Danaparoid is effective and safe for patients with obstetric antiphospholipid syndrome.

Objectives: The objective is to evaluate whether danaparoid is effective in improving the live birth rate in patients with obstetric antiphospholipid syndrome (oAPS).Methods: This prospective study included 91 pregnancies of 60 patients with oAPS diagnosed according to criteria of the International Congress on APS. Live birth rates, adverse pregnancies and perinatal outcomes were compared among patients treated with danaparoid and low dose aspirin (danaparoid group, LDA), unfractionated heparin (UFH) and LDA (UFH group) and LDA and/or prednisolone (LDA group).Results: After excluding 11 miscarriages with abnormal embryonic chromosomes, one chemical pregnancy and one ectopic pregnancy, live birth rates were 87.5% (14/16) for the danaparoid group, 90.0% (36/40) for the UFH group and 63.6% (14/22) for the LDA group, respectively. The live birth rates of patients treated with danaparoid and UFH were similar and tended to be higher than that of patients treated with LDA, respectively (OR 4.0, 95% confidence interval 0.72-22.22 and 5.15, 1.33-20.00). No patient given danaparoid and one patient with UFH developed heparin-induced thrombocytopenia which resulted in a stillbirth. Another patient with UFH suffered a lumbar compression fracture.Conclusion: Danaparoid is effective for improving the live birth rate and is safe for patients with oAPS.

The first genome-wide association study identifying new susceptibility loci for obstetric antiphospholipid syndrome.

Antiphospholipid syndrome (APS) is the most important treatable cause of recurrent pregnancy loss. The live birth rate is limited to only 70-80% in patients with APS undergoing established anticoagulant therapy. Lupus anticoagulant (LA), but not anticardiolipin antibody (aCL), was found to predict adverse pregnancy outcome. Recent genome-wide association studies (GWAS) of APS focusing on aCL have shown that several molecules may be involved. This is the first GWAS for obstetric APS focusing on LA. A GWAS was performed to compare 115 Japanese patients with obstetric APS, diagnosed according to criteria of the International Congress on APS, and 419 healthy individuals. Allele or genotype frequencies were compared in a total of 426 344 single-nucleotide polymorphisms (SNPs). Imputation analyses were also performed for the candidate regions detected by the GWAS. One SNP (rs2288493) located on the 3'-UTR of TSHR showed an experiment-wide significant APS association (P=7.85E-08, OR=6.18) under a recessive model after Bonferroni correction considering the number of analyzed SNPs. Another SNP (rs79154414) located around the C1D showed a genome-wide significant APS association (P=4.84E-08, OR=6.20) under an allelic model after applying the SNP imputation. Our findings demonstrate that a specific genotype of TSHR and C1D genes can be a risk factor for obstetric APS.

Anti-N-methyl-d-aspartate receptor limbic encephalitis associated with mature cystic teratoma of the fallopian tube.

Anti-N-methyl-d-aspartate receptor (NMDAR) limbic encephalitis is the most common form of paraneoplastic encephalitis that is associated with teratomas. Because tumor removal leads to better clinical outcomes, it is essential to reveal the location of the teratomas. This is the first reported case of anti-NMDAR encephalitis associated with teratoma of the fallopian tube. Salpingo-oophorectomy improved neurological symptoms and immunohistochemical examinations indicated the expression of NMDAR on neuroglial cells within the fallopian tube teratoma. Teratomas of the fallopian tube cause anti-NMDAR encephalitis; the imaging analysis and exploratory laparoscopies of the fallopian tube as well as of the ovary should be considered. Surgical removal of both fallopian tubes and ovaries with a normal appearance should be considered for patients in whom immunotherapy is not effective.

Genotyping analysis of protein S-Tokushima (K196E) and the involvement of protein S antigen and activity in patients with recurrent pregnancy loss.

