Livebirth rate after one frozen embryo transfer in ovulatory women starting with natural, modified natural, or artificial endometrial preparation in Viet Nam: an open-label randomised controlled trial.

BACKGROUND: Use of frozen embryo transfer (FET) in in-vitro fertilisation (IVF) has increased. However, the best endometrial preparation protocol for FET cycles is unclear. We compared natural and modified natural cycle strategies with an artificial cycle strategy for endometrial preparation before FET. METHODS: In this randomised, open-label study, we recruited ovulatory women aged 18-45 years at a hospital in Ho Chi Minh City, Viet Nam, who were randomly allocated (1:1:1) to natural, modified natural, or artificial cycle endometrial preparation using a computer-generated random list and block randomisation. The trial was not masked due to the nature of the study interventions. In natural cycles, no oestrogen, progesterone, or human chorionic gonadotropin (hCG) was used. In modified natural cycles, hCG was used to trigger ovulation. In artificial cycles, oral oestradiol valerate (8 mg/day from day 2-4 of menstruation) and vaginal progesterone (800 mg/day starting when endometrial thickness was ≥7 mm) were used. Embryos were vitrified, and then one or two day-3 embryos or one day-5 embryo were warmed and transferred under ultrasound guidance. If the first FET cycle was cancelled, subsequent cycles were performed with artificial endometrial preparation. The primary endpoint was livebirth after one FET. This trial is registered at ClinicalTrials.gov, NCT04804020. FINDINGS: Between March 22, 2021, and March 14, 2023, 4779 women were screened and 1428 were randomly assigned (476 to each group). 99 first FET cycles were cancelled in each of the natural and modified cycle groups, versus none in the artificial cycle group. The livebirth rate after one FET was 174 (37%) of 476 in the natural cycle strategy group, 159 (33%) of 476 in the modified natural cycle strategy group, and 162 (34%) of 476 in the artificial cycle strategy group (relative risk 1·07 [95% CI 0·87-1·33] for natural vs artificial cycle strategy, and 0·98 [0·79-1·22] for modified natural vs artificial cycle strategy). Maternal and neonatal outcomes did not differ significantly between groups, as the power to detect small differences was low. INTERPRETATION: Although the livebirth rate was similar after natural, modified natural, and artificial cycle endometrial preparation strategies in ovulatory women undergoing FET IVF, no definitive conclusions can be made regarding the comparative safety of the three approaches. FUNDING: None.

Developmental outcomes of children born through ICSI versus conventional IVF (cIVF) in couples with non-male factor infertility.

STUDY QUESTION: In non-male factor infertile couples, are there any differences in the developmental outcomes between children born through ICSI and conventional IVF (cIVF)? SUMMARY ANSWER: In this preliminary study, ICSI and cIVF seem to have a comparable effect on developmental outcomes after 12 months in children born to non-male factor infertile couples. WHAT IS KNOWN ALREADY: ICSI, an invasive technique, has raised concerns about potential developmental abnormalities in children. Limited data are available regarding the developmental outcomes of ICSI-conceived infants born to non-male factor infertile couples. STUDY DESIGN, SIZE, DURATION: This prospective cohort study involved a follow-up of all children aged 12 months or older who were born from pregnancies resulting from either ICSI or cIVF as part of a previous randomized controlled trial (RCT) (NCT03428919). PARTICIPANTS/MATERIALS, SETTING, METHODS: In the original RCT, 1064 women were randomly assigned to the ICSI or cIVF groups (532 women for each group). Follow-up was conducted with 155 couples (195 children) in the ICSI group and 141 couples (185 children) in the cIVF group. The Vietnamese version of the Ages & Stages Third Edition Questionnaires (ASQ-3) and the Development Red Flags questionnaires were completed by the participants. A total of 141 (90.1%) women (177 children) in the ICSI group and 113 (80.1%) women (145 children) in the cIVF group returned fully completed questionnaires. The primary outcomes were the developmental outcomes based on responses to the ASQ-3 and the Red Flags questionnaire. MAIN RESULTS AND THE ROLE OF CHANCE: The mean age of children at follow-up was 19.5 ± 5.0 months in the ICSI group and 19.3 ± 5.5 months in the cIVF group. The mean height and weight of children in both groups were similar. The overall proportion of children with any abnormal ASQ-3 score did not differ significantly between the ICSI and cIVF groups (16.9% vs 13.1%, P = 0.34). The proportion of children with Red Flag signs was also comparable between the two groups (6.2% vs 9.2%, P = 0.36, ICSI vs cIVF, respectively). LIMITATIONS, REASONS FOR CAUTION: Despite a reasonably high follow-up response rate, there is a potential risk of sampling bias, and overall, the number of children with developmental abnormalities was very small. The study relied solely on questionnaires as screening tools, rather than incorporating additional behavioral observations or physical developmental tests; this may have affected the statistical power and the significance of between-group comparisons. WIDER IMPLICATIONS OF THE FINDINGS: The current findings contribute to the existing evidence and support the comparative safety of ICSI and cIVF regarding early childhood development. However, more extensive and prolonged follow-up data for these children are needed to draw definitive conclusions. STUDY FUNDING/COMPETING INTEREST(S): No external funding was received for this study, and no authors reported conflicting interests. TRIAL REGISTRATION NUMBER: NCT04866524 (clinicaltrials.gov).

