Maternal cell contamination in embryonic chromosome analysis of missed abortions.

AIM: The fetal sample used for embryonic chromosome analysis is often contaminated with maternal cells, making it difficult to evaluate the fetal chromosomes. We examined on the rate of maternal cell contamination and its relationship with maternal information in the embryonic chromosome analysis of missed abortions using the Giemsabanding method. METHODS: Chromosome analysis was performed in 200 cases of delayed miscarriages in first trimester between July 1, 2000 and May 31, 2019. Chorionic villi were collected and were analyzed using the Giemsa banding method. Among the 20 cells for which chromosomal examination was performed, cells wherein 46,XX chromosomes were found together with normal male karyotype or abnormal chromosomes were defined as maternal cell contamination. RESULTS: Of the 200 cases analyzed, 136 had abnormal chromosomes. The normal female karyotype (n = 52) was four times more prevalent than the normal male karyotype (n = 12). Maternal cell contamination was seen in 15.4% of the abnormal chromosome cases and 8.3% of the normal male karyotype cases. There was no significant difference in the gestational age between the contaminated and noncontaminated groups at the time of miscarriage diagnosis. However, miscarriage before fetal heartbeat confirmation was significantly associated with higher maternal cell contamination. CONCLUSION: We found maternal cell contamination in 15% of all the cases. Moreover, in many cases of the normal female karyotype, it was suspected that only maternal chromosomes were cultured. When performing embryonic chromosome analysis in recurrent miscarriages, we should pay attention to maternal cell contamination and interpret the results accordingly.

Upregulated serum granulysin levels in women with antiphospholipid antibody-associated recurrent miscarriage are downregulated by heparin treatment.

Purpose: Granulysin is a cytotoxic protein that simultaneously activates innate and cellular immunity. The authors aimed to evaluate whether granulysin is associated with the antiphospholipid antibody syndrome and whether heparin changes the granulysin levels. Methods: A cohort study was performed with women with antiphospholipid antibody-positive recurrent pregnancy loss (RPL). The authors examined granulysin levels under RPL and evaluated the changes in serum granulysin levels before and 1 week after the commencement of heparin treatment. Results: Serum granulysin levels before heparin treatment were significantly higher in women who tested positive for one or more types of antiphospholipid antibodies (2.75 ± 1.03 vs. 2.44 ± 0.69, p = 0.0341 by Welch's t test), particularly anti-phosphatidylethanolamine antibodies (IgG: 2.98 ± 1.09 vs. 2.51 ± 0.86, p = 0.0013; IgM: 2.85 ± 1.09 vs. 2.47 ± 0.77, p = 0.0024 by Welch's t test). After heparin treatment for 1 week, serum granulysin levels were significantly reduced (p = 0.0017 by the paired t test). The miscarriage rate was significantly higher in women whose serum granulysin levels were not reduced by heparin treatment (p = 0.0086 by Fisher's exact probability test). Conclusion: The results suggest that heparin may reduce the incidence of miscarriage by suppressing serum granulysin levels.

Is hysteroscopic metroplasty using the incision method for septate uterus a risk factor for adverse obstetric outcomes?

AIM: This study aimed to assess whether hysteroscopic metroplasty using the incision method for septate uterus is a risk factor for adverse obstetric outcomes during pregnancy or delivery. METHODS: This retrospective, single-center cohort study of obstetric complications included 41 patients with recurrent pregnancy loss or unexplained infertility who underwent hysteroscopic metroplasty using the incision method for septate uterus. As controls, we recruited 1139 women who delivered at our hospital during the same period. The primary outcomes were mean weeks of delivery, mean birthweight, rate of cesarean section, rate of breech presentation, rate of post-partum hemorrhage, rate of preterm delivery, rate of placental abruption, rate of placenta previa, rate of placenta accreta and uterine rupture during pregnancy and delivery. RESULTS: The two groups did not differ in terms of age, mean weeks of delivery, mean birthweight, rate of post-partum hemorrhage, rate of preterm delivery, rate of placental abruption, rate of placenta previa or rate of placenta accreta. The rates of cesarean section and breech presentation were significantly higher in the study group than in the control group (56.1 vs 27.7%; P = 0.0002 and 19.5 vs 6.8%; P = 0.007, respectively). There were no cases of uterine rupture during pregnancy or delivery following hysteroscopic metroplasty. CONCLUSION: Hysteroscopic metroplasty using the incision method for septate uterus is not a risk factor for adverse obstetric outcomes. No severe complications, such as placenta abruption, placenta previa, placenta accreta, uterine rupture or heavy hemorrhage, were observed in the postoperative live birth group.

Retrospective cohort study of the risk factors for secondary infertility following hysteroscopic metroplasty of the uterine septum in women with recurrent pregnancy loss.

