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Management of side effects — For patients who experience bleeding while receiving LMWH, protamine sulfate (1 mg/100 anti-Xa units of LMWH) can reduce clinical bleeding, presumably by neutralizing the higher molecular weight fractions of heparin within the product, which are thought to be most responsible for this complication.

Although the frequency of thrombocytopenia is very low, it is not eliminated so we would still recommend following platelet counts in a similar fashion as described above for patients taking unfractionated heparin [39]. Significant uncertainty remains as to whether use of LMWH has a less deleterious effect on maternal bone loss than unfractionated heparin [56,57]. More large studies are needed to clarify this issue. Until these data are available, we administer 1500 mg of calcium and at least 400 IU vitamin D daily as prophylaxis against osteoporosis and order bone densitometry studies after six months of therapy.

Use of LMWH may increase the risk of epidural hematoma formation upon placement of a neuraxial anesthetic (see "Anesthesia" below). For this reason, we recommend stopping therapy at 36 weeks, or earlier if preterm delivery is anticipated. Unfractionated heparin is employed until delivery.

Warfarin — Warfarin gains its anticoagulant effect from its ability to inhibit the action of vitamin K, which is a cofactor in the synthesis of the final molecular forms of factors VII, IX, X, and prothrombin. It readily crosses the placenta [58], but clinically important amounts are not passed into breast milk. There is convincing evidence that warfarin administration between the sixth and ninth weeks of gestation is potentially teratogenic [59-62]. The teratogenic effect appears to be dose related, with doses less than 5 mg/day providing the highest margin of safety [63]. Fetal hemorrhage any time in gestation is another risk, although this is rare. Therefore, warfarin is typically not used during pregnancy and definitely should be avoided in the first few weeks of pregnancy and near term. Pregnant patients with mechanical heart valves are one of the few clinical presentations in which the benefit of warfarin use in the midtrimester may outweigh the risk. (See "Management of pregnant women with prosthetic heart valves" and see "Anticoagulation during pregnancy" section on Warfarin). Warfarin can be used postpartum when long-term anticoagulation is planned.

Newer anticoagulants — Several new anticoagulants have been approved for clinical use. Although little information exists defining their role in pregnant women, direct thrombin inhibitors (DTI) and Specific Factor Xa Inhibitors are listed as pregnancy risk factor B (show table 6). These medications have shown no risk in animal studies; however, controlled human first trimester studies are not available. No evidence of second or third trimester fetal harm exists and the safety in nursing mothers is unknown. These medications are considered investigational in pregnant or breast feeding patients. (See "New anticoagulants" sections on Direct thrombin inhibitors and Factor X inhibitors).

INTRAPARTUM MANAGEMENT — Immobilization and dehydration should be avoided in all pregnant women and they should try to maintain a lateral position when recumbent to minimize stasis in the extremities.

Unfractionated heparin — Anticoagulation is discontinued for labor and delivery, except in women with prosthetic heart valves or who had an iliofemoral thrombosis or pulmonary embolism within the 30 days. The risk of heparin-related bleeding at delivery is minimal after a single prophylactic dose of unfractionated heparin or more than four hours after administration of multiple dose therapy.

In patients who have been on therapeutic doses of unfractionated heparin, an aPTT should be checked and monitored during labor if elevated. Protamine sulfate may be given to reverse a markedly prolonged aPTT at the time of vaginal or cesarean delivery (see above).

Low molecular weight heparin — There are no significant risks of treatment-related bleeding if delivery occurs more than 12 hours after a single prophylactic dose of LMWH or more than 18 to 24 hours after multiple therapeutic doses. If less time has transpired between the last LMWH dose and labor/delivery, then it should be assumed that the patient has a bleeding diathesis; monitoring factor Xa levels is not recommended as the level is not predictive of the risk of bleeding [5]. Protamine can be given if hemorrhage occurs (see above).

