DALTEPARIN

Fetal Risk Summary

Dalteparin is a low molecular weight heparin prepared by depolymerization of heparin obtained from porcine intestinal mucosa. The molecular weight of dalteparin varies from <3000 to >8000, but 65%–78% is in the 3000 to 8000 range (1). Reproduction studies found no evidence of impaired fertility in male and female rats or fetal harm in rats and rabbits (1).

Because of its relatively high molecular weight, dalteparin is not expected to cross the placenta to the fetus (2). Thirty women undergoing elective pregnancy termination in the 2nd trimester (N=15) or 3rd trimester (N=15) for fetal malformations or chromosomal abnormalities were administered a single subcutaneous dose of 2500 IU or 5000 IU, respectively, of dalteparin immediately prior to the procedure (3). Heparin activity was not evident in fetal blood, demonstrating the lack of transplacental passage at this stage of gestation.

Dalteparin was administered as a continuous IV infusion at 36 weeks' gestation in a woman being treated for a deep vein thrombosis that had occurred during the 1st trimester (4). During the 1st trimester, she had been treated with IV heparin and then maintained on SC doses for 4 weeks before developing an allergic reaction. Skin testing revealed immediate type allergic reactions to heparin and some other derivatives, but not to dalteparin. She was changed to warfarin therapy at 14 weeks' gestation, and this therapy was continued until the change to dalteparin at 36 weeks. Following stabilization of the anti-Factor Xa plasma levels with a continuous infusion (400 anti-Factor Xa U/hour), dalteparin therapy was changed to SC dosing and this was continued until delivery at 38.5 weeks of a healthy, 3010-g female infant. No anti-Factor Xa activity was detected in the cord blood.

A 1992 report described the use of dalteparin in seven women at 16–23 weeks' gestation just before undergoing therapeutic termination of pregnancy (5). Dalteparin was given subcutaneously 15 and 3 hours before pregnancy termination. Heparin activity (anti-Factor Xa) was detected in all mothers but not in any of the fetuses. In the second part of the study, 11 pregnant women with a history of severe thromboembolic tendency, as evidenced by recurrent miscarriages, were treated throughout gestation with SC dalteparin (5). All of the women gave birth to healthy infants without complication. As with heparin, maternal osteoporosis may be a complication resulting from the use of low molecular weight heparins, including dalteparin, during pregnancy (see also Heparin and Vitamin D). However, in the 11 patients described above, all had normal mineral mass as determined by bone density scans performed shortly after delivery (5). Moreover, a study published in 1996 compared two groups of pregnant women receiving dalteparin, either 5000 IU SC daily (N=9) or 5000 IU SC daily in the 1st trimester, then twice daily thereafter (N=8), both starting in the 1st trimester, to a control group (N=8) that did not receive heparin (6). Lumbar spine bone density fell by similar amounts in all pregnancies, and the normal physiological change of pregnancy was not increased by dalteparin.

The use of dalteparin in 184 pregnant women for thromboprophylaxis was reviewed in a brief 1994 report (7). No placental passage of the drug was found in the 9 patients investigated. Congenital malformations were observed in 3.3% of the outcomes, a rate believed to be normal for this population. Another 1994 letter Reference described the use of dalteparin in five pregnant women starting between 15 and 18 weeks' gestation (8). Apparently normal infants were delivered.

Dalteparin was used for thromboembolic prophylaxis in 24 pregnant women with a risk of thromboembolic disease (9). The women received total daily doses of 2500 (16 mg) to 10,000 (32 mg) anti-Factor Xa IU. Anti-Factor Xa activity was demonstrated in the blood samples from the mothers but not in the normal newborns, indicating the lack of placental transfer of the drug.

A 1997 case report described the successful use of dalteparin in the 3rd trimester of a pregnant woman with iliofemoral vein thrombosis who was resistant to unfractionated heparin (10). She was treated with 7000 U (100 U/kg) every 12 hours from 30 weeks' gestation until 24 hours before an uncomplicated vaginal delivery at 38 weeks.

In a randomized 1999 trial, unfractionated heparin (N=55; mean 20,569 IU/day) and dalteparin (N=50; mean 4631 IU/day) were compared in 105 pregnant women with previous or current thromboembolism (11). There were no recurrences of thromboembolism or cases of thrombocytopenia in either group, but there were more bleeding complications in the patients receiving unfractionated heparin. The pregnancy outcomes in terms of blood loss at delivery, number of cesarean sections, birth weight, and Apgar scores were similar.

In a 2000 trial, a prophylactic dalteparin dose of 5000 IU/day given during pregnancy was adequate for 25 women (mean weight 70.2 kg), but the dose was decreased in 6 women (mean 58.0 kg) and increased in 2 (mean 102.5 kg) after the first anti-Xa activity measurement (12). An adjusted-weight therapeutic dose (100 IU/kg twice daily) was appropriate during pregnancy based on measured anti-Xa activity.

In summary, the use of dalteparin during pregnancy appears to present no more fetal or newborn risk, and perhaps less, than that from standard, unfractionated heparin or from no therapy.

Breast Feeding Summary

No reports describing the use of dalteparin during lactation or breast feeding have been located. Dalteparin, a low molecular weight heparin, still has a relatively high molecular weight (65%–78% in the range of 3000–8000) and, as such, should not be expected to be excreted into human milk. Because the drug would be inactivated in the gastrointestinal tract, the risk to a nursing infant from ingestion of dalteparin from milk appears to be negligible.

References

1. Product information. Fragmin. Pharmacia & Upjohn Company, 1997.
2. Nelson-Piercy C. Low molecular weight heparin for obstetric thromboprophylaxis. Br J Obstet Gynaecol 1994;101:6–8.
3. Forestier F, Solé Y, Aiach M, Alhenc Gélas M, Daffos F. Absence of transplacental passage of Fragmin (Kabi) during the second and the third trimesters of pregnancy. Thromb Haemost 1992;67:180–1.
4. de Boer K, Heyboer H, ten Cate JW, Borm JJJ, van Ginkel CJW. Low molecular weight heparin treatment in a pregnant woman with allergy to standard heparins and heparinoid. Thromb Haemost 1989;61:148.
5. Melissari E, Parker CJ, Wilson NV, Monte G, Kanthou C, Pemberton KD, Nicolaides KH, Barrett JJ, Kakkar VV. Use of low molecular weight heparin in pregnancy. Thromb Haemost 1992;68:652–6.
6. Shefras J, Farquharson RG. Bone density studies in pregnant women receiving heparin. Eur J Obstet Gynecol Reprod Biol 1996;65:171–4.
7. Wahlberg TB, Kher A. Low molecular weight heparin as thromboprophylaxis in pregnancy. Haemostasis 1994;24:55–6.
8. Manoharan A. Use of low molecular weight heparin during pregnancy. J Clin Pathol 1994;47:94–5.
9. Rasmussen C, Wadt J, Jacobsen B. Thromboembolic prophylaxis with low molecular weight heparin during pregnancy. Int J Gynecol Obstet 1994;47:121–5.
10. Anand SS, Brimble S, Ginsberg JS. Management of iliofemoral thrombosis in a pregnant patient with heparin resistance. Arch Intern Med 1997;157:815–6.
11. Pettila V, Kaaja R, Leinonen P, Ekblad U, Kataja M, Ikkala E. Thromboprophylaxis with low molecular weight heparin (dalteparin) in pregnancy. Thromb Res 1999;96:275–82.
12. Rey E, Rivard GE. Prophylaxis and treatment of thromboembolic diseases during pregnancy with dalteparin. Int J Gynecol Obstet 2000;71:19–24.