The distribution of each cause depends on the characteristics of patients such as women’s age or the number of previous miscarriages. Patients over 40 years old increase year by year in Japan and identifiable causes cannot be found in such patients.
The clinical tests for antiphospholipid antibodies, uterine anomaly, and chromosome karyotype in both partner and the aborted concepti are recommended.
We examined blood test for hypothyroidism and diabetes mellitus and ultrasonography for polycystic ovarian syndrome . Endocrine disturbances have also been postulated to cause RPL, but few randomized controlled trials or cohort studies reporting endocrine disturbances as a cause have withstood scrutiny. It has not been established whether endocrine disturbances, thrombophilia, immune dysfunction, infection, and psychological stress may contribute to RPL [5].
Antiphospholipid Syndrome
The clinical criteria for the diagnosis of APS include the following[7]:
1.
Three or more consecutive unexplained miscarriages before the 10th week of gestation
2.
One or more unexplained death of a morphologically normal fetus at 10 weeks of gestation or later
3.
One or more premature births of a morphologically normal fetus at 34 weeks of gestation or earlier, associated with severe preeclampsia or placental insufficiency
Lupus anticoagulant (LA) by two kinds of reagent such as dilute activated partial thromboplastin time (aPTT) and dilute Russell viper venom time (RVVT) should be examined [8]. β2glycoprotein I (β2GPI) dependent anticardiolipin antibodies (aCL) IgG/IgM or anti-β2glycoprotein I (β2GPI) antibodies IgG/IgM are recommended [7].
Patients can be diagnosed as having APS when positivity for at least one antiphospholipid antibodies (aPLs) persistent for 12 weeks, according to the revised international criteria. The 99th percentile in healthy controls is recommended as the cutoff for the assays.
The reported incidence of APS is 5–15 % [5]. However, the references quoted in this review were published before the International Criteria for APS were published [7]. The incidence of APS was 4.5 % in our previous study though the study included RPL [3].
APS is the most important treatable cause of RPL . Low-dose aspirin plus heparin combined therapy is accepted as the standard treatment for patients with APS [9–17]. The previous studies are listed in Table 11.1. There were difference of assays and cutoff values to diagnose for APS among all facilities. Not only treatment but also difference of assays might influence on the pregnancy outcome.
Table 11.1
Assays for antiphospholipid antibodies and cutoff values and live birth rate according to treatment in patients with antiphospholipid antibodies
aCL | LA | Case (n) | Control (n) | Live birth rate % | ||
|---|---|---|---|---|---|---|
Cowchock et al. (1992) [9] | IgG > 30 IgM > 11 | dRVVT or aPTT | A + scUFH (26) | A + PSL (19) | 73.1 | 68.4 |
Silver et al. (1993) [10] | IgG > 8 IgM > 5 | dRVVT | A + PSL (12) | A (22) | 100 | 100 |
Kutteh et al. (1996) [11] | IgG > =27 IgM > =27 | No | A + scUFH (25) | A (25) | 80.0a | 44.0 |
Rai et al. (1996) [12] | IgG > 5 IgM > 3 | RVVT aPTT (exclude SLE) | A + scUFH (45) | A (45) | 71.1a | 42.2 |
Pattison et al. (2000) [13] | IgG > =5 IgM > =5 | aPTT, dRVVT, KCT | A (20) | A (20) | 80 | 85 |
Farquharson et al. (2002) [14] | IgG > 9 IgM > 5 | dRVVT | A + scLMWH (51) | A (47) | 78.4 | 72.3 |
Franklin and Kutteh (2002) [15] | IgG > 20 IgM > 20 | dRVVT | A + scUFH (25) | 76.0 | ||
Noble and Kutteh (2005) [16] | IgG > 20 IgM > 20 | dRVVT, aPTT | A + scLMWH (25) | A + scUFH (25) | 84 | 80 |
Laskin et al. [17] | IgG > 15 IgM > 25 | dRVVT, aPTT, KCT, dPT (include ANA, thrombophilia) | A + scLMWH (45) | A (43) | 77.8 | 79.1 |
LA is well known to be better correlated with pregnancy morbidity than aCL [18, 19]. The PROMISS study concluded that LA, but not classical aCL, was a predictor of adverse pregnancy outcomes [18]. Harris et al. also confirmed that classical CL IgG and IgM were rarely associated with adverse pregnancy outcomes [19]. Both aPTT and RVVT are suitable for assay of LA, and two tests with different assay principles are recommended [7, 8]. Therefore, a combination of aPTT-based LA and dRVVT-based LA could be used in daily clinical practice.
We conducted a prospective study to examine whether a positive test result for β2GPI-dependent aCL might predict adverse pregnancy by 10 weeks of gestation in 1,125 pregnant women without complications; results obtained using a cutoff value of 1.9 (99th percentile in healthy volunteers) were found to have a predictive value for intrauterine fetal death, intrauterine growth restriction, and preeclampsia [20]. However, in the study, it could not be ascertained whether β2GPI-dependent aCL might have been of predictive value for early miscarriage, because the sampling was conducted only at about 10 weeks of gestation. On the other hand, we established a test for LA by 5×-diluted aPTT with the mixing test (LA-aPTT) and proved that treatment could improve the subsequent live birth in patients with a positive test result [21]. The ascertainment of each assay to improve live birth rate is important in obstetric APS. The true antigens of aPL are not phospholipids, but phospholipid-binding plasma proteins such as β2GPI, prothrombin, kininogen, protein C, and protein S [22, 23]. In fact, there are over 10 commercially available methods in Japan. Standardization is needed for detecting obstetric APS to improve the live birth rate.