Purpose: A hysteroscopic metroplasty was performed for women with recurrent pregnancy loss owing to a uterine septum, following which some women became infertile. The aim of this study was to elucidate the risk factors of secondary infertility 1 year after hysteroscopic metroplasty for a uterine septum. Methods: A retrospective, single-center, cohort study included women with a history of at least two miscarriages that had been attributed to a uterine septum who underwent a hysteroscopic metroplasty. The patients' background data were compared between the patients who conceived and those who remained infertile at 1 year postoperatively. The data were analyzed by using the Mann-Whitney U-test and multivariate analyses. Results: The postoperative live birth rate was 83.9% (n = 26), with persistent infertility in five women at 1 year. When comparing the pregnancy group with the infertile group, the women in the postoperative infertility group were significantly older than those in the postoperative pregnancy group. The multivariate analysis showed that age was an independent risk factor for persistent infertility. Conclusion: Age was identified as an independent risk factor for postoperative secondary infertility. Therefore, surgery as early as possible is recommended.

Successful in Vitro Fertilization Pregnancy and Delivery by an Infertile Woman with Ovotesticular Disorder of Sex Development: A Case Report.

On the basis of postoperative histopathological findings, a 29-year-old nulliparous woman was diagnosed as having ovotesticular disorder of sex development (DSD). She had undergone unilateral gonadectomy at age 6 years and vulvoplasty and vaginoplasty at age 8 years. Her karyotype was 46, XX. She had dyspareunia because of a narrow vagina, but her uterus and left gonad were normal. Spontaneous ovulation was confirmed, but sexual intercourse was impossible because of dyspareunia, despite vaginal self-dilatation with a vaginal dilator. Artificial insemination was initiated; however, five cycles failed to yield a viable pregnancy. We decided to perform in vitro fertilization (IVF), which resulted in conception. During IVF we administered intravenous anesthesia before oocyte collection to reduce her distress due to insufficient lumen expansion after vaginoplasty. The patient delivered a healthy male infant weighing 2,558 g at 37 weeks of gestation via cesarean section, which was performed because of gestational hypertension. This is the eighth report of a viable neonate born from a patient with ovotesticular DSD after gonadectomy and the first such pregnancy achieved by IVF. Therefore, IVF may be an effective option for infertile patients with ovotesticular DSD. Additionally, to prevent dyspareunia, self-management of the plastic vagina is important during the peri- and postoperative periods of early vaginoplasty.

Superfertility and subfertility in patients with recurrent pregnancy loss: A comparative analysis of clinical characteristics and etiology based on differences in fertile ability.

This study aimed to elucidate the etiologies of and risk factors for recurrent pregnancy loss (RPL) according to fertile ability, focusing on the differences between superfertile and subfertile patients. This retrospective observational study included 828 women with RPL between July 2017 and February 2020. Patients were divided into three groups based on time to pregnancy (TTP): superfertile (SUP) (TTP ≤3 months for all previous pregnancies), subfertile (SUB) (previous TTP ≥12 months and use of assisted reproductive technology [ART]), and Normal (N) (TTP >3 or <12 months without ART). All patients were assessed for uterine anatomy, antiphospholipid antibodies (APAs), thyroid function, and thrombophilia. Of the 828 patients, 22%, 44%, and 34% were assigned to the SUP, SUB, and N groups, respectively. The mean ages were 33.9, 38.2, and 35.9 years in the SUP, SUB, and N groups, respectively, revealing a significant difference (P < 0.001). The anti-CL ß2GPI antibody positivity rate was significantly higher in the SUP group (4.6%) than in the N group (0.8%; P = 0.016). The prevalence of APA positivity was lowest in the N group. Overall, the clinical characteristics and etiologies of RPL associated with superfertility and subfertility were strikingly similar, with comparable positivity rates after adjusting for maternal age. Further investigation including chromosomal analysis of products of conception is needed to elucidate the clinical impact of differences in fertility on patients with RPL.

Outcomes of 8 Years of Noninvasive Prenatal Testing at Nippon Medical School Hospital.

