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Thrombophilia and Pre-eclampsia
Abstract & Commentary
By John C. Hobbins, MD, Professor and Chief of Obstetric, University of Colorado Health Sciences Center, Denver, is Associate Editor for OB/GYN Clinical Alert.
Dr. Hobbins reports no financial relationship to this field of study.
Synopsis: Pre-eclampsia in pregnancy may be associated with thrombophilia.
Source: Kahn SR, et al. Inherited thrombophilia and preeclampsia within a multicenter cohort: The Montreal Preeclampsia Study. Am J Obstet Gynecol 2009;200:151.e1-151.e9
One of the most confusing areas in medicine, which spills over into obstetrics, is thrombophilia, and seemingly every year a new antibody affecting the clotting system emerges that causes worry. One of the worries involves a possible link with pre-eclampsia. This recent study from Montreal has addressed the possible relationship between three polymorphisms associated with thrombophilia (prothrombin gene mutation, Factor V Leiden, and methyltetrahydrofolate reductase [MTHFR] deficiency) and pre-eclampsia.
The authors studied 5162 women who were cared for in the McGill University and Montreal University hospital systems between 1993 and 2003. Each had a visit and blood drawn in the first trimester and an ultrasound examination at 16-18 weeks, along with regular clinic visits thereafter. The patients were interviewed during their pregnancies, and their records were reviewed after they delivered. One hundred thirteen (2.2%) developed pre-eclampsia, and 28% were judged to be severe. Four hundred and forty-three patients were chosen as controls.
Not surprisingly, women with pre-eclampsia had much higher rates of intrauterine growth restriction (IUGR), diabetes, preterm birth, and cesarean delivery. There was also a tendency for pre-eclamptics to have higher a body mass index (BMI; odds ratio [OR] = 4.7; 90% confidence interval [CI], 1.1-22.8) and to have higher rates of chronic hypertension (OR = 3.4; 90% CI, 1.3-9.1) and previous pre-eclamptic pregnancies (OR = 4.7; CI, 1.5-15.0). "Under-perfused" placentas were more commonly found in the pre-eclamptics. Interestingly, smoking seemed to have a protective effect — something noted by other investigators.
What did not correlate with pre-eclampsia were any of the above polymorphisms, even in combination. Homocysteine levels were not higher in pre-eclamptics, but folates were lower in those with under-perfused placentas.
Although the above three factors have been implicated in many pregnancy complications, this study shows that pre-eclampsia is not one of them. It should be pointed out that this case-control study does not address other problems, such as thrombotic events, but certainly this study's findings should negate the need for a full thrombophilia work-up in every patient developing pre-eclampsia.
Now, let's move on to another part of the thrombophilia spectrum — the antiphospholipid antibodies (APLs). These are directed against beta-2 glycoprotein-1, resulting in enhanced platelet activation. The three potential troublemakers are anticardiolipin antibodies, lupus anticoagulant, and beta-2 glycoprotein-1 antibodies. First, like the polymorphisms studied in the Montreal case-control study, these APLs are often found in women with normal pregnancies, and only when the latter two antibodies are found in moderate-to-high levels, should they get our attention. Also, they must be persistently present 12 weeks after they initially were found. Even then, for us to consider therapeutic action, the patient should have evidence of antiphospholipid antibody syndrome (APS). This would mean that any patient with these antibodies must have a history of one or more of the following: 1) an unexplained stillbirth after 10 weeks; 2) three consecutive spontaneous abortions prior to 10 weeks; 3) either venous or arterial thrombosis; and/or 4) IUGR. It is of note that studies have shown that pre-eclampsia is not increased in patients with APL alone.1-4
Earlier investigation has demonstrated the benefit of low-dose aspirin in preventing severe pre-eclampsia, in general, but no studies have shown a decrease in the incidence of pre-eclampsia with bigger guns, such as unfractionated heparin (UFH) or a low-molecular-weight heparin (LMWH).5 The standard dose has been one baby aspirin (84 mg) daily, but there is a suggestion in the stroke literature that two pills per day may be better in discouraging micro-clotting. Large studies have shown no downside of low-dose aspirin in the second and third trimester, although in one study there was a suspicion of a slightly higher rate of gastroschisis with aspirin delivered in the first trimester.6
If patients have a past history of venous or arterial thrombosis alone, then they would benefit from prophylactic doses of UFH (5000 U q 12 hrs) or LMWH (Lovenox® 40 mg q 24 hrs). If the patient has documented APS, then an "intermediate" regimen of UFH (5000 U to anti-Xa of 0.1-0.3 U) or LMWH (Lovenox 40 mg q 12 hrs) could be used. This regimen can be used in conjunction with low-dose aspirin, and if thrombosis is a component of the history, prophylactic anticoagulation should be carried out postpartum. If the patient has only APL without APS, prophylaxis would not be necessary, although low-dose aspirin may well be useful if the patient has abnormal uterine artery waveforms.
Lastly, MTHFR has become a thorn in our side. In the Montreal study, 14% of their control population was homozygous for MTHFR. Others have shown that far more pregnant women are heterozygous for this factor. MTHFR affects the clotting process by elevating levels of homocysteine, which in turn is associated with decreased folate levels. It is very rare for a heterozygote (other than upping the dose of folic acid), and in the 14% who are homozygous, we would not treat them unless there was an additional clinical factor of concern. Therefore, our work-up for thrombophilia does not include MTHFR, and has been coned down to the biggest troublemakers: 1) anticardiolipin antibody; 2) Factor V Leiden; 3) beta-2 glycoprotein-1; 4) prothrombin gene mutation; and 5) lupus anticoagulant.