Reproductive Medicine doi: 10.3390/reprodmed5010003
Authors: Nadi Nina Kaonga Yanghee Courbron Emmy Holmgren Eliot Konzal Whitney Williams Mary Brandes Caroline Foust-Wright
Background: Higher levels of pre-operative anxiety are associated with adverse outcomes according to the cardiothoracic and orthopedic literature on emergent surgeries. There are limited data on pre-operative anxiety levels in the gynecologic setting. This study sought to identify predictive variables for high pre-operative anxiety levels in patients undergoing major urogynecologic surgery. Methods: Pre- and post-operative surveys that included demographic data, a modification of the Amsterdam Pre-Operative Anxiety and Information Scale, and open-ended questions regarding anxiety were administered. Descriptive, univariate and multivariate analyses were used to analyze the quantitative elements of the survey data. The qualitative components of the survey data were coded and analyzed using thematic analyses. Results: A total of 54 participants completed the pre-operative survey. The median age was 62 years old, and the majority were employed (n = 34, 60.7%). Roughly 1/3 had been diagnosed with a mental health condition (n = 19, 33.9%) and nearly all had other health conditions (n = 51, 91%). The baseline APAIS score ranged from 9 to 40, with higher scores reflecting higher levels of pre-operative anxiety. The median APAIS score was 24, with a score equal to or greater than 30 being in the highest tertile. Conclusion: No associations were made between the variables and pre-operative anxiety levels. However, useful insights into our patient population were made.
]]>Reproductive Medicine doi: 10.3390/reprodmed5010002
Authors: Sara Yalda Ghaur Pernille Bundgaard Grinderslev Magnus Leth-Møller Per Glud Ovesen Jens Fuglsang Sanne Fisker H. David McIntyre Ulla Kampmann
Pregnancies complicated by type 1 diabetes (TID) are associated with an increased risk of obstetric and neonatal adverse outcomes. Optimal glycemic control prior to and through pregnancy is crucial to reduce complications. The use of diabetes technology is rapidly increasing. The aim of the study was to investigate the use and effects of diabetes technology in pregnant women with type 1 diabetes. A retrospective cohort study was conducted; 84 women were included in the analysis and were divided into subgroups according to their glucose monitoring method and insulin delivery method. HbA1c values declined during pregnancy in all subgroups with no significant difference between the subgroups. A difference was, however, found in birth weight z-scores. Women using a sensor and an insulin pump had larger babies compared to women without these treatment modalities. The results of the study indicate that diabetes technology, including insulin pumps and/or glucose sensors are not superior to self-monitoring blood glucose measurement and multiple daily injection insulin therapy, which is comforting in the light of the unequal access to health benefits.
]]>Reproductive Medicine doi: 10.3390/reprodmed5010001
Authors: Katrina L. Curtis Kelsey M. Hirshi Kary Tsai Evan T. Clark Brendan M. Stapley Benjamin T. Bikman Paul R. Reynolds Juan Arroyo
Exposure to secondhand smoke (SHS) during fetal development results in negative postnatal effects, including altered organ development, changes in metabolism, and increased risk of respiratory illness. Previously, we found the induction of intrauterine growth restriction (IUGR) dependent on the expression of the receptor for advanced glycation end-products (RAGE) in mice treated with SHS. Furthermore, antenatal SHS exposure increases RAGE expression in the fetal lung. Our objective was to determine the postnatal effects of antenatal SHS treatment in 4- and 12-week-old offspring. Pregnant animals were treated with SHS via a nose-only delivery system (Scireq Scientific, Montreal, Canada) for 4 days (embryonic day 14.5 through 18.5), and offspring were evaluated at 4 or 12 weeks of age. Animal and organ weights were measured, and lungs were histologically characterized. Blood pressure and heart rates were obtained, and RAGE protein expression was determined in the lungs of control and treated animals. We observed the following: (1) significant decreases in animal, liver, and heart weights at 4 weeks of age; (2) increased blood pressure in 4-week-old animals; and (3) increased RAGE expression in the lungs of the 4-week-old animals. Our results suggest an improvement in these metrics by 12 weeks postnatally such that measures were not different regardless of RA or SHS exposure. Increased RAGE expression in lungs from 4-week-old mice antenatally treated with SHS suggests a possible role for this important smoke-mediated receptor in establishing adult disease following IUGR pregnancies.
]]>Reproductive Medicine doi: 10.3390/reprodmed4040023
Authors: Meghan C. H. Ozcan Julienne Chaqour Morgan F. Woodman-Sousa Kathryn J. Grive
Current safety data on chemotherapy during pregnancy are based on studies which focus on the mother and do not explore reproductive health and fecundity potential within the exposed offspring. We designed this randomized ex vivo animal study to evaluate the effect of chemotherapy on the developing ovarian reserve in the exposed offspring. Specimens (100 postnatal day zero C57BL/6 mouse ovaries) were randomized to control or chemotherapy drug exposure and maintained in a hanging well organ culture. Murine ovarian reserve establishment mirrors activity seen in the human fetus but with a significant time shift of the transition to meiotic arrest to the postnatal period. Exposures included: doxorubicin, cyclophosphamide, paclitaxel, docetaxel, and cisplatin. Doxorubicin resulted in a significant loss of 95.2% (p < 0.0001) of oocyte density compared to controls. Cyclophosphamide also caused depletion of 50.5% (p < 0.0001) of oocyte density. Cisplatin, docetaxel, and paclitaxel all demonstrated unique phenotypical changes on the ovaries and their oocytes, without a significant decrease in oocyte density over a five-day exposure. Exposure to chemotherapy may result in profound loss of oogonia during the transition to mature oocytes.
]]>Reproductive Medicine doi: 10.3390/reprodmed4040022
Authors: Stephanie C. Laniewski LauraAnne Hirschler Anwar M. Iqbal Neil S. Seligman
This case presents a novel occurrence of a de novo BRCA1 gene deletion in a fetus with a cystic hygroma. Chorionic villus sampling (CVS) was performed for chromosome G-banding analysis, demonstrating a normal karyotype: 46, XX. Chromosome microarray analysis performed as a reflex test revealed an 80 kb deletion on 17q21.31, encompassing the BRCA1 gene. Follow-up FISH analysis performed on parental blood samples yielded negative results, confirming that the deletion was de novo in the fetus. Subsequent anatomic ultrasound evaluation showed no identifiable structural defects, and it was concluded that the microdeletion was unlikely to be the cause of the cystic hygroma. Regardless, it will be imperative that the patient’s daughter be appropriately counseled regarding the implications of carrying a BRCA1 deletion and the need for heightened surveillance in adulthood. As BRCA1 genetic testing is traditionally performed on adult patients with informed consent, this case report highlights the need for ongoing conversations and research in the management of incidental fetal diagnosis discovered during routine prenatal testing, as well as the care and counseling of these patients and their families.
]]>Reproductive Medicine doi: 10.3390/reprodmed4030021
Authors: Angel Chimenea Lutgardo García-Díaz Ana Méndez Guillermo Antiñolo
Background: Transposition of the great arteries (TGA) is a common critical neonatal congenital heart defect. After birth, physiological shunts close rapidly, necessitating early treatment with prostaglandin infusion and balloon-atrial septostomy. Timing of delivery is challenging, balancing the risks and advantages of early-term delivery and specialized care. The aim of this study is to assess the safety of a full-term delivery policy in fetuses diagnosed with TGA. Methods: A retrospective chart review was conducted of 17 women with a prenatal diagnosis of fetal TGA at Virgen del Rocío University Hospital between 2015 and 2021. Primary outcomes included: incidence of preterm, early-term, full-term, and late-term delivery, and rate of cesarean section. Secondary outcomes included: Saturday to Sunday admission and birth, and delivery between 0:00 a.m. and 8:00 a.m. Results: Full-term birth was achieved in 94.1%, reaching a low cesarean delivery rate (17.6%). A total of 82.4% of infants were born on weekdays, and only in three of the cases (17.6%) did delivery occur between 0 a.m. and 8 a.m. The median birth weight was 3300 g. Intravenous prostaglandins were administered in all cases, and 94.1% required balloon-atrial septostomy. Conclusions: In our study favoring full-term delivery, we reduce early-term deliveries and the cesarean section rate in prenatally diagnosed TGA.
]]>Reproductive Medicine doi: 10.3390/reprodmed4030020
Authors: In Ki Cho Charles A. Easley
Recent developments in stem cell technologies have made significant advancements in the field of in vitro gametogenesis. In vitro gametogenesis (IVG) is a promising technology where functional gametes (sperm or egg cells) can be generated from stem cells. Scientists have made continuous advancements in the field and successfully derived fully functional sperm from stem cells in mice. Two recent papers generated excitement in IVG by generating bi-maternal and bi-paternal mice from embryonic stem cells (ESCs) and pluripotent stem cells (PSCs). IVG is a promising technology with potential applications that include infertility treatment, fertility preservation, same-sex reproduction, bypassing oocyte depletion in women with advanced age, conservation biology, genetic disorder prevention, and research into human germ cell development. In vitro spermatogenesis (IVS) is the attempt to recreate the process of spermatogenesis in a culture system. Spermatogenesis is essential for male fertility and reproductive health, but it can be impaired by various factors such as genetic defects, environmental toxicants, infections, aging, or medical therapies. Spermatogenesis is a complex and highly regulated process involving multiple cell proliferation, differentiation, and maturation stages. The main challenges of IVS are to provide a suitable microenvironment that mimics the testis in vivo, to support the survival and development of all the cell types involved in spermatogenesis, and to achieve complete and functional spermatogenesis. Therefore, there is a great interest in developing methods to study spermatogenesis in vitro, both for basic research and clinical applications. This review covers recent developments in in vitro spermatogenesis in the past two years. Advances in tissue engineering and regenerative medicine have introduced techniques like ex vivo tissue culture and technologies such as bioreactors, microfluidic systems, and organoids. Bioreactors and microfluidic systems replicate physiological conditions for tissue and cell cultivation, while organoids model organ functionality. Meanwhile, scaffolds, made from various materials, provide essential structural support, guiding the growth and organization of cells into functional tissues.
]]>Reproductive Medicine doi: 10.3390/reprodmed4030019
Authors: Stefano Palomba
It is a great pleasure to introduce this Special Issue celebrating the third year since the founding of Reproductive Medicine [...]
]]>Reproductive Medicine doi: 10.3390/reprodmed4030018
Authors: Luisa Casadei Ilaria Nacci Veronica Vicomandi Roberto Pietro Sorge Carlo Ticconi
This study, carried out on 94 women with polycystic ovary syndrome (PCOS) and 176 controls without it, investigated the influence of body mass index (BMI) on serum levels of antimüllerian hormone (AMH), follicle stimulating hormone (FSH), luteinizing hormone (LH), and 17ß-estradiol (E2) in infertile patients. Patients were assigned to four subgroups according to age (<35 or ≥35 years) and BMI (<25 kg/m2 or ≥25 kg/m2). Significant differences between PCOS-affected and control women were observed with respect to most of the parameters of interest. In both PCOS-affected and control women, age was inversely correlated with AMH. In the control patients, age was directly correlated with FSH and LH. In women affected by PCOS, no correlation was found between BMI and serum levels of AMH, E2, and LH, except FSH. No correlation was found between BMI and markers of ovarian reserve in control women. BMI was not correlated with AMH in any of the four subgroups considered regardless of the presence of PCOS. An inverse correlation was found only in PCOS-affected women aged ≥35 years between a BMI < 25/FSH and a BMI ≥ 25/LH. The possible association between BMI and ovulation disorder (OD) was investigated in 96 control women aged ≤37 years. In women with OD, the BMI values were significantly higher and FSH and E2 levels were lower than those of patients without OD. Taken together, our data suggest that BMI is not related to hormonal parameters of ovarian reserve, irrespective of the presence of PCOS, and could influence ovulation disorder rather than cause a decrease in ovarian reserve.
]]>Reproductive Medicine doi: 10.3390/reprodmed4030017
Authors: Nariman Hossein-Javaheri Michael Youssef Yaanu Jeyakumar Vivian Huang Parul Tandon
Inflammatory bowel disease (IBD) frequently affects women of childbearing age and often coincides with pregnancy. With an increased incidence of IBD, gastroenterologists and obstetricians are more frequently involved in caring for women of reproductive age. While the development of novel therapies has allowed for successful conception and pregnancy outcomes, many patients may hesitate to conceive due to concerns for presumed adverse IBD effects on maternal and fetal health. As such, a noticeable percentage of patients may choose voluntary childlessness. Indeed, active IBD carries a greater risk of adverse pregnancy outcomes, including a loss of pregnancy, preterm delivery, and emergent C-sections. However, those with a quiescent disease tend to have fewer pregnancy complications. Therefore, it is essential to achieve remission prior to conception to optimize pregnancy outcomes. Dedicated IBD and pregnancy clinics can greatly assist in improving patient knowledge and attitudes towards pregnancy; through individualized pre-conception counseling, education, and medication adherence, the risks of poor pregnancy outcomes can be minimized. Furthermore, it is important for healthcare providers to have a sufficient understanding of the medication safety and tools to measure the disease activity, while counseling patients during gestation and breastfeeding periods. This review article aims to provide the most recent evidence-based management methods for IBD during pregnancy.
]]>Reproductive Medicine doi: 10.3390/reprodmed4030016
Authors: Lada H. Nechval Kathleen M. Antony
Travel is frequent among many populations, including pregnant people. The focus of this online survey was to better understand the travel practices of people who have been pregnant within the last ten years. An online survey was conducted for three months through social media posts on Facebook and Twitter. Previously pregnant people were asked questions about where they traveled, if they cancelled any travel plans, and travel-related discussions with their obstetric provider. During the three months the survey was open, 469 participants completed the survey. A total of 390 (83.2%) participants traveled domestically, while 114 (24.3%) traveled internationally or between non-contiguous states within the United States of America (USA). Of these respondents, 170 (44.2%) of the domestic travelers and 69 (61.1%) of the international travelers reported discussing travel plans with their OB provider. Additionally, 49 (10.5%) participants cancelled at least one domestic trip and 30 (6.41%) cancelled at least one international trip. Regarding travel discussions, 6 (3.6%) participants who traveled domestically and 2 (2.9%) who traveled internationally reported that their OB provider initiated the conversation. Many pregnant people choose to travel domestically and internationally. However, it is also clear that not all travelers discuss plans with their OB provider, and in few cases does the provider initiate the conversation. Given the frequency with which people travel, pregnant people and their OB providers should have conversations regarding travel to minimize potential risks.
]]>Reproductive Medicine doi: 10.3390/reprodmed4030015
Authors: Marwan Habiba Giuseppe Benagiano
Most published research focuses on the amount of menstrual blood loss and, to a lesser extent, on cyclicity. Little attention has been paid to the duration of bleeding, the factors that enable its cessation within a ‘normal’ timeframe, or to patterns that entail interruption and resumption of blood loss. The definition of what constitutes normal remains arbitrary and there is no therapy specifically designed to shorten the duration of bleeding. Here, we critically review the literature that addresses the duration of bleeding and the factors that trigger endometrial breakdown and repair. Available reports used population averages which mask inter- and intra-individual variations. The duration of bleeding is not necessarily linked to the amount of loss but may be influenced by age, ethnicity, habitus, region and altitude of residence, dieting and stress. The onset of bleeding has been linked to declining steroid production by the corpus luteum. There remains considerable controversy around the extent of endometrial shedding at menstruation. This is likely to vary within and between women. The significance of a change from previous patterns, very short or prolonged bleeding, days of light loss or spotting before or after days of bleeding, or of bleed-free days that punctuate flow, remain poorly understood.
