Journal of Postgraduate Medicine Medknow Publications and Staff Society of Seth GS Medical College and KEM Hospital, Mumbai, India ISSN: 0022-3859 EISSN: 0972-2823 Vol. 48, Num. 1, 2002, pp. 3-4

Journal of Postgraduate Medicine, Vol. 48, Issue 1, 2002 pp. 3-4

Antiphospholipid Syndrome and Recurrent Miscarriage

Rajendra Singh Rai

Department of Reproductive Science and Medicine, Faculty of Medicine, Imperial College, St Mary's Hospital, London W2 1PG, United Kingdom

Code Number: jp02001

Recurrent miscarriage, the loss of three or more consecutive pregnancies affects 1% of couples trying to conceive. This is significantly higher than that expected by chance alone and implies that some couples have a persistent underlying abnormality to account for their pregnancy losses. Since its original description almost twenty years ago, the antiphospholipid syndrome (APS) has emerged as the most important treatable cause of recurrent miscarriage. The APS is also an important cause of early onset pre-eclampsia and of intra-uterine growth restriction (IUGR).¹

Antiphospholipid antibodies (aPL) are a family of approximately twenty autoantibodies directed against phospholipid binding plasma proteins. However, the two most clinically important aPL are the lupus anticoagulant (LA) and the anticardiolipin antibodies (aCL). Approximately 15% of women with recurrent miscarriage have persistently positive tests for either LA or aCL, compared to 2% of those with an uncomplicated obstetric history.² In our experience, there is little cross over between LA and aCL positivity and hence it is important to screen for both LA and for IgG and IgM aCL.

In future untreated pregnancies, women with recurrent miscarriage and persistently positive tests for aPL have a prospective miscarriage rate as high as 90%.³ The majority of miscarriages amongst women with aPL occur between 7 and 12 weeks gestation and represent the loss of chromosomally normal fetuses.⁴ Because of the gestational age at which pregnancies amongst women with aPL are lost, it appears that these antibodies may not directly affect the early stages of embryonic implantation but affect subsequent trophoblast invasion and placentation.

A variety of treatments including aspirin, steroids, heparin and more recently intravenous immunoglobulin (IVIG) have been used either as single agent or in combination to improve the poor livebirth rate amongst women with APS. Steroids have fallen into disfavour as their use is associated with an excess risk for the development of gestational diabetes, hypertension and prematurity.^5-6 At the present time, the treatment of choice for pregnant women with APS is low dose aspirin together with heparin. Two prospective randomised studies have reported that this treatment combination leads to a 70% live birth rate in future pregnancies and to be superior to low dose aspirin alone.^7,8 As 15% of clinically recognised pregnancies miscarry due to random fetal karyotype abnormalities,⁹ the live birth rate achieved with aspirin and heparin approaches the theoretical maximum live birth rate of 85% that can be achieved in any large treatment trial. Neither low dose aspirin nor heparin - fractionated or unfractionated - are associated with fetal teratogenicity. In addition, the fear that long term heparin use in pregnancy may be associated with a significant decrease in maternal bone density has been refuted by a recent large prospective study of women with APS being treated with heparin.¹⁰

However, the reported high live birth rate achieved with aspirin and heparin treatment masks the fact that successful pregnancies are characterised by a high complication rate. In a study of 150 consecutive women treated with this therapeutic combination, gestational hypertension complicated 17% of ongoing pregnancies and antepartum haemorrhage 7%.¹¹ Twenty-six babies (24%) were delivered before 37 weeks of gestation and 15% of live births were small for gestational age.

The above limitations of current pharmacological intervention in the treatment of pregnant women with APS, coupled with the fact that there is a small cohort of women who are refractory to aspirin/heparin therapy forces us to re-examine the mechanism(s) of pregnancy loss associated with aPL and the mode of action of heparin in improving pregnancy outcome.

Pregnancy loss associated with aPL has traditionally been ascribed to thrombosis of the utero-placental vasculature.^12,13 However, thrombosis is neither a universal nor a specific finding in aPL pregnancies.¹⁴ The key event in determining the outcome of a pregnancy is implantation of the embryo into the maternal decidua followed by trophoblast invasion and subsequent placentation. Implantation is a continuous process which starts shortly after fertilisation and is largely complete by 20 weeks gestation. In vitro data reports that aPL affects trophoblast differentiation, invasion and function.^15-17 Our Unit has recently reported that aPL pregnancies are characterised by defective endo-vascular trophoblast invasion of maternal uterine spiral arteries, extra-villous trophoblast invasion being normal.¹⁸ Our preliminary data also suggests that aPL affect the expression of markers - Prolactin and insulin like growth factor binding protein (IGFBP)-1 of decidualisation, which is the process by which the endometrial stromal cells are transformed in the second half of the menstrual cycle in readiness for implantation. aPL also has a direct inhibitory effect on the STAT 5 (signal transducer and activator of transcription 5) intra-cellular signalling pathway which is involved in the expression of genes controlling decidualisation.

Whilst heparin has been prescribed for its anticoagulant action, in vitro data suggests that heparin binds to aPL, thus neutralising their action, and that it restores trophoblast function and invasiveness in aPL pregnancies.^19,20 Another intriguing possibility is that heparin improves pregnancy outcome amongst pregnant women with APS via its immunomodulatory action, in particular by antagonising interferon gamma, a deleterious Th 1 cytokine, whose levels are increased amongst pregnant women with recurrent miscarriage.²¹

The APS remains an important cause for recurrent miscarriage and aspirin in combination with heparin its treatment of choice. However, recent in vitro data has allowed us to escape from the narrow confines that aPL pregnancy loss is purely thrombotic in aetiology and has opened new avenues of investigation into the mechanisms of miscarriage associated with aPL and the non-anticoagulant effects of heparin. Amongst the challenges we face over the next few years is to develop different protocols and therapeutic modalities to successfully address the issue of the high perinatal morbidity rate that accompanies successful pregnancies and the treatment of those women refractory to aspirin and heparin therapy.

Rajendra Singh Rai

Department of Reproductive Science and Medicine,
Faculty of Medicine, Imperial College,
St Mary's Hospital, London W2 1PG,
United Kingdom

References

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