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.

Development of children born to women with twin pregnancies treated with cervical pessary or vaginal progesterone: Follow-up of a randomized controlled trial.

INTRODUCTION: Preterm birth is the most common cause of neonatal morbidity and mortality. Women with twin pregnancies and a short cervical length are at high risk for preterm birth. Vaginal progesterone and cervical pessary have been proposed as potential strategies to reduce preterm birth in this high-risk population. Therefore, we aimed to compare the effectiveness of cervical pessary and vaginal progesterone in improving developmental outcomes of children born to women with twin pregnancies and mid-trimester short cervical length. MATERIAL AND METHODS: This was a follow-up study (NCT04295187) of all children at 24 months of age, born from women treated with cervical pessary or progesterone to prevent preterm birth in a randomized controlled trial (NCT02623881). We used a validated Vietnamese version of Ages & Stages Third Edition Questionnaires (ASQ-3) and a red flag questionnaire. In surviving children, we compared the mean ASQ-3 scores, abnormal ASQ-3 scores, the number of children with any abnormal ASQ-3 scores and red flag signs between the two groups. We reported the composite outcome of perinatal death or survival with any abnormal ASQ-3 score in offspring. These outcomes were also calculated in a subgroup of women with a cervical length ≤28 mm (<25th percentile). RESULTS: In the original randomized controlled trial, we randomized 300 women to pessary or progesterone. After counting the number of perinatal deaths and lost to follow-up, 82.8% parents in the pessary group and 82.5% parents in progesterone group returned the questionnaire. The mean ASQ-3 scores of the five skills and red flag signs did not differ significantly between the two groups. However, the percentage of children having abnormal ASQ-3 scores in fine motor skills was significantly lower in the progesterone group (6.1% vs 1.3%, P = 0.01). There were no significant differences in the composite outcome of perinatal death or survival with any abnormal ASQ-3 score in unselected women and in those with cervical length ≤28 mm. CONCLUSIONS: Cervical pessary and vaginal progesterone may have comparable effects on developmental outcomes in children at ≥24 months of age, born to women with twin pregnancies and short cervical length. However, this finding could be likely due to a lack of study power.

Development of children born from IVM versus IVF: 2-year follow-up of a randomized controlled trial.

