Monoamine oxidases activity maintains endometrial monoamine homeostasis and participates in embryo implantation and development.

BACKGROUND: Monoamine oxidases (MAOs) is an enzyme that catalyzes the deamination of monoamines. The current research on this enzyme is focused on its role in neuropsychiatric, neurodevelopmental, and neurodegenerative diseases. Indeed, MAOs with two isoforms, namely, A and B, are located on the outer mitochondrial membrane and are widely distributed in the central nervous system and peripheral tissues. Several reports have described periodic changes in the levels of this enzyme in the human endometrial tissue. RESULTS: The novel role of MAOs in endometrial receptivity establishment and embryonic development by maintaining monoamine homeostasis was investigated in this study. MAOs activity was observed to be enhanced during the first trimester in both humans and mice under normal conditions. However, under pathological conditions, MAOs activity was reduced and was linked to early pregnancy failure. During the secretory phase, the endometrial stromal cells differentiated into decidual cells with a stronger metabolism of monoamines by MAOs. Excessive monoamine levels cause monoamine imbalance in decidual cells, which results in the activation of the AKT signal, decreased FOXO1 expression, and decidual dysfunction. CONCLUSIONS: The findings suggest that endometrial receptivity depends on the maintenance of monoamine homeostasis via MAOs activity and that this enzyme participates in embryo implantation and development.

Analysis of early-pregnancy metabolome in early- and late-onset gestational diabetes reveals distinct associations with maternal overweight.

AIMS/HYPOTHESIS: It is not known whether the early-pregnancy metabolome differs in patients with early- vs late-onset gestational diabetes mellitus (GDM) stratified by maternal overweight. The aims of this study were to analyse correlations between early-pregnancy metabolites and maternal glycaemic and anthropometric characteristics, and to identify early-pregnancy metabolomic alterations that characterise lean women (BMI <25 kg/m2) and women with overweight (BMI ≥25 kg/m2) with early-onset GDM (E-GDM) or late-onset GDM (L-GDM). METHODS: We performed a nested case-control study within the population-based prospective Early Diagnosis of Diabetes in Pregnancy cohort, comprising 210 participants with GDM (126 early-onset, 84 late-onset) and 209 normoglycaemic control participants matched according to maternal age, BMI class and primiparity. Maternal weight, height and waist circumference were measured at 8-14 weeks' gestation. A 2 h 75 g OGTT was performed at 12-16 weeks' gestation (OGTT1), and women with normal results underwent repeat testing at 24-28 weeks' gestation (OGTT2). Comprehensive metabolomic profiling of fasting serum samples, collected at OGTT1, was performed by untargeted ultra-HPLC-MS. Linear models were applied to study correlations between early-pregnancy metabolites and maternal glucose concentrations during OGTT1, fasting insulin, HOMA-IR, BMI and waist circumference. Early-pregnancy metabolomic features for GDM subtypes (participants stratified by maternal overweight and gestational timepoint at GDM onset) were studied using linear and multivariate models. The false discovery rate was controlled using the Benjamini-Hochberg method. RESULTS: In the total cohort (n=419), the clearest correlation patterns were observed between (1) maternal glucose concentrations and long-chain fatty acids and medium- and long-chain acylcarnitines; (2) maternal BMI and/or waist circumference and long-chain fatty acids, medium- and long-chain acylcarnitines, phospholipids, and aromatic and branched-chain amino acids; and (3) HOMA-IR and/or fasting insulin and L-tyrosine, certain long-chain fatty acids and phospholipids (q<0.001). Univariate analyses of GDM subtypes revealed significant differences (q<0.05) for seven non-glucose metabolites only in overweight women with E-GDM compared with control participants: linolenic acid, oleic acid, docosapentaenoic acid, docosatetraenoic acid and lysophosphatidylcholine 20:4/0:0 abundances were higher, whereas levels of specific phosphatidylcholines (P-16:0/18:2 and 15:0/18:2) were lower. However, multivariate analyses exploring the early-pregnancy metabolome of GDM subtypes showed differential clustering of acylcarnitines and long-chain fatty acids between normal-weight and overweight women with E- and L-GDM. CONCLUSIONS/INTERPRETATION: GDM subtypes show distinct early-pregnancy metabolomic features that correlate with maternal glycaemic and anthropometric characteristics. The patterns identified suggest early-pregnancy disturbances of maternal lipid metabolism, with most alterations observed in overweight women with E-GDM. Our findings highlight the importance of maternal adiposity as the primary target for prevention and treatment.

Evaluation of novel biomarkers for early pregnancy outcome prediction†.

