Spontaneous Preterm Birth Phenotyping Based on Cervical Length and Immune-Mediated Factors

Cervical length (CL) screening by ultrasonographic measurement is an established tool widely implemented in the clinical protocols of preterm birth (PTB) prediction and prevention. Growing evidence has shown immune-mediated factors in the etiology of spontaneous PTB (sPTB), with robust biological plausibility supporting deep interrelationships with progressive cervical shortening. We explore a retrospective cohort study that examined the sequential measurement of CL and leucocyte markers in both singleton and twin pregnancies.1 The study’s objective was to identify the clinical presentations associated with sPTB in relation to variations in these parameters.1 Progressive CL shortening was associated with higher rates of sPTB in both singletons (4.1% vs 2.7%) and twins (41.9% vs 18.2%) as compared with cases with stable CL. In addition, in singleton pregnancies, individuals in the early preterm birth subgroup with a shortened or stable CL had elevated total white blood cell count, neutrophil count, and neutrophil-to-lymphocyte ratio, along with a reduced lymphocyte-to-monocyte ratio, in comparison with individuals in the full-term birth subgroup. However, in twins, similar changes were exclusive to those with a shortened cervix. Finally, the study quantified the association between immune-related indicators and risk of sPTB, incorporating CL. In singleton pregnancies, an increase in the white blood cell count and neutrophil count was associated with early sPTB for both stable and shortened CL. Conversely, in twins, there was a significantly higher white blood cell count, neutrophil count, and monocyte count only in the subgroup with shortened C

Reference ranges of uterine artery pulsatility index from first to third trimester based on serial Doppler measurements: longitudinal cohort study

Objective: To provide gestational-age (GA)-specific reference ranges for mean uterine artery (UtA) pulsatility index (PI) based on longitudinal data assessment throughout pregnancy. Methods: This was a prospective longitudinal cohort study of singleton low-risk pregnancies with adequate health and nutritional status at the time of enrolment and without fetal anomaly, receiving prenatal care between January 2018 and July 2021 at the Maternal Fetal Medicine Unit of IRCCS San Raffaele Scientific Institute, Milan, Italy. Women were recruited at ≤ 12 + 6 weeks' gestation and underwent serial standardized ultrasound monitoring, including UtA-PI measurement, by experienced certified operators until delivery. Association of UtA-PI with GA was modeled with fractional polynomial regression. Equations for mean ± SD of the estimated curves were calculated, as well as GA-specific reference charts of centiles for UtA-PI from 10 + 0 to 39 + 0 gestational weeks. Results: We included 476 healthy, low-risk pregnant women and a total of 2045 ultrasound scans (median, 4 (range, 3–9) per patient) were available for analysis. Mean UtA-PI was 1.84 ± 0.55, 1.07 ± 0.38 and 0.78 ± 0.23 in the first, second and third trimesters of pregnancy, respectively. Goodness-of-fit assessment revealed that second-degree smoothing was the most accurate fractional polynomial for describing the course of UtA-PI throughout gestation; therefore, it was modeled in a multilevel framework for the construction of UtA-PI curves. We observed a rapid and substantial decrease in mean UtA-PI before 16 weeks, with subsequent smoother decrement of the slope and more stable values from 20 until 39 weeks. The 3rd, 5th, 10th, 25th, 50th, 75th, 90th, 95th and 97th centiles according to GA for UtA-PI are provided, as well as equations to allow calculation of any value as a centile. Conclusions: UtA-PI shows a progressive non-linear decrease throughout pregnancy. The new reference ranges for GA-specific mean UtA-PI constructed using rigorous methodology may have a better performance compared with previous models for screening for placenta-associated diseases in the early stages of pregnancy and for evaluating the potential risk for pregnancy-induced hypertension and/or small-for-gestational age later in pregnancy

VP36.15: Evaluation of uterine artery pulsatility index and 17β estradiol serum concentration in first trimester pregnancies with oocyte donation

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Maternal prepregnancy weight as an independent risk factor for congenital heart defect: systematic review and meta‐analysis stratified by subtype and severity of defect

