Is there a difference in live birth rate between a freeze-only strategy and fresh embryo transfer, and what is the effect of varying progesterone concentrations on the day of human chorionic ...gonadotrophin (HCG) administration?
A secondary analysis of data from three randomized trials comparing the live birth rate after elective frozen versus fresh embryo transfer, which respectively enrolled 1508 women with polycystic ovary syndrome, 2157 ovulatory women who underwent cleavage-stage embryo transfer and 1650 ovulatory women who underwent single blastocyst transfer. Women were randomly assigned to the frozen or fresh embryo transfer group in the original trials. The primary outcome was live birth rate after the initial embryo transfer.
The live birth rate after a freeze-only strategy was consistently higher than fresh embryo transfer at any progesterone concentration on the day of HCG administration. Nonetheless, the between-group difference in live birth rate after frozen versus fresh embryo transfer was greater in women with progesterone concentrations ≥1.14 ng/ml (52.7% versus 37.3%, odds ratio (OR) 1.88, 95% confidence interval (CI) 1.55–2.27, P = 7.89 × 10–11) than in women with progesterone concentrations <1.14 ng/ml (53.3% versus 48.1%, OR 1.23, 95% CI 1.08–1.41, P = 0.002). In women with progesterone concentration ≥1.14 ng/ml, frozen embryo transfer also resulted in higher rates of conception and clinical pregnancy than fresh embryo transfer.
In women with normal or high ovarian response, a freeze-only strategy resulted in a higher live birth rate than fresh embryo transfer, irrespective of progesterone concentration. Moreover, women with progesterone concentration ≥1.14 ng/ml may benefit more from a freeze-only strategy.
Abstract
STUDY QUESTION
Does oral micronized progesterone result in a non-inferior ongoing pregnancy rate compared to vaginal progesterone gel as luteal phase support (LPS) in fresh embryo transfer ...cycles?
SUMMARY ANSWER
The ongoing pregnancy rate in the group administered oral micronized progesterone 400 mg per day was non-inferior to that in the group administered vaginal progesterone gel 90 mg per day.
WHAT IS KNOWN ALREADY
LPS is an integrated component of fresh IVF, for which an optimal treatment regimen is still lacking. The high cost and administration route of the commonly used vaginal progesterone make it less acceptable than oral micronized progesterone; however, the efficacy of oral micronized progesterone is unclear owing to concerns regarding its low bioavailability after the hepatic first pass.
STUDY DESIGN, SIZE, DURATION
This non-inferiority randomized trial was conducted in eight academic fertility centers in China from November 2018 to November 2019. The follow-up was completed in April 2021.
PARTICIPANTS/MATERIALS, SETTING, METHODS
A total of 1310 infertile women who underwent their first or second IVF cycles were enrolled. On the day of hCG administration, the patients were randomly assigned to one of three groups for LPS: oral micronized progesterone 400 mg/day (n = 430), oral micronized progesterone 600 mg/day (n = 440) or vaginal progesterone 90 mg/day (n = 440). LPS was started on the day of oocyte retrieval and continued till 11–12 weeks of gestation. The primary outcome was the rate of ongoing pregnancy.
MAIN RESULTS AND THE ROLE OF CHANCE
In the intention-to-treat analysis, the rate of ongoing pregnancy in the oral micronized progesterone 400 mg/day group was non-inferior to that of the vaginal progesterone gel group 35.3% versus 38.0%, absolute difference (AD): −2.6%; 95% CI: −9.0% to 3.8%, P-value for non-inferiority test: 0.010. There was insufficient evidence to support the non-inferiority in the rate of ongoing pregnancy between the oral micronized progesterone 600 mg/day group and the vaginal progesterone gel group (31.6% versus 38.0%, AD: −6.4%; 95% CI: −12.6% to −0.1%, P-value for non-inferiority test: 0.130). In addition, we did not observe a statistically significant difference in the rate of live births between the groups.
