The evolving landscape of donor egg treatment: success, women’s choice, and anonymity

Abstract

Purpose

To analyze donor oocyte (DE) data across 6 years for oocyte usage efficiency, trends, and whether changes impacted outcomes.

Methods

From 2014 to 2019, 323 DE embryo transfers were completed in 200 recipients using oocytes derived of 163 donors. We assessed data for oocytes being freshly retrieved (FRESH-EGG) vs. purchased frozen (FROZEN-EGG); embryos transferred fresh (FRESH-ET) vs. frozen (FROZEN-ET); cycles SHARED (two recipients) vs. SOLE (one recipient); single (SET) vs. double (DET) embryo transfers and usage of PGT-A. Primary outcome was ongoing pregnancy plus live birth (OP/LB) rate.

Results

A total of 229 FRESH-EGG (70%) and 94 FROZEN-EGG (30%) cycles were completed. Overall, the use of FRESH-EGG yielded a higher OP/LB compared to FROZEN-EGG (49% vs. 30%, p = 0.001); within the FRESH-EGG group, OP/LB was similar when comparing FRESH-ET vs. FROZEN-ET (58% vs. 45%, p = 0.07). Within the FRESH-ET group, those using FRESH-EGG had a higher OP/LB than those using FROZEN-EGG (58% vs. 27%, p < 0.001). SHARED vs. SOLE cycles (p = 0.6), donor age (21–32 years; p = 0.4), and age of intended parents (maternal p = 0.3, paternal p = 0.2) did not significantly impact OP/LB. Notably, the use of PGT-A did not improve odds for an OP/LB (p = 0.7).

Conclusion

The use of FRESH-EGG with FRESH-ET without PGT-A remains superior to newer DE treatment combinations. Specifically, the use of FROZEN-EGG and PGT-A did not improve outcomes. Although changing DE practices may enhance experience and affordability, patients and providers must appreciate that choices do not always favorably impact success. Additionally, newly available genetic-ancestry testing may pose longer-term ramifications mandating change in treatment and/or counseling.

Introduction

More than 40,000 babies are born annually in the USA from the use of donor gametes (oocyte and sperm), about one-quarter resulting from the use of donor oocytes (DE) [1]. Notably, in 2018, about one-quarter of women over age 40 that succeeded using assisted reproductive technologies (ART) did so through the use of DE [2]. DE treatments are, thus, relatively common practice today as more women delay childbearing in lieu of professional/personal pursuits, often causing them to “age-out” of traditional means to pregnancy including autologous oocyte ART [2]. Other common reasons for DE usage include premature ovarian failure, diminished ovarian reserve, failed in vitro fertilization (IVF) attempts using autologous eggs, oophorectomy, cancer treatment, same-sex male couples seeking parenthood, and maternal single-gene defects [3].

Advances in IVF and oocyte cryopreservation technology have allowed for newer modalities when using DE including the use of previously frozen oocytes purchased from commercial banks (FROZEN-EGG) and the option for preimplantation genetic testing for aneuploidy (PGT-A) of resultant embryos. DE therefore evolved from a treatment where a recipient’s endometrium was hormonally synchronized to a donor’s fresh egg retrieval (FRESH-EGG) with a fresh, often multi-embryo transfer (FRESH-ET) to a non-synchronized frozen embryo transfer (FROZEN-ET) performed remote from the DE retrieval now, more often, done in conjunction with the use of commercially purchased frozen DE (FROZEN-EGG), with or without the use of PGT-A; all meant to optimize DE cycle outcomes. Despite a reported decrease in live birth rates using FROZEN-EGG, a rapid transition from FRESH-EGG to FROZEN-EGG has occurred across US fertility practices, in part, due to lowered treatment cost and convenience, broader donor selection, and increasing numbers of commercial DE banks [4].

Previous studies have analyzed DE treatment outcomes with respect to a variety of areas including outcome comparisons of FRESH-EGG versus FROZEN-EGG, the addition of PGT-A, and the psychosocial implications for both donors and recipients, yet consensus remains conflicted as to what constitutes the most appropriate, optimal DE treatment algorithm [5–10]. The objective of our study was to analyze a single program’s DE data across a 6-year period to assess oocyte usage efficiency as well as trends over time relative to psychology, cost, donor choice, genetics, and treatment ease. Our ultimate study goal was to determine whether modern trends have positively impacted pregnancy outcomes.

