In Vitro Fertilization-embryo Transfer Research Articles

A COMPARISON OF PREGNANCY RATES FOLLOWING IN VITRO FERTILIZATION-EMBRYO TRANSFER IN WOMEN 43 VS. 44 ACCORDING TO DIMINISHED VS. NORMAL EGG RESERVE

To determine the relative negative effect of age 44 vs. 43 and degree of adverse effects of diminished vs. normal oocyte reserve following in vitro fertilization-embryo transfer (IVF-ET) using a low dosage follicle stimulating hormone (FSH) stimulation protocol.

THE CORRELATION BETWEEN OBESITY AND THE PREGNANCY OUTCOMES IN FRESH EMBRYO TRANSFER CYCLE

To evaluate the effect of obesity on in vitro fertilization (IVF) outcomes in fresh embryo transfer (ET) cycles, and further investigate the effect of obesity on IVF outcomes in women with polycystic ovarian syndrome (PCOS) undergoing fresh ET. A total of 7663 fresh IVF or Intracytoplasmic sperm injection (ICSI）ET cycles and 760 fresh ET cycles in PCOS patients from January 2010 to December 2019 in the reproductive medicine center of the Sixth Affiliated Hospital of Sun Yat-sen University were retrospectively analyzed. Patients were divided into four groups according to Asian body mass index (BMI) classification: underweight (BMI <18.5kg/㎡), normal weight (BMI 18.5-22.9kg/㎡),overweight (BMI 23-27.4kg/㎡), and obese ( BMI ≥27.5kg/㎡). Patients’ characteristics and pregnancy outcomes were compared among these groups, and multivariate analyses were conducted to determine the effects of BMI on the live birth rate and perinatal outcomes. Compared with overweight women, significantly higher clinical pregnancy rate (CPR), live birth rate (LBR) and small for gestational age (SGA) rate, and lower large for gestational age (LGA) rate were associated with normal weight women (P< 0.05). Multivariate logistic regression analysis showed that whether or not the patients are obese had no correlation with the chance of live birth (OR=0.994,95% CI:0.770-1.283,P=0.962), while the female age was an independent risk factor for LBR（OR=0.920,95% CI:0.905-0.935,P=0.000）. Underweight women had a significantly higher likelihood of SGA (OR=0.497,95% CI: 285-0.869,P=0.014), while overweight women were more likely to give birth to LGA（OR=4.346, 95%CI: 1.330-14.204, P=0.015). There were no correlation between obesity and the LBR, SGA rate and LGA rate in PCOS patients. Female obesity did not correlate with the chance of live birth in fresh ET cycle. A higher chance of SGA was associated with underweight, and obese patients were more likely to give birth to LGA infants. In PCOS patients, the degree of obesity had no effect on the LBR, SGA rate and LGA rate.

DO EARLY HCG DYNAMICS AFTER EMBRYO TRANSFER DIFFER BASED ON DAY OF EMBRYO BIOPSY?

Serum HCG threshold levels and rate of rise are established predictors of successful pregnancy in IVF embryo transfer cycles. While prior studies on HCG dynamics in early IVF pregnancies have accounted for factors such as stage of embryo development, these studies have not accounted for the speed of embryo development. Day 7 embryos have been shown to have reduced implantation potential.1 However, no study has yet to review the relationship between day 7 embryo transfer and the level of HCG secretion when early pregnancy is achieved. The objective of this study is to compare initial HCG levels and the rate of HCG increase between day 5, 6, and 7 single, euploid frozen embryo transfers (FET). The study included patients who underwent a single, euploid FET, from January 2012 to March 2021. Initial serum HCG levels were reviewed on day 9 post FET, and if positive, the rate of HCG rise, by day 11, was noted. FET cycles were stratified by day of embryo biopsy and cryopreservation (Group A: Day 5; Group B: Day 6; Group C: Day 7). Baseline demographics were compared and analyzed by ANOVA and Kruskal-Wallis. A logistic regression was then performed to evaluate the differences in HCG levels when controlling for Patient Age, Oocyte age, BMI, AMH, BAFC, day 3 FSH, and endometrial thickness at progesterone initiation. A total of 1,707 single euploid FETs were included and separated into three groups: Group A (n = 1,104), Group B (n = 577), and Group C (n = 26). The mean serum HCG value on day 9 after ET was 168.7 in Group A, 143.0 in Group B, and 94.8 in Group C. Initial HCG level and the percent of HCG rise was significantly different between the three groups (p < 0.0001). Day 5 embryos had a significantly higher absolute difference in HCG levels, from day 9 to day 11, compared with day 6 embryos (OR 1.41 [95% CI 1.23-1.75]) and day 7 embryos (OR 4.74 [95% CI 2.16-10.40]). The percent rise of HCG between days 9 and 11 in day 5 embryos was significantly lower than day 7 embryos (OR 2.36 [95% CI 1.079-5.16]), but was similar compared with day 6 embryos (OR 1.19 [95% CI 0.955-1.48]). The HCG dynamics of early pregnancies from a single, euploid FET, are significantly impacted by the day of embryo development. Our findings show that reproductively competent day 7 embryos have lower initial HCG levels, but then a higher rate of HCG rise compared with faster growing day 5/6 embryos. The increased rate of HCG rise in day 7 embryos may reflect a mechanism such as compensation for a delayed activation of the embryonic transcriptome which these slower growing embryos are able to overcome to be able to successfully implant.

