Abstract
Purpose
This work aimed to study clinical and neonatal outcomes of embryos derived from frozen compared to fresh donor oocytes in gestational carrier cycles.
Methods
This is a retrospective cohort study using the Society for Assisted Reproductive Technology Clinic Outcome Reporting System database between 2014 and 2015, comprising of 1284 fresh transfer cycles to gestational carrier recipients of embryos resulting from fresh (n = 1119) and vitrified/thawed (n = 165) donor oocytes. Models were adjusted for gestational carrier age, preimplantation genetic testing (PGT-A), number of embryos transferred, multiple gestation, and fetal heart reduction. As our models were part of a larger analysis, intended parent BMI, smoking status, and parity were also adjusted for, but did not influence outcomes in this analysis.
Results
There was no significant difference in probability of live birth rates when comparing embryos derived from fresh and frozen donor oocytes in gestational carrier cycles. There were also no significant differences in biochemical pregnancy losses or clinical miscarriage. There were no significant differences noted in low birthweight or high birthweight infants derived from fresh versus frozen donor oocyte after transfer into a gestational carrier.
Conclusions
The analysis of fresh and frozen donor oocytes in gestational carrier cycles provides the opportunity to assess for a possible effect of vitrification on the oocyte by controlling for differences in the uterine environment. We observed no significant differences in live birth, pregnancy loss, low birthweight or high birthweight infants when comparing fresh and frozen donor oocytes in gestational carrier cycles.
Keywords: Vitrification, Oocyte, Oocyte freezing, Fertility, Gestational carrier, Gestational surrogate
Introduction
In 2019, the Centers for Disease Control and Prevention (CDC) reported that 8.5% of married American women ages 15–49 struggled with infertility, defined as the failure to achieve pregnancy after 12 months of regular unprotected intercourse. Among this age group, 12.2% of women were reported as having ever received infertility services [1]. Treatments for infertility include ovulation induction, intrauterine insemination, and assisted reproductive technology (ART), where ART encompasses interventions involving the manipulation of eggs or embryos including in vitro fertilization (IVF) and oocyte cryopreservation. IVF cycles can be autologous, in which the oocyte is genetically linked to the carrier; utilize a donor oocyte carried by the intended parent; or involve a gestational carrier, an individual who delivers the child for another but did not provide the oocyte [2, 3]. Many factors inform a patient’s decision to pursue conception via a gestational carrier, including absence or structural abnormality of the uterus, recurrent miscarriage, stigma, and same-sex partnership [3]. From 2011 to 2020, the percentage of cycles in the USA using a gestational carrier more than doubled, from 2.2 to 5.4% [4].
ART has been linked to unfavorable neonatal outcomes including low birthweight and reduced live birth rates [5]. Data suggest a possible impact of both oocyte quality and uterine environment on outcomes. Although there is no single prospective measure of oocyte quality, an oocyte’s developmental competence is associated with younger age and certain morphological indicators [6]. Poor quality oocytes are known to decrease the efficacy of IVF, and CDC data from 2020 reports higher live birth rates with donor oocytes than patients’ own oocytes for all patient ages [4, 6–9]. The uterine environment also may contribute to reproductive success. Investigation using donor oocytes indicates that gestational carriers have improved IVF outcomes compared to their infertile counterparts, suggesting an association between the uterine environment and a history of infertility [10].
Presently, the effect of oocyte freezing on IVF outcomes is uncertain. Oocyte cryopreservation, now performed primarily via vitrification of the oocyte, is increasingly in demand as more women seek to postpone childbearing or otherwise preserve reproductive potential [11, 12]. Modern protocols reduce ice crystal formation and cryoprotectant exposure, reflecting an evolution of the field from early slow-freezing methods [13]. Although investigation suggests altered perinatal outcomes of frozen as compared to fresh autologous embryo cycles, possibly due to the impact of ovarian stimulation on the uterine environment in fresh embryo transfer cycles, little research focuses on the impact of oocyte freezing on perinatal outcomes [14–17]. One systematic review found that oocyte vitrification does not present an increased risk of adverse neonatal outcomes but warned that there are few studies assessing such outcomes and called for additional large-scale studies to provide reliable data [18].
Given the limited data on clinical and neonatal outcomes of oocyte vitrification, there is a pressing need for further research. As results may be confounded by uterine environment or oocyte quality among patients with infertility, we restricted our analysis to IVF with both gestational carriers and donor oocytes to isolate the impact of oocyte freezing. Our primary outcome of interest was live birth, with secondary outcomes including birthweight and pregnancy outcomes such as pregnancy loss.