]]>Reproductive Medicine doi: 10.3390/reprodmed4030014
Authors: Anna S. Koefoed H. David McIntyre Kristen S. Gibbons Charlotte W. Poulsen Jens Fuglsang Per G. Ovesen
Gestational diabetes mellitus (GDM) is associated with adverse pregnancy outcomes including large for gestational age infants. Individualizing the management of women with GDM based on the likelihood of needing insulin may improve pregnancy outcomes. The aim of this study is to identify characteristics associated with a need for insulin in women with GDM, and to develop a predictive model for insulin requirement. A historical cohort study was conducted among all women with GDM in a singleton pregnancy at Aarhus University Hospital from 2012 to 2017. Variables associated with insulin treatment were identified through multivariable logistic regression. The variables were dichotomized and included in a point scoring system aiming to predict the likelihood of needing insulin. Seven variables were associated with needing insulin: family history of diabetes, current smoker, multiparity, prepregnancy body mass index, gestational age at the oral glucose tolerance test (OGTT), 2-h glucose value at the OGTT and hemoglobin A1c at diagnosis. A risk score was calculated assigning one point to each variable. On ROC analysis, a cut-off value of ≥3 points optimally predicted a requirement for insulin. This prediction model may be clinically useful to predict requirement for insulin treatment after further validation.
]]>Reproductive Medicine doi: 10.3390/reprodmed4020013
Authors: Jerome H. Check Diane L. Check Aniela Bollendorf
For over 30 years, defects of the functional integrity of the sperm membrane, as evidenced by a low hypo-osmotic swelling test when evaluating the semen analysis, are not only associated with male infertility (even with sperm that otherwise seem normal), but unless corrected, successful intrauterine pregnancies will rarely ensue. This defect, interestingly, does not impair fertilization of the oocyte, but instead, prevents a normal-appearing embryo from successfully implanting. The frequency in infertile couples increases with advancing age of the male, ranging from 5% in younger males to 25% in men in their late forties or early fifties. It seems to be related to a toxic protein added to the sperm as they traverse the ejaculatory ducts. The defect is very correctable, either by treating the sperm with the protein digestive enzyme chymotrypsin prior to intrauterine insemination and avoidance of unprotected sex prior to ovulation, or in vitro fertilization with intracytoplasmic sperm injection. Unfortunately, this very inexpensive, easy-to-perform test is rarely performed by the large majority of physicians treating infertility. The purpose of this manuscript is to hopefully rekindle interest within the infertility community to add this test to the standard semen analysis.
]]>Reproductive Medicine doi: 10.3390/reprodmed4020012
Authors: David Waynforth
Psychomotor developmental delay in infants includes failure to acquire abilities such as sitting, walking, grasping objects and communication at the ages when most infants have acquired these abilities. Known risk factors include a large number of aspects of family environment, socioeconomic position, problems in pregnancy and birth and maternal health. It is clinically useful to be able to screen for developmental delay so that healthcare interventions can be considered. The present research used machine learning (random forest) to create an algorithm predicting psychomotor delay in 9-month-old infants using information ascertainable at birth and in early infancy. The dataset was the UK longitudinal Millennium Cohort study. In total, 53 predictors measuring socioeconomic indicators, paternal, family and social support for the mother, beliefs about good parenting, maternal health, pregnancy and birth were included in the initial algorithm. Feature reduction showed that of the 53 variables, birthweight, gestational age at birth, pre-pregnancy BMI, family income and parents’ ages had the highest feature importance scores and could alone correctly predict developmental delay with over 99% sensitivity and 100% specificity. No features measuring aspects of early infant care or environment meaningfully added to algorithm performance. The relationships between delay and some of the predictors, particularly income, were nonlinear and complex. The results suggest that the risk of psychomotor developmental delay can be identified in early infancy using machine learning, and that the best predictors are factors present prior to and at birth.
]]>Reproductive Medicine doi: 10.3390/reprodmed4020011
Authors: Johnny S. Younis
Endometriosis-associated ovarian cancer (EAOC) is an evolving clinical entity believed to develop from ovarian endometriosis. Continuous efforts are nowadays invested in exploring its pathogenesis and causality. Since endometrioma is a widespread sub-type of the disease, malignant transformation to EAOC during reproductive age may cause much concern and affect its management. The summary relative risk of developing EAOC in women with endometriosis is 1.93-fold compared to women without endometriosis, but its lifetime risk is relatively low, equivalent to 2.1%. EAOC is an age-dependent disease with a mean age of 51.64 ± 3.24 years at diagnosis; 30.68% of patients are below 50, presumably premenopausal. Only 2.10% and 0.017% of cases are below 45 and 40 years, apparently in reproductive age. The evidence is reassuring and implies that managing an intact endometrioma should not be altered in most women of reproductive age. Particular attention should be focused on sporadic cases with an enlarging endometrioma, atypical findings on transvaginal ultrasound (TVUS), and characteristic magnetic resonance imaging (MRI) features.
]]>Reproductive Medicine doi: 10.3390/reprodmed4020010
Authors: Mami Ishikuro Taku Obara Keiko Murakami Fumihiko Ueno Aoi Noda Tomomi Onuma Fumiko Matsuzaki Masahiro Kikuya Zen Watanabe Naomi Shiga Masahito Tachibana Noriyuki Iwama Hirotaka Hamada Masatoshi Saito Junichi Sugawara Hirohito Metoki Nobuo Yaegashi Shinichi Kuriyama
Infertility treatment is a possible factor in hypertensive disorders of pregnancy (HDP). Identifying the characteristics of pregnant women who have undergone infertility treatment and have a potential risk for HDP is valuable for its prevention and treatment. Using data from 12,456 pregnant Japanese women from the Tohoku Medical Megabank Project Birth and Three-Generation Cohort Study, the association between infertility treatment and HDP was analyzed. A multiple logistic regression model showed an association between infertility treatment and HDP (odds ratio, 1.34; 95% confidence interval, 1.05–1.72). In vitro fertilization/intracytoplasmic sperm injection were also associated with HDP. Moreover, these associations were observed even among women who were not overweight and did not smoke. The application of infertility treatment should be carefully considered, even among women with low modifiable risk factors.
]]>Reproductive Medicine doi: 10.3390/reprodmed4020009
Authors: Itti Munshi Geetanjali Sachdeva
Endometrium, a highly dynamic tissue, is known for its remarkable ability to regenerate, differentiate, and degenerate in a non-conception cycle and transform into a specialized tissue to nurture and protect the embryo in a conception cycle. This plasticity of the endometrium endows the uterus to execute its major function, i.e., embryo implantation. However, this boon becomes a bane, when endometrium- or endometrium-like cells adhere, grow, and invade extrauterine sites, leading to endometriosis. Endometrial deposits at the extrauterine site lead to severe pelvic pain, painful menstruation, and infertility in endometriosis. Although benign, endometriotic lesions share several traits with cancerous cells, excessive proliferation, adhesion, invasion, and angiogenesis make endometriotic lesions analogous to cancer cells in certain aspects. There exists evidence to support that, akin to the cancer cell, endometriotic lesions harbor somatic mutations. These lesions are known to experience higher proliferative stress, oxidative stress, and inflammation, which may contribute to somatic mutations. However, it would be of more interest to establish whether in the eutopic endometriosis also, the mutational burden is higher or whether the DNA Damage Response (DDR) is compromised in the eutopic endometrium, in endometriosis. Such investigations may provide more insights into the pathobiology of endometriosis and may also unravel cellular events associated with the origin of the disease. This review compiles inferences from the studies conducted to assess DNA damage and DDR in endometriosis.
]]>Reproductive Medicine doi: 10.3390/reprodmed4010008
Authors: Bruce I. Rose Kevin Nguyen
Purpose: In vitro maturation (IVM) continues its evolution as new ideas are introduced with the objective of making the IVM procedure easier and more effective. This study combines ideas believed likely to improve the IVM outcome or make the IVM oocyte identification process easier. Methods: A cohort of 45 women underwent an IVM cycle in which letrozole was used with the theoretical objective of improving the competence of small antral follicles, the oocyte aspiration technique was modified to minimize the time between oocyte aspiration and oocyte identification, and blastocysts were transferred during a subsequent cycle with controlled endometrial development. Results: Measures of oocyte competence used for these prospectively followed cycles were as follows: the maturation rate was 90.5%, the fertilization rate was 92.4%, the cleavage rate was 94.6%, the usable blastulation rate per zygote was 50.2%, and the implantation rate was 34.2%. Per transfer, the biochemical pregnancy rate was 63.2%, the clinical pregnancy rate was 55.3% and the ongoing/delivered pregnancy rate at the end of the first trimester was 47.4%. The miscarriage rate for clinical pregnancies in the first trimester was 14.3% and the ongoing twinning rate was 11.1%.
]]>Reproductive Medicine doi: 10.3390/reprodmed4010007
Authors: Virginie Simon Maëliss Peigné Didier Dewailly
Polycystic ovary syndrome is a common endocrine disorder affecting 5–20% of women in association with metabolic disorders and insulin resistance. Patients with PCOS are also at increased risk of developing cardiovascular sound aspects of polycystic ovaries and metabolic complications, a psychosocial impact that exists, which is poorly known, assessed and treated. The delay, sometimes long, for diagnosis and its announcement has a strong impact on the feelings and life projects of these patients. Psychological co-morbidities such as depression, anxiety, eating disorders as well as a decrease in self-esteem and quality of life are frequently described in these patients and must, therefore, be screened and treated.
]]>Reproductive Medicine doi: 10.3390/reprodmed4010006
Authors: Adam Stevens Taqua Khashkhusha Megan Sharps Terence Garner Peter T. Ruane John D. Aplin
Background: Single cell transcriptomics offers an avenue for predicting, with improved accuracy, the gene networks that are involved in the establishment of the first direct cell–cell interactions between the blastocyst and the maternal luminal epithelium. We hypothesised that in silico modelling of the maternal–embryonic interface may provide a causal model of these interactions, leading to the identification of genes associated with a successful initiation of implantation. Methods: Bulk and single cell RNA-sequencing of endometrial epithelium and scRNAseq of day 6 and 7 trophectoderm (TE) were used to model the initial encounter between the blastocyst and the maternal uterine lining epithelium in silico. In silico modelling of the maternal–embryonic interface was performed using hypernetwork (HN) analysis of genes mediating endometrial–TE interactions and the wider endometrial epithelial transcriptome. A hypernetwork analysis identifies genes that co-ordinate the expression of many other genes to derive a higher order interaction likely to be causally linked to the function. Potential interactions of TE with non-ciliated luminal cells, ciliated cells, and glandular cells were examined. Results: Prominent epithelial activities include secretion, endocytosis, ion transport, adhesion, and immune modulation. Three highly correlated clusters of 25, 22 and 26 TE-interacting epithelial surface genes were identified, each with distinct properties. Genes in both ciliated and non-ciliated luminal epithelial cells and glandular cells exhibit significant functional associations. Ciliated cells are predicted to bind to TE via galectin–glycan interaction. Day 6 and day 7 embryonic–epithelial interactomes are largely similar. The removal of aneuploid TE-derived mRNA invoked only subtle differences. No direct interaction with the maternal gland epithelial cell surface is predicted. These functional differences validate the in silico segregation of phenotypes. Single cell analysis of the epithelium revealed significant change with the cycle phase, but differences in the cell phenotype between individual donors were also present. Conclusions: A hypernetwork analysis can identify epithelial gene clusters that show correlated change during the menstrual cycle and can be interfaced with TE genes to predict pathways and processes occurring during the initiation of embryo–epithelial interaction in the mid-secretory phase. The data are on a scale that is realistic for functional dissection using current ex vivo human implantation models. A focus on luminal epithelial cells may allow a resolution to the current bottleneck of endometrial receptivity testing based on tissue lysates, which is confounded by noise from multiple diverse cell populations.
]]>Reproductive Medicine doi: 10.3390/reprodmed4010005
Authors: Thanvi Vatti Kathryn Coyne Sung Tae Kim Joseph Findley Rebecca Flyckt Rachel Weinerman
Single embryo transfer (SET) is a technique used in assisted reproductive treatment (ART) that is used to promote singleton pregnancies. To date, there are five reported cases of dizygotic twin pregnancies with mothers who underwent SET. Here, we present a sixth case of a dichorionic, diamniotic twin pregnancy with sex discordance. The patient is a 34-year-old woman with unexplained secondary infertility who underwent in vitro fertilization (IVF) and frozen-thawed embryo transfer from a SET. The ultrasonographic images from the first and second trimester scans identified dichorionic, diamniotic twin gestations. The delivery was full term and postnatal genetic testing confirmed 46, XX, and 46, XY offspring. Pathology reports of the placental and membrane findings reported diamniotic, dichorionic twins. There was no zygosity testing conducted, thus it is unknown if the twins are monozygotic or dizygotic. Two possible etiologies for sex-discordant twins, in this case, are concurrent natural conception via breakthrough ovulation at the time of SET, or discordant postzygotic nondisjunction of a single embryo. Multiple gestations may still occur in the setting of SET and zygosity testing in these instances would better elucidate our understanding of this occurrence. Moreover, improved data on the zygosity of multiple gestations following SET may enhance patient counseling.
]]>Reproductive Medicine doi: 10.3390/reprodmed4010004
Authors: Peilin Zhang Naureen Shama Arlene Shama Sanford Lederman
Maternal marital status, educational levels, and income levels were associated with adverse pregnancy outcomes and placental inflammatory changes, preterm delivery, and stillbirth. We aimed to examine the association of marital status with maternal and neonatal complications and placental pathology in singleton pregnancy. A total of 3724 singleton placentas with maternal neonatal and placental pathology data were included in the study, and there were statistically significant associations between marital status and maternal age, race/ethnicity, maternal BMI at delivery, neonatal birth weight, preeclampsia, and preterm delivery. There were significant associations between marital status and maternal inflammatory response, maternal vascular malperfusion, and meconium stain of fetal membranes. These data demonstrated that marital status affects not only the maternal well-being during pregnancy, but also neonatal birth data and placental pathology.
]]>Reproductive Medicine doi: 10.3390/reprodmed4010003
Authors: Cynthia Jovet Eloïse Fraison Jacqueline Lornage Nicolas Morel Journel Antoine Gavoille Laurent David Alexandra Montembault Cyrielle Fournier Bruno Salle Elsa Labrune
The aim of the present study was to evaluate the effect of activin A on the activation of in vitro folliculogenesis of human ovarian tissues from transgender men with or without our new compartmented chitosan hydrogel microbioreactor (“three-dimensional (3D)-structure”) enabling a three-dimensional tissue culture. Five fresh ovarian human tissues were cultured in vitro for 20 or 22 days in four groups with 100 ng/mL activin A or without activin A during the last six to eight days of culture, and within a 3D-structure or without the 3D-structure in standard conditions. Follicular density and quality were evaluated, and follicular diameters were measured. Estradiol secretion was quantified. Proliferation and apoptosis through immunostaining were also performed. The proportion of primordial follicles was significantly reduced, and the proportion of primary and secondary follicles was significantly increased in all four groups (p < 0.001). Tertiary follicles were observed in the four culture groups. Activin A supplementation did not significantly affect the follicular density, follicular quality, follicular growth, or estradiol secretion (p > 0.05). The 3D-structure increased the density of primary follicles and decreased the estradiol secretion (p < 0.001). Follicular proliferation was significantly lower in the 3D-structure group compared to the non-3D-structure group (p = 0.008). Regarding follicular apoptosis, it was significantly higher in the activin group compared to the non-activin group (p = 0.006). Activin A did not seem to play a key role in the in vitro folliculogenesis activation in our culture conditions. However, the results may indicate that the 3D-structure could be more physiological and could prevent a detrimental in vitro folliculogenesis flare-up.