Immediate versus delayed frozen embryo transfer in women following a failed IVF-ET attempt: a multicenter randomized controlled trial

BackgroundThe optimal time at which to perform a frozen-thawed embryo transfer (FET) following a failed in-vitro fertilization-embryo transfer (IVF-ET) attempt remains elusive to most reproductive experts. Physicians often delay the introduction of FET due to concerns related to potential residual effects of ovarian hyperstimulation which may interfere with the regular menstrual cycle. Moreover, given that most of the published studies on the topic are retrospective and have inconsistent findings, it is crucial to develop evidence-based randomized control guides for clinical practice. Therefore, this well-designed randomized controlled trial (RCT) was conducted to determine whether it is necessary to delay FET for at least one menstrual cycle after the failure of fresh embryo transfer.MethodsInfertile women eligible for IVF-ET were invited to participate in this multicenter, randomized, non-inferiority, parallel-group, unblinded, controlled trial at the academic fertility centers of four public hospitals in Chinese Mainland. Infertile women scheduled to receive their first FET cycle after a failed IVF-ET attempt were randomly assigned to either (a) the immediate FET group in which FET was performed in the first menstrual cycle following the failed IVF-ET cycle (n = 366) or (b) the delayed FET group in which FET was performed in the second or subsequent menstrual cycle following the failed IVF-ET cycle (n = 366). All FET cycles were performed during hormone replacement cycles for endometrial preparation. The primary outcome was the ongoing pregnancy, defined as a detectable fetal heart beat beyond twelve weeks of gestation. Secondary outcomes were other pregnancy-related outcomes, maternal and neonatal complications. Analysis was performed by both intention-to-treat and per-protocol principles.ResultsA total of 646 FETs were completed. The frequency of moderate to severe depression and high stress level prior to FET in delayed FET group were significantly higher than that in immediate FET group (10.6% vs 6.1%, p = 0.039; 30.3% vs 22.4%, p = 0.022, respectively). Immediate FET resulted in a higher frequency of clinical pregnancy than did delayed FET (41.7% vs 34.1%), for a relative risk (RR) of 1.23 (95% confidence interval [CI], 1.00–1.50; p = 0.045). Women who underwent immediate FET also had a lower frequency of biochemical pregnancy loss (11.7% vs. 30.6%), with a RR of 0.28 (95% CI 0.23–0.63, p < 0.001), and a higher frequency of embryo implantation (25.2% vs. 20.2%), with a RR of 1.25 (95% CI 1.01–1.53; p = 0.038). Although the ongoing pregnancy and live birth rates did not differ significantly between the immediate FET and delayed FET groups (37.1% vs 30.3%, RR 1.22, 95% CI 0.99–1.52, p = 0.067; 36.5% vs 30.0%, RR 1.22, 95% CI 0.98–1.52, p = 0.079, respectively), a multivariate logistic regression analysis adjusted for potential confounders such as depression and stress levels revealed that the immediate FET group had a significantly higher ongoing pregnancy and live birth rates than the delayed FET group (odds ratio 0.68, 95% CI 0.47–0.99, p = 0.041; odds ratio 0.67, 95% CI 0.46–0.96, p = 0.031). The risks of maternal and neonatal complications were comparable between the two groups.ConclusionsIn women with a previous failed IVF-ET attempt, immediate FET resulted in higher ongoing pregnancy and live birth rates than delayed FET. These findings warrant caution in the indiscriminate application of a delayed FET strategy when apparent risk of high stress level is perceived.Trial registrationChiCTR2000033313.

Association between endometrial thickness and birth weight in fresh IVF/ICSI embryo transfers: a retrospective cohort study of 9273 singleton births

Research questionWhat is the association between endometrial thickness (EMT) on HCG trigger day and outcomes related to birth weight in fresh IVF and intracytoplasmic sperm injection (ICSI) embryo transfer cycles? DesignA retrospective cohort study of 9273 singleton live births born to women undergoing fresh IVF/ICSI cycles in a single centre between January 2014 and December 2018. Multivariable logistic regression was used to investigate the associations between EMT, low birth weight (LBW) and small for gestational age (SGA). Multivariable-adjusted linear regression models incorporating restricted cubic splines were used to investigate the dose-response relationship between EMT, birth weight and birth weight z-score, respectively. An EMT of 8 mm was set as a reference value. ResultsCompared with women with an EMT of 8.0 to < 14.0 mm the risk of delivering a SGA infant was increased with EMT < 8.0 mm (adjusted odds ratio [aOR] 1.78, 95% confidence interval [CI] 1.09 to 2.90) and decreased with EMT ≥ 14.0 mm (aOR 0.57, 95% CI 0.35 to 0.93, respectively). Birth weights of infants born to women with an EMT of 8.0 mm compared with women with EMT of 5.0, 6.0, and 7.0 mm were lower by 120 g (95% CI –175 g to –66 g), 80 g (95% CI –116 g to –44 g), and 40 g (95% CI –58 g to –22 g) respectively; infant birth weight z-scores were also decreased by 0.19 (95% CI –0.27 to –0.10), 0.12 (95% CI –0.18 to –0.07) and 0.06 (95% CI –0.09 to –0.03), respectively. ConclusionsA thinner endometrium was associated with lower birth weight and birth weight z-score, and higher risk of SGA. Women with a thin endometrium warrant special attention during pregnancy.