Methods
The data used for this study were obtained from the Society for Assisted Reproductive Technology Clinic Outcome Reporting System (SART CORS). Data were collected through voluntary submission, verified by SART, and reported to the Centers for Disease Control and Prevention (CDC) in compliance with the Fertility Clinic Success Rate and Certification Act of 1992 (Public Law 102–493). SART maintains HIPAA-compliant business associate agreements with reporting clinics. In 2004, following a contract change with the CDC, SART gained access to the SARTCORS data system for the purposes of conducting research. In 2019, 81% of clinics were SART members reporting 90% of all IVF cycles in the USA [19]. The data in the SART CORS are validated annually with some clinics receiving on-site visits for chart review based on an algorithm for clinic selection. During each visit, data reported by the clinic were compared with information recorded in patients’ charts. In 2021, records for 1945 cycles at 33 clinics were randomly selected for full validation, along with 262 fertility preservation cycles selected for partial validation. Nine out of ten data fields selected for validation were found to have discrepancy rates of ≤ 5%. The exception was the diagnosis field, which, depending on the diagnosis, had a discrepancy rate between 0.7 and 9.1% [19].
We utilized the SART CORS database to identify all cycles that resulted in a fresh embryo transfer in a gestational carrier, of embryos created from donor oocytes, from 2014 to 2015. Transfer cycles were classified based on the oocyte source, derived from either fresh or frozen/thawed donor oocytes. Demographic data collected included donor and recipient age, infertility diagnosis, prior in vitro fertilization (IVF) attempt, use of intracytoplasmic sperm injection (ICSI), use of assisted hatching, and number of embryos transferred. This retrospective cohort study was approved by the University Hospitals Cleveland Medical Center Institutional Review Board.
Study outcomes
The primary outcome of the study was live birth. Live birth was defined as a live-born infant delivered at 20 weeks’ gestation or greater. Secondary outcomes included pregnancy and birthweight outcomes. Additional pregnancy outcomes included clinical pregnancy, clinical pregnancy loss, and biochemical pregnancy loss. Clinical pregnancy loss was defined as pregnancy loss after the presence of gestational sac on viability ultrasound. Biochemical pregnancy loss was defined as a pregnancy loss that occurred after positive pregnancy test but prior to viability ultrasound. Birthweight outcomes included (1) low birthweight (LBW) (infants < 2500 g), (2) normal birthweight (infants ≥ 2500 g and ≤ 3999 g), and (3) high birthweight (LGA) (infants > 4000 g).
Statistical analysis
Demographic and cycle characteristics were compared between groups using Fisher’s exact tests and chi-square tests for categorical variables and Student’s t-test for continuous variables. Generalized linear regression models were used to estimate relative risks (RR) and 95% confidence intervals (CIs) to evaluate associations between fresh and frozen donor oocytes and pregnancy outcomes. Models were adjusted for gestational carrier age, infertility diagnosis, preimplantation genetic testing (PGT-A), number of embryos transferred, multiple gestation, and fetal heart reduction to provide adjusted relative risks (aRR). As our models were part of a larger analysis, intended parent BMI, smoking status, and parity were also adjusted for, but did not influence outcomes in this analysis. For recipients who had multiple cycles and transfers between 2014 and 2015, only their first embryo transfer was included.
Results
Patient demographics
The mean ages of oocyte donors, gestational carriers, and intended parent recipients were 26 years (SD ± 3.4), 31.7 years (SD ± 5.2), and 41 years (SD ± 7.9), respectively (Table 1). For the gestational carriers, 73% of women were < 35 years, 15% were 35–37 years, 7% were 38–40 years, 3% were 41–42 years, and 2% were > 42 years old. Infertility diagnoses of intended parents were collected, which included male factor, tubal factor, endometriosis, uterine factor, polycystic ovary syndrome, diminished ovarian reserve, “unexplained,” and “other.” The most common infertility diagnoses reported for intended parents were “other” (58.6%), diminished ovarian reserve (38.2%), and uterine factor (14.1%). Elective single embryo transfer (eSET) was used for a large proportion of cycles (76.2%). Mean number of embryos transferred was 1.6 (± 0.5).
Table 1.
