Successful Twin Delivery Through In Vitro Fertilization in a High-Gestation Age Kidney Transplant Recipient: A Case Report.

BACKGROUND: Numerous successful pregnancy outcomes have been reported after kidney transplantation, but until now, there have been no reports of healthy twin deliveries through in vitro fertilization treatment in high-gestation aged women with a long post-transplant duration. In our report, we present a case of a high-gestation aged kidney transplant recipient who successfully delivered healthy twins with the aid of in vitro fertilization. CASE PRESENTATION: At the age of 29, a woman with end-stage kidney disease caused by immunoglobin A nephropathy underwent kidney transplantation. She had a history of premature ovarian failure and had been on continuous ambulatory peritoneal dialysis since the age of 18. Eleven years after starting dialysis, she received a cadaveric kidney transplant. Despite being infertile for 7 years after transplantation, she wished to have children. In vitro fertilization embryo transfer was conducted after failure of ovarian stimulation, considering her age and premature ovarian failure. The patient successfully delivered twins at 29 weeks gestation via cesarean section, as the first fetus presented in breech position. The first newborn weighed 945 g and the second weighed 855 g, with no other congenital abnormalities found. One year after childbirth, neither the recipient nor her babies experienced any fatal complications. CONCLUSIONS: A woman who underwent kidney transplantation and has stage 3 CKD may successfully deliver healthy twins through in vitro fertilization embryo transfer, even if she is of advanced maternal age and has a long post-transplant period. However, there is a risk of preterm premature rupture of membrane in such cases.

Kisspeptin Regulates Cell Invasion and Migration in Endometrial Cancer.

Kisspeptin (a product of the KISS1 gene and its receptor) plays an important role in obstetrics, gynecology, and cancer cell metastasis and behavior. In hypothalamic-pituitary-gonadal axis and placentation, Kisspeptin/Kisspeptin receptor affects hormone release and represses trophoblast invasion into maternal deciduae. Endometrial cancer is one of the common gynecological cancers and is usually accompanied by metastasis, the risk factor that causes death. Recently, research has demonstrated that Kisspeptin/Kisspeptin receptor expression in aggressive-stage endometrial cancer tissues. However, the detailed mechanism of Kisspeptin/Kisspeptin receptor in regulating the motility of endometrial cancers is not well understood. In this study, we use endometrial cancer cell lines RL95-2, Ishikawa, HEC-1-A, and HEC-1-B as models to explore the molecular mechanism of Kisspeptin on cell motility. First, we discovered that Kisspeptin/Kisspeptin receptor was expressed in endometrial cancer cells, and Kisspeptin significantly regulated the migration and invasion of endometrial cancer cells. Furthermore, we explored the epithelial-mesenchymal transition marker expression and the underlying signals were regulated on Kisspeptin treatment. In conclusion, we suggest that Kisspeptin regulates endometrial cancer cell motility via FAK and Src expression and the ERK1/2, N-Cadherin, E-Cadherin, beta-Catenin, Twist, and matrix metalloproteinase signaling pathways. We expect these molecules could be candidates for the development of new approaches and therapeutic targets.

Gut Microbiome-Estrobolome Profile in Reproductive-Age Women with Endometriosis.

Microbiota is associated with our bodily functions and microenvironment. A healthy, balanced gut microbiome not only helps maintain mucosal integrity, prevents translocation of bacterial content, and contributes to immune status, but also associates with estrogen metabolism. Gut dysbiosis and estrobolome dysfunction have hence been linked to certain estrogen-dependent diseases, including endometriosis. While prior studies on microbiomes and endometriosis have shown conflicting results, most of the observed microbial differences are seen in the genital tract. This case-control study of reproductive-age women utilizes their fecal and urine samples for enzymatic, microbial, and metabolic studies to explore if patients with endometriosis have distinguishable gut microbiota or altered estrogen metabolism. While gut ß-glucuronidase activities, microbial diversity, and abundance did not vary significantly between patients with or without endometriosis, fecal samples of patients with endometriosis were more enriched by the Erysipelotrichia class and had higher folds of four estrogen/estrogen metabolites. Further studies are needed to elucidate what these results imply and whether there indeed is an association or causation between gut microbiota and endometriosis.

