Ask the Experts Archive

Unfortunately, good longitudinal studies that would answer the risk for placental mediated pregnancy complications with the lower frequency hereditary thrombophilias (e.g. antithrombin deficiency, protein C deficiency, protein S deficiency) and previously unaffected women with antiphospholipid antibodies are lacking. However, case control studies have not shown an association between the lower risk hereditary thrombophilias and placental mediated pregnancy complications; therefore, one would expect the risk to be similar to that in women without thrombophilias.

 

Dr. Marc Rodger and colleagues published a systematic review of prospective cohort studies examining the association between the more common hereditary thrombophilias (factor V Leiden mutation and prothrombin gene mutation) and placental mediated pregnancy complications. I've attached a pdf. For women with the factor V Leiden mutation, the risk of fectal loss was 4.2% (3.2% if unaffected), pre-eclampsia was 3.8% (3.2% if unaffected), small for gestational age was 6.5% (7.4% if unaffected) and abruption was 1.3% (0.9% if unaffected). The composite of placental mediated pregnancy complications was 16.5% if factor V Leiden positive and 15.8% if negative. Only the difference for pregnancy loss was statistically significant - however, the absolute difference is not clinically significant. For the prothrombin gene mutation, the risk was 4.7% for fetal loss (3.6% if unaffected), 3.5% for pre-eclampsia (3.0% if unaffected), 5.4% for small for gestational age (5.7% if unaffected), and 1.5% for abruption (1.0%) if unaffected. The risk for the composite of placental mediated pregnancy complications was 20.3% for women with the mutation and 16.1% for those without. None of these differences were statistically significant. 

 

Dr. Shannon Bates, MDCM, MSc, FRCP(C) 

 

The benefit and role of antithrombotic therapy in the prevention of placental mediated pregnancy complications in women with thrombophilia remains controversial.

First, as outlined above, the evidence of an association/causal role for hereditary thrombophilia in these disorders is not strong. Secondly, trial results have been mixed. One study (Gris et l. Blood 2004) suggested that recurrent late loss in women with the factor V Leiden, prothrombin gene mutation, or protein S deficiency could be reduced by about 60% with LMWH prophylaxis compared with aspirin (frequency of life birth 86% vs 29%). However, this study has some important limitations and over the years less importance has been placed on the results. A subgroup analysis of the ALIFE Trial (Kandoorp et al. N Engl J Med 2010 showed no benefit to the use of LMWH + aspirin or aspirin in women with recurrent pregnancy losses and thrombophilia. So, at this juncture, there is no general recommendation for the use of LMWH in this setting.

The role of LMWH prophylaxis (added to aspirin) for prevention of other placental mediated pregnancy complications in women with hereditary thrombophilia remains controversial as well, with some studies showing no benefit and some showing a 10% relative risk reduction. Again, there is no consensus on the use of LMWH here.

Studies in women with antiphospholipid antibodies and a history of recurrent pregnancy losses appear to benefit from the combination of aspirin and prophylactic heparin or LMWH, although the degree of benefit varies between studies (from no benefit to a reduction in the risk of subsequent loss from 60% to 20%). 

Dr. Shannon Bates, MDCM, MSc, FRCP(C) 

 

It sounds like she has tried quite a few hormones (doses unspecified).  With a Mirena, irregular bleeding is expected with gradual reduction in bleeding over time. Another option is Depo Lupron to shut her down centrally; however she may continue to have at least one flare bleed until things down regulate.    

If she does not respond to these approaches, she may need VWF concentrate infusion, particularly if her VWD is more severe.

Jennifer E. Dietrich MD, MSc, FACOG

Associate Professor

Department of Obstetrics and Gynecology and Department of Pediatrics

Baylor College of Medicine

Chief of Pediatric and Adolescent Gynecology Texas Children's Hospital

Division Head Pediatric and Adolescent Gynecology

CME Director Department of Obstetrics and Gynecology

 

Barbara A. Konkle, MD

Director, Clinical and Translational Research, Puget Sound Blood Center

Medical Director, Hemostasis Reference Laboratory, Puget Sound Blood Center

Professor of Medicine/Hematology, University of Washington

 

Dear Dr. Krupp:

Thank-you for your question.

