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From the Centers for Disease Control and Prevention
June 17, 1998

Pregnancy-Related Death Associated With Heparin and Aspirin Treatment for Infertility, 1996

JAMA. 1998;279(23):1860-1861. doi:10.1001/jama.279.23.1860-JWR0617-4-1

MMWR. 1998;47:368-371

In 1996, a 38-year-old nulliparous woman died from complications of a cerebral hemorrhage. She was approximately 9 weeks' pregnant with triplets at the time of her death. The patient had undergone in vitro fertilization (IVF) and was being treated with anticoagulants (heparin and aspirin) and intravenous immunoglobulin at the time of her death. This report summarizes the investigation of this case by state and county health departments with assistance from CDC.

The patient had undergone 3 years of infertility therapy, including the use of clomiphene citrate with intrauterine insemination, before beginning IVF in 1995. She had no history of recurrent pregnancy loss at initiation of IVF. Her infertility workup included a normal hysterosalpingogram; her husband had a normal semen analysis. An autoantibody screen revealed positive antithyroid antibodies (antimicrosomal [76.0 µg/mL] and antithryroglobulin [19.9 µg/mL]; normal: <0.5 µg/mL for both assays). Antiphospholipid antibodies were negative. In 1985, she had a transphenoidal resection of a pituitary adenoma, with normal prolactin levels thereafter.

She underwent three IVF cycles (ovulation induction, IVF, and embryo transfer). The first ended with a spontaneous abortion at 8 weeks in 1995; the second IVF cycle did not result in a pregnancy; and the third cycle resulted in a pregnancy with triplets in 1996. The patient was treated with estrogen and progesterone during each pregnancy. In addition, with each IVF cycle she received 5000 units heparin subcutaneously twice a day, 81 mg aspirin daily, and intravenous gamma globulin each month. Platelets and prothrombin time (PT) and partial thromboplastin time (PTT) were normal throughout her treatment.

During her ninth week of pregnancy, the patient experienced an acute headache, anxiety, and nausea while visiting a clinic. She was transferred to a general hospital and lost consciousness en route. On admission to the hospital, she underwent immediate radiologic and neurosurgic evaluation. Her platelets and PT and PTT were normal. Neurosurgery identified a hemorrhagic arteriovenous malformation, which was surgically clipped. A postoperative computerized axial tomography (CAT) scan revealed no rebleeding, but her condition worsened. Massive cerebral swelling could not be controlled, and her condition became critical. On her third day of hospitalization, she was pronounced brain-dead, and life support was discontinued the following day.

Reported by:

The Executive Council of the Society for Assisted Reproductive Technology, Birmingham, Alabama. Women's Health and Fertility Br and Pregnancy and Infant Health Br, Div of Reproductive Health, National Center for Chronic Disease Prevention and Health Promotion; and an EIS officer, CDC.

CDC Editorial Note:

CDC, in collaboration with state health departments, maintains a pregnancy-related mortality surveillance system. In 1990, CDC received reports of 417 pregnancy-related deaths in the United States. A pregnancy-related death is one that occurs during or within 1 year of pregnancy and was caused by the pregnancy or its complications. No national surveillance system exists for morbidity associated with infertility therapy.

Treatment of IVF patients with immunotherapy (anticoagulation or immunoglobulin) is aimed at preventing early pregnancy loss. Heparin and aspirin therapy substantially reduces the risk for recurrent spontaneous abortion (more than two pregnancy losses) for women with elevated antiphospholipid antibodies (APA)1 by modifying the effect of APA on platelet activity, which can cause placental thrombosis and lead to fetal loss.2 Heparin and aspirin are widely used in the United States to treat women with recurrent spontaneous abortion and APA. However, the woman described in this report had no antiphospholipid antibodies and no history of recurrent spontaneous abortion at the initiation of her infertility therapy.

Two recent studies have investigated the role of treating IVF patients with heparin and aspirin to prevent early pregnancy loss. One study documented higher pregnancy rates among women with APA following IVF cycles treated with heparin and aspirin.3 A prospective nonrandomized study did not demonstrate substantially higher pregnancy rates among women with APA undergoing IVF when treated with heparin and aspirin.4 A randomized prospective study investigating the efficacy of heparin and aspirin in women undergoing IVF is under way.4

