Progesterone in Pregnancy: Evidence-Based Strategies to Reduce Miscarriage and Enhance Assisted Reproductive Technology.

The incidence of miscarriage in early pregnancy, between 5-20 weeks, is common, with a prevalence of between 5-22% of all pregnancies. Miscarriage can have physical, social, and mental health impacts on women and their families. In societies such as Taiwan, where the birth rate is falling and life expectancy is increasing, there is concern that factors that reduce birth rates will have detrimental economic and societal effects. Progesterone has a significant role in maintaining early and successful pregnancy to term. Evidence from preclinical and clinical research on the roles of progesterone has supported recent clinical guidelines in obstetrics and gynecology to reduce rates of early miscarriage and improve methods of assisted reproductive technology (ART). This article aims to present an evidence-based review of current recommendations for the use of progesterone in early pregnancy to reduce miscarriage rates and in luteal phase support for ART, including embryo transfer.

Combinatorial Analysis of Circulating Biomarkers and Maternal Characteristics for Preeclampsia Prediction in the First and Third Trimesters in Asia.

We aim to establish a prediction model for pregnancy outcomes through a combinatorial analysis of circulating biomarkers and maternal characteristics to effectively identify pregnant women with higher risks of preeclampsia in the first and third trimesters within the Asian population. A total of two hundred and twelve pregnant women were screened for preeclampsia through a multicenter study conducted in four recruiting centers in Taiwan from 2017 to 2020. In addition, serum levels of sFlt-1/PlGF ratio, miR-181a, miR-210 and miR-223 were measured and transformed into multiples of the median. We thus further developed statistically validated algorithmic models by designing combinations of different maternal characteristics and biomarker levels. Through the performance of the training cohort (0.848 AUC, 0.73−0.96 95% CI, 80% sensitivity, 85% specificity, p < 0.001) and the validation cohort (0.852 AUC, 0.74−0.98 95% CI, 75% sensitivity, 87% specificity, p < 0.001) from one hundred and fifty-two women with a combination of miR-210, miR-181a and BMI, we established a preeclampsia prediction model for the first trimester. We successfully identified pregnant women with higher risks of preeclampsia in the first and third trimesters in the Asian population using the established prediction models that utilized combinatorial analysis of circulating biomarkers and maternal characteristics.

The impact of prenatal use of oral Clostridium butyricum on maternal group B Streptococcus colonization: A retrospective study.

OBJECTIVE: The aim of this study is to examine the effect of taking Clostridium butyricum (Miyarisan BM) orally for 4 weeks since the 32+0 weeks of gestation on preventing Group B Streptococcus colonization. MATERIALS AND METHODS: We retrospectively collected data on the pregnancy outcomes of 1602 women between October 2017 and August 2019. The control group received standard antenatal care, and the intervention group received standard antenatal care with a daily oral dose of probiotics since the 32+0 weeks of gestation. The daily dose was one pack of C. butyricum (Miyarisan BM) once or twice a day. A vaginal Group B Streptococcus swab was collected between 36+0 and 36+6 weeks of gestation. RESULTS: After applying the designated exclusion criteria, the total number of participants was 1576. The Group B Streptococcus colonization rate was significantly decreased in the intervention group (P = 0.0338; adjusted OR: 0.66 (0.45-0.97)). CONCLUSION: Probiotics can reduce the colonization rate of Group B Streptococcus in the vagina and rectum under three conditions: (1) intervention of adequate length, (2) sufficient probiotic dose, and (3) effective probiotics.

Does Jaundice in Newborn Infants Affect Exclusivity and Duration of Breastfeeding in Taiwan?