Anesthesia — Thromboprophylaxis regimens using low-dose unfractionated heparin are not associated with increased risk of spinal/epidural hematoma. Although these drugs are typically discontinued for labor and delivery, they do not have to be halted prior to spinal or epidural analgesia. If low-dose therapy is continued during labor and delivery, ideally the injection is delayed until after the neuraxial anesthesia has been placed.

In contrast, there are concerns about epidural hematoma formation when neuraxial anesthesia is administered to patients receiving LMWH. The American Society of Regional Anesthesia and Pain Medicine recommends that spinal/epidural anesthesia should not be given until 10 to 12 hours after administration of a prophylactic dose of LMWH to assure normal hemostasis at the time of needle insertion [5]. It is necessary to wait until 24 hours after the last LMWH dose when higher, therapeutic LMWH doses are used (eg, enoxaparin 1 mg/kg every 12 hours, enoxaparin 1.5 mg/kg daily, dalteparin 120 units/kg every 12 hours, dalteparin 200 units/kg daily, tinzaparin 175 units/kg daily). Monitoring factor Xa levels is not recommended as the level is not predictive of the risk of bleeding [5]. For this reason, as noted, we recommend stopping therapy at 36 weeks of gestation, or earlier if preterm delivery is anticipated. Unfractionated heparin is employed until delivery. (See "Prevention and treatment of adverse effects of neuraxial anesthesia" section on Spinal/epidural hematoma).

POSTPARTUM MANAGEMENT — The highest risk period for VTE or pulmonary embolism is postpartum [7,64]. A meta-analysis of nine studies found 66 percent of VTE occurred antepartum and 35 percent occurred postpartum [64]. Using these figures, the estimated relative distribution of VTE events during pregnancy and the puerperium would be 0.23 per day during pregnancy and 0.82 per day in the postpartum period. Thus, the postpartum period is a particularly important time for thromboprophylaxis.

Short term thromboprophylaxis — We feel that women with no history of VTE and no thrombophilia but who have risk factors which raise the clinician's concern about VTE, such as obesity, are candidates for nonpharmacologic or anticoagulant prophylaxis until they achieve full ambulation.

Prolonged postpartum thromboprophylaxis — Higher risk patients should receive thromboprophylaxis regardless of mode of delivery, and therapy should be continued for four to six weeks postpartum. However, the duration of therapy depends upon the reason for prophylaxis and ongoing risk of VTE. Therapy is longer, as an example, in patients who remain immobilized in a cast.

In high risk patients, subcutaneous heparin (5000 units subcutaneously BID) is administered 6 to 12 hours after cesarean delivery or four to six hours after vaginal delivery (if there is no significant bleeding) concurrently with warfarin for the initial four to five days and/or 48 hours after the woman has reached a therapeutic INR (ie, 2.0 to 3.0) on such therapy [23]. This avoids the potential early thrombotic effect of warfarin, which impairs the synthesis of naturally occurring inhibitor of coagulation (proteins C) before producing an anticoagulant effect due to the inhibition of procoagulant clotting factors (factors II, VII, IX, and X). Warfarin is used postpartum instead of heparin because transfer across the placenta is no longer relevant, it can be taken orally, has no osteopenic effects and its use is compatible with breast feeding. It is indicated for postpartum thromboprophylaxis planned for more than a few days duration. Heparin or LMWH is preferred for short-term postpartum anticoagulation. Initiation of warfarin therapy, laboratory monitoring, and management of complications are discussed in detail separately. (See "Clinical use of warfarin").

If LMWH is used postpartum, it also may be initiated 6 to 12 hours after cesarean delivery or four to six hours after vaginal delivery (if there is no significant bleeding). If an epidural catheter is in place, then removal and dosing schedules need to be coordinated to minimize the risk of epidural hematoma from trauma when the catheter is extracted. (See "Prevention and treatment of adverse effects of neuraxial anesthesia" section on Spinal/epidural hematoma).

However, LMWH is generally not indicated for long-term postpartum prophylaxis because of its expense and inconvenience. We would consider using it in a patient who is noncompliant with laboratory monitoring of coumadin therapy.