]]>Reproductive Medicine doi: 10.3390/reprodmed4010002
Authors: Reproductive Medicine Editorial Office Reproductive Medicine Editorial Office
High-quality academic publishing is built on rigorous peer review [...]
]]>Reproductive Medicine doi: 10.3390/reprodmed4010001
Authors: Jeannette M. Larson Mihaela H. Bazalakova Amy Godecker Laura Cooney Melanie DelBeccaro Kjersti M. Aagaard Kathleen M. Antony
The purpose of this project was to evaluate whether screening positive on obstructive sleep apnea questionnaires in the first trimester of pregnancy was associated with miscarriage. This was a secondary analysis of a prospective observational cohort study of participants who were screened for sleep apnea during pregnancy with the Epworth Sleepiness Scale, Berlin Questionnaire, and novel items related to sleep and napping. This secondary analysis was IRB exempt. Our primary outcome was miscarriage in the index pregnancy. An association between responses to the sleep apnea screening questions with miscarriage of the index pregnancy was queried via Poisson regression. We found that gravidae who had elevated scores on both the Epworth Sleepiness Scale and the Berlin Questionnaire were more likely to experience miscarriage than those who had elevated scores on only one questionnaire or neither (p = 0.018). Gravidae who reported snoring (p = 0.042) or hypertension (p = 0.013) in the first trimester were more likely to experience miscarriage than gravidae who did not. Gravidae who reported napping in the first trimester were less likely to experience miscarriage (p = 0.045), even after adjusting for confounding variables (p = 0.007). In conclusion, we found that screening positive on both the Berlin Questionnaire and Epworth Sleepiness Scale was statistically significantly associated with miscarriage prior to adjustment for confounding variables, as did snoring and hypertension. After adjusting for confounding variables, only not napping was associated with miscarriage. Given the small sample size, further investigation into this topic is warranted.
]]>Reproductive Medicine doi: 10.3390/reprodmed3040026
Authors: Clara G. Olson John R. Soehl Zachary N. Stowe Kathleen M. Antony
Anxiety is common during the antepartum, intrapartum, and postpartum period. While the relationship between obstetric pain and depression is well characterized, there are few publications examining the relationship between obstetric pain and anxiety. Our objective was to characterize the association, if any, between postpartum pain and anxiety. This was a survey-based cross-sectional study. The general anxiety disorder (GAD)-7 and American Pain Society patient outcome questionnaire (APS-POQ) were completed by 64 postpartum participants at hospital discharge. Associations between anxiety and pain control were assessed. Participants with moderate to severe scores (greater or equal to 10) on the GAD-7 had more maximum pain scores (0 to 10 scale) in the severe range (greater or equal to 7) in the first (p = 0.049) and second (p = 0.010) 24 h periods after delivery and were more likely to have spent more time in severe pain within these time frames (p = 0.007 and p = 0.010, respectively). Similar relationships were observed when classifying anxiety ordinally. In conclusion, higher postpartum pain scores were associated with greater anxiety in the postpartum period.
]]>Reproductive Medicine doi: 10.3390/reprodmed3040025
Authors: David Waynforth
Prior research on causes of preterm birth has tended to focus on pathophysiological processes while acknowledging the role of socioeconomic indicators. The present research explored a wide range of factors plausibly associated with preterm birth informed by pathophysiological and evolutionary life history perspectives on gestation length. To achieve this, a machine learning ensemble classification data analysis approach, random forest (RF), was applied to the UK Millennium Cohort (18,201 births). The results highlighted the importance of socioeconomic variables and parental age in predicting preterm (before 37 completed weeks) and very preterm (before 32 weeks) birth. Infants born in households with low income and with young fathers had an increased risk of both very preterm and preterm birth. Maternal health and health problems during pregnancy were not found to be useful predictors. The best-performing algorithm was for very preterm birth and had 93% sensitivity and 100% specificity using six variables. Algorithms predicting preterm birth before 37 weeks showed increased error, with out-of-bag error rates of about 7% versus only 1% for those predicting very preterm birth. The poorer performance of algorithms predicting preterm births to 37 weeks of gestation suggests that some preterm birth may not result from pathology related to poor maternal health or social or economic disadvantage, but instead represents normal life-history variation.
]]>Reproductive Medicine doi: 10.3390/reprodmed3040024
Authors: Savannah L. Herbek Marie C. Smithgall Elisabeth A. Murphy Robert E. Schwartz Shuibing Chen Laura E. Riley Heidi Stuhlmann Yawei J. Yang Ria Goswami
Pregnancy is a period of elevated risk for viral disease severity, resulting in serious health consequences for both the mother and the fetus; yet antiviral drugs lack comprehensive safety and efficacy data for use among pregnant women. In fact, pregnant women are systematically excluded from therapeutic clinical trials to prevent potential fetal harm. Current FDA-recommended reproductive toxicity assessments are studied using small animals which often do not accurately predict the human toxicological profiles of drug candidates. Here, we review the potential of human maternal-fetal interface cellular models in reproductive toxicity assessment of antiviral drugs. We specifically focus on the 2- and 3-dimensional maternal placental models of different gestational stages and those of fetal embryogenesis and organ development. Screening of drug candidates in physiologically relevant human maternal-fetal cellular models will be beneficial to prioritize selection of safe antiviral therapeutics for clinical trials in pregnant women.
]]>Reproductive Medicine doi: 10.3390/reprodmed3040023
Authors: Giancarlo Garuti Paola Francesca Sagrada Susanna Delfrati Lorenzo Sogaro Marco Soligo
Relapsing ovarian granulosa-cell tumor (GCT) is a challenge for physicians due to the lack of effective therapy. Current strategies did not improve the 80% death rate of recurrent disease. GCTs synthesize estrogens and express follicle-stimulating hormone, gonadotropin-releasing hormone, and estrogen and progesterone receptors. The FOXL2-C134W mutation is shared in all GCTs, and its downregulation of hormone-related apoptosis appears causal in induction of tumor phenotype. On these assumptions, hormone anti-estrogenic therapies have been proposed for recurrent GCTs. A 32-year-old woman suffering from GCT was first treated by surgery in 2004 and staged as IA disease. Two subsequent pelvic relapses were diagnosed in 2006 and 2007, and the patient underwent surgery and chemotherapy to treat both recurrences. Overall, she underwent five subsequent surgical interventions and two chemotherapy instances. A third single pelvic relapse above the vaginal cuff was diagnosed in 2013. Based on the patient’s refusal to undergo further surgery we proposed an anti-estrogen therapy consisting of combined GnRH analogue leuprolide and the aromatase inhibitor letrozole. Complete remission was obtained after 3 months from the start of therapy. Subsequently, we found that disease-free survival was maintained over 9 years of treatment. Although recent reports indicate poor effectiveness of hormone therapy to treat recurrent GCTs, the success of this case indicates that a subset of patients with recurrent GCT maintain a tumor phenotype highly responsive to anti-estrogen drugs.
]]>Reproductive Medicine doi: 10.3390/reprodmed3040022
Authors: Jeevitha Poorasamy Deepali Garg Juhi Bharti Aruna Nambirajan Asmita Patil Jayasree Sengupta Debabrata Ghosh
The strong association between endometriosis and infertility is of high clinical significance. High proliferative bias in eutopic endometrium during the secretory phase is a hallmark of endometriosis, which may result in high occurrence of implantation failure and resultant infertility in endometriosis. The ErbB family of proteins regulates the proliferation capacity in the endometrium, potentially causing endometrial hostility to the implantation process in endometriosis. However, our knowledge regarding the involvement of the ErbB family in human endometrium during the window of implantation (WOI) in endometriosis-associated infertility is scant. In the present study, the cellular profiles of immunopositive ErbBs-1 to -4 in the endometrium of endometriosis-free, infertile women (Group 1; n = 11) and in eutopic endometrium of infertile women diagnosed with stage IV ovarian endometriosis (Group 2; n = 13) during the mid-secretory phase were compared using standardized guidelines. Computer-aided standardized combinative analysis of immunoprecipitation in different compartments revealed an overexpression of ErbB-1 in the epithelial, stromal and vascular compartments, along with marginally higher ErbB-3 expression (p < 0.06) in the vascular compartment and ErbB-4 expression (p < 0.05) in the glandular epithelium and stroma in the endometrium during the WOI in women with primary infertility associated with stage IV ovarian endometriosis compared with disease-free endometrium of control infertile women. It appears that changes in ErbBs in the eutopic endometrium during WOI induce anomalous proliferative, inflammatory and angiogenic activities in it, which can antagonize endometrial preparation for embryo implantation in endometriosis. This knowledge appears usable in strategizing methods for the treatment of endometriosis-associated infertility, as well as preempting the oncogenic potential of endometriosis.
]]>Reproductive Medicine doi: 10.3390/reprodmed3040021
Authors: Viviane C. L. Gomes Ashley K. Woods Kassandra R. Crissman Camille A. Landry Kalie F. Beckers Bryce M. Gilbert Lucas R. Ferro Chin-Chi Liu Erin L. Oberhaus Jenny L. Sones
Insufficient invasion of conceptus-derived trophoblast cells in the maternal decidua is a key event in the development of early-onset preeclampsia (PE), a subtype of PE associated with high maternal and fetal morbidity and mortality. Kisspeptins, a family of peptides previously shown to inhibit trophoblast cell invasion, have been implicated in the pathogenesis of early-onset PE. However, a role of kisspeptin signaling during the genesis of this syndrome has not been elucidated. Herein, we used the preeclamptic-like BPH/5 mouse model to investigate kisspeptin expression and potential upstream regulatory mechanisms in a PE-like syndrome. Expression of the kisspeptin encoding gene, Kiss1, and the 10-amino-acid kisspeptide (Kp-10), are upregulated in the non-pregnant uterus of BPH/5 females during diestrus and in the maternal-fetal interface during embryonic implantation and decidualization. Correspondingly, the dysregulation of molecular pathways downstream to kisspeptins also occurs in this mouse model. BPH/5 females have abnormal sex steroid hormone profiles during early gestation. In this study, the normalization of circulating concentrations of 17β-estradiol (E2) and progesterone (P4) in pregnant BPH/5 females not only mitigated Kiss1 upregulation, but also rescued the expression of multiple molecules downstream to kisspeptin and ameliorated adverse fetoplacental outcomes. Those findings suggest that uterine Kiss1 upregulation occurs pre-pregnancy and persists during early gestation in a PE-like mouse model. Moreover, this study highlights the role of sex steroid hormones in uteroplacental Kiss1 dysregulation and the improvement of placentation by normalization of E2, P4 and Kiss1.
]]>Reproductive Medicine doi: 10.3390/reprodmed3030020
Authors: Dickson Mawusi Kwame Adu-Bonsaffoh Chrissie Stansie Abaidoo Frederick Kwaku Addai
Background: The emergence of AMH as a reliable biomarker for assessing ovarian reserve and optimization of assisted reproductive technology (ART) remains a promising tool for the evaluation and prediction of controlled ovarian stimulation (COS) outcomes. This study assessed the association between serum AMH levels and maternal age in females receiving in vitro fertilization (IVF) treatment in Ghana. Methods: We conducted a prospective cohort study at a specialized fertility center in Ghana. Descriptive analysis was performed, and the differences between maternal age and AMH categories were assessed by the Kruskal–Wallis test. Results: We included 426 women with mean (±SD) age and AMH levels of 35.25 ± 6.33 years and 2.80 ± 2.60 ng/mL, respectively. Women with very-low AMH levels (0.94 ± 73 ng/mL) were older (>40 years), whereas the younger (20–25 years) group had higher levels (4.85 ± 3.34 ng/mL). There was a significant negative correlation between women’s age and serum AMH levels (R = −0.46; p < 0.001). None of the younger women had AMH levels <0.30 ng/mL, while 70% of women who had AMH levels of <0.30 ng/mL were older women (>40years). In addition, none of the older women had AMH levels >4 ng/mL with only 5% having AMH levels between 2.20 and 4.0 ng/mL. Conclusions: AMH levels ≤0.3 ng/mL are archetypal of 70% of Ghanaian women >40 years old receiving fertility treatment. A combined assessment of AMH levels and age supports clinical decisions in predicting ovarian response to controlled ovarian stimulation (COS) and may be valuable in predicting of IVF success. Further research to evaluate the combined use of age, AMH, and other ovarian reserve markers in assessing ovarian response to COS is recommended.
]]>Reproductive Medicine doi: 10.3390/reprodmed3030019
Authors: Rasha A. Al-Lami
17-α hydroxyprogesterone caproate (17-OHPC) could alter the immune response and inflammation, specifically affecting the risk of preterm labor and preeclampsia. However, the exact immune and inflammatory effects of 17-OHPC remain hard to be identified. The current literature on 17-OHPC immune effects is limited and more research is needed to identify these mechanistic pathways. Further, coronavirus disease 2019 (COVID-19) infection in pregnancy involves heightened immune response, widespread inflammation and high rates of preterm labor and preeclampsia. Since the pathogenesis of preterm labor, preeclampsia and COVID-19 involves inflammation and altered immune response, it is important to explore the possible immune effects of 17-OHPC in pregnant women with COVID-19. This commentary article will explain the immune effects of 17-OHPC and their implications in preterm labor, preeclampsia and COVID-19.
]]>Reproductive Medicine doi: 10.3390/reprodmed3030018
Authors: Rupashree Salvi Ulka Gawde Susan Idicula-Thomas Barnali Biswas
Background: Infertility is a common condition affecting approximately 10–20% of the reproductive age population. Idiopathic infertility cases are thought to have a genetic basis, but the underlying causes are largely unknown. However, the genetic basis underlying male infertility in humans is only partially understood. The Purpose of the study is to understand the current state of research on the genetics of male infertility and its association with significant biological mechanisms. Results: We performed an Identify Candidate Causal SNPs and Pathway (ICSN Pathway) analysis using a genome-wide association study (GWAS) dataset, and NCBI-PubMed search which included 632 SNPs in GWAS and 451 SNPs from the PubMed server, respectively. The ICSN Pathway analysis produced three hypothetical biological mechanisms associated with male infertility: (1) rs8084 and rs7192→HLA-DRA→inflammatory pathways and cell adhesion; rs7550231 and rs2234167→TNFRSF14→TNF Receptor Superfamily Member 14→T lymphocyte proliferation and activation; rs1105879 and rs2070959→UGT1A6→UDP glucuronosyltransferase family 1 member A6→Metabolism of Xenobiotics, androgen, estrogen, retinol, and carbohydrates. Conclusions: We believe that our results may be helpful to study the genetic mechanisms of male infertility. Pathway-based methods have been applied to male infertility GWAS datasets to investigate the biological mechanisms and reported some novel male infertility risk pathways. This pathway analysis using GWAS dataset suggests that the biological process related to inflammation and metabolism might contribute to male infertility susceptibility. Our analysis suggests that genetic contribution to male infertility operates through multiple genes affecting common inflammatory diseases interacting in functional pathways.
