Time to pregnancy in young women with high response to controlled ovarian stimulation undergoing fresh transfer vs. a freeze-all strategy after in vitro fertilization treatment-a nationwide register-based cohort study.

A total of 56,614 patients were included in the analysis. Figure 1 presents the flow of the study sample. In total, 35,058 women (mean [SD] age was 31 [3.28] and mean [SD] BMI was 26.4 [6.23]) underwent fresh ETs, and 21,556 women (mean [SD] age was 31 [3.32] and mean [SD] BMI was 26.3 [6.19]) used a freeze-all strategy. Table 1 summarizes key demographic, clinical, and treatment cycle characteristics. There was no clinically significant difference in age or BMI between the two cohorts. Women who underwent a fresh ET were less likely to have anovulation (28.1% vs. 39.7%), higher total follicle-stimulating hormone dose (mean, 2,491 vs. 2,421), more likely to have an agonist treatment protocol (23.6% vs. 12.5%) and had a lower number of oocytes retrieved (mean, 21.4 vs. 25.6). Intracytoplasmic sperm injection was the most common insemination method for both fresh ETs and freeze-all strategy cycles. Figure 1 Participant selection diagram. IVF = in vitro fertilization; ZIFT = zygote intrafallopian transfer. Table 1 Baseline demographic and treatment characteristics of the study population. Characteristics Initial fresh embryo transfer (n = 35,058) Freeze-all strategy (n = 21,556) P Age (y ± SD) 31 ± 3.28 31 ± 3.32 <.001 BMI (kg/m 2 ) 26.40 ± 6.23 26.30 ± 6.19 .089 Infertility diagnosis a  Male factor (n/%) 13,904 (39.7) 8,557 (39.7) .938  Endometriosis (n/%) 2,963 (8.5) 1,734 (8.0) .091  Anovulation (n/%) 9,852 (28.1) 8,561 (39.7) <.001  Tubal factor (n/%) 5,581 (15.9) 3,463 (16.1) .654  Uterine factor (n/%) 1,210 (3.5) 1,130 (5.2) <.001  RPL (n/%) 377 (1.1) 287 (1.3) .007  DOR/AMA (n/%) 1,257 (3.6) 663 (3.1) .001  Unexplained (n/%) 7,085 (20.2) 3,292 (15.3) <.001 AMH (ng/ml ± SD) 4.17 ± 2.20 4.78 ± 2.27 <.001 Protocol type  Antagonist (n/%) 26,161 (74.6) 18,655 (86.5) <.001  Agonist (n/%) 8,257 (23.6) 2,697 (12.5)  Agonist flare (n/%) 640 (1.8) 204 (0.9) Total FSH dose (IU ± SD) 2,491 ± 1,125 2,421 ± 1,137 <.001 Days of stimulation (d ± SD) 11.5 ± 1.56 11.7 ± 1.65 <.001 Type of trigger injection used for final oocyte maturation  hCG (n/%) 8,757 (25.0) 4,519 (21.0) <.001  GnRH-a (n/%) 1,956 (5.6) 5,432 (25.2)  hCG and GnRH-a (n/%) 2,556 (7.3) 2,675 (12.4)  Unknown trigger 21,789 (62.2) 8,930 (41.4) Insemination type  Standard (n/%) 8,939 (25.5) 4,275 (19.8) <.001  ICSI (n/%) 23,511 (67.1) 15,760 (73.1)  Mixed (n/%) 2,608 (7.4) 1,521 (7.1) Oocytes retrieved 21.4 ± 6.36 25.6 ± 9.35 <.001 Total 2PN 12.9 ± 18.74 15.6 ± 6.86 <.001 2PN/oocytes (%) 61.16 ± 114.21 61.40 ± 17.13 0.757 Total embryos 6.15 ± 3.65 8.16 ± 4.86 <.001 Embryos/2PN (% ± SD) 48.9 ± 24.88 53.1 ± 24.55 <.001 Transfer order  SET (n/%) 1,441 (4.1) 622 (3.1) <.001  eSET (n/%) 19,962 (59.9) 14,147 (65.6)  DET (n/%) 13,496 (38.5) 6,711 (31.1)  MET (n/%) 159 (0.5) 36 (0.2) Total transfer cycles included in dataset 1.47 ± 0.77 1.45 ± 0.76 <.001 Mean interval between transfers b 130 ± 139 125 ± 125 .013 Note: Less than 5% of data missing unless otherwise noted: 48% of the sample missing data on AMH. 13% of the sample had missing data on BMI. AMA = advanced maternal age; AMH = anti-mullerian hormone; BMI = body mass index; DET = double embryo transfer; DOR = diminished ovarian reserve; eSET = elective single embryo transfer; FSH = follicle-stimulating