Materials and methods

This study represents a retrospective cohort analysis of all DE and recipient treatments completed at one academic center from 2014 through 2019. For donors who cycled more than once, only their first cycle was included in the primary analysis. Cycles using FRESH-EGG were completed as follows: donors underwent controlled ovarian hyperstimulation via standard gonadotropin protocols including luteinizing hormone suppression with either a gonadotropin-releasing hormone (GnRH) agonist or antagonist. Ovulation was triggered with either human chorionic gonadotropin (HCG), a combination of a GnRH agonist and HCG, or GnRH alone once the largest follicles reached 18 to 20 mm in size. Oocytes were retrieved approximately 35 h post-trigger and fertilized approximately 4 h post-retrieval via conventional insemination or intracytoplasmic sperm injection (ICSI). Resultant zygotes then underwent standard embryo culture for a maximum of 6 days with the goal to achieve blastulation.

FROZEN-EGG donors underwent gonadotropin stimulation protocols per their original site of harvest, retrieval, stripping, and cryopreservation by vitrification. Once selected by prospective recipient(s), oocytes were transported to the site of usage and immediately transferred to one of the center’s liquid nitrogen cryogenic tanks. When ready for usage, if FRESH-ET was planned, endometrial preparation of the recipient’s uterine lining was performed using oral estradiol supplementation followed by early luteal preparation including the addition of once-daily intramuscular progesterone-in-oil injections. Once adequately prepared, FROZEN-EGG were thawed, underwent ICSI, and cultured to the blastocyst stage. For cycles using PGT-A without FRESH-ET, blastocyst trophectoderm biopsy was performed 5 to 6 days post-oocyte thaw followed by vitrification and storage until a FROZEN-ET was planned utilizing the same uterine preparation as a FRESH-ET.

Treatment data of all cycles were analyzed for the following: donor characteristics, treatment cycle repeats, use of FRESH-EGG vs. FROZEN-EGG and FRESH-ET vs. FROZEN-ET, PGT-A or not, and single (SET) vs. double (DET) embryo transfer. Within FRESH-EGG treatments, a comparison was made between those where DE were used by one (SOLE) vs. two (SHARED) recipient and in FROZEN-EGG cycles, whether duration of storage impacted outcome. The primary outcome assessed was achievement of an ongoing pregnancy (> 8 weeks) plus live birth (OP/LB). Chi-square was used for comparison of categorical data with significance determined at p < 0.05.

Results

Our program completed 323 DE embryo transfers in 200 recipients using oocytes derived from a total of 163 individual donors during the years 2014 to 2019. The overall OP/LB was 43% (140/323). This included a total of 229 (70%) FRESH-EGG and 94 (30%) FROZEN-EGG treatments. Of the FRESH-EGG transfers, 69 (30%) recipients underwent a FRESH-ET while the majority (160; 70%) had a FROZEN-ET. Among patients opting for the use of FROZEN-EGG, 88 (94%) had a FRESH-ET while only 6 (6%) underwent a FROZEN-ET (Table 1).

Table 1.

Fresh versus cryopreserved donor oocyte use in fresh and frozen embryo transfers

	FRESH-EGG n = 229		FROZEN-EGG n = 94
	Total n (%)	OP/LB n (%)	Total n (%)	OP/LB n (%)
FRESH-ET n (%)	69 (30)	*40 (58)	88 (94)	24 (27)
FROZEN-ET n (%)	160 (70)	72 (45)	6 (6)	4 (66.6)
Overall OP/LB n (%)		*112 (49)		28 (30)

