The Pathophysiological, Genetic, and Hormonal Changes in Preeclampsia: A Systematic Review of the Molecular Mechanisms.

Preeclampsia, a serious complication of pregnancy, involves intricate molecular and cellular mechanisms. Fetal microchimerism, where fetal cells persist within maternal tissues and in circulation, acts as a mechanistic link between placental dysfunction and maternal complications in the two-stage model of preeclampsia. Hormones, complements, and cytokines play pivotal roles in the pathophysiology, influencing immune responses, arterial remodeling, and endothelial function. Also, soluble HLA-G, involved in maternal-fetal immune tolerance, is reduced in preeclampsia. Hypoxia-inducible factor 1-alpha (Hif-α) dysregulation leads to placental abnormalities and preeclampsia-like symptoms. Alterations in matrix metalloproteinases (MMPs), endothelins (ETs), chemokines, and cytokines contribute to defective trophoblast invasion, endothelial dysfunction, and inflammation. Preeclampsia's genetic complexity includes circRNAs, miRNAs, and lncRNAs. CircRNA_06354 is linked to early-onset preeclampsia by influencing trophoblast invasion via the hsa-miR-92a-3p/VEGF-A pathway. The dysregulation of C19MC, especially miR-519d and miR-517-5p, affects trophoblast function. Additionally, lncRNAs like IGFBP1 and EGFR-AS1, along with protein-coding genes, impact trophoblast regulation and angiogenesis, influencing both preeclampsia and fetal growth. Besides aberrations in CD31+ cells, other potential biomarkers such as MMPs, soluble HLA-G, and hCG hold promise for predicting preeclampsia and its complications. Therapeutic interventions targeting factors such as peroxisome PPAR-γ and endothelin receptors show potential in mitigating preeclampsia-related complications. In conclusion, preeclampsia is a complex disorder with a multifactorial etiology and pathogenesis. Fetal microchimerism, hormones, complements, and cytokines contribute to placental and endothelial dysfunction with inflammation. Identifying novel biomarkers and therapeutic targets offers promise for early diagnosis and effective management, ultimately reducing maternal and fetal morbidity and mortality. However, further research is warranted to translate these findings into clinical practice and enhance outcomes for at-risk women.

Preeclampsia: Recent Advances in Predicting, Preventing, and Managing the Maternal and Fetal Life-Threatening Condition.

Preeclampsia accounts for one of the most common documented gestational complications, with a prevalence of approximately 2 to 15% of all pregnancies. Defined as gestational hypertension after 20 weeks of pregnancy and coexisting proteinuria or generalized edema, and certain forms of organ damage, it is life-threatening for both the mother and the fetus, in terms of increasing the rate of mortality and morbidity. Preeclamptic pregnancies are strongly associated with significantly higher medical costs. The maternal costs are related to the extra utility of the healthcare system, more resources used during hospitalization, and likely more surgical spending due to an elevated rate of cesarean deliveries. The infant costs also contribute to a large percentage of the expenses as the babies are prone to preterm deliveries and relevant or causative adverse events. Preeclampsia imposes a considerable financial burden on our societies. It is important for healthcare providers and policy-makers to recognize this phenomenon and allocate enough economic budgets and medical and social resources accordingly. The true cellular and molecular mechanisms underlying preeclampsia remain largely unexplained, which is assumed to be a two-stage process of impaired uteroplacental perfusion with or without prior defective trophoblast invasion (stage 1), followed by general endothelial dysfunction and vascular inflammation that lead to systemic organ damages (stage 2). Risk factors for preeclampsia including race, advanced maternal age, obesity, nulliparity, multi-fetal pregnancy, and co-existing medical disorders, can serve as warnings or markers that call for enhanced surveillance of maternal and fetal well-being. Doppler ultrasonography and biomarkers including the mean arterial pressure (MAP), uterine artery pulsatility index (UtA-PI), and serum pregnancy-associated plasma protein A (PAPP-A) can be used for the prediction of preeclampsia. For women perceived as high-risk individuals for developing preeclampsia, the administration of low-dose aspirin on a daily basis since early pregnancy has proven to be the most effective way to prevent preeclampsia. For preeclamptic females, relevant information, counseling, and suggestions should be provided to facilitate timely intervention or specialty referral. In pregnancies complicated with preeclampsia, closer monitoring and antepartum surveillance including the Doppler ultrasound blood flow study, biophysical profile, non-stress test, and oxytocin challenge test can be arranged. If the results are unfavorable, early intervention and aggressive therapy should be considered. Affected females should have access to higher levels of obstetric units and neonatal institutes. Before, during, and after delivery, monitoring and preparation should be intensified for affected gravidas to avoid serious complications of preeclampsia. In severe cases, delivery of the fetus and the placenta is the ultimate solution to treat preeclampsia. The current review is a summary of recent advances regarding the knowledge of preeclampsia. However, the detailed etiology, pathophysiology, and effect of preeclampsia seem complicated, and further research to address the primary etiology and pathophysiology underlying the clinical manifestations and outcomes is warranted.