P–357 The risk factors for early pregnancy loss based on a logistic model following 13,977 infertile patients after in vitro fertilization

Abstract Study question What are the risk factors for early pregnancy loss (EPL) after in vitro fertilization-embryo transfer (IVF-ET)? Summary answer The maternal age, gestational sac diameter, embryonic length, yolk sac diameter, heart rate of day 27–29 and endometrium thickness on transfer day were risk factors. What is known already: The first routine ultrasound scan is commonly arranged on day 27–29 after IVF-ET in most reproductive centers in China to determine the location and viability of the embryo. Individual maternal factors, such as a high maternal age (MA) and abnormal ultrasound parameters such as embryonic bradycardia and excessively large or small yolk sac diameter (YSD) have been shown to be associated with pregnancy failures. However, few studies focused on the risk factors of the IVF population, and little is known about the clinical meaning of ultrasound indicators of 27–29 days after transplantation. Study design, size, duration This was a retrospective study in a single reproductive centre. The infertile patients included in this study underwent IVF treatment between June 2016 to December 2017. Participants/materials, setting, methods: During this period, 13,977 women were identified with a singleton pregnancy by TVS at day 27–29 after IVF-ET. The gestational sac diameter (GSD), embryonic length (EL), embryonic heart rate (EHR) and YSD and the presence of intrauterine hematoma (IUH) were measured. The clinical characteristics were also collected. The first trimester pregnancy outcome of these women was noted at 12 weeks of gestation. A backward Wald logistic regression model was established to screen the risk factors. Main results and the role of chance 1,926 cases of spontaneous miscarriage ≤12 weeks of gestation, which were assigned as EPL and 12,051 women with an ongoing pregnancy for &amp;gt;12 weeks of gestation. When compared with the ongoing pregnancy group, the MA, infertility duration and transfer cycle were significantly higher, and the day–14 human chorionic gonadotrophin and the endometrium (EM) thickness on transfer day were significantly lower in the EPL group (p &amp;lt; 0.001). Based on the TVS measurements, the GSD (18.5±3.6 vs. 13.2±4.8 mm), EL (3.5±0.9 vs. 1.2±1.6 mm), YSD (3.6±0.4 vs. 2.6±1.5 mm) and EHR (114.5±12.2 vs. 42.4±53.5 bpm) were significantly greater in the ongoing pregnancy group than those in the EPL group (p &amp;lt; 0.001). The incidence of IUH (16.0% vs. 18.8%, P = 0.002) was also markedly higher in the EPL group MA, GSD, EL, YSD, EHR and EM on transfer day finally entered the logistic model after stepwise screening. The probability of EPL was: exp(z)/(1 + exp(z)), where z = 2.432 + (0.092 × MA) - (0.074 × EM) - (0.114 ×GSD) - (0.245 × EL) - (0.034 × HR) - (0.159 × YSD). Limitations, reasons for caution Data on smoking and clinical symptoms such as vaginal bleeding or abdominal pain were not included in the final analysis which might be possible risk factors. These predictors were derived from an IVF population, the situation may not be the same in the general population. Wider implications of the findings: The risk factors for EPL after IVF-ET are clearly identified in this study. The logistic model which incorporates readily available data that are routinely collected in clinical practice could be used for calculating the risk of EPL and effectively guide subsequent medical plans. Trial registration number None

P–405 The diagnosis and management of heterotopic intramural pregnancy after in vitro fertilization-embryo transfer: six-case series

Abstract Study question What are the ultrasonic characteristics of heterotopic intramural pregnancy (HIMP)? How to manage and what about the clinical outcomes of HIMP? Summary answer Expectant management may be a considerable choice for an non-viable intramural pregnancy (IMP). Most intrauteine pregnancies (IUPs) of HIMPs seems to have good outcomes. What is known already Heterotopic pregnancy (HP) post in vitro fertilization is very rare in infertility women, with a prevalence of 0.04%. HIMP is one of the rarest types of HP, where one gestational sac (GS) is embedded within the endometrial cavity and the other one GS is implanted in the myometriun. HIMP was firstly and only described by Jiangtao Lyu et al. in 2018. So far, little is known about its natural history and ultrasonic imaging characteristics. And there is no consensus regarding the ultrasound diagnosis and clinical management for HIMP due to few evidence-based medicine records. Study design, size, duration A retrospective observational study was conducted of 6 infertile women who obtained a HIMP through in vitro fertilization-embryo transfer (IVF-ET) between January 2009 and December 2019 at our reproductive centre. Participants/materials, setting, methods Six infertile women conceived a HIMP via IVF-ET were retrospectively retrieved between January 2009 and December 2019 at the Reproductive and Genetic Hospital of CITIC-Xiangya (Changsha City, China). The ultrasound diagnosis, clinical management and pregnancy outcome of these cases were analysed. The ultrasound findings, therapeutic methods and clinical outcomes were obtained from the hospital’s electronic medical records. This study was approved by the local ethics committee. Main results and the role of chance: Six women with HIMPs were retrospectively analysed. Among them, 5 cases were revealed by ultrasound scans; however, one case was misdiagnosed. The diagnostic accuracy was 83.3%. Five cases of HIMP were diagnosed at initial scan. The diagnostic time ranged from 22 to 38 days after ET (5 + 6 - 7 + 6 weeks). Among them, an intramural GS was observed in all 5 cases; embryonic cardiac activity (ECA) was detected in one case by the followed-up scans; there was a yolk sac only in one case; an empty GS was noted in 3 cases. An IUP was revealed in all 6 cases, and ECA was observed in 5 cases at the initial diagnosis or later. A GS with a yolk sac only was showed in one case. Among the 5 diagnostic women, one case with a live IMP was treated with laparoscopy at 8 + 1 weeks, 4 cases were managed expectantly. Of them, the IUPs of 4 cases delivered live infants and one case managed expectantly experienced miscarriage. In one case, IMP was misdiagnosed as interstitial pregnancy at day–28 scan. Exploratory laparoscopy and foetal reduction were performed at 8 + 2 weeks. Laparoscopy confirmed an IMP and the retained IUP delivered a live infant. Limitations, reasons for caution The case numbers are too few to draw any objective conclusions, because of the extreme rarity of HIMP. Thus, a further multi-centre larger prospective study will help to confidently illustrate the clinical significance, and effective and appropriate management method for women with a HIMP. Wider implications of the findings: Our study showed that HIMP may not be as rare as previously reported. Increased awareness of this condition, better comprehension of the diagnostic criteria and improved resolution of ultrasound equipment may result in more frequent and accurate detection of HIMP, which will be helpful for early management to preserve IUP. Trial registration number Not applicable.