hormone; GnRH-a = gonadotropic releasing hormone agonist, hCG = human chorionic gonadotropin; ICSI = intracytoplasmic sperm injection; MET = multiple embryo transfer; RPL = recurrent pregnancy loss; SET = single embryo transfer; 2PN = 2 pronuclei. a Diagnoses are not exclusive. Patients may have had multiple diagnoses; the total across diagnoses may be >100%. b Mean interval between transfers is only presented for patients who had multiple embryo transfers included in the final dataset and were not missing data for any intervals between transfers. Mean for each patient calculated and aggregate means presented. n for fresh = 12,051, n for frozen = 6,968. The unit for interval is days. Participant selection diagram. IVF = in vitro fertilization; ZIFT = zygote intrafallopian transfer. Baseline demographic and treatment characteristics of the study population. Note: Less than 5% of data missing unless otherwise noted: 48% of the sample missing data on AMH. 13% of the sample had missing data on BMI. AMA = advanced maternal age; AMH = anti-mullerian hormone; BMI = body mass index; DET = double embryo transfer; DOR = diminished ovarian reserve; eSET = elective single embryo transfer; FSH = follicle-stimulating hormone; GnRH-a = gonadotropic releasing hormone agonist, hCG = human chorionic gonadotropin; ICSI = intracytoplasmic sperm injection; MET = multiple embryo transfer; RPL = recurrent pregnancy loss; SET = single embryo transfer; 2PN = 2 pronuclei. Diagnoses are not exclusive. Patients may have had multiple diagnoses; the total across diagnoses may be >100%. Mean interval between transfers is only presented for patients who had multiple embryo transfers included in the final dataset and were not missing data for any intervals between transfers. Mean for each patient calculated and aggregate means presented. n for fresh = 12,051, n for frozen = 6,968. The unit for interval is days. Table 2 presents adjusted estimates of each outcome based on the initial transfer strategy. The time to pregnancy mean (SD) in 35,058 women who had a fresh ET was 12.6 (20.6) and 20.8 (21.9) weeks in 21,556 women who used a freeze-all strategy. After adjusting for multiple treatment variables there was a statistically significant shorter time to pregnancy in those who had an initial fresh ET than those who used a freeze-all strategy (adjusted HR, 1.66 [95% confidence interval {CI}, 1.62–1.69], adjusted mean difference, −8.1 [95% CI, −8.64 to −7.55]). Table 2 Treatment outcomes after initial fresh embryo transfer and frozen embryo transfer in women ≤37 years. Outcomes Fresh embryo initial transfer (n = 35,058) Freeze-all (n = 21,556) Hazards ratio (95% CI) Adjusted mean difference (95% CI) Primary outcome  Time to pregnancy in wk, mean (SD) 12.6 ± 20.6 20.8 ± 21.9 1.66 (1.62–1.69) −8.10 (−8.64 to −7.55) Secondary outcomes No./total (%) Adjusted relative risk (95% CI) Adjusted absolute risk difference (95% CI)  Live birth 17,930 (51.1) 12,067 (56.0) 0.91 (0.89–0.92) −6 (−9 to −2)  Clinical pregnancy 20,697 (59.0) 14,271 (66.2) 0.88 (0.87–0.90) −8 (−11 to −5)  Miscarriage 2,531 (12.2) 2,051 (14.4) 0.84 (0.79–0.89) −2 (−5 to 0)  Ectopic 342 (1.0) 96 (0.4) 2.44 (1.89–3.15) 1 (0–1)  OHSS 332 (0.9) 1,022 (4.7) 0.16 (0.14–0.18) −6 (−7 to −5)  Singleton birth weight (g) 3,220 ± 647 3,318 ± 636 0.34 (0.28–0.41) −69 (−120 to −17)  Cumulative live birth 25,752 (73.5) 16,625 (77.1) 0.95 (0.94–0.96) −4 (−6 to −2)  Cumulative miscarriage 3,841 (11.0) 2,739 (12.7) 0.91 (0.86–0.96) −2 (−3 to 0)  Preterm birth 2,746 (18.9) 1,913 (18.7) 1.00 (0.95–1.05) 0 (−4 to 4)  Early preterm birth 354 (2.4) 285 (2.8) 0.83 (0.72–0.97) 1 (−2 to 1) Note: Less than 5% of data missing unless otherwise noted. 