Hyperthermic Intraperitoneal Chemotherapy (HIPEC): An Overview of the Molecular and Cellular Mechanisms of Actions and Effects on Epithelial Ovarian Cancers.

Most patients with epithelial ovarian cancers (EOCs) are at advanced stages (stage III-IV), for which the recurrence rate is high and the 5-year survival rate is low. The most effective treatment for advanced diseases involves a debulking surgery followed by adjuvant intravenous chemotherapy with carboplatin and paclitaxel. Nevertheless, systemic treatment with intravenous chemotherapeutic agents for peritoneal metastasis appears to be less effective due to the poor blood supply to the peritoneal surface with low drug penetration into tumor nodules. Based on this reason, hyperthermic intraperitoneal chemotherapy (HIPEC) emerges as a new therapeutic alternative. By convection and diffusion, the hyperthermic chemotherapeutic agents can directly contact intraperitoneal tumors and produce cytotoxicity. In a two-compartment model, the peritoneal-plasma barrier blocks the leakage of chemotherapeutic agents from peritoneal cavity and tumor tissues to local vessels, thus maintaining a higher concentration of chemotherapeutic agents within the tumor tissues to facilitate tumor apoptosis and a lower concentration of chemotherapeutic agents within the local vessels to decrease systemic toxicity. In this review, we discuss the molecular and cellular mechanisms of HIPEC actions and the effects on EOCs, including the progression-free survival (PFS), disease-free survival (DFS) and overall survival (OS). For primary advanced ovarian cancers, more studies are agreeing that patients undergoing HIPEC have better surgical and clinical (PFS; OS) outcomes than those not, although one study reported no differences in the PFS and OS. For recurrent ovarian cancers, studies have revealed better DFS and OS in patients undergoing HIPEC than those in patients not undergoing HIPEC, although one study reported no differences in the PFS. HIPEC appears comparable to traditional intravenous chemotherapy in treating advanced EOCs. Overall, HIPEC has demonstrated some therapeutic benefits in many randomized phase III trials when combined with the standard cytoreductive surgeries for advanced EOCs. Nevertheless, many unknown aspects of HIPEC, including detailed mechanisms of actions, along with the effectiveness and safety for the treatment of EOCs, warrant further investigation.

The Molecular Mechanisms of Actions, Effects, and Clinical Implications of PARP Inhibitors in Epithelial Ovarian Cancers: A Systematic Review.

Ovarian cancer is the most lethal gynecologic malignancy in the United States. Some patients affected by ovarian cancers often present genome instability with one or more of the defects in DNA repair pathways, particularly in homologous recombination (HR), which is strictly linked to mutations in breast cancer susceptibility gene 1 (BRCA 1) or breast cancer susceptibility gene 2 (BRCA 2). The treatment of ovarian cancer remains a challenge, and the majority of patients with advanced-stage ovarian cancers experience relapse and require additional treatment despite initial therapy, including optimal cytoreductive surgery (CRS) and platinum-based chemotherapy. Targeted therapy at DNA repair genes has become a unique strategy to combat homologous recombination-deficient (HRD) cancers in recent years. Poly (ADP-ribose) polymerase (PARP), a family of proteins, plays an important role in DNA damage repair, genome stability, and apoptosis of cancer cells, especially in HRD cancers. PARP inhibitors (PARPi) have been reported to be highly effective and low-toxicity drugs that will tremendously benefit patients with HRD (i.e., BRCA 1/2 mutated) epithelial ovarian cancer (EOC) by blocking the DNA repair pathways and inducing apoptosis of cancer cells. PARP inhibitors compete with NAD+ at the catalytic domain (CAT) of PARP to block PARP catalytic activity and the formation of PAR polymers. These effects compromise the cellular ability to overcome DNA SSB damage. The process of HR, an essential error-free pathway to repair DNA DSBs during cell replication, will be blocked in the condition of BRCA 1/2 mutations. The PARP-associated HR pathway can also be partially interrupted by using PARP inhibitors. Grossly, PARP inhibitors have demonstrated some therapeutic benefits in many randomized phase II and III trials when combined with the standard CRS for advanced EOCs. However, similar to other chemotherapy agents, PARP inhibitors have different clinical indications and toxicity profiles and also face drug resistance, which has become a major challenge. In high-grade epithelial ovarian cancers, the cancer cells under hypoxia- or drug-induced stress have the capacity to become polyploidy giant cancer cells (PGCCs), which can survive the attack of chemotherapeutic agents and start endoreplication. These stem-like, self-renewing PGCCs generate mutations to alter the expression/function of kinases, p53, and stem cell markers, and diploid daughter cells can exhibit drug resistance and facilitate tumor growth and metastasis. In this review, we discuss the underlying molecular mechanisms of PARP inhibitors and the results from the clinical studies that investigated the effects of the FDA-approved PARP inhibitors olaparib, rucaparib, and niraparib. We also review the current research progress on PARP inhibitors, their safety, and their combined usage with antiangiogenic agents. Nevertheless, many unknown aspects of PARP inhibitors, including detailed mechanisms of actions, along with the effectiveness and safety of the treatment of EOCs, warrant further investigation.