LIMITATIONS, REASONS FOR CAUTION
The primary outcome of our trial was the ongoing pregnancy rate; however, the live birth rate may be of greater clinical interest. Although the results did not show a difference in the rate of live births, they should be confirmed by further trials with larger sample sizes. In addition, in this study, final oocyte maturation was triggered by hCG, and the findings may not be extrapolatable to cycles with gonadotropin-releasing hormone agonist triggers.
WIDER IMPLICATIONS OF THE FINDINGS
Oral micronized progesterone 400 mg/day may be an alternative to vaginal progesterone gel in patients reluctant to accept the vaginal route of administration. However, whether a higher dose of oral micronized progesterone is associated with a poorer pregnancy rate or a higher rate of preterm delivery warrants further investigation.
STUDY FUNDING/COMPETING INTEREST(S)
This research was supported by a grant from the National Natural Science Foundation of China (82071718). None of the authors have any conflicts of interest to declare.
TRIAL REGISTRATION NUMBER
This trial was registered at the Chinese Clinical Trial Registry (http://www.chictr.org.cn/) with the number ChiCTR1800015958.
TRIAL REGISTRATION DATE
May 2018.
DATE OF FIRST PATIENT’S ENROLMENT
November 2018.
Purpose
To determine whether ICSI outcomes are affected by sperm source or genital tract inflammatory status.
Methods
A retrospective cohort study was conducted in all consecutive obstructive ...azoospermia patients who underwent testicular sperm aspiration (TESA) or percutaneous epididymal sperm aspiration (PESA) and ICSI between February 1, 2017, and December 31, 2020. Couples were excluded if they were diagnosed with monogenic disease, abnormal karyotype, or had female uterine malformation. The primary objective was to determine whether ICSI outcomes are affected by the use of testicular or epididymal spermatozoa, and the secondary objective was to explore the effect of granulocyte elastase on ICSI outcomes using epididymal spermatozoa.
Results
Compared with TESA, inflammatory and non-inflammatory PESA patients exhibited a better high-quality embryo rate, with significant differences among the three groups (49.43 vs. 55.39% and 56.03%; odds ratio, 6.345 and 6.631; 95% confidence interval, 0.340–12.350, and 1.712–11.550;
P
= 0.038 and
P
= 0.008, respectively). The fertilization rate, clinical pregnancy rate, live birth delivery rate, and congenital anomaly birth rate were similar in patients who underwent TESA or PESA (with or without inflammation).
Conclusions
The high-quality embryo rate in PESA patients was higher than that in TESA patients. After successful pregnancy, ICSI outcomes did not differ between patients with obstructive azoospermia who experienced TESA or PESA and those with or without genital tract inflammation.
This study attempted to evaluate the potential for biofilm formation and the probiotic properties of lactic acid bacteria (LAB) isolated from the Carassius auratus intestine and to determine their ...antibacterial activity against crucial injurious bacteria of fish. The biological features test was carried out to obtain LAB with well-resistant pH, trypsin, bile and antibiotic challenge, and biofilm formation capacity. The most promising LAB isolates, y11 and y78 were identified as Lactobacillus johnsonii and Weissella confusa using 16S ribosomal RNA gene sequencing. We discovered that oral LAB additives improved immunity in the C. auratus by increasing immune-related expression of immunoglobulin M (IgM), superoxide dismutase (SOD), alkaline phosphatase (AKP), and lysozyme (LYS) in serum and interleukins (IL-10 and IL-1β), interferon-γ (IFN-γ), and tumor necrosis factor-α (TNF-α) in organs. After the introduction of Aeromonas veronii TH0426 for 15 days, the survival rate of C. auratus was determined as follows: the protection rate of group y11 was 45 %, and group y78 was 65 % when challenged with 109 CFU/mL density. This experiment successfully selected two LAB strains as the bioprotective agents and provided theoretical support for further LAB application in aquaculture.