Objective: To assess the association between increased maternal prepregnancy body mass index (BMI) and the risk of congenital heart defect (CHD) in offspring. Methods: This systematic review and meta-analysis searched PubMed/MEDLINE, Web of Science and Scopus from inception to 20 April 2023. Risk estimates were abstracted or calculated for increased BMI categories (overweight, obesity, moderate obesity and severe obesity) compared with normal weight (reference). Fixed-effects or random-effects models were used to combine individual study risk estimates based on the degree of heterogeneity. Sensitivity analyses were conducted to weight pooled estimates for relevant moderators, particularly diabetes before and during pregnancy. Subgroup analyses for specific CHD subtypes were conducted if there were at least two studies with available data. Findings were presented for groups of defects, categorized using severity and topographic–functional criteria, and for individual defects. The certainty of the evidence for each effect estimate was evaluated according to Grading of Recommendations, Assessment, Development and Evaluation (GRADE) guidelines. Results: Overall, 31 studies comprising 4 861 693 patients and 86 136 CHD cases were included. The risk of CHD increased progressively from moderate to severe obesity (pooled odds ratio (OR), 1.15 (95% CI, 1.11–1.20) and 1.39 (95% CI, 1.27–1.53), respectively). Sensitivity analysis indicated that this effect persisted independently of maternal diabetes status before or during pregnancy. In the subgroup analysis, obesity was associated with up to a 1.5-fold increase in the risk of severe CHD (pooled OR, 1.48 (95% CI, 1.03–2.13)). Severe obesity was associated with an even higher risk, with 1.8-times higher odds compared with the reference group for specific CHD subtypes, including tetralogy of Fallot (pooled OR, 1.72 (95% CI, 1.38–2.16)), pulmonary valve stenosis (pooled OR, 1.79 (95% CI, 1.39–2.30)) and atrial septal defect (pooled OR, 1.71 (95% CI, 1.48–1.97)). Conclusions: Maternal weight is a crucial modifiable risk factor for CHD, particularly for severe forms of defect. Further research is needed to investigate whether weight management before pregnancy might serve as a preventive measure against CHD. In pregnant women with obesity, fetal echocardiography should be a routine diagnostic procedure

Uterine artery Doppler pulsatility index at 11-38 weeks in ICSI pregnancies with egg donation

BACKGROUND: Uterine artery Doppler pulsatility index (UtA-PI) may be different in pregnancies with egg donation (ICSI-ED) as compared to conceptions with autologous intra-cytoplasmatic sperm injection (autologous ICSI) and to spontaneous conceptions (SC). METHODS: One hundred and ninety-four pregnant women with different modes of conception (MC) were prospectively evaluated: 53 ICSI-ED, 36 autologous ICSI and 105 SC. To evaluate the effects of different MC on PI, multivariable linear regression (MLR) models predicting UtA-PI were fitted after adjustment for maternal age, body mass index, race, parity, smoking status and gestational age. RESULTS: In the first trimester, at MLR, autologous ICSI was not associated with a significantly different UtA-PI [estimate (EST) 0.01; 95% confidence interval (CI) -0.19, 0.2; P=0.9] when compared to SC. Conversely, MC by ICSI-ED was associated with lower first trimester UtA-PI (EST -0.32; CI -0.55, -0.08; P=0.01) when compared to SC. At MLR, MC by autologous ICSI and by ICSI-ED were not associated with significant differences in the second and third trimester UtA-PI when compared to SC. CONCLUSION: ICSI-ED conception presented lower UtA-PI when compared to SC at 11+0-13+6 weeks but not at later assessments. Correction of UtA-PI measurement specifying the origin of oocyte may be useful in first trimester screening

A Systematic Review of Atypical Endometriosis-Associated Biomarkers

Ovarian endometriosis may increase the risk of malignancy. Several studies have suggested atypical endometriosis as the direct precursor of endometriosis-associated ovarian cancer. We performed an advanced, systematic search of the online medical databases PubMed and Medline. The search revealed n = 40 studies eligible for inclusion in this systematic review. Of these, n = 39 were finally included. The results from included studies are characterized by high heterogeneity, but some consistency has been found for altered expression in phosphoinositide 3-kinase (PI3K)/AKT/mTOR pathway, ARID1a, estrogen and progesterone receptors, transcriptional, nuclear, and growth factors in atypical endometriosis. Although many targets have been proposed as biomarkers for the presence of atypical endometriosis, none of them has such strong evidence to justify their systematic use in clinical practice, and they all need expensive molecular analyses. Further well-designed studies are needed to validate the evidence on available biomarkers and to investigate novel serum markers for atypical endometriosis

Serious Games for Improving Genetic Literacy and Genetic Risk Awareness in the General Public: Protocol for a Randomized Controlled Trial