BACKGROUND: Cases of breastfeeding- and breast-milk-related jaundice tend to increase with increased rates of breastfeeding. Diagnoses of jaundice often lead mothers to discontinue breastfeeding because of assumptions that breastfeeding may exacerbate neonatal jaundice and lengthen the duration of phototherapy treatment. PURPOSE: This study was designed to explore the effect of neonatal jaundice on breastfeeding duration and exclusivity during the first 4 months postpartum. METHODS: This study applied a two-group comparative and follow-up design. The two groups comprised 135 and 160 mothers of infants, respectively, with and without neonatal jaundice. All of the participants were recruited from three certified baby-friendly hospitals in northern Taiwan. Follow-up was conducted by telephone at 1 and 4 months postpartum. RESULTS: Mean breastfeeding duration was longer in the group of participants whose infants had neonatal jaundice (group with neonatal jaundice) than in the group whose infants did not have this condition (group without neonatal jaundice; 102.00 vs. 89.85 days, p = .007). The degree of breastfeeding was higher in the group with neonatal jaundice, although the difference was significant only at 1 month postpartum and not during hospitalization or at 4 months postpartum. The results of a Cox regression model showed that the group without neonatal jaundice was more likely to discontinue breastfeeding (adjusted hazard ratio = 1.68, 95% CI [1.08, 2.62]). A generalized estimating equation model suggests that infants with neonatal jaundice had a higher likelihood of being breastfed for at least half of their feedings (adjusted OR = 1.53, 95% CI [1.04, 2.25]). CONCLUSIONS: On the basis of the results of this study, neonatal jaundice is not an obstacle to breastfeeding in pro-breastfeeding hospital environments. Participants whose infants developed neonatal jaundice were found in this study to breastfeed more often, which promotes breastfeeding success.

Potential surrogate quantitative immunomodulatory potency assay for monitoring human umbilical cord-derived mesenchymal stem cells production.

Mesenchymal stem cells (MSCs) play an important role as immune modulator through interaction with several immune cells, including macrophages. In this study, the immunomodulatory potency of human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) was demonstrated in the in vivo middle cerebral artery occlusion (MCAo)-induced brain injury rat model and in vitro THP-1-derived macrophages model. At 24 h after induction of MCAo, hUC-MSCs was administered via tail vein as a single dose. Remarkably, hUC-MSCs could inhibit M1 polarization and promote M2 polarization of microglia in vivo after 14 days induction of MCAo. Compared with THP-1-derived macrophages which had been stimulated by lipopolysaccharide, the secretion of proinflammatory cytokines, tumor necrosis factor-α (TNF-α) and interferon-γ inducible protein (IP-10), were significantly reduced in the presence of hUC-MSCs. Moreover, the secretion of anti-inflammatory cytokine, interleukin-10 (IL-10), was significantly increased after cocultured with hUC-MSCs. Prostaglandins E2 (PGE2), secreted by hUC-MSCs, is one of the crucial immunomodulatory factors and could be inhibited in the presence of COX2 inhibitor, NS-398. PGE2 inhibition suppressed hUC-MSCs immunomodulatory capability, which was restored after addition of synthetic PGE2, establishing the minimum amount of PGE2 required for immunomodulation. In conclusion, our data suggested that PGE2 is a crucial potency marker involved in the therapeutic activity of hUC-MSCs through macrophages immune response modulation and cytokines regulation. This study provides the model for the development of a surrogate quantitative potency assay of immunomodulation in stem cells production.

Allogeneic human umbilical cord-derived mesenchymal stem cells reduce lipopolysaccharide-induced inflammation and acute lung injury.

Acute lung injury (ALI) is the clinical disorder of acute hypoxemic respiratory deficiency and it is associated with a high mortality rate. Increased lung permeability, infiltration of inflammatory cells, secretion of inflammatory cytokines, and pulmonary edema are hallmarks of ALI. Currently, there is no effective pharmacological agent approved for ALI, and the treatment regimens available are mostly supportive. Mesenchymal stem cells (MSCs) are multipotent stromal cells with immunomodulating potential, which therefore hold great promise for the treatment of ALI. We established an LPS-induced ALI mouse model by intratracheal injection of lipopolysaccharide (LPS). Human umbilical cord-derived MSCs (hUC-MSCs) were delivered through the tail vein to assess the effects of MSCs on relieving LPS-induced ALI. Intratracheal injection of LPS increased the infiltration of neutrophils and enhanced the expression of pro-inflammatory cytokines, such as IL-6, IL-1ß and TNF-α. Administration of hUC-MSCs decreased pathological signs of inflammation, as well as reduced ALI scores. The levels of IL-6, IL-1ß and TNF-α were also dose-dependently inhibited in the bronchoalveolar lavage fluids from damaged lung tissues. Moreover, MPO and BAX levels were decreased by the hUC-MSC treatment, suggesting hUC-MSCs may play the role in inhibiting ROS production and apoptotic death in ALI repair. These results highlight the potential of hUC-MSCs to alleviate bacterial endotoxin-induced inflammation, and may represent an effective modality for the treatment of ALI in clinical settings.