The Utilization of Bevacizumab in Patients with Advanced Ovarian Cancer: A Systematic Review of the Mechanisms and Effects.

Most ovarian cancer cases are diagnosed at an advanced stage (III or IV), in which a primary debulking surgery combined with adjuvant systemic chemotherapy is the standard management. Since targeted therapy is less toxic to human cells than systemic chemotherapy, it has drawn much attention and become more popular. Angiogenesis is a critical process during the proliferation of ovarian cancer cells. Currently, many studies have put emphases on anti-angiogenetic medication, such as bevacizumab, the first and most investigated angiogenesis inhibitor that can exert anti-neoplastic effects. Bevacizumab is a recombinant humanized monoclonal antibody that has been approved for first-line maintenance treatment of advanced ovarian cancer. This review is a summary of current literature about the molecular mechanisms of actions, safety, and effects of bevacizumab for use in advanced epithelial ovarian cancer. Some common side effects of bevacizumab will be also discussed. As an inhibitor of angiogenesis, bevacizumab binds to circulating vascular endothelial growth factor (VEGF) and thereby inhibits the binding of VEGF to its receptors on the surface of endothelial cells. Neutralization of VEGF prevents neovascularization and leads to apoptosis of tumor endothelial cells and a decrease in interstitial fluid pressure within the tumors, which allows greater capacity for chemotherapeutic drugs to reach specific targeted sites. Grossly, bevacizumab has demonstrated some significant therapeutic benefits in many randomized trials in combination with the standard chemotherapy for advanced epithelial ovarian cancer. Based on the available evidence, a higher dosage and a longer duration of bevacizumab appear to achieve better therapeutic effects and progression-free survival. On the other hand, patients with more severe diseases or at a higher risk of progression seem to benefit more from bevacizumab use. However, many unknown aspects of bevacizumab, including detailed mechanisms of actions, effectiveness, and safety for the treatment of ovarian cancer, warrant further investigation.

Low Maternal Serum 25-Hydroxyvitamin D Concentration Is Associated With Postpartum Hemorrhage: A Retrospective Observational Study.

Objective: The primary aim of this study is to investigate the relationship between vitamin D serum level and the incidence of postpartum hemorrhage (PPH). The secondary objective is to determine the relative risk of low vitamin D associated with PPH. Methods: This was a retrospective observational study. A total of 600 women who had delivered their babies in a single tertiary teaching hospital were enrolled. Serum blood test for 25(OH)D was performed at 35 + 0 to 36 + 6 weeks of pregnancy to measure vitamin D. A 25(OH)D level < 20 ng/mL was defined as vitamin D deficient, and a level 21-29 ng/mL as insufficient. Results: Vitamin D levels were deficient in 145 (24.1%) and insufficient in 254 (42.3%) of the women tested. Women with deficient and insufficient vitamin D levels were significantly younger than those with sufficient vitamin D levels (p < 0.001). The overall rates of PPH in the deficient and insufficient groups were 6.9% (10/145) and 6.7% (17/254), respectively, and were significantly higher than the rate of the normal vitamin D group (1.5%, p = 0.009). Women with sufficient vitamin D levels had significantly higher hemoglobin levels than those with low vitamin D levels. Higher vitamin D levels were associated with a significantly low risk of PPH (AOR: 0.93, CI: 0.89-0.98, p = 0.006). Conclusion: Our results suggest that a low vitamin D level is a risk factor for PPH. Low vitamin D also related to high risk of low hemoglobin before delivery. Thus, antepartum care should include vitamin D supplements for all women if possible.

Outcomes and complications of severe acute postpartum hemorrhage treated with or without transarterial embolization in a single tertiary referral center: A 20-year experience.

