virtually no embryopathic events occurred in the 23 pregnancies in which warfarin was discontinued by the sixth week of gestation and not restarted until after the twelfth week.
- Warfarin embryopathy occurred in 25 percent of the 12 pregnancies in which warfarin was not stopped until after the seventh week.
- Embryopathy occurred in 30 percent of the 37 pregnancies in which warfarin was continued throughout the entire pregnancy.
Another smaller study noted embryopathy in 12 of 18 infants born to mothers who took warfarin throughout pregnancy . The most common event was a minor cosmetic defect (nasal hypoplasia); major complications were rare.
There may be a relationship between the warfarin dose and fetal complications that is independent of the INR [12,13]. This association was illustrated in a report of 71 pregnancies in 52 women with mechanical heart valves who were treated with warfarin throughout pregnancy . There were 30 fetal complications, including 23 spontaneous abortions, four warfarin embryopathies, and five stillbirths. Women taking more than 5 mg of warfarin daily were at much higher risk of fetal complications than those taking a lower dose (82 versus 8 percent), regardless of INR. A similar increase in risk with warfarin doses above 5 mg/day (88 versus 15 percent) was noted in another study .
The actual risk of warfarin embryopathy resulting in a deformed, mentally retarded infant is believed to be relatively low , but warfarin-related central nervous system abnormalities probably occur at an incidence greater than first trimester embryopathy, although they are clinically less severe. In light of the possibility that the risk of warfarin embryopathy, central nervous system maldevelopment, and optic injury might increase with warfarin dose and the degree of anticoagulation, therapy should be monitored meticulously using the INR to achieve a therapeutic response at the lowest possible dose. (See “Therapeutic use of warfarin”.)
The long-term physical and neurologic development after prenatal coumarin exposure during pregnancy was evaluated in a case-control study of 274 such children (7 to 15 years of age) who were compared with 231 unexposed controls . Only 5 percent of the children were exposed to coumarins during the sixth to ninth week of development. Data were analyzed by both single and combined effects models to look for adverse outcomes in the coumarin-exposed group. No major differences in growth or overall neurologic status were found. Exposed children were at mildly increased risk for minor neurologic dysfunction and lower IQ. There was a suggestion that the risk of adverse outcome was related to maternal coumarin dose; however, this was not statistically significant.
Fetal hemorrhage — The immaturity of fetal enzyme systems and the relatively low concentration of vitamin K-dependent clotting factors render the fetus more sensitive than the mother to the anticoagulant effects of warfarin [3,17,18]. Thus, the transplacental passage of warfarin increases the risk of hemorrhagic fetal death during vaginal delivery. To minimize this risk, warfarin should be discontinued after 34 to 36 weeks of gestation and/or cesarean delivery should be considered .
Management is more complex if preterm labor develops in a patient on warfarin, because both the mother and the fetus are anticoagulated. Vitamin K administration does not achieve immediate reversal of maternal anticoagulation, which may persist for 24 hours; more rapid reversal requires the transfusion of fresh frozen plasma. Importantly, fetal levels of coagulation factors do not correlate with maternal levels, and infusion of fresh frozen plasma into the mother does not reliably reverse fetal anticoagulation. A cesarean delivery may prevent hemorrhagic fetal death, and fresh frozen plasma should be administered to the neonate. Maternal subcutaneous heparin generally should be resumed no later than six hours after delivery in anticipation of an early return to warfarin. Because only an inactive warfarin metabolite finds its way into breast milk, lactation does not result in neonatal anticoagulation [27,28].
Unfractionated heparin — Heparin is an indirect thrombin inhibitor that complexes with antithrombin and converts this circulating cofactor from a slow to a rapid inactivator of thrombin, factor Xa, and to a lesser extent, factors XIIa, XIa, and IXa [29,30]. (See “Therapeutic use of heparin and low molecular weight heparin”.)
Unfractionated heparin (as distinguished from low-molecular-weight heparin) has a high molecular weight, which precludes transplacental transfer. Heparin is in FDA pregnancy category C (table 1); it is devoid of known teratogenic risk and does not anticoagulate the fetus [3,4]. Early estimates of heparin-related fetal wastage were believed to approximate those of pregnant women receiving warfarin (ie, maternal anticoagulation was considered the major risk factor, regardless of the agent used). However, subsequent studies found a significantly lower heparin-related risk of fetal wastage that was similar to that of untreated women .
A number of concerns are related to sustained administration of unfractionated heparin during pregnancy, including the relative difficulty of maintaining a stable therapeutic response, the inconvenience of parenteral administration, and the complications of heparin-induced thrombocytopenia and bone demineralization in patients treated for more than seven weeks [14,32-36]. Demineralization can result in the fracture of vertebral bodies or long bones, and the defect may not be entirely reversible [35-37]. (See “Therapeutic use of heparin and low molecular weight heparin” and “Drugs that affect bone metabolism”, section on ‘Heparin’.)
