Fresh IVF-ET Cycles Research Articles

The impact of blastocyst grade on singleton birth weight in fresh IVF‒ET cycles in ART: a retrospective study

BackgroundThe positive correlation between embryo quality and pregnancy outcomes has been confirmed in many studies, but there are few on the impact of embryo quality on neonatal weight, especially among neonates from fresh IVF‒ET cycles in ART. Therefore, this study aimed to compare the birth weights of infants from different blastocyst grades in fresh IVF-ET cycles and explore related factors affecting birth weight.MethodsThe main outcome measure was singleton birth weight. A total of 1301 fresh cycles of single blastocyst transplantation and single live birth profiles were retrospectively analyzed and divided into four groups according to blastocyst quality: the excellent group (grade AA), which included 170 cycles; the good group (grade AB/BA), which included 312 cycles; the average group (grade BB/CA/AC), which included 559 cycles; and the poor group (grade BC/CB), which included 260 cycles. The relationships among cystic cavity expansion, endocytic cell mass, ectodermal trophoblast cell grade, and birth weight were studied. Multiple linear regression analysis was performed to investigate the relationship between blastocyst quality and neonatal birth weight and logistic regression for the risk factors for low birth weight newborns.ResultsWith decreases in the blastocyst quality, including ICM, TE quality, and embryo expansion stage, birth weight declined, and Z scores correspondingly decreased. After adjusting for confounders, the average and poor groups (P = 0.01 and P = 0.001, respectively) and blastocysts with TE grade C (P = 0.022) resulted in singletons with lower birth weight. Additionally, the poor group and blastocysts with Grade C TEs had a greater chance of leading to low birth weight infants compared with the other groups.ConclusionOur findings indicated that excellent and good-grade blastocyst transplantation could achieve better pregnancy outcomes and that average and poor-grade blastocyst transplantation, especially with grade C TEs, were associated with single birth weight loss. No association was found between the embryo expansion stage or ICM quality and neonatal birth weight.

P-095 Increased sperm high DNA stainability is associated with a diminished chance of fertilization with IVF cycles: a retrospective study using a propensity score-matching analysis

Abstract Study question To investigate the association of high DNA stainability (HDS) with fertilization, embryonic development and clinical outcome after IVF treatment. Summary answer Increased HDS levels might be associated with decreased fertilization of IVF cycle. What is known already The HDS parameter of sperm suggests loosening and weakening of chromatin condensation structure resulting from the lack of full histone-to-protamine exchange. Elevated HDS may negatively correlate with sperm quality, including sperm morphology and concentration. Study design, size, duration Couples that underwent IVF cycles from January 2016 to December 2020 were retrospectively studied, including a total of 2604 target cycles after IVF treatment consisting of 676 cycles in the HDS > 15% group and 1928 cycles in the HDS ≤ 15% group. In addition, 548 cycles undergoing fresh IVF-embryo transplantation treatment consisting of 151 cycles in the HDS > 15% group and 397 in the HDS ≤ 15% group were included. Participants/materials, setting, methods HDS was assessed by sperm chromatin structure assay method. Couples were classified into HDS > 15% group and HDS ≤ 15% group based on the HDS thresholds recommended by the manufacturer’s instructions. After controlling the bias between groups by the propensity score-matching method, the Mann-Whitney U test or Chi-squared test was used to evaluate the differences between groups. Regression analysis was used to assess the effect of HDS levels on fertilization, embryo quality, and clinical outcome of IVF cycles Main results and the role of chance No significant differences were observed between the HDS > 15% group and HDS ≤ 15% group regarding the number of fertilized oocytes (10.00 [6.00, 15.00] vs. 10.00 [6.00, 15.00], P = 0.230), the number of 2 pronuclei zygotes (8.00 [4.00, 12.00] vs. 8.00 [5.00, 12.00], P = 0.311), the number of cleaved zygotes (10.00 [5.00, 15.00] vs. 10.00 [6.00, 15.00], P = 0.301), and the number of high-quality embryos on day 3 (5.00 [2.00, 9.00] vs. 5.00 [3.00, 9.00], P = 0.729). However, linear regression analysis showed that HDS levels negatively impacted fertilization (adjusted B value = −0.015, 95% CI: −0.028 ∼ −0.002, P = 0.022) and 2 pronuclei formation (adjusted B value = −0.015, 95% CI: −0.029 ∼ 0.000, P = 0.046). The implantation rate (47.1% vs. 50.2%, P = 0.418), clinical pregnancy rate (60.9% vs. 64.5%, P = 0.440), ongoing pregnancy rate (83.7% vs. 86.7%, P = 0.475), early miscarriage rate (16.3% vs. 13.3%, P = 0.475), late miscarriage rate (1.1% vs. 3.5%, P = 0.232), and live birth rate (82.6% vs. 83.2%, P = 0.896) were not significantly different between groups. Linear regression analysis showed that HDS did not affect the implantation rate. Binary logistic regression analysis also showed that HDS did not affect clinical pregnancy, ongoing pregnancy, early miscarriage, late miscarriage, and live birth. Limitations, reasons for caution The main weakness of this study was the nature of the retrospective design, and additionally, patients were not randomized. Wider implications of the findings Although our results are not entirely new, it can be considered as reliable because 2604 IVF cycles and 548 fresh IVF-ET cycles were included and subsequently controlled the bias between groups This study suggested that HDS might be an indicator in predicting the fertilization ability of sperm in IVF treatment. Trial registration number not applicable

The influence of male and female overweight/obesity on IVF outcomes: a cohort study based on registration in Western China