OBJECTIVE: Preston et al. indicated that Protein S (PS) deficiency was associated with stillbirths but not miscarriages. The PS-Tokushima missense variant was reported to serve as a genetic risk factor for deep vein thrombosis in the Japanese population. A previous cross-sectional study showed no increase in the prevalence of PS-Tokushima in patients with recurrent early pregnancy loss or in patients with intra uterine fetal death and/or fetal growth restriction. There has been limited number of prospective studies examining the pregnancy outcome in patients with both a PS deficiency and recurrent pregnancy loss (RPL). We examined the association between PS deficiency, PS-Tokushima and RPL. STUDY DESIGN: The study group consisted of 355 Japanese women with two or more consecutive pregnancy losses and 101 parous women. The frequency of PS-Tokushima and the subsequent live birth rate in relation to a PS deficiency defined as low PS-specific activity (total PS activity/total PS antigen) and the carriage of PS-Tokushima were examined. RESULTS AND CONCLUSIONS: There was no significant difference in the frequency of PS-Tokushima between patients and controls. The 8 patients carriers of PS-Tokushima variant were capable of a subsequent live birth without the use of heparin. There was no significant difference in subsequent live birth rates between patients with low or normal PS-specific activity/PS activity without heparin prophylaxis after excluding miscarriages caused by an abnormal embryonic karyotype using multivariate logistic regression analysis. There was no association between PS-Tokushima and RPL and a PS deficiency or low PS activity was shown not to serve as a reliable clinical predictor of subsequent miscarriage.

Genotyping analysis of the factor V Nara mutation, Hong Kong mutation, and 16 single-nucleotide polymorphisms, including the R2 haplotype, and the involvement of factor V activity in patients with recurrent miscarriage.

: Recurrent miscarriage can arise from a large diversity of causes and the factors responsible have not been fully clarified. The coagulation factor V R506Q (Leiden) mutation is a well known risk factor for recurrent miscarriage, although it has not been found in Japanese populations. We examined whether the factor V Nara and Hong Kong mutations, the factor V gene (F5) 16 single-nucleotide polymorphisms (SNPs), including the factor V R2 haplotype, and plasma factor V activity (FV:C) were risk factors for recurrent miscarriage. A cross-sectional study was conducted among 88 patients with a history of unexplained recurrent miscarriage and 95 fertile controls. None of the patients or controls was homozygous or heterozygous for the factor V Nara or Hong Kong mutation. In the 16 SNPs of F5, frequencies of the G/T and T/T genotypes at Ser156Ser were significantly lower in patients than in controls (OR 0.45, 95% CI 0.22-0.91, OR 0.32, 95% CI 0.14-0.72) and the allele frequency of C at Leu1288Leu was significantly higher in patients than that in controls (OR 1.66, 95% CI 1.02-2.71). The mean FV:C values were not significantly different between patients and controls. However, the prevalence of patients with a high or low FV:C (>95th or

Conservative therapy with a gonadotropin-releasing hormone agonist for a uterine arteriovenous malformation in a patient with congenital heart disease.

Uterine arteriovenous malformation (AVM) is rare but it can cause life-threatening genital bleeding. Conservative therapy with GnRHa can be a useful option for treating a uterine AVM presenting with a congenital heart disease shunt in hemodynamically stable patients.

Real-world practice of obstetricians in respect of assays for antiphospholipid antibodies.

OBJECTIVE: The international classification criteria (CC) for definite antiphospholipid syndrome (APS) recommend confirmation of the sustained presence, for at least 12 weeks, of both lupus anticoagulant (LA), as determined by aPTT and RVVT, and anti ß2glycoprotein I (ß2GPI) or anticardiolipin (aCL) IgG and/or IgM. However, it remains unclear whether obstetricians comply with the aforementioned CC for the diagnosis of APS in daily clinical practice. We performed a nationwide survey to examine the attitudes of Japanese obstetricians toward the use of assays for antiphospholipid antibodies (aPLs). METHODS: A questionnaire was sent to 2,700 obstetric facilities where maternity checkups are carried out. The types of assays conducted for aPLs, ascertainment of persistence of the antibodies for at least 12 weeks, and the cutoff points used for the assays were examined. RESULTS: Of the facilities surveyed, 61.5% carried out the assay(s) only once. In regard to the type of assay performed, 97.1% carried out the assay for aCL IgG and/or ß2GPI-dependent aCL, while 67.9% performed the LA-aPTT and/or LA-RVVT assay. Only 8.8% carried out assays for both LA. As for the cutoff points used, 98% of the facilities used lower cutoff points described in the manufacturers' manuals rather than the cutoff values recommended in the CC. CONCLUSION: Thus, only a limited number of facilities adhered precisely to the CC for the diagnosis of APS. Inappropriate treatment and unnecessary expense are potentially major concerns when facilities overdiagnose APS using lower cutoff points or without ascertaining the persistence of the antibodies for at least 12 weeks. On the other hand, some patients miss the opportunity to be treated for APS because of the absence of testing for LA.