•First, two strains of probiotics were screened, which were resistant to acid and alkali, bile and trypsin and had no adverse effects on fish.•Second, two strains of probiotics can improve the immune level and enhance the immune function of crucian carp.•With TH0426 as the attack strain, the protection of the experimental group could reach about 50 %, while all the control group died.
The number of frozen embryo transfer cycles is increasing, but the optimal method of endometrial preparation for frozen embryo transfer remains controversial. Few studies have investigated the ...healthy live birth outcome after the natural ovulation regimen vs the programmed regimen.
This study aimed to explore whether the likelihood of a healthy live birth after frozen embryo transfer differs between the natural ovulation regimen and the programmed regimen.
We conducted a retrospective cohort study including 7824 ovulatory women who underwent the first frozen embryo transfer cycle of single-blastocyst transfer with endometrial preparation by natural ovulation regimen vs programmed regimen, between June 2017 and June 2021. Propensity score matching was used to control for confounding variables in a 1:1 ratio. The primary outcome was healthy live birth, defined as birth of a live, singleton infant born at term, with an appropriate birthweight for gestational age.
The natural ovulation regimen resulted in a higher probability of achieving healthy live birth compared with the programmed regimen (35.8% vs 30.6%; P<.0001). In addition, a higher rate of singleton live birth was observed after the natural ovulation regimen relative to the programmed regimen (49.6% vs 45.7%; P=.003). Women with the natural ovulation regimen were also less likely to experience clinical pregnancy loss (16.0% vs 19.7%; P=.005) and hypertensive disorders of pregnancy (3.9% vs 6.0%; P=.004) compared with women with the programmed regimen. Singletons born after the programmed regimen had greater mean birthweight (3441.50±539.97 vs 3394.96±503.87; P=.020) and higher risk of being large for gestational age (23.3% vs 18.7%; P=.003) than those conceived after the natural ovulation regimen.
The natural ovulation regimen may be superior to the programmed regimen with regard to higher likelihood of healthy live birth and lower risk of pregnancy loss and maternal hypertensive disorders of pregnancy.
Abstract
STUDY QUESTION
Do oral contraceptives (OCs) and progestins impact live birth rate of IVF when used for cycle scheduling in women with polycystic ovary syndrome (PCOS)?
SUMMARY ANSWER
OCs ...used for scheduling IVF cycle were associated with lowered rates of pregnancy and live birth after fresh embryo transfer, whereas progestins used for this purpose yield higher rates of pregnancy and live birth than OCs.
WHAT IS KNOWN ALREADY
Due to oligo-menorrhea in PCOS, OCs and progestin are extensively used to schedule the start of an IVF cycle in women with PCOS. Little is known about the effect of such pretreatments on outcomes, especially, the rate of live birth.
STUDY DESIGN, SIZE, DURATION
This was a nested cohort study and secondary analysis of a multicenter randomized trial, which was designed to compare live birth rate after fresh embryo transfer vs frozen embryo transfer (FET) in women with PCOS (Frefro-PCOS). A total of 1508 women were enrolled from 14 centers between June 2013 and May 2014.
PARTICIPANTS/MATERIALS, SETTING, METHODS
At the discretion of local investigators, subjects were instructed to wait for spontaneous menses (Control group, n = 323), or were prescribed progestins (P group, n = 283) or OCs (OCs group, n = 902) to induce menstruation prior to the start of ovarian stimulation. GnRH antagonist protocol was initiated at Day 2 or 3 of induced or spontaneous menses cycle. The rates of pregnancy, pregnancy loss and live birth after either fresh embryo transfer or FET were compared among these three groups.
