Regular ArticleThe association of antiphospholipid antibodies with intrauterine fetal death: A case–control study
Introduction
Antiphospholipid antibodies (APAs) are heterogeneous auto-antibodies that may be associated with increased risk of thrombotic and vascular complications [1]. Over the past few decades it has been recognized that APAs may be associated with pregnancy loss and other placenta mediated pregnancy complications (PMPC), such as intrauterine growth restriction, preeclampsia, placental abruption, as well as pregnancy loss in all trimesters [2], [3], [4]. PMPC affect more than one in six pregnancies, are major causes of maternal and fetal morbidity and mortality, and have been attributed to uteroplacental vascular insufficiency [5], [6]. The pathophysiology of PMPC related to APAs probably does not only involve thrombosis of placental vessels, but also impaired conceptus implantation by damage to decidual or chorionic vessels or reduction of trophoblast invasiveness, which can lead to early pregnancy loss, or later in pregnancy, placental insufficiency and PMPC [7].
Previous studies have demonstrated an association of both inherited and acquired thrombophilia with PMPC, and it has been reported that up to 65% of women with PMPC have some form of acquired or inherited thrombophilia [8], [9]. Both case–control and prospective cohort studies have found increased risk of PMPC in APA positive women, and a systematic review reported a positive association between fetal death and the presence of both anticardiolipin (aCL) antibodies of immunoglobulin G (IgG) isotype and lupus anticoagulant (LA) [8], [9], [10], [11], [12].
Studies investigating the association between APAs and intrauterine fetal death (IUFD) have often been of small sample size [13], and they have differed in selection criteria for cases and controls [14], [15]. In addition, laboratory detection of APAs is complicated by the heterogeneity of both the antibodies and the assays used for detection. All these issues can explain the inconsistent findings of the association of APAs with IUFD.
Investigators reporting on the association between APAs and IUFD have usually analyzed the prevalence of APAs in blood samples collected within months after suffering IUFD. To our knowledge the prevalence of APAs several years after the incident, among women with a history of IUFD, has not been reported. Our hypothesis was that women with a history of IUFD were more often APA positive, compared to women with live births only. The aim of our study was to investigate this association between APAs and IUFD.
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Ethics statement
The Norwegian South-Eastern Regional Committee for Medical Research Ethics approved the study. Authorization for the use of information from medical records for research purposes was obtained from the Norwegian Ministry of Health and Social Affairs. The Norwegian Data Inspectorate approved the use of data comprising sensitive personal health information, and the merging of clinical and register-data by using the unique 11-digit personal identification number given to all Norwegian citizens
Results
Information from medical records of the eligible participants gave us the opportunity to compare participating women with the non-participating. There were no significant differences in the demographic and clinical data between the participating and non-participating women (data not shown). The maternal characteristics of cases and controls are displayed in Table 1. At the time of the index pregnancy women with IUFD were younger, smoked more often at first visit, had more often placental
Discussion
In the present study, we found that women with a history of IUFD, as compared with women with live births only, were significantly more often positive for LA 3–18 years after the index pregnancy. This was attributed to women positive for LA in combination with other APAs, although this study does not allow firm conclusions on the importance of multi-positivity.
Our finding of increased prevalence of LA among women with a history of IUFD is in agreement with other studies. However, most
Conflict of Interest
No conflicts of interest.
Acknowledgments
Financial support was received from the South-Eastern Norway Regional Health Authority Trust, Hamar, Norway, the Oslo University Hospital Ulleval Scientific Trust, Oslo, Norway, and the Research Council of Norway. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
References (35)
- et al.
International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS)
J Thromb Haemost
(2006) - et al.
Pregnancy-related mortality in the United States, 1987–1990
Obstet Gynecol
(1996) - et al.
Antiphospholipid immunoglobulin G antibodies reduce annexin-V levels on syncytiotrophoblast apical membranes and in culture media of placental villi
Am J Obstet Gynecol
(1997) - et al.
Prospective studies of the association between anticardiolipin antibody and outcome of pregnancy
Obstet Gynecol
(1995) - et al.
The prevalence and biologic significance of lupus anticoagulant and anticardiolipin antibodies in a general obstetric population
Am J Obstet Gynecol
(1989) - et al.
Absence of association of inherited thrombophilia with unexplained third-trimester intrauterine fetal death
Am J Obstet Gynecol
(2005) - et al.
Ante- and postnatal risk factors of venous thrombosis: a hospital-based case–control study
J Thromb Haemost
(2008) - et al.
The association of antiphospholipid antibodies with pregnancy-related first time venous thrombosis - a population-based case–control study
Thromb Res
(2010) - et al.
Risk of venous thrombosis in pregnancy among carriers of the factor V Leiden and the prothrombin gene G20210A polymorphisms
J Thromb Haemost
(2010) - et al.
A quantitative, semi-automated and computer-assisted test for lupus anticoagulant
Thromb Res
(1993)
How strong is the association between maternal thrombophilia and adverse pregnancy outcome? A systematic review
Eur J Obstet Gynecol Reprod Biol
Lupus anticoagulants are stronger risk factors for thrombosis than anticardiolipin antibodies in the antiphospholipid syndrome: a systematic review of the literature
Blood
Subcommittee on Lupus Anticoagulant/Antiphospholipid Antibody of the Scientific and Standardisation Committee of the International Society on Thrombosis and Haemostasis. Update of the guidelines for lupus anticoagulant detection
J Thromb Haemost
Live-Enox Investigators. Effects of enoxaparin on late pregnancy complications and neonatal outcome in women with recurrent pregnancy loss and thrombophilia: results from the Live-Enox study
Fertil Steril
Low-molecular-weight heparins for thromboprophylaxis and treatment of venous thromboembolism in pregnancy: a systematic review of safety and efficacy
Blood
Laboratory classification categories and pregnancy outcome in patients with primary antiphospholipid syndrome prescribed antithrombotic therapy
Thromb Res
Antiphospholipid antibodies in predicting adverse pregnancy outcome. A prospective study
Ann Intern Med
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