18% of the sample with live birth missing gestational age at delivery. Hazard ratio adjusted for age, BMI, protocol type, insemination method, and days of ovarian stimulation. Relative risks for initial cycle outcomes adjusted for age, BMI, protocol type, insemination method, days of ovarian stimulation, number of embryos transferred in initial transfer cycle, and reporting year of retrieval cycle. Rate ratio for singleton birth weight adjusted for age, BMI, protocol type, insemination method, days of ovarian stimulation, and reporting year of retrieval cycle. Ratio for birth weight presented for every 100 grams. Relative risks for cumulative cycle outcomes adjusted for age, BMI, protocol type, insemination method, days of ovarian stimulation, and reporting year of retrieval cycle. BMI = body mass index; CI = confidence interval; OHSS = ovarian hyperstimulation syndrome. Treatment outcomes after initial fresh embryo transfer and frozen embryo transfer in women ≤37 years. Note: Less than 5% of data missing unless otherwise noted. 18% of the sample with live birth missing gestational age at delivery. Hazard ratio adjusted for age, BMI, protocol type, insemination method, and days of ovarian stimulation. Relative risks for initial cycle outcomes adjusted for age, BMI, protocol type, insemination method, days of ovarian stimulation, number of embryos transferred in initial transfer cycle, and reporting year of retrieval cycle. Rate ratio for singleton birth weight adjusted for age, BMI, protocol type, insemination method, days of ovarian stimulation, and reporting year of retrieval cycle. Ratio for birth weight presented for every 100 grams. Relative risks for cumulative cycle outcomes adjusted for age, BMI, protocol type, insemination method, days of ovarian stimulation, and reporting year of retrieval cycle. BMI = body mass index; CI = confidence interval; OHSS = ovarian hyperstimulation syndrome. The LBR in the initial transfer was significantly lower in a fresh ET, 51.1%, compared with 56% in the freeze-all group (adjusted OR, 0.8 [95% CI, 0.77–0.83]; adjusted risk difference, −6% [95% CI, −9 to −2)]. The CPR was significantly lower in a fresh ET, 59%, compared with 66.2% in the freeze-all group (adjusted OR, 0.71 [95% CI, 0.68–0.74]; adjusted risk difference, −8% [95% CI, −11 to −5]). The rates of miscarriage were significantly lower after a fresh ET, 12.2%, compared with 14.4% in the freeze-all group (adjusted OR, 0.82 [95% CI, 0.77–0.88]; adjusted risk difference, −2% [95% CI, −5 to 0]). The rate of ectopic pregnancy was significantly higher in a fresh ET, 1%, compared with 0.4% in the freeze-all group (adjusted OR, 2.46 [95% CI, 1.91–3.18]; adjusted risk difference, 1% [95% CI, 0–1]). The CLB rate was significantly lower for patients who had a fresh ET, 73.5%, compared with 77.1% in the freeze-all group (adjusted OR, 0.8 [95% CI, 0.77 – 0.84]; adjusted risk difference, −4 [95% CI, −6 to −2]). The preterm birth rate was 18.9% in the fresh ET group compared with 18.7% in the freeze-all group (adjusted OR, 1.02 [95% CI, 0.95–1.1]; adjusted risk difference, 0% [95% CI, −4 to 4]). The rate of early preterm birth was 2.4% in a fresh ET compared with 2.8% in the freeze-all group (adjusted OR, 0.85 [95% CI, 0.71–1.01]; adjusted risk difference, 1% [95% CI, −2 to 1]). The cumulative miscarriage rate was significantly lower in a fresh ET, 11%, compared with 12.7% in the freeze-all group (adjusted OR, 0.84 [95% CI, 0.79–0.89]; adjusted risk difference, −2% [95% CI, −3 to 0]). The mean birth weight was 3,220 gm in singleton live birth from a fresh ET and 3,318 gm in singleton live birth from a FET, adjusted mean difference (g), 69 (95% CI, −120 to −17). The rates of moderate or severe OHSS in women who had a fresh ET was 0.9% compared with 4.75% in those who used a freeze-all strategy (adjusted OR, 0.15 [95% CI, 0.13–0.17]; adjusted risk difference, −6% [95% CI, −7 to −5]). Subgroup analysis of pregnancy, obstetric, and neonatal outcomes with a fresh transfer or freeze-all strategy in six cohorts based on the number of oocytes retrieved: 15–19 (cohort A), 20–24 (cohort B), 25–29 (cohort C), 30–34 (cohort D), 35–39 (cohort E), and ≥40 (cohort F), is displayed in Supplemental Table 1 (available online). In the adjusted subgroup analysis, women who underwent a fresh ET had a statistically significant reduction in time to pregnancy compared with those who had a freeze-all strategy; however, the trend in mean difference (in weeks) for time to pregnancy gradually reduced with an increase in the number of oocytes retrieved. For example, the mean difference in weeks (95% CI) between initial fresh ET and a freeze-all strategy in cohort A was 9.1 (7.3 to 10.8), vs. a difference of 6.3 (−4.7 to 17.5) in cohort F. Similarly, there were statistically significant reductions in LBR and CPR after the initial transfer compared with the freeze-all strategy; the associations of which showed a trend of steady decline with increasing number of oocytes. The adjusted RR, 95% CI for LBR between groups in cohort A was 0.94 (0.92–0.97) and cohort F was 0.79 (0.72–0.87). The adjusted RR, 95% CI for CPR between groups in cohort A was 0.91 (0.89–0.94) and cohort F was 0.80 (0.74–0.87). The data for the subgroup who used hCG or GnRH agonist with hCG as the trigger for final oocyte maturation is presented in Supplemental Table 2 . In women who exclusively had hCG or GnRH agonist with hCG, there was a statistically significant shorter time to pregnancy in those who had an initial fresh ET than those who used a freeze-all strategy (adjusted HR, 1.76 [95% CI, 1.71–1.82], adjusted mean difference, −7.62 [95% CI, −8.02 to −7.22]). The statistically significant trend for LBR, clinical pregnancy, miscarriages, OHSS and the CLB rates followed the same pattern as in the primary analysis. Figure 2 A shows the incidence of pregnancy between a fresh ET and a freeze-all strategy in the whole cohort, and Figure 2 B shows the incidence of pregnancy between a fresh ET and a freeze-all strategy based on the number of oocytes retrieved (cohort A to cohort F). Figure 2 Hazard function for cumulative live birth between fresh and frozen embryo transfers. ( A ) Hazard function for cumulative live birth between fresh and frozen embryo transfers in the full sample. ( B ) Hazard function for cumulative live birth subgroup analysis by number of oocytes retrieved. Hazard function for cumulative live birth between fresh and frozen embryo transfers. ( A ) Hazard function for cumulative live birth between fresh and frozen embryo transfers in the full sample. ( B ) Hazard function for cumulative live birth subgroup analysis by number of oocytes retrieved.