The roles of first phase, second phase insulin secretion, insulin resistance, and glucose effectiveness of having prediabetes in nonobese old Chinese women.

It has been established that prediabetes can causes significant comorbidities, particularly in the elderly. The deterioration of glucose metabolism are generally considered to be results of the impairment of the 4 factors: first, second insulin secretion (FPIS, SPIS, respectively), glucose effectiveness (GE), and insulin resistance. In this study, we enrolled older women to investigate their relationships with prediabetes.Five thousand four hundred eighty-two nonobese, nondiabetic women were included. They were divided into normal glucose tolerance and prediabetes groups. Receiver operating characteristic curve was performed to investigate the effects on whether to have prediabetes for each factors. Two models were built: Model 1: FPIS + SPIS, and Model 2: model 1 + GE. The area under the receiver operating characteristic (aROC) curve was used to determine the predictive power of these models.The aROC curve of GE was significantly higher than the diagonal line followed by SPIS and FPIS accordingly. The aROC curve of Model 1 (0.611) was not different from GE. However, Model 2 improved significantly up to 0.663. Based on this model, an equation was built (-0.003 × GE - 212.6 × SPIS - 17.9 × insulin resistance + 4.8). If the calculated value is equal or higher than 0 (≥0), then the subject has higher chance to have prediabetes (sensitivity = 0.607, specificity = 0.635).Among the 4 factors, GE is the most important contributor for prediabetes in older women. By building a model composed of FPIS, SPIS, and GE, the aROC curve increased significantly. The equation built from this model could predict prediabetes precisely.

A genome-wide comparison of mesenchymal stem cells derived from human placenta and umbilical cord.

OBJECTIVE: The human umbilical cord and placenta have been considered as attractive alternative sources for noninvasive isolation of human mesenchymal stem cells (hMSCs). Different sources of MSC may have individual differentiation potential and phenotype. In this study, we compared the genome-wide expression data of umbilical cord and placenta derived hMSCs to identify specific differential expression genes (DEGs) and corresponding functions. MATERIALS AND METHODS: We collected human placental tissues and umbilical cord from healthy full-term placenta (n = 17). The genome-wide gene expression data of hMSCs were used to analyze and compare with that of fibroblasts. We identified the differential expression genes (DEGs) based on the Student's t-test and one-way ANOVA. RESULTS: According to the DEGs of umbilical cord and placenta, we used the Venn diagram to evaluate the consistence and specific genes. There are 390 umbilical cord specific DEGs which functions are related to movement of sub-cellular component. Then, the DEGs derived from placenta have two major clusters (i.e., placenta-specific (AM-CM-specific) and UC-like (UC-CD-specific)). 247 placenta-specific DEGs are down-regulated and involved in cell communication. 278 UC-like genes are up-regulated and are involved in the cell cycle, cell division, and DNA repair process. Finally, we also identified 239 umbilical cord-placenta consistence DEGs. According to the umbilical cord-placenta consistence DEGs, 175 genes are down-regulated and involved in cell death, cell growth, cell developmental processes. CONCLUSION: We identified the consistence and specific DEGs of human placenta and umbilical cord based on the genome-wide comparison. Our results indicated that hMSCs derived from umbilical cord and placenta have different gene expression patterns, and most of specific genes are involved in the cell cycle, cell division, cell death, and cell developmental processes.

The climate impact on female acute pyelonephritis in Taiwan: A population-based study.

OBJECTIVE: Urinary tract infection (UTI) is the main reason of community-acquired infection which causes large losses in social economy. The individual as well as climate factors make changes on the incidence. Acute pyelonephritis (APN) is one of the most serious UTI in female. The object of our study is to analyze whether climate factors will have effect on the incidence of female APN in Taiwan. MATERIALS AND METHODS: This study consisted of 14,568 female patients with APN from 2001 to 2013 in Taiwan and patients with repeated APN were excluded. The monthly climate data was collected from the Central Weather Bureau. The available monthly climate data included highest, lowest, and average level of temperatures, humidity, rainfall, total rain days, and sunshine hours. RESULTS: The total incidence of female APN was 23.44 each 10,000 populations. The incidence of APN was positively correlated with temperature (r = 0.66), sunshine hours (r = 0.45), rainfall (r = 0.42), rain days (r = 0.29), and humidity (r = 0.23) per month. There is the strongest correlation between the average monthly temperature and the incidence of APN (ß = 0.54). The correlation with the incidence of APN was also followed by rain days (ß = 0.28) and humidity (ß = 0.27). CONCLUSION: There is a significant expression on the incidence of female APN affected by seasonality and climate parameters. The monthly average temperature has the strongest correlation with female APN. The results of this research may facilitate the potential preventive strategies on female APN.