OBJECTIVE: To assess performance and discriminatory capacity of commercially available enzyme-linked immunosorbent assays of biomarkers for predicting first trimester pregnancy outcome in a multi-center cohort. DESIGN: In a case-control study at three academic centers of women with pain and bleeding in early pregnancy, enzyme-linked immunosorbent assays of biomarkers were screened for assay performance. Performance was assessed via functional sensitivity, assay reportable range, recovery/linearity, and intra-assay precision (%Coefficient of Variation). Top candidates were analyzed for discriminatory capacity for viability and location among 210 women with tubal ectopic pregnancy, viable intrauterine pregnancy, or miscarriage. Assay discrimination was assessed by visual plots, area under the curve with 95% confidence intervals, and measures of central tendency with two-sample t-tests. RESULTS: Of 25 biomarkers evaluated, 22 demonstrated good or acceptable assay performance. Transgelin-2, oviductal glycoprotein, and integrin-linked kinase were rejected due to poor performance. The best biomarkers for discrimination of pregnancy location were pregnancy-specific beta-1-glycoprotein 9, pregnancy-specific beta-1-glycoprotein 1, insulin-like growth factor binding protein 1, kisspeptin (KISS1), pregnancy-specific beta-1-glycoprotein 3, and beta parvin (PARVB). The best biomarkers for discrimination of pregnancy viability were pregnancy-specific beta-1-glycoprotein 9, pregnancy-specific beta-1-glycoprotein 3, EH domain-containing protein 3, KISS1, WAP four-disulfide core domain protein 2 (HE4), quiescin sulfhydryl oxidase 2, and pregnancy-specific beta-1-glycoprotein 1. CONCLUSION: Performance of commercially available enzyme-linked immunosorbent assays was acceptable for a panel of novel biomarkers to predict early pregnancy outcome. Of these, six and seven candidates demonstrated good discriminatory capacity of pregnancy location and viability, respectively, when validated in a distinct external population. Four markers demonstrated good discrimination for both location and viability.

Obesity-associated non-oxidative genotoxic stress alters trophoblast turnover in human first-trimester placentas.

Placental growth is most rapid during the first trimester (FT) of pregnancy, making it vulnerable to metabolic and endocrine influences. Obesity, with its inflammatory and oxidative stress, can cause cellular damage. We hypothesized that maternal obesity increases DNA damage in the FT placenta, affecting DNA damage response and trophoblast turnover. Examining placental tissue from lean and obese non-smoking women (4-12 gestational weeks), we observed higher overall DNA damage in obesity (COMET assay). Specifically, DNA double-strand breaks were found in villous cytotrophoblasts (vCTB; semi-quantitative γH2AX immunostaining), while oxidative DNA modifications (8-hydroxydeoxyguanosine; FPG-COMET assay) were absent. Increased DNA damage in obese FT placentas did not correlate with enhanced DNA damage sensing and repair. Indeed, obesity led to reduced expression of multiple DNA repair genes (mRNA array), which were further shown to be influenced by inflammation through in vitro experiments using tumor necrosis factor-α treatment on FT chorionic villous explants. Tissue changes included elevated vCTB apoptosis (TUNEL assay; caspase-cleaved cytokeratin 18), but unchanged senescence (p16) and reduced proliferation (Ki67) of vCTB, the main driver of FT placental growth. Overall, obesity is linked to heightened non-oxidative DNA damage in FT placentas, negatively affecting trophoblast growth and potentially leading to temporary reduction in early fetal growth.

Morphologic development of the first-trimester utero-placental vasculature is positively associated with embryonic and fetal growth: the Rotterdam Periconception Cohort.