This was a retrospective analysis of patients at or below 37 years of age with 15 or more oocytes retrieved during their first autologous IVF retrieval cycle between January 2014 and December 2019. The data used for this study were obtained from the Society for Assisted Reproductive Technology Clinical Outcomes Reporting System (SARTCORS). Approval was granted by the University of Iowa institutional review board. Data were collected through voluntary submission, verified by Society for Assisted Reproductive Technology (SART), and reported to the Centers for Disease Control and Prevention in compliance with the Fertility Clinic Success Rate and Certification Act of 1992 (Public Law 102-493). Society for Assisted Reproductive Technology maintains HIPAA-compliant business associate agreements with reporting clinics. In 2004, after a contract change with the Centers for Disease Control and Prevention, SART gained access to the SARTCORS data system to conduct research. Over 90% of all assisted reproduction technology cycles in the United States are performed at SART-member clinics. Society for Assisted Reproductive Technology annually selects up to 10 clinics, approximately 2.5% of SART clinics, for an on-site validation visit utilizing metrics and a blinded selection process to identify outlier clinics. Medical records are reviewed during the validation visit to verify the designation, outcome, and reporting of cycles. Clinics with significant systematic reporting errors undergo data correction. Six primary metrics and 26 secondary metrics are used for clinic selection. The metrics include low prospective reporting for both egg retrieval cycles and total cycles, high LBRs in the various age groups, low cancellation rate, high percentage of total fertility preservation cycles, high percentage of embryo banking and oocyte banking cycles, high percentage of fertility preservation cycles where oocytes were thawed or embryos were transferred within a year, high percentage of deleted cycles, high percentage of cycles converted from intrauterine insemination, and low percentage of cycles in which no embryos were suitable for transfer with and without preimplantation genetic testing (PGT). Society for Assisted Reproductive Technology does not validate the accuracy of data entry fields such as gonadotropin dosage, number of oocytes retrieved, number of fertilized oocytes, number of embryos cryopreserved, PGT results, or demographic fields such as age and diagnosis (Preliminary National Summary Report for 2020. Accessed February 10, 2024). Patients ≤37 years old with ≥15 oocytes retrieved during their initial autologous IVF retrieval cycle from January 2014 to December 2019 who underwent blastocyst ET were analyzed. We excluded patients using donor or frozen gametes, gestational carriers, or PGT. Given the importance of protocol on OHSS and risk and transfer outcomes ( 10 , 11 , 12 , 13 , 14 , 15 ), patients missing protocol type for their stimulation cycle were excluded. Patients who did not use a trigger or who used a trigger other than human chorionic gonadotropin (hCG), gonadotropin-releasing hormone (GnRH) agonist, or a dual trigger with hCG and GnRH agonist were excluded. We linked subsequent FETs through December 2019 that used embryos from the initial stimulation cycle to determine cumulative outcomes, such as time to pregnancy, LBR, and miscarriage per retrieval cycle. Transfer cycles in which blastocysts from the initial stimulation cycle were mixed with embryos from a subsequent stimulation cycle were excluded, as were transfer cycles which did not exclusively transfer blastocyst-stage embryos. Patients who did not have a linked subsequent ET were excluded. Patients in the fresh group underwent their initial ET during their fresh cycle, whereas patients in the freeze-all group underwent their initial ET with frozen embryo(s) in a subsequent FET cycle. Patient demographics extracted for both cohorts included age, body mass index (BMI), infertility diagnosis at initial cycle, and anti-mullerian hormone level. Cycle characteristics extracted included stimulation protocol, total follicle-stimulating hormone dose, days of stimulation, and type of trigger, insemination method, number of 2 pronuclei, fertilization rate (defined as the number of 2 pronuclei/number of oocytes retrieved), and number of embryos transferred. Patients were then subdivided into six cohorts based on the number of oocytes retrieved: (cohort A: 15–19, cohort B: 20–24, cohort C: 25–29, cohort D: 30–34, cohort E: 35–39, and cohort F: ≥40). The primary outcome point was time to