Heparin

Name: HEPARIN
Class: Anticoagulant
Risk Factor: CM

Fetal Risk Summary

No reports linking the use of heparin during gestation with congenital defects have been located. Other problems, at times lethal to the fetus or neonate, may be related to heparin or to the severe maternal disease necessitating anticoagulant therapy. Hall and co-workers (1) reviewed the use of heparin and other anticoagulants during pregnancy (167 References) (see also Coumarin Derivatives). They concluded from the published cases in which heparin was used without other anticoagulants that significant risks existed for the mother and fetus and that heparin was not a clearly superior form of anticoagulation during pregnancy. Nageotte and co-workers (2) analyzed the same data to arrive at a different conclusion.
Hall Nageotte Total number of cases

• 120 Term liveborn-no complications 86
• Premature-survived without complications 19
• Liveborn-complications (not specified) 1
• Premature-expired Heparin therapy appropriate* 10
• Heparin therapy not appropriate* 4a Severe maternal disease making successful outcome of pregnancy unlikely 1b Spontaneous abortions Unknown cause 2
• Maternal death due to pulmonary embolism
• Stillbirths Heparin therapy appropriate* 17
• Heparin therapy not appropriate* 7c Heparin and Coumadin used
• *Appropriateness as determined by current standards aHypertension of pregnancy (4) bTricuspid atresia (1) cHypertension of pregnancy (6); proliferative glomerulonephritis (1) By eliminating the 15 cases in which maternal disease or other drugs were the most likely cause of the fetal problem, the analysis of Nageotte and co-workers results in a 13% (15 of 120) unfavorable outcome vs. the 22% (30 of 135) of Hall and associates. This new value appears to be significantly better than the 31% (133 of 426) abnormal outcome reported for coumarin derivatives (see Coumarin Derivatives). Furthermore, in contrast to coumarin derivatives in which a definite drug-induced pattern of malformations has been observed (fetal warfarin syndrome), heparin has not been related to congenital defects nor does it cross the placenta (3,4 and 5). Consequently, the mechanism of heparin's adverse effect on the fetus, if it exists, must be indirect. Hall and co-workers theorized that fetal effects may be caused by calcium (or other cation) chelation resulting in the deficiency of that ion(s) in the fetus. A more likely explanation, in light of the report of the Nageotte group, is severe maternal disease that could be relatively independent of heparin. Thus, heparin appears to have major advantages over oral anticoagulants as the treatment of choice during pregnancy (6,7,8,9,10,11,12 and 13).
  A retrospective study, published in 1989, lends support to the argument that heparin therapy is safe for the mother and fetus (14). A total of 77 women were treated with heparin during 100 pregnancies. In 98 pregnancies, therapy was administered for the prevention or treatment of venous thromboembolism, and in 2, treatment was because of prosthetic heart valves. In comparison with normal pregnancies, no difference was seen in the treated mothers in terms of prematurity, spontaneous abortions, stillbirths, neonatal deaths, or congenital malformations (6). Two bleeding episodes occurred, but there were no symptomatic thrombolic events.
  In a surveillance study of Michigan Medicaid recipients involving 229,101 completed pregnancies conducted between 1985 and 1992, 65 newborns had been exposed to heparin during the 1st trimester (F. Rosa, personal communication, FDA, 1993). Seven (10.8%) major birth defects were observed (three expected). Specific data were available for six defect categories, including (observed/expected) 4/0.6 cardiovascular defects, 0/0 oral clefts, 0/0 spina bifida, 1/0 polydactyly, 0/0 limb reduction defects, and 1/0 hypospadias. The data for total malformations and for cardiovascular defects are suggestive of possible associations, but other factors, most likely the mother's disease, but also possibly concurrent drug therapy and chance, are probably involved.
  Long-term heparin therapy during pregnancy has been associated with maternal osteopenia (15,16,17,18 and 19). Both low-dose (10,000 units/day) and high-dose heparin have been implicated, but the latter is more often related to this complication. One study found bone demineralization to be dose related, with more severe changes occurring after long-term therapy (>25 weeks) and in patients who had also received heparin in a previous pregnancy (18). The significant decrease in 1,25-dihydroxyvitamin D levels measured in heparin-treated pregnant patients may be related to the pathogenesis of this adverse effect (16,17). Similar problems have not been reported in newborns.
  