STUDY QUESTION: Is morphologic development of the first-trimester utero-placental vasculature associated with embryonic growth and development, fetal growth, and birth weight percentiles? SUMMARY ANSWER: Using the utero-placental vascular skeleton (uPVS) as a new imaging marker, this study reveals morphologic development of the first-trimester utero-placental vasculature is positively associated with embryonic growth and development, fetal growth, and birth weight percentiles. WHAT IS KNOWN ALREADY: First-trimester development of the utero-placental vasculature is associated with placental function, which subsequently impacts embryonic and fetal ability to reach their full growth potential. The attribution of morphologic variations in the utero-placental vascular development, including the vascular structure and branching density, on prenatal growth remains unknown. STUDY DESIGN, SIZE, DURATION: This study was conducted in the VIRTUAL Placental study, a subcohort of 214 ongoing pregnancies, embedded in the prospective observational Rotterdam Periconception Cohort (Predict study). Women were included before 10 weeks gestational age (GA) at a tertiary referral hospital in The Netherlands between January 2017 and March 2018. PARTICIPANTS/MATERIALS, SETTING, METHODS: We obtained three-dimensional power Doppler volumes of the gestational sac including the embryo and the placenta at 7, 9, and 11 weeks of gestation. Virtual Reality-based segmentation and a recently developed skeletonization algorithm were applied to the power Doppler volumes to generate the uPVS and to measure utero-placental vascular volume (uPVV). Absolute vascular morphology was quantified by assigning a morphologic characteristic to each voxel in the uPVS (i.e. end-, bifurcation-crossing-, or vessel point). Additionally, total vascular length (mm) was calculated. The ratios of the uPVS characteristics to the uPVV were calculated to determine the density of vascular branching. Embryonic growth was estimated by crown-rump length and embryonic volume. Embryonic development was estimated by Carnegie stages. Fetal growth was measured by estimated fetal weight in the second and third trimester and birth weight percentiles. Linear mixed models were used to estimate trajectories of longitudinal measurements. Linear regression analysis with adjustments for confounders was used to evaluate associations between trajectories of the uPVS and prenatal growth. Groups were stratified for conception method (natural/IVF-ICSI conceptions), fetal sex (male/female), and the occurrence of placenta-related complications (yes/no). MAIN RESULTS AND THE ROLE OF CHANCE: Increased absolute vascular morphologic development, estimated by positive random intercepts of the uPVS characteristics, is associated with increased embryonic growth, reflected by crown-rump length (endpoints ß = 0.017, 95% CI [0.009; 0.025], bifurcation points ß = 0.012, 95% CI [0.006; 0.018], crossing points ß = 0.017, 95% CI [0.008; 0.025], vessel points ß = 0.01, 95% CI [0.002; 0.008], and total vascular length ß = 0.007, 95% CI [0.003; 0.010], and similarly with embryonic volume and Carnegie stage, all P-values ≤ 0.01. Density of vascular branching was negatively associated with estimated fetal weight in the third trimester (endpoints: uPVV ß = -94.972, 95% CI [-185.245; -3.698], bifurcation points: uPVV ß = -192.601 95% CI [-360.532; -24.670]) and birth weight percentiles (endpoints: uPVV ß = -20.727, 95% CI [-32.771; -8.683], bifurcation points: uPVV ß -51.097 95% CI [-72.257; -29.937], and crossing points: uPVV ß = -48.604 95% CI [-74.246; -22.961])), all P-values < 0.05. After stratification, the associations were observed in natural conceptions specifically. LIMITATION, REASONS FOR CAUTION: Although the results of this prospective observational study clearly demonstrate associations between first-trimester utero-placental vascular morphologic development and prenatal growth, further research is required before we can draw firm conclusions about a causal relationship. WIDER IMPLICATIONS OF THE FINDINGS: Our findings support the hypothesis that morphologic variations in utero-placental vascular development play a role in the vascular mechanisms involved in embryonic and fetal growth and development. Application of the uPVS could benefit our understanding of the pathophysiology underlying placenta-related complications. Future research should focus on the clinical applicability of the uPVS as an imaging marker for the early detection of fetal growth restriction. STUDY FUNDING/COMPETING INTEREST(S): This research was funded by the Department of Obstetrics and Gynecology of the Erasmus MC, University Medical Centre, Rotterdam, The Netherlands. There are no conflicts of interest. TRIAL REGISTRATION NUMBER: Registered at the Dutch Trial Register (NTR6854).

Serum erythropoietin level is increased during stimulation for IVF but not in OHSS.

BACKGROUND: Erythropoietin (Epo) is a potent vascular growth factor that induces angiogenesis and antiapoptotic signalling. We investigated whether the development of numerous follicles and corpora lutea during in vitro fertilization (IVF) cycle affects circulating Epo levels and further, if Epo could be used as a novel marker for ovarian hyperstimulation syndrome (OHSS). METHODS: 24 women were included in the uncomplicated IVF group and 35 women in the OHSS group. Repeated blood samples from both groups were analysed for Epo, progesterone, blood haemoglobin, and creatinine. Follicular fluid from the IVF group was analysed for Epo and progesterone. Repeated measure analysis was performed for the variables and circulating Epo levels were compared between the IVF group and early OHSS. Furthermore, related growth factors, vascular endothelial growth factor (VEGF) and hypoxia-inducible factor-1 (HIF-1) were analysed from subgroup of women to test for correlation with Epo. RESULTS: During IVF, circulating Epo increased from natural mid-luteal phase to stimulated mid-luteal phase (median 9.5; 95% CI 7.2-13.4 IU/L and 12.5; 10.3-13.4 IU/L; p = 0.003). In cycles resulting in pregnancy, Epo level decreased 14 days after oocyte pick-up (OPU) and remained low thereafter. In cycles not resulting in pregnancy, Epo level increased again 35 days after OPU. Follicle fluid Epo concentration was 1.5 times higher than the serum concentration (median 15.4; 95% CI 10.4-19.2 IU/L vs. 10.2; 8.8-12.7; p = 0.006). There was no difference in circulating Epo concentration between early OHSS and uncomplicated IVF. Circulating Epo did not correlate with VEGF or HIF-1. CONCLUSIONS: Circulating Epo levels fluctuate during IVF cycle. We hypothesise this may suggest Epo's involvement in ovarian physiology and angiogenesis. However, Epo was not a clinical marker for OHSS.

Uric acid and risk of gestational diabetes mellitus: an observational study and mendelian randomization analysis.

OBJECTIVE: Our aim was to explore the relationship between serum uric acid (UA) levels in early pregnancy and the development of gestational diabetes mellitus (GDM), and to further explore whether there is a causal relationship. METHODS: 684 pregnant women with GDM and 1162 pregnant women without GDM participated in this study. 311 pregnant women with GDM and 311 matched controls were enrolled in a 1:1 case-control study. We used conditional logistic regression to explore the relationship between UA levels and the risk of developing GDM. The causal relationship between the two was examined by two-sample Mendelian randomization (MR) analysis. RESULTS: In the 1:1 matched population, the odds ratio (OR) of developing GDM compared with the extreme tertiles of UA levels was 1.967 (95% confidence interval [CI]: 1.475-2.625; P < 0.001). Restricted cubic spline analyses showed a linear relationship between UA and GDM when UA exceeded 222 µmol/L. GDM and UA levels maintained a statistically significant positive correlation in different stratified regression analyses (P < 0.001). However, no evidence of a causal relationship between uric acid and GDM was found by MR analyses with an OR of 1.06 (95% CI: 0.91-1.25) per unit increase in UA. CONCLUSION: There is a positive correlation between UA levels in early pregnancy and the subsequent risk of developing GDM. However, no genetic evidence was found to support a cause-effect relationship between UA and GDM.