pregnancy resulting in a live birth. This was defined as the number of weeks between the start of the stimulation cycle and 10 days after transfer of the outcome cycle resulting in live birth (the standard time for pregnancy testing). Secondary outcomes included CPR, miscarriage rate, LBR per ET, rate of OHSS, birth weight among singleton deliveries, and preterm delivery <37 weeks. We performed a sensitivity analysis for women who underwent treatments that exclusively used hCG or dual trigger with hCG and GnRH agonist for final oocyte maturation. Live birth is defined by SART as a birth in which at least one fetus was liveborn. Cumulative live birth (CLB) was defined as up to one live birth resulting from a retrieval cycle and linked transfer cycles. Cycles with live birth were classified as preterm before 32 and 37-weeks’ gestation if gestational age (calculated by adding 14 to the number of days between the pregnancy outcome date and the transfer date) was ≤32 or 37 weeks, respectively. Clinical pregnancy is defined by SART as either having one or more gestational sacs confirmed on ultrasound or documentation of a birth, spontaneous abortion, or therapeutic abortion in the case of missing ultrasound data. Cycles were classified as “miscarriage” if the pregnancy outcome field was “loss/abortion.” Cumulative miscarriage was defined as having at least one miscarriage resulting from a retrieval cycle and linked transfer cycles. Patients with a complication in their retrieval cycle of moderate or severe hyperstimulation, defined as abdominal distension and discomfort; features of grade 1 plus nausea, vomiting, and/or diarrhea; ovaries enlarged 5–12 cm; ultrasonic evidence of ascites and features of moderate hyperstimulation and clinical evidence of ascites and/or hydrothorax or breathing difficulties; change in blood volume, increased blood viscosity due to hemoconcentration, coagulation abnormalities, and diminished renal perfusion and function–hematocrit >50 respectively, were classified as having OHSS. Length of follow-up was defined as the number of weeks between the start of the stimulation cycle and 10 days after transfer of the outcome cycle. Univariate analyses, including χ 2 and t -test, were performed on patient and cycle characteristics. After confirming proportional hazards through graphical review of the logarithm of time plotted against the log cumulative hazard, hazard ratios were calculated using Cox regression to assess the primary outcome of time to pregnancy resulting in live birth. A modified Poisson regression approach was used to estimate adjusted relative risks (RRs) for binomial outcome data, including clinical pregnancy, miscarriage, and live birth. The potential confounders and effect modifiers accounted for as covariates in the regression models included maternal age, maternal BMI, the type of treatment regime used, type of insemination used, days of COS, number of embryos transferred, and the reporting year of retrieval cycle. Regression models for cumulative outcomes included the same covariates, except the number of embryos transferred in the initial transfer cycle, which was not expected to affect outcomes beyond those in the initial cycle. Descriptive statistics included means and SDs and the number and percent of patients for continuous and categorical variables. Subgroup analyses were performed for each of the six cohorts based on the number of oocytes retrieved. Adjusted hazard ratio (HR) and odds ratio (OR) for all the subgroup analyses were calculated using Cox and logistic regression to adjust for the potential confounders and effect modifiers described earlier for initial and cumulative outcomes. Finally, given that GnRH agonist-only trigger is a known risk factor for suboptimal IVF outcomes in fresh cycles, we performed a sensitivity analysis excluding patients with fresh cycles which used a GnRH trigger alone, as well as patients whose stimulation cycle did not specify trigger type. All statistical analyses were 2-sided, with P <.05 considered statistically significant. All statistical analyses were performed using SPSS version 28.

In women under 37 years with ≥15 oocytes retrieved after IVF treatment; a fresh ET was associated with a statistically significant reduction in time to achieve a pregnancy, a difference of 6–8 weeks compared with a freeze-all strategy. The occurrence of OHSS was <2% in women who underwent a fresh ET. Although a fresh ET is safe and effective, the benefit of reduction in time to pregnancy was compromised by a significant decline in LBRs with increasing number of oocytes retrieved.