]]>Reproductive Medicine doi: 10.3390/reprodmed3030017
Authors: Cristina Taliento Noemi Salmeri Pantaleo Greco Danila Morano
Soft markers are sonographic structural, nonspecific signs with little pathological significance, often transient, usually considered as normal variants. However, they may also be associated with chromosomal abnormalities. The most widely examined soft markers include absent or hypoplastic nasal bone (NB), intracardiac echogenic focus (IEF), ventriculomegaly (VM), thickened nuchal fold (NF), choroid plexus cyst (CPC), echogenic bowel, short long bones, and urinary tract dilation (UTD). Although the use of noninvasive prenatal testing (NIPT) has been spreading quickly in maternal–fetal medicine, it is not a diagnostic test and it still remains unavailable or cost-prohibitive for most of the population in many countries. After normal screening test results in the first trimester, there is no uniform consensus regarding the clinical significance of isolated soft markers for aneuploidy. Nowadays, the search for soft markers in an ultrasound is still part of clinical evaluation, and the interpretation of these findings is often a matter of debate. In the present review, we summarize the recent literature about the role of soft markers in the era of NIPT and propose an overview of the different clinical guidelines.
]]>Reproductive Medicine doi: 10.3390/reprodmed3030016
Authors: Rosita Verteramo Erica Santi Francesca Ravennati Gennaro Scutiero Pantaleo Greco Danila Morano
Infectious diseases during pregnancy are still a major cause of fetal mortality and morbidity worldwide. The most common teratogenic pathogens are cytomegalovirus (CMV), varicella-zoster virus (VZV), rubeovirus, parvovirus B19, herpes simplex virus (HSV), Toxoplasma gondii, Treponema pallidum and the emergent Zika virus (ZIKV). Ultrasound findings include cerebral anomalies, orbital defects, micrognathia, cardiac defects, hepatosplenomegaly, liver calcifications, abdominal anomalies, skin and limb anomalies, edema, placental and amniotic fluid anomalies and altered Doppler analyses. The classification of ultrasound markers of congenital infections by anatomical region is reported to guide differential diagnosis and prenatal care.
]]>Reproductive Medicine doi: 10.3390/reprodmed3020015
Authors: Atsuya Tsuru Mikihiro Yoshie Ryo Yonekawa Junya Kojima Mana Azumi Kazuya Kusama Hirotaka Nishi Kazuhiro Tamura
Human endometrial stromal cells (ESCs) differentiate into decidual cells for embryo implantation during the mid-secretory phase of the menstrual cycle. Decidualization is characterized by enhanced production of insulin-like growth factor-binding protein 1 (IGFBP1) and prolactin (PRL) by ESCs and their morphological transformation into polygonal cells. Progesterone (P4) receptor membrane component 1 (PGRMC1) is a member of a P4-binding complex implicated in function in female reproduction. In this study, we explored the mechanisms that regulate PGRMC1 during decidualization of human ESCs. Immunohistochemical analysis of endometrial samples showed that PGRMC1 was expressed in endometrial glandular and luminal epithelial cells and stromal cells throughout the menstrual cycle; however, the protein level in stroma was reduced in the secretory phase. Incubation of ESCs with dibutyryl (db)-cAMP and P4 in vitro, which induces decidualization, decreased the PGRMC1 protein abundance. Further, treatment with a PGRMC1-targeting siRNA or PGRMC1 inhibitor (AG-205) promoted mRNA expression of the db-cAMP/P4- and db-cAMP-induced decidual markers IGFBP1 and PRL. Moreover, the microRNA miR-98, a potential repressor of PGRMC1, was upregulated during decidualization, and transfection of ESCs with a miR-98 mimic decreased the PGRMC1 protein level. These findings suggest that miR-98-mediated downregulation of endometrial PGRMC1 may promote decidualization for the establishment of pregnancy.
]]>Reproductive Medicine doi: 10.3390/reprodmed3020014
Authors: Ashley U. Amukamara Ina E. Amarillo
Copy number variations (CNVs) have been implicated in various conditions of differences of sexual development (DSD). Generally, larger genomic aberrations are more often considered disease-causing or clinically relevant, but over time, smaller CNVs have been associated with various forms of DSD. The main objective of this study is to identify small CNVs and the smallest regions of overlap (SROs) in patients with atypical female genitalia (AFG) and build a CNV map of AFG. We queried the DECIPHER database for recurrent duplications and/or deletions detected across the genome of AFG individuals. From these data, we constructed a chromosome map consisting of SROs and investigated such regions for genes that may be associated with the development of atypical female genitalia. Our study identified 180 unique SROs (7.95 kb to 45.34 Mb) distributed among 22 chromosomes. The most SROs were found in chromosomes X, 17, 11, and 22. None were found in chromosome 3. From these SROs, we identified 22 genes as potential candidates. Although none of these genes are currently associated with AFG, a literature review indicated that almost half were potentially involved in the development and/or function of the reproductive system, and only one gene was associated with a disorder that reported an individual patient with ambiguous genitalia. Our data regarding novel SROs requires further functional investigation to determine the role of the identified candidate genes in the development of atypical female genitalia, and this paper should serve as a catalyst for downstream molecular studies that may eventually affect the genetic counseling, diagnosis, and management of these DSD patients.
]]>Reproductive Medicine doi: 10.3390/reprodmed3020013
Authors: Gillian L. Hsieh Matthew K. Wagar Kathleen M. Antony Ramya Masand Matthew L. Anderson
Our objective is to define a standard protocol for post-partum salpingectomy and provide a prospective assessment of safety and feasibility of such a procedure. Thus, a protocol for performing post-partum salpingectomy in limited-resource environments was created based on contemporary practices for tubal ligation. Gravidae presenting for post-partum tubal ligation following vaginal delivery or at time of cesarean were prospectively approached and, if consent was obtained, enrolled. Outcomes were compared to a historical cohort of gravidae who underwent standard post-partum tubal ligation following vaginal birth or at the time of cesarean as per institutional standard of care. The primary outcome was operative time. One hundred and fifty-seven subjects underwent post-partum salpingectomy following cesarean or vaginal delivery (on post-partum days 0–2). Post-partum salpingectomy performed after vaginal delivery (n = 97) resulted in slightly longer operative times (39.1 ± 11.8 vs. 34.3 ± 13.1 min, p = 0.003) and slightly greater blood loss (21.0 ± 22.0 vs. 13.4 ± 17.3 mL, p = 0.001) than modified Pomeroy tubal ligation (n = 200). Post-partum salpingectomy at cesarean resulted in no difference in estimated blood loss, but slightly longer operative times compared to Parkland tubal ligations (99.5 ± 47.3 vs. 86.5 ± 33.9 min, p = 0.048). Surgical complications for post-partum salpingectomy were similar to controls, regardless of when the procedure was performed. In conclusion, a standardized protocol created for post-partum salpingectomy using suture ligation is feasible and safe.
]]>Reproductive Medicine doi: 10.3390/reprodmed3020012
Authors: Ryosuke Akino Shogo Nishii Kei Odawara Megumi Saito Miwa Sakamoto Tetsuro Kondo Akihiko Sekizawa
Fertility preservation is an important concern for young cancer patients. Oocyte or embryo cryopreservation prior to chemotherapy administration is desirable but often difficult for patients with hematopoietic and lymphoid tissue tumors. In this study, we examined the results of fertility preservation therapy in patients with hematopoietic and lymphoid tissue tumors. We retrospectively examined hematopoietic and lymphoid tissue tumors of five patients who underwent oocyte cryopreservation as a fertility preservation therapy after chemotherapy, at Showa University Hospital from February 2017 to September 2020. Eleven treatment cycles were administered (one of which was cancelled). The mean age of the patients was 28.6 years. The mean controlled ovarian stimulation duration for 10 cycles was 15.9 days, the mean total gonadotropin dose was 3705 IU, and the mean peak E2 was 502.8 (pg/mL). The mean number of eggs retrieved was 3.2, the mean number of mature oocytes was 2.1, and the mean maturation rate (mature oocytes/returned oocytes) was 70.7%. Fertility preservation procedures in the early period after chemotherapy may be viable because they allow for the acquisition of mature oocytes, even though the procedures may take longer and yield fewer oocytes.
]]>Reproductive Medicine doi: 10.3390/reprodmed3020011
Authors: David Lukanović Borut Kobal Katarina Černe
Despite advances in surgical techniques and chemotherapy, ovarian cancer is still a leading cause of death among gynecological cancers. In addition to the late detection of the disease, the main reason for poor prognosis is resistance to pharmacotherapy, mostly platinum compounds. About a third of patients do not respond to primary platinum-based chemotherapy treatment, and over time, eventually, 80% of other patients develop chemoresistance, which makes the recurrence of disease incurable. In this review, we describe a difficult clinical hurdle faced in ovarian cancer therapy as a result of platinum resistance, as well as resistance to newer targeted therapy with PARP inhibitors and bevacizumab. We, furthermore, give attention also to the role of the tumor microenvironment as it is less well understood than the tumor cell-intrinsic mechanism. Because a central goal in ovarian cancer research is the development of novel strategies to overcome chemoresistance, treatment for cancer is moving toward personalized therapy.
]]>Reproductive Medicine doi: 10.3390/reprodmed3020010
Authors: Atsushi Furuta Tomoko Shima Mihoko Kawaguchi Akemi Yamaki-Ushijima Ippei Yasuda Sayaka Tsuda Satoshi Yoneda Kazuma Higashisaka Shi-Bin Cheng Kenji Matsumoto Yasuo Tsutsumi Surendra Sharma Shigeru Saito Akitoshi Nakashima
Poor placentation is closely related with the etiology of preeclampsia and may impact fetal growth restriction. For placental developmental growth, we have demonstrated that dysregulation of autophagy, a key mechanism to maintain cellular homeostasis, in trophoblasts contributes to the pathophysiology of preeclampsia, a severe pregnancy complication, associated with poor placentation. It remains, however, unknown whether autophagy inhibition affects trophoblast syncytialization. This study evaluated the effect of autophagy in an in vitro syncytialization method using BeWo cells and primary human trophoblasts (PHT). In this study, we observed that autophagic activity decreased in PHT and BeWo cells during syncytialization. This decreased activity was accompanied by downregulation of the transcription factor, TFEB. Next, bafilomycin A1, an inhibitor of autophagy via suppressing V-ATPase in lysosomes, inhibited hCG production, CYP11A1 expression (a marker of differentiation), p21 expression (a senescence marker), and cell fusion in BeWo cells and PHT cells. Finally, LLOMe, an agent inducing lysosomal damage, also inhibited syncytialization and led to TFEB downregulation. Taken together, the autophagy-lysosomal machinery plays an important role in cytotrophoblast fusion, resulting in syncytiotrophoblasts. As autophagy inhibition contributed to the failure of differentiation in cytotrophoblasts, this may result in the poor placentation observed in preeclampsia.
]]>Reproductive Medicine doi: 10.3390/reprodmed3020009
Authors: Ana Luísa Areia Anabela Mota-Pinto
Inflammatory mechanisms have a critical role in parturition, which results from a gathering of different stimuli that collectively initiate labour. In fact, a sophisticated interaction occurs between contractile and immuno-inflammatory pathways, whereby proinflammatory amplification is intensified by collaborative connections between cells, ligands, and tissues. Preterm birth (PTB) is one of the major challenges of modern obstetrics and still lacks an efficient treatment. Therefore, the scientific research of modern therapies is warranted. This systematic review aims to provide an overview of recent research into inflammation and PTB. The main inclusion criterion was articles concerning birth and inflammation, and searches were performed in the electronic databases MEDLINE, Embase, Scopus, Web of Science and Cochrane Library, from 2017 to 2021. A literature search from all databases yielded 1989 results which, applying the specified eligibility criteria, resulted in the 16 articles included in this review. Delivery is the consequence of an inequity between maternal inflammation and hormonal-driven uterine quiescence. Studies show that the distinction between term and preterm labour could consist of a pre-existing disproportion of decidual inflammatory signalling, or an unusual stimulus eliciting inflammatory pathways, comparable to both. Thus, controlling inflammation could be hopeful for detaining PTB.
]]>Reproductive Medicine doi: 10.3390/reprodmed3020008
Authors: Julia C. Shaw Rebecca M. Dyson Hannah K. Palliser Gabrielle K. Crombie Mary J. Berry Jonathan J. Hirst
(Background) The transition from in utero to ex utero life is associated with rapid changes in the brain that are both protective and required for newborn functional activities, allowing adaption to the changing environment. The current study aimed to reveal new insights into adaptations required for normal ongoing brain development and function after birth. (Methods) Time-mated dams were randomly allocated to fetal collection at gestational age 68 or spontaneous term delivery followed by neonatal collection within 24 h of birth. Immunohistochemistry was performed to examine mature myelin formation and neuronal nuclei coverage. RT-PCR was used to quantify the mRNA expression of key markers of the oligodendrocyte lineage, neuronal development, and GABAergic/glutamatergic pathway maturation. (Results) Mature myelin was reduced in the subcortical white matter of the neonate, whilst neuronal nuclei coverage was increased in both the hippocampus and the overlying cortical region. Increased mRNA expression in neonates was observed for oligodendrocyte and neuronal markers. There were also widespread mRNA changes across the inhibitory GABAergic and excitatory glutamatergic pathways in neonates. (Conclusions) This study has identified important adaptations in the expression of key neurodevelopmental structures, including oligodendrocytes and neurons, that may be essential for appropriate transition in neurodevelopment to the postnatal period.
]]>Reproductive Medicine doi: 10.3390/reprodmed3020007
Authors: Adi Sharabi-Nov Nataša Tul Kristina Kumer Tanja Premru Sršen Vesna Fabjan Vodušek Teja Fabjan Josko Osredkar Kypros H. Nicolaides Hamutal Meiri
Objectives—To conduct a secondary analysis of prediction accuracy of biophysical markers for suspected Preeclampsia (PE), Fetal Growth Restriction (FGR) and the two combined near delivery in a Slovenian cohort. Methods—This was a secondary analysis of a database of a total 125 Slovenian pregnant women attending a high-risk pregnancy clinic due to suspected PE (n = 31), FGR (n = 16) and PE + FGR (n = 42) from 28–39 weeks gestation and their corresponding term (n = 21) and preterm (PTD, n = 15) controls. Data for Mean Arterial blood Pressure (MAP) and Uterine artery pulsatility index (UtA PI) estimated by Doppler sonography were extracted from the database of patients who were tested at admission to the high-risk clinic with the suspected complications. The reactive hyperemia index (RHI), and the Augmentation Index (AIX%) were extracted from the patient database using measured values obtained with the assistance of the Endo PAT, a device set to measure the signal of the peripheral arterial tone (PAT) from the blood vessels endothelium. Linear regression coefficients, Box and Whisker plots, Area under the Curve (AUC) of receiver Operation Characteristic (ROC) curves, and multiple regression were used to assess the marker accuracy using detection rate (DR) and false-positive rate (FPR) and previously reported cut-offs for estimating the positive and negative predictive value (NPV and PPV). The SPSS non-parametric statistics (Kruskal Wallis and Mann–Whitney) and Spearman’s regression coefficient were used to assess marker accuracy; p < 0.05 was considered significant. Results—MAP values reached diagnostic accuracy (AUC = 1.00, DR = 100%) for early PE cases delivered < 34, whereas UtA Doppler PI values yielded such results for early FGR < 34 weeks and the two combined reached such accuracy for PE + FGR. To reach diagnostic accuracy for all cases of the complications, the Endo PAT markers with values for MAP and UtA Doppler PI were required for cases near delivery. Multiple regression analyses showed added value for advanced maternal age and gestational week in risk assessment for all cases of PE, FGR, and PE + FGR. Spearman’s regression coefficient yielded r > 0.6 for UtA Doppler PI over GA for PE and FGR, whereas for RHI over BMI, the regression coefficient was r > 0.5 (p < 0.001 for each). Very high correlations were also found between UtA Doppler PI and sFlt-1/PlGF or PlGF (r = −0.495, p < 0.001), especially in cases of FGR. Conclusion—The classical biophysical markers MAP and UtA Doppler PI provided diagnostic accuracy for PE and FGR < 34 wks gestation. A multiple biophysical marker analysis was required to reach diagnostic accuracy for all cases of these complications. The UtA Doppler PI and maternal serum sFlt-1/PlGF or PlGF were equally accurate for early cases to enable the choice of the markers for the clinical use according to the more accessible method.
