Cause
Recommended tests
Secondary RPL
Clinical features
Antiphospholipid antibody
Lupus anticoagulant (at least two kinds of reagent such as dRVVT and aPTT)
Anticardiolipin antibodies
Anti-β2-glycopritein I antibodies
Rare
Intrauterine fetal death
Recurrent early miscarriage
Pre-eclampsia
Uterine anomaly
Ultrasound, sonohysterograpy and hysterosalpingography
Rare
Recurrent early miscarriage
Intrauterine fetal death
Preterm birth
Breech presentation
Abnormal chromosome
Chromosome analysis of father and mother
Yes
Early miscarriage
Abnormal embryonic karyotype
Chromosome analysis of products of conception
Yes
Early miscarriage
Fig. 10.1
Comparison of the distribution of causes (a) 1676 patients in our previous study. Sugiura-Ogasawara et al. Fertil Steril. 2010. (b) 482 patients with RM, including those with an abnormal embryonic karyotype. Sugiura-Ogasawara et al. Hum Reprod. 2012
The distribution of each cause depends on the characteristics of patients such as women’s age or the number of previous miscarriages. Women’s age, obesity, assisted conception, smoking, and alcohol are associated with RPL.
The “causes of RPL” should be strong predictors for subsequent miscarriage in the prospective study. It has not been established whether endocrine disorders such as hypothyroidism, diabetes mellitus and polycystic ovarian syndrome, thrombophilia, immune dysfunction, infection, and psychological stress may contribute to RPL because there were a limited number of randomized control trials concerning these issues.
10.2 Antiphospholipid Syndrome
APS is the most important treatable etiology. Low-dose aspirin plus heparin combined therapy is accepted as the standard treatment for patients with APS [10–12]. However, the live birth rate is limited to be 70–80%. The international classification criteria for the diagnosis of APS include obstetric clinical features as follows: [13].
- 1.
Three or more consecutive unexplained miscarriages before the 10 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.
10.2.1 Fetal Death is Priority to Early Miscarriage
Recommended tests are lupus anticoagulant (LA) by at least two kinds of reagent such as dilute activated partial thromboplastin time (aPTT) and dilute Russell’s viper venom time (RVVT) and β2glycoprotein I (β2GPI)-dependent anticardiolipin antibodies (aCL) IgG/IgM or anti-β2GPI antibodies IgG/IgM (Table 10.1) [13, 14]. Patients can be diagnosed as having APS when positive for at least one antiphospholipid antibody (aPL) persistent for 12 weeks to avoid pseudo positivity. The 99th percentile in healthy controls is recommended as the cutoff for the assays. The incidence of APS was 4.5% in our RPL previous study according to the international criteria [6].
The prospective studies concerning treatment methods are listed in Table 10.2. [8]. Combination of unfractionated heparin and low-dose aspirin is the standard treatment method [10–12, 15–20]. However, there were differences of assays and cutoff values to diagnose for APS among all facilities. The kinds of assays and titer might influence on the pregnancy outcome. The methods for detecting obstetric APS have not been established.
Table 10.2
Assays for antiphospholipid antibodies and cutoff values and live birth rate according to treatment in patients with antiphospholipid antibodies
Anticardiolipin antibody | Lupus anticoagulant | Case (n) | Control (n) | Live birth rate % | ||
|---|---|---|---|---|---|---|
Cowchock et al. [10] | IgG > 30 IgM > 11 | dRVVT or aPTT | A + scUFH (26) | A + PSL (19) | 73.1 | 68.4 |
Silver et al. [15] | IgG > 8 IgM > 5 | dRVVT | A + PSL (12) | A (22) | 100 | 100 |
Kutteh et al. [11] | IgG > =27 IgM > =27 | No | A + scUFH (25) | A (25) | 80.0a | 44.0 |
Rai et al. [12] | IgG > 5 IgM > 3 | RVVT aPTT (exclude SLE) | A + scUFH (45) | A (45) | 71.1a | 42.2 |
Pattison et al. [16] | IgG > =5 IgM > =5 | aPTT, dRVVT, KCT | A (20) | 80 | ||
Farquharson et al. [17] | IgG > 9 IgM > 5 | dRVVT | A + scLMWH (51) | A (47) | 78.4 | 72.3 |
Franklin and Kutteh [18] | IgG > 20 IgM > 20 | dRVVT | A + LMWH (25) | 76.0 | ||
Noble and Kutteh [19] | IgG > 20 IgM > 20 | dRVVT, aPTT | A + scLMWH (25) | A + scUFH (25) | 84 | 80 |
Laskin et al. [20] | 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 [21, 22]. The PROMISE study concluded that LA, but not classical aCL, was a predictor of adverse pregnancy outcomes [21]. Harris et al. also confirmed that classical CL IgG and IgM were rarely associated with adverse pregnancy outcomes [22]. Both aPTT and RVVT are suitable for assay of LA, and two tests with different assay principles are recommended [13, 14]. 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 1125 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 [23]. 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 [24]. The ascertainment of each assay to improve live birth rate has not been performed in obstetric APS though the clinical significance of the assay is to improve live birth rate. The true antigens of antiphospholipid antibodies are not phospholipids, but phospholipid-binding plasma proteins such as β2GPI, prothrombin, kininogen, protein C, and protein S [25, 26]. In fact, there are over ten commercially available methods in Japan. We determined clinical significance of LA-aPTT (StaClot) and phosphatidylserine-dependent antiprothrombin antibody but not aCL IgG, IgM, IgA, β2GPI IgG, IgM, and IgA (Phadia). Standardization is needed for detecting obstetric APS to improve the live birth rate [27].