P–501 Deep in the Maze: The psychosocial trajectory and decision making of Women with recurrent implantation failure of IVF

Abstract Study question To understand the psychosocial trajectory of Chinese women who have experienced recurrent implantation failure (RIF) of IVF and their decision making accordingly. Summary answer Chinese women experience despair, doubt, and disorientation along with the cumulative failure cycles of IVF, and stick to IVF as the ultimate option. What is known already Recurrent implantation failure, the absence of implantation after repeated embryo transfers is a stressful event for people undergoing treatment for infertility. Numerous researches have focused on the psychological wellness of women undertaking IVF, but pay less attention to the subgroup who have undergone repeated failures. Current studies have shown that women after repeated unsuccessful IVF might endure anxiety, depression, and other psychosocial distress; however, the feelings brought by the different times of failure are unlike, and these experiences will affect their treatment decisions accordingly, which is rarely studied. Study design, size, duration Semi-structured interview was adopted with sixteen Chinese women from March 2020 to July 2020. The interview lasted 90 minutes. A follow-up survey was conducted three months after the interview. Driven by grounded theory, data is analyzed by thematic analysis. Participants/materials, setting, methods Convenience sampling was used to recruit female participants who have failed to achieve clinical pregnancy after two consecutive cycles of fresh or frozen IVF embryo transfers with a cumulative number of transferred embryos of four or more cleavage-stage embryos or two or more blastocysts. Chinese-speaking women who were undertaking IVF treatment in the reproductive center of hospital in Shenzhen City were recruited by pamphlets and doctors’ referral. Main results and the role of chance Chinese women with recurrent implantation failures experience the following psychosocial trajectory during the cumulative failure cycles of IVF: despair, doubt, and disorientation. Despair usually comes after the first failure: the high expectation for success rates makes the initial failure exceptionally shocking and desperate. Huge distress brings two kinds of decisions: start a new IVF cycle quickly to welcome the positive results in the imagination, or wait for a period of time to avoid the pain of failure again. Doubt usually appears after the second failure. In addition to doubting the health function of their body, recurrent failure makes the patients particularly doubt the efficacy of IVF and doctors’ clinical judgment. Some patients would do ‘hospital shopping’ and consider change clinics. Disorientation can be seen in patients who have experienced more than three cycles of failure. Past experience and meaning cannot help them understand and solve the current dilemma. The inherent concept of fertility continues to strengthen their belief of having a baby as ultimate goal. The follow-up survey found that most women still choose to continue IVF treatment after repeated failure. They are like being in the maze of fertility, wandering for a long time but unable to get out. Limitations, reasons for caution Several limitations are identified: self-selection bias due to convenience sampling; narrow sampling approach may limits the generalizability; the exclusion of men may ignore the marital interdependence during the infertility treatment. Wider implications of the findings: Patients who have experienced recurrent implantation failure demand promising intervention during and after infertility treatment. The findings demonstrate the need for both supportive and implication counseling to facilitate them cope with the psychosocial distress, and make value-based decision making, so as to enhance their self-agency. Trial registration number Not applicable

Metabonomics Study on the Infertility Treated With Zishen Yutai Pills Combined With In Vitro Fertilization-embryo Transfer.

Zishen Yutai Pills (ZYP) is a safe and well quality-controlled TCM preparation with promising effects in many fields of reproduction, including prevention of miscarriage, increase of pregnancy rate during in vitro fertilization-embryo transfer (IVF-ET). The plasma of patients was collected from a clinical trial, namely, “Effect of Traditional Chinese Medicine vs placebo on live births among women undergoing in vitro fertilization, a multi-center randomized controlled trial.” Plasma samples were analyzed with metabonomics method. UPLC-MS technology was used to establish the plasma metabolic fingerprint. Multivariate statistical analysis was applied for comparing the differences of plasma metabolites between ZYP group and placebo group, 44 potential metabolites were screen out and identified. Pathway analysis was conducted with database mining. Compared with placebo, chemicals were found to be significantly down-regulated on HCG trigger day and 14 days after embryo transplantation, including trihexosylceramide (d18:1/26:1), glucosylceramide(d18:1/26:0), TG(22:6/15:0/22:6), TG(22:4/20:4/18:4). Compared with placebo, some chemicals were found to be significantly up-regulated on HCG trigger day and 14 days after embryo transplantation, i.e., PIP3(16:0/16:1), PIP2(18:1/18:1), tauroursodeoxycholic acid, L-asparagine, L-glutamic acid, kynurenic acid, 11-deoxycorticosterone, melatonin glucuronide, hydroxytyrosol. These metabolites were highly enriched in pathways including sphingolipid metabolism, alanine, aspartic acid and glutamic acid metabolism, aminoacyl tRNA biosynthesis, taurine and hypotaurine metabolism. This study revealed metabolic differences between subjects administered with ZYP and placebo. Relating metabolites were identified and pathways were enriched, providing basis on the exploration on the underlying mechanisms of ZYP combined with IVF-ET in the treatment of infertility.