]]>Reproductive Medicine doi: 10.3390/reprodmed3010006
Authors: Carole A. McBride Ira M. Bernstein Amelia B. Sybenga Kelley C. McLean Thomas Orfeo Maria Cristina Bravo
Characteristics of maternal vascular malperfusion (MVM) are frequently observed in placentas from pregnancies impacted by preeclampsia, intrauterine growth restriction, preterm labor, and intrauterine fetal demise. We sought to evaluate the associations of features of MVM with subclinical measures of cardiovascular health and coagulation potential in healthy young women. Sixty-three healthy young women were recruited and assessed prior to pregnancy on cycle day 9 ± 4, at gestational age 90 ± 6 of early pregnancy, and gestational age 216 ± 5 of late pregnancy. Women were assessed for plasma volume, blood pressure, response to volume loading, cardiac output, and uterine hemodynamics. Platelet-poor plasma was collected to assess thrombin generation on a subset of 33 women at all time points. Following delivery, placentas were collected and analyzed for evidence of MVM. Thrombin generation (TG) was evaluated in the presence of tissue factor (TF) with and without recombinant soluble thrombomodulin (TM). For each, we compared TG lagtime, peak level, and endogenous thrombin potential (ETP). Comparisons were made between dichotomized presence and absence of each individual feature of MVM and cardiovascular and coagulation features. Mean ± standard deviation are presented. Women were 31 ± 4 years of age, body mass index of 24 ± 5 kg/m2, 86% white race, and 80% nulliparous. MVM occurred in 70% of placentas, with infarcts and agglutination (44%), decidual arteriopathy (40%), accelerated villous maturation (32%), placental hypoplasia (29%), and distal villous hypoplasia (17%) documented. Decidual arteriopathy and distal villous hypoplasia were associated with prepregnancy maternal physiology, including decreased plasma volume and subclinical cardiovascular variations. All assessed MVM characteristics had identifiable early pregnancy physiologic characteristics consistent with altered cardiovascular function and decreased uterine response to pregnancy when compared with women who did and did not develop MVM. Accelerated villous maturation was the only MVM feature to differ by thrombin generation parameters in early pregnancy. Thrombin generation potential and blood pressure were elevated in late pregnancy in women who developed decidual arteriopathy. Prepregnancy health status and adaptation to pregnancy play important roles in pregnancy outcomes. Both cardiovascular health and thrombin generation potential may influence early placentation. Longitudinal assessment of subclinical maternal factors may allow for better understanding of the etiologies of MVM lesions, as well as allow for identification of a timeline of the origins of placental pathologies.
]]>Reproductive Medicine doi: 10.3390/reprodmed3010005
Authors: Mahtab Zaghi Katrien Janssens Wim Hectors Philip Loquet Bettina Blaumeiser
Tetrasomy 9p is a chromosomal disorder characterized by the presence of a supernumerary chromosome. This rare abnormality exhibits a broad phenotypic variability and is not clearly distinguishable from other more frequent aneuploidies in the prenatal setting. We present two prenatal cases with dissimilar phenotypes, one with solely increased fetal nuchal translucency and one with multiple congenital anomalies, and discuss prior studies. These cases illustrate the difficulty of prenatally diagnosing this condition based on phenotypic information alone. We conclude that invasive prenatal diagnosis with (molecular) karyotyping is the best choice for the prenatal detection of tetrasomy 9p.
]]>Reproductive Medicine doi: 10.3390/reprodmed3010004
Authors: Brindusa Cimpoca-Raptis Anca Marina Ciobanu Nicolae Gica Ana Maria Scutelnicu Alexandra Bouariu Mihaela Popescu Anca Maria Panaitescu
Autoimmune Congenital Heart Block (CHB) is an immune-mediated disease caused by transplacental passage of maternal circulating anti-Ro/SSA and anti-La/SSB antibodies which can bind to fetal cardiac tissue, damaging conduction tissues by inflammation and fibrosis. Approximately 2% of pregnancies with positive anti-Ro antibodies will be complicated by fetal atrioventricular block and the risk of recurrence in subsequent pregnancies is 10 times higher. We report a case of a clinically asymptomatic patient diagnosed with anti-Ro antibodies who had two pregnancies complicated by CHB with different outcomes. Despite preventive treatment with hydroxychloroquine (HCQ) from 6 weeks of pregnancy onward, the fetus developed second to third degree CHB. Dexamethasone was added. The pregnancy evolved to near-term with persistent intermittent CHB. It is not clear how pregnancies with recurrent fetal CHB despite prophylaxis with HCQ should be managed and there is a need for controlled studies to answer the remaining questions in relation to this subject.
]]>Reproductive Medicine doi: 10.3390/reprodmed3010003
Authors: Muzaffer Bhat Meraj Khan P.G.L. Lalitkumar Jeevitha Poorasamy Jayasree Sengupta Debabrata Ghosh
There is no report on preimplantation phase endometrial transcriptomics in natural conception cycles of primates. In the present study, the whole-genome expression array of endometrium on Days 2, 4, and 6 post-ovulation (pov) in proven natural conception (Group 1; n = 12) and non-mated, ovulatory (Group 2; n = 12) cycles of rhesus monkeys was examined, compared, and validated. Of fifteen (15) genes showing differential expression (>2-fold; pFDR < 0.05), six genes (CHRND, FOXD3, GJD4, MAPK8IP3, MKS1, and NUP50) were upregulated, while eight genes (ADCY5, ADIPOR1, NNMT, PATL1, PIGV, TGFBR2, TOX2, and VWA5B1) were down regulated on Day 6 pov as compared to Day 2 pov in conception cycles. On Day 6 pov, four genes (ADCY5, NNMT, TOX2, and VWA5B1) were down regulated, and AVEN was upregulated in conception cycles compared with the non-conception cycle. These observations were orthogonally validated at protein expression level. Group-specifically expressed unique genes in conception cycles influence the process of induction of immune-tolerance, while the genes expressed in both groups influence processes of protein targeting and metabolism. A triad of timed-actions of progesterone, seminal plasma, and preimplantation embryo putatively regulate several input molecules to CREB, NF-kB, and STAT regulatory networks during secretory phase towards evolution of endometrial receptivity in the rhesus monkey.
]]>Reproductive Medicine doi: 10.3390/reprodmed3010002
Authors: Reproductive Medicine Editorial Office Reproductive Medicine Editorial Office
Rigorous peer-reviews are the basis of high-quality academic publishing [...]
]]>Reproductive Medicine doi: 10.3390/reprodmed3010001
Authors: Amir Naeh Esther Maor-Sagie Mordechai Hallak Rinat Gabbay-Benziv
Gestational diabetes mellitus (GDM) complicates between 5 and 12% of pregnancies, with associated maternal, fetal, and neonatal complications. The ideal screening and diagnostic criteria to diagnose and treat GDM have not been established and, currently, diagnostic use with an oral glucose tolerance test occurs late in pregnancy and produces poor reproducibility. Therefore, in recent years, significant research has been undertaken to identify a first-trimester biomarker that can predict GDM later in pregnancy, enable early intervention, and reduce GDM-related adverse pregnancy outcomes. Possible biomarkers include glycemic markers (fasting glucose and hemoglobin A1c), adipocyte-derived markers (adiponectin and leptin), pregnancy-related markers (pregnancy-associated plasma protein-A and the placental growth factor), inflammatory markers (C-reactive protein and tumor necrosis factor-α), insulin resistance markers (sex hormone-binding globulin), and others. This review summarizes current data on first-trimester biomarkers, the advantages, and the limitations. Large multi-ethnic clinical trials and cost-effectiveness analyses are needed not only to build effective prediction models but also to validate their clinical use.
]]>Reproductive Medicine doi: 10.3390/reprodmed2040019
Authors: Hannah L. Christianson Alea A. Sabry Jinan E. G. Sous Jacquelyn H. Adams Kara K. Hoppe Kathleen M. Antony
We assessed the prevalence of neonatal abstinence syndrome (NAS) and fetal growth outcomes in neonates exposed to methadone compared to buprenorphine in utero. Three authors assessed the titles and abstracts of all potentially eligible studies. The selection criteria were randomized controlled trials and observational cohort studies from January 2000 to January 2020 which indexed and reported original data for occurrence of NAS and fetal growth outcomes in pregnant people who received methadone vs. buprenorphine treatment. The quality and possible bias of each study was assessed using the Cochrane-risk-of-bias tool. Data were pooled to compare the occurrence of NAS and fetal growth restriction among women who received methadone vs. buprenorphine treatment. Of the 106 articles screened, 1 randomized controlled trial and 5 observational cohort studies including 2041 pregnancies fulfilled the inclusion criteria. Buprenorphine is associated with less NAS and improved growth outcomes compared to methadone. (OR = 0.515; p-value < 0.001). Compared to methadone, buprenorphine is associated with less adverse neonatal outcomes in terms of gestational age at birth, birthweight, and head circumference. With the prevalence of NAS continuing to rise, this study adds to the expanding academic research aimed at creating safer treatment protocols.
]]>Reproductive Medicine doi: 10.3390/reprodmed2040018
Authors: Giuseppe Benagiano Marwan Habiba Donatella Lippi Ivo A. Brosens
Bleeding in newborns and young girls fascinated writers for more than a millennium. Initially, there was confusion between neonatal bleeding, early menstruation due to precocious puberty, and hemorrhage due to disease. During the 19th century descriptions appeared of what is referred to today as ‘neonatal menstruation’ or ‘neonatal uterine bleeding’. By the turn of the century, Halban linked bleeding to active substances present during pregnancy and hypothesized that, while the maternal uterus reacts with decidua formation, the “weaker” fetal uterus reacts only with menstrual-like changes. Despite this clear description, several alternative theories endured for decades. Bleeding was believed to be due to a ‘catarrhal’ or neoplastic state of the genital tract, pulmonary circulatory disorder, congenital heart malformations, closure of the umbilical cord or affections of the intestine. During the 1950s, progesterone response and resistance were proposed to explain the pathogenesis of bleeding and its low incidence. The fetal endometrium is resistant to the high circulating progesterone. A decidual response is infrequent and results in menstrual shedding upon progesterone withdrawal after birth. Further research linked fetal stress consequent to pregnancy complications and post-maturity to increased incidence and preterm birth to reduced incidence of neonatal uterine bleeding.
]]>Reproductive Medicine doi: 10.3390/reprodmed2040017
Authors: Gerarda Gaeta Mirko Pozzoni Audrey Serafini Arianna Lesma Pier Luigi Paesano Massimo Candiani Paolo Ivo Cavoretto
A case of severe fetal hydronephrosis due to isolated bilateral stenosis of the pyelo-ureteral junction was diagnosed at our centre. Surprisingly, a negative renal ultrasound scan was performed on the 3rd postnatal day. An ultrasound follow-up showed severe bilateral pyelectasis a few weeks later. The infant underwent bilateral pyeloplasty at six months of age with an excellent outcome. Such a neonatal picture may be due to the reduction of urinary output secondary to excessive postnatal weight loss and dehydration. In this case, prenatal ultrasound result was more reliable than postnatal ultrasound, emphasizing the importance of postnatal urologic follow-up after prenatal indication.
]]>Reproductive Medicine doi: 10.3390/reprodmed2040016
Authors: John L. Yovich Peter M. Hinchliffe
Since 2010, numerous studies reported from PIVET, a pioneer IVF facility established over 40 years ago, have explored the use of three adjuvants designed to improve laboratory and clinical outcomes in cases where a poor prognosis has been demonstrated. The adjuvants reported commenced with recombinant growth hormone (rGH), followed by dehydroepiandrosterone (DHEA) after developing a unique troche to avoid the first-pass effect and, subsequently, melatonin. The studies show that rGH is beneficial in the situation where women have poor-quality embryos in the setting of additional poor prognosis factors, such as advanced female age, a very low ovarian reserve, an insulin growth factor profile in the lowest quartile or recurrent implantation failure. The studies also imply that the adjuvants may actually reduce live birth productivity rates if used on women without poor prognosis factors; hence, further studies, which can now be better designed, should be undertaken to explore the notion of underlying adult growth hormone deficiency in some cases as well as the suggestion that DHEA can provide equivalent benefits in some poor prognosis settings. Melatonin showed no suggestive benefits in any of the studies and can be excluded from consideration in this context. Future studies should compare rGH and DHEA with a focus on those women who have poor embryo quality with additional poor prognosis factors. Such trials should be extended to 12 weeks to cover the entire period of oocyte activation.
]]>Reproductive Medicine doi: 10.3390/reprodmed2040015
Authors: Roman V. Kapustin Elizaveta M. Tcybuk Andrew V. Korenevsky Ekaterina V. Kopteeva Elena N. Alekseenkova Alena V. Tiselko Olga N. Arzhanova
Background: The effective approach to preventing preeclampsia (PE) is administering acetylsalicylic acid (ASA) to high-risk patients. However, there are not enough data analyzing the effectiveness of ASA intake by pregnant women with diabetes mellitus (DM). This study aims to evaluate the effect of ASA on perinatal outcomes in pregnant women with different types of pregestational DM. Methods: This retrospective study included 735 pregnant women with DM (types 1 and 2). At 12–14 weeks of gestation, some patients were prescribed daily ASA at a 100–150 mg dose continuously for up to 36 weeks. The effect of ASA on the development of PE and other outcomes of pregnancy was assessed. The times of delivery and the onset of PE were evaluated as well. Results: When taking ASA, PE developed significantly less frequently in pregnant women with DM. This was significantly more evident in patients with type 2 DM (OR 0.65; 95% CI: 0.52–0.79). In patients with type 1 DM, the mean period of development of PE was 1.5 weeks later relative to those pregnant women who did not take the drug and was 35.5 weeks of gestation. The OR for the development of preterm birth was reduced by 3 times (OR 0.33; 95% CI: 0.15–0.62). In women with DM who took ASA during pregnancy, babies were born with greater body weight, and the frequency of small for gestational age births decreased. Conclusions: ASA administration is associated with a reduction of the incidence of PE, a delay in its manifestations, and a mitigating the risk of other adverse perinatal outcomes typical for pregnant women with DM.