Higher doses of heparin are necessary for pregnant women to achieve therapeutic levels for both prophylaxis and therapy. The increased requirement is a result of increases in heparin-binding proteins, plasma volume, renal clearance, coagulation factors, and heparin degradation by the placenta during pregnancy [38-40].
When full anticoagulation is desired, the dose can be adjusted based upon the activated partial thromboplastin time (aPTT) or heparin levels, as in nonpregnant individuals. However, there is no consensus regarding the optimal dose of prophylactic heparin for pregnant women. In these patients, 5000 units given subcutaneously every 12 hours probably is not sufficient to maintain a mid-interval level of 0.05 to 0.25 U/mL [39,41]. The appropriate dose of prophylactic heparin should be determined based on mid-interval heparin levels; if this is not possible, a dose of 7500 to 10,000 units given subcutaneously every 12 hours is a reasonable alternative .
Women who are anticoagulated with heparin until the onset of labor generally experience vaginal delivery with no greater blood loss than nonanticoagulated gravidas. However, cesarean delivery in heparinized patients is accompanied by a significantly greater blood loss than would otherwise be anticipated. The heparin infusion should be stopped approximately four hours before cesarean delivery. If preterm labor develops in a patient receiving heparin, only the mother is anticoagulated, and protamine sulfate has been used to reverse maternal heparinization.
LMW heparin — Low-molecular-weight heparin (LMW heparin) represents a class of anticoagulants possessing a shorter polysaccharide chain and therefore a lower molecular weight than standard, unfractionated heparin [43-45]. The commercially available LMW heparins are made via different processes, including nitrous acid, alkaline, or enzymatic depolymerization. These agents differ chemically and pharmacokinetically; however, the clinical significance of these differences and their potential importance in pregnancy are unclear [43,46]. Enoxaparin, the most commonly used LMW heparin in the United States, is listed by the FDA in pregnancy category B (table 1). (See “Therapeutic use of heparin and low molecular weight heparin”.)
LMW heparin may resolve the difficulty in achieving a sustained, stable therapeutic response and may reduce the inconvenience of parenteral administration because increased bioavailability and a longer half-life produce a more predictable anticoagulant response to fixed doses administered once or twice daily [44,45]. Laboratory monitoring of the anticoagulant effect of LMW heparin is generally not performed in nonpregnant patients, but some authors recommend measuring anti-factor Xa levels four hours after injection in pregnant patients . The dose of LMW heparin is then titrated to achieve the manufacturer’s recommended peak anti-Xa level.
Pregnant women may need dose adjustments as the pregnancy continues because of weight gain and other factors [47-51]. One study of LMW heparin pharmacokinetics in 24 women at 12, 24, and 36 weeks of gestation and 6 weeks postpartum found peak anti-X activity levels during pregnancy were lower than in nonpregnant (postpartum) women and occurred later after injection, 4 versus 2 hours .
LMW heparin causes less in vitro clot inhibition while retaining its in vivo antithrombotic effect, theoretically making the risk of bleeding less than with unfractionated heparin; it also appears less likely to precipitate heparin-associated thrombocytopenia .
It is unclear whether bone loss may be significantly reduced or prevented by using LMW instead of unfractionated heparin. A study that randomly assigned 44 pregnant women to receive either dalteparin (target anti-Xa greater than 0.20 IU/mL three hours after injection) or unfractionated heparin (mean dose 17,250 units/day) found that mean bone density (BMD) in the lumbosacral spine was significantly lower one week to three years postpartum among women receiving unfractionated heparin . In addition, there was no difference in the BMD of women treated with LMW heparin compared with controls (healthy postpartum women not exposed to either heparin therapy). However, other studies have not found a difference in BMD changes between the two heparin preparations (enoxaparin versus unfractionated heparin) , or among patients treated with LMW heparin and matched controls . Therefore, significant uncertainty remains regarding the relationship between different heparin preparations and maternal bone loss. Accordingly, more large studies are needed to clarify whether LMW heparin is less deleterious to BMD than unfractionated heparin in pregnant women. (See “Drugs that affect bone metabolism”.)
Clinical experience with LMW heparin during pregnancy largely has been favorable [14,55-59], and the American College of Obstetricians and Gynecologists has stated that LMW heparin can be considered in women who are candidates for prophylactic or therapeutic anticoagulation during pregnancy . One study, for example, evaluated the efficacy of enoxaparin (20 to 40 mg/day) in 69 pregnancies in 61 women at high risk for venous thromboembolism (VTE); one woman (1.6 percent) had a postpartum pulmonary embolus . In addition, a 1999 review found that, after adjustment for comorbid conditions, the incidence of adverse pregnancy outcomes of 486 women treated with LMW heparin was comparable to that in the general population . Danaparoid has been used in pregnant patients who require continuing anticoagulation despite the development of heparin-associated thrombocytopenia or other heparin-induced complications [32,61].
