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For patients with recurrent pregnancy loss

Examination and causes of RPL

The first report on the lupus anticoagulant Lupus (LA), appeared in 1952. LA is a substance that prolongs the clotting time in the blood and in 1975 a link between this substance and intrauterine fetal death was reported. In the 1980s, autoantibodies to cardiolipin (CL), phosphatidylglycerol, phosphatidylcholine, phosphatidic acid, phosphatidylinositol, and phospatidyethanolamine (PE) were assayed extensively and later became known as causes of Antiphospholipid Syndrome (APS).
According to the diagnostic criteria for antiphospholipid syndrome proposed by the International Society for Antiphospholipid Antibodies (Table 4, Ref. 6), there must be

  • 3 or more consecutive unexplained miscarriages at less than 10 weeks of pregnancy
  • one or more intrauterine fetal deaths with no fetal malformations after 10 weeks of gestation
  • one or more preterm births before 34 weeks of pregnancy due to severe gestational hypertensive nephropathy or placental insufficiency

A single intrauterine fetal death or preterm birth due to severe gestational hypertensive nephropathy or placental insufficiency is not crippling, but the measurement of antiphospholipid antibodies is recommended because of the possibility of preventing a similar event with the next pregnancy. This syndrome is also characterized by intrauterine fetal growth retardation, amniotic fluid shortage, and thrombocytopenia in the case of antiphospholipid syndrome. Patients with systemic lupus erythematosus (SLE) also need to have these antibodies measured because 40% of patients with SLE are positive for them.

Table 4: Diagnostic criteria for antiphospholipid syndrome proposed by the International Society for Antiphospholipid Antibodies.

Antiphospholipid Syndrome
Clinical features Thromboembolism
Pregnancy complications
  • ・3 or more consecutive unexplained miscarriages of less than 10 weeks of pregnancy
  • ・One or more intrauterine fetal deaths with no fetal malformations after 10 weeks of gestation
  • ・One or more preterm births before 34 weeks of pregnancy due to severe gestational hypertensive nephropathy or placental insufficiency
Tests
  • ・Lupus-anticoagulant-positive
    (Two kinds of tests including aPTT and RVVT)
  • ・Anti-CL/b2GPI complex antibodies or anti-cardiolipin antibodies

Miyakis et al. J Thromb Haemost 2006

The phospholipid neutralization method (LA by APTT) and the diluted Russell snake venom method (LA by RVVT) are both recommended because different patients will test positive with each.
Anti-CL/β2GPI complex antibodies and anti-cardiolipin antibodies are available for authorized testing, and you can choose one or the other. Anti-CL and β2GPI complex antibodies are superior because they can rule out false positives due to infection (7). Also, this test requires simultaneous testing for β2GPI-independent anti-CL antibodies to confirm that the level of β2GPI-dependent antibodies is greater than that of β2GPI-independent antibodies in order to establish the presence of β2GPI. In addition, the International Society of Health Sciences stipulates that the standard value should be at the 99 percentile of healthy people, and the standard used in our study was 1.9 IU, which is different from the standard of 3.5 set by the testing company.
Since both tests often result in false positives, a diagnosis of antiphospholipid syndrome is made when the positives status persists for periods of 12 weeks or more.
According to a survey conducted in 2013, 61.5% of facilities handling antenatal health examinations in Japan performed the examination only once (8). It is unacceptable to have to tell an older patient to "wait three more months to get pregnant," as that would lead to unnecessary treatment. In addition, APS is an intractable disease that can cause stroke or myocardial infarction even at a young age. A proper diagnosis is recommended.

There are several antiphospholipid antibodies that can be requested, but in general, positive reactions in clinical trials have not been associated with high rates of miscarriage, and live birth rates can be improved with anticoagulant therapy. If you choose a test with a high positive rate, it can be positive for a number of reasons and may lead to unnecessary treatment.

We performed an LA assay using a 5-fold dilution of APTT reagent and a 1:1 mixture of standard and patient plasma, and confirmed that a subsequent miscarriage rate of 53.8% in the absence of treatment could be reduced to 19.6% with anticoagulation (LA-APTT laboratory, 9).
The University is currently measuring four antiphospholipid antibodies recommended by the International Society, and it has been found that APS lasting 12 weeks occurs less than 5% of the time, and that patients with genuine APS that show high antibody titers on multiple assays have a rare and intractable disease with less than 1% of cases with malnutrition. Related genes have also been identified in genuine APS (10) and we hope that further research will lead to a cure for this intractable disorder.

Antiphospholipid antibodies are found in about 40% of patients with collagen diseases such as SLE, and there has been much discussion about what to do in the case of positive antinuclear antibodies. We reported in the medical journal LANCET that the level of antinuclear antibodies is higher in patients who have had an antiphospholipid antibody-negative repeat miscarriage than in healthy pregnant women, but the rate of miscarriage in the next pregnancy was found not to be significantly different in patients with a positive or negative status (11). Some patients have been given aspirin or steroids when they are antinuclear-antibody-positive, but it is not necessary to measure antinuclear antibodies or administer medication.

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