Definition
Thrombophilia is broadly defined as a predisposition to thrombosis resulting from abnormalities in the coagulation system.
All women with a medical history of venous thromboembolism (VTE) who are planning pregnancy should be evaluated for thrombophilia.
Additionally, thrombophilia testing should be considered in pregnancies complicated by fetal loss, severe preeclampsia, or advanced intrauterine growth restriction (IUGR).
However, testing after pregnancy losses occurring before 10 weeks remains controversial.
Recent studies suggest performing genetic testing in cases of two consecutive pregnancy losses when no other cause has been identified.
Scientific Evidence and Genetic Panels
A 2008 study demonstrated that thrombophilia testing in white women with a history of preeclampsia may be useful for pregnancy management and counseling.
The most common thrombophilic mutations include:
- Factor V Leiden (G1691A) mutation
- Prothrombin G20210A mutation
A recent comprehensive study on recurrent pregnancy loss (RPL) utilized a panel including the following gene variants:
- Factor V G1691A
- Factor V H1299R (R2)
- Factor II Prothrombin G20210A
- Factor XIII V34L
- PAI-1 4G/5G
- HPA1 a/b (L33P)
- MTHFR C677T
- MTHFR A1298C
In recent years, inclusion of the angiotensin-converting enzyme (ACE I/D) polymorphism has also been recommended.
Nevertheless, there is still no consensus regarding which genetic panels have established clinical significance.
Evaluation of antithrombin, protein C, and protein S levels should also be part of the assessment.
Protein S levels must be interpreted differently during pregnancy.
According to Lockwood’s criteria:
- In non-pregnant women, Protein S <60% is considered low.
- In pregnant women, Protein S <35% is considered low.
If Protein S deficiency is detected, both free and total Protein S levels should be re-measured.
All thrombophilia testing should be performed when the patient is not experiencing an acute thrombotic episode and is not on anticoagulant therapy.
Recent studies have also suggested that Protein Z deficiency may contribute to pregnancy complications such as preterm birth.
Management During Pregnancy
For patients with Protein S deficiency, prophylactic anticoagulant therapy during pregnancy or postpartum warfarin for 4–6 weeks may be considered depending on clinical history.
If there is a history of active thrombosis, heparin therapy during pregnancy and warfarin prophylaxis postpartum are recommended.
Routine anticoagulant use in pregnancy is not indicated unless medically necessary. However, postpartum prophylaxis may be appropriate in women who undergo cesarean section or have a strong family history of thrombosis.
Recurrent Pregnancy Loss (RPL)
Recurrent pregnancy loss is defined as two or more consecutive miscarriages and affects approximately 1% of women of reproductive age.
According to ACOG guidelines, comprehensive evaluation should be performed after two consecutive pregnancy losses.
Possible Causes Include:
- Parental chromosomal abnormalities (e.g., balanced translocations)
- Recurrent embryonic aneuploidy
- Polycystic ovary syndrome (due to hyperandrogenism)
- Type 1 diabetes mellitus
- Uterine anomalies (particularly septate uterus)
- Infections such as Listeria, Toxoplasma, and certain viral agents
- Antiphospholipid antibody syndrome and autoimmune diseases
In 50–75% of cases, no clear cause can be identified.
Recommended Evaluations
The following investigations are advised in cases of recurrent pregnancy loss:
- Parental karyotype analysis
- Uterine cavity imaging
- Antiphospholipid antibodies (APA) and lupus anticoagulant (LA) testing
- Diabetes screening (HbA1c) and additional assessments if indicated
Treatment and Medication Use
A comprehensive 2008 study from India found that anticardiolipin, anti-annexin V, anti-β2 glycoprotein I antibodies, and lupus anticoagulant may be associated with unexplained recurrent pregnancy loss (URPL).
An important observation is that even without treatment, up to 70% of women with unexplained RPL may go on to have successful pregnancies, suggesting that some losses may not necessarily recur.
A 2005 Cochrane meta-analysis reported the following:
- In women without anticardiolipin antibodies, aspirin or heparin prophylaxis did not show clear efficacy in preventing miscarriage.
- Current clinical practice favors prophylactic heparin only in high-risk cases, such as those with venous thrombosis or antiphospholipid syndrome.
- Although small-scale studies have suggested potential benefits of heparin in reducing pregnancy complications, larger placebo-controlled trials are still needed.
In Summary
For women at risk of venous thromboembolism or with antiphospholipid antibody syndrome, heparin and/or aspirin therapy should be administered in accordance with established guidelines.
In cases of unexplained recurrent pregnancy loss, prophylactic use of aspirin or heparin should be based on individual risk assessment.
Before initiating therapy, a multidisciplinary approach involving hematology, perinatology, and obstetrics specialists is essential.
Ultimately, in pregnancies without documented thrombophilia or antibody positivity, a personalized approach and close monitoring—rather than routine pharmacologic intervention—represent the most appropriate strategy.