Seminal Exosomal miR-181a-5p Protects from Early Pregnancy Loss Via Promoting the Biological Function of Trophoblast Cells Through PROX1/Notch1 Signaling Pathway

Background: Early pregnancy loss is the most common complication in pregnancy. Recently, semen has been identified as regulator of female reproductive function. Here, we investigate latent promising seminal exosomal miRNA as a clinically applicable bio-regulator that can promote the biological function of trophoblast cells in early pregnancy. Objective: To study the regulation and mechanism of semen on embryonic trophoblasts. Methods: Compare the expression of Notch1 in fetal villi of in vitro fertilization-embryo transfer (IVF-ET)-conceived and intercourse-conceived by immunohistochemical staining. Seminal exosome (SE) and miR-181a-5p highly expressed in SE were co-cultured with trophoblast cell line HTR-8/Svneo cells to detect the effect and mechanism of SE and miR-181a-5p on the biological functions of trophoblasts. Results: The expression of Notch1 in the villi tissue from IVF (in vitro fertilization)-conceived women was significantly decreased compared with that from intercourse-conceived women, this may be the reason why IVF pregnancy complications are higher than natural pregnancy. In vitro experiments, we found that both SE and miR-181a-5p significantly increased the migration, invasion and angiogenesis of HTR-8/Svneo cells through inhibiting the expression of PROX1 and then activating Notch1 signaling pathway in HTR-8/Svneo cells. Conclusions: We found that the decreased expression of villous Notch1 may be one of the causes of early pregnancy loss (EPL) in IVF. Semen exosomes can protect the establishment and maintenance of pregnancy by promoting the biological function of trophoblast cells through the miR181-PROX1-Notch1 signaling pathway. Funding: This study was supported by the National Natural Science Foundation of China (CSFC) (grant No. 81471455 and No. 81100418). Declaration of Interest: None to declare. Ethical Approval: The study was approved by the Research Ethics Committee of Renmin Hospital of Wuhan University (No. WDRY2021-K044).

The Role of Traditional Chinese Formula Ding-Kun Pill (DKP) in Expected Poor Ovarian Response Women (POSEIDON Group 4) Undergoing In Vitro Fertilization-Embryo Transfer: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial

ObjectiveThe primary objective of the study was to assess traditional Chinese formula DKP supplementation in terms of efficacy and safety on reproductive outcomes of expected poor ovarian responder (POR, POSEIDON Group 4) undergoing in vitro fertilization-embryo transfer (IVF-ET).Design, Setting, and ParticipantsWomen eligible for IVF-ET were invited to participate in this randomized, double-blind, placebo-controlled, superiority trial at academic fertility centers of ten public hospitals in Chinese Mainland. A total of 462 patients (35–44 years) equally divided between DKP and placebo groups with antral follicle count (AFC) <5 or anti-müllerian hormone (AMH) <1.2 ng/ml were randomized.InterventionsAll participants were given DKP or 7 g placebo twice daily on the previous menstrual cycle day 5 until oocyte retrieval, which took approximately 5 to 6 weeks.Main Outcome MeasureThe primary outcome was the ongoing pregnancy defined as more than 20 gestational weeks of an intrauterine living fetus confirmed by pelvic ultrasonography.ResultsDemographic characteristics were equally distributed between the study populations. Intention-to-treat (ITT) analysis revealed that ongoing pregnancy rate (OPR) was not significantly different between DKP and placebo groups [26.4% (61/231) versus 24.2% (56/231); relative risk (RR) 1.09, 95% confidence interval (CI) 0.80 to 1.49, P = 0.593]. No significant differences between groups were observed for the secondary outcomes. The additional per protocol (PP) analysis was in line with ITT results: OPR in DKP group was 27.2% (61/224) versus 24.1% (55/228) in placebo group [RR 1.13, 95%CI (0.82 to 1.55), P = 0.449]. After subgroup analysis the findings concluded that POR population of 35–37 years had a significantly higher OPR after 5–6 weeks of oral DKP (41.8%, 33/79) versus placebo (25.4%, 18/71) [RR 1.65, 95% CI (1.02 to 2.65), P = 0.034, P for interaction = 0.028].ConclusionThis well-designed randomized controlled trial (RCT) offers new high-quality evidence to supplement existing retrospective literature concerning DKP performance in expected PORs. DKP could be recommended as a safe and natural remedy for expected PORs (aged 35–37 years) who fulfill the POSEIDON group 4 criteria. However, additional interventional clinical studies are undoubtedly required to be conducted in the future to validate this hypothesis.Clinical Trial Registration www.chictr.org.cn, identifier ChiCTR1900026614.

Serum zinc concentration and risk of adverse outcomes to in vitro fertilization and embryo transfer: A prospective cohort study in northern China

Zinc (Zn) plays an important role in female reproductive health. Few studies have currently assessed the effects of female Zn level on the outcome of in vitro fertilization-embryo transfer (IVF-ET). This study investigated the association between serum Zn concentration and IVF-ET outcomes, and the potential effects of some lifestyles on this association. A prospective cohort study design was adopted, and 305 women undergoing IVF-ET were recruited from two cities, Beijing and Shandong, in northern China. Fasting blood specimens were obtained on the day prior to the first treatment cycle. A questionnaire was used to collect demographic characteristics and lifestyle information. Serum Zn concentration was measured using inductively coupled plasma-mass spectrometry. Female serum Zn levels in Beijing center were found to be significantly higher than those in Shandong center. Women who failed to achieve clinical pregnancy had significantly lower Zn concentrations among Shandong subjects, but not in Beijing or the total participants in both centers. For Beijing participants, no statistically significant associations were found between Zn concentrations and the failure risk of IVF-ET [adjusted relative risk (aRR) = 0.65, 95% confidence interval (CI): 0.37–1.15]. For Shandong participants, lower Zn concentrations (< 610.3 ng/mL) were associated with a 66% increased risk of IVF-ET failure (aRR = 1.66, 95% CI: 1.10–2.51). Also, significantly positive correlations were observed between Zn concentrations and the habitual consumption of two food types, including fresh vegetables and beans or bean products, but this was not the case in Beijing. It was concluded that the effect of serum Zn concentrations on IVF-ET outcome may vary by the geographic location. Lower Zn levels might be a risk factor for IVF-ET failure among Shandong women, which can be addressed by adjusting the food intakes. These findings have implications for human infertility treatment and public health problem addressing.