Women with endometriosis have higher comorbidities: Analysis of domestic data in Taiwan.

Endometriosis, defined by the presence of viable extrauterine endometrial glands and stroma, can grow or bleed cyclically, and possesses characteristics including a destructive, invasive, and metastatic nature. Since endometriosis may result in pelvic inflammation, adhesion, chronic pain, and infertility, and can progress to biologically malignant tumors, it is a long-term major health issue in women of reproductive age. In this review, we analyze the Taiwan domestic research addressing associations between endometriosis and other diseases. Concerning malignant tumors, we identified four studies on the links between endometriosis and ovarian cancer, one on breast cancer, two on endometrial cancer, one on colorectal cancer, and one on other malignancies, as well as one on associations between endometriosis and irritable bowel syndrome, one on links with migraine headache, three on links with pelvic inflammatory diseases, four on links with infertility, four on links with obesity, four on links with chronic liver disease, four on links with rheumatoid arthritis, four on links with chronic renal disease, five on links with diabetes mellitus, and five on links with cardiovascular diseases (hypertension, hyperlipidemia, etc.). The data available to date support that women with endometriosis might be at risk of some chronic illnesses and certain malignancies, although we consider the evidence for some comorbidities to be of low quality, for example, the association between colon cancer and adenomyosis/endometriosis. We still believe that the risk of comorbidity might be higher in women with endometriosis than that we supposed before. More research is needed to determine whether women with endometriosis are really at risk of these comorbidities.

EphA2 is a biomarker of hMSCs derived from human placenta and umbilical cord.

OBJECTIVE: The heterogeneous nature of mesenchymal stem cells (MSCs) and the absence of known MSC-specific biomarkers make it challenging to define MSC phenotypes and characteristics. In this study, we compared the phenotypic and functional features of human placenta-derived MSCs with those of human dermal fibroblasts in vitro in order to identify a biomarker that can be used to increase the purity of MSCs in a primary culture of placenta-derived cells. MATERIALS AND METHODS: Liquid chromatography-tandem mass spectrometry analysis was used to analyze and compare the proteome of human placenta-derived MSCs with that of fibroblasts. Quantitative real-time polymerase chain reaction, immunofluorescence, and flow cytometry were used to determine expression levels of EphA2 in placenta-derived MSCs. EphA2-positive cells were enriched by magnetic-activated cell sorting or with a cell sorter. An shRNA-mediated EphA2 knockdown was used to assess the role of EphA2 in MSC response to Tumor necrosis factor (TNF)-α stimulation. RESULTS: Analysis of proteomics data from MSCs and fibroblasts resulted in the identification of the EphA2 surface protein biomarker, which could reliably distinguish MSCs from fibroblasts. EphA2 was significantly upregulated in placenta-derived MSCs when compared to fibroblasts. EphA2 played an important role in MSC migration in response to inflammatory stimuli, such as TNF-α. EphA2-enriched MSCs were also more responsive to inflammatory stimuli in vitro when compared to unsorted MSCs, indicating a role for EphA2 in the immunomodulatory functionality of MSCs. CONCLUSION: EphA2 can be used to distinguish and isolate MSCs from a primary culture of placenta-derived cells. EphA2-sorted MSCs exhibited superior responsiveness to TNF-α signaling in an inflammatory environment compared with unsorted MSCs or MSC-like cells.

Primary fallopian tube cancer: domestic data and up-to-date review.