Priming of macrophage by glycosphingolipids from extracellular vesicles facilitates immune tolerance for embryo-maternal crosstalk.

Glycosphingolipids (GSLs) display diverse functions during embryonic development. Here, we examined the GSL profiles of extracellular vesicles (EVs) secreted from human embryonic stem cells (hESCs) and investigated their functions in priming macrophages to enhance immune tolerance of embryo implantation. When peripheral blood mononuclear cells were incubated with ESC-secreted EVs, globo-series GSLs (GHCer, SSEA3Cer, and SSEA4Cer) were transferred via EVs into monocytes/macrophages. Incubation of monocytes during their differentiation into macrophages with either EVs or synthetic globo-series GSLs induced macrophages to exhibit phenotypic features that imitate immune receptivity, i.e., macrophage polarization, augmented phagocytic activity, suppression of T cell proliferation, and the increased trophoblast invasion. It was also demonstrated that decidual macrophages in first-trimester tissues expressed globo-series GSLs. These findings highlight the role of globo-series GSLs via transfer from EVs in priming macrophages to display decidual macrophage phenotypes, which may facilitate healthy pregnancy.

EGF-Enhanced GnRH-II Regulation in Decidual Stromal Cell Motility through Twist and N-Cadherin Signaling.

Crucial roles in embryo implantation and placentation in humans include the invasion of the maternal decidua by extravillous trophoblasts and the motile behavior of decidual endometrial stromal cells. The effects of the epidermal growth factor (EGF) and GnRH-II in the endometrium take part in early pregnancy. In the present study, we demonstrated the coaction of EGF- and GnRH-II-promoted motility of human decidual endometrial stromal cells, indicating the possible roles of EGF and GnRH-II in embryo implantation and early pregnancy. After obtaining informed consent, we obtained human decidual endometrial stromal cells from decidual tissues from normal pregnancies at 6 to 12 weeks of gestation in healthy women undergoing suction dilation and curettage. Cell motility was evaluated with invasion and migration assays. The mechanisms of EGF and GnRH-II were performed using real-time PCR and immunoblot analysis. The results showed that human decidual tissue and stromal cells expressed the EGF and GnRH-I receptors. GnRH-II-mediated cell motility was enhanced by EGF and was suppressed by the knockdown of the endogenous GnRH-I receptor and EGF receptor with siRNA, revealing that GnRH-II promoted the cell motility of human decidual endometrial stromal cells through the GnRH-I receptor and the activation of Twist and N-cadherin signaling. This new concept regarding the coaction of EGF- and GnRH-promoted cell motility suggests that EGF and GnRH-II potentially affect embryo implantation and the decidual programming of human pregnancy.

A Lifelong Impact on Endometriosis: Pathophysiology and Pharmacological Treatment.

Endometriosis is a chronic inflammatory disease associated with bothersome symptoms in premenopausal women and is complicated with long-term systemic impacts in the post-menopausal stage. It is generally defined by the presence of endometrial-like tissue outside the uterine cavity, which causes menstrual disorders, chronic pelvic pain, and infertility. Endometriotic lesions can also spread and grow in extra-pelvic sites; the chronic inflammatory status can cause systemic effects, including metabolic disorder, immune dysregulation, and cardiovascular diseases. The uncertain etiologies of endometriosis and their diverse presentations limit the treatment efficacy. High recurrence risk and intolerable side effects result in poor compliance. Current studies for endometriosis have paid attention to the advances in hormonal, neurological, and immunological approaches to the pathophysiology and their potential pharmacological intervention. Here we provide an overview of the lifelong impacts of endometriosis and summarize the updated consensus on therapeutic strategies.

Endothelial dysfunction in subfertile women with polycystic ovary syndrome.