OBJECTIVE: PPH is usually unpredictable; and such fast, urgent and sudden massive life-threating hemorrhage. This study is to assess the efficacy of transarterial embolization (TAE) in treating severe PPH in a single institution over a period of 20 years. MATERIALS AND METHODS: From January 2000 to October 2019, all women with acute PPH more than 1500 cc and/or DIC were enrolled in this retrospective study. These women were divided into two groups according to whether they have received TAE as the second-line treatment. Group 1 (n = 27) included women without receiving TAE from January 1, 2000 to October 31, 2009, and group 2 (n = 30) included those who receiving TAE from November 1, 2009 to October 31, 2019. RESULTS: The overall success rate of TAE in control the PPH and preserved the uterus is 80%. The hemoglobin 12 h after PPH in group 2 is significantly lower than in group 1 (7.64 ± 1.6 vs. 8.58 ± 1.9, respectively. P = 0.05). Total unit of packed red blood cell (pRBC) transfusion is significantly higher in the group 2 than group 1 (9.8 ± 5.7 vs. 6.8 ± 3.9; p = 0.03). The rate of hysterectomy is significantly higher in group 1 than group 2 (46.7 vs. 20%; p < 0.001). CONCLUSION: In conclusion, TAE is safe and effective in control bleeding in PPH with a high success rate to preserve uterus and prevent DIC. TAE should be routinely used as a secondary line of treatment during PPH in all hospitals.

Progestin primed ovarian stimulation using corifollitropin alfa in PCOS women effectively prevents LH surge and reduces injection burden compared to GnRH antagonist protocol.

Utilizing corifollitropin alfa in GnRH antagonist (GnRHant) protocol in conjunction with GnRH agonist trigger/freeze-all strategy (corifollitropin alfa/GnRHant protocol) was reported to have satisfactory outcomes in women with polycystic ovary syndrome (PCOS). Although lessening in gonadotropin injections, GnRHant were still needed. In addition to using corifollitropin alfa, GnRHant was replaced with an oral progestin as in progestin primed ovarian stimulation (PPOS) to further reduce the injection burden in this study. We try to investigate whether this regimen (corifollitropin alfa/PPOS protocol) could effectively reduce GnRHant injections and prevent premature LH surge in PCOS patients undergoing IVF/ICSI cycles. This is a retrospective cohort study recruiting 333 women with PCOS, with body weight between 50 and 70 kg, undergoing first IVF/ICSI cycle between August 2015 and July 2018. We used corifollitropin alfa/GnRHant protocol prior to Jan 2017 (n = 160), then changed to corifollitropin alfa/PPOS protocol (n = 173). All patients received corifollitropin alfa 100 µg on menstruation day 2/3 (S1). Additional rFSH was administered daily from S8. In corifollitropin alfa/GnRHant group, cetrorelix 0.25 mg/day was administered from S5 till the trigger day. In corifollitropin alfa/PPOS group, dydrogesterone 20 mg/day was given from S1 till the trigger day. GnRH agonist was used to trigger maturation of oocyte. All good quality day 5/6 embryos were frozen, and frozen-thawed embryo transfer (FET) was performed on subsequent cycle. A comparison of clinical outcomes was made between the two protocols. The primary endpoint was the incidence of premature LH surge and none of the patients occurred. Dydrogesterone successfully replace GnRHant to block LH surge while an average of 6.8 days of GnRHant injections were needed in the corifollitropin alfa/GnRHant group. No patients suffered from ovarian hyperstimulation syndrome (OHSS). The other clinical outcomes including additional duration/dose of daily gonadotropin administration, number of oocytes retrieved, and fertilization rate were similar between the two groups. The implantation rate, clinical pregnancy rate, and live birth rate in the first FET cycle were also similar between the two groups. In women with PCOS undergoing IVF/ICSI treatment, corifollitropin alfa/PPOS protocol could minimize the injections burden with comparable outcomes to corifollitropin alfa/GnRHant protocol.

Increased regulated on activation, normal T-cell expressed and secreted levels and cysteine-cysteine chemokine receptor 5 upregulation in omental adipose tissue and peripheral blood mononuclear cells are associated with testosterone level and insulin resistance in polycystic ovary syndrome.

OBJECTIVE: To study the relationship between circulating chemokine cysteine-cysteine motif ligand (CCL) 5 levels and cysteine-cysteine chemokine receptor type 5 (CCR5) expression in peripheral blood mononuclear cells (PBMCs) and adipose tissue with hyperandrogenism and insulin resistance in patients with polycystic ovary syndrome (PCOS). DESIGN: Case-control study. SETTING: University teaching hospital. PATIENT(S): Fifteen women with PCOS and 15 controls matched for body mass index and age were enrolled in this study. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Plasma levels of CCL3, CCL4, and CCL5 were determined using enzyme-linked immunosorbent assay kits, and omental adipose tissue and PBMCs were analyzed using real-time polymerase chain reaction to determine the expression level of CCR5 in participants. RESULT(S): Levels of CCL5 were significantly higher in women with PCOS. Expression of CCR5 in adipose tissue and PBMCs was significantly higher in women with PCOS compared with that in women in the control group. Cysteine-cysteine chemokine receptor type 5 expression also was upregulated in THP-1 cells after chronic exposure to testosterone. Levels of CCL5 had a significant positive correlation with testosterone levels in women with PCOS. Moreover, CCR5 showed a positive correlation with fasting glucose levels, homeostasis model insulin resistance index, and C-reactive protein. CONCLUSION(S): Increased levels of CCL5 and overexpression of CCR5 in PBMCs and adipose tissue are associated with hyperandrogenism and insulin resistance in women with PCOS. Additionally, CCR5 and CCL5 may be used as biomarkers in the pathogenesis of PCOS.