Regarding antinuclear antibody (ANA), the frequency was significantly higher in 225 patients with two miscarriages than that in 740 normal pregnant controls; however, the ANA positive and ANA negative did not predict the subsequent miscarriage rate [28].
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.
Regarding occasional aPL, but not APS, it is not yet established how to treat them. The live birth rate with low-dose aspirin was 84.6% (44/52) and that was 95.7% (44/46) when miscarriage cases caused by an abnormal embryonic karyotype were excluded [29].
10.3 Congenital Uterine Anomaly
A 3.2–10.4% likelihood of having a major uterine anomaly except arcuate uterus is reported in patients with RPL [30–33]. The variation largely depends on the methods and the criteria selected for the diagnoses. The associations between arcuate uterus and RPL 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 relative large number of patients are summarized in Table 10.3 [30, 31]. 35–66% of patients with bicornuate or septate uteri give live births after correctional surgery [34–40]. All studies had no controls without surgery.
Table 10.3
Live birth rate with and without surgery in patients with congenital uterine anomalies
Surgery | No surgery | ||||||||
|---|---|---|---|---|---|---|---|---|---|
Makino et al. [34] | Candiani et al. [35] | Ayhan et al. [36] | DeCherney et al. [37] | Daly et al. [38] | Hickok et al. [39] | Kormanyos et al. [40] | Sugiura-Ogasawara et al. [6] | Ghi et al. [41] | |
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 Preterm 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% (39/71) | 66.0% (95/144) | 61.2% (63/103) | 84.6% (22/26) | 35.1% (33/94) Cumulative 54.3% (51/94) | 59.5% (25/42) Cumulative 78.0% (32/41) | 33.3% (8/24) | ||
In contrast, we conducted a case-control study to examine the live birth rate without surgery in 1676 patients with a history of 2–12 consecutive miscarriages whose subsequent pregnancies were ascertained at least one time in our medical records [6]. 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). 78.0% of patients (32/41) with anomalies and 85.5% of patients (1307/1528) patients with normal uteri could cumulatively have live babies within the follow-up period (not significant). 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. The large defect/cavity ratio was predictor of the subsequent miscarriage. Ghi et al. showed poorer outcome of 33.3% than our data [41].
We conducted the first multi-center prospective study to compare the live birth rate between with and without surgery in 170 patients with RPL associated with anomalies [42]. In 124 patients with a septate uterus, the live birth rate at the first pregnancy after ascertainment of anomalies with surgery tended to be higher than that in those without surgery (81.3% vs. 61.5%). The infertility rates were similar in both groups. Surgery showed no benefit in improving live birth rate in 46 patients with a bicornuate uterus, though it tended to decrease the preterm birth rate. A randomized control trial (RCT) is necessary to compare the live birth rates, also taking into consideration the infertility rate.
10.4 Abnormal Chromosomes in Either Partner
A review of the data including 22,199 couples with a history of two or more miscarriages indicated that the rate of chromosomal structural rearrangements was 4.7% [43].
We conducted the first prospective study of 1284 couples to examine whether translocations constituted a risk factor for RPL [7]. Our findings indicated a live birth rate of 31.9% (15/47) in the first pregnancy after ascertainment of the carrier status, and a cumulative live birth rate was 68.1% (32/47), which is much less than that in cases with normal chromosomes (71.7%, 849/1184). We concluded that the prognosis of RPL patients with reciprocal translocations is poor, given that the study was conducted over a 17-year period and included severe cases with a history of 10–13 miscarriages.
Franssen et al. reported cumulative live birth rates with reciprocal translocations, Robertsonian translocations, and a normal karyotype of 83.0%, 82.0%, and 84.1%, respectively, based on a prospective case-control study [44]. They concluded that the chance of having a healthy child was as high as that in noncarrier couples, despite the higher risk of miscarriage.
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