ENOXAPARIN

Drugs in Pregnancy and Lactation.

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Name: ENOXAPARIN
Class: Anticoagulant
Risk Factor:    BM

Fetal Risk Summary

Enoxaparin is a low molecular weight heparin (LMWH) product prepared from porcine intestinal mucosa heparin. The anticoagulant is not teratogenic or embryotoxic in rats and rabbits (1).

Enoxaparin has an average molecular weight of about 4500 (1). Because this is a relatively large molecule, it does not cross the placenta (2,3) and, thus, presents a low risk to the fetus. Several reports have described the use of enoxaparin during pregnancy without maternal or fetal complications (4,5,6,7,8,9,10,11,12,13,14 and 15).

A woman with an extensive lower limb venous thrombosis was treated with unfractionated heparin for 2 weeks starting at 11 weeks' gestation and then changed to enoxaparin (4). She was continued on enoxaparin until delivery of a healthy infant at 34 weeks' gestation.

A 1992 Reference described the use enoxaparin in six pregnant women for the treatment and prophylaxis of thromboembolism (5). In two women treated from the 8th or 9th gestational week, one ended with a healthy term infant and the other was progressing normally at 18 weeks (outcome was not available at time of the report). Three other women were treated during the 2nd and/or 3rd trimesters and had normal term deliveries. In the remaining case, a woman with Sjogren's syndrome and a history of deep venous thrombosis (DVT) and pulmonary embolism, developed a DVT at 18 weeks' gestation. She was treated for 10 days with IV heparin and then started on enoxaparin 40 mg twice daily. The DVT recurred at 25 weeks' gestation and she was again treated with a course of IV heparin followed by SC heparin. Due to severe fetal distress after 5 days of SC heparin, an emergency cesarean section was performed. The infant died a few minutes after birth, but permission for an autopsy was refused. An examination of the placenta showed multiple hemorrhages (5).

The use of enoxaparin for the achievement of successful thromboprophylaxis in 16 women during 18 pregnancies was described in a 1994 communication (6). The mean gestational age at the start of therapy was 10 weeks. Eight women had a history of thromboembolism, six had thrombophilia, and two had systemic lupus erythematosus. A 20 mg SC dose once daily was used in the first 11 women, but because of low anti-Factor Xa levels, the dose was increased to 40 mg SC once daily in the last 7 pregnancies. From the 18 pregnancies, there were 2 missed abortions and 2 mid-trimester abortions, all in pregnancies of women with anticardiolipin syndrome (6).

The thromboprophylaxis of 41 pregnancies (34 women), most with 40 mg enoxaparin SC daily, was described in a 1996 report (7). Some of these cases had been reported earlier in a 1995 abstract (8). Only one thromboembolic event occurred, a hepatic infarction in a woman treated with 20 mg/day SC. No maternal hemorrhages were observed even though the therapy was continued throughout labor, delivery, and the immediate postpartum period. Nineteen of the women underwent 24 surgical procedures while receiving enoxaparin, including cervical cerclage (N=2), amniocentesis (N=5), 2nd trimester terminations (N=4), and cesarean section (N=13). Epidural anesthesia during labor was used in nine women. No abnormal bleeding was observed in any of these cases and there were no reports of intraventricular hemorrhage in the neonates (7).

Enoxaparin, usually 40 mg SC daily starting in the 1st trimester, was used for prophylaxis in 61 women (69 pregnancies) at high risk for thromboembolism in a prospective study published in 1997 (9). Some of these patients (N=18) had been reported earlier (6). Mean steady-state plasma heparin levels, as determined by anti-Factor Xa assay, following a 40 mg dose were three times as high as those with 20 mg, 0.09 U/mL vs. 0.03 U/mL, respectively, but were not affected by gestational age. No increased bleeding risk during pregnancy was observed and no episodes of thromboembolism in pregnancy occurred, although one patient, treated with 20 mg, had a postpartum pulmonary embolus. Further, no cases of epidural hematomas were observed in the 43 patients receiving regional analgesia or anesthesia. Six pregnancy losses were recorded, four described earlier (6) and two new cases of fetal deaths at 18 and 26 weeks, both in women with lupus anticoagulant and previous fetal loss. Other than seven preterm deliveries, none of which were attributable to drug therapy, the remaining fetal and newborn outcomes were normal. Decreased bone density after delivery (lumbar spine or hip; 1 SD below the mean for nonpregnant age-matched women) was measured in 9 of 26 women after 28 pregnancies. In seven of these cases, unfractionated heparin had been used previously. Based on other published studies, the investigators could not determine whether the low bone density was present before treatment with enoxaparin, or if it was caused by pregnancy and breast feeding, but a previous study with another LMWH (see Dalteparin) found no effect on bone density (9).