Effect of single versus grouped culture of human cumulus-oocyte complexes in PCOS women treated with biphasic in vitro maturation: A sibling oocyte pilot study.

Purpose: This study investigated the differences in the maturation rate of single versus grouped cumulus-oocyte complexes (COCs) culture methods for capacitation in vitro maturation (CAPA-IVM) in women with polycystic ovary syndrome (PCOS). Methods: This study was performed at My Duc Phu Nhuan Hospital, Vietnam from October 1, 2020 to October 24, 2021. Women aged 18-37 years with a diagnosis of PCOS were recruited. COCs from each woman were randomly divided into two groups: single or grouped culture during CAPA-IVM culture. The primary outcome was the maturation rate. Results: A total of 322 COCs from 15 eligible women included were randomly assigned to the two study groups. The maturation rate was comparable between the single and grouped culture groups (61.3% vs. 64.8%; p = 0.56). There were no significant differences in the number of 2-pronuclei fertilized oocytes, number of day-3 embryos, and number of good-quality embryos in the two culture method groups. In the single culture group, COCs morphology was associated with the day-3 embryo formation rate but not the maturation rate. Conclusions: Comparable oocyte maturation and embryology outcomes between single and grouped COCs culture utilizing sibling COCs derived from women with PCOS suggest the feasibility of both methods for CAPA-IVM culture.

In vitro fertilization outcome based on the detailed early luteal phase trajectory of hormones: a prospective cohort study.

BACKGROUND: Ovarian stimulation and the use of human chorionic gonadotropin (hCG) for triggering oocyte maturation in women undergoing in vitro fertilisation (IVF) introduces several differences in luteal phase hormone levels compared with natural cycles that may negatively impact on endometrial receptivity and pregnancy rates after fresh embryo transfer. Exogenous luteal phase support is given to overcome these issues. The suitability of a pragmatic approach to luteal phase support is not known due to a lack of data on early phase luteal hormone levels and their association with fertility outcomes during IVF with fresh embryo transfer. This study determined early luteal phase profiles of serum progesterone, 17-hydroxyprogesterone and hCG, and associations between hormone levels/hormone level profile after hCG trigger and the live birth rate in women undergoing IVF with fresh embryo transfer. METHODS: This prospective single center, cohort study was conducted in Vietnam from January 2021 to December 2022. Women aged 18-38 years with normal ovarian reserve and undergoing controlled ovarian stimulation using a gonadotropin-releasing hormone antagonist protocol were included. Serum hormone levels were determined before trigger, at 12, 24 and 36 h after hCG, and daily from 1 to 6 days after oocyte pick-up. Serum hormone level profiles were classified as lower or upper. The primary outcome was live birth rate based on early luteal phase hormone level profile. RESULTS: Ninety-five women were enrolled. Live birth occurred in 19/69 women (27.5%) with a lower progesterone profile and 13/22 (59.1%) with an upper progesterone profile (risk ratio [RR] 2.15; 95% confidence interval [CI] 1.28-3.60), and in 6/31 (19.4%) versus 26/60 (43.3%) with a lower versus upper serum 17-hydroxyprogesterone profile (RR 2.24; 95% CI 1.03-4.86). Nearly 20% of women had peak progesterone concentration on or before day 3 after oocyte pick-up, and this was associated with significantly lower chances of having a life birth. CONCLUSIONS: These data show the importance of proper corpus luteum function with sufficient progesterone/17-hydroxyprogesterone production for achievement of pregnancy and to maximize the chance of live birth during IVF. TRIAL REGISTRATION: NCT04693624 ( www. CLINICALTRIALS: gov ).

