Mary King, MD, and Peter S. Bernstein, MD, MPH


November 15, 2005


A 30-year-old G7P2042 transferred to my practice recently. Review of her records showed a history of 3 first-trimester losses, 1 ectopic pregnancy, and 2 term spontaneous vaginal deliveries. Because of the history of 3 spontaneous losses (which were not consecutive), she underwent a thrombophilia workup at her first prenatal visit. Her prior obstetrician noted a "protein S deficiency" and started her on daily baby acetylsalicylic acid (ASA). Please comment.

Response From Expert

Mary King, MD, and Peter S. Bernstein, MD, MPH 
Mary King, MD, fellow in Maternal-Fetal Medicine, Albert Einstein College of Medicine/Montefiore Medical Center, Bronx, New York                                                                                    

Peter S. Bernstein, MD, MPH, FACOG, Associate Professor of Clinical Obstetrics and Gynecology and Women's Health, Albert Einstein College of Medicine/Montefiore Medical Center, Bronx, New York; Medical Director of Obstetrics and Gynecology, Comprehensive Family Care Center, Montefiore Medical Center, Bronx, New York


Protein S plays a role in inhibition of the clotting cascade. Protein S and protein C inactivate factors VIIIa and Va, required cofactors for factors IXa and Xa. This is important because the most important natural inhibitor of clotting, the tissue factor pathway inhibitor, can be short-circuited by factor IXa; so inhibition of the clotting cascade requires inhibition of factors IXa and Xa. This is achieved with the complex of activated protein C and protein S. Sixty percent of protein S circulates in a protein bound form, and only the remaining 40% free form is biologically active. Certain conditions, such as pregnancy, inflammation, and surgical stress, lead to increased levels of the complement 4b-binding protein, which binds to protein S, and thereby decrease protein S activity.

In addition, pregnancy is a thrombogenic state because of other alterations in the coagulation pathway. There is a 20% to 200% increase in levels of fibrinogen and some clotting factors. At the same time, the tissue factor pathway inhibitor increases only minimally, whereas antithrombin and protein C levels remain constant. Also, the level of plasminogen activator inhibitor, the main inhibitor of fibrinolysis, increases 3-fold during pregnancy.

Protein S deficiency is an autosomal dominant mutation that confers a modest risk of thromboembolism -- 5% to 20% risk during pregnancy and the postpartum period. The risk of miscarriage does not seem to be increased with a deficiency of protein S or protein C. However, there may be an increased risk of fetal loss later in pregnancy, severe preeclampsia, abruptio placenta, and fetal growth restriction with protein C or S deficiency. There are no randomized prospective trials to show the efficacy of different anticoagulation regimens in affected patients, so the best recommendations are based on expert opinion.

All women with a history of thromboembolism who are planning pregnancy should be tested for inherited thrombophilias. In addition, women with a history of fetal loss, abruption, severe preeclampsia, and severe intrauterine growth restriction should also be tested. It is not yet clear whether patients with a history of recurrent early pregnancy losses at <10 weeks' gestation should be tested.

Testing should include assessment of functionally active protein C and S. However, protein S levels during pregnancy must be interpreted differently. Lockwood[1] recommends a cutoff of < 60% for protein S level in the nonpregnant patient and < 35% in the pregnant patient. If the protein S level is low, both free and total protein S levels should be tested to further define the type of deficiency. All thrombophilia testing should be done when the patient is off heparin or anticoagulants and remote from the time of thrombosis.

Patients with a protein S deficiency may be candidates for prophylactic anticoagulation during pregnancy and warfarin for 4 to 6 weeks postpartum, according to their history. If they have had thromboembolism or adverse pregnancy outcomes, they should be offered prophylaxis with heparin or warfarin postpartum. If they have no significant history, anticoagulation in pregnancy is not recommended; postpartum prophylaxis is recommended, however, if the patient has had a cesarean delivery or has an affected first-degree relative.[1]

Recurrent pregnancy loss is defined as 2 or more consecutive losses, most often occurring in the first trimester. This problem affects approximately 1% of reproductive-age women. According to the American College of Obstetricians and Gynecologists' practice bulletin, women with 2 consecutive pregnancy losses should be offered an evaluation.[2]

There are various causes of recurrent pregnancy loss that may involve genetic, anatomic, or medical problems. Parental genetic abnormalities, including balanced translocations, can cause recurrent pregnancy loss; in addition, recurrent aneuploidy despite normal parental chromosomes may be a factor. There is an association between polycystic ovarian syndrome and pregnancy loss, with higher levels of circulating androgens reported in women who miscarry. Type 1 diabetes is known to be associated with increased risk of miscarriage. Uterine anomalies, most commonly septate uterus, typically cause second-trimester loss. Infections with Listeria monocytogenes, Toxoplasma gondii, and some viruses are associated with sporadic pregnancy loss. In addition, autoimmune disorders and antiphospholipid antibodies can cause recurrent pregnancy loss.

In 50% to 75% of all couples with recurrent pregnancy loss, no cause is found. The recommended evaluation includes parental karyotypes, imaging of the uterine cavity, antiphospholipid antibody and lupus anticoagulant testing, as well as a careful medical history, possibly with the addition of a screen for diabetes such as a hemoglobin A1c test.[2] Of interest is that live birth rates of 70% have been reported in the subsequent pregnancy without treatment in couples with unexplained recurrent pregnancy loss.[3]

It is therefore debatable whether an evaluation for thrombophilias may have been indicated in the current case. It is not clear whether this patient meets the criteria for recurrent pregnancy loss. The interpretation of the lab results needs to be considered with the information that protein S decreases during pregnancy, and a protein S deficiency may only be able to be diagnosed during pregnancy when a value is obtained that is < 35% of the expected level. Whether to offer the patient prophylactic heparin in this clinical scenario is also controversial. A 2005 Cochrane group meta-analysis looked at anticoagulation for the prevention of recurrent pregnancy loss in patients without anticardiolipin antibodies and found that the available evidence is insufficient to recommend aspirin or heparin prophylaxis in this setting.[4]


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