HEREDITARY THROMBOPHILIA IN RECURRENT IVF FAILURE

Background: The predominant part of IVF cycles results in embryo transfer, but only about one third of all cycles reach clinically achieved pregnancy. This is evidence that most embryos failed in an early stage of pregnancy achievement. Recurrent implantation failure after IVF procedures emphasize the clinical importance of this crucial step in assisted reproductive technology. Repeated unsuccessful IVF attempts force efforts to investigate the firm mechanism of the implantation and to find approach to increase pregnancy outcome success. Plenty of factors have been recognized to affect either success, or failure rate of IVF embryo transfer. Maternal side factors include age, parity, hormonal levels before stimulation, antral follicles count, endometrial thickness and quality of transformed endometrium. Other factors, having functions in coagulation and fibrinolysis cascades, were found to be connected with the transformation processes in the endometrium during the implantation.Aim of work: The aim from this study is to evaluate the relation between hereditary thrombophilia and recurrent IVF failure. This will be done by comparing the prevalence of thrombophilia factors mutation in patients with repeated IVF failure and in normal population.Methods: Thirty patients with recurrent IVF failure underwent genetic testing of thrombophilia markers by PCR: Factor II prothrombin mutation, Factor V leiden mutation (FVL), and Methylene tetrahydrofolate reductase (MTHFR) mutation.Results: 13.3% were tested positive for factor V mutation G1619A, 56.7% were positive for MTHFR c667t mutation. While in healthy normal Mediterranean population the percentage of mutation were 3.7% for FVL mutation and 11.1% for MTHFR mutation.Conclusion: hereditary thrombophilia may be considered as a factor in recurrent IVF failure, proper management is to be considered.

Comparison of clinical outcomes between the depot gonadotrophin-releasing hormone agonist protocol and gonadotrophin-releasing hormone antagonist protocol in normal ovarian responders

BackgroundThe gonadotrophin-releasing hormone (GnRH) antagonist protocol has some advantages, such as a simple method, short medication duration, and low incidence of ovarian hyperstimulation syndrome, but whether the GnRH antagonist protocol is suitable for normal ovarian responders has been controversial. We compared the clinical outcomes of fresh and frozen-thawed transfer cycles between the depot GnRH agonist protocol and GnRH antagonist protocol in normal ovarian responders.MethodsData of normal ovarian responders who underwent in vitro fertilization-embryo transfer (IVF-ET) or intracytoplasmic sperm injection-embryo transfer (ICSI-ET) between January 2017 and December 2018 in our hospital were retrospectively analysed. In this study, there were 1119 fresh transfer cycles, including 502 GnRH antagonist cycles (GnRH antagonist group) and 617 depot GnRH agonist cycles (depot GnRH agonist group), as well as 468 frozen-thawed transfer cycles, includng 191 GnRH antagonist cycles (GnRH antagonist group) and 277 depot GnRH agonist cycles (depot GnRH agonist group). The clinical outcomes were compared between the GnRH antagonist group and the depot GnRH agonist group.ResultsWith the fresh transfer cycles, there were no statistically significant differences in the anti-Mullerian hormone level, number of transferred embryos or high-quality embryo rate between the two groups. The total dosage of gonadotropin (Gn), duration of Gn stimulation, number of oocytes retrieved, clinical pregnancy rate and incidences of moderate and severe ovarian hyperstimulation syndrome (OHSS) were significantly lower but the abortion rate was significantly higher in the GnRH antagonist group than in the depot GnRH agonist group (all P < 0.05). With the frozen-thawed transfer cycles, there were no statistically significant differences in the number of transferred embryos, clinical pregnancy rate or abortion rate between the two groups (all P > 0.05).ConclusionsWith the fresh transfer cycles, the GnRH antagonist protocol had a lower clinical pregnancy rate and lower incidences of moderate and severe OHSS than the depot GnRH agonist protocol, but with the frozen-thawed transfer cycles, both protocols had similar clinical pregnancy rates. These results remain to be further confirmed through large-sample, prospective, randomized and controlled studies.

Antenatal diagnosis of placenta accreta spectrum after in vitro fertilization-embryo transfer: a systematic review and meta-analysis

Increasing evidence suggests a relationship between in vitro fertilization-embryo transfer (IVF-ET) and placenta accreta spectrum (PAS). Some studies have reported a lower rate of antenatal diagnosis of PAS after IVF-ET compared to PAS with spontaneous conception. This study aimed to review the diagnostic accuracy of PAS after IVF-ET and to explore the relationship between IVF-ET pregnancy and PAS. According to the PRISMA guidelines, a comprehensive systematic review of the literature was conducted through August 31, 2020 to determine the effects of IVF-ET on PAS. In addition, a meta-analysis was conducted to explore the relationship between IVF-ET pregnancy and PAS. Twelve original studies (2011–2020) met the inclusion criteria. Among these, 190,139 IVF-ET pregnancies and 248,534 spontaneous conceptions met the inclusion criteria. In the comparator analysis between PAS after IVF-ET and PAS with spontaneous conception (n = 2), the antenatal diagnosis of PAS after IVF-ET was significantly lower than that of PAS with spontaneous conception (22.2% versus 94.7%, P < 0.01; < 12.9% versus 46.9%, P < 0.01). The risk of PAS was significantly higher in women who conceived with IVF-ET than in those with spontaneous conception (odds ratio [OR]: 5.03, 95% confidence interval [CI]: 3.34–7.56, P < 0.01). In the sensitivity analysis accounting for the type of IVF-ET, frozen ET was associated with an increased risk of PAS (OR: 4.60, 95%CI: 3.42–6.18, P < 0.01) compared to fresh ET. Notably, frozen ET with hormone replacement cycle was significantly associated with the prevalence of PAS compared to frozen ET with normal ovulatory cycle (OR: 5.76, 95%CI 3.12–10.64, P < 0.01). IVF-ET is associated with PAS, and PAS after IVF-ET was associated with a lower rate of antenatal diagnosis. Therefore, clinicians can pay more attention to the presence of PAS during antenatal evaluation in women with IVF-ET, especially in frozen ET with hormone replacement cycle.

