warfarinfo

WARFARIN HAS SERIOUS SIDE EFFECTS WHICH CAN CAUSE DEATH TO THE FETUS OR BIRTH DEFECTS IF A CHILD IS BORN.

THERE ARE SOME POSSIBILITIES OF WORKING AROUND THESE PROBLEMS. HOWEVER, THESE WILL BE VERY HIGH RISK PREGNANCIES. NO WOMAN TAKING WARFARIN SHOULD UNDERESTIMATE THE SERIOUSNESS OF THIS CONDITION.

THE PURPOSE OF THIS SECTION IS NOT TO PRESENT MEDICAL ADVICE, BUT TO PROVIDE INFORMATION FOR A WOMAN TO HAVE A DISCUSSION WITH HER PHYSICIAN.

This page will present some reviews of the recent medical literature on this topic and links to some other sites providing useful information.

The two primary reasons for taking warfarin during pregnancy are having a mechanical heart valve and having the antiphospholipid antibody syndrome. Conclusions drawn from one condition will not necessarily be applicable to the other.

This is such new and important information that I am printing it in bold and italics. Because of reports of valve thrombosis, a recommendation against the use of enoxaparin (Lovenox) in women with prosthetic heart valves has been added to the warnings section of the labeling for this drug. Information on serious maternal and fetal effects of warfarin have been added to the Precautions section. In a clinical study, clots developed in two of the seven pregnant women who received enoxaparin 1 mg/kg twice a day to reduce the risk of thromboembolism; the two women and their fetuses died. Congenital anomalies have developed in infants born to women who received enoxaparin during pregnancy. Pregnant women and women of childbearing age should be warned of the potential hazards of enoxaparin therapy during pregnancy. Am J Health-syst Pharm 2002;59:606.

The most recent comprehensive review of anticoagulation in pregnant women with mechanical heart valves was published by Chan et al in the Archives of Internal Medicine. Their article reviewed 28 previously-published articles that included 976 women having 1,234 pregnancies. This is a large enough group to be able to draw valid conclusions. However, there are still some unanswered questions because the studies date back to 1966 and include some information that is no longer standard medical care.

There were four categories of treatments given to the mothers. Regimen 1 used anticoagulation (usually warfarin) throughout pregnancy. Regimen 2 used heparin for the first trimester, then oral anticoagulation (usually warfarin), Regimen 3 used heparin throughout the pregnancy. Regimen 4 used no anticoagulation during pregnancy.

The birth defects caused by warfarin are small noses, bone abnormalities, hydrocephalus, mental retardation, cleft lip and cleft palate, and others reported in only one case each.

Regimen 1 resulted in 24.7% miscarriages and 6.4% birth defects in live births. Regimen 2 resulted in 24.8% miscarriages and 3.4% birth defects. Regimen 3 resulted in 23.8% miscarriages and 0% birth defects. Regimen 4 resulted in 9.8% miscarriages and 3.3% birth defects. Before you jump to a conclusion as to whether this is acceptable or not, you need to read about the effects on the mother.

Regimen 1 resulted in 3.9% experiencing blood clots and 1.8% deaths. Regimen 2 resulted in 9.2% experiencing blood clots and 4.2% deaths. Regimen 3 resulted in 33.3% experiencing blood clots and 15% deaths. Regimen 4 resulted in 24.3% having blood clots and 4.7% deaths. It appears that what is good for the fetus is bad for the mother and vice versa.

Because the articles ranged back to 1966, many women had valves of a type that are no longer inserted today. The St. Jude and Duromedics valves implanted today are less likely to cause clotting. Less than half of the studies reported the target prothrombin times. These articles would not be accepted for publication today. However, without the women in them, this review would have contained many less women, making conclusions harder to draw. In those who reported target INRs, they ranged from 2.0 to 4.0. (We know now that maintaining an INR below 2.5 is inadequate. Also, INRs between 3.5 and 4.0 are not in keeping with current guidelines.) Some studies were done when prothrombin time ratios were the standard. The mothers' PTs were kept at 1.5 to 2.5 times control. (In some instances, 2.5 times control may have corresponded to an INR of 8.0. This would not be acceptable today.)

The heparin used in the studies was unfractionated heparin. Its use by physicians is falling into disfavor today.

Vitale et al present evidence that warfarin-related problems of pregnancy may be dose related. They studied 43 women who had 58 pregnancies and continued warfarin throughout their pregnancy to maintain an INR of 2.5 to 3.5. In the women who required 5 mg (or less) of warfarin daily, 85% had healthy babies (usually delivered by Caesarian Section at 38 weeks). The group who required more than 5 mg of warfarin had adverse outcomes 88% of the time. The warfarin dose during pregnancy remained in the same group as before the pregnancy occurred.

Nelson-Piercy et al responded to this article with a letter stating that they did not find routine, elective Cesarian Sections to be justified in these patients.

Fukuda et al report on a woman with a St. Jude mitral valve who had a successful pregnancy and a spontaneous normal vaginal delivery. The technique of managing anticoagulation involved replacing warfarin with subcutaneous heparin from weeks 6 to 13 of gestation. The dose of heparin was adjusted to maintain a partial thromboplastin time of 2.0 to 2.5 times the control value. At the 32nd week of gestation, warfarin was again stopped and heparin re-started.