Primary fallopian tube carcinoma (PFTC) is a rare gynecological malignancy with the following characteristics: its preoperative diagnosis is easy to miss or delay because of a lack of specific symptoms and signs; it is difficult to distinguish from serous epithelial ovarian cancer or primary peritoneal serous carcinoma during or even after operation because they have the same histopathological features; and there is uncertainty regarding the optimal management because of the lack of available standard guidelines. All of these factors contribute to the major challenge of undertaking a comprehensive study of this disease. To improve our understanding of this rare disease, the domestic data were summarized first. We searched PubMed on this topic, using the term "primary fallopian tube tumor and Taiwan" (from January 1, 1990 to November 3, 2013) and identified 15 published articles, but only 11 studies focused on the outcome of patients with PFTC in Taiwan. These limited data were not enough to increase our knowledge in dealing with this disease; therefore, the addition of large series or published review articles addressing this topic was needed. According to these reports, we concluded: (1) the main type of PFTC was serous type, often poorly differentiated; (2) the diagnosis of PFTC is frequently missed or delayed; (3) PFTC is often of an earlier International Federation of Gynecology and Obstetrics (FIGO) stage than is epithelial ovarian cancer (EOC), because of the appearance of earlier but nonspecific symptoms or signs, such as abdominal pain, vaginal bleeding, and watery discharge or mass; (4) the most important clinicopathological prognostic factor was FIGO stage; (5) the therapeutic strategy is still uncertain, but is often based on the guidelines for treating EOC. An intensive surgical effort such as a complete surgical resection or optimal cytoreduction surgery with a minimal residual tumor followed by a platinum-paclitaxel combination chemotherapy with/without targeted therapy (for example, antiangiogenesis agents) may provide the best possibility of disease-free or overall survival.

Comprehensive treatment for infertile women with severe Asherman syndrome.

OBJECTIVE: Many preoperative, intraoperative, and postoperative methods have been described that improve the outcomes of women with severe Asherman syndrome, and it is likely that an integrated application of all of these methods may provide better reproductive outcomes; however, there is as yet no report on this type of integrated approach. MATERIALS AND METHODS: The cases of four infertile women with severe Asherman syndrome were analyzed retrospectively. The comprehensive therapeutic plan for the four women included (1) preoperative office hysteroscopy to confirm the diagnosis and evaluate the severity of disease; (2) the use of ultrasound-guided intraoperative abdominal procedures during the surgical procedure, including hysteroscopic adhesiolysis to ensure the entire the hysteroscopic dissection, and placement of a Hyalobarrier(®) gel and an intrauterine balloon catheter at the end of the surgery; (3) postoperative oral estrogen supplementation to enhance endometrial proliferation, removal of the balloon catheter, and a second-look office hysteroscopy; and (4) in vitro fertilization and embryo transfer (IVF & ET) for three of the four patients. RESULT: After treatment, the endometrium was significantly thicker than at baseline (median endometrial thickness, 7.5 mm versus 3.0 mm, p < 0.05). All the women (100%, 4/4) conceived successfully (three undergoing IVF & ET, and one had a spontaneous pregnancy), but only two patients had a term pregnancy with cesarean section (one placenta previa and the other placental abruption), contributing to 50% of successful term pregnancies. One patient had the complication of abortion after amniocentesis. The last one woman underwent an abortion because of thyroid problems. CONCLUSION: Comprehensive management offers promising reproductive outcomes for infertile women with severe Asherman syndrome.

Prognostic factors of primary fallopian tube cancer in a single institute in Taiwan.

OBJECTIVE: To improve the understanding of primary fallopian tube carcinoma (PFTC) through an analysis of possible clinical and pathologic determinants of prognosis. METHODS: A retrospective review of the database of a tertiary hospital in Taiwan for 1978-2007 was conducted to identify patients with a diagnosis of PFTC and to evaluate the clinicopathologic features associated with PFTC outcome. RESULTS: Fifty-eight patients (mean age 62.5 years) had a diagnosis of PFTC. Stage III/IV disease (55%) and poorly differentiated tumors (52%) were most common. The median follow-up was 93 months (range, 11-333 months). The 5-year disease-free survival rate was 59%, and the overall survival rate was 64%. Factors important in disease-free and overall survival in univariate analysis included the presence of pelvic and/or para-aortic lymph node metastases, International Federation of Gynecology and Obstetrics stage, high preoperative carbohydrate antigen 125 serum level, completion of optimal debulking surgery, and the use of paclitaxel-based chemotherapy; however, only patients with optimal cytoreduction had a decreased hazard of recurrence (hazard ratio [HR] 0.06; 95% confidence interval [CI] 0.01-0.23) and mortality (HR 0.08; 95% CI, 0.02-0.31) in multivariate analysis. CONCLUSION: Advanced tumor stage, in particular the presence of lymph node metastases, worsened the prognosis of patients with PFTC. However, optimal debulking surgery significantly improved the prognosis, emphasizing the importance of the treatment strategy.