  Breast Feeding Summary

  Heparin is not excreted into breast milk because of its high molecular weight (15,000) (20).

  References

  1. Hall JG, Pauli RM, Wilson KM. Maternal and fetal sequelae of anticoagulation during pregnancy. Am J Med 1980;68:122–40.
  2. Nageotte MP, Freeman RK, Garite TJ, Block RA. Anticoagulation in pregnancy. Am J Obstet Gynecol 1981;141:472.
  3. Flessa HC, Kapstrom AB, Glueck HI, Will JJ, Miller MA, Brinker B. Placental transport of heparin. Am J Obstet Gynecol 1965;93:570–3.
  4. Russo R, Bortolotti U, Schivazappa L, Girolami A. Warfarin treatment during pregnancy: a clinical note. Haemostasis 1979;8:96–8.
  5. Moe N. Anticoagulant-therapy in the prevention of placental infarction and perinatal death. Obstet Gynecol 1982;59:481–3.
  6. Hellgren M, Nygards EB. Long-term therapy with subcutaneous heparin during pregnancy. Gynecol Obstet Invest 1982;13:76–89.
  7. Cohen AW, Gabbe SG, Mennuti MT. Adjusted-dose heparin therapy by continuous intravenous infusion for recurrent pulmonary embolism during pregnancy. Am J Obstet Gynecol 1983;146:463–4.
  8. Howell R, Fidler J, Letsky E. The risks of antenatal subcutaneous heparin prophylaxis: a controlled trial. Br J Obstet Gynaecol 1983;90:1124–8.
  9. Vellenga E, van Imhoff GW, Aarnoudse JG. Effective prophylaxis with oral anticoagulants and low-dose heparin during pregnancy in an antithrombin III deficient woman. Lancet 1983;2:224.
  10. Bergqvist A, Bergqvist D, Hallbook T. Deep vein thrombosis during pregnancy. Acta Obstet Gynecol Scand 1983;62:443–8.
  11. Michiels JJ, Stibbe J, Vellenga E, van Vliet HHDM. Prophylaxis of thrombosis in antithrombin III-deficient women during pregnancy and delivery. Eur J Obstet Gynecol Reprod Biol 1984;18:149–53.
  12. Nelson DM, Stempel LE, Fabri PJ, Talbert M. Hickman catheter use in a pregnant patient requiring therapeutic heparin anticoagulation. Am J Obstet Gynecol 1984;149:461–2.
  13. Romero R, Duffy TP, Berkowitz RL, Chang E, Hobbins JC. Prolongation of a preterm pregnancy complicated by death of a single twin in utero and disseminated intravascular coagulation: effects of treatment with heparin. N Engl J Med 1984;310:772–4.
  14. Ginsberg JS, Kowalchuk G, Hirsh J, Brill-Edwards P, Burrows R. Heparin therapy during pregnancy: risks to the fetus and mother. Arch Intern Med 1989;149:2233–6.
  15. Wise PH, Hall AJ. Heparin-induced osteopenia in pregnancy. Br Med J 1980;281:110–1.
  16. Aarskog D, Aksnes L, Lehmann V. Low 1,25-dihydroxyvitamin D in heparin-induced osteopenia. Lancet 1980;2:650–1.
  17. Aarskog D, Aksnes L, Markestad T, Ulstein M, Sagen N. Heparin-induced inhibition of 1,25-dihydroxyvitamin D formation. Am J Obstet Gynecol 1984;148:1141–2.
  18. De Swiet M, Dorrington Ward P, Fidler J, Horsman A, Katz D, Letsky E, Peacock M, Wise PH. Prolonged heparin therapy in pregnancy causes bone demineralization. Br J Obstet Gynaecol 1983;90:1129–34.
  19. Griffiths HT, Liu DTY. Severe heparin osteoporosis in pregnancy. Postgrad Med J 1984;60:424–5.
  20. O'Reilly RA. Anticoagulant, antithrombotic, and thrombolytic drugs. In Gilman AG, Goodman LS, Gilman A, eds. The Pharmacological Basis of Therapeutics. 6th ed. New York, NY:MacMillan, 1980:1350.

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