BackgroundOverweight/obesity can affect fertility, increase the risk of pregnancy complications, and affect the outcome of assisted reproductive technology (ART). However, due to confounding factors, the accuracy and uniformity of published findings on IVF outcomes have been disputed. This study aimed to assess the effects of both male and female body mass index (BMI), individually and in combination, on IVF outcomes.MethodsThis retrospective cohort study included 11,191 couples undergoing IVF. Per the Chinese BMI standard, the couples were divided into four groups: normal; female overweight/obesity; male overweight/obesity; and combined male and female overweight/obesity. The IVF outcomes of the four groups were compared and analysed.ResultsRegarding the 6569 first fresh IVF-ET cycles, compared with the normal weight group, the female overweight/obesity and combined male/female overweight/obesity groups had much lower numbers of available embryos and high-quality embryos (p < 0.05); additionally, the fertilization (p < 0.001) and normal fertilization rates (p < 0.001) were significantly decreased in the female overweight/obesity group. The combined male/female overweight/obesity group had significant reductions in the available embryo (p = 0.002), high-quality embryo (p = 0.010), fertilization (p = 0.001) and normal fertilization rates (p < 0.001); however, neither male or female overweight/obesity nor their combination significantly affected the clinical pregnancy rate (CPR), live birth rate (LBR) or abortion rate (p > 0.05).ConclusionOur findings support the notion that overweight/obesity does not influence pregnancy success; however, we found that overweight/obesity affects the fertilization rate and embryo number and that there are sex differences.

P-425 Premature follicular-phase progesterone increase in ART cycles and endometrial receptivity: evaluation of new, more reliable predictors

Abstract Study question Is plasma Progesterone (P) at HCG administration more sensitive in predicting endometrial receptivity in fresh IVF cycles than PFI (progesterone-follicles index) and POI (progesterone-oocytes index)? Summary answer Our data suggest that POI predicts endometrial receptivity defect better than the P assay alone, thus allowing better decision making. What is known already The premature increase in plasma P in the follicular phase of stimulated IVF cycles has been associated with a lower embryo implantation rate because of reduced endometrial receptivity. There is still no consensus on how this impediment to implantation should occur and what threshold should be used. Moreover,since the efficacy of P increase in conditioning reproductive outcomes is more intense in patients with normo- and poor-response and generally inversely proportional to the ovarian response to stimulation, PFI and POI, which better reflect the average amount of P secreted from the follicles, have been suggested as potential additional markers of receptivity. Study design, size, duration Retrospective analysis of fresh IVF-ET cycles. PFI was obtained dividing the plasma P level on the day of hCG administration by the number of follicles ≥14 mm; POI by the number of oocytes retrieved. Pearson correlations, ROC curves, multivariate logistic regression analysis and Cox regression were performed to evaluate the predictive value of PFI and POI for the main outcomes we considered: ongoing pregnancy rate (OPR) and live birth rate (LBR). Participants/materials, setting, methods Women undergoing IVF cycles at San Paolo University Hospital in Milan between 2016 and 2021 were enrolled. As exclusion criteria, we considered previous ovarian surgery, endometriosis, severe male factor and cycle interruption before the embryo transfer. We collected the following data: age of the woman; stimulation protocol; total amount of FSH administered; P and Estradiol (E2) levels and number of follicles &amp;gt;14 mm on induction day; number of oocytes collected; OPR and LBR. Main results and the role of chance A total of 662 fresh embryo transfers (ETs) were performed and 214 pregnancies were achieved. We observed a statistically significant difference in age, number of total embryos and POI between women who became pregnant and those who did not. Specifically, Pearson’s correlation revealed a significant positive correlation between pregnancy and number of total embryos (r = 0.165, p &amp;lt; 0.001), and a significant negative correlation between pregnancy and age (r = 0.201, p &amp;lt; 0.001) and POI (r=-0.096, p = 0.013). Multivariate logistic regression revealed POI to be the most significant predictive parameter of pregnancy, with a odds ratio of 4.374 (p = 0.007, CI: 1.496-12.797). The ROC curve confirmed the highest predictive value of POI for OPR. Finally, Cox regression showed that POI &amp;lt;0.18 was correlated with better OPR (odds ratio=1.419, p = 0.012), suggesting the potential clinical impact of identifying an optimal cut-off of POI to reconsider patient management. Limitations, reasons for caution The results of this study are limited by the small population size. Wider implications of the findings Since the effect on endometrial receptivity of increased plasma P is inversely proportional to ovarian response,we suggest using a marker that accounts for response characteristics. POI has been found to be a reliable index for predicting IVF-ET cycle outcomes,supporting a limit beyond which the fresh embryo transfer should be reconsidered. Trial registration number N/A

The Effect of Bisphenol A on the IVF Outcomes Depending on the Polymorphism of the Detoxification System Genes.

The aim of the study was to analyze the relationship between the level of bisphenol A (BPA) in the blood and follicular fluid, the polymorphism of the detoxification system genes, and the outcomes of IVF cycles. The data of 300 infertile patients with fresh IVF-ET cycles were analyzed. The level of BPA in the blood and follicular fluid was determined by HPLC-MRM-MS/MS. Determination of genotypes of the detoxification system genes was carried out by the real-time PCR. The threshold level for determining BPA was 0.1 ng/mL. BPA was detected in 92.3% (277/300) blood and in 16.8% (49/292) follicular fluid (FF) samples. There was no correlation between BPA level in the blood and FF. In patients with the absence of the A allele of the SULT1A1 gene, BPA was detected in FF significantly more often (22.6% vs. 13.5%, p = 0.0341). There was an association (not statistically significant) between the level of BPA in the blood and the presence of the G allele of the GSTP1 gene (rs1695) and the C allele in the GSTP1 gene (rs1138272). Our data suggests the role of detoxification system genes in the metabolism of BPA in the human body. The influence of BPA and detoxification system genes on the IVF outcomes requires further research.