Cysteine-Cysteine Motif Chemokine Receptor 5 Expression in Letrozole-Induced Polycystic Ovary Syndrome Mice.

Polycystic ovary syndrome (PCOS), which affects 5-10% of women of reproductive age, is associated with reproductive and metabolic disorders, such as chronic anovulation, infertility, insulin resistance, and type 2 diabetes. However, the mechanism of PCOS is still unknown. Therefore, this study used a letrozole-exposed mouse model in which mice were orally fed letrozole for 20 weeks to investigate the effects of letrozole on the severity of reproductive and metabolic consequences and the expression of cysteine-cysteine motif chemokine receptor 5 (CCR5) in letrozole-induced PCOS mice. The letrozole-treated mice showed a disrupted estrous cycle and were arrested in the diestrus phase. Letrozole treatment also increased plasma testosterone levels, decreased estradiol levels, and caused multicystic follicle formation. Furthermore, histological analysis of the perigonadal white adipose tissue (pgWAT) showed no significant difference in the size and number of adipocytes between the letrozole-treated mice and the control group. Further, the letrozole-treated mice demonstrated glucose intolerance and insulin resistance during oral glucose and insulin tolerance testing. Additionally, the expression of CCR5 and cysteine-cysteine motif ligand 5 (CCL5) were significantly higher in the pgWAT of the letrozole-treated mice compared with the control group. CCR5 and CCL5 were also significantly correlated with the homeostasis model assessment of insulin resistance (HOMA-IR). Finally, the mechanisms of insulin resistance in PCOS may be caused by an increase in serine phosphorylation and a decrease in Akt phosphorylation.

Molecular Mechanisms of Laparoscopic Ovarian Drilling and Its Therapeutic Effects in Polycystic Ovary Syndrome.

Polycystic ovary syndrome (PCOS) is a common endocrinopathy, characterized by chronic anovulation, hyperandrogenism, and multiple small subcapsular cystic follicles in the ovary during ultrasonography, and affects 5-10% of women of reproductive age. PCOS is frequently associated with insulin resistance (IR) accompanied by compensatory hyperinsulinemia and, therefore, presents an increased risk of type 2 diabetes mellitus (DM). The pathophysiology of PCOS is unclear, and many hypotheses have been proposed. Among these hypotheses, IR and hyperandrogenism may be the two key factors. The first line of treatment in PCOS includes lifestyle changes and body weight reduction. Achieving a 5-15% body weight reduction may improve IR and PCOS-associated hormonal abnormalities. For women who desire pregnancy, clomiphene citrate (CC) is the front-line treatment for ovulation induction. Twenty five percent of women may fail to ovulate spontaneously after three cycles of CC treatment, which is called CC-resistant PCOS. For CC-resistant PCOS women, there are many strategies to improve ovulation rate, including medical treatment and surgical approaches. Among the various surgical approaches, one particular surgical method, called laparoscopic ovarian drilling (LOD), has been proposed as an alternative treatment. LOD results in an overall spontaneous ovulation rate of 30-90% and final pregnancy rates of 13-88%. These benefits are more significant for women with CC-resistant PCOS. Although the intra- and post-operative complications and sequelae are always important, we believe that a better understanding of the pathophysiological changes and/or molecular mechanisms after LOD may provide a rationale for this procedure. LOD, mediated mainly by thermal effects, produces a series of morphological and biochemical changes. These changes include the formation of artificial holes in the very thick cortical wall, loosening of the dense and hard cortical wall, destruction of ovarian follicles with a subsequently decreased amount of theca and/or granulosa cells, destruction of ovarian stromal tissue with the subsequent development of transient but purulent and acute inflammatory reactions to initiate the immune response, and the continuing leakage or drainage of "toxic" follicular fluid in these immature and growth-ceased pre-antral follicles. All these factors contribute to decreasing local and systemic androgen levels, the following apoptosis process with these pre-antral follicles to atresia; the re-starting of normal follicular recruitment, development, and maturation, and finally, the normalization of the "hypothalamus-pituitary-ovary" axis and subsequent spontaneous ovulation. The detailed local and systematic changes in PCOS women after LOD are comprehensively reviewed in the current article.