Clinical studies on acupuncture assisting in vitro fertilization-embryo transfer: a review and thoughts

Acupuncture has a long history of application in the field of reproduction, and in the past 20 years, numerous clinical studies have been conducted to explore the value of acupuncture in assisted reproductive technology. However, due to inconsistent research findings, there are still controversies over the clinical safety and efficacy of acupuncture in assisting in vitro fertilization-embryo transfer (IVF-ET), which may be closely associated with lacking of standardized treatment regimen in clinical trials of acupuncture. For that reason, this article reviews 16 representative clinical trials of acupuncture assisting IVF-ET published worldwide in 1999-2020, summarizes the grouping design, acupuncture method (acupuncture timing, acupuncture frequency, acupoints, and acupuncture types), and pregnancy outcome (pregnancy rate, clinical pregnancy rate, ongoing pregnancy rate, and live birth rate), and discusses several key links in clinical protocol design, so as to provide references for future clinical research.

Effect of parental and ART treatment characteristics on perinatal outcomes.

STUDY QUESTIONDo parental characteristics and treatment with ART affect perinatal outcomes in singleton pregnancies?SUMMARY ANSWERBoth parental and ART treatment characteristics affect perinatal outcomes in singleton pregnancies.WHAT IS KNOWN ALREADYPrevious studies have shown that singleton pregnancies resulting from ART are at risk of preterm birth. ART children are lighter at birth after correction for duration of gestation and at increased risk of congenital abnormalities compared to naturally conceived children. This association is confounded by parental characteristics that are also known to affect perinatal outcomes. It is unclear to which extent parental and ART treatment characteristics independently affect perinatal outcomes.STUDY DESIGN, SIZE, DURATIONAll IVF clinics in the Netherlands (n = 13) were requested to provide data on all ART treatment cycles (IVF, ICSI and frozen-thawed embryo transfers (FET)), performed between 1 January 2000, and 1 January 2011, which resulted in a pregnancy. Using probabilistic data-linkage, these data (n = 36 683) were linked to the Dutch Perinatal Registry (Perined), which includes all children born in the Netherlands in the same time period (n = 2 548 977).PARTICIPANTS/MATERIALS, SETTING, METHODSAnalyses were limited to singleton pregnancies that resulted from IVF, ICSI or FET cycles. Multivariable models for linear and logistic regression were fitted including parental characteristics as well as ART treatment characteristics. Analyses were performed separately for fresh cycles and for fresh and FET cycles combined. We assessed the impact on the following perinatal outcomes: birth weight, preterm birth below 37 or 32 weeks of gestation, congenital malformations and perinatal mortality.MAIN RESULTS AND THE ROLE OF CHANCEThe perinatal outcomes of 31 184 out of the 36 683 ART treatment cycles leading to a pregnancy were retrieved through linkage with the Perined (85% linkage). Of those, 23 671 concerned singleton pregnancies resulting from IVF, ICSI or FET. Birth weight was independently associated with both parental and ART treatment characteristics. Characteristics associated with lower birth weight included maternal hypertensive disease, non-Dutch maternal ethnicity, nulliparity, increasing duration of subfertility, hCG for luteal phase support (compared to progesterone), shorter embryo culture duration, increasing number of oocytes retrieved and fresh embryo transfer. The parental characteristic with the greatest effect size on birth weight was maternal diabetes (adjusted difference 283 g, 95% CI 228–338). FET was the ART treatment characteristic with the greatest effect size on birth weight (adjusted difference 100 g, 95% CI 84–117) compared to fresh embryo transfer. Preterm birth was more common among mothers of South-Asian ethnicity. Preterm birth was less common among multiparous women and women with ‘male factor’ as treatment indication (compared to ‘tubal factor’).LIMITATIONS, REASONS FOR CAUTIONDue to the retrospective nature of our study, we cannot prove causality. Further limitations of our study were the inability to adjust for mothers giving birth more than once in our dataset, missing values for several variables and limited information on parental lifestyle and general health.WIDER IMPLICATIONS OF THE FINDINGSMultiple parental and ART treatment characteristics affect perinatal outcomes, with birth weight being influenced by the widest range of factors. This highlights the importance of assessing both parental and ART treatment characteristics in studies that focus on the health of ART-offspring, with the purpose of modifying these factors where possible. Our results further support the hypothesis that the embryo is sensitive to its early environment.STUDY FUNDING/COMPETING INTEREST(S)This study was funded by Foreest Medical School, Alkmaar, the Netherlands (grants: FIO 1307 and FIO 1505). B.W.M. reports grants from NHMRC and consultancy for ObsEva, Merck KGaA, iGenomics and Guerbet. F.B. reports research support grants from Merck Serono and personal fees from Merck Serono. A.C. reports travel support from Ferring BV. and Theramex BV. and personal fees from UpToDate (Hyperthecosis), all outside the remit of the current work. The remaining authors report no conflict of interests.TRIAL REGISTRATION NUMBERN/A.