*denotes significance

Overall, embryo transfers using FRESH-EGG yielded a significantly higher OP/LB compared to those using FROZEN-EGG (49% vs. 30%, p = 0.001; Table 1). Within the FRESH-EGG group, OP/LB was not different when comparing embryos transferred in a FRESH-ET (58%) vs. a FROZEN-ET (45%; p = 0.07). Within the FRESH-ET group, those using FRESH-EGG had a significantly higher OP/LB compared to those using FROZEN-EGG (58% vs. 27%, respectively; p < 0.001) (Table 1). SOLE vs. SHARED cycle data is shown in Table 2. As anticipated, when comparing these two groups, SOLE recipients (n = 160) received an average of 17 metaphase II oocytes, whereas recipients sharing oocyte batches (n = 67) received only 9 (p = < 0.001). Despite this, the OP/LB rate in SOLE cycles (50%) was similar to that of SHARED (46%; p = 0.6) cycles. Notably, 59/80 (73%) SOLE and 23/25 (92%) SHARED cycles produced at least 1 OP/LB. Data for PGT-A usage are shown in Table 2. Adding PGT-A did not positively impact OP/LB in DE cycles as a whole (p = 0.7). Despite this, PGT-A usage in DE treatments increased over time (2014 to 2015, 0.2%; 2016 to 2017, 4.1%; 2018 to 2019, 13%; p = 0.003). When excluding PGT-A cycles, the OP/LB remained similar when comparing transfers in SOLE-vs. SHARED cycles (53% vs. 43%; p = 0.17) . Last, length of oocyte freeze as well as donor age (mean age 27 years, range 21–32 years) did not impact OP/LB outcomes (p = 0.6 and p = 0.4, respectively; Table 3).

Table 2.

SOLE versus SHARED donor cycles, PGT use in donor cycles

Cycle type	Average # of MII’s per cycle (n)	OP/LB n (%)
SOLE-ET n = 160	17	80 (50)
SHARED-ET n = 67	9	31 (46)
PGT n = 54	15	25 (46)
No PGT n = 269	10	117 (43)

Table 3.

Age of donor and length of freeze

Age of donor per cycle	OP/LB n (%)
20–25y n = 145	59 (41)
26–30y n = 141	64 (45)
31–32y n = 37	18 (48)
Length of freeze
0–2 months n = 150	73 (48)
3–6 months n = 67	29 (43)
7–12 months n = 39	14 (36)
13–24 months n = 27	8 (30)
25–48 months n = 28	12 (43)
49–68 months n = 10	4 (40)

*2 FROZEN-EGG retrieval dates were unavailable

Ages of the intended parents (i.e., age of recipient and the age of the person producing sperm used to create the embryos) were analyzed for any impact on OP/LB outcome. Donor sperm samples were excluded from the analysis. When comparing OP/LB from intended parents < 45 years and those ≥ 45 years, no difference was noted (maternal 45% vs. 40%; p = 0.3, paternal 49% vs. 40%; p = 0.2) (Table 4).

Table 4.

Recipient and male partner age

	Female (recipient)		Male partner (sperm)
	< 45 n = 194	≥ 45 n = 129	< 45 n = 170	≥ 45 n = 97
Average age	40.1 ± 4.1	46.7 ± 2.1	38.2 ± 4.4	49 ± 3.7
Age range	27–44	45–55	24–44	45–61
Overall OP/LB n (%)	89 (45)	52 (40)	83 (49)	40 (41)

When assessing data by the number of embryos replaced, notably, no difference was demonstrated in OP/LB when comparing DETs versus SETS (51/104; 49% vs. 91/216; 42%; p = 0.24); however, DETs were associated with a 12.5% (13/104) twin delivery outcome. The program trended away from DET to SET over the 6-year study span, with DET decreasing from 42 to 19% (p < 0.05); the predominant practice of SET continues to dominate at our program. Like SET, as the years progressed, a trend toward SOLE over SHARED cycles and fewer FROZEN-EGG was seen due to SOLE and FRESH-EGG cycles having superior OP/LB per ET.

When evaluating all cycles of the 163 individual donors used (Table 5), 98 (60%) had oocytes freshly retrieved (FRESH-EGG), whereas, in 65 (40%) cases, the oocytes had been commercially purchased (FROZEN-EGG). Secondary data evaluation revealed that 29 (30%) donors where FRESH-EGG were retrieved donated more than once (REPEATS) with 385 resultant embryos created transferred to a total of 108 recipients. Subgroup data analysis including all cycles from both single-use and REPEAT donors (totaling 462 transfers and 241 recipients) demonstrated similar OP/LB outcomes with the exception of SOLE vs. SHARED cycles where OP/LB was noted to be significantly better in the SOLE group (53% vs. 41%; p = .02). On average, REPEATS underwent 3 retrievals (range: 2–6), were transferred to an average of four recipients (range: 2–9), and oocytes from all their donations resulted in an average of 7 embryo transfers (range: 2–23) creating 84 OP/LB (an average of three per individual donor; range 1–9). A total of 78 “genetic half-siblings” were born to 70 recipients from 23 donors. This is in addition to any other offspring conceived of the same donor used elsewhere at another ART facility; especially in the case of FROZEN-EGG lacking governing mandate re: the number of times a given donor can undergo ovarian stimulation.