Association of serum vitamin D concentration and miscarriage rate in women with first-trimester threatened miscarriage.

RESEARCH QUESTION: Is low serum 25-hydroxyvitamin D (25(OH)D) associated with an increased risk of miscarriage in women who presented with threatened miscarriage to the Early Pregnancy Assessment Clinic (EPAC)? DESIGN: This was a secondary retrospective analysis using archived serum samples from a randomized, double-blind, placebo-controlled trial. Stored serum samples from 371 women presenting to the EPAC with threatened miscarriage during the first trimester were assayed for 25(OH)D by liquid chromatography-mass spectrometry. RESULTS: The overall miscarriage rate was 45/371 (12.1%) in the whole cohort. After grouping vitamin D insufficiency and vitamin D sufficiency together into a 'non-deficient' group and excluding participants who underwent termination of pregnancy, there was no difference in the miscarriage rate between those who were vitamin D deficient compared with those who were not (25/205, 12.2% versus 20/157, 12.7%, P= 0.877, odds ratio 0.951, 95% CI 0.507-1.784). When analysed according to the number of gestational weeks, the miscarriage rate was significantly higher in the vitamin D non-deficient group than the vitamin D-deficient group in women who presented at 6 gestational weeks or earlier (13/33 [39.4%] versus 10/58 [17.2%], P= 0.019), but there were no statistically significant differences between the two groups presenting at later gestations. There was no difference in the vitamin D level in women who had a miscarriage compared with those who had a live birth (48 [37-57] versus 47 [37-58] nmol/l, P= 0.725 median [25th-75th percentile]). CONCLUSIONS: A low serum vitamin D concentration was not associated with an increased risk of miscarriage in women with threatened miscarriage presenting to the EPAC.

Antibiotic cured chronic endometritis remains a risk factor for early pregnancy loss in the subsequent frozen euploid embryo transfer.

RESEARCH QUESTION: Do patients with antibiotic-cured chronic endometritis (CCE) have a comparable pregnancy outcome to those with non-chronic endometritis (NCE) in the subsequent frozen embryo transfer (FET) cycle? DESIGN: A retrospective cohort analysis included 833 patients in their first FET cycles with single euploid embryo transfer. Chronic endometritis (≥5 CD138+ plasma cells per high-power field [CD138+/HPF]) was treated with standard antibiotic therapy. Patients were classified into two groups: the NCE group (n = 611, <5 CD138+/HPF) and the CCE group (n = 222, ≥5 CD138+/HPF and cured after antibiotic treatment). Pregnancy outcomes were compared. NCE group was divided into subgroup 1 (CD138+/HPF = 0) and subgroup 2 (CD138+/HPF = 1-4) for further analysis. RESULTS: The rate of early pregnancy loss (EPL), incorporating all losses before 10 weeks' gestation, was significantly higher in the CCE group than the NCE group (21.2% versus 14.2%, P = 0.016), and the difference was statistically significant (adjusted odds ratio [AOR] 1.68, 95% confidence interval [CI] 1.11-2.55). No significant differences were observed between the two groups with regard to other pregnancy outcomes. In the subgroup analysis, the EPL rate and biochemical pregnancy rate were significantly higher in subgroup 2 than subgroup 1 (17.2% versus 9.4%, AOR 2.21, 95% CI 1.30-3.74; 12.2% versus 6.9%, AOR 2.01, 95% CI 1.09-3.68). CONCLUSIONS: Chronic endometritis cured by standard antibiotic therapy remains a risk factor for EPL in FET cycles, although no differences were found in live birth rates between patients with CCE or with NCE.

Beta-human chorionic gonadotrophin point of care testing for the management of pregnancy of unknown location.

RESEARCH QUESTION: Does a commercially available quantitative beta-human chorionic gonadotrophin (BHCG) point of care testing (POCT) device improve workflow management in early pregnancy by performing comparably to gold standard laboratory methods, and is the performance of a validated pregnancy of unknown location (PUL) triage strategy maintained using POCT BHCG results? DESIGN: Women classified with a PUL between 2018 and 2021 at three early pregnancy units were included. The linear relationship of untreated whole-blood POCT and serum laboratory BHCG values was defined using coefficients and regression. Paired serial BHCG values were then incorporated into the validated M6 multinomial logistic regression model to stratify the PUL as at high risk or at low risk of clinical complications. The sensitivity and negative predictive value were assessed. The timings required for equivocal POCT and laboratory care pathways were compared. RESULTS: A total of 462 PUL were included. The discrepancy between 571 laboratory and POCT BHCG values was -5.2% (-6.2 IU/l), with a correlation coefficient of 0.96. The 133 PUL with paired 0 and 48 h BHCG values were compared using the M6 model. The sensitivity for high-risk outcomes (96.2%) and negative predictive values (98.5%) was excellent for both. Sample receipt and laboratory processing took 135 min (421 timings), compared with 12 min (91 timings) when using POCT (P < 0.0001). CONCLUSIONS: POCT BHCG values correlated well with laboratory testing measurements. The M6 model retained its performance when using POCT BHCG values. Using the model with POCT may improve workflow and patient care without compromising on effective PUL triage.