A 1997 case report described the use of enoxaparin (dose not specified) throughout most of the gestation, including labor, in a woman with congenital hypofibrinogenemia and protein S deficiency (10). A male infant with hypofibrinogenemia was delivered by cesarean section at 38 week's gestation.

A number of other studies (11,12,13,14 and 15) and reviews (3,16,17,18,19,20,21 and 22) have described the safe use of enoxaparin and other LMWH agents during pregnancy. Use of LMWH within 2 hours prior to cesarean section, however, was associated with an increase in wound hematoma (23). Also, lower maximum enoxaparin concentrations and anti-Factor Xa activity levels occur during pregnancy compared to the nonpregnant state, thus requiring dose adjustments (24).

In summary, the use of enoxaparin during pregnancy appears to present no more fetal and/or newborn risk, and perhaps less, than that from standard, unfractionated heparin or from no therapy. An opinion of the American College of Obstetricians and Gynecologists (ACOG) states that LMWH is at least as effective in pregnant patients with venous thrombosis, pulmonary embolism, or thrombophilic disorders as unfractionated heparin (25). Moreover, LMWHs have the advantages of ease of administration and less frequent laboratory monitoring. LMWHs may also reduce maternal complications, compared to standard heparin, such as bleeding, osteoporosis, and thrombocytopenia (3). However, there is inadequate information to recommend the use of LMWH in a pregnant woman with a mechanical heart valve (25).

Breast Feeding Summary

No reports describing the use of enoxaparin during lactation have been located. However, due to the relatively high molecular weight of this drug, and its inactivation in the gastrointestinal tract if it was ingested orally, its passage into milk and subsequent risk to a nursing infant should be considered negligible.

