Use of Fondaparinux During Pregnancy

I felt the comment below from a reader deserved a more thorough response than could be accommodated under the post upon which it was left and also might be of interest to other readers and providers who frequent this site. Anticoagulation during pregnancy has become more widely used to treat, both prophylactically and therapeutically, women who have had problems with thromboembolic complications, unexplained recurrent pregnancy loss, and those who have been identified as being ‘at risk’ because of acquired or genetic thrombophilias (e.g., antiphospholipid antibody syndrome; lupus anticoagulants; Factor V Leiden; MTHFR polymorphisms; prothrombin mutations,; antithrombin III deficiency; protein C and S deficiencies, etc.). The treatment of choice in recent years during pregnancy has been either unfractionated or low-molecular weight heparins. These are used because of their efficacy and relative safety for both mother and baby (they do not cross the placenta to the fetal circulation).

However, their use is not without risks. Prolonged use of heparins can lead to reduction in bone density (osteopenia and osteoporosis), cutaneous and systemic allergic reactions (accompanied in some cases by decreased efficacy), and heparin-induced thrombocytopenias that may place the patient at risk for hemorrhagic complications. When such complications arise, alternative medications such as fondaparinux (Arixtra) have been offered as alternative therapy. Although very few of us have a vast experience with the use of this drug in pregnancy and, currently, I am not aware of recommended regimens for the same, there is a growing need and a growing body of evidence to support that use when in indicated situations. Following our reader’s comment, I provide general information related to fondaparinux and, specifically, to its use during pregnancy….


jen27 has left a new comment on your post "Tales of Two Thrombophilias":

I am so happy to have found your blog! I have another take on thrombophilia and pregnancy. I am 39 years old, first time pregnancy and presented with bilateral PE (pulmonary emboli) at 8 weeks. Was placed on lovenox--allergic! Then placed on Heparin--allergic! I am now on Arixtra and I seem to be tolerating it well. My concern is with the delivery and also with a possible amniocentesis (of course, I am high-risk for Down's). This is a new drug and my OB is has never used it before. How do we plan for delivery? He is talking about inducing me around 37 weeks to have some control over bleeding. My hematologist has not used this drug with a pregnancy before and is not sure how we should proceed. Also, I am scheduled for a possible amniocentesis in two weeks and have started to worry about internal bleeding. Any advice would be most appreciated!


Fondaparinux is not a heparin substance. It is a synthetic pentasaccharide (5-sugar) compound that has been found to be a selective inhibitor of Factor Xa. In the blood-clotting system, Factor Xa functions at the common point at which both the intrinsic and extrinsic clotting cascades come together and, therefore, it is a highly efficient inhibitor of thrombin formation and, subsequently, fibrin formation (which is the foundation upon which blood clotting occurs). Fondaparinux actually binds, quite specifically, to antithrombin III (ATIII) which then facilitates the binding of ATIII to Factor Xa, inactivating it and interrupting the clotting cascade. Interestingly, once the ATIII-fondaparinux complex binds to Factor Xa, the fondaparinux is actually released intact and can then bind with another ATIII molecule to repeat the process.

Fondaparinux is administered by subcutaneous (not intramuscular) injection. It is rapidly absorbed and reaches peak serum concentrations about 2 hours after dosing. “It has a terminal half-life of 13 to 21 h, permitting once daily dosing” and a “linear pharmacokinetic profile which exhibits minimal intrasubject and intersubject variability, suggesting that individual dose adjustments will not be required for the vast majority of the population and there will be no need for routine hemostatic monitoring.” (Bauer, et al., Cardiovasc Drug Rev 2002;20:37-52). The drug also has minimal binding to plasma proteins usually involved in drug binding, therefore, the risk of complications related to drug interactions associated with displacement of drugs that do bind to these proteins is very low. The drug is cleared intact by the kidneys so dosing regimens in patients with renal compromise must be adjusted accordingly.

In studies performed both in vitro (Lagrange ,et al., Thromb Haemost 2002;87:831-5) and in vivo (Dempfle, N Engl J Med 2004;350:1914-5) there appears to be minimal transplacental passage of fondaparinux, placing the baby at low risk for hemorrhagic complications. Furthermore, studies performed in pregnant rats and rabbits at 32 times and 65 times, respectively, the recommended human dose have not shown impairment of fertility or a teratogenic effect on the fetus, resulting in the drug being classified as "class B." However, it should be recognized that pregnant women were excluded from all controlled clinical trials conducted with fondaparinux so there are to date no controlled trials during the first trimester of pregnancy.