STUDY QUESTION: Is there any difference in developmental outcomes in children born after capacitation IVM (CAPA IVM) compared with conventional IVF? SUMMARY ANSWER: Overall development up to 24 months of age was comparable in children born after CAPA IVM compared with IVF. WHAT IS KNOWN ALREADY: IVM has been shown to be a feasible alternative to conventional IVF in women with a high antral follicle count (AFC). In addition to live birth rate, childhood development is also a relevant metric to compare between the two approaches to ART and there are currently no data on this. STUDY DESIGN, SIZE, DURATION: This study was a follow-up of babies born to women who participated in a randomized controlled trial comparing IVM with a pre-maturation step (CAPA IVM) and IVF. Developmental assessments were performed on 231 children over 24 months of follow-up. PARTICIPANTS/MATERIALS, SETTING, METHODS: Participants in the randomized controlled trial had an indication for ART and a high AFC (≥24 follicles in both ovaries). They were randomized to undergo one cycle of either IVM (n = 273) or IVF (n = 273). Of these, 96 women and 118 women, respectively, had live births. Seventy-six women (94 children, 79.2%) and 104 women (137 children, 88.1%), respectively, completed Ages & Stages Third Edition Questionnaire assessment (ASQ-3), and underwent evaluation of Developmental Red Flags at 6, 12 and 24 months of age. MAIN RESULTS AND THE ROLE OF CHANCE: Baseline characteristics of participants in the follow-up study between the IVM and IVF groups were comparable. Overall, there were no significant differences in ASQ-3 scores at 6, 12 and 24 months between children born after IVM or IVF. The proportion of children with developmental red flags was low and did not differ between the two groups. Slightly, but significantly, lower ASQ-3 problem solving and personal-social scores in twins from the IVM versus IVF group at 6 months were still within the normal range and had caught up to the IVF group in the 12- and 24-month assessments. The number of children confirmed to have abnormal mental and/or motor development after specialist assessment was four in the IVM group and two in the IVF group (relative risk 2.91, 95% CI 0.54-15.6; P = 0.23). LIMITATIONS, REASONS FOR CAUTION: This study is an open-label follow-up of participants in a randomized controlled trial, and not all original trial subjects took part in the follow-up. The self-selected nature of the follow-up population could have introduced bias, and the sample size may have been insufficient to detect significant between-group differences in developmental outcomes. WIDER IMPLICATIONS OF THE FINDINGS: Based on the current findings at 2 years of follow-up, there does not appear to be any significant concern about the effects of IVM on childhood development. These data add to the evidence available to physicians when considering different approaches to fertility treatment, but require validation in larger studies. STUDY FUNDING/COMPETING INTEREST(S): This work was funded by the Vietnam National Foundation for Science and Technology Development (NAFOSTED) under grant number FWO.106-YS.2017.02. L.N.V. has received speaker and conference fees from Merck, grant, speaker and conference fees from Merck Sharpe and Dohme, and speaker, conference and scientific board fees from Ferring; T.M.H. has received speaker fees from Merck, Merck Sharp and Dohme, and Ferring; R.J.N. has receives grant funding from the National Health and Medical Research Council (NHMRC) of Australia; B.W.M. has acted as a paid consultant to Merck, ObsEva and Guerbet and is the recipient of grant money from an NHMRC Investigator Grant; J.E.J.S. reports lecture fees from Ferring Pharmaceuticals, Biomérieux and Besins Female Healthcare, grants from Fund for Research Flanders (FWO) and is co-inventor on granted patents on CAPA-IVM methodology in the USA (US10392601B2) and Europe (EP3234112B1); T.D.P., M.H.N.N., N.A.N., T.T.L., V.T.T.T., N.T.N., H.L.T.H. and X.T.H.L. have no financial relationships with any organizations that might have an interest in the submitted work in the previous 3 years, and no other relationships or activities that could appear to have influenced the submitted work. TRIAL REGISTRATION NUMBER: NCT04296357 (www.clinicaltrials.gov). TRIAL REGISTRATION DATE: 5 March 2020. DATE OF FIRST PATIENT'S ENROLMENT: 7 March 2020.

Development of children born after in vitro maturation with a prematuration step versus natural conception: a prospective cohort study.

PURPOSE: IVM preceded by a prematuration step (capacitation [CAPA]-IVM) improves the acquisition of oocyte developmental competence and can enhance embryo quality. There is currently no follow-up data on babies born from CAPA-IVM. This study investigated developmental outcomes in children born after CAPA-IVM versus natural conception. METHODS: This prospective cohort study was conducted at a fertility clinic in Vietnam in August/September 2019. Children born after CAPA-IVM were propensity score-matched with those born after natural conception. All parents were asked to complete the Developmental Red Flags and Ages & Stages Third Edition (ASQ-3) questionnaires. RESULTS: A total of 46 parents (23 in each group) of 55 babies (31 CAPA-IVM and 24 natural conception) were included in the study. Baseline characteristics, including mother's age and body mass index, gestational age at delivery, and birth weight, were comparable. The mean age of children at the end of follow-up was 15 months. The overall proportion of children with any abnormal ASQ-3 score was 6.5% in the CAPA-IVM group and 20.8% in the natural conception group (p = 0.24). The proportion of children with a developmental red flag did not differ significantly between the CAPA-IVM and natural conception groups (9.7% vs. 4.2%; p = 0.80). CONCLUSIONS: The use of CAPA-IVM did not have any significant impact on childhood physical and mental development compared with children born as a result of natural conception.

Positive effects of amphiregulin on human oocyte maturation and its molecular drivers in patients with polycystic ovary syndrome.