RESEARCH QUESTION: Is there an association between post-occlusive reactive hyperaemia (PORH) and ovarian stimulation in women with normoandrogenaemic polycystic ovary syndrome (PCOS)? DESIGN: Women eligible for IVF at an academic fertility centre were invited to join this prospective study. Microvascular endothelial function was measured as PORH by laser Doppler flowmetry (LDF) before and after ovarian stimulation. Metabolic characteristics, hormone profiles and biochemical markers were analysed. RESULTS: Thirty-four normoandrogenaemic women with PCOS and 36 normoandrogenaemic women without PCOS were included. The PCOS group displayed higher C-reactive protein levels and insulin resistance (P = 0.048 and P = 0.025, respectively). No significant difference was found in microcirculatory function between the groups at baseline. After ovarian stimulation, PORH was enhanced in the control group (slope 7.1 ± 3.3 versus 9.7 ± 4.5; P = 0.007; peak flow 30.7 ± 16.3 versus 43.5 ± 17.3, P = 0.008; however, the PCOS group experienced a blunting response to supraphysiological hormone status (slope 8.2 ± 5.1 versus 7.2 ± 4.3, P = 0.212; peak flow, 38.8 ± 19.4 versus 37.0 ± 21.8, P = 0.895). CONCLUSIONS: Impaired microcirculatory function could be found using a non-invasive LDF technique in normoandrogenaemic women with PCOS undergoing IVF, indicating early changes in vascular endothelial dysfunction. Future observational studies should clarify whether PORH measurement might help predict IVF prognosis or obstetric complications.

Altered Expression of Interleukin-18 System mRNA at the Level of Endometrial Myometrial Interface in Women with Adenomyosis.

Adenomyosis is a uterine pathology characterized by a deep invasion of endometrial glands and stroma, disrupting the endometrial−myometrial interface (EMI). Interleukin-18 (IL-18) system is a dominant cytokine involved in the menstrual cycle of human endometrium. IL-18 may play a defensive role against maternal immune response in the uterine cavity. The present study was designed to determine IL-18-mediated immune response at the level of EMI. We uncovered that mRNA of IL-18 system, including IL-18, IL-18 receptor (IL-18R), and its antagonist, IL-18 binding protein (IL-18BP), expressed in eutopic, ectopic endometrium, and corresponding myometrium in patients with adenomyosis. IL-18 system was demonstrated in paired tissue samples by immunochemistry and immunofluorescence study. According to RT-PCR with CT value quantification and 2−∆∆Ct method, a significant down-regulation of IL-18BP in corresponding myometrium in comparison to eutopic endometrium (p < 0.05) indicates that the IL-18 system acts as a local immune modulator at the level of EMI and regulating cytokine networks in the pathogenesis of adenomyosis. Furthermore, an increased IL-18 antagonist to agonist ratio was noted in ectopic endometrium compared with corresponding myometrium. We suggest that altered IL-18 system expression contributes to immunological dysfunction and junctional zone disturbance in women with adenomyosis.

Immune Tolerance of Embryo Implantation and Pregnancy: The Role of Human Decidual Stromal Cell- and Embryonic-Derived Extracellular Vesicles.

Embryo-endometrial communication plays a critical role in embryo implantation and the establishment of a successful pregnancy. Successful pregnancy outcomes involve maternal immune modulation during embryo implantation. The endometrium is usually primed and immunomodulated by steroid hormones and embryo signals for subsequent embryo implantation and the maintenance of pregnancy. The roles of extracellular vesicles (EVs) and microRNAs for the embryo-maternal interactions have been elucidated recently. New evidence shows that endometrial EVs and trophectoderm-originated EV cargo, including microRNAs, proteins, and lipids in the physiological microenvironment, regulate maternal immunomodulation for embryo implantation and subsequent pregnancy. On the other hand, trophoblast-derived EVs also control the cross-communication between the trophoblasts and immune cells. The exploration of EV functions and mechanisms in the processes of embryo implantation and pregnancy will shed light on a practical tool for the diagnostic or therapeutic approaches to reproductive medicine and infertility.

Segmented in vitro fertilization and frozen embryo transfer in dienogest-treated patient with adenomyosis: A case report and lierature review.