Indeed, there are only a few case reports published in the scientific literature (Dempfle, N Engl J Med 2004;350:1914-5; Wijesiriwardana, et al., Blood Coagul Fibrinolysis 2006;17:147-9; Mazzolai, et al., Blood 2006;108:1569-70; Harenberg, Thromb Res 2007;119:385-8; Gerhardt, et al., Thromb Haemost 2007;97:496-7). Although the drug appeared safe and was well-tolerated with no untoward maternal or fetal effects in any of these reports, and none of the few patients described developed recurrent episodes of thromboembolic disease or allergic reaction, it is hard to generalize the safety and efficacy of the drug during pregnancy based on only a handful of patients. Safety of the drug in nursing women has also not been studied to date although, again, in lactating rats, only a small amount were found in breast milk.

With all that said and done, how should fondaparinux be used during pregnancy? None of the case reports agreed on a common regimen. In most of the clinical trials leading to its approval, fondaparinux has been employed only as a prophylactic agent in the perioperative period in ‘at risk’ patients or in the acute management of a thromboembolic condition while the patient was being transferred to warfarin over the course of 5 to 9 days. For both of these indications, fondaparinux has been found to be more efficacious than either heparin or low-molecular-weight heparin and to have comparable safety profiles. It has been found that fondaparinux is associated with hemorrhagic complications if given less than 6 hours after an operative procedure.

In the case reports, various approaches to therapy during pregnancy were described. As examples, Wijesiriwardana and colleagues (referenced above) described the case of a woman who had had deep venous thrombosis in a previous pregnancy who then developed an allergic reaction to low molecular weight heparin after three weeks of therapy during a subsequent pregnancy. She was placed on warfarin until 36 weeks’ gestation and then switched to fondaparinux 2.5 mg SQ daily. The latter was discontinued the day she began induction of labor and then restarted 6 hours after her uncomplicated vaginal delivery while she was transitioned back to a therapeutic level of warfarin. Neither she nor the baby had hemorrhagic complications related to this approach, nor did she develop recurrent thrombosis during the treatment period. In the report by Mazzolai and colleagues (also referenced above), a woman with protein S deficiency, who also had a history of deep venous thrombosis and developed allergies to both heparin and low-molecular weight heparin, was treated successfully, and without complications, for 150 days during pregnancy. Either approach seems very reasonable in the patient at high risk for thromboembolic complications and hypersensitivity to heparin compounds. Indeed, judging from the safety profile of fondaparinux to date, some thought may have to be given to its use as a first-line agent under these circumstances at some point in the future.

I realize that I have been long-winded, so in fairness to our reader, I should try to answer her questions! It would be helpful, however, if I had some more information, specifically, related to her medical history and identified risk factors for her bilateral pulmonary emboli in early pregnancy. Regardless, I would offer the following suggestions: 1) Consider maternal serum screening and a ‘targeted ultrasound’ to reevaluate your risk for Down syndrome and trisomy 18 before proceeding with an amniocentesis based on your ‘age alone’ risk; 2) If you do decide to proceed with the amniocentesis, stop the fondaparinux take your last dose 24 hours before the procedure and then resume dosing 6-8 hours afterwards; 3) Unless you have or develop other risk factors, elective delivery before 39 weeks is probably not indicated (unless you have another amniocentesis to document fetal lung maturity first); 4) Since anticoagulation therapy places you at increased risk for complications related to spinal and epidural anesthesia, and the effects of fondaparinux cannot be readily ‘reversed’ in a short period of time, consider third trimester consultation with an anesthesiologist who can suggest a plan of management in the peripartum period; 5) If an induction is planned, discontinue the drug the day before and resume 6-8 hours following delivery; 6) Consider leg compression boots throughout the time you are not taking fondaparinux before, during, and after delivery to minimize your risks for deep venous thrombosis; 7) Convert to warfarin after delivery while being covered with fondaparinux until a therapeutic INR level is reached.

Thanks for a great comment Jen and best wishes for the rest of the pregnancy! Please let us know how things turn out.
Dr T

Labels: fondaparinux, heparin, lovenox, thromboembolic complications and pregnancy, thrombophilias

Permalink | 6 Comments| Email Post

Post your comment

When to Start Anticoagulation Therapy for Recurrent Early Pregnancy Loss

For many years now, we have placed women with recurrent early pregnancy loss on low-dose aspirin (81 mg) and heparin, or low molecular-weight heparin such as lovenox, to help them improve their prospects for pregnancy outcome. In some instances this regimen is used because an acquired (e.g., lupus anticoagulant; antiphospholipid antibodies) or genetic (e.g., Factor V Leiden; MTHFR polymorphism; protein C, protein S, and antithrombin III deficiencies; prothrombin G20210 mutations, etc.) ‘thrombophilia’ (tendency to form or maintain blood clots) has been identified. In other instances it is used simply as ‘empiric therapy’ because no particular reason has been identified and, quite frankly, we know that we do NOT have all the answers, because patients request that “anything be done that can be,” and because on the whole it is a fairly safe regimen, although it can be somewhat expensive.

