anticoagulation of pregnant women with mechanical heart valves

Anticoagulation of Pregnant WomenWith Mechanical Heart ValvesJeffrey S. Ginsberg, MD, FRCPC; Wee Shian Chan, MD; Shannon M. Bates, MDCM; Scott Kaatz, DO

T he management of pregnant women with mechanical heart valves is challenging. Re-cently, based on small numbers of patients and poor-quality data, correspondence fromAventis Pharmaceuticals Inc has described treatment “failures” and concerns about tera-togenicity with the use of the low-molecular-weight heparin (LMWH) enoxaparin. The

company issued a “Warning” that enoxaparin should not be used in patients with prosthetic heartvalves and a “Precaution” about potential teratogenicity. This has created a huge problem for phy-sicians managing pregnant women with prosthetic heart valves because the alternatives, unfrac-tionated heparin and warfarin, are problematic. There have been case reports of failures (includ-ing death from thrombosed valves) with unfractionated heparin, whereas the package insert forwarfarin states that the drug is contraindicated during pregnancy because of potential teratogenic-ity. Initially, LMWHs appeared suitable for pregnant patients with prosthetic heart valves. Unfor-tunately, the company correspondence, presumably supported by the Food and Drug Administra-tion (FDA), raises medicolegal concerns with use of any LMWH. We believe that pharmaceuticalcompanies and the FDA should not endorse scientifically unsupported claims that eliminate ac-ceptable therapeutic options. This correspondence has created considerable confusion among pa-tients and treating physicians and is likely to lead to frivolous lawsuits and preclude the perfor-mance of properly designed trials in pregnant women. We believe a consensus conference amongexperts in the field to identify key unresolved issues and a commitment by the FDA and industryto perform appropriate studies are now critical. Arch Intern Med. 2003;163:694-698

North American women, including thosewithmechanicalheartvalves, expectanun-eventfulpregnancyandahealthybaby.Un-fortunately, women with mechanical heartvalves have a high risk of both adversefetal and maternal experiences, primarilydue to thromboembolic complicationsand the antithrombotic therapy given toprevent thesecomplications.Asaresult, themanagement of pregnant women with me-chanical heart valves is difficult. This wasexacerbated by a recent “Warning” and“Precaution” issuedbyAventisPharmaceu-ticals Inc, the manufacturers of Lovenox

(enoxaparin sodium) Injection, a low-molecular-weight heparin (LMWH).1

The warning referred to the manage-mentofpregnantandnonpregnantpatientswith mechanical heart valves and stated:

The use of Lovenox is not recommended forthromboprophylaxis in patients with pros-thetic heart valves. Cases of prosthetic heartvalve thrombosis have been reported in pa-tients with prosthetic valves who have re-ceived enoxaparin for thromboprophylaxis.Some of these cases were pregnant women inwhom thrombosis led to maternal deaths andfetal deaths. Pregnant women with prostheticheart valves may be at higher risk for throm-boembolism.

The precaution was specific for theuse of enoxaparin during pregnancy andunder the headings “Pregnancy” and“Teratogenic Effects” stated:

From the Departments of Medicine, McMaster University, Hamilton, Ontario(Drs Ginsberg and Bates), University of Toronto, Toronto, Ontario (Dr Chan), andHenry Ford Hospital, Detroit, Mich (Dr Kaatz). Dr Kaatz has received researchfunding from Aventis Pharmaceuticals Inc, Roche Diagnostics, DuPont PharmaPharmaceuticals, Astra-Zeneca, Merck, Sandoz, and NPS, and serves as a consultantfor Astra Zeneca and Aventis Pharmaceuticals Inc.

ORIGINAL INVESTIGATION

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There have been reports of congenital anomalies in infants bornto women who received enoxaparin during pregnancy includ-ing cerebral anomalies, limb anomalies, hypospadias, periph-eral vascular malformation, fibrotic dysplasia, and cardiac de-fects. A cause and effect relationship has not been establishednor has the incidence been shown to be higher than in the gen-eral population.