Cost-effectiveness analysis of expectant vs active management for treatment of persistent pregnancies of unknown location.

BACKGROUND: Persistent pregnancies of unknown location are defined by abnormally trending serum human chorionic gonadotropin with nondiagnostic ultrasound. There is no consensus on optimal management. OBJECTIVE: This study aimed to assess the cost-effectiveness of 3 primary management strategies for persistent pregnancies of unknown location: (1) expectant management, (2) empirical 2-dose methotrexate, and (3) uterine evacuation followed by methotrexate, if indicated. STUDY DESIGN: This was a prospective economic evaluation performed concurrently with the Expectant versus Active Management for Treatment of Persistent Pregnancies of Unknown Location multicenter randomized trial that was conducted from July 2014 to June 2019. Participants were randomized 1:1:1 to expectant management, 2-dose methotrexate, or uterine evacuation. The analysis was from the healthcare sector perspective with a 6-week time horizon after randomization. Costs were expressed in 2018 US dollars. Effectiveness was measured in quality-adjusted life years and the rate of salpingectomy. Incremental cost-effectiveness ratios and cost-effectiveness acceptability curves were generated. Sensitivity analyses were performed to assess the robustness of the analysis. RESULTS: Methotrexate had the lowest mean cost ($875), followed by expectant management ($1085) and uterine evacuation ($1902) (P=.001). Expectant management had the highest mean quality-adjusted life years (0.1043), followed by methotrexate (0.1031) and uterine evacuation (0.0992) (P=.0001). The salpingectomy rate was higher for expectant management than for methotrexate (9.4% vs 1.2%, respectively; P=.02) and for expectant management than for uterine evacuation (9.4% vs 8.1%, respectively; P=.04). Uterine evacuation, with the highest costs and the lowest quality-adjusted life years, was dominated by both expectant management and methotrexate. In the base case analysis, expectant management was not cost-effective compared with methotrexate at a willingness to pay of $150,000 per quality-adjusted life year given an incremental cost-effectiveness ratio of $175,083 per quality-adjusted life year gained (95% confidence interval, -$1,666,825 to $2,676,375). Threshold analysis demonstrated that methotrexate administration would have to cost $214 (an increase of $16 or 8%) to favor expectant management. Moreover, expectant management would be favorable in lower-risk patient populations with rates of laparoscopic surgical management for ectopic pregnancy not exceeding 4% of pregnancies of unknown location. Based on the cost-effectiveness acceptability curves, the probability of expectant management being cost-effective compared with methotrexate at a willingness to pay of $150,000 per quality-adjusted life year gained was 50%. The results were dependent on the cost of surgical intervention and the expected rate of methotrexate failure. CONCLUSION: The management of pregnancies of unknown location with a 2-dose methotrexate protocol may be cost-effective compared with expectant management and uterine evacuation. Although uterine evacuation was dominated, expectant management vs methotrexate results were sensitive to modest changes in treatment costs of both methotrexate and surgical management.

The association of post-embryo transfer SARS-CoV-2 infection with early pregnancy outcomes in in vitro fertilization: a prospective cohort study.

BACKGROUND: The influence of SARS-CoV-2 infection after embryo transfer on early pregnancy outcomes in in vitro fertilization or intracytoplasmic sperm injection-embryo transfer treatment remains inadequately understood. This knowledge gap endures despite an abundance of studies investigating the repercussions of preceding SARS-CoV-2 infection on early pregnancy outcomes in spontaneous pregnancies. OBJECTIVE: This study aimed to investigate the association between SARS-CoV-2 infection within 10 weeks after embryo transfer and early pregnancy outcomes in patients undergoing in vitro fertilization/intracytoplasmic sperm injection treatment. STUDY DESIGN: This prospective cohort study was conducted at a single public in vitro fertilization center in China. Female patients aged 20 to 39 years, with a body mass index ranging from 18 to 30 kg/m2, undergoing in vitro fertilization/intracytoplasmic sperm injection treatment, were enrolled between September 2022 and December 2022, with follow-up extended until March 2023. The study tracked SARS-CoV-2 infection time (≤14 days, ≤28 days, and ≤10 weeks after embryo transfer), symptoms, vaccination status, the interval between vaccination and embryo transfer, and early pregnancy outcomes, encompassing biochemical pregnancy rate, implantation rate, clinical pregnancy rate, and early miscarriage rate. The study used single-factor analysis and multivariate logistic regression to examine the association between SARS-CoV-2 infection status, along with other relevant factors, and the early pregnancy outcomes. RESULTS: A total of 857 female patients undergoing in vitro fertilization/intracytoplasmic sperm injection treatment were analyzed. In the first stage, SARS-CoV-2 infection within 14 days after embryo transfer did not have a significant negative association with the biochemical pregnancy rate (adjusted odds ratio, 0.74; 95% confidence interval, 0.51-1.09). In the second stage, SARS-CoV-2 infection within 28 days after embryo transfer had no significant association with the implantation rate (36.6% in infected vs 44.0% in uninfected group; P=.181). No statistically significant association was found with the clinical pregnancy rate after adjusting for confounding factors (adjusted odds ratio, 0.69; 95% confidence interval, 0.56-1.09). In the third stage, SARS-CoV-2 infection within 10 weeks after embryo transfer had no significant association with the early miscarriage rate (adjusted odds ratio, 0.77; 95% confidence interval, 0.35-1.71). CONCLUSION: Our study suggests that SARS-CoV-2 infection within 10 weeks after embryo transfer may not be negatively associated with the biochemical pregnancy rate, implantation rate, clinical pregnancy rate, and early miscarriage rate in patients undergoing in vitro fertilization/intracytoplasmic sperm injection treatment. It is important to note that these findings are specific to the target population of in vitro fertilization/intracytoplasmic sperm injection patients aged 20 to 39 years, without previous SARS-CoV-2 infection, and with a body mass index of 18 to 30 kg/m2. This information offers valuable insights, addressing current concerns and providing a clearer understanding of the actual risk associated with SARS-CoV-2 infection after embryo transfer.

