Reproductive Medicine

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. Full article

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. Full article

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. Full article

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. Full article

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. Full article

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. Full article

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. Full article

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. Full article

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%. Full article

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. Full article

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. Full article

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. Full article

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. Full article

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. Full article

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. Full article

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. Full article

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. Full article

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. Full article