]]>Reproductive Medicine doi: 10.3390/reprodmed2030014
Authors: Pierre-Yves Robillard Malik Boukerrou Gustaaf Dekker Marco Scioscia Francesco Bonsante Brahim Boumahni Silvia Iacobelli
Objectives: To develop a multivariate model for risk factors specific to early onset preeclampsia (EOP) and late onset preeclampsia (LOP) in our entire population (singleton and twin pregnancies). Material and methods: 20 year-observational population-based historical cohort study (2001–2020). All consecutive births delivered at the Centre Hospitalier Universitaire Hospitalier Sud Reunion’s maternity ward. A standardized validated epidemiological perinatal database was used. Results: During the 20-year period, there were 81,834 pregnancies and 83,497 infants born, 1232 dichorionic and 350 monochorionic twin pregnancies. There were 2120 cases of preeclampsia, of which 2001 were preeclamptic singleton pregnancies and 119 twin pregnancies (incidence 7.5% in twin pregnancies vs. 2.5% singletons, OR 3.0, p < 0.001). Independent risk factors for EOP and LOP in a multivariate model (controlling for the two major confounders: maternal ages—both risks for EOP and LOP, and maternal pre-pregnancy BMI—specific risk factor for LOP) were: history of preeclampsia (adjusted OR (aOR) 11.7 for EOP, 7.8 for LOP, p < 0.0001), chronic hypertension (aOR 7.3 for EOP, 3.9 for LOP, p < 0.0001), history of perinatal death (aOR 2.2 for EOP, p < 0.0001 and 1.48 for LOP, p = 0.007), primipaternity (aOR 3.0 for EOP and 3.6 for LOP, p = 0.001), dizygotic twin pregnancies (aOR 3.7 for EOP, p < 0.0001 and 2.1 for LOP, p = 0.003), monozygotic twin pregnancies (aOR 3.98 for EOP, p = 0.003 and non-significant (NS) for LOP), ovulation induction (aOR 5.6 for EOP, p = 0.004 and NS for LOP), and in vitro fertilization (aOR 2.8 for EOP, p = 0.05 and NS for LOP). Specific to LOP and NS for EOP: renal diseases (aOR for LOP 2.9, p = 0.007) and gestational diabetes mellitus (aOR 1.2, p = 0.04). Conclusions: Maternal ages over 35 years, chronic hypertension, history of preeclampsia, ovulation induction, in vitro fertilizations, history of perinatal deaths and twin pregnancy (in our experience, especially mono zygotic twin pregnancies) are significant risk factors for EOP. New paternity is an independent factor for both EOP and LOP.
]]>Reproductive Medicine doi: 10.3390/reprodmed2030013
Authors: Chelsey A. Leisinger Glen Adaniya Melanie R. Freeman Erica J. Behnke Martha Aguirre Matthew D. VerMilyea Mitchel C. Schiewe
A prospective, multicenter, randomized, sibling oocyte study was conducted with 86 couples to evaluate if a microfluidic sperm separation device improved ICSI sperm selection and subsequent cycle outcomes of fertilization, blastocyst utilization, ploidy, and clinical pregnancy rate when applied to a general patient population. Patients with at least 10 metaphase II oocytes were enrolled in the study and sibling oocyte groups were split in half. One half of the oocytes underwent ICSI with the control processed sperm and the other half were injected with sperm sorted by the ZyMōt microfluidic sperm separation device. Fertilization rate was recorded and resulting blastocysts were biopsied and evaluated for ploidy status with NGS. Euploid, non-mosaic embryos were randomly selected for single embryo transfer. A total of 787 oocytes were evaluated in the ZyMōt group and 777 in the control group. No statistical differences were observed between ZyMōt and control processing methods in any of the study outcomes evaluated. It is possible that the selection of normal, progressive sperm for ICSI, and the repair capacity of oocytes are sufficient to promote normal embryonic development in the general infertility population.
]]>Reproductive Medicine doi: 10.3390/reprodmed2030012
Authors: Olivier Leroij Lennart Van der Veeken Bettina Blaumeiser Katrien Janssens
We present a case of a fetus with cranial abnormalities typical of open spina bifida but with an intact spine shown on both ultrasound and fetal MRI. Expert ultrasound examination revealed a very small tract between the spine and the skin, and a postmortem examination confirmed the diagnosis of a dorsal dermal sinus. Genetic analysis found a mosaic 3q23q27 duplication in the form of a marker chromosome. This case emphasizes that meticulous prenatal ultrasound examination has the potential to diagnose even closed subtypes of neural tube defects. Furthermore, with cerebral anomalies suggesting a spina bifida, other imaging techniques together with genetic tests and measurement of alpha-fetoprotein in the amniotic fluid should be performed.
]]>Reproductive Medicine doi: 10.3390/reprodmed2020011
Authors: Martina Chiurazzi Mauro Cozzolino Tilman Reinelt Thi Dao Nguyen Stefanie Elke Chie Giancarlo Natalucci Maria Consolata Miletta
Human milk is considered the most advantageous source of nourishment for infants. Even though there is no ideal composition of human milk, it still contains a unique combination of components that contribute to brain development. The aim of this review is to provide an overview on the possible correlation of human milk with the neurodevelopment of infants, with a special emphasis on myelination and epigenetic modifications. Research in human milk is a rapidly expanding field and cutting-edge technologies might contribute to identify specific mechanisms underlying the beneficial effects on human milk on neurodevelopment.
]]>Reproductive Medicine doi: 10.3390/reprodmed2020010
Authors: Barbara Illi Barbara Vasapollo Herbert Valensise Pierangela Totta
SARS-CoV-2 represents the greatest epidemiological, clinical, and social challenge the human being has had to face in this century. SARS-CoV-2 is not merely a respiratory virus, as its target cells range from upper airway respiratory cells to pulmonary cells but also and above all to the cardiovascular cells, such as pericytes and endothelial cells. Indeed, the pathology related to SARS-CoV-2, COVID-19, may be defined as a thromboinflammatory syndrome in its most severe form, characterized by sepsis-induced coagulopathy (SIC) and disseminated intravascular coagulopathy (DIC), which is prevalent in individuals already presenting a chronic level of inflammation (e.g., obese individuals, elderly) and hypertension. Pregnancy is not only an inflammatory-prone condition but is characterized by a consistent rearrangement of the blood circulation and coagulation profile. Cardiac output increases while arterial systolic and diastolic pressure decrease, regardless of the activation of the RAS system. ACE2, the SARS-CoV-2 entry receptor into the host cells, which transforms Ang II in Ang 1–7, is highly expressed in endothelial, smooth muscle cells and pericytes of placental villi, regulating blood pressure and fetal development. Pre-eclampsia is a pregnancy disorder characterized by hypertension and low levels of ACE2, endothelial dysfunction, and a high production of pro-inflammatory cytokines, resembling COVID-19 manifestations. Whereas pre-eclampsia and COVID-19 have overlapping clinical features, a role for SARS-CoV-2 as a leading cause of pre-eclampsia in COVID-19 positive pregnant women has not been clarified yet. In this mini-review, we will explore the possibility of the existence of such a link, focusing on the role of endothelial dysfunction and RAS in both pre-eclampsia and SARS-CoV-2-induced COVID-19 pathogenesis.
]]>Reproductive Medicine doi: 10.3390/reprodmed2020009
Authors: Andrea Dall’Asta Monica Minopoli Tullio Ghi Tiziana Frusca
Early fetal growth restriction (FGR) remains a challenging entity associated with an increased risk of perinatal morbidity and mortality as well as maternal complications. Significant variations in clinical practice have historically characterized the management of early FGR fetuses. Nevertheless, insights into diagnosis and management options have more recently emerged. The aim of this review is to summarize the available evidence on monitoring, delivery and outcome in early-onset FGR.
]]>Reproductive Medicine doi: 10.3390/reprodmed2020008
Authors: Marwan Habiba Donatella Lippi Giuseppe Benagiano
Through microscopy, early researchers identified the epithelium on the inner surfaces of the uterus, cervix and Fallopian tubes. The identification of ectopic epithelium was gradual, starting from the gross pathology study of unusual cystic lesions. Towards the end of the nineteenth century, attention focused on the epithelium as a critical component. The term ‘adenomyoma’ was coined around eighteen eighty to designate the majority of mucosa-containing lesions. Several theories were advanced to explain its aetiology. In the main, lesions were considered to arise from invasion from uterine epithelium; implantation of endometrium through retrograde menstruation; hematogenous or lymphatic spread; or from embryonic remnants. Although initially widely rejected, around 1920, an almost unanimous consensus formed on the endometrial nature of epithelial invasions. During the following years, adenomyosis and endometriosis came to be used to distinguished lesions within or outside the uterus. Adenomyosis was attributed to direct infiltration of uterine mucosa into the myometrium, and endometriosis to the implantation of endometrial cells and stroma into the peritoneal cavity through retrograde menstruation. Around the same time, ovarian lesions, initially described as ovarian hematomas or chocolate cysts, were regarded as a form of endometriosis. Three variants of endometriosis were thus described: superficial peritoneal, deep nodular and ovarian endometriomas. Ectopic epithelium has long been recognised as having similarities to tubal, or cervical epithelium. Lesions containing mixed epithelium are often termed Müllerianosis. This article demonstrates the stepwise evolution of knowledge, the role of the pioneers and the difficulties that needed to be overcome. It also demonstrates the value of collaboration and the inter-connected nature of the scientific endeavour.
]]>Reproductive Medicine doi: 10.3390/reprodmed2010007
Authors: Anders Jacobsen Christentze Schmiegelow Bjarke Sørensen Omari A. Msemo Karsten Nielsen Birgitte Bruun Nielsen Sofie Lykke Møller John P. A. Lusingu Daniel T. R. Minja Morten Hedegaard Diana Riknagel
One strategy for improving detection of fetal growth restriction (FGR) is developing biosensors identifying placental dysfunction as a leading pathogenesis for FGR. The aim of this pilot study was to investigate the performance of a biosensor specified to detect placental dysfunction by means of maternal arterial turbulence acoustics in a low-resource setting. A cohort of 147 singleton pregnant women were prospectively followed with double-blinded biosensor tests, sonographic estimation of fetal weight (EFW) and Doppler flow at 26–28, 32–34 and 37–39 weeks of pregnancy. Full term live births with recorded birth weights (BWs) and without major congenital malformations were included. Outcomes were defined as (A) a solitary biometric measure (BW < 3rd centile) and as (B) a biometric measure and contributory functional measure (BW < 10th centile and antenatally detected umbilical artery pulsatility index > 95th centile). Data from 118 women and 262 antenatal examinations were included. Mean length of pregnancy was 40 weeks (SD ± 8 days), mean BW was 3008 g (SD ± 410 g). Outcome (A) was identified in seven (6%) pregnancies, whereas outcome (B) was identified in one (0.8%) pregnancy. The biosensor tested positive in five (4%) pregnancies. The predictive performance for outcome (A) was sensitivity = 0.29, specificity = 0.97, p = 0.02, positive predictive value (PPV) was 0.40 and negative predictive value (NPV) was 0.96. The predictive performance was higher for outcome (B) with sensitivity = 1.00, specificity = 0.97, p = 0.04, PPV = 0.20 and NPV = 1.00. Conclusively, these pilot-study results show future potential for biosensors as screening modality for FGR in a low-resource setting.
]]>Reproductive Medicine doi: 10.3390/reprodmed2010006
Authors: Daniele Farsetti Francesca Pometti Grazia Maria Tiralongo Damiano Lo Presti Ilaria Pisani Giulia Gagliardi Barbara Vasapollo Gian Paolo Novelli Herbert Valensise
Objectives: To assess umbilical vein (UV) blood flow in fetal growth restriction (FGR) and in pregnancy with small for gestational age (SGA) fetus. To evaluate the predictive capacity of UV blood flow (QUV) in the discrimination of SGA fetuses from FGR before and after 32 weeks of pregnancy. Methods: Sixty-five women with a recent diagnosis of FGR or SGA fetuses were enrolled and underwent a complete fetal Doppler examination comprehending QUV. We collected SGA (n = 34), early-FGR (n = 9), and late-FGR (n = 22) fetuses. Results: UV diameter was lower in early and late-FGR compared to SGA, while time-averaged maximum velocity (TAMXV) was lower only in early-FGR. UV blood flow (QUV) and QUV corrected for estimated fetal weight (cQUV) were significantly lower in early-FGR and late-FGR compared to SGA. The receiver operating characteristic (ROC) curves analysis of cQUV showed a significant predictive capacity for SGA diagnosis before and after 32 weeks. Conclusions: The evaluation of UV blood flow allows distinguishing SGA fetuses from FGR. The assessment of UV flow should be taken into consideration in future research of new parameters to differentiate SGA from FGR.
]]>Reproductive Medicine doi: 10.3390/reprodmed2010005
Authors: Adi Sharabi-Nov Tanja Premru Sršen Kristina Kumer Vesna Fabjan Vodušek Teja Fabjan Nataša Tul Hamutal Meiri Kypros H. Nicolaides Joško Osredkar
Objective: We previously provided evidence to confirm that maternal serum levels of soluble Fms-like tyrosine kinase-1 (sFlt-1), placental growth factor (PlGF), and their ratio are useful tools to direct the management of preeclampsia (PE), fetal growth restriction (FGR), and PE+FGR near delivery. In this secondary analysis, we further examine the potential additive value of maternal serum Inhibin-A, which is a hormone marker of the transforming growth factor family, to the accuracy provided by maternal serum PlGF and sFlt-1. Methods: We conducted a secondary analysis where we extracted the data of a cohort of 125 pregnant women enrolled near delivery at the clinics of the University Medical Center of Ljubljana, Slovenia. The dataset included 31 cases of PE, 16 of FGR, 42 of PE+FGR, 15 preterm delivery (PTD), and 21 unaffected controls with delivery of a healthy baby at term. Cases delivered before 34 weeks’ gestation included 10 of PE, 12 of FGR, 28 of PE+FGR, and 6 of PTD. In addition to the recorded demographic characteristics and medical history and the maternal serum levels of PlGF and sFlt-1/PlGF ratio, which were previously published, we evaluated the added value of maternal serum Inhibin-A. The predictive accuracy of each biomarker, their ratios, and combinations were estimated from areas under the curve (AUC) of receiver operating characteristics (ROC) curves, Box and Whisker plots, and by multiple regression. We estimated accuracy by the continuous marker model and a cutoff model. Results: In this study, we combined Inhibin-A with PlGF or with the sFlt-1/PlGF ratio and showed a 10–20% increase in AUCs and 15–45% increase in the detection rate, at 10% false positive rate, of PE, and a lower, but significant, increase for PE+FGR and FGR in all cases but not for FGR in early cases delivered < 34 weeks. The use of a cutoff model was adequate, although a bit higher accuracy was obtained from the continuous model. The highest correlation was found for PlGF with all three complications. Conclusion: In this secondary analysis, we have found that maternal serum Inhibin-A improves the accuracy of predicting PE and PE+FGR provided by maternal serum angiogenic markers alone, bringing the results to a diagnostic level; thus, it could be considered for directing clinical management. Inhibin-A had smaller or no added value for the accuracy of predicting FGR alone, mainly of early cases delivered <34 weeks.