We report findings from a large US-based cohort study investigating the time to pregnancy in women ≤37 years of age with ≥15 oocytes retrieved after COS undergoing a fresh vs. a freeze-all strategy after IVF treatment. We observed a statistically significant reduction in time to achieve a pregnancy (defined as start of stimulation cycle through ten days after the ET resulting in live birth) between those who had a fresh vs. a freeze-all strategy. A pregnancy was achieved 6–8 weeks sooner in women who underwent a fresh ET compared with those who used a freeze-all strategy. As the field of reproductive medicine shifts toward elective freeze-all cycles, this important finding cannot be understated. During infertility treatment, patient goals and desires must be addressed and play a central role in clinical decision-making. For some, if not all, infertility patients, time to pregnancy is of utmost importance as any delay can be detrimental to the mental health of the patient ( 17 ). The study is noteworthy in the context that, to our knowledge, we have investigated one of the biggest theoretical advantages of fresh ETs— the time to achieve a pregnancy . We performed statistical analysis to adjust for multiple demographic, clinical, and treatment variables in addition to the subgroup analysis based on the increasing number of oocytes retrieved. Furthermore, the use of data from SARTCORS provided increased generalizability, as well as a significant treatment cycle numbers in each of the six cohorts used in the subgroup analysis. Although our study observed a new finding of reduction in time to pregnancy with a fresh ET, the benefit of this difference was compromised by a statistically significant decline in LBRs. The amplitude of difference in the suboptimal secondary outcomes in this study is more pronounced with increasing number of oocytes retrieved. This finding concurs with several previously published studies. Many studies have compared IVF outcomes in women with high response to COS. A large cohort study using SART data in 69,102 patients with a fresh ET and 13,833 with FET concluded that women with ≥15 oocytes benefited from a freeze-all policy. Women who had a FET had a higher CPR (61.5% vs. 57.4%) and LBR (52% vs. 48.9%) ( 18 ). Another matched cohort study using 2,910 treatment cycles concluded that the implantation and ongoing pregnancy rates were statistically significantly higher in the freeze-only transfer cohort than in the matched fresh transfer cohort, 52.0% (95% CI, 49.4–54.6) and for fresh was 45.3% (95% CI, 42.7–47.9), OR 1.31 (95% CI, 1.13–1.51) ( 19 ). Several other studies have explored this idea further, seeking to analyze the success rates of fresh vs. FET cycles in cohorts of patients based on the number of oocytes retrieved per cycle ( 20 ). Further, in a meta-analysis of five randomized controlled trials with 2,728 women, a subgroup analysis of the outcomes based on the number of oocytes retrieved found that the freeze-all strategy appeared beneficial when a high number of oocytes was collected ( 21 ). The earlier studies had the limitation that none of the studies investigated the time to pregnancy, and most of the studies grouped ‘high responders’ into a single category defined as more than 15 oocytes in some studies and more than 25 oocytes per cycle in some other studies. Our study could not distinguish the biological pathways by which women in the fresh ET cohort had adverse reproductive outcomes with the increasing number of oocytes retrieved. However, potential mechanisms include the following considerations. First, an increasing number of oocytes can be a surrogate marker for circulating estradiol levels, and this supraphysiological estradiol level and further sudden decline after the egg retrieval is a risk factor for suboptimal IVF outcomes. Second, high response to COS has been associated with premature elevation of progesterone level affecting the IVF outcomes negatively by decreasing the endometrial receptivity. Third, the exaggerated response to COS could be secondary to polycystic ovarian syndrome, and subsequent suboptimal IVF outcomes can be explained through metabolic dysfunction affecting women with polycystic ovarian syndrome. Fourth, an increasing number of oocytes may be a result of high doses of gonadotrophic injections or longer days of stimulation, both of which are associated with suboptimal reproductive outcomes. Fifth, the higher number of oocytes may result in a high number of immature oocytes, negatively affecting the ooplasmic maturation or poor oolemma maturation, which may lead to embryos with lower implantation potential ( 22 ). Our study