Association of the Cervical Microbiota With Pregnancy Outcome in a Subfertile Population Undergoing In Vitro Fertilization: A Case-Control Study.

The microorganisms of the reproductive tract have been implicated to affect in vitro fertilization (IVF) outcomes. However, studies on the reproductive tract microbiota of infertile women are limited and the correlation between cervical microbiota and IVF outcome remains elusive. This study aimed to characterize the cervical microbiota of IVF patients undergoing embryo transfer (ET) and assess associations between the cervical microbiota and pregnancy outcomes while exploring the underlying contributing factors. We launched a nested case-control study of 100 patients with two fresh or frozen-thawed cleavage embryos transferred per IVF cycle. Cervical swabs were collected on the day of ET and divided into four groups according to clinical pregnancy outcomes. Variable regions 3 and 4 (V3-V4) of the 16S rRNA gene were amplified and sequenced on the Illumina MiSeq platform. In fresh IVF-ET cycles, the clinical pregnancy group (FP, n = 25) demonstrated higher α diversity (P = 0.0078) than the non-pregnancy group (FN, n = 26). Analysis of similarity (ANOSIM) revealed a significant difference in β diversity between the two groups (R = 0.242, P = 0.001). In frozen-thawed ET cycles, though not significant, similar higher α diversity was found in the clinical pregnancy group (TP, n = 27) compared to the non-pregnancy group (TN, n = 22) and ANOSIM analysis showed a significant difference between the two groups (R = 0.062, P = 0.045). For patients in fresh IVF-ET groups, Lactobacillus, Akkermansia, Desulfovibrio, Atopobium, and Gardnerella showed differentially abundance between pregnant and non-pregnant women and they accounted for the largest share of all taxa investigated. Among them, Lactobacillus was negatively correlated with the other genera and positively correlated with serum estradiol levels. Logistic regression analysis suggested that the composition of the cervical microbiota on the day of ET was associated with the clinical pregnancy in fresh IVF-ET cycles (P = 0.030). Our results indicate that cervical microbiota composition has an impact on the outcome of assisted reproductive therapy.

Optimal waiting period for fresh embryo transfer after hysteroscopic adhesiolysis: a retrospective cohort study.

Very few studies have been conducted regarding the optimal time interval between hysteroscopic adhesiolysis and the embryo transfer (ET). Investigation of this optimal time may be helpful for assisted reproductive technology. Therefore, we investigated effects of the interval between hysteroscopic adhesiolysis and ET upon in vitro fertilization (IVF) cycle outcomes. Patients were recruited between January 2014 and September 2017 at the Reproductive Hospital Affiliated to Shandong University. Patients who were diagnosed with intra-uterine adhesion (IUA) and underwent hysteroscopic adhesiolysis before fresh IVF-ET or intra-cytoplasmic sperm injection cycles were classified into three groups according to the interval between hysteroscopic adhesiolysis and ET: less than 90 days (Group 1), 90 to 180 days (Group 2), and greater than 180 days (Group 3). Baseline characteristics, controlled ovarian stimulation (COS) response, and pregnancy outcomes after ET were compared. Analysis of variance or non-parametric tests were used to test numerical data. The Pearson's Chi-squared test was used to test categorical data. A total of 312 patients were recruited as follows: 112 in Group 1, 137 in Group 2, and 63 in Group 3. There were no differences in baseline and COS characteristics among the three groups. The live-birth rate in Group 2 (40.1%) was significantly higher than that in Group 1 (17.9%; χ = 14.545, P < 0.001). There were no significant differences in the rates of biochemical, ongoing, and clinical pregnancy, and biochemical and clinical pregnancy abortion, as well as stillbirth among the groups. In the mild IUA patients, the live-birth rate was significantly higher in Group 2 (42.6%) compared with Group 1 (22%; χ = 8.413, P = 0.004). In the moderate IUA patients, Group 2 (35.7%) had a higher frequency of live births than Group 1 (6.7%; χ = 8.187, P = 0.004). The optimal waiting period for fresh ET after hysteroscopic adhesiolysis was 90 to 180 days in the current study.

The impact of a thin endometrial lining on fresh and frozen–thaw IVF outcomes: an analysis of over 40 000 embryo transfers