Table 5.

Donor characteristics

Donor type	n
FRESH-EGG	98 (60%)
FROZEN-EGG	65 (40%)
Repeat donors (stimulated more than once)	29
Average number of repeat DE retrievals	3 (range 2–6)
Repeat DE recipient	108
Average number of repeat recipient	4 (range 2–9)
Average number of repeat DE embryo transfers	7 (range 2–23)
Total OP/LB from repeat DE embryo transfers	84 (3 per donor, range 1–9)

Discussion

Clearly, ART has continued to evolve. As overall OP/LB rates in ART have become almost universally acceptable, primary treatment emphasis has expanded from best-pregnancy-rate-only to include healthy baby (and mother) and, importantly, meeting patient needs and concerns including cost, timing, treatment ease, donor choice, and non-family genetic siblings. Trends in practice require continuous reevaluation.

In our study, the use of freshly retrieved oocytes in combination with an endometrially synchronized recipient continues to provide the best absolute OP/LB in DE treatment cycles but the use of FROZEN-EGG and FROZEN-ET expand donor choice and enhance convenience. The superiority of FRESH-EGG over FROZEN-EGG DE was similarly reported by Kushnir et al. who analyzed 30,160 DE IVF treatments from SART and concluded that cryopreserved oocytes produced lower pregnancy and live birth outcomes when compared to FRESH-EGG [5]. A recent JAMA article also concluded that live birth rates were higher in FRESH-EGG compared to FROZEN-EGG, even when PGT-A was performed [11]. These findings do not align with those for autologous IVF treatment cycles where randomized trials and meta-analyses have consistently demonstrated that cryopreserved, thawed-embryo transfers now have higher or at least equivalent live birth rate compared to FRESH-ET in women with a high oocyte yield at retrieval [12, 13]. A possible non-oocyte related explanation for this difference includes the fact that recipient endometrium is prepared in a physiologically optimal way as opposed to supraphysiologic estrogen stimulation of the endometrium seen in fresh, autologous embryo transfers, the latter potentially associated with disorganized endometrial development [14]. However, it is the authors’ opinion that decreased oocyte competence after cryopreservation, thawing, and manipulation plays a significant role in the differences cited.

Sharing a donor between multiple recipients, whether through FRESH-EGG or FROZEN-EGG, decreases cost and, theoretically, the number of supernumerary embryos produced but also increases the number of recipients per donor and therefore the number of genetically related offspring in the background of newly available consumer testing unraveling anonymity [5]. Multiple studies have demonstrated the benefits of donor sharing including excellent pregnancy outcomes while additionally decreasing the number of supernumerary embryos produced [15–17]. Some studies advocate that a cohort of four to six metaphase II DE is sufficient to achieve a satisfactory pregnancy outcome for FRESH-ET [16, 17]. Our study suggests that OP/LB was not improved when comparing SOLE vs. SHARED cycles evaluating first-time usage of the donor’s oocytes. However, when we included REPEAT cycles (multiple cycles using the same donor), SOLE cycles produced a higher chance of OP/LB than SHARED cycles. As one would expect, SOLE cycles are associated with 1.7 times higher number of oocytes assigned per recipient which may explain this advantage. “Proven” donors (those producing pregnancy) are routinely used by both banks and ART programs more than once.

From our and other data, PGT-A does not appear to have a role in DE when younger (i.e., < age 32 years) oocytes are utilized. An exception might include the use of DE in conjunction with a gestational carrier, a situation where efficiency is paramount, decreasing overall treatment cost as well as lowering the gestational carrier’s pregnancy and gestational risks. The literature cites arguments for and against the use of PGT-A in DE cycles; at this point, no consensus has been determined but appears to be leaning toward not using it with DE. Multiple recipient studies have found that PGT-A did not improve the likelihood of a live birth in DE cycles [8, 11, 18]. Another study comparing the outcomes of FRESH-ET DE vs. FROZEN-ET DE with and without PGT-A found no benefit when PGT-A was added, suggesting that the refreezing of embryos resulting in frozen-thawed oocytes may negatively impact embryo competence and, thus, pregnancy outcome (6). Others have argued the contrary, i.e., that PGT-A could lead to improved DE outcomes and therefore may be beneficial to these treatments [3]. Despite this current ongoing debate, an increase in DE PGT-A was reported between 2010 and 2013 in the USA [8] as well as in our study.

