The Evolving Story of Pregnancy Outcome, Thromboembolism and Thrombophilia

Michael J. Paidas, M.D.
Associate Professor
Co-Director, Yale Women and Children’s Center for Blood Disorders

Pregnancy Outcome Thromboembolism

Pregnancy and Coagulation (Blood Clotting)

Pregnancy poses unique challenges to the blood clotting equilibrium in humans, probably more than in any other species.  In order to orchestrate a healthy and clot free pregnancy, the body must achieve just the right balance between bleeding and clotting.  In the beginning of pregnancy, preventing maternal bleeding and loss of the pregnancy is of prime importance. Closer to birth, the body prepares to prevent against the major risk for pregnant women: too much bleeding during childbirth. As part of this preparation, clotting factors increase during pregnancy, and protein S—a factor regulating clot breakdown—decreases. In addition, the effects of the pregnancy hormones, especially progesterone, cause blood vessels to dilate, creating a situation in which the blood pools, particularly in the legs. All of these changes place a pregnant woman at increased risk for thromboembolism (a blood clot).

How common are blood clots during pregnancy?

The risk of developing a blood clot is higher during pregnancy, delivery, and the six week period after birth. The chance of developing a blood clot is about 4-6 times more likely in pregnant women compared to non-pregnant women who are the same age. A blood clot occurs only in about one pregnant woman in 1,000-1,500. Blood clots remain a leading cause of maternal death in all parts of the world, and account for 11% of maternal deaths in the US.

What types of blood clots occur? When in pregnancy is a woman most at risk? 

Deep vein thrombosis (DVT), a blood clot that occurs in the deep veins, usually in one leg, accounts for about 75% of all blood clots that happen during or right after pregnancy. An embolism happens when a blood clot in the leg travels to the lungs, and pulmonary embolism (PE) accounts for about 25% of blood clots in pregnancy.   PE is typically more acute and more likely to be fatal than DVT. DVT and PE may occur during pregnancy or up to six weeks after birth. DVT is about three times more likely to occur during pregnancy than after delivery. In fact, about half of the women who develop a DVT during pregnancy experience it around the four month mark or right about the beginning of the second trimester. In contrast, about 60% of PE develops soon after delivery or in the six weeks following it.

Are there certain factors that put women at greater risk to develop a blood clot related to pregnancy?

The most common risk factors for PE in the postpartum period are Cesarean delivery and obesity. Given the steadily increasing use of Cesarean section as a delivery choice (currently done in about 3 out of every 10 women), coupled with the obesity epidemic, the risk of having a blood clot related to pregnancy is rising in the United States. Recently, scholars have highlighted the blood clotting risk associated with maternal obesity and recommended that obesity be managed in an effort to prevent thromboembolism (Duhl A, Paidas MJ et al. Am J Obstet Gynecol 2007).
 
Inherited thrombophilic conditions may also predispose women to develop blood clots in pregnancy. Understanding of thrombophilias (predisposition to clotting) and their impact on pregnancy continues to advance. As is often the case in medical research, initial small studies tend to magnify the impact of inherited risk factors for clotting, while further research either contradicted the initial findings or showed a weaker risk. For example, a case control study published in the New England Journal of Medicine (Gerhardt, 2000) compared the frequency of common thrombophilic conditions (factor V Leiden, prothrombin gene mutation, antithrombin deficiency and protein C deficiency) in two groups of pregnant women: one group of women who developed blood clots with or after pregnancy, and another group who were clot free.
 
The study found that the pregnant women who developed clots had significantly higher rates of the inherited thrombophilic conditions. In fact, factor V Leiden alone was found in more than 2 out of every 5 women with clots, as compared to fewer than 1 in 10 women who did not have any clots. However, when a large prospective (looking forward in time) study was performed on almost 5,000 women across the United States, the findings were different.
 
This study found that among women with no history of blood clots, having factor V Leiden was not found to be associated with clotting in pregnancy (Dizon Townson D, et al, Obstet Gynecol 2005). Because of these inconsistent results, it is difficult to analyze or conclude what the true risk is of developing a blood clot in pregnancy when a woman has an inherited thrombophilia. At this time, typically quoted risk estimates for thromboembolism in pregnancy consist of 0.2% for heterozygous factor V Leiden and 0.5% for heterozygous prothrombin gene mutation.

Does thrombophilia pose other risks to the pregnancy?

Thrombophilia might predispose a pregnant woman to complications associated with damage to the blood vessels of, or blood clots in, the placenta. A group of obstetrical outcomes, known as “placenta mediated complications” are worth considering. These complications include:

Collectively, these aberrations or complications occur in approximately 8 out of about 100 pregnancies.  In 1999, a case control study in connection with severe pregnancy complications associated with three thrombophilias (factor V Leiden, prothrombin gene mutation, methylene tetrahydrofolate reductase mutation) was published in the New England Journal of Medicine (Kupferminc,1999).
 