STUDY QUESTION: Does use of medium containing amphiregulin improve meiotic maturation efficiency in oocytes of women with polycystic ovary syndrome (PCOS) undergoing in vitro maturation (IVM) preceded by a capacitation culture step capacitation IVM (CAPA-IVM)? SUMMARY ANSWER: Use of medium containing amphiregulin significantly increased the maturation rate from oocytes retrieved from follicles with diameters <6 or ≥6 mm pre-cultured in capacitation medium. WHAT IS KNOWN ALREADY: Amphiregulin concentration in follicular fluid is correlated with human oocyte developmental competence. Amphiregulin added to the meiotic trigger has been shown to improve outcomes of IVM in a range of mammalian species. STUDY DESIGN, SIZE, DURATION: This prospective, randomized cohort study included 30 patients and was conducted at an academic infertility centre in Vietnam from April to December 2019. Patients with PCOS were included. PARTICIPANTS/MATERIALS, SETTING, METHODS: In the first stage, sibling oocytes from each patient (671 in total) were allocated in equal numbers to maturation in medium with (CAPA-AREG) or without (CAPA-Control) amphiregulin 100 ng/ml. After a maturation check and fertilization using intracytoplasmic sperm injection (ICSI), all good quality Day 3 embryos were vitrified. Cumulus cells (CCs) from both groups were collected at the moment of ICSI denudation and underwent a molecular analysis to quantify key transcripts of oocyte maturation and to relate these to early embryo development. On return for frozen embryo transfer (second stage), patients were randomized to have either CAPA-AREG or CAPA-Control embryo(s) implanted. Where no embryo(s) from the randomized group were available, embryo(s) from the other group were transferred. The primary endpoint of the study was meiotic maturation efficiency (proportion of metaphase II [MII] oocytes; maturation rate). MAIN RESULTS AND THE ROLE OF CHANCE: In the per-patient analysis, the number of MII oocytes was significantly higher in the CAPA-AREG group versus the CAPA-Control group (median [interquartile range] 7.0 [5.3, 8.0] versus 6.0 [4.0, 7.0]; P = 0.01). When each oocyte was evaluated, the maturation rate was also significantly higher in the CAPA-AREG group versus the CAPA-Control group (67.6% versus 55.2%; relative risk [RR] 1.22 [95% confidence interval (CI) 1.08-1.38]; P = 0.001). No other IVM or embryology outcomes differed significantly between the two groups. Rates of clinical pregnancy (66.7% versus 42.9%; RR 1.56 [95% CI 0.77-3.14]), ongoing pregnancy (53.3% versus 28.6%; RR 1.87 [95% CI 0.72-4.85]) and live birth (46.7% versus 28.6%; RR 1.63 [95% CI 0.61-4.39]) were numerically higher in the patients who had CAPA-AREG versus CAPA-Control embryos implanted, but each fertility and obstetric outcome did not differ significantly between the groups. In the CAPA-AREG group, there were significant shifts in CC expression of genes involved in steroidogenesis (STAR, 3BHSD), the ovulatory cascade (DUSP16, EGFR, HAS2, PTGR2, PTGS2, RPS6KA2), redox and glucose metabolism (CAT, GPX1, SOD2, SLC2A1, LDHA) and transcription (NRF2). The expression of three genes (TRPM7, VCAN and JUN) in CCs showed a significant correlation with embryo quality. LIMITATIONS, REASONS FOR CAUTION: This study included only Vietnamese women with PCOS, limiting the generalizability. Although 100 ng/ml amphiregulin addition to the maturation culture step significantly improved the MII rate, the sample size in this study was small, meaning that these findings should be considered as exploratory. Therefore, a larger patient cohort is needed to confirm whether the positive effects of amphiregulin translate into improved fertility outcomes in patients undergoing IVM. WIDER IMPLICATIONS OF THE FINDINGS: Data from this study confirm the beneficial effects of amphiregulin during IVM with respect to the trigger of oocyte maturation. The gene expression findings in cumulus indicate that multiple pathways might contribute to these beneficial effects and confirm the key role of the epidermal growth factor system in the stepwise acquisition of human oocyte competence. STUDY FUNDING/COMPETING INTEREST(S): This work was funded by the Vietnam National Foundation for Science and Technology Development (NAFOSTED; grant number FWO.106-YS.2017.02) and by the Fund for Research Flanders (FWO; grant number G.OD97.18N). L.N.V. has received speaker and conference fees from Merck, grants, speaker and conference fees from Merck Sharpe and Dohme, and speaker, conference and scientific board fees from Ferring. T.M.H. has received speaker fees from Merck, Merck Sharp and Dohme and Ferring. J.S. reports speaker fees from Ferring Pharmaceuticals and Biomérieux Diagnostics and grants from FWO Flanders, is co-inventor on granted patents on CAPA-IVM methodologies in USA (US10392601B2), Europe (EP3234112B1) and Japan (JP 6806683 registered 08-12-2020) and is a co-shareholder of Lavima Fertility Inc., a spin-off company of the Vrije Universiteit Brussel (VUB, Brussels, Belgium). NA, TDP, AHL, MNHN, SR, FS, EA and UDTH report no financial relationships with any organizations that might have an interest in the submitted work in the previous three years, and no other relationships or activities that could appear to have influenced the submitted work. TRIAL REGISTRATION NUMBER: NCT03915054.