The warning was based on the results of a very smalltrial and an undisclosed number of postmarketing reportsof thrombosed valves in patients receiving enoxaparin. Therandomized controlled trial, conducted in South Africa andnot sponsored by Aventis Pharmaceuticals, of pregnantwomen with prosthetic heart valves was stopped after 12patients were enrolled. In this study, women were ran-domly allocated to receive enoxaparin (1 mg/kg twice daily)or a regimen consisting of unfractionated heparin (UFH)and warfarin given sequentially. Few details are available;however, according to Aventis Pharmaceuticals, 2 of 7enoxaparin-treated women developed thrombosis and out-flow obstruction of their prosthetic valves, causing mater-nal (and fetal) death. The postmarketing reports con-sisted of an undisclosed number of valve thromboses inenoxaparin-treated patients (including pregnant women)with prosthetic heart valves. Based on the small numbersin the trial, and the inability to determine accurate inci-dence rates from postmarketing data, the true incidenceof valve thrombosis in enoxaparin-treated pregnant womenwith mechanical heart valves, and whether thrombosis ratesare higher in such women than warfarin-treated nonpreg-nant patients, are unknown.

Teratogenicity can result from numerous causes, in-cluding use of drugs, or simply by chance. The com-pany claims a “cause and effect relationship has not beenestablished nor has the incidence been shown to be higherthan in the general population,” thereby avoiding directindictment of physicians who prescribe enoxaparin dur-ing pregnancy. However, the “Precaution” was presum-ably issued to minimize potential liability against AventisPharmaceuticals and has the potential to inhibit physi-cians from prescribing enoxaparin and other LMWHs inpregnant women. In view of the evidence that neither UFHnor LMWH crosses the placenta, an increase in terato-genicity seems biologically implausible.

Subsequently, a “Dear Health Care Professional” let-ter from Aventis summarizing the additions to the Warn-ing and Precaution sections of the Lovenox prescribinginformation was disseminated, presumably supported bythe Food and Drug Administration (FDA).1 Both the warn-ing and the precaution are based on poor evidence andare likely to affect physicians’ practices, as well as the fea-sibility of further research into the management of preg-nant women with mechanical heart valves. When an ad-verse pregnancy outcome occurs, the likelihood ofmedicolegal action against the attending physician is high,even if the care given was reasonable. Undoubtedly, manyphysicians will avoid enoxaparin (and other LMWHs) inpregnant women with mechanical heart valves and, per-haps, particularly unnecessarily, for other indications inpregnancy. Physicians who use an LMWH in pregnantwomen with mechanical heart valves face a high prob-ability of being sued if an adverse experience occurs inthe mother or the neonate.

So, how should pregnant women with mechanicalprosthetic heart valves be managed?

Antithrombotic therapy is essential, because the riskof valve thrombosis and death or systemic embolism ishigh if it is not given. With currently used regimens (in-cluding warfarin, UFH, and LMWH, either alone or insequence), pregnancy in a woman with a mechanical heartvalve carries a risk of maternal mortality from valve throm-bosis estimated at 1% to 4%.2 Many factors determine therisk of valve thrombosis, including valve type and posi-tion, presence of atrial fibrillation, left atrial size, his-tory of previous thrombosis, number of mechanical valves,and adequacy of anticoagulation. Valve designs havechanged significantly over the last few years and there isless thrombogenic potential associated with newer bileaf-let valves. Management is problematic because thesewomen require anticoagulant therapy and there are nocontrolled clinical trials to provide guidelines with re-spect to the optimal antithrombotic agent or the inten-sity of anticoagulant therapy. Unfortunately, pregnantwomen (and often women of childbearing potential) areusually excluded from trials that involve evaluation ofdrugs. Performing studies involving only pregnant womenis extraordinarily difficult, because of “ethical” con-cerns, often resulting in the refusal of institutional ethi-cal review boards to approve such studies. Conse-quently, the best available evidence for the managementof most diseases in pregnant women is very poor, usu-ally consisting of case reports, small series, and “expertopinion.” A further problem is the philosophy of mostpharmaceutical companies of avoidance of the develop-ment of drugs for use in pregnancy because of medico-legal concerns and the perception that the potential prof-its are not worth the liability.