]]>Reproductive Medicine doi: 10.3390/reprodmed2010004
Authors: Channing Burks Kristin Van Heertum Rachel Weinerman
Since the birth of the first IVF baby, Louise Brown, in 1978, researchers and clinicians have sought ways to improve pregnancy outcomes through embryo selection. In the 1990s, blastomere biopsy and fluorescence in situ hybridization (FISH) were developed in human embryos for the assessment of aneuploidy and translocations. Limitations in the number of chromosomes that could be assayed with FISH lead to the development of comparative genomic hybridization (CGH); however, pregnancy rates overall were not improved. The later development of trophectoderm biopsy with comprehensive chromosome screening (CCS) technologies, as well as the subsequent development of next-generation sequencing (NGS), have shown much greater promise in improving pregnancy and live birth rates. Recently, many studies are focusing on the utilization of non-invasive preimplantation genetic testing (niPGT) in an effort to assess embryo ploidy without exposing embryos to additional interventions.
]]>Reproductive Medicine doi: 10.3390/reprodmed2010003
Authors: Kristina Kumer Adi Sharabi-Nov Vesna Fabjan Vodušek Tanja Premru Sršen Nataša Tul Teja Fabjan Hamutal Meiri Kypros Herodotos Nicolaides Joško Osredkar
Objective—the objective of this study was to assess the accuracy of placental growth factor (PlGF), soluble Fms-like Tyrosine Kinase 1 (sFlt-1), and endoglin (sEng) in the diagnosis of suspected preeclampsia (PE) with and without fetal growth restriction (FGR) near delivery. Methods—this is a secondary analysis of a dataset of 125 pregnant women presenting at the high risk pregnancy clinic with suspected PE, FGR or PE + FGR in the University Medical Center of Slovenia. The dataset included 31 PE cases, 16 FGR cases, 42 PE + FGR cases, 15 cases who developed with unrelated complications before 37 weeks (wks) (PTD), and 21 unaffected controls who delivered a healthy baby at term. We also analyzed a sub-group of women who delivered early (<34 wks) including 10 PE, 12 FGR, 28 PE + FGR, and six PTD. Clinical management adhered to hospital guidelines. Marker levels were extracted from the dataset and were used to develop Receiver Operating Characteristic (ROC) curves and to calculate the area under the curve (AUC), the detection rates (DRs), and the false positive rates (FPRs). Previously published marker cutoffs for yes/no admission to hospital wards were extracted from the literature. Negative and positive predictive values (NPVs and PPVs) were evaluated for their value in determining whether hospital admission was required. Non-parametric tests were applied for statistical analysis; p < 0.05 was considered significant. Results—near delivery, all the pro-and anti-angiogenic markers provided diagnostic (ROC = 1.00) accuracy for the early (<34 wks) group of FGR. Diagnostic or near diagnostic (ROC = 0.95) accuracy was achieved by all marker for early PE + FGR but lower accuracy was achieved for early PE. For all cases, all markers, especially PlGF reached diagnostic or near diagnostic accuracy for FGR and PE + FGR. At this accuracy level, they can contribute to the clinical management of FGR, and PE + FGR. All the markers were less accurate for all PE cases. The use of published cutoffs was adequate for clinical management of FGR, whether early or for all cases, using an NPV > 90%. For PE + FGR, the PPV value approached 100%, especially for early cases, and can thus be implemented in clinical management. Neither NPV nor PPV were high enough for managing all cases of PE. There was no added value in measuring the PlGF/(sFlt-1 + sEng) ratio. Conclusion—This is the first study on a Slovenian population. It shows that near-delivery angiogenic biomarkers tests may be useful for confirming the diseases in cases where there is a diagnostic doubt. However, the clinical use of the biomarkers needs to be weighed against resources available and degree of certainty of the diagnosis made with and without them for managing suspected FGR and PE + FGR requiring delivery <34 wks, where they are very accurate, and furthermore in the management of all cases of FGR and FGR+PE. The markers were less accurate for the clinical diagnosis of PE.
]]>Reproductive Medicine doi: 10.3390/reprodmed2010002
Authors: Jarmila A. Zdanowicz Muriel Disler Roland Gerull Luigi Raio Daniel Surbek
Fetuses with an estimated weight (EFW) below the 10th percentile are at risk for adverse perinatal outcome and clinical management remains a challenge. We examined EFW and cerebro-placental ratio (CPR) with regard to their predictive capability in the management and outcome of such cases. Fetuses were first diagnosed as small after 34 weeks of gestation with an actual EFW below the 10th percentile at our tertiary academic center. We determined the optimum cutoff value for CPR and EFW in predicting adverse neonatal outcome. Mean gestational age at diagnosis was 36 weeks. One hundred and two cases were included in our study. We determined a CPR of 1.4 and an EFW of 2152 g to be the best cutoff value for predicting adverse fetal outcome, with an area under the curve (AUC) of 0.65 (95% CI 0.54–0.76); p = 0.009, and 0.76 (95% CI 0.66–0.86); p < 0.0001, respectively. However, when comparing EFW with CPR, EFW seems to be slightly better in predicting adverse fetal outcome in our group. While the use of CPR alone for the management of small fetuses is not sufficient, it is an important additional tool that may be of value in the clinical setting.
]]>Reproductive Medicine doi: 10.3390/reprodmed2010001
Authors: Reprod. Med. Editorial Office Reprod. Med. Editorial Office
Peer review is the driving force of journal development, and reviewers are gatekeepers who ensure that Reproductive Medicine maintains its standards for the high quality of its published papers [...]
]]>Reproductive Medicine doi: 10.3390/reprodmed1030017
Authors: Olga Mutter Jordan Hylton Stacey Jeronis David Jaspan Marisa Rose
While standardized national residency education curricula have been successfully implemented in other specialties, there is no such curriculum in Obstetrics & Gynecology (Ob/Gyn). With this study, we sought to evaluate: (1) the current state of and satisfaction with resident didactic education (2) perceptions regarding centralization and standardization of resident didactic education and (3) the need for a standardized national Ob/Gyn residency education curriculum. In 2019, a web-based needs assessment survey was administered to residents and program leadership from all 267 Ob/Gyn residency programs nationwide. Main outcomes were reported with descriptive statistics. A total of 782 (83 program directors, 46 assistant program directors, and 653 residents) participants completed the survey. Respondents represented a diverse range of regions, program types, and program sizes. Almost all (97%) participants agreed or strongly agreed that residents nationwide should have equal access to high quality Ob/Gyn educational resources. Further, 92% agreed or strongly agreed that core resources should be centrally located. A majority (78%) agreed or strongly agreed that there is a need for a national Ob/Gyn residency education curriculum. Our results demonstrate a perceived need for a centrally located, standardized, national residency education curriculum in Ob/Gyn.
]]>Reproductive Medicine doi: 10.3390/reprodmed1030016
Authors: Ryosuke Akino Daisuke Matsui Ryouka Kawahara-Miki Mitsuyoshi Amita Kuniko Tatsumi Eri Ishida Woojin Kang Shuji Takada Kenji Miyado Akihiko Sekizawa Takakazu Saito Tomohiro Kono Hidekazu Saito
Background: Dysmature cumulus cells are lower fertilization rates and abnormalities in embryonic development compared to maturation cumulus cells. Morphological evaluation of cumulus–oocyte complexes (COCs) considered the possibility that differences may also be found in gene expression. Purpose: To identify hallmarks for evaluating oocyte quality by investigating gene expression patterns in human cumulus cells surrounding oocytes. Methods: Cumulus cells were obtained from the cumulus–oocyte complex of infertile women treated with assisted reproductive technology. Based on maturity level, the cumulus cells were classified into two categories, i.e., dysmature cumulus cell (DCC) and maturation cumulus cell. DCCs were subjected to gene expression analysis using next-generation sequencing and compared with COCs that are in the process of maturation as controls. Results: The expression levels of genes involved in the Wnt signal/β-catenin pathway were significantly reduced in DCCs compared with those in control cells. Moreover, the expression levels of genes involved in multiple pathways associated with apoptosis were also significantly reduced compared with those in control cells. Conclusions: DCCs showed significant decreases in apoptosis- and Wnt/β-catenin signaling-associated gene expression. DCCs could be classified by morphological evaluation, and the method described in this study may be useful as an oocyte quality estimation tool.
]]>Reproductive Medicine doi: 10.3390/reprodmed1030015
Authors: Olga Mutter Jordan Hylton Stacey Jeronis David Jaspan Marisa Rose
At the completion of training in obstetrics and gynecology (Ob/Gyn), residents are expected to have comprehensive knowledge of the field. However, there is no comprehensive Ob/Gyn residency education curriculum. We hypothesize that there is a need for a standardized curriculum. A needs assessment survey was administered to determine the current state of resident didactic education, the perceptions that Ob/Gyn residents, program directors (PDs), and assistant program directors (APDs) have regarding centralization and standardization of education, and the need for a standardized Ob/Gyn residency education curriculum. In 2019, a web-based survey was distributed to Ob/Gyn residents and program leadership from three institutions. The main outcomes were measured on a 5-pt Likert scale. A total of 50 (3 PDs, 5 APDs, and 42 residents) participants completed the survey with a response rate of 68% (50/73). Almost all (94%) participants agreed or strongly agreed that residents nationwide should have equal access to high-quality Ob/Gyn educational resources. Further, 92% agreed or strongly agreed that core Ob/Gyn resources should be centrally located. A majority, 76%, agreed or strongly agreed that there is a need for a national curriculum. This study demonstrates a perceived need for a centrally located, standardized Ob/Gyn residency education curriculum.
]]>Reproductive Medicine doi: 10.3390/reprodmed1030014
Authors: Beatriz Brás de Guimarães Leonardo Martins José Luís Metello Fernando Luís Ferreira Pedro Ferreira José Manuel Fonseca
The aim of this study was to build an Artificial Neural Network (ANN) complemented by a decision tree to predict the chance of live birth after an In Vitro Fertilization (IVF)/Intracytoplasmic Sperm Injection (ICSI) treatment, before the first embryo transfer, using demographic and clinical data. Overall, 26 demographic and clinical data from 1193 cycles who underwent an IVF/ICSI treatment at Centro de Infertilidade e Reprodução Medicamente Assistida, between 2012 and 2019, were analyzed. An ANN was constructed by selecting experimentally the input variables which most correlated to the target through Pearson correlation. The final used variables were: woman’s age, total dose of gonadotropin, number of eggs, number of embryos and Antral Follicle Count (AFC). A decision tree was developed considering as an initial set the input variables integrated in the previous model. The ANN model was validated by the holdout method and the decision tree model by the 10-fold cross method. The ANN accuracy was 75.0% and the Area Under the Receiver Operating Characteristic (AUROC) curve was 75.2% (95% Confidence Interval (CI): 72.5–77.5%), whereas the decision tree model reached 75.0% and 74.9% (95% CI: 72.3–77.5%). These results demonstrated that both ANN and decision tree methods are fair for prediction the chance of conceive after an IVF/ICSI cycle.
]]>Reproductive Medicine doi: 10.3390/reprodmed1030013
Authors: Juan Miguel Martínez-Galiano Naomi Cano-Ibáñez Antonio Hernández-Martínez Miguel Delgado-Rodríguez
During the gestational period, women need to have optimal health to meet fetal requirements for growth and development. Nutrition is one of the most important factors that can ensure a mother`s health and also that of their offspring. The role of maternal diet, before and during pregnancy, has been associated with adverse birth outcomes and a worsening of maternal health. Medical conditions that are closely related to dietary intake and may affect women before or during pregnancy have also been associated with the appearance of pathology in a newborn. To date, several studies have been carried out in order to identify the role of diet as a factor associated with child physiological and psychological health, both in the short and long term. Educating mothers regarding the influence of maternal dietary intake during pregnancy on infants’ health could represent a simple but effective target for public health policies to improve pregnancy nutrition, and therefore help to avoid newborn diseases through the development.
]]>Reproductive Medicine doi: 10.3390/reprodmed1030012
Authors: Peilin Zhang
Decidual vasculopathy at late gestation was shown to be associated with spiral artery remodeling at implantation. Dramatic decidual vascular transformation from early to late stage pregnancy suggests a dynamic spatiotemporal relationship between the various vascular components in spiral artery remodeling and decidual vasculopathy. The central and peripheral portions of 105 placentas with decidual vasculopathy at term were examined with or without preeclampsia to see if temporal vascular regeneration was present. Central and peripheral vasculopathy and central and peripheral regeneration were compared. The peripheral portion showed more decidual vasculopathy (88 of total 105, 83.8%) than central portion (72 of total 105, 68.6%, p < 0.0001). However, central portion showed more vascular regeneration (51 of total 105, 48.6%) than the peripheral portion (23 of total 105, 21.9%, p < 0.0001). There was no difference in vasculopathy or regeneration with or without preeclampsia. Spiral artery remodeling is non-synchronous during placental growth and vascular regeneration. This spatiotemporal sequence may help interpretation of morphologic changes of decidual vasculopathy.
]]>Reproductive Medicine doi: 10.3390/reprodmed1020011
Authors: Pierre Vanderzwalmen Fabien Ectors Yannis Panagiotidis Maximilian Schuff Maximilian Murtinger Barbara Wirleitner
Nowadays, cryopreservation of gametes and embryos is a fundamental, integral, and indispensable part of infertility treatment or fertility preservation. Cryopreservation is not only needed for the policy of single embryo transfer and cryopreservation of surplus embryos, but for deferring embryo transfer in the case of ovarian hyperstimulation syndrome, uterine pathologies, and suboptimal endometrium built-up or when preimplantation genetic testing is needed. Several current strategies in assisted reproduction technology (ART) would be inconceivable without highly efficient cryopreservation protocols. Nevertheless, cryopreservation hampered for a long time, especially in terms of low survival rates after freezing and thawing. Only the technical progress during the last decades, namely, in regard to the implementation and advancement of vitrification, leveraged its application, and thus, even allows the cryopreservation of human oocytes—a process that is far from being easy. This review aims to provide a deeper insight into the physical processes of cryopreservation and to explore the character of the vitrified state in the extra and intracellular milieu in order to demonstrate that the common denominator to all cryopreservation procedures is the establishment of an intracellular amorphous condition that hinders the likelihood of crystallization.
]]>Reproductive Medicine doi: 10.3390/reprodmed1020010
Authors: Daniela Haluza Isabella Böhm
Smartphones have become the most important commodity for today’s digitalized society. Besides direct interpersonal communication, their most used features are third-party applications (apps). Apps for monitoring health parameters (health apps) are extremely popular, and their users are part of the Quantified Self movement. Little knowledge is available on how health apps are perceived by a female target audience, the Quantified Woman. We conducted a study among Austrian females of reproductive age (n = 150) to analyze prevalence, perceived benefits, and readiness for health app use. In the cross-sectional online German survey, nearly all participants used these apps (98.0%), predominantly for monitoring physical activity and female health (both 31.3%). For the latter, participants used a large variety of different apps for monitoring contraception and menstruation. Perceived benefits and readiness of health app use were only of medium range. Our study assessed aspects of health app use in an understudied segment of the general population. From a Public Health perspective, the Quantified Woman could be empowered by health data collection by enabling her to take active control over how her health graphs develop. We suggest assuring data security and privacy for sensitive female health data collected by health apps.