Patient demographics
| Variable | Fresh oocyte gestational carrier cycles |
Frozen oocyte gestational carrier cycles |
P value |
|---|---|---|---|
| Cycle type, n (%) | 1,119 (87.9) | 165 (12.9) | |
| Patient age | |||
| Intended parent age (y), mean ± SD | 40.9 ± 8.1 | 41.3 ± 6.7 | 0.6085 |
| Carrier age (y), mean ± SD | 31.6 ± 5.2 | 32.4 ± 5.4 | 0.0755 |
| Carrier age (y), n (%) | |||
| < 35 | 709 (71.5) | 102 (63) | 0.0361 |
| 35–37 | 157 (15.8) | 31 (19.1) | |
| 38–40 | 71 (7.2) | 22 (13.6) | |
| 41–42 | 31 (3.1) | 3 (1.9) | |
| > 42 | 23 (2.3) | 4 (2.5) | |
| Donor age (y), mean ± SD | 25.9 ± 3.3 | 26.5 ± 3.5 | 0.0365 |
| Intended parent infertility diagnosis, n (%) | |||
| Male factor | 67 (6) | 19 (11.5) | 0.0119 |
| Tubal factor | 19 (1.7) | 8 (4.8) | 0.0161 |
| Endometriosis | 23 (2.1) | 6 (3.6) | 0.2533 |
| Uterine factor | 143 (12.8) | 38 (23) | 0.0011 |
| Polycystic ovary syndrome | 10 (0.9) | 2 (1.2) | 0.6596 |
| Diminished ovarian reserve | 423 (37.8) | 68 (41.2) | 0.44 |
| Unexplained | 46 (4.1) | 4 (2.4) | 0.3901 |
| Other | 660 (59) | 93 (56.4) | 0.5537 |
| ART factors used, n (%) | |||
| Assisted hatching | 106 (12.8) | 21 (24.7) | 0.0047 |
| ICSI | 961 (85.9) | 162 (98.2) | < 0.0001 |
| PGT-A | 367 (32.8) | 10 (6.1) | < 0.0001 |
| No. embryos transferred, mean ± SD | 1.6 ± 0.5 | 1.5 ± 0.5 | 0.0395 |
| Elective single embryo transfer (eSET) | 241 (76) | 54 (77.1) | 1 |
Pregnancy outcomes
Of the 1284 gestational carrier cycles that resulted in a fresh embryo transfer, 1119 cycles (87.1%) utilized embryos derived from fresh donor oocytes and 165 cycles (12.9%) utilized embryos derived from frozen donor oocytes (Table 2). Overall, there were 534 live births following transfer of embryos derived from fresh oocytes to gestational carriers including 341 singleton deliveries (63.9%) and 193 multiples (36.1%). No significant difference in live birth was observed when comparing embryos derived from frozen compared to fresh donor oocytes in gestational carrier cycles, 46.1% (frozen) versus 47.7% (fresh) (aRR 0.89, 95% CI 0.7–1.13). Additionally, there were no differences in clinical pregnancy (54.5% [frozen] versus 54.6% [fresh], aRR 1.01, 95% CI 0.82–1.24). We observed trends towards increased clinical pregnancy loss in the cycles in which frozen oocytes were utilized, but these were not statistically significant in our adjusted analysis. Biochemical pregnancy loss occurred in 10.3% of cycles involving frozen oocytes and 5.9% of cycles involving fresh oocytes (aRR 1.00, 95% 0.46-2.19). Clinical pregnancy loss occurred in 17.6% of cycles utilizing frozen oocytes and in 11.8% of cycles utilizing fresh oocytes (aRR 1.13; 95% CI 0.65-1.97).
Table 2.
Clinical and neonatal outcomes of frozen donor oocytes relative to fresh donor oocytes among gestational carriers
| Outcome | Fresh donor oocyte and gestational carrier (n = 1119) | Frozen donor oocyte and gestational carrier (n = 165) | RR (95% CI) | aRR (95% CI)* |
|---|---|---|---|---|
| Pregnancy Outcomes, n (%) | ||||
| Live birth | 534 (47.7) | 76 (46.1) | 0.97 (0.81, 1.15) | 0.89 (0.70, 1.13) |
| Clinical pregnancy | 611 (54.6) | 90 (54.5) | 1.00 (0.86, 1.16) | 1.01 (0.82, 1.24) |
| Biochemical pregnancy loss | 66 (5.9) | 17 (10.3) | 1.75 (1.05, 2.9) | 1.00 (0.46, 2.19) |
| Clinical pregnancy loss | 132 (11.8) | 29 (17.6) | 1.49 (1.03, 2.15) | 1.13 (0.65, 1.97) |
| Birthweight, n (%) | ||||
| Low birthweight (< 2500 g) | 190 (26.6) | 22 (23.7) | 0.92 (0.63, 1.35) | 0.85 (0.52, 1.39) |
| Normal birthweight (≥ 2500 g and ≤ 3999 g) | 480 (67.2) | 62 (66.7) | Ref | Ref |
| High birthweight (> 4000 g) | 44 (6.2) | 9 (9.7) | 1.51 (0.77, 2.96) | 0.50 (0.14, 1.88) |
| Pregnancy plurality, n (%) | ||||
| Singleton | 341 (63.9) | 58 (76.3) | Ref | Ref |
| Multiple | 193 (36.1) | 18 (23.7) | 0.66 (0.43, 1) | 0.77 (0.47, 1.29) |
Among liveborn infants, we did not observe statistically significant differences in birthweight outcomes between the two groups, although results trended toward a lower probability of low birthweight infants (23.7% [frozen] versus 26.6% [fresh], aRR 0.85, 95% CI 0.52–1.39) and a higher probability of high birthweight infants (9.7% [frozen] versus 6.2% [fresh], aRR 0.5, 95% CI 0.14–1.88) among frozen donor oocyte cycles as compared to fresh donor oocyte cycles in gestational carriers.
