Thrombophilias, miscarriage and bloodthinners - a research review

If you have suffered one or more miscarriages, and are trying to figure out whether or not you may need blood thinners (heparin or lovenox) next time you get pregnant, here is some data to ponder (and share with your doctor):

[Treatment with enoxaparin (“Lovenox”) adapted to the fertility programs in women with recurrent abortion and
thrombophilia]
Sarto A, Rocha M, Geller M, Capmany C, Martinez M, Quintans C, Donaldson M, Pasqualini RS.

Acquired and inherited thrombophilia are associated with recurrent pregnancy loss (RPL). Antithrombotic therapy could restore hemostatic balance and improve early placentation and gestational outcome. We evaluated the efficacy of enoxaparin adapted to the fertility program for prevention of pregnancy loss in 35 women (W) with early RPL and thrombophilia. Previous to the diagnosis of thrombophilia, they had had a total of 105 gestations of which 89 (85%) ended in early pregnancy loss. After diagnosis of thrombophilia, 35 subsequent pregnancies were treated with enoxaparin. In 5 cases assisted reproductive techniques were necessary to achieve pregnancy due to couple infertility. In 17 W who had had at least one preclinical pregnancy loss, enoxaparin (20 mg/d/s.c.) was started previous to conception and adapted to the fertility program. All the women continued with the gestational regime. Eighteen W with only clinical pregnancy loss started enoxaparin (20 mg twice per day s.c.) after biochemical pregnancy diagnosis. During gestations heparin dose was adjusted with anti Xa test, maintaining a range between 0.3 at 0.6 u/ml. With antithrombotic therapy, 30/35 (85%) of the pregnancies ended in live birth versus 16/105 (15%) of the pregnancies without treatment (p < 0.001).

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American Journal Of Reproductive Immunology
Volume 49 Issue 2 Page 90 - February 2003

Successful Pregnancy with Low Molecular Weight Heparin in Two Women with Recurrent Miscarriage of Unknown Etiology

Yoshihiro Miyashita, Masako Waguri, Isao Nakanishi, Noriyuki Suehara, and Tomio Fujita

We report here two cases of recurrent miscarriages that were successfully treated with continuous intravenous administration of low molecular weight heparin (LMWH). One patient experienced 11 spontaneous abortions, and the other eight abortions. Previous treatments including prednisone, aspirin and mononuclear-cell immunization were all unsuccessful. They were negative for anticardiolipin antibodies and lupus anticoagulant, and had no inherited thrombophilic disorder. Intravenous administration of LMWH, 4800 units of dalteparin, was started as soon as the conception was confirmed, and was continued until 34 weeks of gestation. They were delivered of live born infants.

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Clin Appl Thromb Hemost. 2005 Jan;11(1):1-13.
Recurrent miscarriage syndrome and infertility due to blood coagulation protein/platelet defects: a review and update.

Bick RL, Hoppensteadt D.

University of Texas Southwestern Medical Center, Dallas, Texas 75231, USA. rbick@thrombosis.com

Three-hundred fifty-one women were referred for thrombosis and hemostasis evaluation after suffering recurrent miscarriages. All patients were referred by a high-risk obstetrician or reproductive medicine specialist after anatomic, hormonal or chromosomal defects had been ruled out. These patients were assessed over a three year period. The mean patient age at referral was 34 years and the mean number of miscarriages was 2.9 (2-9). All patients underwent a thorough evaluation for thrombophilia and, when indicated, a hemorrhagic disorder. Of the 351 patients, 29 (8%) had no defect. Of the remaining 322 patients, 7 (2%) had a bleeding disorder: 3 with platelet dysfunction, 1 with Factor XIII deficiency, 3 with von Willebrand's and 3 with Osler-Weber-Rendu. The remainder of the patients had a thrombophilia as follows: 195 (60%) had antiphospholipid syndrome, 64 (20%) had Sticky Platelet Syndrome, 38 (12%) had MTHFR mutation, 23 (7.1%) had PAI-1 polymorphism, 12 (3.7%) had Protein S deficiency, 12 (3.7%) had Factor V Leiden, 3 (1%), had AT deficiency, 3 (1%) had Heparin-Cofactor II deficiency, 3 (1%) had TPA deficiency, and 6 (2%) had Protein C deficiency. There were a total of 364 defects found in the 312 patients harboring thrombophilia; thus, several harbored two and a few harbored three separate defects. All patients with thrombophilia were treated with preconception ASA at 81 mg/day with the immediate post-conception addition of heparin or LMW heparin (Dalteparin). Both ASA and heparin/LMW heparin were used to term. The first 120 patients were treated with unfractionated heparin at 5,000 U every 24 hours, subcutaneously and the last 192 have been treated with Dalteparin at 5,000 U/day subcutaneously. The patients with MTHFR were also treated with folate at 5 mg/day + pyridoxine at 50 mg/day. All patients were carefully monitored with CBC and platelet counts, anti-Xa levels, frequent ultrasounds and physical exams. Only 2 of the thrombophilia patients suffered another miscarriage; all others had a normal term delivery. There were no pregnancy-related thromboses, no delivery complications and no episodes of post-partum thrombosis. The only bleeding consisted of 1-4 cm bruises at injection sites. No episodes of thrombocytopenia (HIT) were noted. In our experience, thrombophilia is a common cause of recurrent miscarriage and all patients with no anatomical, hormonal or chromosomal defect should be evaluated for thrombophilia or a bleeding disorder. The success rate of normal term delivery in these 312 patients was 94% using ASA + heparin or Dalteparin. In addition, side effects of therapy were minimal.