BACKGROUND: Noninvasive prenatal testing (NIPT) is used to screen for fetal chromosomal abnormalities, such as fetal aneuploidy, and has been offered at our hospital since 2013. We analyzed data from our center to determine if NIPT screenees could be given more-accurate information on NIPT outcomes. METHODS: This retrospective observational study included 819 pregnant women who requested NIPT at Nippon Medical School Hospital from November 2013 to October 2021. We examined medical records for data on NIPT results and clinical outcomes. RESULTS: Of the 819 women, 764 (93.2%) underwent NIPT, and 55 (6.7%) did not. Of the 764 women who underwent NIPT, 17 received a positive result (2.2%), of whom 2 (11.8%), 4 (23.5%), and 11 (64.7%) received a positive result for trisomy 13, 18, and 21, respectively. The true-positive rates after definitive diagnoses of trisomy 13, 18, and 21 were 1 (50%), 3 (75%), and 11 (100%), respectively. Of the 17 positive results, there were two false-positive results (11.8%) (for trisomy 13 and trisomy 18). Eleven women with fetal aneuploidy terminated their pregnancies, and four cases resulted in intrauterine fetal death. Five neonates with negative NIPT results had congenital disease without chromosomal abnormality. Two patients had indeterminate results from the first blood sampling, possibly because of treatment with unfractionated heparin. The results of repeat testing after heparin cessation were negative. CONCLUSIONS: Our results were generally similar to nationwide data for Japan. NIPT providers can provide more detailed and individualized genetic counseling for each situation by understanding their own medical facility's data in detail.

Effects of Thrombophilia and Antithrombotic Therapy on Embryonic Chromosomal Aberration Rates in Patients with Recurrent Pregnancy Loss.

BACKGROUND: Miscarriage occurs in 10-15% of pregnancies and recurrent pregnancy loss (RPL) occurs in 1% of couples hoping for a child. Various risk factors, such as thrombophilia, uterine malformation, and embryonic chromosomal aberration cause RPL. We hypothesized that antithrombotic therapy for RPL patients with thrombophilia would reduce miscarriage due to thrombophilia, which would reduce the total miscarriages and result in a relative increase in miscarriage due to embryonic chromosomal aberrations. In this study, we investigated the incidence of chromosomal aberrations in products of conception in RPL patients with and without antithrombotic therapy. METHODS: We performed a single-center, retrospective review of cases diagnosed as miscarriage with embryo chromosome analysis between July 1, 2000, and May 31, 2019. Rates of chromosomal aberration were compared between RPL patients with and without thrombophilia or antithrombotic therapy. RESULTS: One hundred and-ninety RPL cases were analyzed. The average age was 37.4 ± 4.3 years, and the average number of previous pregnancy losses was 2.2 ± 1.1. The overall chromosomal aberration rate was 67.4% (128/190). There was no difference in the chromosomal aberration rate between the factors for RPL, with or without thrombophilia, and antithrombotic therapy. Only advancing maternal age had significant correlation to increased embryo chromosomal aberration rates. CONCLUSIONS: With or without antithrombotic therapy, miscarriage was caused by embryonic chromosome abnormalities at a certain rate. Antithrombotic therapy in RPL patients with thrombophilia may reduce abortions due to thrombophilia, which may also normalize the rate of embryonic chromosome aberrations in the subsequent miscarriages.

Preeclampsia in a pregnant woman with severe aplastic anemia: A case report.

A pregnant woman with severe aplastic anemia was managed using biweekly red blood cell transfusion and oral eltrombopag olamine administration during pregnancy. She was diagnosed with preeclampsia at 35 weeks of gestation. The severity of aplastic anemia is very important for predicting the course of pregnancy.

Clinical significance of singleton pregnancies complicated by placental abruption associated with histological chorioamnionitis.

The aim of this study was to determine the perinatal outcomes of placental abruption associated with the presence of histological chorioamnionitis. We reviewed the obstetric records of 96 singleton deliveries complicated by placental abruption after 22 weeks' gestation. Of these 96 cases, 37 cases (39%) were diagnosed as having histological chorioamnionitis in the placenta. The incidence of premature delivery, preterm rupture of the membranes and low birth weight in the cases of placental abruption with chorioamnionitis were higher than in cases without chorioamnionitis. However, there were no significant differences in the incidence of other outcomes, such as fetal demise, low Apgar score, or low umbilical artery pH, between the cases of placental abruption with and without histological chorioamnionitis. Although the incidence of prematurity in the cases of placental abruption with chorioamnionitis was higher than that in cases without chorioamnionitis, there were no significant differences in fetal and neonatal conditions between the abruption cases with and without chorioamnionitis.

Unique Clinical and Histological Features of Placental Mesenchymal Dysplasia Complicated by Severe Preeclampsia in the Midtrimester.

Detailed clinical and pathological features of placental mesenchymal dysplasia (PMD) complicated by preeclampsia (PE) are unknown. A 39-year-old nulliparous woman was referred at 19 weeks gestation. Ultrasound examination identified a fetus with severe growth restriction (-2.8 SD) and a markedly thickened placenta with many cystic structures suggestive of PMD. At 21 weeks, the patient developed severe hypertension (180/95 mm Hg) with marked proteinuria and an elevated serum soluble fms-like tyrosine-kinase-1 (sFlt-1) level (47,000 pg/L). The pregnancy was terminated to protect maternal health. Placental weight was 450 g and no histopathological findings of either proliferation or dysplasia were observed in the trophoblast. Villous chromosome examination revealed a 46XX karyotype, consistent with the diagnosis of PMD. In addition to the pathological findings of vascular endothelial dysfunction characteristic of the placenta in PE cases, enhanced expression of sFlt-1 in the syncytiotrophoblast of the enlarged villi was confirmed by immunohistochemistry as a novel finding in this condition. Monitoring of the serum sFlt-1 value is suggested to be a useful predictor of the pathological change associated with extremely early severe PE in PMD cases.

