Characterization of a New Variant in ARHGAP31 Probably Involved in Adams-Oliver Syndrome in a Family with a Variable Phenotypic Spectrum.

Adams-Oliver syndrome is a rare inherited condition characterized by scalp defects and limb abnormalities. It is caused by variants in different genes such as ARHGAP31. Here, we used an interdisciplinary approach to study a family with lower limb anomalies. We identified a novel variant in the ARHGAP31 gene that is predicted to result in a truncated protein with a constitutively activated catalytic site due to the loss of 688 amino acids involved in the C-terminal domain, essential for protein auto-inhibition. Pathogenic variants in ARHGAP31 exon 12, leading to a premature protein termination, are associated with Adams-Oliver syndrome. Bioinformatic analysis was useful to elucidate the impact of the identified genetic variant on protein structure. To better understand the impact of the identified variant, 3D protein models were predicted for the ARHGAP31 wild type, the newly discovered variant, and other pathogenetic alterations already reported. Our study identified a novel variant probably involved in Adams-Oliver syndrome and increased the evidence on the phenotypic variability in patients affected by this syndrome, underlining the importance of translational research, including experimental and bioinformatics analyses. This strategy represents a successful model to investigate molecular mechanisms involved in syndrome occurrence.

Late Third Transcatheter Aortic Valve Replacement for Treatment of Persistent Paravalvular Regurgitation.

Paravalvular regurgitation remains a frequent finding after transcatheter aortic valve replacement and is associated with unfavorable outcomes if more-than-mild grade. In this case, a patient underwent a third transcatheter aortic valve replacement procedure for worsening symptoms due to severe paravalvular regurgitation. The case underlines the role of preprocedural planning in achieving treatment success.

Coronary Cannulation Following TAVR Using Self-Expanding Devices With Commissural Alignment: The RE-ACCESS 2 Study.

BACKGROUND: Coronary re-engagement after transcatheter aortic valve replacement (TAVR) using self-expanding transcatheter heart valves (THVs) systematically implanted using commissural alignment (CA) techniques has been poorly investigated. OBJECTIVES: The aim of this study was to evaluate unsuccessful coronary cannulation, and its predictors, after TAVR using self-expanding devices implanted using CA techniques. METHODS: RE-ACCESS 2 (Reobtain Coronary Ostia Cannulation Beyond Transcatheter Aortic Valve Stent 2) was an investigator-driven, single-center, prospective study that enrolled consecutive TAVR patients receiving Evolut and ACURATE THVs implanted using CA techniques. The primary endpoint was unsuccessful coronary cannulation after TAVR. The secondary endpoint was the identification of postprocedural predictors of unfeasible, selective coronary ostia re-engagement on computed tomographic angiography performed after TAVR. RESULTS: Among 127 patients enrolled from September 2021 to December 2022, 7 (5.5%) had unsuccessful coronary cannulation after TAVR, and 6 of them received Evolut THVs (7.5% vs 2.3%; P = 0.26). Failure of left coronary artery cannulation was similar between Evolut and ACURATE THVs (2.5% vs 2.1%; P = 1.00), whereas that of right coronary artery cannulation was prevalent in the Evolut group (6.3% vs 0.0%; P = 0.16). Coronary overlap was associated with the inability to selectively cannulate the right coronary artery (OR: 5.6; 95% CI: 1.2-25.8; P = 0.03), but not in ACURATE recipients (P = 0.39). Severe misalignment of Evolut THVs was associated with the inability to selectively cannulate both coronary arteries (OR: 24.7; 95% CI: 1.9-312.9; P = 0.01). CONCLUSIONS: Unsuccessful coronary cannulation after TAVR using self-expanding THVs implanted using CA techniques was reported in 5.5% of cases, with the majority involving the Evolut THV. Commissural misalignment affected coronary cannulation after TAVR mostly in Evolut recipients.