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Acta Obstet Gynecol Scand. 2000 Aug;79(8):655-9.
Birth outcomes in pregnant women treated with low-molecular-weight heparin.

Sorensen HT, Johnson SP, Larsen H, Pederson L, Nielsen GL, Moller M

The Danish Epidemiology Science Center at the Department of Medicine V, Aarhus University Hospital.

BACKGROUND: Pregnancy and puerperium are associated with an increased risk of venous thromboembolism. Low-molecular-weight heparin is the anticoagulant of choice in pregnant women because, unlike warfarin, it does not cross the placenta. However, there are limited data on the risk of adverse birth outcomes following use of low-molecular-weight heparin in pregnancy. PATIENTS AND METHODS: We performed a population-based cohort study to examine the safety of low-molecular-weight heparin use in pregnancy using data from the Pharmacoepidemiological Prescription Database, The Danish Medical Birth Registry and the Regional Hospital Discharge Registry in North Jutland County, Denmark. The birth outcomes in a cohort of 66 pregnant women treated with low-molecular-weight heparin between 1991-98 were compared with the birth outcomes of 17,259 pregnant women who did not receive any prescriptive drugs during pregnancy. RESULTS: No increased risk of malformations, low birth weight or stillbirth was found. However, an increased risk of pre-term delivery was found (odds ratio: 2.11, 95%, confidence interval: 0.96-4.65), which could reflect inherited thrombophilia as an indication of low-molecular-weight heparin. CONCLUSION: We have provided additional evidence of the safety of low-molecular-weight heparin use in pregnancy.

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Fertil Steril. 2005 Sep;84(3):770-3.
Effects of enoxaparin on late pregnancy complications and neonatal outcome in women with recurrent pregnancy loss and thrombophilia: results from the Live-Enox study.
Brenner B, Ellis M, Yarom I, Yohai D, Samueloff A, Live-Enox Investigators

Rambam Medical Center, Haifa, Israel. b_brenner@rambam.health.gov.il

Women with thrombophilia and a history of recurrent pregnancy loss have poor pregnancy outcomes. Prophylaxis with enoxaparin 40 mg/day or 80 mg/day resulted in favorable gestational and neonatal outcomes.

PMID: 16169422 [PubMed - in process]

All about Hughes Syndrome

An interesting article from the UK:

Hughes is a relatively new condition that is just beginning to become recognised by the wider medical community outside the specialised area of auto-immune diseases (in which the body's immune systems attacks itself). The professor first began to note the condition in the mid-Seventies when he was working in a rheumatology clinic in Jamaica. "I noticed there were a whole group of women, paralysed, and forced to use wheelchairs, with the same antibodies in their blood."

When he returned to the UK a few years later, he set up a working party to study the antibodies he had found. Very quickly, his unit had collected up hundreds of patients whose blood carried the antibodies and whose symptoms all resulted from clotting around major organs. "They weren't just suffering clots in their veins but also in their arteries which led to strokes and heart attacks."

Significantly, the clots were also found to have serious effects when they occurred at two particular organs: the placenta and the brain. In the former cases, this led to multiple and unexplained miscarriages. In the latter, they starved the brain of oxygen, leading to migraines, memory loss and what many patients simply described as 'fogginess'.

By 1983, Prof Hughes' team had gathered enough evidence for two papers to be published: one in the British Medical Journal and the other in the Lancet. For the team, this felt like a 'eureka' moment. "We were finally getting our message across. We all celebrated with a long lunch at the local Italian restaurant," says Hughes.

Gynecologists picked up the news fast; the respected royal gynaecologist Dr Anthony Kenny called it the major discovery in obstetrics in the 20th century, and it has revolutionised treatment of women with recurrent miscarriage. Where the antibodies are present, and blood thinners are given, to prevent clotting at the placenta, the rate of successful pregnancy soars from about 20 per cent to 80 per cent.

The MTHFR-Miscarriage debate

Does MTHFR in and of itself lead to a higher miscarriage risk? Or is it only when MTHFR actually manifests as higher homocysteine levels that it presents a risk? Here's a clear overview of the current debate on this topic in the medical community.

A MTHFR discussion forum

Lots of women discussing MTHFR and pregnancy issues right here.

Lisa Marie Presley opens up about miscarriages before twins

It sounds like she has some type of genetic thrombophilia. Presley says:

I really wanted these babies," says Presley, 40, who tried for two years to get pregnant before conceiving the twins.

"My blood was too thick and would clot, which caused several miscarriages," she tells PEOPLE. "The moment I took blood thinners, I got pregnant."

RESEARCH: MTHFR and other thrombophilic factors in recurrent pregnancy loss

I think that this study concludes that having several thrombophilic genetic markers (as opposed to just one) significantly impacts the risk for recurrent pregnancy loss.

However, I may not be interpreting the conclusion correctly. I welcome your thoughts on the meaning of this study in the comments below.

-Katie

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All about MTHFR

No, MTHFR (which I also have) is not a cussword. Find out more about this common, yet significant genetic thrombophilia condition.