Epigenetic variation in neonatal tissues in infants conceived using capacitation-in vitro maturation vs. in vitro fertilization.

OBJECTIVE: To investigate alterations of the global DNA methylation profile in placenta, cord blood, and neonatal buccal smears in infants conceived using in vitro maturation (IVM) with a prematuration step (capacitation-IVM [CAPA-IVM]) vs. in vitro fertilization (IVF). DESIGN: Analysis of data from the offspring of participants in a randomized controlled trial. SETTING: Private clinic. PATIENTS: Forty-six women with polycystic ovary syndrome and/or high antral follicle count and their offspring (58 newborns). INTERVENTION(S): Women with polycystic ovary syndrome and/or a high antral follicle count participating in the clinical trial were randomized to undergo CAPA-IVM or conventional IVF. MAIN OUTCOME MEASURE(S): At delivery, biological samples including cord blood, placental tissue, and a neonatal buccal smear were collected. Genome-wide DNA methylation was determined using the Illumina Infinium MethylationEPIC BeadChip. Variability in methylation was also considered, and mean variances for the two treatment categories were compared. RESULTS: In neonatal buccal smears, there were no significant differences between the CAPA-IVM and conventional IVF groups on the basis of the CpG probe after linear regression analysis using a significant cut-off of false-discovery rate <0.05 and |Δß|≥0.05. In cord blood, only one CpG site showed a significant gain of methylation in the CAPA-IVM group. In the placenta, CAPA-IVM was significantly associated with changes in methylation at five CpG sites. Significantly more variable DNA methylation was found in five probes in the placenta, 54 in cord blood, and two in buccal smears after IVM of oocytes. In cord blood samples, 20 CpG sites had more variable methylation in the conventional IVF vs. IVM group. Isolated CpG sites showing differences in methylation in cord blood were not associated with changes in gene expression of the overlapping genes. CONCLUSION(S): Capacitation-IVM appeared to be associated with only a small amount of epigenetic variation in cord blood, placental tissue, and neonate buccal smears. CLINICAL TRIAL REGISTRATION NUMBER: NCT03405701 (www. CLINICALTRIALS: gov).

Predictors of twin pregnancy in in vitro fertilization with intracytoplasmic sperm injection cycles with day 3 double embryo transfer.

OBJECTIVE: The purpose of this study was to identify factors associated with twin pregnancy following day 3 double embryo transfer (DET). METHODS: This retrospective cohort study incorporated data from 16,972 day 3 DET cycles. The participants were women aged between 18 and 45 years who underwent in vitro fertilization with intracytoplasmic sperm injection (IVF/ICSI) at My Duc Assisted Reproduction Technique Unit (IVFMD), My Duc Hospital, located in Ho Chi Minh City, Vietnam. RESULTS: Of the 16,972 day 3 DET cycles investigated, 8,812 (51.9%) resulted in pregnancy. Of these, 6,108 cycles led to clinical pregnancy, with 1,543 (25.3% of clinical pregnancies) being twin pregnancies. Factors associated with twin pregnancy included age under 35 years (odds ratio [OR], 1.5; 95% confidence interval [CI], 1.32 to 1.71; p<0.001) and cycles involving the transfer of at least one grade I embryo. Relative to the transfer of two grade III embryos, the risk of twin pregnancy was significantly elevated following the transfer of two grade I embryos (OR, 1.40; 95% CI, 1.16 to 1.69; p<0.001) or a combination of one grade I and one grade II embryo (OR, 1.27; 95% CI, 1.05 to 1.55; p=0.001). CONCLUSION: By analyzing a large number of IVF/ICSI cycles, we identified several predictors of twin pregnancy. These findings can assist medical professionals in tailoring treatment strategies for couples with infertility.

An Instrument for High-throughput Testing of Heart Tissue In Vitro.

