An International Registry of Pregnancies among Women with Mechanical Heart Valves
Providers who wish to submit cases should download the data collection form, print it, complete it and fax it to Betty Thames at 919-681-7861.
Prosthetic Valves in Pregnancy – Patient Data Form
Background and Significance
Patients with mechanical heart valves are at high risk for significant morbidity or mortality during pregnancy. Valve thromboses, which can occur in up to 50% of those not treated with anticoagulants, 1 are fatal in 30-67% of cases. 2-8 Warfarin is 4 to 5 times more effective in preventing thromboses than heparin. 9 Consequently, warfarin is the preferred anticoagulant to minimize maternal morbidity and mortality. 10
Warfarin, however, is associated with a 14.6 to 56% reported risk of miscarriage, 10, 11 1, 8, 12, 13 a 5 to 33% reported risk of stillbirth, 8, 11-13 a 0 to 30% (depending on the series) reported risk of congenital anomalies or warfarin embryopathy, 10-12 7, 8, 14, 15 a 2% reported risk of hydrocephalus from fetal or neonatal intracranial hemorrhage, 15, 16 a 14% reported risk of adverse neurological outcome 17 and a 4% reported risk of low intelligence quotient (IQ). 17 While warfarin is the preferred anticoagulant to minimize maternal morbidity and mortality, the maternal risks are still substantial. Mortality due to hemorrhage and thrombosis is approximately 2%. 10
Due to the concerns for the fetus, various protocols utilizing unfractionated heparin have been tried. Heparin does not cross the placenta 18 and is not associated with fetal effects beyond those associated with the mother’s underlying condition. 18 With heparin alone, however, the risk of life-threatening thrombosis is 29 to 33%. 8, 10 and the risk of mortality is 7 to15%. 8, 10
Low-molecular-weight heparins are equally as safe as unfractionated heparin for the fetus. 18 They, too, do not cross the placenta and are also not associated with fetal effects beyond those associated with the mother’s underlying condition. 18 With their advent, clinicians were hopeful that low-molecular-weight heparins, with their longer duration of action, would provide a safer alternative for pregnant women with mechanical valves than unfractionated heparin. In 1996, Lee et al 19 published their successful experience with two cases using nadroparin. Since then, there have been 25 or more reports of low-molecular-weight heparin as the sole anticoagulant for patients with mechanical valves, but at least 20% of the cases have been complicated by life-threatening thromboses. 20 Two cases of fatal valve thrombosis among 8 pregnant women randomized to the enoxaparin (Lovenox®, Aventis Pharmaceuticals) arm of a South African trial prompted the United States Food and Drug Administration to require that that information be added to the package insert. 21, 22 No patients in the heparin/warfarin group (0 of 4 women) died. There is no other evidence, however, that in pregnant women with mechanical valves, unfractionated heparin is superior to low-molecular-weight heparin.
Women with mechanical valves are generally counseled against attempting pregnancy. If they do become pregnant, termination of pregnancy is usually offered. If they choose to pursue a pregnancy despite the risks to themselves and their fetuses, the options for anticoagulation are limited.
Properly designed studies comparing various anticoagulation regimens in pregnant women with mechanical heart valves have not been performed. 18 Randomized controlled trials, however, are unlikely to be funded due to the uncommon and high-risk nature of the problem. At a minimum, a multicenter registry of pregnant women with mechanical heart valves would provide better guidance for the management of this challenging situation.
In recognition of the need for a multicenter registry, the Women’s Issues Scientific Subcommittee of the International Society of Hemostasis and Thrombosis (ISTH) has endorsed the development of such a registry that will be housed at Duke University .
Description of Registry:
Purpose:
The purpose of this registry or database will be to store information for future research on pregnancies among women with mechanical heart valves. Anticipated research will include studies of both the fetal and maternal outcomes of these pregnancies No specimens will be collected. While data will be submitted from around the world, the database will be housed at Duke University Medical Center .
Future resesarch:
Separate IRB approval will be requested for each specific research study that uses data from the repository.
Data to be included in the registry:
Data that will be included will be de-identified. Data will include pertinent medical history including risk factors for thrombosis, obstetrical history, anticoagulation agents used during pregnancy, and pregnancy data including fetal outcome and maternal complications. The data collection form is attached. This will be made available to outside data collectors and will be posted on the International Society of Thrombosis and Hemostasis (ISTH) website. The database will be publicized, not only on the website, but through annual meetings. Additionally, permission will be sought from the Society of Maternal-Fetal Medicine (SMFM) to post the data collection form on its website as well. Local IRB approval, where required, will be provided to the DUHS IRB for each site contributing data. Data collectors will complete the data collection form and fax or mail it to the project coordinator. The project coordinator will assign a study number to each subject and report the study number to the data collector. The number of subjects will not be limited.
Security and confidentiality:
This electronic Access database will be housed on a secure server that Duke Health Technical Services supports. De-identified data will be faxed or mailed to the Project Coordinator at Duke who will enter the data into the Access database. A HIPAA waiver for review preparatory to research is requested for cases at Duke. Subjects will be identified by their providers at the High Risk OB Clinic. The project coordinator will be notified and will consent and enroll subjects. For the cases at Duke, any personal identifying information collected during the review preparatory to research will be destroyed. No personal data will not be recorded on the data collection forms or entered into the database. All data collection forms will be stored in a locked file in the project coordinator’s office. Any studies using data from the database will not contain any identifying information.
