Department of Obstetrics & Gynecology

Recurrent Pregnancy Loss

Study Title:

Prospective Randomized Controlled Trial of Low Molecular Weight Heparin in Women With Unexplained Fetal Thrombophilia

Study #: 13823
       
Description:

The cause of pregnancy loss is uncertain but may be related to the clotting of blood in your blood vessel (thrombophilia). This may be due to blood clots in the placenta (afterbirth – the source of food and oxygen for the baby) leading to decreased food and oxygen for the baby. Thus, the use of blood thinner (to prevent blood clots) may improve pregnancy results in women with thrombophilia and prior pregnancy problems. Also, some blood thinners may actually improve the growth of the placenta (afterbirth). However, blood thinners have some side effects and it is not clear whether or not they help the odds of having a healthy baby. The only way to tell if it is good for women like you to take blood thinners during pregnancy is to do a study.

There are several drugs that help to prevent blood clots from forming. Two very commonly used blood thinners are aspirin and a low-molecular weight heparin called Enoxiparin. There is recent information showing that both aspirin and Enoxiparin may improve pregnancy results in subsequent pregnancies in women with thrombophilia. Both of these medications are being used during pregnancy in the hopes of improving results. However, it is uncertain if they work, or if one is better than the other. The purpose of this study is to see which of the two drugs is better at improving pregnancy results.

Objective: 

The objective of this study is to determine whether low molecular weight heparin therapy can improve fetal outcome in women with previous unexplained fetal death(s) and testing positive for heritable thrombophilia.

Inclusion Criteria:

  1. Patients must have had at least one previous fetal death with no more than one live birth. Fetal deaths must be well documented by either: a) the passage of a conceptus measuring ( 30 mm in length, b) ultrasonographic documentation of a dead conceptus with measurements consistent with a fetus (( 10 weeks gestation), or c) loss of a conceptus after documented fetal cardiac activity at or beyond 10 weeks gestation.

  2. At least one fetal death should have occurred between 10 and 36 weeks gestation.

  3. The fetal death should be unexplained. At a minimum there should be documentation of a morphologically normal fetus with no clinical history of abruption. Ideally, patients should have negative testing for syphilis, parvovirus, indirect Coombs, Klihauer-Betke, toxicology screen, normal karyotype, and normal autopsy. However, subjects will not be excluded if such testing was not obtained.

  4. Negative testing for lupus anticoagulant and either negative or low-positive levels of IgG anticardiolipin antibodies. Low-positive levels of IgG or any titer of IgM anticardiolipin antibodies do not confer a greater risk for disorders associated with antiphospholipid antibodies than negative tests.26 Thus, such patients will not be considered to have antiphospholipid syndrome and will be eligible for the study.

  5. Positive testing for 1) factor V Leiden mutation or 2) prothrombin gene G20210A mutation or 3) protein S deficiency.

  6. Documentation of a live singleton intrauterine gestation with positive cardiac activity ( 12 weeks gestation.

Exclusion Criteria:
       

  1. Patients with any indication for anticoagulant therapy including previous thromboses, current thrombosis, major thrombophilia such as antithrombin II deficiency, homozygosity for the factor V Leiden mutation or prothrombin gene mutation, compound hetrozygosity for these mutations, or mechanical prosthetic valves.

  2. Gestational age greater than 12 weeks.

  3. Positive test for lupus anticoagulant or IgG anticardiolipin antibodies.

  4. More than one previous live birth.

  5. Contraindication to heparin or aspirin therapy, e.g. heparin induced thrombocytopenia or aspirin allergy.

Study Procedure:
       
Your expected time in this study will be from the time of study enrollment and randomization (at a gestational age less than 12 weeks) until delivery – approximately 28 weeks.

Sometimes, because we do not know which way of treating patients is best, we need to make comparisons. People will be put into two groups and then compared. A computer decides which people are in which groups and has no information about the individual – i.e. by chance. Patients in each group then have a different treatment and these are compared. You will be randomly assigned to receive either 1) low dose aspirin (81 mg daily), or 2) low dose aspirin (81 mg daily) and low-molecular weight heparin (7,500 unit, twice daily injections).

This study is a randomized study, which means that when you volunteer to go on the study, you will have a 50% chance of getting either the aspirin alone or the aspirin and low-molecular weight heparin. You will not know which drug you will be given until you have decided to join the study. You will only know this information once you have been entered into the study.

If you are randomized to the low-molecular weight heparin group, you will receive the low-molecular weight heparin and aspirin upon enrollment in the study. You will also be placed on calcium and Vitamin D supplementation and be encouraged to engage in axial skeleton weight bearing exercise (for example, walking for 20 minutes three times per week). This is because low-molecular weight heparin may cause slight thinning of the bones. You will be required to take 81 mg of aspirin to be swallowed on a daily basis and will receive one 7,500 unit injection of low-molecular weight heparin to be administered twice daily. You will have your blood drawn and your platelet (type of cell in the blood) count evaluated in a routine fashion through the first three weeks of therapy. This is because very rarely, low-molecular weight heparin can cause a low platelet count (decrease in blood cells that allow blood clots to form). Upon delivery, your placenta (after birth) will be evaluated for study purposes.

If you are randomized to receive aspirin alone, you will be given 81 mg of aspirin (baby aspirin) to be swallowed once a day. Upon delivery, your placenta (after-birth) will be evaluated for study purposes.

All study-related blood draws will occur at the same time as clinically indicated blood draws. An additional 3-4 teaspoonfuls of blood will be collected for study purposes. The samples we collect will be used in the following ways:

  • For the identification and/or evaluation of known thrombophilias that are passed from one generation to the next. Identifiable results associated with this evaluation will be shared with you.

  • For the creation of a sample bank for future evaluation and identification of unknown thrombophilias. Identifiable results will not be disclosed to you or anyone else. We will not be contacting you and/or your family members with any results.

Principal Investigator: Robert M. Silver, MD

Co-Investigators: Michael W. Varner, MD, D. Ware Branch, MD, Amy Sullivan, MD, T. Flint Porter, MD, Beth Plunkett, MD, MPH     

For further information, or to enroll in this study, please call:

Jess Dalton, Research Coordinator: (801) 585-9805