The Health Impact of Surgical Techniques and Assistive Methods Used in Cesarean Deliveries: A Systemic Review.

Cesarean delivery is one of the most frequently performed surgeries in women throughout the world. However, the most optimal technique to minimize maternal and fetal morbidities is still being debated due to various clinical situations and surgeons' preferences. The contentious topics are the use of vacuum devices other than traditional fundal pressure to assist in the delivery of the fetal head and the techniques of uterine repair used during cesarean deliveries. There are two well-described techniques for suturing the uterus: The uterus can be repaired either temporarily exteriorized (out of abdominal cavity) or in situ (within the peritoneal cavity). Numerous studies have attempted to compare these two techniques in different aspects, including operative time, blood loss, and maternal and fetal outcomes. This review provides an overview of the assistive method of vacuum devices compared with fundal pressure, and the two surgical techniques for uterine repair following cesarean delivery. This descriptive literature review was performed to address important issues for clinical practitioners. It aims to compare the advantages and disadvantages of the assistive methods and surgical techniques used in cesarean deliveries. All of the articles were retrieved from the databases Medline and PubMed using the search terms cesarean delivery, vacuum, and exteriorization. The searching results revealed that after exclusion, there were 9 and 13 eligible articles for vacuum assisted cesarean delivery and uterine exteriorization, respectively. Although several studies have concluded vacuum assistance for fetal extraction as a simple, effective, and beneficial method during fetal head delivery during cesarean delivery, further research is still required to clarify the safety of vacuum assistance. In general, compared to the use of in situ uterine repairs during cesarean delivery, uterine exteriorization for repairs may have benefits of less blood loss and shorter operative time. However, it may also carry a higher risk of intraoperative complications such as nausea and vomiting, uterine atony, and a longer time to the return of bowel function. Clinicians should consider these factors during shared decision-making with their pregnant patients to determine the most suitable techniques for cesarean deliveries.

Prenatal diagnosis of partial monosomy 2q (2q37.3→qter) and partial trisomy 10q (10q24.31→qter) of paternal origin associated with increased nuchal translucency and abnormal maternal serum screening results.

OBJECTIVE: We present prenatal diagnosis of terminal 2q deletion and distal 10q duplication of paternal origin in a fetus associated with increased nuchal translucency and abnormal maternal serum screening results. CASE REPORT: A 26-year-old woman who had experienced spontaneous abortion twice underwent amniocentesis at 16 weeks of gestation because of an increased nuchal translucency thickness of 3.5 mm at 12 weeks of gestation and abnormal maternal serum screening results of 2.573 multiples of the median (MoM) of free ß-human chorionic gonadotrophin (ß-hCG) and 1.536 MoM of pregnancy-associated plasma protein-A (PAPP-A) resulting in a trisomy 21 risk of 1:64. Amniocentesis revealed a derivative chromosome 2. Simultaneous array comparative genomic hybridization (aCGH) analysis on the DNA extracted from uncultured amniocytes revealed arr [hg19] 2q37.3 (238,294,223-242,782,258) × 1, 10q24.31q26.3 (102,018,246-135,426,386) × 3. Cytogenetic analysis of parental bloods revealed a karyotype of 46,XX in the mother and a karyotype of 46,XY,t(2;10)(q37.3;q24.3) in the father. The fetal karyotype was 46,XX,der(2)t(2;10)(q37.3;q24.3)pat. The pregnancy was terminated at 20 weeks of gestation, and a malformed fetus was delivered with facial dysmorphism. Postnatal analysis of the cord blood confirmed the results of prenatal diagnosis. The fetus had a 4.693-Mb deletion of 2q37.3 encompassing the genes of HDAC4, KIF1A, PASK, HDLBP, FARP2 and D2HGDH, and a 33.34-Mb duplication of 10q24.31-q26.3 encompassing the gene of NFκB2. CONCLUSION: First-trimester ultrasound and maternal serum biochemistry screening may help to identify an unexpected unbalanced familial translocation at prenatal diagnosis.

The use of dehydroepiandrosterone-treated rats is not a good animal model for the study of metabolic abnormalities in polycystic ovary syndrome.