I'm not sure why this patient was tested for an underlying thrombophilia
after a single early pregnancy loss. This would not have been my practice.
Although these events are very sad; they are very common and do not necessarily
indicate any underlying pathology. Most affected women go on to have a
subsequent normal pregnancy without any intervention.

The data regarding the role of hereditary thrombophilia in pregnancy
loss (even recurrent or late loss) is by no means definitive. This is very much
the case with respect to the two thrombophilias you mention. Available data are
inconsistent. Even when positive associations have been reported, they are weak
- e.g. odds ratios of less than two in case control studies. Case control
studies almost always exaggerate the strength of association so that when
methodologically stronger cohort studies are conducted, the association
invariably becomes weaker or even disappears. The available data have not
convinced me that that either of the MTHFR or the prothrombin gene mutation is
associated with an increased risk of pregnancy loss.

There are no good studies demonstrating benefit to intervention with
LMWH in women with a single early loss, regardless of the presence of absence
of thrombophilia.

As you have mentioned, homozygosity for the MTHFR mutation is not
considered thrombophilic (in the absence of elevated homocysteine levels). We
no longer offer routine testing for this thrombophilia at our centre.

In the absence of a personal or family history of VTE, there is no role
for either antepartum or postpartum prophylaxis in asymptomatic women with
thrombophilias other than those considered high risk (e.g. homozzygosity for
factor V Leiden).  I would not consider this patient's thrombophilia to be
high risk.

Therefore, unless I have missed something, I do not see any role for
antepartum or postpartum LMWH in this setting.  This patient should ensure
that she is taking appropriate folate supplementation during any subsequent
pregnancy. As for any pregnant woman, she should be vigilant for signs and
symptoms of venous thromboembolism and seek medical attention urgently should
they occur. Her need for thrombosis prophylaxis should be re-evaluated if
intervening risk factors develop.

I hope that is of some help,

Best regards,

Shannon

Shannon M. Bates MDCM, MSc, FRCP(C)

Associate Professor, Department of Medicine

McMaster University

Director, Division of Hematology & Thromboembolism 

Discipline Director for Hematology in Laboratory Medicine

Telephone: 905 521-2100, ext. 73928

Fax: 905 521-4997

E-mail: batesm@mcmaster.ca

In a woman with ITP who has not had a history of blood clots, we have no objections to birth control pills.  We also have no objections to the levonorgestrel (progestin) IUD which REDUCES menstrual blood flow from the uterus, although it does not prevent ovulation, and ovarian cysts can still form.  We DO object to the copper IUD, which increases menstrual blood.  Most women do not see an effect on their counts and benefit from having their menstrual bleeding controlled when they are not trying to become pregnant.

Andra James, MD, MPH
Director/Founder of the Women's Hemostasis and Thrombosis Clinic
Duke University Medical Center
Professor of Obstetrics & Gynecology
Duke University School of Medicine
Durham, NC

 

 

We'd like her on low-dose ASA during pregnancy, the intrapartum period and for 6 weeks PP. If she has no other risk factors for thrombosis, I would reserve LMWH for the postpartum period only (i.e., enoxparin 40 mg qd for the first 3 weeks postpartum. We'd recommend fetal surveillance (detailed ultrasound in the second trimester, monthly ultrasounds in the third trimester, at least weekly testing in the last two months of pregnancy and delivery at 39 weeks). Although these women have an increased chance of poor pregnancy outcome, there is a good chance things will turn out well.