Prior to the development of LMWHs, 2 regimenswere commonly recommended in pregnant women withmechanical heart valves: (1) warfarin, for most of the preg-nancy, usually with substitution of UFH between 6 and12 weeks of gestation (to avoid warfarin embryopathy;see below) and near term (to avoid neonatal hemor-rhage), and (2) UFH throughout pregnancy.3 Evidencesupporting the use of these regimens is poor and is de-rived from case reports, case series, small cohort stud-ies, and questionnaires. Further, the use of both warfa-rin and UFH is problematic during pregnancy. Warfarincrosses the placenta and can cause fetal abnormalities aswell as hemorrhage, particularly during and immedi-ately after delivery. Although UFH does not cross theplacenta and does not harm the fetus, it must be givenparenterally (usually by subcutaneous injection twicedaily) and like warfarin can cause maternal hemor-rhage, and also can cause maternal osteoporosis andthrombocytopenia.3

Many experts have suggested that LMWHs may bea suitable option for prophylaxis of systemic embolismin pregnant women with mechanical heart valves.3 LikeUFH, they do not cross the placenta and, therefore, itseems biologically implausible that they could be tera-togenic. In support of this, a recent overview found noincrease in teratogenicity with LMWH use during preg-nancy.4 Further, when compared with UFH, LMWHs havedistinct advantages, including the potential for subcuta-




neous administration once, rather than twice, daily pos-sibly less bleeding for an equivalent antithromboticeffect, less osteoporosis, and less heparin-inducedthrombocytopenia.5 In addition, because they producea predictable antithrombotic effect when given to pa-tients subcutaneously on a weight-adjusted basis, nolaboratory monitoring is required in this patient popu-lation.5 However, the pharmacokinetics of LMWHs aredifferent in pregnant than in nonpregnant subjects be-cause of changes in volume of distribution resultingfrom an increase in plasma volume and changes in renalclearance of LMWH. Consequently, although empiric,we recommend periodic anti-factor Xa level monitor-ing, with dose adjustments to ensure a consistent anti-coagulant effect.3 Nevertheless, many experts werehopeful that LMWHs would improve the managementof pregnant women with mechanical heart valves.

Until properly designed, adequately powered trialsof currently available agents are performed or new anti-thrombotics suitable for use in pregnant women are de-veloped, recommendations for the management of preg-nant women with mechanical heart valves must be basedon case reports, case series, and expert consensus.

BASIS FOR RECOMMENDATIONS

To make sensible recommendations, the following ques-tions should be addressed. For warfarin: (1) What arethe true incidence and the clinical impact of warfarin em-bryopathy? (2) Does warfarin truly cause other fetal prob-lems when given to pregnant women? For UFH andLMWH: (1) What is the true incidence of failure (valvethrombosis)? (2) What is the incidence of other adverseexperiences (bleeding, osteoporosis, thrombocytope-nia)? For LMWH: Does LMWH truly cause fetal prob-lems when given to pregnant women?