Previous literature supports that recipient age up to age 50 does not impact OP/LB [19, 20]. Studies on the impact of advanced paternal age on pregnancy outcomes remain controversial. A meta-analysis looking at 12 articles using the DE model found no association [21], whereas a recent study using sibling donor oocytes from shared recipients found paternal age ≥ 45 years to negatively impact pregnancy rates [22]. Our study found that neither recipient nor paternal age influenced OP/LB.

We feel that, in accordance with the American Society for Reproductive Medicine (ASRM) guidelines, SET should be advocated for all DE treatments where the donor’s age is < 35 years [23]. It has now been clearly demonstrated that SET over DET is associated with a 35 times lower multiple birth rate with only a 7.4% decrease in overall live birth chance [24]. Our data echoes these findings. Like the ASRM, we strongly advocate SET in DE treatments and in all transfers where the oocyte used to create an embryo is retrieved before age 36 y.

Although changing DE practices may enhance patient experience and affordability, patients and providers must be cognizant that choices may not always favorably impact pregnancy outcomes and may be associated with other longer-term untoward ramifications. Above and beyond whether a pregnancy is created, DE cycles are associated with other obstetrical and perinatal risks as compared with autologous oocyte IVF treatments and naturally conceived pregnancies. These include a 2–3-fold higher risk of preeclampsia, low birth weight, and preterm birth and an increased risk of obstetrical emergencies [25, 26].

Donors and intended parents require full and appropriate genetic counseling prior to treatment as risks of consanguinity can occur if the donor is used by two or more unrelated families [27]. With the proliferation of direct-to-consumer DNA tests, the idea on anonymity among gamete donors is slowly becoming obsolete. A recent study looking at sperm donor’s attitudes re: the loss of anonymity as a result of these tests found that a majority of sperm donors had no regrets and would donate again [28]. However, it remains unclear how these tests will impact the landscape of donor gamete usage now and in the future. Regardless, the new reality, i.e., the potential loss of anonymity, needs to be explained to all participants.

Strengths of this study include that it was performed at a single institution where all treatments were managed and performed in one laboratory setting, using the same techniques over a 6-year time period. Regardless, the now relatively routine use of commercially purchased frozen oocytes has an intrinsic learning curve for all programs. Limitations of the study include its retrospective nature. Furthermore, the type of PGT-A (comparative genomic hybridization vs. next-generation sequencing) was not delineated which may cause differences in interpretation of PGT-A results. In addition, the use of PGT-A in the donor population is not fully reflective of modern PGT-A practice and represents another limitation to this study. The indication for patients who utilized PGT-A was not elucidated in our cohort, although we can assume the majority would be for aneuploidy and a minority (< 5%) for sex selection. The substantial use of DET in the earlier cohort years producing a large amount of twin gestations is also not standard practice today.

Conclusion

Young oocytes yield sufficient-quality embryos to produce live birth without the use of preimplantation genetic evaluation. That oocytes from 32- and 21-year-old donors yielded similar OP/LB is an important finding that is useful when counseling persons pursing fertility preservation through autologous oocyte cryopreservation, a burgeoning technology that potentially allows them to be their own “donors” in the future. DE considerations now go beyond OP/LB and include enhanced DE choice (FROZEN-EGG), easier scheduling and coordination (FROZEN-ET and FROZEN-EGG), and lower cost (SHARED). Patients utilizing DE should be counseled that PGT-A in association with DE remains of unproven benefit and may actually lower pregnancy outcomes when used with previously cryopreserved oocytes. Larger prospective studies with DE use are still warranted.

Authors’ contributions

NN and AP designed the study. AP collected and reviewed the data. AP, NN, and MR analyzed the data. AP, SB, MR, and NN were major contributors writing the manuscript. All authors read and approved the manuscript.

Data Availability

The datasets used and analyzed during the current study are available from the corresponding author on reasonable request.

Code availability

Not applicable

Declarations

Competing interests

The authors declare that they have no competing interests.