Under these circumstances and, particularly, when used as ‘empiric therapy’, even when a successful pregnancy results, we cannot be entirely sure if our treatment was the deciding factor or it if was simply the result of chance. The original thinking was that somehow the anticoagulation properties of these agents prevented abnormal clotting of the placenta that was preventing the early pregnancy from developing normally. In recent years, we have discovered that other factors may be equally, if not more, important in early growth and development of the placenta as I allude to in my response to our reader’s questions below…

• At Sat Jan 19, 02:46:00 PM 2008, ONE OUT OF SIX said…

Dr. T - what are your thoughts on starting lovenox prior to implantation - either right before, or right after ovulation? And is your opinion the same in regard to a natural cycle as opposed to an ovulation induction cycle in which ovulation is then triggered with HCG? Also - does the patient already being on a daily baby aspirin have an impact one way or the other?

It has been suggested to me that being on both baby aspirin and lovenox (40mg/once a day) could actually inhibit implantation by causing a bleed at implantation site.

Others have said this is not the case at all - and in fact the opposite is true - healthier blood flow to uterus will assist with implantation (that may have been prevented in the past by diagnosed clotting disorders - homo MTHFR C677T and hetero Factor V.)

Last question - can you move to Pittsburgh, PA so I can become a patient? ;-)
Thanks for your insight.

• At Fri Jan 25, 10:53:00 AM 2008, Kenneth F. Trofatter, Jr., MD, PhD said…

To One out of Six: Flattery will get you an answer EVERY TIME! Personally, I rarely will start lovenox or heparin before midway through the luteal phase after spontaneous ovulation or ovulation induction (about day 20-21) unless you have documented antiphospholipid syndrome or another condition that requires chronic anticoagulation. The reasons for that are it may increase bleeding from the ovarian ovulatory site (and, personally, I have taken two young women, who were not even on lovenox or aspirin, to the operating room in the past month with bellies full of blood from that very thing) and I sincerely doubt it does much good until the embryo has reached the uterine cavity and attachment has actually taken place. With all that said and done, on prophylactic doses of lovenox such as you are taking, it probably would not hurt or put you at much risk.

With regard to recurrent early pregnancy loss, however, the anticoagulation properties of lovenox and aspirin may be LESS important than their roles in improving trophoblast invasion and migration! This may be especially true under those circumstances in which 'thrombophilic antibodies' such as lupus anticoagulants, antiphospholipid antibodies, and anti-β2-glycoprotein-1 antibodies are present. These antibodies can bind to the trophoblasts in association with β2-glycoprotein-1 and impair both trophoblast invasion and migration that are necessary for early pregnancy success. Interestingly, heparin and lovenox can reverse the effects of these antibodies by blocking their binding to β2-glycoprotein-1. Anyway, I will put your question and my answer into a brief post on this subject soon (and perhaps a larger series later on) so, thanks for reading, for the excellent questions, and best of luck!

Dr T

Labels: heparin, lovenox, recurrent pregnancy loss, thrombophilias

Permalink | 21 Comments| Email Post

Post your comment

Plasminogen Activator Inhibitor 1 (PAI 1) and Recurrent Pregnancy Loss

Back in June, a reader I.R. left a comment on my post "Recurrent Early Pregnancy Loss - 7 - Immunologic a...". Her specific question related to the possible role of plasminogen activator inhibitor 1 (PAI 1) activity and polymorphisms in recurrent pregnancy loss. The question interested me so much at the time, that rather than answering it in cursory fashion, I promised her I would review the current literature and devote a full post to the issue “in the near future.” Despite my having been, repeatedly, sidetracked, I.R. has remained a loyal reader, and insightful patient, and updated me regularly on her progress. Today, in the paragraphs below, I am going to summarize (and modify for clarity) her story with excerpts from her comments and then summarize my thoughts on the issues she has raised in a follow-up post ….

Dr. Trofatter, I have been diagnosed with Recurrent Pregnancy Loss. I've lost three early pregnancies- 6 weeks, 7 weeks, and 4 1/2 weeks- over the last year. After the third loss, my husband and I went through testing in March 2007 and it's been determined that I have a PAI 1 (4G4G) genetic mutation… I am a healthy 26 year old. I have found a wonderful hematologist that goes above and beyond for me. However, I'd like to know your perspective of how PAI 1 correlates with early first trimester miscarriages… I am having a difficult time finding much information on PAI 1 and miscarriages. It seems that most blood clotting disorders cause second trimester miscarriages; however, I feel that scientists and doctors are still building correlations between clotting and early first trimester losses. Thanks for any advice! I.R.