MAIN RESULTS AND THE ROLE OF CHANCE
With fresh embryo transfer, women with OC-induced menses had lower rates of clinical pregnancy (48.8% vs 63.6%, relative rate (RR): 0.77, 95% CI: 0.66–0.89) and live birth (36.1% vs 48.1%, RR: 0.75, 95% CI: 0.61–0.92) than women with spontaneous menses. With freeze-all and deferred FET, women with OC-induced menses had a similar pregnancy rate but a higher pregnancy loss rate (27.7% vs 13.0%, RR: 2.13, 95% CI: 1.28–3.52) after FET than women with spontaneous menses. The live birth rate after FET in women with OC-induced menses, progestin-induced menses and spontaneous menses was 49.4%, 50.7% and 60.2%, respectively (P = 0.06). Progestin-induced menses was associated with similar rates of pregnancy, pregnancy loss and live birth after transfer of either fresh or frozen embryos compared with spontaneous menses. Multivariate logistic regression analysis showed that OCs used for menses induction was associated with lower rate of live birth.
LIMITATIONS, REASONS FOR CAUTION
The methods for menses induction were not assigned randomly, thus selection bias was highly likely because of the study design and significant differences that were observed in the baseline characteristics of the women in the different groups. The mean BMI in this study population was relatively normal; the applicability of this result to obese PCOS women needs to be evaluated in further study.
WIDER IMPLICATIONS OF THE FINDINGS
Our results suggest that either waiting for a spontaneous menses or using progestin is a better option than using OCs to induce menses in women with PCOS prior to ovarian stimulation using GnRH antagonist protocol for IVF. Further randomized controlled studies are needed to confirm our findings.
STUDY FUNDING/COMPETING INTEREST(S)
This study was funded by National Basic Research Program of China (973 Program) (2012CB944700), the State Key Program of National Natural Science Foundation of China (81430029), National Natural Science Foundation of China (81471428) and Thousand Talents Program (Drs Legro and Zhang H). Dr Legro reports receiving consulting fees from Euroscreen, Kindex, Bayer and Millendo Pharmaceuticals and research funding from Ferring. Others report no disclosures.
TRIAL REGISTRATION NUMBER
Frefro-PCOS was registered at Clinicaltrials.gov: NCT01841528.
Frozen embryo transfer resulted in a higher birthweight and an increased risk of macrosomia than fresh embryo transfer. However, the mechanism was still unclear. When the impact of frozen embryo ...transfer on fetal growth began was unknown. Crown-rump length at 11–13 weeks had been regarded as a good indicator of fetal growth in the first trimester and had been used for gestational age calculation in women with uncertain last menstrual periods.
To evaluate the association between frozen embryo transfer and early fetal growth, particularly the crown-rump length, then fresh embryo transfer. The secondary objective was to investigate the potential correlation between crown-rump length and birthweight.
This was a retrospective cohort study conducted at the Reproductive Medical Center of Shandong University. A total of 4949 patients who obtained singleton pregnancy after frozen embryo transfer and 1793 patients who got singleton pregnancy after fresh embryo transfer between January 1, 2017 and December 31, 2022 were included. The primary outcome was the crown-rump length measured via ultrasound at 11–13 weeks gestation. The secondary outcomes were perinatal outcomes, including birthweight and the risk of large for gestational age, small for gestational age, macrosomia, low birthweight, and premature delivery. Multivariable linear regression models were used to adjust for potential confounders of crown-rump length.
A total of 6742 live singleton births after frozen embryo transfer or fresh embryo transfer were included in this study. In the univariable analysis, the frozen embryo transfer group had a larger crown-rump length (5.75±0.53 cm vs 5.57±0.48 cm, P<.001) and an increased risk of larger-than-expected crown-rump length (13.5% vs11.2%, P=.013) than the fresh embryo transfer group. After adjusting for confounders in multivariable linear regression models, frozen embryo transfer was still associated with a larger crown-rump length (regression coefficient, 3.809 95% confidence intervals, 3.621–3.997, P<.001). When subgrouped by fetal gender, the crown-rump length of the frozen embryo transfer group was larger than the fresh embryo transfer group in both male and female fetuses. In addition, the crown-rump length was consistently larger in the frozen embryo transfer group than the fresh embryo transfer group in subgroups of the peak estradiol levels. The comparisons among different crown-rump length groups showed that smaller-than-expected crown-rump length was associated with increased risks of small for gestational age (6.3% vs 3.0%, P<.001) and preterm delivery (9.6% vs 6.7%, P=.004) than normal crown-rump length.
