The Association Between Thrombophilia & Pregnancy Complications
A number of studies have examined the association between thrombophilias and complications of pregnancy; however, methodologic limitations have made it difficult to obtain an accurate assessment of association and risk.
Thrombophilia & Pregnancy-related Venous Thromboembolism
In a systematic review of nine case–control studies that evaluated the risk of pregnancy-related VTE in women with an inherited thrombophilia but not necessarily a family history of VTE, the highest VTE risks were associated with homozygosity for factor V Leiden or the prothrombin G20210A mutation (odds ratio [OR]: 34.4; 95% CI: 9.9–120.1 and OR: 26.4; 95% CI: 1.2–559.3, respectively). Pregnant women with the most common heritable thrombophilias (i.e., heterozygosity for factor V Leiden [OR: 8.3; 95% CI: 5.4–12.7] or the prothrombin G20210A mutation [OR: 6.8; 95% CI: 2.5–18.8]) had lower risks. Deficiencies of the endogenous anticoagulants were associated with similar moderate risk increases (OR for antithrombin, protein S and protein C deficiency of 4.7 [95% CI: 1.30–17.0], 4.8 [95% CI: 2.2–10.7] and 3.2 [95% CI: 1.5–6.0], respectively). However, the wide 95% CI and, therefore, instability of these point estimates are important to note. If the authors assume a background risk of VTE during pregnancy of one out of 1000, these results suggest that the absolute risk in asymptomatic thrombophilic women without a family history is in the range of five to 12 out of 1000 deliveries for most of the inherited thrombophilias. Homozygous carriers of the factor V Leiden or the prothrombin mutation probably have a higher risk of approximately 4%.
Thrombophilic women with a positive family history of VTE may be at higher risk.[34,35] A family history of VTE results in a two- to fourfold increase in the risk for this complication, even in the absence of an inherited hypercoagulable state. Thrombophilic subjects without a personal or family history of DVT or PE have lower rates of VTE than patients with thrombophilia and a positive family history. Family-based cohort studies not included in the abovementioned systematic review suggest that the risk of developing a first VTE during pregnancy or the postpartum period is 3.0% (95% CI: 0.08–15.8%), 1.7% (95% CI: 0.4–8.9%) and 6.6% (95% CI: 2.2–14.7%) for women with antithrombin, protein C and protein S deficiency, respectively. For homozygous carriers of the factor V Leiden mutation, the risk is 14.0% (95% CI: 6.3–25.8%).[10,39–41] The reported risk is 3.1% (95% CI: 2.1–4.6%)[10,42–46] for those who are heterozygous for the factor V Leiden mutation and 2.6% (95% CI: 0.9–5.6%)[10,47–49] for those heterozygous for the prothrombin gene mutation. Two small studies that investigated the risk of pregnancy-related VTE in women with both the factor V Leiden and prothrombin mutations found similar risk estimates to those seen in single heterozygous carriers.[41,48]
The risk estimates for the deficiencies of the natural anticoagulants quoted above are lower than one may expect given that these have traditionally been classified as 'high-risk thrombophilias'. The older literature has typically reported higher VTE risks in pregnant women;[50,51] however, these reports often included women with a history of prior recurrent VTE and included episodes of clinically diagnosed VTE as outcomes. These early estimates, therefore, probably overestimated the risk of pregnancy-related VTE associated with these thrombophilias.
Acquired thrombophilias have been less well studied but repeated APLA positivity (lupus anticoagulants [nonspecific inhibitors], ACLA or anti-β2 glycoprotein 1 antibodies) is associated with an increased risk of VTE.[27,52] The VTE risk in pregnant women with APLAs and no previous venous thrombosis is uncertain;[53,54] however, in small prospective cohort studies (n = 12; n = 87), the risk did not appear high.[55,56]
Compared with individuals without a history of VTE, patients with previous events are at increased risk of future episodes of DVT and PE. In a retrospective study of 109 women who had at least one pregnancy without receiving prophylaxis after an episode of VTE, pregnancy was associated with a higher risk of VTE (relative risk [RR] during pregnancy: 3.5; 95% CI: 1.6–7.8%). In a prospective study of 125 pregnant women with a history of a single prior VTE in which antepartum prophylaxis was withheld, the overall risk of symptomatic recurrence prior to delivery was 2.4% (95% CI: 0.2–6.9%). No antepartum recurrences were diagnosed in the women without a thrombophilia whose previous event had been associated with a temporary risk factor (risk of antepartum recurrence: 0%; 95% CI: 0–8.0%). A history of unprovoked VTE and/or positive thrombophilia testing was associated with a higher risk of antepartum recurrence (risk of antepartum recurrence: 5.9%; 95% CI: 1.2–6.2%). This study has been criticized for its small sample size, late mean gestational age at enrollment and exclusion of women with known thrombophilias, however, the frequency of antepartum recurrence is consistent with that reported in subsequent larger retrospective studies.[60,61] In these retrospective reports, thrombophilia was not a predictor of recurrent pregnancy-associated VTE.[60,61]
Data from the retrospective studies suggest that women with prior VTE associated with pregnancy, the postpartum period or oral contraceptive use had a higher risk of subsequent pregnancy-related VTE than those whose first VTE was unprovoked or associated with nonhormonal transient risk factors.[60,61] These findings are consistent with those from a large administrative data set in which women with a first VTE associated with pregnancy or the postpartum period had a higher risk of recurrence during a subsequent pregnancy than those who had suffered an unprovoked first event, that is, 4.5 versus 2.7%; (RR: 1.71; 95% CI: 1.0–2.8).