Hormone-free vs. follicle-stimulating hormone-primed infertility treatment of women with polycystic ovary syndrome using biphasic in vitro maturation: a randomized controlled trial.

OBJECTIVE: To compare oocyte maturation rates and pregnancy outcomes in women with polycystic ovary syndrome (PCOS) undergoing biphasic in vitro maturation (capacitation in vitro maturation [CAPA-IVM]) with vs. without follicle-stimulating hormone (FSH) priming. DESIGN: Randomized, controlled, assessor-blinded trial. SETTING: Private hospital. PATIENT(S): Women aged 18-37 years with PCOS and an indication for CAPA-IVM. INTERVENTION(S): Participants were randomized (1:1) to undergo CAPA-IVM with or without FSH priming. The FSH priming group had 2 days of FSH injections before oocyte pickup; no FSH was given in the non-FSH group. After CAPA-IVM, day-5 embryos were vitrified for transfer in a subsequent cycle. MAIN OUTCOME MEASURE(S): The primary endpoint was number of matured oocytes. Secondary outcomes included rates of live birth, implantation, clinical pregnancy, ongoing pregnancy, pregnancy complications, obstetric and perinatal complications, and neonatal complications. RESULT(S): The number (interquartile range) of matured oocytes did not differ significantly in the non-FSH vs. FSH group (13 [9-18] vs. 14 [7-18]; absolute difference -1 [95% confidence interval -5 to 4]); other oocyte and embryology outcomes did not differ between groups. Rates of ongoing pregnancy and live birth were 38.3% in the non-FSH group and 31.7% in the FSH group (risk ratio for both outcomes: 1.21, 95% confidence interval 0.74-1.98). Maternal complications were infrequent and occurred at a similar rate in the two groups; there were no preterm deliveries before 32 weeks gestation. CONCLUSION(S): These findings open the possibility of a new, hormone-free approach to infertility treatment of women with PCOS.

Down Syndrome Patients with Congenital Portosystemic Shunts: A Case Report and Review.

Introduction: Down syndrome is due to trisomy 21 and is characterized by intellectual disability, dysmorphic facial features, congenital malformations, and gastrointestinal abnormalities. There is an increased appreciation of congenital portosystemic shunts in Down syndrome patients. Congenital portosystemic shunts have been associated with many defects in body systems, including cardiac, metabolic, and neurological. Case Presentation: Herein, we describe a portosystemic shunt in a Down syndrome patient that resulted in hyperammonemia with altered mental status and choreiform movements. Computed tomography angiography of the abdomen and pelvis identified a connection between the right portal vein and inferior vena cava. An 18 mm Amplatzer PFO closure device was placed within the congenital shunt, significantly improving symptoms. The patient has no sequelae from the related shunt or the device at the 2-year follow-up. We extensively reviewed the literature and identified cases of portosystemic shunts in Down syndrome patients. Shunts can either be extrahepatic or intrahepatic and are classified by vasculature connections. Conclusion: From our literature review and case presentation, we identify other conditions in patients, including cardiac and gastrointestinal defects. We then review the available treatment options, whether observation or surgical, depending on the patient's clinical picture.