Society for Maternal-Fetal Medicine Statement: RhD immune globulin after spontaneous or induced abortion at less than 12 weeks of gestation.

Guidelines for the management of first-trimester spontaneous and induced abortion vary in terms of rhesus factor D (RhD) testing and RhD immune globulin (RhIg) administration. These existing guidelines are based on limited data that do not convincingly demonstrate the safety of withholding RhIg for first-trimester abortions or pregnancy losses. Given the adverse fetal and neonatal outcomes associated with RhD alloimmunization, prevention of maternal sensitization is essential in RhD-negative patients who may experience subsequent pregnancies. In care settings in which RhD testing and RhIg administration are logistically and financially feasible and do not hinder access to abortion care, we recommend offering both RhD testing and RhIg administration for spontaneous and induced abortion at <12 weeks of gestation in unsensitized, RhD-negative individuals. Guidelines for RhD testing and RhIg administration in the first trimester must balance the prevention of alloimmunization with the individual- and population-level harms of restricted access to abortion.

Association of sleep duration and sleep quality with gestational diabetes mellitus in pregnant women after treatment with assisted reproductive technology: A birth cohort study.

Maternal sleep is closely related to subsequent gestational diabetes mellitus (GDM) in natural pregnancies. However, whether this connection exists in pregnant women conceiving with the help of assisted reproductive technology (ART) has not been confirmed. Hence, in this study, we evaluated whether early pregnancy sleep duration or sleep quality is associated with gestational diabetes mellitus in ART-pregnant women, as well as the influence of maternal age on this association. This prospective birth cohort study included 856 pregnant women who successfully conceived with the help of ART treatment. The sleep parameters of ART-pregnant women were assessed using the Pittsburgh Sleep Quality Index (PSQI) in early pregnancy. We explored the association between sleep and the risk of gestational diabetes mellitus using an unconditional binary logistic regression model. Different models were constructed to examine the robustness of the estimation by incorporating different confounding factors. Multivariable logistic regression revealed that sleep duration of more than 10 h among ART-pregnant women was significantly associated with the risk of GDM, and the association between sleep duration and gestational diabetes mellitus varied by maternal age. We found an increased risk of subsequent gestational diabetes mellitus with increasing sleep duration only in pregnant women aged <35 years. Additionally, no statistically significant association between sleep quality and gestational diabetes mellitus was found in this study. In conclusion, excessive sleep duration (≥10 h) is associated with a high risk of gestational diabetes mellitus in pregnant women who conceived with the help of assisted reproductive technology, and maternal age may modify this effect.

Early-pregnancy BMI, maternal gestational weight gain, and asthma and allergic diseases in children.

BACKGROUND: Association of early pregnancy body mass index (BMI) and maternal gestational weight gain (GWG), and asthma and allergic disease in children is unclear. METHODS: We analyzed data from 3176 mother-child pairs in a prospective birth cohort study. Maternal anthropometric measurements in the first and last antenatal clinic visits were obtained through post-delivery questionnaires to calculate early pregnancy BMI and maternal GWG. Asthma and allergic diseases in children by the age of 5 years was assessed using a validated questionnaire. Furthermore, serum samples were analyzed for IgE antibodies to eight allergens. We applied Cox proportional hazards and logistic regression analyses to estimate the association of early pregnancy BMI and maternal GWG (as continuous variables and categorized into quarters), and asthma, atopic eczema, atopic sensitization, and allergic rhinitis in children. RESULTS: Neither early pregnancy BMI nor maternal GWG was associated with asthma and allergic disease in children when analyzed as continuous variables. However, compared to the first quarter of GWG (a rate <0.32 kg/week), mothers in the third quarter (rate 0.42-0.52 kg/week) had children with significantly higher odds of developing atopic eczema (adjusted OR 1.49, 95% CI [1.13-1.96]) by 5 years of age. CONCLUSION: Association of early pregnancy BMI and maternal GWG, and asthma and allergic disease in children, is inconsistent. High maternal GWG may be associated with increased odds of atopic eczema.