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References

  1. Product information. Lovenox. Rhone-Poulenc Rorer, 1993.
  2. Nelson-Piercy C. Low molecular weight heparin for obstetric thromboprophylaxis. Br J Obstet Gynaecol 1994;101:6–8.
  3. American College of Obstetricians and Gynecologists. Thromboembolism in pregnancy. ACOG Practice Bulletin. No. 19, August 2000.
  4. Priollet P, Roncato M, Aiach M, Housset E, Poissonnier MH, Chavinie J. Low-molecular-weight heparin in veinous thrombosis during pregnancy. Br J Haematol 1986;63:605–6.
  5. Gillis S, Shushan A, Eldor A. Use of low molecular weight heparin for prophylaxis and treatment of thromboembolism in pregnancy. Int J Gynecol Obstet 1992;39:297–301.
  6. Sturridge F, de Swiet M, Letsky E. The use of low molecular weight heparin for thromboprophylaxis in pregnancy. Br J Obstet Gynaecol 1994;101:69–71.
  7. Dulitzki M, Pauzner R, Langevitz P, Pras M, Many A, Schiff E. Low-molecular-weight heparin during pregnancy and delivery: preliminary experience with 41 pregnancies. Obstet Gynecol 1996;87:380–3.
  8. Dulitzki M, Seidman DS, Sivan E, Horowitz A, Barkai G, Schiff E. Low-molecular-weight heparin in pregnancy and delivery: experience with 24 cases. Society of Perinatal Obstetricians Abstracts. Am J Obstet Gynecol 1995;172:363.
  9. Nelson-Piercy C, Letsky EA, de Swiet M. Low-molecular-weight heparin for obstetric thromboprophylaxis: experience of sixty-nine pregnancies in sixty-one women at high risk. Am J Obstet Gynecol 1997;176:1062–8.
  10. Funai EF, Klein SA, Lockwood CJ. Successful pregnancy outcome in a patient with both congenital hypofibrinogenemia and protein S deficiency. Obstet Gynecol 1997;89:858.
  11. Casele H, Laifer S. Prospective evaluation of bone density changes in pregnant women on low molecular weight heparin (abstract). Am J Obstet Gynecol 1998;178:S65.
  12. Laifer SA, Stiller RJ, Dunston-Boone G, Whetham JCG. Low-molecular weight heparin for treatment of pulmonary embolism in a pregnant woman. Thromb Haemost 1999;82:1361–2.
  13. Ellison J, Walker ID, Greer IA. Antenatal use of enoxaparin for prevention and treatment of thromboembolism in pregnancy. Br J Obstet Gynaecol 2000;107:1116–21.
  14. Magdelaine A, Verdy E, Coulet F, Berkane N, Girot R, Uzan S, Soubrier F. Deep vein thrombosis during enoxaparin prophylactic treatment in a young pregnant woman homozygous for factor V Leiden and heterozygous for the G127-A mutation in the thrombomodulin gene. Blood Coagul Fibrinolysis 2000;11:761–5.
  15. Younis JS, Ohel G, Brenner B, Haddad S, Lanir N, Ben-Ami M. The effect of thrombophylaxis on pregnancy outcome in patients with recurrent pregnancy loss associated with factor V Leiden mutation. Br J Obstet Gynaecol 2000;107:415–9.
  16. Schulman S. Long-term prophylaxis in venous thromboembolism: LMWH or oral anticoagulation? Haemostasis 1998 (Suppl 3):17–21.
  17. Conard J, Horellou MH, Samama MM. Management of pregnancy in women with thrombophilia. Haemostasis 1999;29(Suppl 1):98–104.
  18. Bates SM. Optimal management of pregnant women with acute venous thromboembolism. Haemostasis 1999;29(Suppl 1):107–11.
  19. Chan WS, Ray JG. Low molecular weight heparin use during pregnancy: issues of safety and practicality. Obstet Gynecol Sur 1999;54:649–54.
  20. Robin F, Lecuru F, Desfeux P, Boucaya V, Taurelle R. Anticoagulant therapy in pregnancy. Eur J Obstet Gynecol Reprod Biol 1999;83:171–7.
  21. Sanson BJ, Lensing AWA, Prins MH, Ginsberg JS, Barkagan ZS, Lavenne-Pardonge E, Brenner B, Dulitzky M, Nielsen JD, Boda Z, Turi S, MacGillavry MR, Hamulyak K, Theunissen IM, Hunt BJ, Buller HR. Safety of low-molecular-weight heparin in pregnancy: a systematic review. Thromb Haemost 1999;81:668–72.
  22. Ensom MHH, Stephenson MD. Low-molecular-weight heparin in pregnancy. Pharmacotherapy 1999;19:1013–25.
  23. Wolf H, Piek JMJ, van Wijk FH, Buller HR. Administration of low molecular weight heparin within two hours prior to cesarean section increases the prevalence of wound hematoma (abstract). Am J Obstet Gynecol 2000;182:S158.
  24. Casele HL, Laifer SA, Woelkers DA, Venkataramanan R. Changes in the pharmacokinetics of the low-molecular-weight heparin enoxaparin sodium during pregnancy. Am J Obstet Gynecol 1999;181:1113–7.
  25. American College of Obstetricians and Gynecologists. Anticoagulation with low-molecular-weight heparin during pregnancy. Committee Opinion. No. 211, November 1998.

Index

Q&A about Enoxaparin

Shrek
does enoxaparin sodium speed up the hart rate.and if its fast is that bad.?
abitmish...
Only if you are having a hypersensitivity reaction to it. Enoxaparin initaites anticoagulation, but has no affect on heart rate.
pratikba...
What is meaning of ICH in medical terms?
In TIMI-25 trial it was also found that uses of enoxaparin along with thrombolytics is associated with the risk of getting ICH.
NumberSi...
intracranial hemorrhage
rajsons2...
what is pre eclampsia? What is the treatment for it, does it repeat in every pregnancy, how can v prevant it?
My wife had pre eclampsia in last pregnancy, she is 16 Weeks pregnant now, We r giving her Enoxaparin Sodium 20 mg Subcutanous as a precautionary medicine along with Aspirin 37.5 mg.
ali4sls
Pre eclampsia is pregnancy induced hypertension - or high blood pressure. Treatment usually includes a high protein diet and bed rest.

My midwife stated that pre eclampsia usually only occurs in a first pregnancy, and will not recur with subsequent children. There are exceptions to that, however, and your wife should be monitored carefully.

Quick question - did the doctor advise/prescribe the medication your wife is taking? And if so, did he know that she was pregnant at the time? Or has he been informed of her pregnancy since? If not, call the doctor immediately to inform him - they may alter treatment.