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Infertility and spontaneous abortion  - Spontaneous abortion, habitual abortion - Miscarriage : Guidelines, reviews

Treatment of antiphospholipid syndrome in pregnancy

Royal College of Obstetricians and Gynaecologists. The investigation and treatment of recurrent miscarriage [Internet]. Guideline No 17. London: RCOG Press; 2003 May [cited 2009 Feb 8]. 13 p. Available from: http://www.rcog.org.uk/womens-health/clinical-guidance/investigation-and-treatment-couples-recurrent-miscarriage-green-top-

  • To diagnose antiphospholipid syndrome (APS) it is mandatory that the patient should have two positive tests at least six weeks apart for either lupus anticoagulant or anticardiolipin (aCL) antibodies of IgG and/or IgM class present in medium or high titre. (C)
  • Currently there is no reliable evidence to show that steroids improve the live birth rate of women with recurrent miscarriage associated with aPL when compared with other treatment modalities; their use may provoke significant maternal and fetal morbidity. (A)
  • In women with a history of recurrent miscarriage and antiphospholipid antibodies (aPL), future live birth rate is significantly improved when a combination therapy of aspirin plus heparin is prescribed. (A)
    • A randomised controlled trial showed that the live birth rate of women with recurrent miscarriage associated with aPL treated with low-dose aspirin only is 40% and this is significantly improved to 70% when they are treated with low-dose aspirin in combination with low-dose heparin.
    • A meta-analysis of two controlled trials concluded that, in women with a history of recurrent miscarriage associated with aPL, treatment with low-dose heparin plus low-dose aspirin significantly reduced the pregnancy losses by 54% when compared with aspirin alone. However, these trials do not exclude the possibility of placebo effect from heparin treatment.
    • The same meta-analysis examined the role of aspirin alone compared with placebo or supportive care and found no significant benefit (three trials).
    • A recent randomised controlled trial reported a high success rate with aspirin alone and no significant benefit in live birth rate with the addition of heparin. However, this study included women with low titres of aPL, some of whom were randomised at up to 12 weeks of gestation, by which time most of aPL-related pregnancy losses would have already occurred.
  • Pregnancies associated with aPL treated with aspirin and heparin remain at high risk of complications during all three trimesters. (B)

Grades of recommendations

A Requires at least one randomised controlled trial as part of a body of literature of overall good quality and consistency addressing the specific recommendation.
B Requires the availability of well controlled clinical studies but no randomised clinical trials on the topic of recommendations.
C Requires evidence obtained from expert committee reports or opinions and/or clinical experiences of respected authorities. Indicates an absence of directly applicable clinical studies of good quality.

Guidelines for the investigation and management of antiphospholipid syndrome. British Society for Haematology, 2000

Aspirin, 75 mg/d, should be commenced as soon as the urine pregnancy test becomes positive.
Low-dose heparin, by self-administered subcutaneous injection, should be commenced when fetal heart activity is seen on ultrasonography: unfractionated heparin (5000 IU) twice daily subcutaneously or low molecular weight heparin in once-daily subcutaneous doses.
The ideal duration of heparin therapy has not been determined, but should not be unnecessarily extended because of the potential risk of heparin-induced osteopenia. Discontinuation at 34 weeks gestation is a reasonable compromise in women with no history of thrombosis in whom early pregnancy loss has been a feature. When late pregnancy complications have occurred previously, continuation of antithrombotic therapy to delivery is reasonable and postpartum thromboprophylaxis will usually also be indicated in those women with a history of thrombosis. Delivery by Caesarean section carries an additional thrombotic risk and perioperative thromboprophylaxis is indicated.
After commencement of heparin, the platelet count should be monitored. A weekly platelet count for the first 3 weeks and every 4-6 weeks thereafter is generally practicable. Regular obstetric assessment, including Doppler ultrasound fetal scanning, allows early detection of complications.

Ensom MH, Stephenson MD. Pharmacokinetics of low molecular weight heparin and unfractionated heparin in pregnancy. J Soc Gynecol Investig. 2004 Sep;11(6):377-83

In APS, our original dosing protocol of dalteparin yielded significant differences (P <.05) in drug exposure throughout pregnancy. Based on these results, we recommend a prophylactic dalteparin dosing regimen of 2500 U every 24 hours pre-pregnancy (and for 6 weeks postpartum), and 5000 U every 24 hours during the first, second, and third trimesters.

Stephenson MD, Ballem PJ, Tsang P, Purkiss S, Ensworth S, Houlihan E, Ensom MH. Treatment of antiphospholipid antibody syndrome (APS) in pregnancy: a randomized pilot trial comparing low molecular weight heparin to unfractionated heparin. J Obstet Gynaecol Can. 2004 Aug;26(8):729-34

OBJECTIVE: To compare low molecular weight heparin (LMWH), specifically dalteparin, to unfractionated heparin (UFH) for the treatment of antiphospholipid antibody syndrome (APS) in pregnancy.
METHODS: The women were randomized to receive either prophylactic dosing of dalteparin or UFH starting either preconceptionally or early in pregnancy. All women also received low-dose acetylsalicylic acid, started preconceptionally. The primary outcome was a live birth. The secondary outcomes were maternal and fetal complications.
RESULTS: Of the 14 women who received the LMWH, dalteparin, and the 14 women who received UFH, 1 woman in each group did not conceive. Nine of the 13 women (69%) given dalteparin had a successful pregnancy (95% confidence interval [CI], 39-91%), compared to 4 out of the 13 women (31%) in the UFH group (95% CI, 9-61%).
CONCLUSION: Dalteparin may be an effective alternative to UFH for treatment of APS in pregnancy.

Triolo G, Ferrante A, Ciccia F, Accardo-Palumbo A, Perino A, Castelli A, Giarratano A, Licata G. Randomized study of subcutaneous low molecular weight heparin plus aspirin versus intravenous immunoglobulin in the treatment of recurrent fetal loss associated with antiphospholipid antibodies. Arthritis Rheum. 2003 Mar;48(3):728-31

METHODS: We examined 40 women with recurrent abortion (at least 3 occurrences) and repeatedly positive test results for anticardiolipin or lupus anticoagulant. The subjects were randomly assigned to treatment with IVIG or LMW heparin plus low-dose aspirin. Both therapies were started when the women were pregnant as documented by a positive urine test. IVIG was stopped at the thirty-first week of gestation, aspirin at the thirty-fourth week, and heparin at the thirty-seventh week. The primary outcome of interest was the rate of live births with the 2 treatments.
RESULTS: The characteristics of the 2 groups were similar at the time of randomization. The women treated with LMW heparin plus low-dose aspirin had a higher rate of live births (84%) than those treated with IVIG (57%).
CONCLUSION: Treatment with LMW heparin plus low-dose aspirin should be considered as the standard therapy for recurrent pregnancy loss due to aPL.