Background: Genetic testing and genetic risk information are gaining importance in personalized medicine and disease prevention. However, progress in these fields does not reflect increased knowledge and awareness of genetic risk in the general public. Objective: Our aim is to develop and test the efficacy of a suite of serious games, developed for mobile and Web platforms, in order to increase knowledge of basic genetic concepts and promote awareness of genetic risk management among lay people. Methods: We developed a new ad-hoc game and modified an arcade game using mechanics suitable to explain genetic concepts. In addition, we developed an adventure game where players are immersed in virtual scenarios and manage genetic risk information to make health-related and interpersonal decisions and modulate their lifestyle. The pilot usability testing will be conducted with a convenience sample of 30 adults who will be categorized into 3 groups and assigned to one game each. Participants will be asked to report any positive or negative issues arising during the game. Subsequently, they will be asked to complete the Game Experience Questionnaire. Finally, a total of 60 teenagers and adults will be enrolled to assess knowledge transfer. Thirty participants will be assigned to the experimental group and asked to play the serious games, and 30 participants will be assigned to the control group and asked to read leaflets on the genetic concepts conveyed by the games. Participants of both groups will fill out a questionnaire before and after the intervention to assess their topic-specific knowledge of genetics. Furthermore, both groups will complete the self-efficacy questionnaire, which assesses the level of confidence in using genetic information. Results: We obtained evidence of game usability in 2017. The data will be submitted to a peer-reviewed journal and used to improve the game design. Knowledge-transfer testing will begin in 2018, and we expect to collect preliminary data on the learning outcomes of serious games by December 2018. Conclusions: It is important to educate the general public about the impact of genetics and genetic testing on disease prevention and the consequent decision-making implications. Without such knowledge, individuals are more likely to make uninformed decisions or handover all decisions regarding genetic testing to their doctors. Technological innovations such as serious games might become a valid instrument to support public education and empowerment

The maternal-fetal neurodevelopmental groundings of preterm birth risk

Background: Altered neurodevelopment is a major clinical sequela of Preterm Birth (PTB) being currently unexplored in-utero. Aims: To study the link between fetal brain functional (FbF) connectivity and preterm birth, using resting-state functional magnetic resonance imaging (rs-fMRI). Study design: Prospective single-centre cohort study. Subjects: A sample of 31 singleton pregnancies at 28–34 weeks assigned to a low PTB risk (LR) (n = 19) or high PTB risk (HR) (n = 12) group based on a) the Maternal Frailty Inventory (MaFra) for PTB risk; b) a case-specific PTB risk gradient. Methods: Fetal brain rs-fMRI was performed on 1.5T MRI scanner. First, directed causal relations representing fetal brain functional connectivity measurements were estimated using the Greedy Equivalence Search (GES) algorithm. HR vs. LR group differences were then tested with a novel ad-hoc developed Monte Carlo permutation test. Second, a MaFra-only random forest (RF) was compared against a MaFra-Neuro RF, trained by including also the most important fetal brain functional connections. Third, correlation and regression analyses were performed between MaFra-Neuro class probabilities and i) the GA at birth; ii) PTB risk gradient, iii) perinatal clinical conditions and iv) PTB below 37 weeks. Results: First, fewer fetal brain functional connections were evident in the HR group. Second, the MaFra-Neuro RF improved PTB risk prediction. Third, MaFra-Neuro class probabilities showed a significant association with: i) GA at birth; ii) PTB risk gradient, iii) perinatal clinical conditions and iv) PTB below 37 weeks. Conclusion: Fetal brain functional connectivity is a novel promising predictor of PTB, linked to maternal risk profiles, ahead of birth, and clinical markers of neurodevelopmental risk, at birth, thus potentially “connecting” different PTB phenotypes

The OSMR gene is involved in Hirschsprung associated enterocolitis susceptibility through an altered downstream signaling

Hirschsprung (HSCR) Associated Enterocolitis (HAEC) is a common life-threatening compli-cation in HSCR. HAEC is suggested to be due to a loss of gut homeostasis caused by impairment of immune system, barrier defense, and microbiome, likely related to genetic causes. No gene has been claimed to contribute to HAEC occurrence, yet. Genetic investigation of HAEC by Whole-Exome Sequencing (WES) on 24 HSCR patients affected (HAEC) or not affected (HSCR-only) by enterocolitis and replication of results on a larger panel of patients allowed the identification of the HAEC susceptibility variant p.H187Q in the Oncostatin-M receptor (OSMR) gene (14.6% in HAEC and 5.1% in HSCR-only, p = 0.0024). Proteomic analysis on the lymphoblastoid cell lines from one HAEC patient homozygote for this variant and one HAEC patient not carrying the variant revealed two well distinct clusters of proteins significantly up or downregulated upon OSM stimulation. A marked enrichment in immune response pathways (q < 0.0001) was shown in the HAEC H187 cell line, while proteins upregulated in the HAEC Q187 lymphoblasts sustained pathways likely involved in pathogen infection and inflammation. In conclusion, OSMR p.H187Q is an HAEC susceptibility variant and perturbates the downstream signaling cascade necessary for the gut immune response and homeostasis maintenance