also contrasts with several relevant studies. A Cochrane review of four randomized clinical trials with a total sample size of 1,892 women concluded no difference in CLB rate between the freeze-all strategy and a fresh ET strategy (OR 1.09, 95% CI 0.91–1.31) ( 23 ). As one might expect, the study investigators did find a lower rate of OHSS in freeze-all strategy cycles. Interestingly, most patients in the study were “high responders”, with >13 oocytes retrieved during IVF stimulation. Another multicenter randomized trial of 2,157 normo-ovulatory women investigated the outcomes after a fresh ET or embryo cryopreservation followed by FET and concluded no difference between LBRs in fresh ET vs. FET ( 24 ). The LBR between the freeze-all strategy group and the fresh embryo group was 48.7% and 50.2%, respectively (RR, 0.97; 95% CI, 0.89–1.06; P =.50). However, women in this study had an average of 12 oocytes retrieved per cycle and up to two cleavage-stage embryos transferred. It was also interesting to examine the trends in miscarriage after the first ET, the cumulative miscarriage rate and the difference in birthweight in singleton pregnancies between fresh transfer and freeze-all strategies. Both the miscarriage and the cumulative miscarriage rates were higher in women who used a freeze-all strategy. Based on recent evidence, it may be postulated that the observed higher rate of miscarriage could be related to the use of hormone replacement therapy in FETs ( 25 ). Similarly, we also found that the birthweight was higher in singleton infants after freeze-all strategy compared with fresh ET. This finding is also consistent with multiple previous studies ( 26 , 27 , 28 ). In our study, we also found a statistically significant increase in singleton birth weights in all cohorts in our subgroup analysis except cohort E. The finding of lower OHSS rates in this study in the initial fresh ET is an expected finding, given that a freeze-all strategy is an established means to reduce the risk of OHSS. It is also very likely that women exhibiting symptoms of severe OHSS may have been converted to a freeze-all strategy, or those with mild/moderate OHSS symptoms may have been less likely to be reported to SART after fresh ET. The mean interval between transfers for patients who had multiple ETs was 130 days (initial fresh ET strategy) and 125 days (for freeze-all strategy). We could not analyze the reason for this significant delay between transfers. Although there are certainly patient factors which can result in delay between transfers, care providers should improve patient counseling and optimize the logistics of transitioning from a failed transfer to starting the next cycle; especially the time between freeze-all/embryo creation cycle and first ET. This study has several limitations. First, the SARTCORS database includes missing data for select variables; race being one of the most notable. Second, to protect patient confidentiality, clinic-level data were not included in our dataset. It is possible that clinic-level factors may impact protocol selection and outcomes such as LBR. Third, we excluded patients undergoing PGT. However, previous, good-quality studies have proved that PGT-A does not improve clinical outcomes in women under 38 years of age ( 10 , 29 ). Fourth, based on the retrospective nature of the study, we were unable to control for unmeasured confounders that could have affected the treatment outcome, such as serum estradiol and progesterone levels and the mean endometrial thickness. Fifth, the CLB rates are an estimation because not all patients in the study used all the cryopreserved embryos. Sixth, we were unable to distinguish the indications for an FET due to a true clinical indication, for e.g., endometrial polyps or ultrasound evidence of bilateral hydrosalpinx. Seventh, this study only included women ≤37 and those who had ≥15 oocytes. Therefore, the findings are not applicable for women over 37 and those who are considered to have diminished ovarian reserve or those with suboptimal response to COS. For our study, it was essential to analyze treatment cycles which included fresh ETs. However, we acknowledge that the data used in this study was from between 2014 and 2019, and the current trends have changed where most IVF clinics are recommending a freeze-all approach for women with high response to COS.

E.J. has nothing to disclose. K.S. reports consulting fees from Society for Assisted Reproductive Technology for training statistician on database. A.S. reports American Society for Reproductive Medicine Board of Directors. B.V.V. has nothing to disclose. A.E. has nothing to disclose.