Amniotic sac reference interval in early pregnancy between 7 and 10 weeks' gestation.

OBJECTIVE: To establish a normal reference interval for amniotic sac measurements between 7 and 10 weeks of gestation and its relative size in relation to the gestational sac and the embryo. METHOD: This was a prospective, cross-sectional study of consecutive women presenting to UCLH Early Pregnancy Unit between August 2022 to June 2023. We included live, normally sited, singleton pregnancies with a normal 20-week anomaly scan. We collected 120 cases per gestational week totaling 360 cases. We performed an inter and intra-observer variability assessment in the measurement of mean ASD in 30 patients. Regression analyses were used to establish reference intervals for GSD to CRL, ASD to CRL, GSD to ASD and GSD:ASD ratio to CRL. The fitted regression line was calculated, along with a 90% prediction interval and the R2 value. RESULTS: There was good interobserver agreement (difference 0.007mm ± 1.105 (95%CI -2.160 to 2.174)) and good intra-observer agreement between Observer A (0.007 ± 1.105 (-2.160 to 2.174)) and Observer B (-0.014 ± 0.919 (-1.814 to 1.786)) in the measurement of mean ASD in 30 patients. Regression analyses showed a highly statistically significant association between each pair of values (all p-values <0.001). There were significant quadratic associations between mean GSD and CRL (R2 = 56%) and mean GSD and ASD (R2 = 60), significant cubic association between ASD and CRL (R2 = 90%) and significant quadratic association between GSD to ASD ratio and CRL (R2 = 68%). The regression equations were used to quantify the values of ASD and GSD to ASD ratios for a range of CRL values and gestational age in days. CONCLUSION: Our study has produced comprehensive reference intervals for amniotic sac size in early pregnancy which could be used in routine clinical practice. This article is protected by copyright. All rights reserved.

Detection of non-cardiac fetal abnormalities on ultrasound at 11-14 weeks: systematic review and meta-analysis.

OBJECTIVES: To assess the diagnostic accuracy of two-dimensional ultrasound at 11-14 weeks' gestation as a screening test for individual fetal anomalies and to identify factors impacting on screening performance. METHODS: This was a systematic review and meta-analysis that was developed and registered with PROSPERO (CRD42018111781). MEDLINE, EMBASE, Web of Science Core Collection and the Cochrane Library were searched for studies evaluating the diagnostic accuracy of screening for 16 predefined, non-cardiac, congenital anomalies considered to be of interest to the early anomaly scan. We included prospective and retrospective studies from any healthcare setting conducted in low-risk, mixed-risk and unselected populations. The reference standard was the detection of an anomaly on postnatal or postmortem examination. Data were extracted to populate 2 × 2 tables and a random-effects model was used to determine the diagnostic accuracy of screening for the predefined anomalies (individually and as a composite). Secondary analyses were performed to determine the impact on detection rates of imaging protocol, type of ultrasound modality, publication year and index of sonographer suspicion at the time of scanning. Post-hoc secondary analysis was conducted to assess performance among studies published during or after 2010. Risk of bias assessment and quality assessment were undertaken for included studies using the Quality Assessment of Diagnostic Accuracy Studies-2 tool. RESULTS: From 5684 citations, 202 papers underwent full-text review, resulting in the inclusion of 52 studies comprising 527 837 fetuses, of which 2399 were affected by one or more of the 16 predefined anomalies. Individual anomalies were not equally amenable to detection on first-trimester ultrasound: a high (> 80%) detection rate was reported for severe conditions, including acrania (98%), gastroschisis (96%), exomphalos (95%) and holoprosencephaly (88%); the detection rate was lower for open spina bifida (69%), lower urinary tract obstruction (66%), lethal skeletal dysplasias (57%) and limb-reduction defects (50%); and the detection rate was below 50% for facial clefts (43%), polydactyly (40%) and congenital diaphragmatic hernia (38%). Conditions with a low (< 30%) detection rate included bilateral renal agenesis (25%), closed spina bifida (21%), isolated cleft lip (14%) and talipes (11%). Specificity was > 99% for all anomalies. Secondary analysis showed that detection improved with advancing publication year, and that the use of imaging protocols had a statistically significant impact on screening performance (P < 0.0001). CONCLUSIONS: The accurate detection of congenital anomalies using first-trimester ultrasound is feasible, although detection rates and false-positive rates depend on the type of anomaly. The use of a standardized protocol allows for diagnostic performance to be maximized, particularly for the detection of spina bifida, facial clefts and limb-reduction defects. Highlighting the types of anomalies amenable to diagnosis and determining factors enhancing screening performance can support the development of first-trimester anomaly screening programs. © 2024 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Association of PM2.5 exposure in early pregnancy and maternal liver function: A retrospective cohort study in Shenzhen, China.

