SNOWMASS, COLO. – How would you manage anticoagulation in a newly pregnant 23-year-old with a mechanical heart valve who has been on warfarin at 3 mg/day?
A) Weight-adjusted low-molecular-weight heparin during the first trimester, then warfarin in the second and third until switching to unfractionated heparin for delivery.
B) Low-molecular-weight heparin throughout pregnancy.
C) Warfarin throughout pregnancy.
D) Unfractionated heparin in the first trimester, warfarin in the second and third until returning to unfractionated heparin peridelivery.
The correct answer, according to both the ACC/AHA guidelines (Circulation. 2014 Jun 10;129[23]:e521-643) and European Society of Cardiology guidelines (Eur Heart J. 2011 Dec;32[24]:3147-97), is C in women who are on 5 mg/day of warfarin or less.
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“Oral anticoagulants throughout pregnancy are much better for the mother, and this is where the guidelines have moved,” Dr. Carole A. Warnes said at the Annual Cardiovascular Conference at Snowmass.
Both sets of guidelines give a class I recommendation to warfarin during the second and third trimesters, because the risk of warfarin embryopathy is confined to weeks 6-12. During the first trimester, warfarin at 5 mg/day or less gets a class IIa rating – making it preferable to unfractionated or low-molecular-weight heparin – because heparin is a far less effective anticoagulant. Plus, multiple small studies indicate the risk of embryopathy is low – roughly 1%-2% – when the mother is on warfarin at 5 mg/day or less.
In a woman on more than 5 mg/day of warfarin, the risk of warfarin embryopathy is about 6%, so the guidelines recommend replacing the drug with heparin during weeks 6-12.
“It’s not a walk in the park,” said Dr. Warnes, director of the Snowmass conference and professor of medicine at the Mayo Clinic in Rochester, Minn.
The major concern in using heparin for anticoagulation in pregnancy is valve thrombosis. It doubles the risk.
“Pregnancy is the most prothrombotic state there is,” she said. “It’s not like managing a patient through a hip replacement or prostate surgery. Women with a mechanical prosthetic valve should be managed by a heart valve team with expertise in treatment during pregnancy.”
The alternatives to warfarin are adjusted-dose unfractionated heparin, which must be given in a continuous intravenous infusion with meticulous monitoring of activated partial thromboplastin time, or twice-daily low-molecular-weight heparin with dose adjustment by weight and maintenance of a target anti–Factor Xa level of 1.0-1.2 IU/mL.
“If you use low-molecular-weight heparin, you’re going to be seeing that patient every week to monitor anti–Factor Xa 4-6 hours post injection. You’ll find it’s not that easy to stay in the sweet spot, with excellent anticoagulation without an increased risk of maternal thromboembolism, or at the other extreme, fetal bleeding. What might look initially as a relatively easy strategy with a lot of appeal turns out to entail considerable risk,” Dr. Warnes said.
This was underscored in a cautionary report by highly experienced University of Toronto investigators. In their series of 23 pregnancies in 17 women with mechanical heart valves on low-molecular-weight heparin throughout pregnancy with careful monitoring, there was one maternal thromboembolic event resulting in maternal and fetal death despite a documented therapeutic anti–Factor Xa level (Am J Cardiol. 2009 Nov 1;104[9]:1259-63).
Although warfarin is clearly the better anticoagulant for the mother, the fetus pays the price. This was highlighted in a recent report from the ESC Registry of Pregnancy and Cardiac Disease (ROPAC) that compared pregnancy outcomes in 212 patients with a mechanical heart valve, 134 with a tissue valve, and 2,620 women without a prosthetic heart valve. Use of warfarin or another vitamin K antagonist in the first trimester was associated with a higher rate of miscarriage than heparin – 28.6% vs. 9.2% – as well as a 7.1% incidence of late fetal death, compared with just 0.7% with heparin.
On the other hand, the mechanical valve thrombosis rate was 4.7%, with half of those serious events occurring during the first trimester in patients after they’d been switched to heparin (Circulation. 2015 Jul 14;132[2]:132-42).
Hemorrhagic events occurred in 23.1% of mothers with a mechanical heart valve, 5.1% of those with a bioprosthetic valve, and 4.9% of patients without a prosthetic valve. A point worth incorporating into prepregnancy patient counseling, Dr. Warnes noted, is that only 58% of ROPAC participants with a mechanical heart valve had an uncomplicated pregnancy with a live birth, in contrast to 79% of those with a tissue valve and 78% of controls.
Because warfarin crosses the placenta, and it takes about a week for the fetus to eliminate the drug following maternal discontinuation, the guidelines recommend stopping warfarin at about week 36 and changing to a continuous infusion of dose-adjusted unfractionated heparin peridelivery. The heparin should be stopped for as short a time as possible before delivery and resumed 6-12 hours post delivery in order to protect against valve thrombosis.