Warfarin

Warfarin is the drug of choice in nonpregnant patientswith mechanical heart valves and is highly effective inpreventing thromboembolic complications. In preg-nant women, it can cause a specific embryopathy, con-sisting of nasal hypoplasia and epiphyseal stippling, al-beit only when administered between 6 and 12 weeks ofgestation.6 In a recent critical review of the available pub-lished literature, the authors estimated that the true in-cidence of warfarin embryopathy with exposure be-tween 6 and 12 weeks of gestation was low (�5%)2; thiscontrasted with estimates of 30% or higher.7 Further, inrecent follow-up studies of children born with warfarinembryopathy, major morbidity was uncommon, and manyof these infants developed normally.8-11

Other problems, such as fetal central nervous sys-tem abnormalities, have been reported in association withwarfarin use at any stage of pregnancy.12 However, theseevents are rare and it is unclear whether the incidenceof any of these complications is higher than in pregnan-cies not associated with warfarin use. Finally, since war-farin crosses the placenta, maternal use can cause fetalhemorrhage, particularly during and immediately afterdelivery.12 However, this is likely to be rare and can be

avoided by using a heparin (instead of warfarin) for thelast part (2-4 weeks) of pregnancy.

Unfractionated Heparin

Since it does not cross the placenta, UFH is not terato-genic. However, multiple reports of thrombosed valves withthe use of UFH, causing maternal morbidity and mortal-ity, have raised serious concerns about its effective-ness.2,13-16 One plausible explanation for the failure of UFHis inadequate dosage. It is known that low-dose heparin(5000 IU every 8-12 hours subcutaneously) is inadequatefor prevention of thrombosis of mechanical prosthetic heartvalves during pregnancy16; it is unclear whether 12-hourly subcutaneous UFH adjusted to prolong a mid-interval activated partial thromboplastin time (aPTT) re-sult to 1.5 to 2.5 times control is adequate. After initialheparin therapy, this regimen has been shown to be as ef-fective as warfarin (with a target international normalizedratio [INR] of 2.0-3.0) for the prevention of recurrence innonpregnant patients with acute venous thromboembo-lism.17 However, based on several considerations, this regi-men of UFH might be less effective in pregnant women withmechanical heart valves. First, 1.5 times control, the usuallower limit of the therapeutic range, corresponds to sub-therapeutic heparin levels (anti-factor Xa levels �0.3 U/mL)using most currently available aPTT reagents.18 Second, ex-cept for patients who have bileaflet mechanical aortic valvesand do not have atrial fibrillation, the recommended tar-get INR range for patients with mechanical heart valves (2.5-3.5) is higher than the corresponding target INR range forthe treatment of acute venous thromboembolism (2.0-3.0), suggesting that more intense antithrombotic therapyis appropriate.19 Further, although warfarin, with a targetINR of 2.0 to 3.0, is highly effective in the long-term treat-ment of acute venous thromboembolism, even with the useof a more intense warfarin regimen (INR of 2.5-3.5), theaddition of aspirin to the warfarin regimen improves effi-cacy for patients with mechanical heart valves (albeit at thecost of an increase in the rate of minor bleeding).20 Giventhis information, we recommend that if subcutaneous UFHis used to prevent thrombosis in pregnant women with me-chanical heart valves, the starting dose should be high(17500-20000 U every 12 hours) and adjusted aggres-sively to achieve a mid-interval aPTT of at least 2.0 timescontrol or a result that corresponds to an anti-factor Xa hep-arin level of at least 0.3 to 0.5 U/mL. Finally, adjunctiveaspirin therapy should be considered in high-risk women,such as those with previous systemic embolism and thosewith atrial fibrillation.

The rate of major bleeding in pregnant patientstreated with UFH has been reported to be approxi-mately 2%, which is consistent with the reported ratesof bleeding associated with heparin therapy in nonpreg-nant patients and with warfarin therapy when used forthe treatment of deep vein thrombosis.21 Unfortunately,adjusted-dose subcutaneous UFH can cause a persistentanticoagulant effect at the time of delivery, which can com-plicate its use prior to labor.22 Approximately 3% of non-pregnant patients receiving UFH develop immune, IgG-mediated thrombocytopenia, which is frequentlycomplicated by extension of preexisting venous throm-




boembolism or new arterial thrombosis.23 In pregnantwomen, the true incidence of IgG-mediated thrombocy-topenia is unknown. Long-term heparin therapy has beenreported to cause osteoporosis in both laboratory ani-mals and humans.3,24 Further, symptomatic vertebral frac-tures have been reported to occur in about 2% to 3% ofpatients receiving UFH for periods of 1 month or moreand significant reductions in bone density have been re-ported in up to 30% of patients receiving long-term UFH.24