Thrombophilia & Adverse Pregnancy Outcomes
The association between placental-mediated pregnancy complications and thrombophilia has been examined in several studies. However, the available data is difficult to interpret in light of methodologic limitations and heterogeneity in study design (especially with respect to patient ethnicity, completeness of thrombophilia testing, and severity of the pregnancy complication under investigation).
Pregnancy loss complicates 12–15% of all clinically recognized pregnancies;[20,63] however, recurrent loss occurs in a smaller proportion of women. Other placental-mediated pregnancy complications include preeclampsia, fetal growth restriction and placental abruption. Preeclampsia, which is characterized by new onset of hypertension during pregnancy in combination with proteinuria, occurs in 3–7% of all pregnancies and is a leading cause of both fetal and maternal morbidity and mortality. Although placental abruption is relatively uncommon (0.5% of gestations), it is a major cause of antepartum hemorrhage and carries a high risk of fetal mortality.[65,66] Small-for-gestational-age newborns may suffer long-term effects including developmental delay, poor school performance and a significantly lower likelihood of academic and professional success.
There is convincing evidence of an association between APLAs and increased risk of recurrent and late pregnancy loss.[9,68–73] The link between these antibodies and other placental-mediated pregnancy complications remains controversial (Table 1).[9,73] Most of the data supportive of an association are derived from small case–control studies with important methodologic limitations, including selection and recall bias. A recent systematic review and meta-analysis of 28 studies examining the association between APLAs and placental-mediated complications in women without autoimmune disease analyzed the methodologically stronger cohort studies separately from case–control studies. As shown in Table 1, nonspecific inhibitors were associated with preeclampsia, intrauterine growth restriction and late fetal loss among case–control studies but only with late fetal loss among cohort studies. Similarly, while ACLAs were associated with preeclampsia and late loss among case–control studies, the only statistically significant association seen in the cohort studies was with fetal loss less than 10 weeks.
There has been substantial interest in examining whether heritable thrombophilias are also associated with adverse pregnancy outcomes. In a meta-analysis of 25 studies (predominantly case–control) that examined the association between thrombophilia and various pregnancy complications in 7167 women, the factor V Leiden and prothrombin gene mutations were associated with early (first or second trimester) and recurrent first trimester loss, as well as preeclampsia and placental abruption; although wide confidence intervals around the point estimates of some associations illustrate the uncertainty of the findings. In this meta-analysis, statistically significant associations were also seen between late loss and the factor V Leiden mutation, the prothrombin gene mutation and protein S deficiency, although the latter positive association was based on a total of 15 patients with this thrombophilia. However, in a meta-analysis limited to methodologically stronger prospective cohort studies, the pooled OR for pregnancy loss in women with factor V Leiden (absolute risk: 4.2%) compared with women without this mutation (absolute risk: 3.2%) was only minimally elevated at 1.52 (95% CI: 1.06–2.19). This meta-analysis was unable to establish or refute an association between the presence of factor V Leiden and preeclampsia (OR: 1.23; 95% CI: 0.89–1.70) or fetal growth restriction (OR: 1.0; 95% CI: 0.80–1.25). Results also failed to demonstrate or exclude an association between the prothrombin mutation and either preeclampsia (OR: 1.25; 95% CI: 0.79–1.99), fetal growth restriction (OR: 1.25; 95% CI: 0.92–1.70) or pregnancy loss (OR: 1.13; 95% CI: 0.64–2.01) These results suggest that these thrombophilias are probably, at most, contributing factors (perhaps due to the severity of disease expression once the condition arises), rather than causal agents, in the multifactorial pathogenesis of placental-mediated complications.
Expert Rev Hematol. 2013;6(3):287-300. © 2013 Expert Reviews Ltd.