Frozen embryo transfer was associated with a larger crown-rump length than fresh embryo transfer, suggesting that the effect of frozen embryo transfer on fetal growth may begin in the early trimester. Suboptimal fetal growth in the first trimester may be associated with low birthweight and premature delivery.
The diagnostic criteria and phenotypes in polycystic ovary syndrome are heterogeneous. Currently, it is unclear how to assess a patient's prognosis based on the onset time of menstruation ...disturbance. Evidence on this topic is scarce and has mainly focused on menstrual patterns.
This study aimed to assess the association between the onset time of menstrual disturbance and clinical features and in vitro fertilization pregnancy outcomes in patients with polycystic ovary syndrome.
Our study was a secondary analysis of data collected as part of a randomized controlled trial conducted to compare live birth rates between fresh embryo transfer and frozen embryo transfer in 1508 individuals with polycystic ovary syndrome. Here, 1500 participants were classified into 2 groups according to the onset time of menstrual disturbance: immediately after menarche (early group) and after at least 1 year of regular menstruation (late group). We compared the prepregnancy clinical features, variables of ovarian stimulation, pregnancy outcomes after the initial cycle of embryo transfer, and perinatal and neonatal complications in the 2 groups.
Compared with the late group, the early group had more antral follicles (32.00 range, 27.25–39.50 vs 28.00 range, 24.00–36.00; P<.001), an elevated level of antimüllerian hormone (7.02 ng/mL range, 3.60–11.47 vs 5.66 ng/mL range, 3.65–8.92; P=.024), a higher level of baseline luteinizing hormone (10.01±5.93 vs 8.51±5.53 IU/l; P<.001) and luteinizing hormone–to–follicle-stimulating hormone ratio (1.51 range, 1.00–2.32 vs 1.45 range, 0.92–2.13; P<.001), lower levels of fasting glucose (5.47 mmol/L range, 5.11–5.73 vs 5.50 mmol/L range, 5.17–5.76; P<.001), and insulin at 2 hours after 75-g oral glucose tolerance test (56.85 µU/mL range, 34.63–94.54 vs 59.82 µU/mL range, 33.56–94.67; P=.027), a higher level of high-density lipoprotein (1.26 mmol/L range, 1.04–1.37 vs 1.21 mmol/L range, 1.07–1.45; P=.006). During in vitro fertilization, the early group had a higher level of peak estradiol (4596.50 pg/mL range, 2639.25–6321.00 vs 3954.00 pg/mL range, 2378.75–6113.50; P=.013), and luteinizing hormone (2.52 IU/L range, 1.40–4.21 vs 1.93 IU/L range, 0.91–3.32; P=.010) on the day of human chorionic gonadotropin trigger. There was no statistically significant difference observed in the number of oocytes and embryos, the rates of pregnancy and live birth, and the risks of obstetrical and neonatal between the 2 groups.
An early onset of menstrual disturbance in patients with polycystic ovary syndrome may be associated with slightly more severe reproductive features and slightly milder metabolic features. Nonetheless, the outcomes of in vitro fertilization and the initial cycle of embryo transfer were comparable between the 2 groups.