Evolut PRO and SAPIEN ULTRA Performance in Small Aortic Annuli: The OPERA-TAVI Registry.

BACKGROUND: The performance of latest iteration transcatheter aortic valve replacement platforms in patients with small aortic anatomy remains underexplored. OBJECTIVES: The aim of this study was to evaluate effectiveness and performance between the self-expanding (SE) Evolut PRO and PRO+ and the balloon-expandable (BE) SAPIEN ULTRA in patients with small aortic annuli. METHODS: Data from the OPERA-TAVI (Comparative Analysis of Evolut PRO vs. SAPIEN 3 ULTRA Valves for Transfemoral Transcatheter Aortic Valve Implantation) registry were used, with 1:1 propensity score matching. Primary endpoints included 1-year effectiveness composite (all-cause mortality, disabling stroke, or heart failure hospitalization) and 30-day device-related (hemodynamic structural valve dysfunction and nonstructural valve dysfunction) outcomes. RESULTS: Among 3,516 patients, 251 matched pairs with aortic annular area <430 mm2 were assessed. The 1-year primary effectiveness outcome did not differ significantly between cohorts (SE 10.8% vs BE 11.2%; P = 0.91). The 30-day device-oriented composite outcome was more favorable in the Evolut PRO group (SE 4.8% vs BE 10.4%; P = 0.027). Notably, SE valve recipients showed higher rates of disabling stroke (SE 4.0% vs BE 0.0%; P < 0.01) and paravalvular leaks (mild or greater: SE 48.5% vs BE 18.6% [P < 0.001]; moderate: SE 4.5% vs BE 1.2% [P = 0.070]). The BE group had higher rates of prosthesis-patient mismatch (moderate or greater: SE 16.0% vs BE 47.1% [P < 0.001]; severe: SE 1.3% vs BE 5.7% [P = 0.197]) and more patients with residual mean gradients >20 mm Hg (SE 1.0% vs BE 13.5%; P < 0.001). CONCLUSIONS: In patients with small aortic annuli, transcatheter aortic valve replacement with latest iteration devices is safe. SE platforms are associated with more favorable device performance in terms of hemodynamic structural and nonstructural dysfunction. Randomized data are needed to validate these findings and guide informed device selection.

Comparison of two self-expanding transcatheter heart valves for degenerated surgical bioprostheses: the AVENGER multicentre registry.

BACKGROUND: There is a lack of comparative data on transcatheter aortic valve implantation (TAVI) in degenerated surgical prostheses (valve-in-valve [ViV]). AIMS: We sought to compare outcomes of using two self-expanding transcatheter heart valve (THV) systems for ViV. METHODS: In this retrospective multicentre registry, we included consecutive patients undergoing transfemoral ViV using either the ACURATE neo/neo2 (ACURATE group) or the Evolut R/PRO/PRO+ (EVOLUT group). The primary outcome measure was technical success according to Valve Academic Research Consortium (VARC)-3. Secondary outcomes were 30-day all-cause mortality, device success (VARC-3), coronary obstruction (CO) requiring intervention, rates of severe prosthesis-patient mismatch (PPM), and aortic regurgitation (AR) ≥moderate. Comparisons were made after 1:1 propensity score matching. RESULTS: The study cohort comprised 835 patients from 20 centres (ACURATE n=251; EVOLUT n=584). In the matched cohort (n=468), technical success (ACURATE 92.7% vs EVOLUT 88.9%; p=0.20) and device success (69.7% vs 73.9%; p=0.36) as well as 30-day mortality (2.8% vs 1.6%; p=0.392) were similar between the two groups. The mean gradients and rates of severe PPM, AR ≥moderate, or CO did not differ between the groups. Technical and device success were higher for the ACURATE platform among patients with a true inner diameter (ID) >19 mm, whereas a true ID ≤19 mm was associated with higher device success - but not technical success - among Evolut recipients. CONCLUSIONS: ViV TAVI using either ACURATE or Evolut THVs showed similar procedural outcomes. However, a true ID >19 mm was associated with higher device success among ACURATE recipients, whereas in patients with a true ID ≤19 mm, device success was higher when using Evolut.