OBJECTIVE: To assess the effects of dienogest on segmented in vitro fertilization (IVF) and frozen-thawed embryo transfer (FET) for a patient with adenomyosis. CASE REPORT: A 33-year-old female with primary infertility for 3 years had dysmenorrhea and hypermenorrhea. Diagnosis of adenomyosis was made with a sonographic exam and an elevated cancer antigen 125 (CA-125, 310 U/mL). Her early follicular hormone profile (anti-müllerian hormone, AMH, 8 ng/mL) was normal. After repeated controlled ovarian stimulation (COS) and failed intrauterine insemination (IUI), she underwent IVF. Controlled ovarian stimulation using gonadotropin-releasing hormone (GnRH) antagonist protocol was performed with the blastocyst freeze-all IVF cycle. Pretreatment with two months of GnRH agonist (GnRHa) and frozen-thawed embryo transfer did not result in pregnancy. Subsequently, three months of long-term pretreatment with dienogest was given, and the CA-125 level was markedly reduced. Frozen-thawed blastocyst stage embryo transfer was provided, and a singleton pregnancy was achieved. CONCLUSION: Dienogest, a novel progestin highly selective for progesterone receptors, may benefit the pregnancy outcomes of infertile patients with adenomyosis adopting segmented IVF with FET.

Extracellular Vesicle-Associated MicroRNA-138-5p Regulates Embryo Implantation and Early Pregnancy by Adjusting GPR124.

Functional embryo-maternal interactions occur during the embryo implantation and placentation. Extracellular vesicles with microRNA (miR) between cells have been considered of critical importance for embryo implantation and the programming of human pregnancy. MiR-138-5p functions as the transcriptional regulator of G protein-coupled receptor 124 (GPR124). However, the signaling pathway of miR138-5p- and GPR124-adjusted NLRP3 inflammasome activation remains unclear. In this study, we examine the roles of the miR138-5p and GPR124-regulated inflammasome in embryo implantation and early pregnancy. Human decidual stromal cells were isolated from the abortus tissue and collected by curettage from missed abortion patients and normal pregnant women at 6- to 12-week gestation, after informed consent. Isolated extracellular vesicles from decidua and decidual stromal cells were confirmed by transmission electron microscopy (TEM). Next-Generation Sequencing (NGS) and microarray were performed for miR analysis. The predicated target genes of the differentially expressed miR were analyzed to identify the target genes and their pathway. We demonstrated the down-regulation of miR-138-5p and the overexpression of GPR124 in spontaneous miscarriage compared to normal pregnancy. We also showed the excessive activation of the NLRP3 inflammasome in spontaneous miscarriage compared to normal pregnancy. Here, we newly demonstrate that the miR-138-5p and GPR124-adjusted NLRP3 inflammasome were expressed in extracellular vesicles derived from decidua and decidual stromal cells, indicating that the miR-138-5p, GPR124 and NLRP3 (NACHT, LRR, and PYD domains-containing protein 3) inflammasome have a potential modulatory role on the decidual programming and placentation of human pregnancy. Our findings represent a new concept regarding the role of extracellular vesicles, miR-138-5p, GPR124, and the NLRP3 inflammasome in normal early pregnancy and spontaneous miscarriage.

Impact of growth hormone-releasing hormone antagonist on decidual stromal cell growth and apoptosis in vitro†.

Endometrial stromal cells remodeling is critical during human pregnancy. Growth hormone-releasing hormone and its functional receptor have been shown to be expressed in gynecological cancer cells and eutopic endometrial stromal cells. Recent studies have demonstrated the potential clinical uses of antagonists of growth hormone-releasing hormone as effective antitumor agents because of its directly antagonistic effect on the locally produced growth hormone-releasing hormone in gynecological tumors. However, the impact of growth hormone-releasing hormone antagonists on normal endometrial stromal cell growth remained to be elucidated. The aim of this study was to investigate the effect of a growth hormone-releasing hormone antagonist (JMR-132) on cell proliferation and apoptosis of human decidual stromal cells and the underlying molecular mechanisms. Our results showed that growth hormone-releasing hormone and the splice variant 1 of growth hormone-releasing hormone receptor are expressed in human decidual stromal cells isolated from the decidual tissues of early pregnant women receiving surgical abortion. In addition, treatment of stroma cells with JMR-132 induced cell apoptosis with increasing cleaved caspase-3 and caspase-9 activities and decrease cell viability in a time- and dose-dependent manner. Using a dual inhibition approach (pharmacological inhibitors and siRNA-mediated knockdown), we showed that JMR-132-induced activation of apoptotic signals are mediated by the activation of ERK1/2 and JNK signaling pathways and the subsequent upregulation of GADD45alpha. Taken together, JMR-132 suppresses cell survival of decidual stromal cells by inducing apoptosis through the activation of ERK1/2- and JNK-mediated upregulation of GADD45alpha in human endometrial stromal cells. Our findings provide new insights into the potential impact of growth hormone-releasing hormone antagonist on the decidual programming in humans.