Discussion
We sought to study the effects of oocyte vitrification on neonatal outcomes by controlling for uterine environment and oocyte quality with the utilization of gestational carriers and donor oocytes. To our knowledge, this question has not previously been addressed using such methodology. We found no meaningful differences in live birth, clinical pregnancy loss, plurality, or low birthweight between the embryos derived from fresh and frozen donor oocytes in gestational carrier cycles. Furthermore, although some potential differences were observed in live birth and high birthweight, results were imprecise and not statistically significant due to small sample sizes in some groups. Overall, these findings support the safety and efficacy of oocyte cryopreservation, an increasingly utilized mechanism of fertility preservation [12], although additional research is needed to confirm these results. Although rate of plurality was not significantly different between groups (23.7% [frozen] vs 36.1% [fresh], aRR 0.77, 95% CI 0.047–1.29), the rates were still concerning given ASRM’s recommendations to limit the number of embryos transferred per cycle, in all but rare circumstances, to reduce the risk of complications in both fetuses and carriers [20].
Our results are notably different from studies of fresh versus frozen embryos which observed lower rates of low birthweight and higher rates of live birth with frozen embryo transfer [14–17]. By restricting our analysis to donor oocytes transferred to gestational carriers, we did not have to control for differences in the uterine environment resulting from the effects of ovarian stimulation, hypothesized to cause alteration of early placentation [2]. Instead, in gestational carriers, the uterus is exposed to a consistent program of estrogen and progesterone to prepare for implantation. As we found no significant difference in outcomes between frozen compared to fresh donor oocytes transferred to gestational carriers, this may lend support to the hypothesis that the uterine environment caused by ovarian hyperstimulation may be an important factor in differences in success previously observed between autologous fresh and frozen embryos transferred to intended parent recipients [2].
Examining outcomes among gestational carriers not only allowed us to control for the effects of ovarian hyperstimulation but also may have reduced confounding effects of infertility on the uterine environment. Even without supraphysiologic hormonal stimulation, the uterine environment may affect neonatal outcomes including low birthweight and live birth. This was demonstrated in a study comparing donor cycles in gestational carriers and intended parent recipients [10]. Outcomes were consistent even when controlling for parity and age, suggesting the contribution of other infertility-associated factors. Thus, our population of gestational carriers further allowed us to isolate the effect of vitrification. As for other factors that could influence uterine environment, we found no significant differences in carrier age, reproductive history, or smoking status. Our findings of similar clinical outcomes between cohorts indicate that cryopreservation is not harmful to oocytes, supporting the work of Cobo et al. in donor oocytes [13].
The strengths of this study include its novelty and the use of a large national registry that allowed for analysis of frozen and fresh oocytes in donor oocyte cycles with gestational carriers. However, as a retrospective database study dependent on clinics’ self-reported data, our study does have inherent limitations, including missing data and reporting accuracy. For example, although federally mandated, a small minority of clinics do not report IVF data [4]. Additionally, we had relatively few frozen donor oocyte cycles compared to fresh, and a lack of power might prohibit the detection of some meaningful differences between groups. Future studies may wish to stratify cycles by their use of natural timing versus hormonal programming where possible to further control for uterine environment, a distinction not made by SART CORS. Further studies may also wish to analyze gestational age at delivery in addition to birthweight.
Conclusion
Our study found no significant differences in live birth, pregnancy loss, low birthweight or high birthweight infants between fresh and frozen donor oocytes in gestational carrier cycles. Our use of gestational carriers and donor oocytes enabled us to isolate the impact of vitrification on development. As oocyte cryopreservation grows in popularity, our study lends support to the small but important body of evidence that vitrification does not lead to adverse neonatal outcomes, although larger studies will be necessary to confirm these findings.
Acknowledgements
The authors thank SART for the dataset, as well as all SART members for providing clinical information to the SART CORS database for use by researchers. Without the efforts of SART members, this research would not have been possible.
Author contribution
Conceptualization: RW; methodology: CB, APS, SM, RW; formal analysis and investigation: CB APS, ED, SM, RW; writing — original draft preparation: JK, RW; writing — review and editing: JK, CB, APS, ED, SM, RW.
Funding
This research was supported in part by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health, Bethesda, Maryland.
Data availability
Request to release SART data is required to be processed by the SART research committee (https://www.sart.org/professionals-and-providers/research/).
Declarations
Ethics approval
Not applicable.
Conflict of interest
The authors declare no competing interests.
Footnotes
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
Request to release SART data is required to be processed by the SART research committee (https://www.sart.org/professionals-and-providers/research/).