Cardiac trabeculae are small samples of heart muscle tissue that can be dissected and studied in vitro to better understand the underlying physiology of cardiac muscle. However, instruments for such experimentation often (1) involve delicate mounting of the muscle, (2) constrain investigations to one muscle at a time and, thus, (3) cannot retain the muscle in the same experimental configuration for post-experimental assessment including imaging analysis. Here, we present a novel device that allows trabeculae to be secured by a visible-light photo-initiated hydrogel, manipulated via a force sensor, and stimulated while being imaged. We use our robust, accurate image registration techniques to measure cantilever and gel deformation during trabecula contraction and thereby provide a measure of trabecula force production during twitches. A variety of experiments can then be conducted, with the potential for the trabecula to be fixed in place using hydrogel for further post-experiment analysis, as well as longitudinal evaluation. The device has multiple wells making it amenable to high-throughput testing.Clinical Relevance- These methods may allow longitudinal and high-throughput studies of cardiac tissue samples in health and disease.

Robotic natural orifice specimen extraction surgery (NOSES) for anterior resection.

Minimally invasive colorectal surgery is currently well-accepted, with open techniques being reserved for very difficult cases. Laparoscopic colectomy has been proven to have lower mortality, complication, and ostomy rates; a shorter median length of stay; and lower overall costs when compared to its open counterpart. This trend is seen in both benign and malignant indications. Natural orifice specimen extraction surgery (NOSES) in colorectal surgery was first described in the early 1990s. Three recent meta-analyses comparing transabdominal extraction against NOSES concluded that NOSES was superior in terms of overall postoperative complications, recovery of gastrointestinal function, postoperative pain, aesthetics, and hospital stay. However, NOSES was associated with a longer operative time. Herein, we present our technique of robotic NOSES anterior resection using the da Vinci Xi platform in diverticular disease and sigmoid colon cancers.

Resolving an inconsistency in the estimation of the energy for excitation of cardiac muscle contraction.

In the excitation of muscle contraction, calcium ions interact with transmembrane transporters. This process is accompanied by energy consumption and heat liberation. To quantify this activation energy or heat in the heart or cardiac muscle, two non-pharmacological approaches can be used. In one approach using the "pressure-volume area" concept, the same estimate of activation energy is obtained regardless of the mode of contraction (either isovolumic/isometric or ejecting/shortening). In the other approach, an accurate estimate of activation energy is obtained only when the muscle contracts isometrically. If the contraction involves muscle shortening, then an additional component of heat associated with shortening is liberated, over and above that of activation. The present study thus examines the reconcilability of the two approaches by performing experiments on isolated muscles measuring contractile force and heat output. A framework was devised from the experimental data to allow us to replicate several mechanoenergetics results gleaned from the literature. From these replications, we conclude that the choice of initial muscle length (or ventricular volume) underlies the divergence of the two approaches in the estimation of activation energy when the mode of contraction involves shortening (ejection). At low initial muscle lengths, the heat of shortening is relatively small, which can lead to the misconception that activation energy is contraction mode independent. In fact, because cardiac muscle liberates heat of shortening when allowed to shorten, estimation of activation heat must be performed only under isometric (isovolumic) contractions. We thus recommend caution when estimating activation energy using the "pressure-volume area" concept.

Specific Genotypes Associated with Differences in Fasting Insulin Levels and Body Mass Index in Healthy Young Males: Implications for Gene-Nutrient Interactions-an Exploratory Study.

Background: Genetic variation may significantly impact an individual's susceptibility to diseases, particularly when combined with specific nutrients. Additionally, genetic variations can lead to interindividual differences in metabolic responses. Objective: The present study explores the association between gene variants and observed interindividual differences in metabolic responses. Methods: The study included 30 healthy males (aged 20-34) who underwent a fasting period and subsequently consumed a standardized meal. Blood samples were collected both before and after the meal to assess metabolic changes. BMI served as an indirect measure for assessing physiological responses associated with body composition. Appetite changes were assessed using an online Visual Analog 100-point Scale. Buccal swabs were collected to analyze genetic variants in single nucleotide polymorphisms (SNPs). Results: The data underwent multiple regression analysis, revealing significant associations with 3 SNPs and their metabolic status: the insulin-receptor substrate 1 (IRS1) gene variant rs2943641, genotypes CT and CC, with elevated fasting insulin levels (R2 = 0.639, P = < 0.0001); the mitochondrial uncoupling protein 1 (UCP1) gene variant rs1800592, genotypes GG and GA, with increased BMI (R2 = 0.261, P = 0.007); and the peroxisome proliferator-activated receptor γ2 (PPARγ2) gene variant rs1801282, genotypes GG and GC, with increased BMI (R2 = 0.200, P = 0.024). Conclusions: Therefore, our study established significant associations between these 3 SNPs and differences in fasting insulin levels and BMI within our cohort.