STUDY QUESTIONDoes each millimeter decrease in endometrial thickness lead to lower pregnancy and live birth rates in fresh and frozen IVF cycles?SUMMARY ANSWERClinical pregnancy and live birth rates decline as the endometrial thickness decreases below 8 mm in fresh IVF-ET and below 7 mm in frozen–thaw embryo transfer (ET) cycles.WHAT IS KNOWN ALREADYPrevious studies have been heterogenous and have shown conflicting results on the impact of endometrial thickness on IVF outcomes. Most studies do not include many patients with an endometrial thickness below 6 mm, and there are few studies of frozen–thaw ET cycles.STUDY DESIGN, SIZE, DURATIONThis study is a retrospective cohort analysis of all Canadian IVF fresh and frozen–thaw ET cycles from the CARTR-BORN database for autologous and donor fresh and frozen–thaw IVF-ET cycles from 1 January 2013 to 31 December 2015. A total of 24 363 fresh and 20 114 frozen–thaw IVF-ET cycles were reported during this timeframe.PARTICIPANTS/MATERIALS, SETTING, METHODS33 Canadians clinics participated in voluntary reporting of IVF and pregnancy outcomes to the CARTR-BORN database. The impact of endometrial thickness on pregnancy, live birth and pregnancy loss rates were analyzed for fresh IVF-ET and frozen–thaw cycles.MAIN RESULTS AND THE ROLE OF CHANCEIn fresh IVF-ET cycles, clinical pregnancy and live birth rates decreased (P < 0.0001) and pregnancy loss rates increased (P = 0.01) with each millimeter decline in endometrial thickness below 8 mm. Live birth rates were 33.7, 25.5, 24.6 and 18.1% for endometrial thickness ≥8, 7–7.9, 6–6.9 and 5–5.9 mm, respectively. In frozen–thaw ET cycles, clinical pregnancy (P = 0.007) and live birth rates decreased (P = 0.002) with each millimeter decline in endometrial thickness below 7 mm, with no significant difference in pregnancy loss rates. Live birth rates were 28.4, 27.4, 23.7, 15 and 21.2% for endometrial thickness ≥8, 7–7.9, 6–6.9, 5–5.9 and 4–4.9 mm, respectively. The likelihood of achieving an endometrial thickness ≥8 mm decreased with age (89.7, 87.8 and 83.9% in women <35, 35–39 and ≥40, respectively) (P < 0.0001).LIMITATIONS, REASONS FOR CAUTIONThis study only included cycles which proceeded to ET, which may overestimate pregnancy outcomes. Approximately 8% of cycles could not be included in the analysis due to data irregularity related to data entry. Demographic data aside from age were unavailable but may be important as lower endometrial thickness may be associated with poor ovarian response.WIDER IMPLICATIONS OF THE FINDINGSAlthough pregnancy and live birth rates decrease with endometrial thickness, reasonable outcomes were obtained even with lower endometrial thickness measurements. These data provide valuable guidance for both physicians and patients when confronted with decisions related to a persistently thin endometrium.STUDY FUNDING/COMPETING INTEREST(S)This study was not funded. The authors do not have any conflicts of interests to declare.TRIAL REGISTRATION NUMBERN/A.

Asian ethnicity is an independent determinant of ovarian reserve and response in women undergoing fresh IVF-ET cycles

Studies have shown that ethnicity can be an independent determinant of ovarian reserve and response in IVF-embryo transfer (ET) cycles. In this context, we investigate if ovarian reserve and response parameters differ among Asian and Caucasian women. Cross-sectional study. Women <37 years, with baseline follicle stimulating hormone (FSH) <12 mIU/mL, AMH >1 ng/mL and antral follicle count (AFC) >5 undergoing fresh IVF-ET for unexplained infertility during a 5-year period were assessed for inclusion. Women with poor ovarian reserve (defined as AMH<1, FSH >12, or AFC<5), PCOS, or a history of oophorectomy were excluded. Of those included, ovarian reserve and response parameters were compared between Asians and Caucasians. Ovarian reserve was assessed by day 3 FSH, AMH, and AFC. Ovarian response was determined by stimulation duration, total gonadotropins and number of oocytes retrieved, with the primary outcome being the number of mature oocytes retrieved. A multivariate regression model was constructed for the primary outcome to account for potential confounders. 1378 women were included, of which 390 (28.3%) and 988 (71.7%) were Asian and Caucasian, respectively. Asians were slightly older (33.7±2.7 vs. 33.3±2.9 years; P=0.02) with lower BMIs (22.1±4.3 vs. 22.9±5.5 kg/m2; P=0.01). Asians had lower AFCs than Caucasians (13.9±4.4 vs. 14.7±4.3; P=0.01). While still within normal range, Asians had higher day 3 FSH levels (5.5±2.8 vs. 4.8±2.8 mIU/mL; P<0.001). There was no difference in AMH levels between the groups. Despite a comparable stimulation duration and gonadotropin dosage, the total oocyte yield (13.6±6.2 vs. 14.8±7.0; P=0.003) and mature oocyte yield (10.1±6.1 vs. 12.0±5.6; P<0.001) was lower in Asians. Overall, the number of oocytes per unit of AMH was lower in Asians compared to Caucasians (4.3±3.4 vs. 5.3±3.4; P<0.001). Multivariate regression suggested that Asian women yield approximately 3 fewer mature oocytes than Caucasians (co-efficient +2.8; 95% CI 1.68-3.67; P=0.003; R2 0.63). Despite these differences, the live birth rate in Asians (42.6%) was comparable to Caucasians (48.6%). Despite similar ages, AMH levels, ovarian stimulation duration and gonadotropin doses, Asian women have decreased AFCs and a lower yield of total and mature oocytes compared to their Caucasian counterparts. These results suggest a decreased ovarian response in Asian women undergoing IVF-ET.Tabled 1Comparison of baseline demographics, ovarian reserve and ovarian response parameters (n=1378)ParameterAsian (n=390)Caucasian (n=988)PAge (years)33.7 (±2.7)33.3 (±2.9)0.02BMI (kg/m2)22.1 (±4.3)22.9 (±5.5)0.01Baseline FSH (mIU/mL)5.5 (±2.8)4.8 (±2.8)<0.001Baseline AMH (ng/mL)3.2 (±2.6)3.2 (±2.9)NSBaseline AFC13.9 (±4.4)14.7 (±4.3)0.002Total stimulation days9.3 (±1.7)9.5 (±1.8)NSTotal gonadotropins (IU)2460.9 (±1287.6)2358.1 (±1157.4)NSTotal oocytes retrieved13.6 (±6.2)14.8 (±7.0)0.003Mature oocytes retrieved10.1 (±6.1)12.0 (±5.6)<0.001% Mature oocytes74.9 (±27.2)82.0 (±15.8<0.001Mature oocyte retrieved: AMH4.3 (±3.4)5.3 (±3.4)<0.001 Open table in a new tab

Supraphysiologic estradiol is an independent predictor of low birth weight in full-term singletons born after fresh embryo transfer.