Abstract This retrospective cohort study observed the live birth rates as well as cumulative live birth rates in women with poor ovarian response (POR) undergoing IVF–embryo transfer treatment, ...stratified for age and cycle number. Four hundred and one patients with POR diagnosed according to the Bologna criteria were enrolled and 700 IVF–ET cycles were analysed. The overall live-birth rate per cycle was 18.3%. From cycle 1 up to cycle 3, the live-birth rates decreased significantly from 22.2% to 11.1%. The live-birth rate fell to 2.4% in cycles 4 and over. When age advanced, the live birth rates decreased obviously ( P < 0.01): 30.0% for women <35 years old, 17.0% for those 35–40 years old, and 9.0% for women older than 40 years. Similarly, the cumulative live birth rates dropped from 48.0% (<35 years) to 16.9% (≥40 years) accordingly. Younger patients (<35 years old) with POR achieved better pregnancy results compared with patients of advanced age. Extremely low live-birth rates could be anticipated after three unsuccessful cycles; therefore it may not be appropriate to suggest more IVF cycles in POR women.
STUDY QUESTION
What is the direct genetic contribution of the polycystic ovary syndrome (PCOS) susceptibility single nucleotide polymorphisms (SNPs), identified by previous genome-wide association ...studies (GWAS) to the definitive clinical features of the syndrome?
SUMMARY ANSWER
Each single PCOS clinical feature had a specific genetic association, and rs4385527 in the chromosome 9 open reading frame 3 (C9orf3) conferred a particular risk to the three defined PCOS clinical features in this study, which suggested its fundamental role in the etiology of PCOS.
WHAT IS KNOWN ALREADY
PCOS is a heterogeneous disorder characterized by anovulation (OA), hyperandrogenism (HA) and polycystic ovary morphology (PCOM). Two previous GWAS in China have identified 15 independent susceptibility SNPs related to PCOS (PCOS-SNPs). However, little is known about the candidate gene of each clinical feature.
STUDY DESIGN, SIZE, DURATION
Case–control study. Three independent groups of women were recruited from 2010 to 2012: 746 subjects with OA only, 278 subjects with HA only and 536 subjects with PCOM only. A total of 1790 healthy women with none of the above pathological characteristics were also enrolled as control subjects during the same time period.
PARTICIPANTS/MATERIALS, SETTING, METHODS
All participants were women of reproductive age. Genotype and allelic frequencies of 15 PCOS-SNPs were determined in all subjects using direct sequencing and Sequenom Arrays. The allelic frequencies of each case group were compared with the controls.
MAIN RESULTS AND THE ROLE OF CHANCE
After adjustment for age and BMI, variants in luteinizing hormone/choriogonadotropin receptor (LHCGR) (rs13405728), C9orf3 (rs4385527) and insulin receptor gene (INSR) (rs2059807) were strongly associated with OA (Padjust < 0.01, <0.001 and <0.05, respectively); rs4385527 in C9orf3 was strongly associated with HA (Padjust< 0.001); variants in the thyroid adenoma associated gene (THADA) (rs13429458 and rs12478601), DENN/MADD domain containing 1A (DENND1A)(rs10818854), and C9orf3 (rs4385527) were significantly associated with PCOM (Padjust < 0.01, <0.001, <0.05 and <0.001, respectively).
LIMITATIONS, REASONS FOR CAUTION
The sample size of some case groups was relatively small, which therefore limited the statistical power of the analysis to a certain extent.
WIDER IMPLICATIONS OF THE FINDINGS
The present study indicates a potential common genetic basis of three PCOS clinical features. Other specific associated genes may play a synergistic role, leading to heterogeneous pathophysiological changes. Additionally, the increased frequency of PCOS-risk alleles in women with single PCOS clinical features suggests that these subjects have an elevated risk of developing the syndrome, although they cannot be currently diagnosed.
STUDY FUNDING/COMPETING INTEREST(S)
This research was supported by the National Basic Research Program of China (973 Program) (2012CB944700, 2011CB944502), the National Key Technology Research and Development Program(2011BAI17B00), the National Natural Science Foundation of China (81430029, 81201441, 81490743, 31371453), the Scientific Research Foundation of Shandong Province of Outstanding Young Scientist (2012BSE27089) and the Fundamental Research Funds of Shandong University(2014GN025). There were no competing interests.
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