Anticoagulation therapy can increase the risk for fatal hemorrhagic stroke.5,6 The inhibition of platelet activity with aspirin doses lower than 81 mg daily are well documented.7 Although heparin decreases the risk for death from pulmonary embolism in surgical patients, it has been associated with increased postoperative bleeding.8 A meta-analysis of randomized clinical trials of low-dose heparin (5000 units/twice daily) to prevent thromboembolism demonstrated an increase in wound hematoma formation associated with heparin treatment.9 In surgical patients receiving heparin, the concomitant use of aspirin has been associated with increased risk for serious bleeding.10

Although data about the risks and benefits of anticoagulation and immunoglobulin therapy in IVF patients are limited, use of this therapy is becoming more common in the United States. Neither aspirin or heparin, alone or in combination, are approved by the Food and Drug Administration (FDA) for this use. In July 1997, a survey of medical practices that provide assisted reproductive technology services indicated that combination therapies of heparin and aspirin for infertility treatment were used at least once by 74% of respondents (Society for Assisted Reproductive Technology, unpublished data, 1997). Of those providing immunotherapy treatment, 94% reported that they considered women who had had recurrent spontaneous abortions as potential candidates for anticoagulation treatment. In addition, 49% considered women who previously had an unsuccessful IVF attempt as potential candidates for immunologic treatment, and 19% considered new IVF patients as potential candidates for therapy.

This case is the first reported pregnancy-related death associated with the use of heparin and aspirin for infertility. The patient died from a cerebral hemorrhage associated with a congenital arteriovenous malformation. Although a causal relation between anticoagulation and hemorrhage from an arteriovenous malformation cannot be established, pregnant women have the risks for bleeding associated with anti-coagulation therapy found in the general population (cerebrovascular accidents, gastric ulcers, and trauma) in addition to unique hemorrhagic risks such as ectopic pregnancy. Both heparin and aspirin therapy have been associated with increased risks for and severity of bleeding. The patient in this report did not have recurrent spontaneous abortions or a history of antiphospholipid antibodies, widely accepted as indications for heparin and aspirin therapy. Because the potential for bleeding exists with heparin and aspirin, the risks for and benefits of anticoagulation therapy to improve success rates in IVF patients require vigorous scientific investigation before being accepted as routine practice.

The regular monitoring of all pregnancy-related deaths is essential to the reproductive health of women. To further assess the potential health threat of anticoagulation therapy in the treatment of infertility, CDC requests that deaths or severe morbidity associated with the use of heparin and aspirin for the prevention of pregnancy loss be reported to CDC, telephone (770) 488-5372, or to FDA's MEDWATCH, telephone (800) 332-1088. Until the results of further studies are available, women undergoing IVF and their health-care providers should carefully review all information about the risks and benefits of heparin and aspirin therapy.

References
1.
Kutteh  WH Antiphospholipid antibody-associated recurrent pregnancy loss: treatment with heparin and low-dose aspirin is superior to low-dose aspirin alone. Am J Obstet Gynecol. 1996;1741584- 89Article
2.
Silver  RMBranch  DW Recurrent miscarriage: autoimmune considerations. Clin Obstet Gynecol. 1994;37745- 60Article
3.
Sher  GFeinman  MZouves  C  et al.  High fecundity rates following in-vitro fertilization and embryo transfer in antiphospholipid antibody seropositive women treated with heparin and aspirin. Hum Reprod. 1994;92278- 83
4.
Kutteh  WHYetman  DLChantilis  SJCrain  J Effect of antiphospholipid antibodies in women undergoing in-vitro fertilization: role of heparin and aspirin. Hum Reprod. 1997;121171- 5Article
5.
The SALT Collaborative Group, Swedish Aspirin Low-dose Trial (SALT) of 75 mg aspirin as secondary prophylaxis after cerebrovascular ischaemic events. Lancet. 1991;3381345- 9Article
6.
Steering Committee of the Physicians Health Study Research Group, Final report on the aspirin component of the ongoing Physicians' Health Study. N Engl J Med. 1989;321129- 35Article
7.
Patrignani  PFilabozzi  PPatrono  C Selective cumulative inhibition of platelet thromboxane production by low-dose aspirin in healthy subjects. J Clin Invest. 1982;691366- 72Article
8.
Collins  RScrimgeour  AYusuf  SPeto  R Reduction in fatal pulmonary embolism and venous thrombosis by perioperative administration of subcutaneous heparin: overview of results of randomized trials in general, orthopedic, and urologic surgery. N Engl J Med. 1988;3181162- 73Article
9.
Clagett  GPReisch  JS Prevention of venous thromboembolism in general surgical patients: results of a meta-analysis. Ann Surg. 1988;208227- 40Article
10.
Walker  AMJick  H Predictors of bleeding during heparin therapy. JAMA. 1980;2441209- 12Article
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