Is supraphysiologic estradiol (E2) an independent predictor of low birth weight (LBW) in singletons born after fresh IVF-embryo transfer (ET) cycles? Our results suggest that E2 > 2500 pg/ml is an independent predictor for LBW in full-term singletons born to normal responder patients undergoing fresh IVF-ET cycles. The pathogenesis of LBW in IVF singletons remains unknown. However, recent studies have suggested that the hyperestrogenic milieu generated during ovarian stimulation may create a sub-optimal peri-implantation environment, leading to placental dysfunction, and therefore, LBW. Retrospective cohort study of normal responder patients, <40 years old, undergoing fresh IVF-ET cycles resulting in live singleton births between January 2005 and June 2014. A total of 6419 patients had live births after fresh IVF-ET during the study period,of which 2348 (36.6%) patients were excluded due to multiple gestation, vanishing twins or incomplete records. Perinatal outcomes recorded for all patients included birth weight, gestational age (GA) at delivery, mode of delivery and gender. Term birth, preterm birth (PTB) and LBW incidence proportions were plotted against E2 level on the day of trigger. The term LBW incidence proportion (i.e. singletons born at GA ≥ 37 weeks with birth weight <2500 g) was considered the primary outcome of interest. A total of 4071 patients with live singleton births were included. The median age, BMI, E2 level and birth weight for the study cohort was 36 (33-39) years, 22.3 (20.4-25.0) kg/m2, 1554 (1112.7-2179) pg/ml and 3289 (2920-3628) g, respectively. The incidence proportion of LBW rose from 6.4% (E2 2001-2500 pg/ml) to 20.7% (E2 3501-4000 pg/ml), without a corresponding rise in the incidence proportion of PTB. The odds of term LBW with E2 > 2500 pg/ml were 6.1-7.9 times higher compared to the referent E2 group. Multivariable logistic regression analysis revealed that E2 was an independent predictor for term LBW, even after adjusting for age, BMI, race, parity, infertility diagnosis, duration of ovarian stimulation, gonadotropin dosage and method of insemination (adjusted odds ratio 10.8, 95% CI 9.2-12.5). Receiver operating characteristic analysis generated an AUC estimate of 0.85 for E2 level as a predictor of LBW. The current study did not include analyses of hypertensive disorders of pregnancy or placental abnormalities. Furthermore, all patients were normal responders and of normal BMI, possibly limiting the overall generalizability of the study. Finally, as with any retrospective study, prospective data are required to validate the role of E2 in predicting LBW. Our results emphasize the importance of minimizing the supraphysiologic elevations of E2 levels during ovarian stimulation in fresh IVF-ET cycles. This, in turn, can optimize the early peri-implantation environment and mitigate adverse perinatal outcomes such as LBW. Dr Paul J. Christos was partially supported by the following grant: Clinical and Translational Science Center at Weill Cornell Medical College (UL1-TR000457-06). N/A.

Hyperestrogenic milieu during fresh in vitro fertilization cycles and low birth weight: does a supraphysiologic threshold exist?

Recent studies have suggested a detrimental effect of the hyperestrogenic milieu during ovarian stimulation on perinatal outcomes. To this effect, we investigate the existence of a supraphysiologic estradiol (E2) threshold for the pathogenesis of adverse perinatal outcomes. Retrospective cohort study. All patients <40 years undergoing fresh IVF-embryo transfer (ET) at our center between 2004 and 2013 resulting in live singleton births were included. Patients with vanishing twins or multiple gestations were excluded. Demographics and ovarian stimulation parameters of the study cohort were recorded. Perinatal outcomes analyzed included LBW (<2500 grams), very LBW (<1500 grams), early PTB (<34 weeks), and late PTB (>34 to <37 weeks). LBW was further classified as term LBW or term very LBW. Rates of the aforementioned perinatal outcomes were plotted against peak E2 levels, in increments of 500 pg/mL (<500 to >4000 pg/mL). Odds ratios (OR) for perinatal outcomes at various peak E2 levels were calculated by using the median E2 level of study cohort as the referent group. A receiving-operator-characteristic (ROC) curve was constructed to identify a E2 threshold, with a corresponding area-under-the-curve (AUC) calculation. A total of 4071 patients with live singleton births were included. The median age, peak E2 level and birth weight for the study cohort was 36 (33-39) years, 1554 (1112.7-2179) pg/mL, and 3289 (2920-3628) grams, respectively. The overall rate of LBW was 209/4071 (5.14%) and PTB was 378/4071 (9.29%). Although there was no difference in the odds of PTB across all E2 quartiles, the odds of LBW were higher in the top E2 quartile compared to the median E2, suggesting an E2-dependent effect. Upon analyzing the LBW group as term LBW or term very LBW, the odds of term LBW with E2 levels >2500 pg/mL were 6.11-7.89 times higher compared to the median E2. In contrast, the odds of term very LBW remained unchanged across all E2 quartiles. The ROC curve indicated an E2 level of 2900 pg/mL as the threshold beyond which statistically significant odds of term LBW was observed (AUC=0.83). Using term LBW as a surrogate, our results suggest that an E2 level >2900 pg/mL may serve as a supraphysiologic threshold for adverse perinatal outcomes in fresh IVF-ET cycles. These results emphasize the importance of utilizing conservative step-down stimulation protocols and careful monitoring of serum E2 to minimize the supraphysiologic elevations of E2 levels in fresh IVF-ET cycles, and thereby circumvent adverse perinatal outcomes.Tabled 1Odds of Term LBW According to Various E2 Cut-offsComparisonOdds Ratio (95% CI)PE2 1501-2000 vs. E2 1554 pg/mL1.74 (0.24-2.8)0.58E2 2001-2500 vs. E2 1554 pg/mL3.37 (0.55-4.8)0.17E2 2501-3000 vs. E2 1554 pg/mL6.11 (1.8-7.33)0.02E2 3001-3500 vs. E2 1554 pg/mL7.35 (1.33-9.42)0.001E2 3501-4000 vs. E2 1554 pg/mL7.28 (1.32-9.03)<0.001E2>4000 vs. E2 1554 pg/mL7.89 (1.44-9.43)<0.001 Open table in a new tab