OBJECTIVE: Hyperandrogenism is the hallmark of polycystic ovary syndrome (PCOS). The use of dehydroepiandrosterone (DHEA)-treated rats is thought to be a suitable animal model to study PCOS. In the present study, we assessed the severity of reproductive and metabolic abnormalities in DHEA-treated rats. MATERIAL AND METHODS: Immature female Sprague-Dawley rats were divided into control and DHEA-treated groups. Reproductive parameters including estrus cycle and sex hormones were measured after sexual maturity. Adiposity, insulin sensitivity, and plasma lipid profiles were analyzed to assess metabolic profiles. After sacrifice, the insulin signaling pathway and lipogenic genes were analyzed by immunoblotting and polymerase chain reaction, respectively. RESULTS: An abnormal estrus cycle was observed in the DHEA-treated rats. DHEA treatment also increased plasma testosterone levels and caused multiple cystic follicle formation, which is compatible with the definition of PCOS. There were no significant changes in fasting glucose, fasting insulin, plasma lipid profiles, and blood pressure levels. The adiposity of the DHEA-treated rats was also lower than in the control rats. Moreover, glucose tolerance and insulin sensitivity were only mildly impaired in the DHEA-treated rats after oral glucose tolerance and insulin tolerance tests, even though insulin signaling in skeletal muscles was decreased in the DHEA-treated group. CONCLUSION: DHEA-treated rats had reproductive abnormalities which mimicked symptoms of human PCOS. In metabolic parameters, DHEA treatment did not show insulin resistance in the female rats, suggesting that the use of DHEA-treated rats is not a good animal model for the study of metabolic abnormalities in PCOS.

Feasibility of corifollitropin alfa/GnRH antagonist protocol combined with GnRH agonist triggering and freeze-all strategy in polycystic ovary syndrome patients.

BACKGROUND/PURPOSE: The long-acting corifollitropin alfa is comparable to FSH in terms of pregnancy outcomes in normal responders and poor responders. Corifollitropin alfa has never been studied in polycystic ovary syndrome (PCOS) patients because of concerns of excessive ovarian stimulation and ovarian hyperstimulation syndrome (OHSS). The purpose of the study was to evaluate if corifollitropin alfa can be used in PCOS patients. METHODS: Forty PCOS patients who were going to undergo in vitro fertilization were enrolled in this study. A single injection of corifollitropin alfa was administered on cycle day 2 or day 3. From stimulation day 8 onwards, daily FSH was administered until the day of final oocyte maturation. Cetrorelix was administered from stimulation day 5 to prevent premature LH surge. Final oocyte maturation was triggered by: acetate. All embryos were cryopreserved and replaced in subsequent cycles. RESULTS: All 40 patients were subjected to oocyte retrieval, and none developed moderate or severe ovarian hyperstimulation syndrome (0%, 95% CI 0-0.088). For each patient, an average of 23.4 (±7.4; 95% CI 21.0-25.7) oocytes were retrieved and a mean of 11.7 (±6.4; 95% CI 9.6-13.8) embryos were frozen. Mean serum estradiol level on the day of GnRHa triggering was 7829.9 pg/ml (±3297; 95% CI 6775-8885). The cumulated ongoing pregnancy rate after 3 frozen-thawed embryo transfers was 75.0% (95% CI 61.6%-88.4%). CONCLUSION: The results suggest that corifollitropin alfa/GnRH antagonist protocol can be used in PCOS patients, in combination with GnRHa triggering and embryo cryopreservation.

Fertility outcomes following pelvic embolization in women with acquired uterine arteriovenous malformation.

OBJECTIVE: Acquired uterine arteriovenous malformation (UAVM) is a rare, life-threatening disease. Angiography with uterine arterial embolization (UAE) is the diagnostic tool and a choice of fertility-sparing treatment. Here, we present a series of five successful pregnancies after embolization of UAVM. CASE REPORTS: Three reproductive aged women were treated for UAVM, resulting in five successful pregnancies. Their past history suggested that three cases had had previous uterine procedures, including second trimester abortion and elective dilatation and curettage. Intermittent heavy vaginal bleeding was the primary symptom of UAVM. One patient with anemia had two ineffective embolizations and achieved a singleton pregnancy after the third embolization. However, intrauterine fetal demise with severe fetal growth retardation was noted on the 28th gestation week. The other two women had temporary ovulation disorder after UAE. After Clomiphene Citrate (CC) treatment, successful pregnancies were achieved and carried to term uneventfully. CONCLUSION: UAE is an acceptable method for preserving fertility and treatment in women with symptomatic UAVMs.

Progression of gestational hypertension to pre-eclampsia: A cohort study of 20,103 pregnancies.