Pregnancy outcomes of infertile women with ultrasound-diagnosed adenomyosis for in vitro fertilization and frozen-thawed embryo transfer.

This study aimed to investigate the effect of ultrasound-diagnosed adenomyosis on assisted pregnancy outcomes, i.e., in vitro fertilization-embryo transfer (IVF-ET). This was a retrospective cohort study of 18,568 women who had received their first frozen-thawed ET cycle in Center of Reproductive Medicine, Children's Hospital of Shanxi and Women Health Center of Shanxi and the Reproductive Medicine Center of Tianjin Central Obstetrics and Gynecology Hospital from January 2014 to May 2019. A total of 5,087 patients met the inclusion and exclusion criteria, and they were divided into two groups: adenomyosis with tubal factor infertility (study group, n = 193) and only tubal factor infertility (control group, n = 4894). After a 1:1 propensity score match (caliper value = 0.005), 360 cases were matched in the end. There was no statistical difference in the embryo implantation rate, clinical pregnancy rate, or multiple pregnancy rate between the two groups (28.4% vs. 31.7%, 42.2% vs. 42.8%, and 11.7% vs. 12.8%, respectively; P > 0.05). However, the early miscarriage rate in the adenomyosis group was significantly higher than that in the control group (13.3% vs. 5.6%, respectively; P = 0.012). The live birth rate was 22.8% in the women with adenomyosis and was observed to be significantly lower than 33.3% in the control group (P = 0.026). The patients with adenomyosis had a higher incidence of pregnancy complications than those without (4.4% vs. 0.6%, respectively; P = 0.018), but the neonatal birth weight was not related to adenomyosis. Women with adenomyosis should be treated as being at high risk of early miscarriage. However, maternal adenomyosis has no effect on the birth weight of the newborn.

Low basal serum testosterone level is detrimental to the embryo implantation in the patients with severe endometriosis.

Androgens have been reported to be associated with female fertility. The mean serum testosterone concentration in the patients with endometriosis was reported to be significantly lower than that without endometriosis. Our study was designed to investigate the influence of basal serum testosterone levels on the clinical outcome of in vitro fertilization (IVF) in the patients with III-IV stage endometriosis. This retrospective cohort study included 407 patients with III-IV stage endometriosis diagnosed by laparoscopic surgery. We studied the association of the basal serum testosterone level and the reproductive outcome of IVF. The basal serum testosterone concentration was significantly higher in the pregnant group of patients with III-IV stage endometriosis. The further analyses demonstrated that the implantation rate of the basal serum testosterone concentration < 0.305 ng/mL group was significantly lower than the testosterone ≥ 0.305 ng/mL group (24.1% vs. 32.7%, p=0.007). The clinical pregnancy and live birth rate of the basal serum testosterone < 0.305 ng/mL group were also lower than that of the testosterone ≥ 0.305 ng/mL group. Both initial and total dose of gonadotropins in the testosterone <0.305 ng/mL group are significantly higher than that of the testosterone ≥0.305 ng/mL group. Our study demonstrated, for the first time, that the basal serum testosterone <0.305 ng/mL had an adverse impact on pregnancy outcomes of IVF-embryo transfer in the patients with III-IV stage endometriosis. Besides, the basal serum testosterone is also helpful in making individual stimulation protocol for the patients with advanced endometriosis before entering IVF cycles.

Association between serum oestradiol level on the hCG administration day and neonatal birthweight after IVF-ET among 3659 singleton live births

Oestradiol, an important hormone in follicular development and endometrial receptivity, is closely related to clinical outcomes of fresh in vitro fertilization-embryo transfer (IVF-ET) cycles. A supraphysiologic E2 level is inevitable during controlled ovarian hyper-stimulation (COH), and its effect on the outcome of IVF-ET is controversial. The aim of this retrospective study is to evaluate the association between elevated serum oestradiol (E2) levels on the day of human chorionic gonadotrophin (hCG) administration and neonatal birthweight after IVF-ET cycles. The data of 3659 infertile patients with fresh IVF-ET cycles were analysed retrospectively between August 2009 and February 2017 in First Hospital of Zhengzhou University. Patients were categorized by serum E2 levels on the day of hCG administration into six groups: group 1 (serum E2 levels ≤ 1000 pg/mL, n = 230), group 2 (serum E2 levels between 1001 and 2000 pg/mL, n = 524), group 3 (serum E2 levels between 2001 and 3000 pg/mL, n = 783), group 4 (serum E2 levels between 3001 and 4000 pg/mL, n = 721), group 5 (serum E2 levels between 4001 and 5000 pg/mL, n = 548 ), and group 6 (serum E2 levels > 5000 pg/mL, n = 852). Univariate linear regression was used to evaluate the independent correlation between each factor and outcome index. Multiple logistic regression was used to adjust for confounding factors. The LBW rates were as follows: 3.0% (group 1), 2.9% (group 2), 1.9% (group 3), 2.9% (group 4), 2.9% (group 5), and 2.0% (group 6) (P = 0.629), respectively. There were no statistically significant differences in the incidences of neonatal LBW among the six groups. We did not detect an association between peak serum E2 level during ovarian stimulation and neonatal birthweight after IVF-ET. The results of this retrospective cohort study showed that serum E2 peak levels during ovarian stimulation were not associated with birth weight during IVF cycles. In addition, no association was found between higher E2 levels and increased LBW risk. Our observations suggest that the hyper-oestrogenic milieu during COS does not seem to have adverse effects on the birthweight of offspring after IVF. Although this study provides some reference, the obstetric-related factors were not included due to historical reasons. The impact of the high estrogen environment during COS on the birth weight of IVF offspring still needs future research.