Genotyping analysis for the 46 C/T polymorphism of coagulation factor XII and the involvement of factor XII activity in patients with recurrent pregnancy loss.

BACKGROUND: Established causes of recurrent pregnancy loss (RPL) include antiphospholipid syndrome, uterine anomalies, parental chromosomal abnormalities, particularly translocations and abnormal embryonic karyotype. A systematic review concluded that coagulation factor XII (FXII) deficiency was associated with RPL. However, it could not be established whether the 46 C/T SNP of FXII or low activity of FXII was a risk factor for RPL, because of the small sample size. METHODS AND FINDINGS: We conducted a cross-sectional and cohort study in 279 patients with two or more unexplained consecutive pregnancy losses and 100 fertile women. The association between the lupus anticoagulant (LA) activity and FXII activity was examined. The frequency of the CC, CT and TT genotypes and the FXII activity were also compared between the patients and controls. Subsequent miscarriage rates among the CC, CT, TT genotypes and according to the FXII activity was examined. LA was associated with reduced FXII activity. The CT, but not the TT, genotype was confirmed to be a risk factor for RPL in the cross-sectional study using multivariate logistic regression analysis (OR, 2.8; 95% CI, 1.37-5.85). The plasma FXII activity in the patients was similar to that in the controls. Neither low FXII activity nor the CT genotype predicted the subsequent pregnancy outcome in the cohort study. On the other hand, and intermediate FXII activity level of 85-101% was predictive of subsequent miscarriage. CONCLUSIONS: Low FXII activity was not associated with RPL. The FXII gene was found to be one of the significant susceptibility genes for RPL, similar to the FV Leiden mutation. However, the clinical influence of the CT genotype might be relatively small, because the presence/absence of this genotype did not have any predictive value for the subsequent pregnancy outcome. This was the first study indicating the influence of FXII 46C/T on further pregnancy outcomes.

Peripheral natural killer cell activity as a predictor of recurrent pregnancy loss: a large cohort study.

OBJECTIVE: To determine the predictive value of preconceptional peripheral blood natural killer (pNK) cell activity in patients with recurrent pregnancy loss (RPL). DESIGN: Cohort study. SETTING: University department. PATIENT(S): A total of 552 patients with a history of two to six consecutive miscarriages. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): The predictive value of preconceptional pNK cell activity for subsequent miscarriage was analyzed using multivariable logistic regression analysis, with age, number of previous miscarriages, and presence/absence of previous live births and bed rest as covariates. RESULT(S): Age and number of previous miscarriages, but not high pNK cell activity, were found to be independent risk factors for a subsequent miscarriage. No effect of bed rest and previous live birth on the likelihood of live birth was observed (odds ratios 1.28 [95% confidence interval 0.81-2.02] and 0.91 [0.52-1.59], respectively). CONCLUSION(S): Elevated pNK cell activity was found to not be an independent risk factor for subsequent miscarriage. Clinicians should not measure the plasma NK activity as a systematic recurrent pregnancy loss examination, because its clinical significance is yet to be established.

Frequency of recurrent spontaneous abortion and its influence on further marital relationship and illness: the Okazaki Cohort Study in Japan.

AIMS: The aim of this study was to examine the influence of recurrent spontaneous abortion (RSA) on marital relationships, and the association between past/present illness and RSA. MATERIAL AND METHODS: A total of 2733 Japanese women who underwent a medical examination responded to the questionnaire. RESULTS: The frequency of recurrent miscarriage and two or more consecutive RSA were 0.88% and 4.2%, respectively. Women with a history of miscarriages (hazard ratio: 1.596) and RSA (hazard ratio: 3.103) were at a higher risk of their relationships ending as compared with the women without a history of miscarriage. Existence of a relation was seen between a history of RSA and the occurrence of gastric ulcer, gastritis, fatty liver, and atopic dermatitis. Overall, 89.5% of the women with RSA experienced cumulative live births. CONCLUSIONS: Miscarriage was found to be a severe life event with an influence on marital relationships, and to be associated with an elevated risk of gastric disease or atopic dermatitis.