Supplementation with human menopausal gonadotropin in the gonadotropin-releasing hormone antagonist cycles of women with high AMH: Pregnancy outcomes and serial hormone levels.

OBJECTIVE: To evaluate the value of using both HMG and recombinant FSH (r-FSH) in the GnRH antagonist protocol for women with high AMH. MATERIALS AND METHODS: This retrospective, single-center cohort study was conducted from January 2013 to December 2018. Of 277 GnRH antagonist IVF/ICSI cycles in women with anti-Mullerian hormone (AMH) ≥5 µg/L, 170 cycles receiving the combination of r-FSH and HMG (77 with HMG added at the beginning of the GnRH antagonist cycle and 93 with HMG added after GnRH antagonist administration) and 107 cycles receiving r-FSH alone were analyzed. The dynamic hormone profiles and embryonic and clinical outcomes of the patients were evaluated. RESULTS: We observed significantly lower serum LH levels in the r-FSH + HMG groups during ovarian stimulation. The serum estradiol and progesterone levels were lower in the r-FSH + HMG groups on the trigger day. Nevertheless, there were no significant differences with respect to the number of oocytes retrieved, maturation, fertilization, blastocyst formation rate or ovarian hyperstimulation syndrome (OHSS). The implantation and live birth rates were increased in the r-FSH + HMG groups compared with the r-FSH alone group, with no statistical significance. CONCLUSIONS: HMG for LH supplementation in the GnRH antagonist protocol for patients with high AMH is not significantly superior to r-FSH alone in terms of ovarian response and pregnancy outcome. Nevertheless, HMG supplementation might be appropriate for women with an initially inadequate response to r-FSH or intracycle LH deficiency.

The potential role of assisted oocyte activation in the management of a POSEIDON group 3 patient with fertilization failure: A case report and literature review.

OBJECTIVE: Assisted oocyte activation combined with ICSI (ICSI-AOA) has been reported to improve fertilization outcomes of couples with oocyte activation deficiency (OAD). Although there's no sufficient evidence to support ICSI-AOA as routine use, it might be beneficial for POSEIDON group 3 patients with suspected oocyte-related OAD. CASE REPORT: A 29-year-old female presented with a history of primary infertility for two years. She was classified as a POSEIDON group 3 patient and had a total fertilization failure history. With the help of ICSI-AOA, six oocytes were successfully fertilized. Pregnancy was later confirmed after embryo transfer. A living infant was born after 34 weeks of pregnancy. CONCLUSION: OAD should be taken into consideration for POSEIDON group 3 patients since low Antimüllerian hormone is associated decreased quality. Further research needs to be done to understand the mechanism underlying oocyte-related OAD and the potential role of ICSI-AOA in young patients with suboptimal ovarian response.

Association of family history with incidence and gestational hypertension outcomes of preeclampsia.

BACKGROUND: Gestational hypertension and preeclampsia are hypertensive disorders related to pregnancy that can cause maternal morbidity and fetal growth retardation. The association of these disorders with family history remains unclear. OBJECTIVES: To examine the degree of family aggregation of preeclampsia and gestational hypertension in Taiwan. METHODS: The study was conducted using the data from the National Health Insurance Database of Taiwan. Delivery events in Taiwan from 1999 to 2013 were collected. Preeclampsia was identified based on the hospital diagnosis of index delivery. The family aggregation pattern of preeclampsia was assessed and analyzed using the relationship registered in the database with the patients. RESULTS: A total of 60,314 preeclampsia events were identified among 4,091,641 deliveries, accounting for 1.5% of the cohort. The incidence of preeclampsia increased with maternal age. A total of 768 preeclampsia events occurred in mothers who had a sororal history of preeclampsia (n = 20,704), accounting for 1.3% of all preeclampsia events (n = 60,314). Mothers who had a sororal history of preeclampsia had a relative risk (RR) of 2.6 (95% confidence interval [CI]: 2.41-2.80) for preeclampsia compared with mothers who did not have a sororal history of preeclampsia. The RR for gestational hypertension was 2.79 (95% CI: 2.36-3.3) in mothers with a positive sororal history of gestational hypertension. CONCLUSIONS: Having a sororal history of preeclampsia was a strong risk factor for preeclampsia and gestational hypertension in mothers in Taiwan. The pattern of family aggregation was similar at all maternal ages.