Association between sequence variants in the FSHR gene and reproductive outcomes following IVF in predicted normoresponders.

RESEARCH QUESTION: Is there an association between FSHR sequence variants and reproductive outcomes following IVF in predicted normoresponders? DESIGN: Multicentre prospective cohort study conducted from November 2016 to June 2019 in Vietnam, Belgium and Spain including patients aged <38 years, and undergoing IVF with a predicted normal response with fixed-dose 150 IU rFSH in an antagonist protocol. Genotyping was performed for three FSHR (c.919A>G, c.2039A>G, c.-29G>A) and one FSHB sequence variants (c.-211G>T). Clinical pregnancy rate (CPR), live birth rate (LBR) and miscarriage rate in the first embryo transfer and cumulative live birth rate (CLBR) were compared between the different genotypes. RESULTS: A total of 351 patients underwent at least one embryo transfer. Genetic model analysis that adjusted for patient age, body mass index, ethnicity, type of embryo transfer, embryo stage and number of top-quality embryos transferred revealed a higher CPR for homozygous patients for the variant allele G of c.919A>G when compared to patients with genotype AA (60.3% versus 46.3%, adjusted odds ratio [ORadj] 1.96, 95% confidence interval [CI] 1.09-3.53). Also, c.919A>G genotypes AG and GG presented a higher CPR and LBR when compared with genotype AA (59.1% versus 46.3%, ORadj 1.80, 95% CI 1.08-3.00, and 51.3% versus 39.0%, ORadj 1.69, 95% CI 1.01-2.80, respectively). Cox regression models revealed a statistically significantly lower CLBR for c.2039A>G genotype GG in the codominant model (hazard ratio [HR] 0.66, 95% CI 0.43-0.99). CONCLUSION: These results demonstrate a previously unreported association between variant c.919A>G genotype GG and higher CPR and LBR in infertile patients and reinforce a potential role for genetic background in predicting the reproductive prognosis following IVF.

Thyroid Peroxidase Antibodies in Infertile Women with Polycystic Ovary Syndrome.

To compare the rate of positive thyroid peroxidase antibodies (TPO Ab) between women with different polycystic ovary syndrome (PCOS) phenotypes and women without PCOS. This is a retrospective cohort study. Women with PCOS at My Duc Hospital between June 1, 2020, and March 27, 2021, were matched with non-PCOS women by age. TPO Ab (cut-off: 34 IU/mL) and thyroid-stimulating hormone (TSH) levels were measured as markers of Hashimoto thyroiditis and thyroid function, respectively. One thousand eight hundred eight infertile women were included, 904 with PCOS (mean age 29.0 ± 3.58 years) and 904 without PCOS (29.1 ± 3.4 years; controls). Women with PCOS had a higher body mass index (22.8 ± 3.84 vs. 19.9 ± 2.23 kg/m2, p < 0.001), but most were not overweight/obese. Rates of positive TPO Ab in women with versus without PCOS were 8.2% and 8.4%, respectively (p = 0.932). Rates of positive TPO Ab in patients with PCOS phenotype A, B, C, or D were not statistically different (7.5%, 2.9%, 20.0%, and 7.8%, respectively). Median TSH concentrations were similar in the PCOS and control groups (1.84 mIU/L vs. 1.78 mIU/L, respectively; p = 0.194). Based on a linear regression model, there was no correlation between either BMI or the estradiol to progesterone ratio and TPO Ab status. In a large population of infertile women with PCOS who were mostly lean patients, rates of positive TPO Ab across all four PCOS phenotypes did not differ significantly from those in women without PCOS. These findings did not support the hypothesis that PCOS is a risk factor for Hashimoto thyroiditis.