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Chapter 151 Hematologic Changes in Pregnancy 2213

double heterozygosity, and antithrombin III deficiency were at recurrent miscarriage, anticoagulation has been used in efforts to
highest risk. Given the increased risk of VTE, prophylactic anticoagu- improve rates of live birth. There have been varied results in clinical
lation is warranted. trials using anticoagulation in the setting of recurrent miscarriage.
Screening for inherited thrombophilia in patients with recurrent However, in the large, multicenter, randomized, placebo-controlled
miscarriage or pregnancy complications such as preeclampsia or study examining the use of aspirin or aspirin plus heparin in women
placental abruption is not indicated. Thrombophilia screening is with unexplained miscarriage, there was no improvement in the live
indicated only in patients with a prior thromboembolic event or a birth rate compared with placebo. 210
high likelihood of thrombophilia. Selective screening based on per-
sonal and family history is recommended (see box on The TIPPS
(Thrombophilia in Pregnancy Prophylaxis Study) Trial and box on Antiphospholipid Antibody Syndrome
Thrombophilia During Pregnancy).
Prophylactic treatment of carriers of low-risk mutations with any The antiphospholipid antibody syndrome (Table 151.3) is the most
211
personal or family history of VTE is not indicated. In patients with common form of acquired thrombophilia. Antiphospholipid
antibodies include lupus anticoagulant antibodies and anticar-
diolipin antibodies. They can occur as a manifestation of various
The TIPPS (Thrombophilia in Pregnancy Prophylaxis Study) Trial conditions, such as systemic lupus erythematosus (SLE) and other
rheumatic diseases, infection, and drug reactions. Antiphospho-
The TIPPS trial was the first large randomized controlled trial in which lipid antibodies exert their prothrombotic effect through several
researchers examined the effect of low-molecular-weight heparin mechanisms. For example, they inhibit the activity of anticoagulants
(LMWH) in pregnant patients with thrombophilia and a history of on thrombomodulin, protein S, protein C, β 2 -glycoprotein I, and
adverse pregnant outcomes or venous thromboembolism (VTE). The prostacyclin. 212–214 They interact with phospholipids on the surface
TIPPS investigators studied 292 pregnant women who were randomly of platelets, increasing platelet adhesiveness and production of von
assigned to dalteparin or no dalteparin. The primary objective of the Willebrand mulitmers. 215,216 In pregnant patients, antiphospholipid
study was to identify if LMWH prophylaxis in thrombophilic pregnant antibodies decrease levels of annexin V, a potent vascular endothelial
women results in a greater than 33% relative risk reduction in the 217
composite outcome measure of severe or early-onset preeclampsia, anticoagulant produced by placental trophoblasts. Nonpregnant
small-for-gestational-age infants (<10th percentile), pregnancy loss, or individuals with antiphospholipid antibody syndrome can develop
VTE. Dalteparin did not reduce the incidence of the primary composite arterial and venous thromboses. In pregnant women, antiphos-
outcome in both intention-to-treat analysis (dalteparin, 25 [17.1%] of pholipid antibody syndrome can manifest as thrombotic events,
146; 95% confidence interval [CI], 11.4%–24.2%; vs. no dalteparin, spontaneous abortion, preeclampsia, and HELLP syndrome, as well
27 [18.9%] of 143; 95% CI, 12.8%–26.3%; risk difference, –1.8%; as IUGR. 218–221
95% CI, −10.6% to 7.1%) and on-treatment analysis (dalteparin 28 Antiphospholipid antibodies can be detected in 5% of healthy
[19.6%] of 143 vs. no dalteparin 24 [17.0%] of 141; risk difference, pregnant women and 37% of pregnant women with SLE.
222
+2.6%; 95% CI, –6.4% to 11.6%). Major bleeding did not differ. More Thrombotic events occur in approximately 5% of pregnant women
minor bleeding was seen in the dalteparin group (28 [19.6%] of 143) 221
than in the no-dalteparin group (13 [9.2%] of 141; risk difference, with antiphospholipid antibodies. All pregnant women with SLE
10.4%; 95% CI, 2.3–18.4; p = .01). should undergo testing for antiphospholipid antibodies. Women who
The conclusion from the study was that prophylactic dalteparin did sustain recurrent spontaneous abortions or a thromboembolic event
not reduce the occurrence of venous thromboembolism, pregnancy during pregnancy should also undergo evaluation for the disorder. A
loss, or placenta-mediated pregnancy complications in pregnant history of either vascular thrombosis or fetal loss coupled with the
women with thrombophilia. presence of either lupus anticoagulant antibodies or anticardiolipin
Some debate and controversy exist regarding the trial and its antibodies establishes the diagnosis of antiphospholipid antibody
conclusions. syndrome. 223
Cons: It took 12 years to randomize 292 women from 21 referral False-negative laboratory results do occur and do so more fre-
centers. Some physicians raised concern over the amount of time
it took to accrue the number of patients and the accuracy of the quently in pregnant than in nonpregnant women. This may be
patient base it represents. Others argued that eligibility criteria because of the increased concentration of clotting factors observed in
224
were based on a rationale that had already changed by the time pregnancy. Women with antiphospholipid antibody syndrome who
the study was concluded. have sustained prior thrombotic events receive therapeutic anticoagu-
Pros: The article confirms that women who are at low risk of lation during pregnancy. Those with antiphospholipid antibodies but
thrombosis should not be treated with low-molecular-weight no manifestations of the clinical syndrome should receive prophylac-
heparin and that this widespread practice should be stopped. tic anticoagulation.
Cons: Many of these women were women who would be placed in
“lower-risk” categories to begin with, such as women who were
heterozygous for thrombophilic mutations such as factor V Leiden
mutation with one family member with a history of thrombosis.
TABLE Antiphospholipid Antibody Syndrome
151.3
Vascular Thrombosis
Thrombophilia During Pregnancy One or more episodes of arterial or venous thrombosis confirmed by
imaging
A 25-year-old woman wishes to become pregnant. Her mother expe- Pregnancy morbidity
rienced a deep vein thrombosis at the age of 70 years, underwent Death of a fetus beyond 10 weeks of gestation with normal fetal
thrombophilia evaluation, and was found to be heterozygous for the morphology
factor V Leiden mutation. She herself has never had a thrombotic Premature birth before 34 weeks of gestation
episode, just recently discontinued her birth control, and was told to Three or more consecutive spontaneous abortions before 10 weeks of
see a hematologist before she became pregnant. Her primary care
physician tested her for factor V Leiden, and she was found to be gestation
heterozygous for the mutation. She is asking if she should be on Laboratory criteria (all measured on two or more occasions at least
anticoagulation during her pregnancy. 12 weeks apart)
Every case of thrombophilia during pregnancy needs to be assessed Lupus anticoagulant on two or more occasions at least 12 weeks apart
on a case-by-case basis. Asymptomatic women who harbor thrombo- Anticardiolipin antibody
philic conditions but have never manifested clinical manifestations do Anti-B 2 glycoprotein IgM or IgG
not require anticoagulation. Ig, Immunoglobulin.