Gonadotropin-releasing hormone analogs: Mechanisms of action and clinical applications in female reproduction.

Extra-hypothalamic GnRH and extra-pituitary GnRH receptors exist in multiple human reproductive tissues, including the ovary, endometrium and myometrium. Recently, new analogs (agonists and antagonists) and modes of GnRH have been developed for clinical application during controlled ovarian hyperstimulation for assisted reproductive technology (ART). Additionally, the analogs and upstream regulators of GnRH suppress gonadotropin secretion and regulate the functions of the reproductive axis. GnRH signaling is primarily involved in the direct control of female reproduction. The cellular mechanisms and action of the GnRH/GnRH receptor system have been clinically applied for the treatment of reproductive disorders and have widely been introduced in ART. New GnRH analogs, such as long-acting GnRH analogs and oral nonpeptide GnRH antagonists, are being continuously developed for clinical application. The identification of the upstream regulators of GnRH, such as kisspeptin and neurokinin B, provides promising potential to develop these upstream regulator-related analogs to control the hypothalamus-pituitary-ovarian axis.

Obstetric and perinatal outcomes of pregnancy in patients with repeated implantation failure.

OBJECTIVE: Despite the great advance of assisted reproductive technology (ART) in recent decades, many IVF patients failed to achieve a pregnancy even after multiple IVF-ET attempts. These patients are considered to have repeated implantation failure (RIF). While exhausting efforts have been devoted to the improvement of pregnancy rate in RIF patients, it is not clear whether RIF patients have aberrant obstetric or perinatal outcomes after they eventually achieved a pregnancy. MATERIALS AND METHODS: Taking advantage of a relatively large database of IVF-ET cycles at the Chang Gung Memorial Hospital, we compared obstetric and perinatal outcomes of RIF patients who have a successful pregnancy after IVF-ET treatment(s) to those of control IVF-ET patients. RESULTS: Because multiple pregnancies are associated with a high risk of obstetric complications, we restricted the analysis to patients who had singleton pregnancies. Analysis of a total of 596 control and 46 RIF cases showed the rates of almost all obstetric and perinatal outcomes investigated are not different between the two groups. However, the rate of placental abruption in the RIF group (4.35%) appeared to be significantly higher than that of controls (0.50%; OR = 8.99). This difference is still statistically significant after adjustment with the age (adjusted OR = 8.2). CONCLUSION: While the rates of a spectrum of obstetric and perinatal outcomes are normal in RIF patients, these patients could have an enhanced risk of placental abruption. However, investigations with a large sample size are needed to substantiate this inference.

Application of non-invasive detection of peripheral vascular dysfunction in ovarian hyperstimulation syndrome (OHSS): A pilot study of clinical relevance.

OBJECTIVE: The current study tested the hypothesis that vascular endothelial function, as reflected by the reactive hyperemia index (RHI), and biochemical factors, including VEGF, TNFα, CRP, inhibin A, and inhibin B, were involved in the pathogenesis of ovarian hyperstimulation syndrome (OHSS). MATERIALS AND METHODS: This study was conducted between June 2010 and June 2012, enrolling 15 patients with OHSS and 6 healthy control subjects <45 years of age. Detailed clinical parameters were reviewed, including serum VEGF, TNFα, CRP, inhibin A, inhibin B, and hematocrit. RHI assessed by novel automatic peripheral arterial tonography was used to evaluate the vascular endothelial function. RESULTS: Twenty-one subjects were evaluated. There was no significant difference between patients with OHSS and control subjects with respect to VEGF, TNFα, CRP, inhibin A and inhibin B. The RHI was not significantly different between patients with OHSS and control subjects (mean, 1.8 ± 0.4 vs. 1.7 ± 0.2). The hematocrit was significantly different between patients with OHSS and control subjects. CONCLUSIONS: Our preliminary data did not reveal direct evidence of vascular endothelial dysfunction in patients with OHSS. To identify whether RHI could reflect vascular endothelial dysfunction in patients with OHSS, more cases with different severities of OHSS should be recruited in the future study.