Significance of Anti-Phosphatidylethanolamine Antibodies in the Pathogenesis of Recurrent Pregnancy Loss.

Anti-phosphatidylethanolamine antibody (aPE), an anti-phospholipid autoantibody (aPL), has been proposed as a factor in recurrent pregnancy loss (RPL). However, conflicting views exist on the pathogenicity of RPL, and aPE has not yet been included in the classification criteria for antiphospholipid syndrome (APS). Here, we aimed to determine the clinical importance of examining aPE. aPE (IgG, IgM) was measured in 1705 patients with a history of RPL and re-examined after a 12-week interval in patients who tested positive. Persistent positive patients were administered low-dose aspirin during the subsequent pregnancy and clinical outcomes depending on the presence, type, and persistence of aPE were evaluated. Among the patients positive for aPE IgG and aPE IgM in the first examination (n = 117; 6.87%, and n = 235; 13.6%, respectively), 31.5% and 37.6% were negative upon re-examination, respectively. Moreover, among the cases with known pregnancy outcome, the miscarriage rate in the cumulative positive aPE group was 32.6% (29/89), which did not differ significantly from that of the aPE negative group (27.7%; 80/209; P = 0.178). Alternatively, the miscarriage rate in the persistently positive group was 40.7% (22/54), which was significantly higher than that in the transient positive group, 20.0% (7/35) (P = 0.041). Particularly, this difference become more significant when focusing on aPE IgM, 46.9% (15/32) in the persistent, compared with 16.7% (4/24) in the transient positive group (P = 0.024). aPE IgM is suggested to serve as a pathogenic aPL together with anti-cardiolipin antibodies and lupus anticoagulants, particularly if these factors persist over an extended period of time.

Successful Management of Complicated Uterine Displacement Caused by Unilateral Incarceration of the Bicornuate Uterus.

Uterine incarceration is a serious complication of pregnancy, in which the gravid uterus becomes trapped in the posterior pelvis. When labor occurs, delivery does not progress, and the uterus may rupture. Therefore, preoperative diagnosis of uterine incarceration is important, and a caesarian section is indispensable except when the polarity of the uterus can be successfully restored. We report the case of a 35-year-old primipara with a complication of a bicornuate uterus who became pregnant after in vitro fertilization and embryo transfer. No abnormality was observed on regular checkups until the second trimester. At 28 weeks' gestation, the uterine cervix revealed marked dislocation, and, at 31 weeks, magnetic resonance imaging (MRI) revealed uterine cervix elongation and left horn incarceration. At 37 weeks' gestation, an elective cesarean section was performed. On laparotomy, the uterus was found to be markedly dislocated, and distended blood vessels were observed on the surface. Ultrasound examination was performed directly on the uterine wall to decide the incision site. After delivery of the baby, manual repositioning of the uterus revealed the unique concurrent clockwise rotation and retro-vertical deflection. Thus, we concluded that incarceration accompanied by a bicornuate uterus can cause complicated uterine displacement, and preoperative MRI and intraoperative ultrasound examination are useful for managing this condition.

Diversity of progesterone action on lipopolysaccharide-induced expression changes in cultured human cervical fibroblasts according to inflammation and treatment timing.

PROBLEM: The effectiveness of progesterone (P4) treatment for preventing preterm births is unclear. Its effects on the uterine cervix were tested using cultured human uterine cervical fibroblasts (UCFs). METHOD OF STUDY: UCFs were incubated with lipopolysaccharide (LPS) in the presence or absence of P4 under various conditions. mRNA was subjected to PCR arrays and real-time RT-PCR to assess IL-6, IL-8, IL-1beta, PTGS2, MMP-1, and CXCL10 expression. RESULTS: When exposed to a high-LPS concentration (2.0 µg/mL), expression of these genes was not suppressed by simultaneous P4 (1.0 µmol/L) treatment, but it was significantly inhibited when P4 was administered 1 hour prior to LPS, with the exception of the chemokines IL-8 and CXCL10. Expression of all genes was restricted by P4 under low-level LPS (0.2 µg/mL) stimulation, especially when administered prior to LPS treatment. CONCLUSION: These data suggest that early or prophylactic P4 administration is an effective and important measure for reducing preterm birth risk.