In August, this was followed by another comment on my post "Diabetes in Pregnancy - 2 - Glucose Metabolism and...":

Dr. Trofatter, I have yet another question. My last miscarriage was in February. I have been trying to get pregnant all summer…using ovulation sticks. Does PAI 1 have anything to do with me not being able to conceive? I've mentioned to two of my doctors the connection of PCOS (polycystic ovary syndrome) and PAI 1 and they all agree that I do not fit any of the typical picture of PCOS; however, after asking for a glucose/insulin test, I am now scheduled to get one. Do you think this is a good step? I know that PAI 1 has something to do with insulin which has to do with the endocrine system which can affect ovulation. I've never had issues in the past getting pregnant, just maintaining my pregnancies. I do not have diabetes. Any advice would be greatly appreciated! No matter how much I try to research PAI 1 and recurrent pregnancy loss, I can’t seem to understand it. Thanks so much for your time! I.R.

A few weeks later, I.R. left another comment on the same post…"Diabetes in Pregnancy - 2 - Glucose Metabolism and..." (sometime I have really got to finish up that series too!)…

Hi Dr. Trofatter, Low and behold, after a few months of asking for an insulin/glucose test, my wish was granted last week. I received my results yesterday and both fasting tests were normal and my two hour glucose was normal as well; however, my two hour insulin levels were elevated which is evidence of insulin resistance…I have mentioned the correlation of PAI 1 and insulin to my doctors a couple of times before but was essentially dismissed because I don't fit the "criteria" of a person who has insulin resistance. I'm not overweight at all and I'm not inactive…I start glucophage with hopes of increasing the quality of my ovulation. I do ovulate "regularly" on CD 15. What are your thoughts of taking glucophage (Metformin) while pregnant?...I know that it is controversial either way. I would appreciate any insight about the connection of PAI 1 and early trimester pregnancy loss as well as its connection to insulin.
Hope you're doing well! IR

I actually did respond briefly to this query and my comment included the following thoughts: There indeed appears to be a need to increase insulin sensitivity in first trimester to aid in proper implantation and placentation...I bet you will be home free from the baby's standpoint if you can get past twelve weeks...You will still be at increased risk for gestational diabetes...While you're at it, why don't you throw the progesterone support, baby aspirin, extra folic acid, and heparin or Lovenox into the mix as well...The latter I would not begin until a pregnancy is confirmed chemically (just about the time you miss a period)... Hang in there girl. I wish you the best on this and think you are going to be a great MOM! Dr T

Then, within two weeks of the above, the following comment was received from I.R.…

Hi Dr. Trofatter, I am on calendar day (CD) 31 and had a positive pregnancy test on CD 27. :) I started Lovenox and am continuing low dose aspirin, my prenatal vitamin and because of the insulin resistance diagnosis, I began glucophage on CD 23. I talked with my nurse today about a calcium supplement and also mentioned the glucophage. She talked with my doctor and she said that he wants me to stop taking glucophage. According to him, since I never made it to the maintenance dose (the 3 pills each day), then it isn't doing anything to help me. I've read elsewhere though that it can help prevent MC. She said that they only wanted me on it to regulate my ovulatory pattern, which does make sense to me, even though I do ovulate regularly just at a later day than 14. My question/concern is that my doctor isn't giving any thought to his decision of stopping glucophage and my diagnosis with PAI 1. This is such a big deal to me…I want to call again tomorrow, but would like a second opinion about my feelings as to whether they're rational or not! I really do like my RE (reproductive endocrinologist) and know that he's performed miracles for many women… Thoughts??!! Thanks again for your insight and time! It means so much! I.R.

To summarize I.R.’s many questions and to throw in a few of my own…
1) What is PAI 1 and what are its roles?
2) What is the association between PAI 1 activity and recurrent pregnancy loss?
3) Should screening for PAI 1 be a part of our regular evaluation of the couple with recurrent pregnancy loss?
4) What is the association between PAI 1 activity and insulin resistance?
5) Could PAI 1 activity be associated with infertility?
6) What role might glucophage play in the management of women with recurrent pregnancy loss and abnormalities of PAI 1 activity?
7) If glucophage is used in women with ‘insulin resistance’, is there a benefit to continuing it during pregnancy or should it be stopped, and when?
8) In the absence of clinical indication other than recurrent pregnancy loss, should the other medications (Lovenox and aspirin) be continued or stopped and when?

Actually, if I had all the answers to the above questions (and I am sure I will come up with a few more as I try to answer these), I would probably be quite famous, but in our next post on this subject, I will at least give you my thoughts! And, to I.R., thanks for your loyalty and your patience and best of luck with this pregnancy!

Labels: diabetes; insulin resistance, glucophage, lovenox, PAI 1, PCOS, plasminogen activator inhibitor 1, recurrent pregnancy loss, thrombophilias

Permalink | 22 Comments| Email Post

Post your comment