Sex-Related Outcomes of Transcatheter Aortic Valve Implantation With Self-Expanding or Balloon-Expandable Valves: Insights from the OPERA-TAVI Registry.

Evidence regarding gender-related differences in response to transcatheter aortic valve implantation according to the valve type is lacking. This study aimed to evaluate the impact of gender on the treatment effect of Evolut PRO/PRO+ (PRO) or SAPIEN 3 Ultra (ULTRA) devices on clinical outcomes. The Comparative Analysis of Evolut PRO vs SAPIEN 3 Ultra Valves for Transfemoral Transcatheter Aortic Valve Implantation (OPERA-TAVI) is a multicenter, multinational registry including patients who underwent the latest-iteration PRO or ULTRA implantation. Overall, 1,174 of 1,897 patients were matched based on valve type and compared according to gender, whereas 470 men and 630 women were matched and compared according to valve type. The 30-day and 1-year outcomes were evaluated. In the PRO and ULTRA groups, men had a higher co-morbidity burden, whereas women had smaller aortic root. The 30-day (device success [DS], early safety outcome, permanent pacemaker implantation, patient-prosthesis mismatch, paravalvular regurgitation, bleedings, vascular complications, and all-cause death) and 1-year outcomes (all-cause death, stroke, and heart failure hospitalization) did not differ according to gender in both valve groups. However, the male gender decreased the likelihood of 30-day DS with ULTRA versus PRO (p for interaction = 0.047). A higher risk of 30-day permanent pacemaker implantation and 1-year stroke and a lower risk of patient-prosthesis mismatch was observed in PRO versus ULTRA, regardless of gender. In conclusion, gender did not modify the treatment effect of PRO versus ULTRA on clinical outcomes, except for 30-day DS, which was decreased in men (vs women) who received ULTRA (vs PRO).

One-year clinical outcomes of transcatheter aortic valve implantation with the latest iteration of self-expanding or balloonexpandable devices: insights from the OPERA-TAVI registry.

BACKGROUND: Midterm comparative analyses of the latest iterations of the most used Evolut and SAPIEN platforms for transcatheter aortic valve implantation (TAVI) are lacking. AIMS: We aimed to compare 1-year clinical outcomes of TAVI patients receiving Evolut PRO/PRO+ (PRO) or SAPIEN 3 Ultra (ULTRA) devices in current real-world practice. METHODS: Among patients enrolled in the OPERA-TAVI registry, patients with complete 1-year follow-up were considered for the purpose of this analysis. One-to-one propensity score matching was used to compare TAVI patients receiving PRO or ULTRA devices. The primary endpoint was a composite of 1-year all-cause death, disabling stroke and rehospitalisation for heart failure. Five prespecified subgroups of patients were considered according to leaflet and left ventricular outflow tract calcifications, annulus dimensions and angulation, and leaflet morphology. RESULTS: Among a total of 1,897 patients, 587 matched pairs of patients with similar clinical and anatomical characteristics were compared. The primary composite endpoint did not differ between patients receiving PRO or ULTRA devices (Kaplan-Meier [KM] estimates 14.0% vs 11.9%; log-rank p=0.27). Patients receiving PRO devices had higher rates of 1-year disabling stroke (KM estimates 2.6% vs 0.4%; log-rank p=0.001), predominantly occurring within 30 days after TAVI (1.4% vs 0.0%; p=0.004). Outcomes were consistent across all the prespecified subsets of anatomical scenarios (all pinteraction>0.10). CONCLUSIONS: One-year clinical outcomes of patients undergoing transfemoral TAVI and receiving PRO or ULTRA devices in the current clinical practice were similar, but PRO patients had higher rates of disabling stroke. Outcomes did not differ across the different anatomical subsets of the aortic root.