Low-Molecular-Weight Heparin

The true incidence of valve thrombosis in enoxaparin- (orother LMWH-) treated pregnant women with mechanicalheart valves and the optimal LMWH treatment regimen fortheir patients are unknown. Based on published data, therehave been a small number of patients treated with LMWH,most successfully.25,26 The small numbers of patients withvalve thrombosis in the randomized trial of enoxaparin (2 of7, 29%) have very wide confidence intervals (4%-71%) and,when combined with the limitations of the postmarketingdata, preclude an accurate estimate of the true rate of fataland nonfatal valve thrombosis despite the information con-tained in the recent “Precaution” and “Dear Health CareProfessional” letter.1

The potential for teratogenicity of LMWHs lacks bio-logic plausibility because it has been demonstrated thatthese agents do not cross the placenta. In support of this,a recent comprehensive overview concluded that therewas no teratogenicity associated with LMWHs.4

OTHER ISSUES

Warfarin, with a target INR of 2.5 to 3.5 (except in pa-tients with uncomplicated bileaflet mechanical aorticvalves), is standard antithrombotic therapy for nonpreg-nant patients with mechanical prosthetic heart valves.19

It is highly likely that warfarin therapy is safe during preg-nancy when used up to 6 weeks of gestation and from12 weeks of gestation until just prior to (�2 weeks) de-livery.4 It is also likely that both the incidence and themorbidity of warfarin embryopathy have been overesti-mated with warfarin use between 6 and 12 weeks of ges-tation; the true incidence is probably less than 5% andthe morbidity is low.2,8-11

However, the use of warfarin during pregnancy hasimportant medicolegal implications (especially in NorthAmerica) as the package insert for the most commonlyprescribed brand (Coumadin; DuPont Pharma, Wilm-ington, Del) states that warfarin is contraindicated dur-ing pregnancy.

Neither UFH nor LMWH crosses the placenta andboth are highly unlikely to be teratogenic. Reports of treat-ment failures with UFH and LMWH, resulting in throm-bosed valves and sometimes death, have been pub-lished, leading many to conclude that these agents shouldnot be used in pregnant patients with mechanical pros-thetic heart valves.16 Many of these failures were associ-ated with inadequate dosing (eg, UFH, 5000 U every 12hours or “prophylactic” doses of LMWH). The true in-cidence of failure with either drug, given in adequatedoses, is unknown and it is unclear whether the risk is

higher than that associated with warfarin adjusted to tar-get an INR of 2.5 to 3.5. If UFH or LMWH is used, suf-ficient doses must be initiated and the doses adjusted ac-cording to the results of appropriate laboratory tests,preferably anti-factor Xa levels or, with UFH, the aPTT.

To summarize, there are still insufficient groundsto make definitive recommendations about optimal an-tithrombotic therapy in pregnant patients with mechani-cal heart valves because properly designed studies havenot been performed. Based on the above considerations,UFH and LMWH are unlikely to be teratogenic. Al-though warfarin almost certainly can cause an embry-opathy if given between 6 and 12 weeks of gestation, ithas probably been overestimated in frequency and clini-cal impact. If UFH is used, it should be initiated in highdoses (17500-20000 U every 12 hours) and adjusted ac-cording to a 6-hour postinjection aPTT (minimum tar-get of twice control) or anti-factor Xa heparin level (mini-mum target of 0.3 U/mL).3 If an LMWH is used, it shouldalso be initiated in high doses and adjusted according toa 4- to 6-hour postinjection anti-Xa heparin level (mini-mum target of 0.5 U/mL).3 In addition, for some high-risk patients (eg, those with a history of systemic embo-lism), aspirin, 80 to 325 mg/d, should be administeredin an attempt to reduce the risk of thrombosis, recog-nizing that it increases the risk of bleeding.20