 

 

Andra James, MD, MPH
Director/Founder of the Women's Hemostasis and Thrombosis Clinic
Duke University Medical Center
Professor of Obstetrics & Gynecology
Duke University School of Medicine
Durham, NC

 

 

In general combined oral contraceptives increase risk of thrombosis in susceptible women. Medroxyprogesterone acetate (DMPA) has also been shown to increase risk of thrombosis about 2-fold (so similarly). We usually recommend levonorgestrel releasing IUD or copper IUD for patient where we are concerned about thrombosis risk. The other alternative for an oral agent is the mini pill, but some women don't tolerate side effects. If the patient chooses barrier methods, be sure she uses two things (e.g., condoms and spermicide).

Mary Cushman, M.D., M.Sc.
Professor of Medicine, Hematology/Oncology Division
Department of Medicine
Professor of Pathology
University of Vermont

The baby is, as you say, at 50/50 risk for VWD, but not severe - only mild or mod.  The OB should avoid operative vaginal delivery and scalp electrode. (No one does scalp sampling any more) If the patient is in the third stage of labor and at a point of "no return" with fetal distress, the OB should choose forceps over vacuum, otherwise have a low threshold for C/S.  Otherwise, C/S should be used for obstetric reasons only.

The OB should get two tubes of cord blood, light blue topped, so that studies can be run on the infant.  Is it a girl or boy?  If a boy, circumcision should be postponed until we know his status with respect to VWF/FVIII.

Andra James, MD, MPH
Director/Founder of the Women's Hemostasis and Thrombosis Clinic
Duke University Medical Center
Professor of Obstetrics & Gynecology
Duke University School of Medicine
Durham, NC

 

 

The four new oral agents for long-term anticoagulation, the direct thrombin inhibitor dabigatran and the factor Xa inhibitors rivaroxaban, apixaban, and edoxaban have not been studied in pregnancy. Two of the four have been approved by the United States Food and Drug Administration (FDA) - dabigatran for the treatment of atrial fibrillation and rivoroxaban for VTE prophylaxis after orthopedic surgery.  There are no published data on edoxaban.  For apixaban, unpublished animal studies do not yet indicate direct or indirect harmful effects.[1]  Rivaroxaban reportedly crosses the placenta in animals.[2]  For both rivaroxaban and dabigatran, while there were no structural malformations in rats or rabbits, post-implantation losses were noted in rats.[2, 3]  The therapeutic formulation of dabigatran, however, is polar, and prevents it from crossing membranes.  The drug has not been found to cross the placenta in the mouse, rat or rabbit (from drug development research). Therefore, while dabigatran does not necessarily need to be stopped prior to conception, there are, nonetheless, insufficient data to justify continuing its use during pregnancy.  Even in a non-continuing pregnancy, the lack of a reversing agent for these anticoagulants would preclude their use.

With respect to the four new oral agents for long-term anticoagulation, a high milk to plasma ratio in rats suggests active transport of apixaban into breast milk.[4]   There are no data about the presence of edoxaban,  rivaroxaban or dabigatran in breast milk. 

1. ELiquis: summary of product characteristics.  2011  [cited 2011 November 18, 2011]; Available from: http://www.eliquis.com/PDF/ELIQUIS®SmPC.pdf.

2. Prescribing information for Xarelto (rivaroxaban) tablets for oral use.  2011  [cited 2011 November 18, 2011]; Available from: http://www.xareltohcp.com/sites/default/files/pdf/xarelto_0.pdf#zoom=100.

3. Pradaxa prescribing information.  2011  [cited 2011 November 18, 2011]; Available from: http://bidocs.boehringer-ingelheim.com/BIWebAccess/ViewServlet.ser?docBase=renetnt&folderPath=/Prescribing%20Information/PIs/Pradaxa/Pradaxa.pdf.

4. Wang, L., et al., Tissue distribution and elimination of [14C]apixaban in rats. Drug Metab Dispos, 2011. 39(2): p. 256-64.

