Thrombophilia in pregnancy: Whom to screen, when to treat

Thrombophilia has been widely investigated—and that may be one of the main challenges in detecting and managing it during pregnancy: Numerous studies have yielded different estimates of the incidence of various clotting disorders in pregnancy—itself a hypercoagulable state—and conflicting screening and prevention recommendations. The authors offer whatever recommendations have emerged.

Why thrombophilia matters

During pregnancy, clotting factors I, VII, VIII, IX, and X rise; protein S and fibrinolytic activity diminish; and resistance to activated protein C develops.^1,2 When compounded by thrombophilia—a broad spectrum of coagulation disorders that increase the risk for venous and arterial thrombosis—the hypercoagulable state of pregnancy may increase the risk of thromboembolism during pregnancy or postpartum.³

Pulmonary embolism is the leading cause of maternal death in the United States.¹ Concern about this lethal sequela has led to numerous recommendations for screening and subsequent prophylaxis and therapy.

Two types

Thrombophilias are inherited or acquired (TABLE 1). The most common inherited disorders during pregnancy are mutations in factor V Leiden, prothrombin gene, and methylenetetrahydrofolate reductase (MTHFR) (TABLE 2). Caucasians have a higher rate of genetic thrombophilias than other racial groups.

Antiphospholipid antibody (APA) syndrome is the most common acquired thrombophilia of pregnancy. It can be diagnosed when the immunoglobulin G or immunoglobulin M level is 20 g per liter or higher, when lupus anticoagulant is present, or both.⁴

TABLE 1

Thrombophilias are inherited or acquired

INHERITED Protein S deficiency Protein C deficiency Protein Z deficiency Antithrombin III Factor V Leiden mutation MTHFR mutation Homozygosity to MTHFR C677T Homozygosity to 4G/4G mutation in PAI-1 gene Prothrombin G20210A mutation Polymorphisms in thrombomodulin gene
ACQUIRED Antiphospholipid antibody syndrome Hyperhomocysteinemia
MTHFR=methylenetetrahydrofolate reductase

TABLE 2

Prevalence of thrombophilias in women with normal pregnancy outcomes

THROMBOPHILIA	PREVALENCE (%)
Factor V Leiden mutation	2–10
MTHFR mutation	8–16
Prothrombin gene mutation	2–6
Protein C and S deficiencies	0.2–1.0*
Anticardiolipin antibodies	1–7
* Combined rate
MTHFR=methylenetetrahydrofolate reductase

Link to adverse pregnancy outcomes

During the past 2 decades, several epidemiologic and case-control studies have explored the association between thrombophilias and adverse pregnancy outcomes,^2-6 which include the following maternal effects:

• Venous thromboembolism, including deep vein thrombosis, pulmonary embolism, and cerebral vein thrombosis
  
• Arterial thrombosis (peripheral, cerebral)
  
• Severe preeclampsia
  

Placental and fetal abnormalities include:

• Thrombosis and infarcts
  
• Abruptio placenta
  
• Recurrent miscarriage
  
• Fetal growth restriction
  
• Death
  
• Stroke
  

Preeclampsia and thrombophilia

The association between preeclampsia and thrombophilia remains somewhat unclear because of inconsistent data. Because of this, we do not recommend routine screening for thrombophilia in women with preeclampsia.

An association between inherited thrombophilias and preeclampsia was reported by Dekker et al in 1995.⁷ Since then, numerous retrospective and case-controlled studies have assessed the incidence of thrombophilia in women with severe preeclampsia.^7-25 Their findings range from:

• Factor V Leiden: 3.7% to 26.5%
  
• Prothrombin gene mutation: 0 to 10.8%
  
• Protein S deficiency: 0.7% to 24.7%
  
• MTHFR variant: 6.7% to 24.0%
  

A meta-analysis of all case-controlled studies suggests that factor V Leiden is the only thrombophilia associated with an increased risk of preeclampsia.⁵ However, almost all studies included in this analysis involved women with severe preeclampsia who were referred to a tertiary-care obstetric center, whereas women in the control groups had a normal term pregnancy. These studies were therefore subject to selection bias because they overestimated the rate of thrombophilias in study groups and underestimated it in control groups.

Other points of contention are the varying levels of severity of preeclampsia and of gestational age at delivery, as well as racial differences. For example, most studies found an association between thrombophilia and severe preeclampsia at less than 34 weeks’ gestation, but not between thrombophilia and mild preeclampsia at term. In addition, a recent prospective observational study at multiple centers involving 5,168 women found a factor V Leiden mutation rate of 6% among white women, 2.3% among Asians, 1.6% in Hispanics, and 0.8% in African Americans.⁸ This large study found no association between thrombophilia and preeclampsia in these women. Therefore, based on available data, we do not recommend routine screening for factor V Leiden in women with severe preeclampsia.

Preeclampsia and APA syndrome

In 1989, Branch et al²⁶ first reported an association between APA syndrome and severe preeclampsia at less than 34 weeks’ gestation. They recommended that women with severe preeclampsia at this gestational age be screened for APA syndrome and treated when the screen is positive. Several later studies supported or refuted the association between APA syndrome and preeclampsia,^26,27 and a recent report concluded that routine testing for APA syndrome in women with early-onset preeclampsia is unwarranted.²⁶ Therefore, we do not recommend routine screening for APA in women with severe preeclampsia.