A systematic review of 64 studies involving 2777 pregnancies reported on the safety and efficacy of LMW heparin when used to treat or prevent VTE or for prior adverse pregnancy outcomes :
- VTE and arterial thrombosis were reported in 0.86 and 0.50 percent, respectively. There were no maternal deaths.
- Significant bleeding, generally associated with obstetric causes, occurred in 1.98 percent, allergic skin reactions in 1.80 percent, and osteoporotic fractures in 0.04 percent. There were no cases of heparin-induced thrombocytopenia.
- Live births were reported in 94.7 percent, including 85.4 percent in those receiving LMW heparin for recurrent pregnancy loss.
The report concluded that LMWH is both safe and effective to prevent or treat VTE in pregnancy.
Some reports in nonpregnant patients have described a higher incidence of epidural hematoma associated with LMW heparin administration near the time of epidural catheter placement or removal [62,63]. For this reason, patients should be switched to subcutaneous unfractionated heparin about two weeks prior to the expected delivery; this will permit regional anesthesia for labor and possible operative delivery.
Use of LMW heparins has not been associated with a risk of birth defects above the baseline risk in the general population or with a specific type of anomaly. Prefilled, single dose syringes are preservative free. The multidose vial contains benzyl alcohol, which can have adverse fetal effects and is contraindicated in pregnancy.
Mechanical prosthetic heart valves — Concern has been raised about the safety and efficacy of LMWH in pregnant women with mechanical prosthetic heart valves. Small observational studies and case reports have suggested that the serious complication of valve thrombosis may be more common in women treated with LMWH than with UFH or warfarin. (See “Complications of prosthetic heart valves”, section on ‘Valve thrombosis’.)
In July 2002, the United States Food and Drug Administration issued an addition to the warnings section of product labeling for enoxaparin, indicating that this product is not recommended for thromboprophylaxis in pregnant women with prosthetic heart valves. Similar warnings have been given by the American College of Obstetricians and Gynecologists and the European Society of Cardiology. However, other expert panels disagree, and the American College of Chest Physicians recommended that LMWH remain a therapeutic option in this setting. Detailed discussion of the management of pregnant women with prosthetic heart valves is presented separately. (See “Management of pregnant women with prosthetic heart valves”.)
MANAGEMENT OF SPECIFIC CONDITIONS REQUIRING ANTICOAGULATION — The need for anticoagulation during pregnancy is most commonly related to valvular heart disease or venous thromboembolism. The optimal management of these conditions during pregnancy remains controversial because of the absence of definitive clinical trials.
General recommendations — The 2008 ACCP Guidelines for antithrombotic therapy recommended one of three approaches for anticoagulation during pregnancy :
- Aggressive adjusted-dose unfractionated heparin throughout the pregnancy; heparin is administered subcutaneously every 12 hours in doses adjusted to keep the mid-interval aPTT at least twice control or to attain an anti-Xa level of 0.35 to 0.70 U/mL. After a stable dose is achieved, the aPTT should be measured at least weekly.
- Adjusted-dose subcutaneous LMW heparin therapy throughout the pregnancy in doses adjusted according to weight to achieve the manufacturer’s recommended anti-Xa level four hours after subcutaneous injection.
- Unfractionated or LMW heparin therapy (as above) until the thirteenth week, a change to warfarin until the middle of the third trimester, and then restarting unfractionated or low molecular weight heparin until delivery.
Long-term anticoagulation should be resumed postpartum regardless of which regimen is used. Heparin can be restarted 12 hours post-cesarean delivery and 6 hours post-vaginal birth, if no significant bleeding has occurred. Heparin is either continued or replaced with warfarin (stopping the heparin when the INR is therapeutic). (See “Management of anticoagulation before and after elective surgery”.)
Women attempting to become pregnant — For women who are taking long-term vitamin K antagonists and are attempting to become pregnant, the 2008 ACCP Guidelines suggest performing frequent pregnancy tests and substituting treatment with a heparin preparation (unfractionated or LMW heparin) as soon as pregnancy is achieved .
We believe that this is a reasonable option for a woman who meets all of the following criteria:
- She has regular monthly menstrual cycles.
- She agrees to have a blood pregnancy test within the first seven days of the missed first day of expected menses. This can be facilitated by having a standing order at a laboratory or giving her laboratory requisitions in advance.
- She can be switched to a heparin preparation promptly if the pregnancy test is positive, and will have a second blood pregnancy test if the first test is negative and menses have not begun within 10 days of the missed first day of expected menses.