Polyphenolic Profile and Antioxidant Activity of Green Extracts from Grape Pomace Skins and Seeds of Italian Cultivars.

The possibility of industrial exploitation of winemaking products, as for all byproducts of vegetal origin, constantly deals with a raw material (grape pomace, GP) whose chemical composition and functional properties vary over time depending on the varietal and geographical origin of the grapes, the climatic conditions (vintage effect), and the winemaking technique. This work studied the compositional variability of polyphenolic skin and seed extracts from GP derived from white and red winemaking of different Italian grape varieties. The total polyphenolic content (GAE), the main classes of polyphenolic compounds, and the DPPH index were determined. Seed extracts were always richer in total polyphenols and condensed tannins and had higher antiradical activity (DPPH) than skin extracts: 144-298 mg GAE/g d.w. extract for skins and 327-540 mg GAE/g for seeds; the DPPH values were 1.77-3.40 mg AAE/g for skins and 3.10-10.48 mg AAE/g for seeds. Furthermore, it was verified that the evaluation of the GAE index of seed extracts, offering a good estimate of the antiradical properties (DPPH index), could represent a simple and rapid method for selecting the best lots of seeds to be used. Conversely, GP skins could be used as flour in the food industry due to their high content of dietary fiber and the presence of flavonols, which possess very interesting functional properties. Important differences in the flavonols profile were observed both between cultivars and between unfermented and fermented pomace.

Long-term outcomes of concomitant transcatheter aortic valve implantation and percutaneous coronary intervention.

BACKGROUND: The safety of concomitant percutaneous coronary intervention (PCI) during transcatheter aortic valve implantation (TAVI) setting is still highly debated. This study aimed to assess the safety and the effectiveness of TAVI and PCI performed in the same session compared with TAVI alone. METHODS: Patients with severe aortic stenosis and coronary artery disease (CAD) (N.=786) who underwent TAVI from June 2007 to April 2021 were divided into two groups: patients who underwent TAVI alone (N.=633) and patients treated with TAVI and concomitant PCI (N.=153). The propensity-score matching adjustment was used to account for baseline confounding variables. RESULTS: A total of 302 TAVI with CAD patients (151 matched pairs), undergoing either isolated TAVI or TAVI+PCI were compared. In-hospital death (6% vs. 4%; P=0.427), stroke (2% vs. 0.7%; P=0.314), myocardial infarction (MI) (0% vs. 0.7%; P=0.317), major and life-threatening bleeding (14.6% vs. 15.9%; P=0.749), and acute kidney injury (9.3% vs. 10.6%; P=0.700) were similar for both groups. At 3 years, the rates of all-cause death (25.2% vs. 19.2%; P=0.615), the composite endpoints of all-cause death and MI (27.2% vs. 21.2%; P=0.699) and all-cause death, MI, and stroke (28.5% vs. 22.5%; P=0.739) were also comparable between the two groups. Achieving complete coronary revascularization in the TAVI setting did not impact on long-term mortality (P=0.257). CONCLUSIONS: In patients with severe aortic stenosis and CAD, concomitant TAVI and PCI was as safe and effective as TAVI alone up to 3-year follow-up.

Treatment in patients with severe asymptomatic aortic stenosis: is it best not to wait?

New insights into the natural history and pathophysiology of patients with aortic stenosis (AS), coupled with the dramatic evolution of transcatheter aortic valve implantation (TAVI), are fuelling intense interest in the management of asymptomatic patients with severe AS. This patient presenting for elective intervention poses a unique challenge. These patients are not traditionally offered surgical aortic valve replacement or TAVI given their lack of symptoms; however, they are at increased risk given the severity of their AS. Furthermore, clinical experience has shown that symptoms can be challenging to ascertain in many sedentary, deconditioned, and/or elderly patients. In addition, evolving data based on imaging and biomarker evidence of adverse ventricular remodelling, hypertrophy, inflammation, or fibrosis may radically transform existing clinical decision paradigms. However, management of asymptomatic severe AS is otherwise controversial and the decision to intervene requires careful assessment of the benefits and risks in an individual patient. Further randomized trials [EARLY TAVI (NCT03042104), AVATAR (NCT02436655), EVOLVED (NCT03094143)] will help determine future recommendations.