Andra James, MD, MPH
Director/Founder of the Women's Hemostasis and Thrombosis Clinic
Duke University Medical Center
Associate Professor of Obstetrics & Gynecology
Duke University School of Medicine
Durham, NC

 

 

At our institution, we fully anticoagulate a patient who gets a clot in pregnancy throughout pregnancy and for at least 3 months PP, usually 6 months PP. We know from studies of clot incidence that there is still signal related to the increased incidence surrounding pregnancy as far out as 3 months. We do not image them until we are making a decision to stop anticoagulation and that is usually 6 months PP. I say "we," but at that time it is our Heme/Coag team who is making the decision. They will also check a d-dimer and assess other risk factors when deciding whether to stop or continue. In Europe, our heme/epi colleagues are concerned about the high rate of recurrence among their patients who receive low dose anticoag for a history of clot, let alone for a clot during that pregnancy. I just been asked to participate on a steering committee for an international randomized trial of low vs full dose anticoag for women with a history of clot. My impression is that the risk of recurrent clot is MUCH higher among women who have had a clot during that pregnancy. I am just not comfortable reducing a woman's anticoag to a low dose when she has had a clot during pregnancy, especially when all the risk factors that gave her a clot in the first place are still present. Then, PP, her risk increases another 5- to 20-fold higher than it was during pregnancy.

Andra James, MD, MPH
Founder of the Women's Hemostasis and Thrombosis Clinic
Duke University Medical Center
Associate Professor of Obstetrics & Gynecology
Duke University School of Medicine
Durham, NC

It is unlikely that there was any risk to the fetus from the CVT. In all probability this patient has an underlying hypercoagulable disorder that predisposed her to DVT, PE, CVT as well as the fetal demise.

 

Would like to think that women could be encouraged to persevere during the first few weeks/months with the levonorgestrel-releasing IUD when a pre-eisting thickened endometrium may be shedding.  If women/girls continue to have irregular bleeding with a levonorgestrel-releasing IUD, we can cycle them with low-dose estrogen or a low-dose birth control pill (BCP), such as norethindrone/ethinyl estradiol, with only 3 days off of hormone. 

Before starting aminocaproic acid, we would suggest starting the new oral tranexamic preparation, which we believe is better tolerated than aminocaproic acid.  This can be used with levonorgestrel-releasing IUD in place or in lieu of levonorgestrel-releasing IUD.

I hope this helps.

Andra James, MD, MPH
Director/Founder of the Women's Hemostasis and Thrombosis Clinic
Duke University Medical Center
Associate Professor of Obstetrics & Gynecology
Duke University School of Medicine
Durham, NC

 

 

Dear Carolyn,
Concerning your question to us on the FWGBD Ask-the-Experts Web page:

In our evaluation, we would want to know how old this young woman is, how severely affected she is with VWD and how far from menarche she is.  

We would be interested to know the hormonal treatments that have been attempted and the extent to which a gynecologist has been involved.

We do know she has failed hormonal treatments, including the levonorgestrel IUD, and you are trying desmopressin.

We would be interested to know her thyroid function, her current hemoglobin and a current assessment of her iron stores. 

With 8 periods in 2 months, she is having irregular bleeding, not just heavy bleeding and we would not expect that her bleeding is going to respond to hemostatic therapy alone; it will likely require the joint efforts of the hematologist and the gynecologist.  She will need cycle control and hemostasis.

It is not clear that all potentially tolerable hormonal manipulations have been tried, such as monthly short courses of progestin to induce withdrawal bleeding.  This may give her cycle control, especially when used in conjunction with desmopressin or antifibrinolytic. 

Concerning tranexamic acid, there are no clinical trials in adolescents.  As far as the dosing, if she is adult weight/size, then we would expect the same dose as that for an adult woman.

In a young woman with VWD, when cycle control is achieved, and antifibrinolytics and desmopressin have failed, we have no reservations about using VWF concentrates to achieve hemostasis.

Andra James, MD, MPH
Founder of the Women's Hemostasis and Thrombosis Clinic
Duke University Medical Center
Associate Professor of Obstetrics & Gynecology
Duke University School of Medicine
Durham, NC