Laskin et al. concluded that there was no difference in the live birth rates between treatment with low-molecular-weight heparin plus aspirin (77.8 %) and aspirin alone (79.1 %) based on the detection of aPLs, inherited thrombophilia, and antinuclear antibodies (Table 11.1) [17]. The live birth rate in patients treated with aspirin alone was high as compared with the rates reported from Rai’s or Kutteh’s study [11, 12]. In our study, the frequency of antinuclear antibody (ANA) in 225 RPL patients was significantly higher than that in 740 normal pregnant controls; however, there was no significant difference in the subsequent miscarriage rate between the ANA-positive and ANA-negative cases [24].
We usually carry out LA-aPTT, LA-RVVT, and β2GPI-dependent aCL in clinical practice. The prevalence of at least one positive test is 10.7 %, and in 4.5 %, the positive finding is sustained for 12 weeks until APS is diagnosed. Precise calculation of the gestational weeks can be made from the basal body temperature chart. Combined treatment with low-dose aspirin and heparin calcium at 10,000 IU/day (twice a day) should be started from 4 weeks of gestation. We discontinue aspirin by 35 weeks of gestation and continue heparin until the onset of labor. A live birth can be expected in 70–80 % of the patients treated thus [11, 12].
We found that the live birth rate in 52 patients with occasional aPL, but not APS, treated with aspirin alone was significantly higher than that in 672 patients with unexplained RPL who received no medication [25]. The live birth rate was 84.6 % (44/52) and that was 95.7 % (44/46) when miscarriage cases caused by an abnormal embryonic karyotype were excluded. However, it is not yet established how to treat patients with occasional aPL.
Congenital Uterine Anomaly
Women with a history of RPL have been estimated to have a 3.2–10.4 % likelihood of having a major uterine anomaly except arcuate uterus, the variation largely depending on the methods and the criteria selected for the diagnoses [26–29]. The associations between arcuate uterus and RPL and between anomalies and infertility remain controversial.
Affected patients have been offered surgery in an attempt to restore the uterine anatomy. The live birth rates after surgery in studies including a relatively large number of patients are summarized in Table 11.2 [26, 30–37]. 35.1–65.9 % of patients with bicornuate or septate uteri give live births after correctional surgery. While this may provide hope that the operations would increase the rate of successful pregnancies , to the best of our knowledge, there have been no prospective studies comparing the pregnancy outcomes between cases of RPL with uterine anomalies treated and not treated by surgery.
Table 11.2
Live birth rate with and without surgery in patients with congenital uterine anomalies
surgery | No surgery | ||||||||
Makino et al. 1992 (n=71) [30] | Candiani et al. 1990 (144) [31] | Ayhan et al. 1992 (89) [32] | DeCherney et al. 1986 (103) [33] | Daly et al. 1989 (55) [34] | Hickok et al. 2000 (40) [35] | Kormányos et al. 2006 (94) [36] | Sugiura-Ogasawara et al. 2010 (42) [3] | Ghi et al. 2012 (24)[37] | |
Type of anomaly | Arcuate, septate | Septate Bicornuate | Septate Bicornuate | Septate | Septate | Septate | Septate | Septate Bicornuate | Septate Subseptate |
Indication | Recurrent SAB | Recurrent SAB Infertility | Recurrent SAB Preterm delivery | Recurrent SAB | Recurrent SAB Peterm delivery | Pregnancy loss Complication of pregnancy Infertility | 2 or more SAB | 2 or more SAB | First pregnancy |
Method of surgery | Abdominal | Tompkins Jones Te Linde Strassman | Tompkins Jones Strassman | Resectoscope | Scissors | Resectoscope | Resectoscope | – | – |
Live birth rate per pregnancy | 84.8% (39/46) | 68% (45/66 ) septate 76% (50/66) bicornuate | 65% (30/46) septate 83% (45/54) Bicornuate | 80% (63/72) successful resection | 80% (60/75) | 77.3% (17/22) | 68.8% (33/48) Cumulative 71.8% (51/71) | ||
Live birth rate per patient | 54.9 % | 65.9 % | 61.2 % | 64.3 % | 35.1 % Cumulative 54.3 % | 59.5% Cumulative 78.0% | 33.3% | ||
We conducted a case-control study of 1676 patients with a history of 2–12 consecutive miscarriages whose subsequent pregnancies were ascertained at least one time in our medical records [3]. Uterine anomalies were diagnosed by HSG and laparoscopy/laparotomy .
Of the total, 3.2 % (54) had major uterine anomalies, including 38 with a partial bicornis unicolli, 10 with a septum, 5 with a unicornis, and 1 with a didelphys. Of the 42 patients with a septate or bicornuate uterus not treated by any kind of surgery, 59.5 % (25) had a successful outcome, while this was the case in 71.7 % (1096/1528) women with normal uteri at the subsequent first pregnancy (p = 0.084). The normal chromosomal karyotype rates in the aborted concepti in cases with anomalies were significantly higher than that in those without anomalies (84.6 % vs. 42.5 %, p = 0.006).
In 78.0 % of patients (32/41) with anomalies, one patient was treated by surgery after further miscarriage, and 85.5 % of patients (1307/1528) with normal uteri could cumulatively have live babies within the follow-up period (not significant). Live birth rates in patients with congenital uterine anomalies tended to be lower both at the first pregnancy after diagnosis and from the cumulative standpoint.
The defect/cavity ratio was also significantly higher in the subsequent miscarriage group than that in the live birth group. Because of a value of 0.8 for the area under curve of the ROC, major uterine anomalies clearly have a negative impact on the reproductive outcome in women with RPL, being associated with a higher risk of further miscarriage with a normal embryonic karyotype.
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