Transcatheter Aortic Valve Replacement With the Latest-Iteration Self-Expanding or Balloon-Expandable Valves: The Multicenter OPERA-TAVI Registry.

BACKGROUND: The latest iterations of devices for transcatheter aortic valve replacement (TAVR) have brought refinements to further improve patient outcomes. OBJECTIVES: This study sought to compare early outcomes of patients undergoing TAVR with the self-expanding (SE) Evolut PRO/PRO+ (Medtronic, Inc) or balloon-expandable (BE) Sapien 3 ULTRA (Edwards Lifesciences) devices. METHODS: The OPERA-TAVI (Comparative Analysis of Evolut PRO vs Sapien 3 Ultra Valves for Transfemoral Transcatheter Aortic Valve Implantation) registry collected data from 14 high-volume centers worldwide on patients undergoing TAVR with SE or BE devices. After excluding patients who were not eligible for both devices, patients were compared using 1:1 propensity score matching. The primary efficacy and safety outcomes were Valve Academic Research Consortium-3 device success and early safety, respectively. RESULTS: Among 2,241 patients eligible for the present analysis, 683 pairs of patients were matched. The primary efficacy outcome did not differ between patients receiving SE or BE transcatheter aortic valves (SE: 87.4% vs BE: 85.9%; P = 0.47), but the BE device recipients showed a higher rate of the primary safety outcome (SE: 69.1% vs BE: 82.6%; P < 0.01). This finding was driven by the higher rates of permanent pacemaker implantation (SE: 17.9% vs BE: 10.1%; P < 0.01) and disabling stroke (SE: 2.3% vs BE: 0.7%; P = 0.03) in SE device recipients. On post-TAVR echocardiography, the rate of moderate to severe paravalvular regurgitation was similar between groups (SE: 3.2% vs BE: 2.3%; P = 0.41), whereas lower mean transvalvular gradients were observed in the SE cohort (median SE: 7.0 vs BE: 12.0 mm Hg; P < 0.01). CONCLUSIONS: The OPERA-TAVI registry showed that SE and BE devices had comparable Valve Academic Research Consortium-3 device success rates, but the BE device had a higher rate of early safety. The higher permanent pacemaker implantation and disabling stroke rates in SE device recipients drove this composite endpoint.

COMPARISON OF OSL AND TL DOSEMETERS WITH DATA COLLECTED AT THE MT25 CYCLIC ELECTRON ACCELERATOR.

The Microtron MT25 is a cyclic electron accelerator with a Kapitza resonator, maximum beam energy of 25 MeV, standard repetition frequency of 423 Hz, pulse length of 3.5 µs and mean current of 30 µA. Studies at conventional particle accelerators allow to understand the response of dosemeters in known and controllable radiation fields. Subsequently, it is possible to develop models and predict their behavior in complex radiation fields, such as those generated at laser and FLASH facilities. Therefore, response of thermally and optically stimulated luminescence detectors outside of the beam was studied at the Microtron MT25. The detectors were placed on a Plexiglas phantom inside a lead and iron bunker to shield-off background radiation. In addition, GAFChromic™ films and track detectors were used. Two irradiations were performed: with and without an 8-cm thick polyethylene moderator. This paper presents a comparison of the responses of the different detection systems.

[Evolution of transcatheter aortic valve implantation from a high-volume Italian center: report of 2058 procedures over 15-year experience]. / Evoluzione dell'impianto transcatetere di valvola aortica in un centro italiano ad alto volume: report di 2058 procedure in 15 anni di esperienza.