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.

Electrical status epilepticus during sleep in a child with Prader-Willi syndrome: a case report.

Prader-Willi syndrome (PWS) is a rare and complex genomic imprinting disorder caused by an absence of expression of paternal genes from chromosome 15q11.2-q13. Clinical manifestations of PWS depends on age. In early infancy, PWS patients is characterized by hypotonia and failure to thrive. Later in life, they can also exhibit hyperphagia, obesity, short stature, hypogonadism, behavioral issues and cognitive disability. Multiple sleep abnormalities including obstructive and/or central sleep apnea, daytime hypersomnolence, and impaired responses to hypercapnia and hypoxia have been described in patients with PWS. Recent studies also demonstrated an increased risk of seizures in PWS patients. Electrical status epilepticus in sleep (ESES) is an age-limited epilepsy with various seizure types, neurophysiological and motor impairment. The classic electroencephalogram (EEG) pattern of ESES involves continuous epileptic activity at 2-3 Hz occupying greater than 85% of non-rapid eye movement (REM) sleep. Treatment of the ESES syndrome consists of anti-epileptic drugs in routine cases, and corticosteroids, gamma globulins, the ketogenic diet, and surgery in refractory cases. In this project, we describe ESES during polysomnography in a 5-year-old female with PWS and no history of seizure disorder. To the best of our knowledge, this is the first case report on ESES in a PWS patient.

Eighteen-year-old man with syncope with Helicobacter pylori as the culprit: a case report.

Helicobacter pylori (H. pylori) is amongst the most common chronic bacterial infection in humans. Pediatric patients appear to differ from their adult counterparts in terms of the prevalence, the complication rate, and the rate of antibiotic resistance. In this report, we present an 18-year-old man without any past medical history who was evaluated after an episode of syncope. Evaluation revealed a case of chronic H. pylori gastritis leading to gastrointestinal (GI) bleeding and weight loss, and his syncope was the byproduct of symptomatic anemia and physical exertion. Pediatricians should think of peptic ulcer disease (PUD) in evaluating poor weight gain/feeding in younger patients, and abdominal pain in older patients. Early diagnosis can prevent complications such as perforation, bleeding and obstruction. Endoscopy is the gold standard of diagnosis for H. pylori infection. Noninvasive testing with urease breath test and stool antigen test is reserved for post-treatment testing only. Treatment consists of a 14-day course of a proton-pump inhibitor (PPI) and amoxicillin. A third agent, either clarithromycin or metronidazole, is added depending on regional resistance patterns. Testing for eradication at least 4 weeks later is recommended. This case serves as a reminder to primary care providers to be aware of H. pylori infection, diagnosis, treatment and complications.

Bartonella endocarditis in patients with right ventricle-to-pulmonary artery conduit: 2 case reports and literature review.

Bartonella species are Gram-negative bacilli and fastidious bacteria that can cause a number of clinical syndromes, including blood culture-negative infective endocarditis (IE). The two most commonly isolated species in humans are Bartonella quintana, the agent of trench fever, and Bartonella henselae, mostly known for causing cat scratch disease (Edouard et al., 2015 [1]; Edouard and Raoult, 2010 [2]). Both species also cause bacillary angiomatosis, primarily in immunocompromised patients (Edouard et al., 2015 [1]; Fournier et al., 2001 [3]). The risk of B. henselae IE is increased in patients with cardiac valvular disease and congenital heart disease (CHD) (Edouard and Raoult, 2010 [2]; Das et al., 2009 [4]; Abandeh et al., 2012 [5]; Ouellette et al., 2016 [6]; Hoffman et al., 2007 [7]; Georgievskaya et al., 2014 [8]). In this article, we detail two cases of Bartonella IE in patients with right ventricle-to-pulmonary artery (RV-PA) conduits who presented to our institution. We also perform a literature review on Bartonella IE in patients with a history of RV-PA conduit or pulmonary valve replacement.