TREATMENT RECOMMENDATIONS

Women with mechanical heart valves should be care-fully counseled about the risks associated with availableanticoagulant options prior to, or shortly after, becom-ing pregnant. The practice of substituting warfarin withUFH or an LMWH between 6 and 12 weeks of gestationprobably eliminates the risk of warfarin embryopathy (orother teratogenic effects) but might subject women to anincreased risk of thromboembolism if inadequate dosesare used.

One of the following approaches is recommended:

1. “Aggressive” adjusted-dose UFH throughout preg-nancy; ie, administered subcutaneously every 12 hoursin doses adjusted to maintain the mid-interval aPTT at aminimum of twice control or an anti-factor Xa heparinlevel of at least 0.3 U/mL.

2. Adjusted-dose LMWH throughout pregnancy; ie,administered subcutaneously every 12 hours in doses ad-justed to maintain a 4- to 6-hour postinjection anti-factor Xa heparin level at a minimum of 0.5 U/mL.

3. UFH or LMWH (as above) until the 13th weekof pregnancy, then warfarin with a target INR of 2.5 to3.5 until the middle of the third trimester, followed byreinitiation of UFH or LMWH until delivery.

With any of the 3 above regimens, adjunctive aspi-rin therapy should be considered. Long-term anticoagu-lants should be resumed post partum with all regimens.

CONCLUSIONS

The management of pregnant women with mechanicalvalves is a particularly difficult challenge. The paucity ofmethodologically sound studies has hampered the devel-




opment of definitive treatment recommendations. With theinformation contained in the package insert for warfarin,the concern about treatment failures with UFH, and therecent “Warning,” “Precaution,” and “Dear Health Care Pro-fessional” letter from Aventis Pharmaceuticals, physi-cians treating these patients have been left without a widelyaccepted treatment option and their medicolegal expo-sure is very high. The precaution about teratogenic effectsalso unnecessarily complicates the treatment and prophy-laxis of venous thromboembolism during pregnancy. In ad-dition, this new “information” will undoubtedly hamperthe feasibility of conducting clinical trials designed to im-prove the management of pregnant women with mechani-cal valves. Pharmaceutical companies and the FDA have aresponsibility to disseminate information about drugs thataffect patient safety. However, the FDA and other regula-tory agencies must not endorse scientifically unsupportedclaims that have the potential to “close the door” on ac-ceptable therapeutic options. In this instance the result hasbeen confusion and worry among patients and treating phy-sicians, and will likely lead to frivolous lawsuits and theabandonment of research designed to improve the man-agement of pregnant women with mechanical heart valves.

In our opinion, the next steps should include (1) aconsensus among experts in the field to systematicallygather the best available evidence and generate recom-mendations for the management of pregnant women withmechanical heart valves; (2) identification of key unre-solved issues that will lead to the performance of appro-priate studies to address these issues; and (3) a commit-ment by the FDA (and industry) to support appropriatelydesigned trials to solve, rather than create problems. Thestatus quo is unacceptable.

Accepted for publication December 3, 2002.Dr Ginsberg is a Career Investigator of the Heart and

Stroke Foundation of Ontario and the recipient of a Re-search Chair from the Canadian Institutes of Health Research/Astra Zeneca. Dr Bates is the recipient of a New Investiga-tor Award from the Canadian Institutes of Health Research/bioMerieux, Inc.

Corresponding author and reprints: Jeffrey S. Gins-berg, MD, FRCPC, McMaster University Medical Center,1200 Main St W, Room 3X28, Hamilton, Ontario, CanadaL8N 3Z5 (e-mail: [email protected]).

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anticoagulation of pregnant women with mechanical heart valves

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