BACKGROUND: To assess the longitudinal changes in transcatheter aortic valve implantation (TAVI) practice and patients' outcomes in a high-volume Italian center. METHODS: We analyzed all patients undergoing TAVI at our Institution from June 2007 to August 2021. We stratified the overall population considering four time periods according to procedural advancements and changes in clinical practice: period 1 (2007-2009, n=107) vs period 2 (2010-2014, n=449) vs period 3 (2015-2019, n=864) vs period 4 (2019-2021, n=638). Baseline and procedural characteristics, and in-hospital outcomes among the four groups were compared. RESULTS: A total of 2058 patients underwent TAVI receiving all the available devices. Patients had a median age of 82 years (78-85) with no differences among time periods. A stepwise reduction of median Society of Thoracic Surgeons mortality risk score (3.7 [2.8-5.3] vs 3.6 [2.6-5.4] vs 3.6 [2.5-5.5] vs 3.3 [2.2-4.9]; p=0.01) was observed. In-hospital all-cause-death (7.5% vs 5.1% vs 2.9% vs 3.0%; p<0.05), major stroke (4.7% vs 0.7% vs 1.0% vs 0.8%; p<0.05), major vascular complications (17.8% vs 8.7% vs 10.5% vs 5.8%; p<0.05) and permanent pacemaker implantation (23.4% vs 12.0% vs 8.7% vs 8.8%; p<0.05) rates significantly lowered over time. Device success markedly improved (80.4% vs 87.1% vs 95.0% vs 96.3%; p<0.05) with significant improvement of paravalvular regurgitation after TAVI (moderate-to-severe 16.8% vs 8.1% vs 0.7% vs 0.2%; mild 61.4% vs 38.2% vs 38.5% vs 25.6%; p<0.05). CONCLUSIONS: All-cause death and in-hospital outcomes of patients undergoing TAVI significantly improved accordingly to technical advancements and changes in clinical practice over 15-year experience.

Correction: Rondinone et al. Extensive Placental Methylation Profiling in Normal Pregnancies. Int. J. Mol. Sci. 2021, 22, 2136.

In the original publication [...].

Intentional Misalignment of a Transcatheter Aortic Valve to Preserve Reaccess to Coronaries of Anomalous Origin.

Achieving patient-specific commissural alignment of transcatheter aortic valves is particularly important to ensure coronary reaccess after transcatheter aortic valve implantation. Nevertheless, in case of uncommon origin of coronary arteries, commissural alignment could be counterproductive. This case shows how alignment techniques could serve to intentionally misalign the neocommissures in this subset of patients. (Level of Difficulty: Intermediate.).

Transcatheter aortic valve implantation during COVID-19 pandemic: An optimized model to relieve healthcare system overload.

BACKGROUND: The coronavirus 2019 (COVID-19) pandemic upset healthcare systems and their logistics worldwide. We sought to assess safety and effectiveness of an optimized logistics for transcatheter aortic valve implantation (TAVI) pathway developed during the COVID-19 pandemic. METHODS: This is a retrospective analysis. An optimized TAVI logistics based on performing TAVI work-up and procedure during the same hospitalization was used during the COVID-19 pandemic. In-hospital and 30-day outcomes of patients treated during the pandemic were compared with an historical cohort of patients undergoing TAVI with staged work-up before the pandemic within an homogeneous timeframe. RESULTS: Of 536 patients, 227 (42.4%) underwent TAVI during the COVID-19 pandemic with a reduction of 26.5% compared to the pre-pandemic period (n = 309). The median age was 81 (77-85) years and STS score was 3.4 (2.2-5.6)%. Lower rates of in-hospital major vascular complications (2.2% vs. 8.7%; p < 0.01) and life-threatening bleeding (0.4% vs. 4.2%; p = 0.01) were reported in the COVID-19 period, whereas no difference in acute kidney injury (7.0% vs. 7.4%, p = 0.85) rate was reported between COVID-19 and pre-COVID-19 periods. No difference in 30-day rates of all-cause death (4.0 vs. 4.5, p = 0.75) and of major adverse cardiovascular events (4.0 vs. 6.1, p = 0.26) were reported between COVID-19 and pre-COVID-19 periods. CONCLUSIONS: The use of optimized single-hospitalization logistics for TAVI workup and procedure developed during the COVID-19 pandemic, showed to be as safe and effective as the two-stage TAVI pathway previously adopted, allowing the minimization of potential exposure to COVID-19 infection and shortening times to treatment for severely symptomatic patients.