Vanishing Twin Syndrome is Associated With Adverse Perinatal Outcomes in Fresh In Vitro Fertilization Cycles [23G

INTRODUCTION: To investigate whether the presence of a vanishing sac (VS) is associated with adverse perinatal outcomes in women undergoing fresh in vitro fertilization (IVF)—embryo transfer (ET) cycles. METHODS: Retrospective cohort study of women with live singleton births with and without a VS after fresh IVF-ET between January 2004 and June 2013. Baseline demographics and ovarian stimulation response between the two groups were compared. Additional characteristics compared included incidence of preterm birth (PTB), birth weight, low birth weight (LBW), very low birth weight (VLBW), and term LBW. Odds ratios (OR) with 95% confidence intervals (CI) were calculated and adjusted with multivariate logistic regression analysis when indicated. RESULTS: 4049 patients with live singleton births met inclusion criteria—853 and 3196 with and without a VS, respectively. There was no difference in the baseline demographics or ovarian stimulation response between the groups. The VS group had a lower overall birth weight compared to the group without a VS (3279.5±369.9 grams vs 3368.6±567.5 grams; P<.01). The findings of a VS was also associated with an increased odds of overall LBW (OR 1.75, 95% CI 1.36–2.25; P<.01) and an increased odds of term LBW (OR 3.44, 95% CI 2.14–5.53; P<.01). VS was not associated with a higher incidence of PTB or overall VLBW. CONCLUSION: Our findings suggest that a VS is associated with lower overall birth weight and higher odds of overall LBW and term LBW in live singleton births after fresh IVF-ET cycles.

Perinatal Outcomes of Singletons Following In Vitro Fertilization in Women With Polycystic Ovarian Syndrome [22G

INTRODUCTION: To investigate whether the diagnosis of polycystic ovarian syndrome (PCOS) is independently associated with adverse perinatal outcomes in live singletons born to women undergoing fresh in vitro fertilization (IVF)—embryo transfer (ET) cycles. METHODS: Retrospective cohort study of women with PCOS undergoing fresh IVF-ET cycles between January 2004 and June 2013 resulting in a live singleton birth. Women with PCOS were compared to age-matched controls undergoing IVF for male factor infertility. The incidence of term birth, preterm birth (PTB), low birth weight (LBW), term LBW and very low birth weight (VLBW) between the two groups were compared. Odds ratios (OR) with 95% confidence intervals (CI) were calculated and adjusted with multivariate logistic regression analysis. RESULTS: One thousand five patients met inclusion criteria: 164 (PCOS) and 841 (control). There was no difference in baseline demographics or IVF characteristics of the groups. Singletons in the PCOS group had a lower birth weight compared to controls (3,103.1±576.9 grams vs 3,258.4±554.3 grams; P<.01). PCOS was also associated with increased odds of term LBW singletons compared to controls (OR=2.53; 95% CI=1.17–5.50; P=.04). The increased odds remained unchanged when adjusting for total stimulation days, total gonadotropins administered, and number of oocytes retrieved. There was no difference in the incidence of term birth, PTB, or overall VLBW between the two groups. CONCLUSION: PCOS is associated with lower birth weights and higher odds of term LBW singletons in women undergoing IVF-ET cycles. Prospective studies are needed to confirm these findings, especially at the utero-placental unit.

Pretreatment of normal responders in fresh in vitro fertilization cycles: A comparison of transdermal estradiol and oral contraceptive pills.

ObjectiveThe aim of this study was to investigate the impact of pretreatment with transdermal estradiol (E2) compared to oral contraceptive pills (OCPs) on controlled ovarian stimulation (COS) response in normal responders undergoing fresh in vitro fertilization (IVF)-embryo transfer (ET) cycles.MethodsA retrospective cohort study was performed of normal responders undergoing fresh IVF-ET cycles who received pretreatment with transdermal E2 versus OCPs prior to fresh IVF-ET. The total days of ovarian stimulation, total dosage of gonadotropins, total number of oocytes, and mature oocytes retrieved were noted. Pregnancy outcomes after ET were also recorded.ResultsA total of 2,092 patients met the inclusion criteria: 1,057 and 1,035 patients in the transdermal E2 and OCP groups, respectively. Patients in the OCP group had a longer duration of COS (10.7±1.63 days, p<0.01) than the E2 group (9.92±1.94 days). Patients in the OCP group also required higher cumulative doses of gonadotropins (2,657.3±1,187.9 IU) than those in the E2 group (2,550.1±1,270.2 IU, p=0.002). No statistically significant differences were found in the total and mature oocytes retrieved or in the rates of biochemical pregnancy, clinical pregnancy, spontaneous miscarriage, and live birth between the groups.ConclusionOur findings suggest that compared to OCPs, pretreatment with transdermal E2 is associated with a shorter duration of ovarian stimulation and lower gonadotropin utilization, without compromising the oocyte yield or pregnancy outcomes in normal-responder patients undergoing fresh IVF.