Access to the data:
Only the principal investigator, Dr. James, and the project coordinator will have direct access to the data. Requests for research studies may be directed to Dr. James and a separate IRB protocol will be submitted.
Consent and authorization:
Consent and authorization will be obtained from subjects at their individual sites. The consent and authorization form that is ultimately approved by the IRB at Duke will be offered on the ISTH and SMFM websites as an example that can be modified and submitted to local IRBs. The form clearly states that subjects are giving permission for their data to be stored in the database and to be used for future research regarding pregnancy in women with mechanical heart valves.
Risks and benefits of participation:
The subject’s involvement is limited to the information that is collected. There are potential risks of loss of privacy. There is no compensation or reimbursement for participation. The cost of participation is any inconveniences incurred. Information that is learned through the database may benefit pregnant women with mechanical heart valves in the future. Subjects may withdrawal at any time during the pregnancy. If the data has already been entered in the registry, a request to have the data removed can be
submitted by the data collector.
References:
1. Vural KM, Ozatik MA, Uncu H, et al. Pregnancy after mechanical mitral valve replacement. J Heart Valve Dis. May 2003;12(3):370-376.
2. Larrea JL, Nunez L, Reque JA, Gil Aguado M, Matarros R, Minguez JA. Pregnancy and mechanical valve prostheses: a high-risk situation for the mother and the fetus. Ann Thorac Surg. 1983;36(4):459-463.
3. Born D, Martinez EE, Almeida PA, et al. Pregnancy in patients with prosthetic heart valves: the effects of anticoagulation on mother, fetus, and neonate. Am Heart J. 1992;124(2):413-417.
4. Sahnoun-Trabelsi I, Jimenez M, Choussat A, Roudaut R. [Prosthetic valve thrombosis in pregnancy. A single-center study of 12 cases]. Arch Mal Coeur Vaiss. 2004;97(4):305-310.
5. Sbarouni E, Oakley CM. Outcome of pregnancy in women with valve prostheses. Br Heart J. 1994;71(2):196-201.
6. Salazar E, Izaguirre R, Verdejo J, Mutchinick O. Failure of adjusted doses of subcutaneous heparin to prevent thromboembolic phenomena in pregnant patients with mechanical cardiac valve prostheses. J Am Coll Cardiol. 1996;27(7):1698-1703.
7. Iturbe-Alessio I, Fonseca MC, Mutchinik O, Santos MA, Zajarias A, Salazar E. Risks of anticoagulant therapy in pregnant women with artificial heart valves. N Engl J Med. 1986;315(22):1390-1393.
8. Sadler L, McCowan L, White H, Stewart A, Bracken M, North R. Pregnancy outcomes and cardiac complications in women with mechanical, bioprosthetic and homograft valves. Bjog. 2000;107(2):245-253.
9. Hanania G, Thomas D, Michel PL, et al. Pregnancy and prosthetic heart valves: a French cooperative retrospective study of 155 cases. Eur Heart J. Dec 1994;15(12):1651-1658.
10. Chan WS, Anand S, Ginsberg JS. Anticoagulation of pregnant women with mechanical heart valves: a systematic review of the literature. Arch Intern Med. 2000;160(2):191-196.
11. Nassar AH, Hobeika EM, Abd Essamad HM, Taher A, Khalil AM, Usta IM. Pregnancy outcome in women with prosthetic heart valves. Am J Obstet Gynecol. 2004;191(3):1009-1013.
12. Blickstein D, Blickstein I. The risk of fetal loss associated with Warfarin anticoagulation. Int J Gynaecol Obstet. Sep 2002;78(3):221-225.
13. Cotrufo M, De Feo M, De Santo LS, et al. Risk of warfarin during pregnancy with mechanical valve prostheses. Obstet Gynecol. 2002;99(1):35-40.
14. Srivastava AK, Gupta AK, Singh AV, Husain T. Effect of oral anticoagulant during pregnancy with prosthetic heart valve. Asian Cardiovasc Thorac Ann. 2002;10(4):306-309.
15. Meschengieser SS, Fondevila CG, Santarelli MT, Lazzari MA. Anticoagulation in pregnant women with mechanical heart valve prostheses. Heart. Jul 1999;82(1):23-26.
16. Chen WW, Chan CS, Lee PK, Wang RY, Wong VC. Pregnancy in patients with prosthetic heart valves: an experience with 45 pregnancies. Q J Med. 1982;51(203):358-365.
17. Wesseling J, Van Driel D, Heymans HS, et al. Coumarins during pregnancy: long-term effects on growth and development of school-age children. Thromb Haemost. 2001;85(4):609-613.
18. Bates SM, Greer IA, Hirsh J, Ginsberg JS. Use of antithrombotic agents during pregnancy: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest. 2004;126(3 Suppl):627S-644S.
19. Lee LH, Liauw PC, Ng AS. Low molecular weight heparin for thromboprophylaxis during pregnancy in 2 patients with mechanical mitral valve replacement. Thromb Haemost. 1996;76(4):628-630.
20. Leyh RT, Fischer S, Ruhparwar A, Haverich A. Anticoagulant therapy in pregnant women with mechanical heart valves. Arch Gynecol Obstet. Apr 2003;268(1):1-4.
21. Ginsberg JS, Chan WS, Bates SM, Kaatz S. Anticoagulation of pregnant women with mechanical heart valves. Arch Intern Med. 2003;163(6):694-698.
22. Lovenox (enoxaparin sodium injection). Aventis Pharmaceuticals. Available at: http://www.lovenox.com/consumer/default.aspx, 2004.