Assessment of pregnancy dietary intake and association with maternal and neonatal outcomes.

BACKGROUND: Maternal dietary habits are contributors of maternal and fetal health; however, available data are heterogeneous and not conclusive. METHODS: Nutrient intake during pregnancy was assessed in 503 women with uncomplicated pregnancies, using the validated Food Frequency Questionnaire developed by the European Prospective Investigation into Cancer and Nutrition (EPIC-FFQ). RESULTS: In all, 68% of women had a normal body mass index at the beginning of pregnancy, and 83% of newborns had an appropriate weight for gestational age. Maternal pre-pregnancy body mass index (BMI), gestational weight gain (GWG), and placental weight were independently correlated with birth weight. GWG was not related to the pre-pregnancy BMI. EPIC-FFQ evaluation showed that 30% of women adhered to the European Food Safety Authority (EFSA) ranges for macronutrient intake. In most pregnant women (98.1%), consumption of water was below recommendations. Comparing women with intakes within EFSA ranges for macronutrients with those who did not, no differences were found in BMI, GWG, and neonatal or placental weight. Neither maternal nor neonatal parameters were associated with the maternal dietary profiles. CONCLUSIONS: In our population, maternal pre-pregnancy BMI, GWG, and placental weight are determinants of birth weight percentile, while no association was found with maternal nutrition. Future studies should explore associations through all infancy. IMPACT: Maternal anthropometrics and nutrition status may affect offspring birth weight. In 503 healthy women, maternal pre-pregnancy body mass index (BMI), gestational weight gain (GWG), and placental weight were independently correlated to neonatal birth weight. GWG was not related to the pre-pregnancy BMI. In all, 30% of women respected the EFSA ranges for macronutrients. Neither maternal nor neonatal parameters were associated with maternal dietary profiles considered in this study. Maternal pre-pregnancy BMI, GWG, and placental weight are determinants of neonatal birth weight percentile, while a connection with maternal nutrition profiles was not found.

Extensive Placental Methylation Profiling in Normal Pregnancies.

The placental methylation pattern is crucial for the regulation of genes involved in trophoblast invasion and placental development, both key events for fetal growth. We investigated LINE-1 methylation and methylome profiling using a methylation EPIC array and the targeted methylation sequencing of 154 normal, full-term pregnancies, stratified by birth weight percentiles. LINE-1 methylation showed evidence of a more pronounced hypomethylation in small neonates compared with normal and large for gestational age. Genome-wide methylation, performed in two subsets of pregnancies, showed very similar methylation profiles among cord blood samples while placentae from different pregnancies appeared very variable. A unique methylation profile emerged in each placenta, which could represent the sum of adjustments that the placenta made during the pregnancy to preserve the epigenetic homeostasis of the fetus. Investigations into the 1000 most variable sites between cord blood and the placenta showed that promoters and gene bodies that are hypermethylated in the placenta are associated with blood-specific functions, whereas those that are hypomethylated belong mainly to pathways involved in cancer. These features support the functional analogies between a placenta and cancer. Our results, which provide a comprehensive analysis of DNA methylation profiling in the human placenta, suggest that its peculiar dynamicity can be relevant for understanding placental plasticity in response to the environment.