Kupferminc and his colleagues found that one of these three forms of thrombophilia was identified in approximately half of total miscarriages, preeclampsia, placental abruption and fetal growth restriction, or failure of the baby to grow in the womb. However, larger studies and analysis of compilations of smaller studies have either not confirmed an association, or found only a weak one.
 
Importantly, it must be noted that to date, a large enough study has not been performed from which to derive any meaningful information. The challenge is to find at least 400-800 women with each pregnancy complication to participate in such a large study to accurately assign actual risk level in what is already a relatively rare group of pregnant women with underlying thrombophilias. Fortunately a large, population-based study is underway in a collaboration between Yale University, the University of Copenhagen and Celera, Inc (see Lekke J. Semin Perinatol. 2007 Aug;31(4):219-22). Studies such as this will allow us to better understand the true risks of thrombophilia in pregnancy.

Are women who have thrombophilia managed differently during pregnancy?

Presently, if a pregnant patient has a thrombophilia and has had a blood clot prior to becoming pregnant, anticoagulation (i.e. use of a “blood thinning” medication) is recommended during and after pregnancy. Typically, low molecular weight heparin or heparin is the treatment of choice. In most ‘lower risk’ scenarios, low molecular weight heparin does not require any monitoring of blood levels.
 
However, with higher dosing to achieve greater levels of anticoagulation (therapeutic levels), monitoring of blood levels (factor Xa level) is usually performed, to ensure an adequate level of anticoagulation and prevent bleeding complications with ‘too high’ levels. Low molecular weight heparin is more expensive than heparin. Recently, the unfractionated heparin recall (Baxter) has created shortages in unfractionated heparin, further encouraging the use of low molecular
weight heparin.
 
If a woman does not have an identified thrombophilia, and her prior clotting event occurred because of a temporary risk factor, the risk of a repeat clot in pregnancy is low. In this case, only postpartum anticoagulation (with low molecular weight heparin, heparin or warfarin) is recommended.  It is less clear whether or not anticoagulation is needed in women who have a thrombophilia without a prior history of a blood clot. Options during pregnancy might include being alert to signs and symptoms of DVT/PE, using prophylactic support hose or compression stockings, treatment with anticoagulants only during the six weeks after pregnancy, or in certain unusual clinical situations, anticoagulation during pregnancy.
 
Since certain research has shown a relationship between some of the inherited thrombophilias and adverse pregnancy outcomes, several investigators have evaluated whether or not the drug heparin, alone or in combination with aspirin, might be helpful in preventing a poor outcome in subsequent pregnancies. Most of the published studies are retrospective (looking at what happened in the past). Women who have already had a poor outcome in pregnancy are screened for thrombophilia and if they do have thrombophilia, they are treated during subsequent pregnancies to increase the likelihood of an uneventful pregnancy with a safe and term childbirth.
 
In most circumstances, such preventive treatment works. However, only recently have pregnant women with a known thrombophilia and a previous pregnancy that resulted in a poor outcome been followed prospectively in subsequent pregnancies. Fortunately, the live birth rate in this group has ranged from 89-98%, even without treatment (Lindqvist PG & Merlo J. J Thromb Haemost 2006), raising questions about the need for any medical intervention.
 
Several studies are underway to examine the value of treatment of thrombophilia in pregnancy. For example, the Thrombophilia in Pregnancy Prophylaxis Study (TIPPS) is ongoing in several
countries, including the United States and Canada (www.healthypregnancy.ca). Below is a list of other current trials (Hossain N, Paidas MJ. Semin. Perinatol 2007).
 
Properly designed clinical trials are critical to answer these complicated questions about what constitutes proper management of women with thrombosis and thrombophilia. Such rigorous trials address both safety and efficacy questions and can propose sound treatment recommendations after careful analysis to weigh risks and benefits of a particular treatment. For now, until the trials are complete, each patient needs to have thoughtful discussions with her health care providers to navigate the potential options of screening and treating for thrombophilic conditions to avoid blood clots and maximize the chances of a healthy mother and baby.

Clinical Trials

STUDY   www.controlled-trials.com

TIPPS Thrombophilia in pregnancy prophylaxis study (isrctN87441504)

FRUIT  Fragmin in pregnant women with a history of uteroplacental insufficiency and thrombophilia study (isrctN87325378)

ALIFE  Anticoagulants for living fetuses (isrctN58496168)

SPIN Scottish pregnancy iNtervention study (isrctN06774126)

Posted October 7, 2008

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