Effectiveness and appropriateness in the application of office hysteroscopy.

With the advances in miniature instruments, office hysteroscopy on conscious patients has been the standard to explore the intrauterine pathology, with the ability to perform some minor procedures concomitantly. Patients usually appreciate the efficient "see and treat" procedures with such minimal discomfort that exempt from the inconvenience of going into the operating room and the need for anesthesia. However, controversies exist in the appropriateness of its application in some clinical situations. Concerns include (1) the criteria for hysteroscopy applied in the vast number of patients suffering from abnormal uterine bleeding or subfertility, and (2) the frequency for repeated hysteroscopy on some kinds of patients, such as those of endometrial cancer with fertility-sparing treatment for monitoring the disease, or those of severe intrauterine adhesion who need adhesiolysis for subsequent conception, in whom the appropriate protocol of repeatedly applying hysteroscopy lacks consensus. This article reviews the literature to find the best available evidence on the effectiveness of office hysteroscopy in comparison with other clinical diagnostic tools, as well as the current opinions on such controversies in its application.

Population-based trends and risk factors of early- and late-onset preeclampsia in Taiwan 2001-2014.

BACKGROUND: Preeclampsia, a multisystem disorder in pregnancies complicates with maternal and fetal morbidity. Early- and late-onset preeclampsia, defined as preeclampsia developed before and after 34 weeks of gestation, respectively. The early-onset disease was less prevalent but associated with poorer outcomes. Moreover, the risk factors between early -and late- onset preeclampsia could be differed owing to the varied pathophysiology. In the study, we evaluated the incidences, trends, and risk factors of early- and late- onset preeclampsia in Taiwan. METHODS: This retrospective population-based cohort study included all ≧20 weeks singleton pregnancies resulting in live-born babies or stillbirths in Taiwan between January 1, 2001 and December 31, 2014 (n = 2,884,347). The data was collected electronically in Taiwanese Birth Register and National Health Insurance Research Database. The incidences and trends of early- and late-onset preeclampsia were assessed through Joinpoint analysis. Multivariate logistic regression was used to analyze the risk factors of both diseases. RESULTS: The age-adjusted overall preeclampsia rate was slightly increased from 1.1%(95%confidence interval [CI], 1.1-1.2) in 2001 to 1.3% (95%CI, 1.2-1.3) in 2012 with average annual percentage change (AAPC) 0.1%/year (95%CI, 0-0.2%). However, the incidence was remarkably increased from 1.3% (95%CI, 1.3-1.4) in 2012 to 1.7% (95%CI, 1.6-1.8) in 2014 with AAPC 1.3%/year (95%CI,0.3-2.5). Over the study period, the incidence trend in late-onset preeclampsia was steadily increasing from 0.7% (95%CI, 0.6-0.7) in 2001 to 0.9% (95%CI, 0.8-0.9) in 2014 with AAPC 0.2%/year (95%CI, 0.2-0.3) but in early-onset preeclampsia was predominantly increase from 0.5% (95%CI, 0.4-0.5) in 2012 to 0.8% (95%CI, 0.8-0.9) in 2014 with AAPC 2.3%/year (95%CI, 0.8-4.0). Advanced maternal age, primiparity, stroke, diabetes mellitus, chronic hypertension, and hyperthyroidism were risk factors of preeclampsia. Comparing early- and late-onset diseases, chronic hypertension (ratio of relative risk [RRR], 1.71; 95%CI, 1.55-1.88) and older age (RRR, 1.41; 95%CI 1.29-1.54) were more strongly associated with early-onset disease, whereas primiparity (RRR 0.71, 95%CI, 0.68-0.75) had stronger association with late-onset preeclampsia. CONCLUSIONS: The incidences of overall, and early- and late-onset preeclampsia were increasing in Taiwan from 2001 to 2014, predominantly for early-onset disease. Pregnant women with older age and chronic hypertension had significantly higher risk of early-onset preeclampsia.