OBJECTIVE: Studies have shown that fine particulate matter (PM2.5) has adverse effects on the liver function, but epidemiological evidence is limited, especially regarding pregnant women. This study aims to investigate the association between PM2.5 exposure in early pregnancy and maternal liver function during pregnancy. METHODS: This retrospective cohort study included 13,342 pregnant participants. PM2.5 and Ozone (O3) exposure level, mean temperature, and relative humidity for each participant were assessed according to their residential address. The levels of serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), and total bilirubin (TBIL) were measured during the second and third trimesters. Data on PM2.5 and O3 exposure level were sourced from Tracking Air Pollution in China (TAP), while the mean temperature and relative humidity were obtained from the ERA5 dataset. The Generalized Additive Model (GAM) was used to analyze the associations between PM2.5 exposure and maternal liver function during pregnancy, adjusting for potential confounding factors. RESULTS: According to the results, each 10 µg/m3 increase in PM2.5 was associated with an increase of 3.57% (95% CI: 0.29%, 6.96%) in ALT and 4.25% (95% CI: 2.33%, 6.21%) in TBIL during the second trimester and 4.51% (95% CI: 2.59%, 6.47%) in TBIL during the third trimester, respectively. After adjusting for O3, these associations remained significant, and the effect of PM2.5 on ALT during the second trimester was further strengthened. No significant association observed between PM2.5 and AST. CONCLUSIONS: PM2.5 exposure in early pregnancy is associated with increasement of maternal ALT and TBIL, suggesting that PM2.5 exposure may have an adverse effect on maternal liver function. Although this finding indicates an association between PM2.5 exposure and maternal liver function, more research is needed to confirm our findings and explore the underlying biological mechanisms.

Systemic inflammation, enteropathogenic E. Coli, and micronutrient insufficiencies in the first trimester as possible predictors of preterm birth in rural Bangladesh: a prospective study.

BACKGROUND: An incomplete understanding of preterm birth is especially concerning for low-middle income countries, where preterm birth has poorer prognoses. While systemic proinflammatory processes are a reportedly normal component of gestation, excessive inflammation has been demonstrated as a risk factor for preterm birth. There is minimal research on the impact of excessive maternal inflammation in the first trimester on the risk of preterm birth in low-middle income countries specifically. METHODS: Pregnant women were enrolled at the rural Bangladesh site of the National Institute of Child Health Global Network Maternal Newborn Health Registry. Serum samples were collected to measure concentrations of the inflammatory markers C-reactive protein (CRP) and Alpha-1-acid glycoprotein (AGP), and stool samples were collected and analyzed for enteropathogens. We examined associations of maternal markers in the first-trimester with preterm birth using logistic regression models. CRP and AGP were primarily modeled with a composite inflammation predictor. RESULTS: Out of 376 singleton births analyzed, 12.5% were preterm. First trimester inflammation was observed in 58.8% of all births, and was significantly associated with increased odds of preterm birth (adjusted odds ratio [aOR] = 2.23; 95% confidence interval [CI]: 1.03, 5.16), independent of anemia. Maternal vitamin B12 insufficiency (aOR = 3.33; 95% CI: 1.29, 8.21) and maternal anemia (aOR = 2.56; 95% CI: 1.26, 5.17) were also associated with higher odds of preterm birth. Atypical enteropathogenic E. coli detection showed a significant association with elevated AGP levels and was significantly associated with preterm birth (odds ratio [OR] = 2.36; 95% CI: 1.21, 4.57), but not associated with CRP. CONCLUSIONS: Inflammation, anemia, and vitamin B12 insufficiency in the first trimester were significantly associated with preterm birth in our cohort from rural Bangladesh. Inflammation and anemia were independent predictors of premature birth in this low-middle income setting where inflammation during gestation was widespread. Further research is needed to identify if infections such as enteropathogenic E. coli are a cause of inflammation in the first trimester, and if intervention for infection would decrease preterm birth.

Predictors of successful expectant and medical management of miscarriage: A systematic review.

INTRODUCTION: 15.3% of pregnancies result in miscarriage, management options include expectant, medical, or surgical. However, each patient has a range of variables, which makes navigating the available literature challenging when supporting individual patient decision-making. This systematic review aims to investigate whether there are any specific predictors for miscarriage management outcome. MATERIAL AND METHODS: The following databases were searched, from the start of each database up to April 2023: PubMed, Medline, and Google Scholar. Inclusion criteria were studies interrogating defined predictors for expectant or medical management of miscarriage success. Exclusion criteria were poor quality, review articles, trial protocols, and congress abstracts. Data collection was carried as per PRISMA guidelines. Quality assessment for each study was assessed using the QUIPS proforma. RESULTS: Relevant predictors include demographics, ultrasound features, presenting symptoms, and biochemical markers. Across the 24 studies there is heterogeneity in miscarriage definition, predictors reported, and management outcomes used. Associations with certain variables and miscarriage management outcomes are described. Ten studies assessed the impact of miscarriage type on expectant and/or medical management. The majority found that a diagnosis of incomplete miscarriage had a higher success rate following expectant or medical management compared to missed miscarriage or anembryonic pregnancy. CONCLUSIONS: We conclude that there is evidence supporting the possibility to offer personalized miscarriage management advice with case specific predictors. Further larger studies with consistent definitions of predictors, management, and outcomes are needed in order to better support women through the decision-making of miscarriage management.