OBJECTIVE: To investigate previously un-identified risk factors for the progression of gestational hypertension (GH) to pre-eclampsia (PE) by considering Grade III preterm placental calcification (PPC) and excessive weight gain (≧10kgw) at 28weeks gestation. METHODS: At a tertiary teaching hospital, obstetric ultrasonography was performed at 28weeks gestation to establish a diagnosis of grade III PPC. Weight gain during pregnancy was recorded at the same time. Pregnancies complicated with chronic hypertension, major fetal congenital anomalies, termination before 24weeks gestation, and abortion before 20 weeks gestation were excluded. RESULTS: In the current cohort study, 20,103 pregnancies were enrolled and categorized as normal blood pressure (NBP; n=18,223) and GH-PE (n=1880) groups. According to severity of the diseases, the GH-PE group was further divided into GH (n=1088), PE (n=792), and severe PE (n=209) groups. There were significant differences between the NBP and GH-PE groups in known factors, including maternal age, BMI, parity, multi-fetal pregnancy, and co-morbidities (all p<0.001), all of which increased the risk for GH-PE. Regarding the progression of GH to PE and severe PE, there was a much greater frequency of excessive weight gain (51.2% and 49.0% vs. 9.3%) or PPC (63.2% and 61.6% vs. 12.1%) in the severe PE and PE groups than the GH group. Logistic regression analysis revealed that PPC was a significant and independent risk factor for progression of GH to PE (OR, 13.71; 95% CI, 10.25-18.33) and severe PE (OR, 12.42; 95% CI, 8.89-17.35), as well as excessive weight gain during pregnancy (OR, 8.92; 95% CI, 6.67-11.92 and OR, 10.25; 95% CI, 7.30-12.40). CONCLUSION: Being a pathologic implication, the presence of PPC or excessive weight gain during pregnancy may precede progression of GH, and can serve as a warning or marker that requires closer surveillance for maternal and fetal well-being. Based on the findings of PPC and excessive weight gain, at-risk pregnant woman should be counseled to facilitate early intervention or referral. In addition, avoiding excessive weight gain during pregnancy may reduce the risk of GH progression to PE.

Carbetocin versus oxytocin for prevention of postpartum hemorrhage in infertile women with twin pregnancy undergoing elective cesarean delivery.

OBJECTIVE: To compare the efficacy and safety of carbetocin with those of oxytocin infusion in women with twin pregnancy undergoing elective cesarean delivery. MATERIAL AND METHODS: The present observational study conducted from January to December 2014 at a single center in Taiwan enrolled 64 women with twin pregnancy induced using in vitro fertilization-embryo transfer. The women were divided into a carbetocin group who received a single injection of 100 µg carbetocin (n = 25) and a control group who received a continuous intravenous infusion of 10 IU oxytocin in 500 mL 0.9% NaCl solution (125 mL/h) for 24 h (n = 39). Operative outcomes were compared between the groups. RESULTS: The mean estimated blood loss during surgery was lower in the carbetocin group compared with the control group (871 ± 305 and 922.8 ± 430 mL, respectively), but the difference was not significant (P = 0.06). There was also no significant difference in the drop in hemoglobin level between two groups. The mean operative time was significantly shorter in the carbetocin group compared with the control group (P = 0.001). CONCLUSION: Carbetocin is as effective as oxytocin in preventing primary postpartum hemorrhage in infertile women with twin pregnancy undergoing elective cesarean delivery.

Uterine Suspension With Adjustable Sutures for Difficult Laparoscopic Myomectomy.

STUDY OBJECTIVE: To assess whether transabdominal uterine suspension with adjustable sutures (USAS) is beneficial when performed concomitantly with laparoscopic myomectomy in patients with unfavorably localized leiomyomas in whom uterine manipulators are not an option. DESIGN: A retrospective cohort study (Canadian Task Force classification II-2). SETTING: A university teaching hospital. PATIENTS: Patients (N = 158) with posterior deep intramural, intraligamental, or cervical leiomyomas; 81 patients underwent USAS (suspension group), and 77 patients did not (control group) concomitantly with laparoscopic myomectomy. INTERVENTIONS: Transabdominal USAS was performed for all eligible patients undergoing laparoscopic myomectomy using a 2-0 synthetic, monofilament, nonabsorbable polypropylene suture. One end of the double-headed straight needles of the polypropylene suture was inserted into the pelvic cavity through the abdomen to "lift" or "retract" the uterus to allow for the main tumor to be completely exposed and excised. MEASUREMENTS AND MAIN RESULTS: The average time to create USAS was 2.5 minutes. For the suspension and control groups, the average number of abdominal ports was 3 and 4.4 (p < .001), the average blood loss was 96.3 and 201.5 mL (p < .001), and the average operative time was 50.8 and 91.2 minutes (p < .001), respectively. There was no significant difference in complications (4.9% vs 9.1%, p = .303), but there was a significant difference in conversion to laparotomy (1.2% vs 10.4%, p = .009). At the 3-year follow-up, there were no significant differences in gynecologic and reproductive outcomes, including leiomyoma recurrence, uterine rupture, and pregnancy and live birth rates. The ratio of conversion to laparotomy (odds ratio = 0.108; 95% confidence interval, 0.013-0.884) was much lower in the suspension group. CONCLUSION: USAS is an easy, safe, and feasible alternative to uterine manipulation when performed concomitantly with laparoscopic myomectomy for unfavorably localized uterine leiomyomas.