Van Driel et al. studied 307 children who were exposed to coumarin derivatives before they were born. Between the ages of 8 and 15, they did not vary from comparison controls in height, weight, head circumference or body proportions. Even children exposed to coumarins during the first trimester showed no evidence of growth impairment. One child who was born with coumarin embryopathy was shorter than normal at school age. (This study was done in The Netherlands. Some of the children were exposed to anticoagulants other than warfarin, which is commonly used in the United States.)

Another group from the same institution in The Netherlands studied the behavioural outcome of school-age children after prenatal exposure to coumarins. Again, I caution that this likely includes drugs other than warfarin and that I read only the abstract. Their conclusion was that, "...:behavioural development may be negatively influenced in school-age children after in utero exposure to coumarins, leading to less favourable task-oriented and social-emotional behaviour. However, the frequency of clinically relevant 'problem behaviour' was not increased in relation to coumarin exposure..."

The use of unfractionated heparin is declining. This has been a mainstay of anticoagulation for many years. LMWH are gaining favor because of their ease of use. However, there is little published data about their proper dose in pregnancy. Berndt et al. report on a case of a woman with a mechanical heart valve who was getting LMWH during pregnancy. She developed a massive valve thrombosis and pulmonary edema when the LMWH was given at too low a dose.

This following was added, and is up-to-date as of March 3, 2002. It is a question and my answer to a reader.

I spent quite a bit of time researching this question so that you could have the most up-to-date answer. I went to the National Library of Medicine's website and queried for dalteparin or enoxaparin (the most often used Low-molecular weight heparins in the US) and pregnancy. I asked for all articles published in English since 1/1/2000.

This produced 32 possibilities. Most were review articles and since I already knew what was in them, I did not look any further at them. All but three then discussed use of these medications to treat blood clots that had already developed and not necessarily in women with valves. Two of those that were left were reports of women who inadequately dosed with heparin and ruined their valves during pregnancy. The last was a follow-up report from New Zealand on 11 women with mechanical heart valves who were treated with enoxaparin (Lovenox) 1 mg/kg twice daily (the highest recommended dose) AND aspirin 100 to 150 mg/day. There were 14 pregnancies between 1997 and 1999 in these women. The results were 9 live births, 3 miscarriages and 2 terminations. One woman had a valve thrombosis at 8 weeks. She had another at 20 weeks even though treated adequately. I did not read the entire article (only the abstract is available via this route) but it appears that there was not necessarily planning for treatment ahead of these pregnancies. All institutions have a review board which must pass on any plans for research being done there. I doubt that any would approve a plan to do a study on pregnant women which involved randomizing them to an unknown treatment. This is the "gold standard" for a study, so we have to settle for less reliable types of reports.

The authors conclude, "Successful pregnancy outcome may be achieved with ... enoxaparin, but its efficacy at preventing valve thrombosis remains uncertain. Further data are required before use of exoxaparin during pregnancy in women with mechanical heart valves can be recommended."

High pregnancy loss and birth defects rates are associated with warfarin throughout pregnancy. It is likely that the dose of warfarin required by a woman before she becomes pregnant will predict whether or not the fetus will have a healthy outcome. (Keep in mind however, that many will consider a 15% likelihood of an adverse event in the fetus unacceptably high.) Poor maternal outcomes are associated with heparin. Low-molecular weight heparin may prove to be an acceptable alternative. Children exposed to warfarin while their mothers were pregnant with them tend to develop normally -- at least in physical proportions.

Chan WS et al. Anticoagulation of Pregnant Women with Mechanical Heart Valves. Arch Intern Med 2000;160:191-196

Sadler L et al. Pregnancy outcomes and cardiac complications in women with mechanical, bioprosthetic and homograft valves. BJOG 2000;107:245-253

Arnaout et al. Is there a safe anticoagulation protocol for pregnant women with prosthetic valves? Clin Exp Obstet Gynecol 1998;25:101-104

Vitale N et al. Dose-Dependent Fetal Complications of Warfarin in Pregnant Women with Mechanical Heart Valves. J Am Coll Cardiol 1999;33:1637-1641

Nelson-Piercy C et al. Routine elective cesarian section is not justified for women with mechanical heart valves. J Am Coll Cardiol 2000;35:1365-1366

VanDriel D et al. Growth until puberty after in utero exposure to coumarins. Am J Med Genet. 2000;95:438-443.

Berndt N et al. A complication in anticoagulation using low-molecular weight heparin in a patient with a mechanical valve prosthesis. A case report. J Heart Valve Dis 2000;9:844-846.

Wesseling J et al. Behavioural outcome of school-age children after prenatal exposure to coumarins. Early Hum Dev 2000;58:213-24.

Rowan JA et al. Enoxaparin treatment in women with mechanical heart valves during pregnancy. Am J Obstet Gynecol 2001;185:633-7

Lev-Ran O. Low-molecular-weight heparin for prosthetic heart valves: treatment failure. Ann Thorac Surg 2000;69:264-5

Fukuda T et al. Successful planned pregnancy in a patient with St. Jude medical prosthetic mitral valve. Circ J 2002;66:204-6

Greer IA. Anticoagulation In Pregnancy. Anticoagulation Forum Eighth National Conference on Anticoagulant Therapy. Orlando FL May 6-7, 2005.