Prognostic value of growth of 4-cell embryos on the day of transfer in fresh IVF-ET cycles.

To investigate the prognostic value of growth of 4-cell embryos on the day of transfer in determining clinical pregnancy and live birth rates after fresh in vitro fertilization (IVF)-embryo transfer (ET) cycles. Retrospective cohort study of all patients between January 2008 and January 2013 initiating fresh IVF-ET cycles resulting in embryos that were not more than 4 cells 72 h after oocyte retrieval in the morning of their transfer. Patients were stratified into 2 groups based on whether embryos did or did not grow more than the 4-cell stage on the afternoon of ET. The odds of clinical pregnancy and live birth were considered as primary outcomes. Student's t-tests and Chi-square (χ2) tests were used as indicated, with logistic regression controlling for maternal age and number of embryos transferred. Three hundred forty three patients were identified for inclusion: 165 and 178 patients had 4-cell embryos with and without growth on the afternoon of ET, respectively. The demographic and baseline IVF cycle characteristics of the study cohort were comparable. Patients with embryo growth had higher clinical pregnancy (13.9 % vs. 4.49 %) and live birth (10.9 % vs. 3.37 %) rates compared to patients without embryo growth. This represented an overall increased odds of clinical pregnancy [Odds ratio (OR) = 3.44; 95 % Confidence Intervals (CI) 1.49-7.93; P = 0.004)] and live birth (OR = 3.51; 95 % CI 1.36-9.07; P = 0.01). The increased odds remained unchanged after adjusting for maternal age and number of embryos transferred. Transfer of 4-cell embryos 3 days after oocyte retrieval can result in clinical pregnancies and live births, albeit at a low rate. Growth of an embryo more than the 4-cell stage on the afternoon of ET may serve as a positive prognostic factor for IVF-ET cycle outcome.

Impact of elevated peak serum estradiol levels during controlled ovarian hyperstimulation on the birth weight of term singletons from fresh IVF-ET cycles.

To investigate the impact of elevated serum estradiol (E2) levels on the day of hCG trigger on the birth weight of term singletons after fresh In Vitro Fertilization (IVF)-Embryo Transfer (ET) cycles. Retrospective cohort study of all patients initiating fresh IVF-ET cycles resulting in live births between January 2004 and February 2013. The incidence of low birthweight (LBW) term singletons in patients with E2 levels on day of hCG trigger above or below the 95 % cutoff for E2 values in our clinic (3,069.2 pg/mL) was estimated. Multiple gestations and vanishing twin pregnancies were excluded. Two thousand nine hundred thirty-nine singleton live births were identified for inclusion. One hundred forty seven (5 %) and 2792 (95 %) live singleton births occurred in patients with peak E2 levels above and below 3,069.2 pg/mL, respectively. The overall incidence of term LBW was 5.4 % in the >3,069.2 pg/mL group compared to 2.4 % in the ≤3,069.2 pg/mL group (P = .038). An E2 level >3,069.2 pg/mL on the day of hCG administration was associated with increased odds of LBW term singletons (OR = 2.29; 95 % CI = 1.03-5.11). The increased odds remained unchanged when adjusting for maternal age (aOR = 2.29; 95 % CI = 1.02-5.14; P = .037), gestational age at delivery (aOR = 2.04; 95 % CI = 1.22-3.98; P = .025), and day 3 versus blastocyst transfer (aOR = 2.5; 95 % CI = 1.11-5.64; P = .023). Peak E2 level >3,069.2 pg/mL is associated with increased odds of LBW term singletons after fresh IVF-ET cycles. Conservative stimulation protocols aiming not to exceed an E2 level of 3,000 pg/mL may be advantageous for placentation and fetal growth if a fresh transfer is planned.

Comparison of the effect of different media on the clinical outcomes of the density-gradient centrifugation/swim-up and swim-up methods.

ObjectiveSperm must be properly prepared in in vitro fertilization (IVF)-embryo transfer (ET) programs in order to control the fertilization rate and ensure that embryos are of high quality and have appropriate developmental abilities. The objective of this study was to determine the most optimal sperm preparation method for IVF.MethodsPatients less than 40 years of age who participated in a fresh IVF-ET cycle from November 2012 to March 2013 were included in this study. Poor responders with less than three mature oocytes were excluded. Ham's F-10 medium or sperm-washing medium (SWM) was used in combination with the density-gradient centrifugation/swim-up (DGC-SUP) or SUP methods for sperm preparation. A total of 429 fresh IVF-ET cycles were grouped according to the media and methods used for sperm preparation and retrospectively analyzed (DGC-SUP/Ham's F-10, n=82; DGC-SUP/SWM, n=43; SUP/Ham's F-10, n=181; SUP/SWM, n=123).ResultsThere were no significant differences among these four groups with respect to the mean age of the female partners, duration of infertility, number of previous IVF cycles, and retrieved oocytes. We determined that both the DGC-SUP and SUP methods for sperm preparation from whole semen, using either Ham's F-10 or SWM media, result in comparable clinical outcomes, including fertilization and pregnancy rates.ConclusionWe suggest that both media and both methods for sperm preparation can be used for selecting high-quality sperm for assistive reproductive technology programs.