- She understands the baseline risk of birth defects (3 percent ) in the population and the further increased risk and types of embryopathy if she continues to take her long-term vitamin K antagonist during or after the sixth week of pregnancy (ie, ≥14 days after the missed first day of expected menses).
(See ‘Teratogenic effects’ above.)
Prosthetic heart valves — In pregnant women with mechanical prosthetic valves, anticoagulants are, with few exceptions, obligatory, especially in light of the hypercoagulable state during late pregnancy. This important issue is discussed in detail separately. (See “Management of pregnant women with prosthetic heart valves”.)
Venous thromboembolism — The risk of venous thromboembolism (VTE) is increased in association with pregnancy, occurring primarily during the postpartum period . This phenomenon may relate in part to the progressive increase in resistance to activated protein C that is normally observed in the second and third trimesters . Other coagulation changes that contribute to the development of VTE include: a progressive increase in several coagulation factors, such as factors I, II, VII, VIII, and X [66-68]; increased activity of the fibrinolytic inhibitors PAI-1 and PAI-2 [69,70]; increased venous stasis; and vascular damage at the time of delivery. (See “Deep vein thrombosis and pulmonary embolism in pregnancy: Epidemiology, pathogenesis, and diagnosis”.)
The risk during both the intrapartum and the postpartum periods appears to be accentuated in those women who have an inherited abnormality or deficiency of a naturally occurring anticoagulant, such as factor V Leiden, prothrombin G20210A, antithrombin, protein C, or protein S . In several studies, for example, the frequency of developing VTE during pregnancy or the postpartum period was at least eightfold greater in women with protein C or S deficiency, factor V Leiden, or prothrombin gene mutation G20210A than in normals [72,73].
LMW heparin is the prophylactic regimen of choice for pregnant patients who are at high risk for deep venous thrombosis and pulmonary embolism; however, data on efficacy from controlled trials are lacking [74,75]. Anti-factor Xa monitoring is not required. The advantages of LMW heparin are a good safety profile with less thrombocytopenia, bleeding, and osteopenia than unfractionated heparin and more predictable and rapidly achieved anticoagulation . Included among this high-risk group are women with:
- An inherited deficiency of a naturally occurring anticoagulant
- A prior episode of venous thromboembolism
- Antiphospholipid antibodies and a prior fetal death, pregnancy loss, or thrombotic event 
Prophylactic dosing of subcutaneous unfractionated heparin is an alternative [5,14,75]. Data on efficacy from controlled trials are lacking.
Despite the absence of firm clinical data, it has been suggested that such women might benefit from use of LMH or unfractionated heparin prophylaxis until delivery, followed by warfarin for four to six weeks postpartum [5,72,75]. LMW heparins should be switched to unfractionated heparin two weeks prior to the expected delivery and followed with warfarin postpartum as previously described.
Another approach that has been advocated is clinical surveillance of such women during pregnancy, followed by four to six weeks of postpartum warfarin therapy, particularly in women with prior VTE that occurred in the setting of a known risk factor such as trauma .
Acute deep venous thrombosis or pulmonary embolism which is diagnosed during pregnancy should be managed initially in an identical fashion to that used when these conditions occur in nonpregnant patients; the mainstay of initial therapy is heparin to rapidly achieve a heparin level of 0.2 to 0.4 U/mL by the protamine titration assay (usually with a PTT that is 1.5 to 2.0 times the control value). (See “Treatment of acute pulmonary embolism”.)
Subcutaneous heparin (preferably LMW heparin) at treatment doses should be continued until delivery, and a four to six week course of warfarin should be completed after delivery [5,14]. Alternatively, LMW heparin can be given until two weeks prior to the expected delivery, followed by subcutaneous unfractionated heparin and warfarin as described previously. (See “Deep vein thrombosis and pulmonary embolism in pregnancy: Prevention”.)
Other — Anticoagulation may be warranted in several other conditions during pregnancy which are discussed in detail elsewhere. These include:
- Atrial fibrillation associated with significant underlying heart disease, but not lone atrial fibrillation (see “Antithrombotic therapy to prevent embolization in nonvalvular atrial fibrillation”)
- Antiphospholipid antibody syndrome (see “Treatment of the antiphospholipid syndrome”)
- Heart failure, particularly in the presence of a ventricular thrombus (see “Management of heart failure in pregnancy” and “Peripartum cardiomyopathy”)
- Eisenmenger syndrome (see “Medical management of Eisenmenger syndrome”, section on ‘Pregnancy’)
- Paroxysmal nocturnal hemoglobinuria (see “Diagnosis and treatment of paroxysmal nocturnal hemoglobinuria”, section on ‘Prophylactic anticoagulation’).
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