Abnormal embryonic karyotype is the most frequent cause of recurrent miscarriage.

BACKGROUND: We previously found that a normal karyotype in a previous miscarriage is a predictor of subsequent miscarriage. However, the prevalence of recurrent miscarriage caused by an abnormal embryonic karyotype has not yet been reported, since embryonic karyotype is not typically analyzed during conventional examinations. METHODS: A total of 482 patients who underwent both embryonic karyotype determination and conventional examinations for recurrent miscarriage were enrolled in this study. The distribution of the causes and the live birth rate for each cause were examined. RESULTS: The total percentage of subjects in whom conventional causes of recurrent miscarriage could be detected was 29.5%. The prevalence of the abnormal embryonic karyotype was 41.1% in the subjects in whom no conventional causes of miscarriage could be identified. The prevalence of recurrent miscarriage of truly unexplained cause, that is, of subjects without conventional causes in whom the embryonic karyotype was ascertained to be normal, was 24.5%. Among the patients in whom the first determination revealed an abnormal embryonic karyotype, 76.2% (32/42) showed an abnormal embryonic karyotype in the repeat determination as well. The cumulative live birth rate (71.9%) in women with recurrent miscarriages caused by the abnormal embryonic karyotype was significantly higher than that (44.7%) in women with recurrent miscarriages associated with the embryonal euploidy. CONCLUSION: An abnormal embryonic karyotype was found to represent the commonest cause of recurrent miscarriage, and the percentage of cases with recurrent miscarriage of truly unexplained cause was limited to 24.5%.The two groups should be distinguished for both clinical and research purposes.

Uterine anomaly and recurrent pregnancy loss.

Women with recurrent pregnancy loss have a 3.2 to 6.9% likelihood of having a major uterine anomaly and a 1.0 to 16.9% chance of having an arcuate uterus. Bicornuate and septate uterine have a negative impact on reproductive outcomes and are associated with subsequent euploid miscarriage. The impact of an arcuate uterus on pregnancy outcome remains unclear. There are no definitive criteria to distinguish among the arcuate, septate, and bicornuate uteri. The American Fertility Society classification of Müllerian anomalies is the most common standardized classification of uterine anomalies. According to estimates, 65 to 85% of patients with bicornuate or septate uteri have a successful pregnancy outcome after metroplasty. However, 59.5% of the patients with such anomalies have a successful subsequent pregnancy without surgery, with a cumulative live birthrate of 78.0%. There is no case-control study to compare live birthrates in women who had surgery compared with those who did not. Strict criteria to distinguish between the bicornuate and septate uterus should be established. Further study is needed to confirm the benefits of metroplasty.

[Diagnosis and treatment methods in recurrent miscarriage].

Recurrent miscarriage is classically defined as three or more consecutive pregnancy losses. Established causes of recurrent miscarriage are antiphospholipid antibodies, uterine anomalies and abnormal chromosomes in either partner, particularly translocations. Embryonic aneuploidy is the most important cause of miscarriage before ten weeks' gestation. It can be speculated that about 51% of patients with a history of three miscarriages experienced these because of abnormal embryonic karyotypes. It is not necessary to give any medication for such cases caused by an abnormal embryonic karyotype. Psychological support might be the most important requirement to continue conceiving till live birth results.

Antiphosphatidylethanolamine antibodies might not be an independent risk factor for further miscarriage in patients suffering recurrent pregnancy loss.

The prevalence of antiphosphatidylethanolamine antibodies (aPEs) is higher in recurrent pregnancy loss patients than that in women with normal pregnancy. We conducted a cohort study to examine the predictive value of aPE for recurrent pregnancy loss and to determine its clinical significance. We examined plasma protein dependent (P+) and independent (P-) aPE IgG and IgM antibodies in 367 women with two or more unexplained consecutive pregnancy losses. We also examined conventional antiphospholipid antibodies (aPL) such as beta2-glycoprotein I-dependent anticardiolipin antibodies (beta2GPI-dependent aCL), lupus anticoagulant with reference to the dilute activated partial thromboplastin time (aPTT) and the diluted Russell's viper venom time (RVVT). Subsequent pregnancy outcome without medication was examined, and patients with and without aPE were compared. Totals of 37 (10.1%), 14 (3.8%), 23 (6.3%), 6 (1.6%), 9 (2.5%), 10 (2.7%) and 50 (13.6%) of the 367 patients were, respectively, positive for P+aPE IgG, P-aPE IgG, P+aPE IgM, P-aPE IgM, beta2GPI-dependent aCL, lupus anticoagulant by RVVT and LA by aPTT. The patients with aPE differed from patients with beta2GPI-dependent aCL or lupus anticoagulant by RVVT. No difference in live birth rate was apparent between positive and negative aPE patients with no medication. The areas under the curves for each ROC curve for the four aPEs were 0.535, 0.612, 0.546 and 0.533, respectively, so there was no significant variation in diagnostic capacity. We did not obtain any evidence that aPE elevation is an independent risk factor to predict further miscarriage in recurrent pregnancy loss patients.