Premature formation of nucleolar channel systems indicates advanced endometrial maturation following controlled ovarian hyperstimulation

To evaluate the temporal appearance of nucleolar channel systems (NCSs) in the human secretory endometrium in natural cycles (Nat) and following ovarian hyperstimulation with (OH+S) and without (OH) vaginal progesterone (P4) (Endometrin; Ferring Pharmaceuticals). Is there a shift in NCS formation following controlled ovarian hyperstimulation (COH)? Prospective two-cohort study. Consecutive endometrial biopsies were obtained from healthy, oocyte donors on cycle days (CD) 16, 20 and 26 (cohort I, n=7), or CDs 14, 22 and 24 (cohort II, n=8) following random assignment to a Nat, OH or OH+S group, with at least one ‘wash-out’ cycle between groups. NCS prevalence in the nuclei of endometrial epithelial cells (EECs) was quantified (#NCSs/#EECs x 100, %) using indirect immunofluorescence with an antibody directed against certain nuclear pore complex proteins, that are major constituents of NCSs. Estradiol and P4 levels were measured on the day of each biopsy. Nat group exhibited peak NCS prevalence on CD20 (53%; interquartile range [IQR] 28.5-55.8), rapid decline on CD22, 24 and 26, and no NCSs on CD14 and 16. In contrast, after OH and OH+S, NCS prevalence was high already on CD16 (40.4%; IQR 22.6-53.4 and 35.6%; IQR 26.4-44.5, respectively; p=0.001, Mann-Whitney). No other significant differences were noted between the groups on any of the other five cycle days (p>0.1). In these healthy oocyte donors, NCS prevalence occurs when expected in the mid-luteal phase of natural cycles. In contrast, premature appearance of NCSs and hence maturation of the endometrium is observed following COH. This is the first study of this kind that is based on consecutive endometrial biopsies within the same cycle and that reports all-or-none data. Our observation of advanced endometrial maturation following COH may contribute to the reduced implantation success rates in fresh vs. frozen IVF-ET cycles.

Comparison of the clinical outcomes of day 4 and 5 embryo transfer cycles

ObjectiveThe majority of embryo transfers (ETs) to date have been performed on day 3 to reduce the potential risk of developmental arrest of in vitro cultured embryos before ET. Development of sequential media has significantly improved culture conditions and allowed blastocyst transfer on day 5. While day 5 ET provides higher clinical pregnancy outcomes with reduced risks of multiple pregnancies, it still has potential risks of developmental arrest of IVF embryos. The aim of this study was to evaluate the clinical outcomes of day 4 ETs and compare the efficacy of day 4 ET with day 5 ET.MethodsFrom 2006 to 2009, a total of 747 fresh IVF-ET cycles were retrospectively analyzed (day 4, n=440 or and day 5, n=307). The cycles with any genetic factors were excluded. The rates of matured oocytes, fertilization, good embryos, and clinical pregnancy of the two groups were compared. The chi-square test and t-test were used for statistical analysis.ResultsThere were no significant differences between the two groups with respect to the mean age of the females and rates of matured oocytes. The pregnancy outcomes of day 4 ET (40.7%) were similar to those of day 5 ET (44.6%). The implantation rate of day 5 ET (24.2%) was significantly higher than that of day 4 ET (18.4%) (p=0.003).ConclusionDay 4 ET can be chosen to avoid ET cancellation in day 5 ET resulting from suboptimal circumstances in the IVF laboratory, but the decremented quality of embryos for transfer and the decreased pregnancy rate must be taken into consideration.

Study on the incidence and influences on ectopic pregnancy from embryo transfer of fresh cycles and frozen-thawed cycles

To investigate ectopic pregnancy from embryo transfer (ET)of in-vitro fertilization (IVF) cycle and intracytoplasmic sperm injection (ICSI) cycle and frozen-thawed (FET) cycle. From Jan.2005 to Dec. 2010, a total of 9037 IVF-ET or ICSI-ET cycles and 4034 FET cycles were performed in our reproductive medicine center, Affiliated First Hospital of Zhengzhou University. The incidence of ectopic pregnancy rate was studied in fresh cycles IVF-ET (5998) and ICSI-ET (3039) cycles, and natural FET (2198) and hormone replacement (E-P) FET (1836) cycles. Of 4034 FET cycles, 1090 clinical pregnancies and 26 ectopic pregnancies were observed, the incidence of ectopic pregnancy was 2.38% (26/1090). Of 9037 fresh cycles, 3602 cycles were clinical pregnancy, and 133 cycles were ectopic pregnancy, and the incidence of ectopic pregnancy was 3.69% (133/3602). The ectopic pregnancy rate in FET cycles was lower than in fresh cycles significantly (P < 0.05). Of 3039 fresh ICSI-ET cycles, the incidence of ectopic pregnancy was 2.62% (34/1298) in 1298 clinical pregnancies. Of 5998 IVF-ET cycles, 2304 clinical pregnancies were observed, the incidence of ectopic pregnancy was 4.30% (99/2304). Ectopic pregnancy rate in the fresh ICSI-ET cycles was lower than that of IVF-ET group significantly (P < 0.01). The ectopic pregnancy rate in the natural FET cycles was 1.46% (8/547), which was significantly lower than 3.31% (18/543) in E-P group (P < 0.05). The incidence of ectopic pregnancy of FET cycles was significantly lower than that of fresh embryo transfer cycles. The application of exogenous sex hormones in assisted reproductive cycles might increase occurrence of ectopic pregnancy.