]]>Reproductive Medicine doi: 10.3390/reprodmed1020009
Authors: Monika Korenc Joško Osredkar Ksenija Gersak Kristina Kumer Teja Fabjan Sasa Sterpin Miha Lucovnik
Purpose: To determine whether high-dose intravenous vitamin C reduces oxidative stress in patients with severe preeclampsia in the first days postpartum. Methods: Biomarkers of oxidative stress were assessed as secondary outcomes of a single-center, randomized, placebo-controlled trial. Thirty-four patients with singleton pregnancies complicated by severe features of preeclampsia were randomized into two groups: intravenous vitamin C (1.5 g/6 h) (n = 17) or placebo (n = 17). Urinary concentrations of dityrosine, 8-hydroxy-2-deoxyguanosine (8-OHdg), 8-isoprostane, and N epsilon-(hexanoyl) lysine (HEL) were measured at days one and three after delivery and normalized for urinary creatinine in 22 of patients included (12 in vitamin C and 10 in placebo group). The Mann–Whitney U-test was used to compare values of oxidative stress biomarkers at days one and three after delivery in vitamin C vs. placebo groups (p ≤ 0.05 significant). Results: Dityrosine and 8-OHdg values did not differ significantly between the two study groups at day one after delivery (p = 0.23 and p = 0.77, respectively), but were significantly lower in the vitamin C group compared to the placebo group at day three after delivery (p = 0.04 and p = 0.03, respectively). Values of 8-isoprostane and HEL did not differ significantly between the two study groups at day one (p = 0.41 and p = 0.42, respectively), as well as at day three, after delivery (p = 0.25 and p = 0.24, respectively). Conclusion: High-dose intravenous vitamin C treatments in patients with severe preeclampsia reduced urinary levels of dityrosine and 8-OHdg (markers of protein and DNA oxidative damage, respectively) on day three after delivery. Vitamin C treatment had no significant effect on lipid peroxidation biomarkers, i.e., 8-isoprostane and HEL.
]]>Reproductive Medicine doi: 10.3390/reprodmed1020008
Authors: Shervin Assari Shanika Boyce Mohsen Bazargan Cleopatra H. Caldwell
Although early sexual initiation and childbearing are major barriers against the upward social mobility of American adolescents, particularly those who belong to a low socioeconomic status (SES) and racial minorities such as Blacks, less is known on how SES and race correlate with adolescents’ sex hormones. An understanding of the associations between race and SES with adolescents’ sex hormones may help better understand why racial, and SES gaps exist in sexual risk behaviors and teen pregnancies. To extend the existing knowledge on social patterning of adolescents’ sex hormones, in the current study, we studied social patterning of sex hormones in a national sample of male and female American adolescents, with a particular interest in the role of race and SES. For this cross-sectional study, data came from the baseline data (wave 1) of the Adolescent Brain Cognitive Development (ABCD) study, a national longitudinal prospective study of American adolescents. This analysis included 717 male and 576 female non-Hispanic White or Black adolescents ages 9–10. The dependent variables were sex hormones (testosterone for males and estradiol for females). Independent variables were age, race, family marital status, parental education, and financial difficulties. For data analysis, linear regression models were used. Age, race, parental education, and financial difficulties were associated with estradiol in female and testosterone levels in male adolescents. Associations were not identical for males and females, but the patterns were mainly similar. Low SES explained why race is associated with higher estradiol in female adolescents. Marital status of the family did not correlate with any of the sex hormones. Being Black and low SES were associated with a higher level of sex hormones in male and female adolescents. This information may help us understand the social patterning of sexual initiation and childbearing. Addressing racial and economic inequalities in early puberty, sexual initiation, and childbearing is an essential part of closing the racial and economic gaps in the US.
]]>Reproductive Medicine doi: 10.3390/reprodmed1020007
Authors: Laura L. Jelliffe-Pawlowski Scott P. Oltman Larry Rand Karen A. Scott Miriam Kuppermann Rebecca Baer April Bell Gretchen Bandoli Jean Costello Nadia Diamond-Smith Elissa Epel Rebecca Jackson Fei Jiang Deborah A. Karasek Christina Lindan Allison O’Leary Jeffrey Olgin Matt Pantell Alison Paquette Nisha Parikh Noah Peyser Xianhua Piao Aric Prather George Rutherford Kelli K. Ryckman Martina Steurer-Muller Jodi Stookey Ganapati Srinivasa Hollis Wright Charles E. McCulloch Brian Piening Elizabeth E. Rogers Christina Chambers
The 2019 novel coronavirus disease (COVID-19) pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continues to spread and worsen in many parts of the world. As the pandemic grows, it is especially important to understand how the virus and the pandemic are affecting pregnant women and infants. While early data suggested that being infected with the virus did not increase the risk of adverse pregnancy or infant outcomes, as more information has emerged, it has become clear that risks for some adverse pregnancy and infant outcomes are increased (e.g., preterm birth, cesarean section, respiratory distress, and hospitalization). The Healthy Outcomes of Pregnancy for Everyone in the time of novel coronavirus disease-19 (HOPE COVID-19) study is a multi-year, prospective investigation designed to better understand how the SARS-CoV-2 virus and COVID-19 impact adverse pregnancy and infant outcomes. The study also examines how the pandemic exacerbates existing hardships such as social isolation, economic destabilization, job loss, housing instability, and/or family member sickness or death among minoritized and marginalized communities. Specifically, the study examines how pandemic-related hardships impact clinical outcomes and characterizes the experiences of Black, Latinx and low-income groups compared to those in other race/ethnicity and socioeconomic stratum. The study includes two nested cohorts. The survey only cohort will enroll 7500 women over a two-year period. The survey+testing cohort will enroll 2500 women over this same time period. Participants in both cohorts complete short surveys daily using a mobile phone application about COVID-19-related symptoms (e.g., fever and cough) and complete longer surveys once during each trimester and at 6–8 weeks and 6, 12 and 18 months after delivery that focus on the health and well-being of mothers and, after birth, of infants. Participants in the survey+testing cohort also have testing for SARS-CoV-2 and related antibodies during pregnancy and after birth as well as testing that looks at inflammation and for the presence of other infections like Influenza and Rhinovirus. Study results are expected to be reported on a rolling basis and will include quarterly reporting for participants and public health partners as well as more traditional scientific reporting.
]]>Reproductive Medicine doi: 10.3390/reprodmed1020006
Authors: Peilin Zhang
Aim: Spiral artery remodeling at early pregnancy is characterized by two distinct mechanisms with two morphologic features, namely, trophoblastic-dependent vascular invasion with “plugging”, and trophoblastic-independent mural muscular hypertrophy/hyperplasia, both of which lead to the blocking or narrowing of the arterial lumen with the consequence of reduced maternal blood flow to the developing embryo. Methods: Review of historic literature in light of the new discovery of CD56 (NCAM) expression on endovascular trophoblasts at late gestation, in relation to placental lateral growth with vascular regeneration. Results: Reduced maternal blood flow to the embryo results in a hypoxic condition critical for trophectoderm differentiation and proliferation. Hypoxia is also important for the development of hemangioblasts of vasculogenesis, and hematopoiesis of the placental villi. Up to 13 weeks, both uteroplacental and fetoplacental circulations are established and hypoxic condition relieved for normal fetal/placenta development by ultrasonography. The persistence of trophoblastic plugging and/or mural muscular hypertrophy/hyperplasia leads to persistent reduced maternal blood flow to the placenta, resulting in persistent hypoxia and increased angiogenesis, with a constellation of pathologic features of maternal vascular malperfusion atlate gestation. Wilm’s tumor gene (WT1) expression appears to be central to steroid and peptide hormonal actions in early pregnancy, and vascular regeneration/restoration after pregnancy. Conclusions: Spiral artery remodeling at early pregnancy leads to hypoxia with vascular transformation, and the establishment of uteroplacental circulation results in relief of hypoxia. The hypoxia–re-oxygenation sequence may provide insights into the mechanism of normal fetal/placental development and associated pregnancy complications, such as preeclampsia.
]]>Reproductive Medicine doi: 10.3390/reprodmed1020005
Authors: Shervin Assari Shanika Boyce Mohsen Bazargan Cleopatra H. Caldwell
Background: Brookings Institution has identified postponing childbirth from teenage to adulthood as a major strategy that is needed for upward social mobility of women. However, according to the Minorities’ Diminished Returns (MDRs), the associations between aspirations, investments, behaviors, and socioeconomic position (SEP) may be diminished for marginalized groups such as African Americans. Objective: To extend the existing knowledge on the MDRs, the current study had two aims: First to compare White and African American women for the association between postponing childbearing to adulthood and SEP in a national sample of American women. Second, to test correlates of postponing childbearing to adulthood and SEP at birth with long term outcomes 15 years later when the child was 15 years old. Methods: For this longitudinal study, data came from the Fragile Families and Child Well-being Study (FFCWS), a national longitudinal prospective study in the United States (US) that followed an ethnically diverse sample of women from childbirth for 15 years from 1998 to 2016. For the first aim, this study included 2679 women composed of 723 Whites and 1956 African Americans. For the second aim, among 1842 individuals who had available data 15 years later, we measured various economic, behavioral, and mental health outcomes when the child was 15 years old. For aim 1 we ran linear regression. Postponing childbearing to adulthood was the independent variable. The dependent variable, SEP (poverty) was treated as a continuous measure with higher score indicating more poverty. Confounders included marital status and delivery characteristics. For the aim 2, we ran Pearson correlation test (exploratory analysis) to test if baseline SEP correlates with future outcomes. Results: Postponing childbearing from adolescence to adulthood was associated with higher SEP in adulthood, net of all confounders including marital status and education. We found a significant interaction between postponing childbearing from adolescence to adulthood and race on SEP, suggesting that the economic reward of postponing childbearing may be weaker for African American women than for White women. Conclusions: Although postponing the age at childbirth is a recommended strategy for women who wish to maximize their chance of upward social mobility, this strategy may be associated with smaller economic returns for African American women than White women. The results can also be interpreted as MDRs in investments in terms of a postponing childbearing. In a fair society, the same investment should be similarly rewarded across diverse racial groups. In the reality, however, the US society differently rewards White and African American women who postpone childbearing. Research should explore the roles of social stratification, blocked opportunities, and concentrated poverty in explaining the unequal return of such an investment for African American and White women.
]]>Reproductive Medicine doi: 10.3390/reprodmed1010004
Authors: Debabrata Ghosh Ludmila Filaretova Juhi Bharti Kallol K. Roy Jai B. Sharma Jayasree Sengupta
Women with endometriosis are often under stress due to the associated pain, infertility, inflammation-related and other comorbidities including cancer. Additionally, these women are also under stress due to taboos, myths, inter-personal troubles surrounding infertility and pain of the disease as well as due to frequent incidences of missed diagnosis and treatment recurrence. Often these women suffer from frustration and loss of valuable time in the prime phase of life. All these complexities integral to endometriosis posit a hyperstructure of integrative stress physiology with overt differentials in effective allostatic state in women with disease compared with disease-free women. In the present review, we aim to critically examine various aspects of pathophysiological basis of stress surrounding endometriosis with special emphasis on pain and subfertility that are known to affect the overall health and quality of life of women with the disease and promising pathophysiological basis for its effective management.
]]>Reproductive Medicine doi: 10.3390/reprodmed1010003
Authors: Peilin Zhang
Background: Wilm’s tumor 1 gene (WT1) is a transcription factor with versatile cellular functions in embryonic development, the maintenance of adult tissue functions, and regeneration. WT1 is known to be regulated by progesterone and it is abundantly expressed in endometrium, but its function is unclear. Design: in this observational and descriptive study, WT1 expression was detected by immunohistochemical staining in endometrium of various physiological and pathological conditions. Result: WT1 was detected in endometrial stromal cells and vascular smooth muscle cells, in both proliferative and secretory phases of menstrual cycles. WT1 appeared increased in vascular smooth muscle cells in spiral artery in early pregnancy and it was also detected in regenerative endothelial cells and smooth muscle cells in decidual vasculopathy at term. WT1 expression appeared decreased in endometrial stromal cells in adenomyosis (endometriosis). Conclusion: WT1 potentially links the hormonal effects on endometrial decidualization and may play a role in gestational vascular transformation during pregnancy and restoration after pregnancy.
]]>Reproductive Medicine doi: 10.3390/reprodmed1010002
Authors: Berthold Huppertz
The journal Reproductive Medicine just started as an open access journal with an excellent editorial team. As founding editor-in-chief it is my belief that this new journal will find its specific niche in the field of reproduction. It is not only the free access to scientific data that is very important today and that comes with this journal; this journal also builds the bridge between IVF (In Vitro Fertilization) and ART (Assisted Reproductive Technology) on the one hand and pregnancy and pregnancy pathologies on the other hand, combined in one journal. This interdisciplinary approach is needed as the last decade has shown that there are more links between the mode of conception and the outcome of pregnancy than we ever thought. We encourage our readers to scroll through the list of papers that will be published in this journal to open their view for all aspects of reproduction from the ovarian reserve to the epigenetic changes of a newborn due to fetal programming.
]]>Reproductive Medicine doi: 10.3390/reprodmed1010001
Authors: Mitchel C. Schiewe Shane Zozula Nancy L. Nugent John B. Whitney Ilene Hatch C. Terence Lee Robert E. Anderson
Objective: To develop and validate a reliable in vitro culture system for human embryos. Design: Retrospective analyses of a series of four studies were conducted between 2006 and 2010 to assess the effect of incubator type (CO2 box versus Tri-gas minibox), media type, oil type, and hyaluronate supplementation. Optimization of in vitro blastocyst development was verified by assessing our National CDC/ART Surveillance reports between 2010 and 2016. Material and Methods: All patients experienced controlled ovarian hyperstimulation, followed by egg retrieval 35 h post-hCG. Cumulus-oocyte complexes were temporarily cultured in P1 or LG Fert medium plus HSA. Eggs were moved to a more complex media (G-medium or Global®-LG medium) containing a synthetic protein and embryo adhesion supplement (SPS and EAS, respectively; mLG) post-ICSI insemination. Zygotes were assigned to group culture in 25 µl droplets under oil (light mineral oil or paraffin oil; 37 °C) and embryo development was evaluated on Days 3, 5, and 6 and transferred on Day 3 to 5 depending on the number/quality of embryos available and the IVF history of the patient. Transfers were performed under ultrasound guidance, primarily using a Sureview-Wallace catheter, and enriched ET medium containing 500 µg/mL EAS. Results: Pilot study results (Expt. 1) showed that a mLG single-step medium could be effectively used in combination with Sanyo MCO-5 tri-gas (TG) incubators. Once adapted to SCIRS Lab in 2007 (Expt. 2), the latter culture system yielded improved blastocyst production and pregnancy outcomes compared to CO2 in air sequential incubation in P1/Multi-blast medium. In Expt. 3, the mLG/TG system yielded high levels of ≥2BB quality blastocysts (51 to 66%) across all age groups, and greater (p < 0.05) pregnancy success/live birth rates using fewer embryos transferred on Day 5 versus Day 3. After validating its clinical effectiveness, mLG was then prospectively compared to a new generation G-media (1.5 & 2.5; Expt. 4) and determined that the crossover treatment using paraffin oil (Ovoil™) allowed the mLG system to be optimized. Subsequently, a compilation of our Annual CDC/ART reported data over six years verified the overall viability of in vitro cultured and vitrified blastocysts produced in the mLG/TG system. Conclusion: By systematically evaluating and implementing various components of an embryo culture system we were able to optimize blastocyst development over the last decade. Our mLG/TG culture system modified an exceptionally well designed KSOMAA LG medium using endotoxin-free EAS and SPS additives to support cellular membrane wellness under stressful in vitro conditions (e.g., culture, cell biopsy, vitrification). Our use of the mLG/TG culture system has proven to be effective, creating reliably high blastocyst production, implantation, and healthy live births.
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