Peritoneal fluid concentrations of epithelial neutrophil-activating peptide-78 correlate with the severity of endometriosis.

OBJECTIVE: To assess the release of epithelial neutrophil-activating peptide-78 (ENA-78) into peritoneal fluid in women with and without endometriosis. DESIGN: Retrospective study. SETTING: Nagoya City University Hospital. PATIENT(S): Surgery was scheduled in the proliferative or secretory phase of the menstrual cycle for 59 women with (n = 35) and without (n = 24) endometriosis. INTERVENTION(S): Peritoneal fluid samples were obtained at laparotomy or laparoscopy. MAIN OUTCOME MEASURE(S): The ENA-78 concentrations in the peritoneal fluid were measured using enzyme-linked immunosorbent assay (ELISA). RESULT(S): The concentrations of ENA-78 in the peritoneal fluid were markedly elevated in the endometriosis patients as compared with the controls, especially in women with severe stage disease. CONCLUSION(S): We conclude that ENA-78 is an important factor that may contribute to the pathogenesis of endometriosis, possibly promoting neovascularization.

Women with endometriosis have increased levels of placental growth factor in the peritoneal fluid compared with women with cystadenomas.

BACKGROUND: To assess the release of placental growth factor (PlGF) into peritoneal fluid in women with and without endometriosis, we measured its concentration with reference to disease stage, the presence of red endometriotic lesions and the phase of menstrual cycle. METHODS: Surgery was scheduled in the proliferative or secretory phase of the menstrual cycle for 59 women with (n = 35) or without (n = 24) endometriosis. The latter group comprised women undergoing surgery for ovarian cystadenomas. PlGF concentrations in the peritoneal fluid were measured using an enzyme-linked immunosorbent assay. RESULTS: PlGF concentration in the peritoneal fluid was markedly elevated in the endometriosis patients (median 189 pg/ml, interquartile range 84-475 pg/ml) as compared with the controls (88 pg/ml, 41-213 pg/ml; P < 0.001), especially in women with red lesions. Significantly greater values during the secretory phase of the menstrual cycle as compared with the proliferative phase were observed in both the control (cystadenoma) group (P < 0.05) and the endometriosis group (P < 0.001). CONCLUSIONS: Our findings suggest that production of PlGF is sensitive to the cyclic changes in ovarian steroids and may contribute to the pathogenesis of endometriosis, especially that of red lesions, by promoting neovascularization.

Conservative treatment by angiographic artery embolization of an 11-week cervical pregnancy after a period of heavy bleeding.

OBJECTIVE: To describe a rare case of conservative treatment of an 11-week cervical pregnancy after a period of heavy bleeding. DESIGN: Case report. SETTING: A university hospital. PATIENT(S): A 33-year-old woman was admitted to our hospital for treatment of a cervical pregnancy. Two-and-a-half years thereafter, she gave birth to a healthy baby by vaginal delivery at 38 weeks of gestation. INTERVENTION(S): Systemic methotrexate treatment, ligation of descending branches of uterine arteries, cervical cerclage, and unilateral internal iliac artery embolization. MAIN OUTCOME MEASURE(S): Transvaginal ultrasound, magnetic resonance imaging, and arteriography findings. RESULT(S): The patient was successfully treated with unilateral internal iliac artery embolization on the same side as the pregnancy in the 11th gestational week. CONCLUSION(S): After failed methotrexate and vessel ligation in cervical pregnancy, unilateral internal iliac artery embolization is an effective and conservative treatment that allows preservation of reproduction potential.