Abstract
STUDY QUESTION
How does ovarian stimulation in an oocyte donor affect the IVF cycle and obstetric outcomes in recipients?
SUMMARY ANSWER
Higher donor oocyte yields may affect the proportion of usable embryos but do not affect live birth delivery rate or obstetric outcomes in oocyte recipients.
WHAT IS KNOWN ALREADY
In autologous oocyte fresh IVF cycles, the highest live birth delivery rates occur when ~15–25 oocytes are retrieved, with a decline thereafter, perhaps due to the hormone milieu, with super-physiologic estrogen levels. There are scant data in donor oocyte cycles, wherein the oocyte environment is separated from the uterine environment.
STUDY DESIGN, SIZE, DURATION
This was a retrospective cohort study from 2008 to 2015 of 350 oocyte donors who underwent a total of 553 ovarian stimulations and oocyte retrievals. The oocytes were vitrified and then distributed to 989 recipients who had 1745 embryo transfers. The primary outcome was live birth delivery rate, defined as the number of deliveries that resulted in at least one live birth per embryo transfer cycle.
PARTICIPANTS/MATERIALS, SETTING, METHODS
The study included oocyte donors and recipients at a donor oocyte bank, in collaboration with an academic reproductive endocrinology division. Donors with polycystic ovary syndrome and recipients who used gestational carriers were excluded. The donors all underwent conventional ovarian stimulation using antagonist protocols. None of the embryos underwent pre-implantation genetic testing. The average (mean) number of embryos transferred to recipients was 1.4 (range 1–3).
MAIN RESULTS AND THE ROLE OF CHANCE
Per ovarian stimulation cycle, the median number of oocytes retrieved was 30 (range: 9–95). Among the 1745 embryo transfer cycles, 856 of the cycles resulted in a live birth (49.1%). There were no associations between donor oocyte yield and probability of live birth, adjusting for donor age, BMI, race/ethnicity and retrieval year. The results were similar when analyzing by mature oocytes. Although donors with more oocytes retrieved had a higher number of developed embryos overall, there was a relatively lower percentage of usable embryos per oocyte warmed following fertilization and culture. In our model for the average donor in the data set, holding all variables constant, for each additional five oocytes retrieved, there was a 4% (95% CI 1%, 7%) lower odds of fertilization and 5% (95% CI 2%, 7%) lower odds of having a usable embryo per oocyte warmed. There were no associations between donor oocyte yield and risk of preterm delivery (<37 weeks gestation) and low birthweight (<2500 g) among singleton infants.
LIMITATIONS, REASONS FOR CAUTION
Ovarian stimulation was exclusively performed in oocyte donors. This was a retrospective study design, and we were therefore unable to ensure proportional exposure groups. These findings may not generalizable to older or less healthy women who may be vitrifying oocytes for planned fertility delay. There remain significant risks to aggressive ovarian stimulation, including ovarian hyperstimulation. In addition, long-term health outcomes of extreme ovarian stimulation are lacking. Lastly, we did not collect progesterone levels and are unable to evaluate the impact of rising progesterone on outcomes.
WIDER IMPLICATIONS OF THE FINDINGS
Live birth delivery rates remain high with varying amounts of oocytes retrieved in this donor oocyte model. In a vitrified oocyte bank setting, where oocytes are typically sent as a limited number cohort, recipients are not affected by oocyte yields.
STUDY FUNDING/COMPETING INTEREST(S)
Additional REDCap grant support at Emory was provided through UL1 TR000424. Dr. Audrey Gaskins was supported in part by a career development award from the NIEHS (R00ES026648).
Keywords: oocyte donor, egg donor, IVF, live birth delivery rate, ovarian stimulation, obstetric outcomes
Introduction
With a trend toward delayed childbearing in the USA (Martin et al., 2017) and concordant increasing rates of infertility, there has been more widespread use of donor oocytes by couples; in 2016, donor oocyte IVF accounted for 12.3% of all reported cycles (Centers for Disease Control and Prevention, 2018). Pregnancy rates with donor oocytes are high (Crawford et al., 2017) as they compensate for age-related decreases in success with IVF due to aneuploidy. There have been prior publications that have investigated which factors contribute to a successful donor oocyte IVF cycle, emphasizing the importance of an oocyte donor being young (Cohen et al., 1999), healthy (Cardozo et al., 2016) and having normal ovarian reserve (Delesalle et al., 2016). The impact of the ovarian stimulation is less clear.
The majority of oocyte donors have the ability to recruit numerous oocytes. A higher number of oocytes retrieved results in an increased number of embryos available for transfer and cryopreservation for a recipient. Aggressive ovarian stimulation, however, may cause a detrimental impact on embryo quality and, more importantly, live birth delivery rates for recipients. Many of the prior studies have been conducted with autologous oocyte IVF with fresh transfers; they have found a ‘sweet spot’ of oocyte recruitment with ovarian stimulation, with highest live birth delivery rates when approximately 15–25 oocytes are retrieved (Sunkara et al., 2011; Steward et al., 2014). Much of this may be due to the effects of super-physiologic estrogen levels on the endometrium in fresh autologous cycles. Other investigators have not found an upward limit on number of autologous oocytes and relationship with live birth delivery rate, especially when considering cumulative live birth delivery rate (Baker et al., 2015; Polyzos et al., 2018).
With the advent of vitrification (Vajta et al., 2006), oocyte cryopreservation both for fertility preservation (Centers for Disease Control and Prevention, 2018) and for donor oocyte banking have become increasingly routine (Nagy et al., 2009b; Cobo et al., 2011; Nagy et al., 2013). There has also been growth of donor oocyte banks (Nagy et al., 2009a; Quaas et al., 2018). With these changes, the ovarian stimulation question becomes more pertinent: namely, are there changes in live birth delivery rate following embryo transfer with increasing number of oocytes retrieved? Donor oocyte cycles have the added ability to separate out the influence of the stimulation on the endometrial lining, with many recipients presumably having an optimal physiologic environment for transfer. Prior studies specifically analyzing donor oocytes have been smaller and limited to single centers (Cohen et al., 1999; Letterie et al., 2005; Hariton et al., 2017). Using data from a large donor oocyte bank, we analyzed the impact of ovarian stimulation on recipient IVF and obstetric outcomes.
Materials and Methods
Study design
This is a retrospective cohort study of oocyte donation IVF cycles (2008–2015) at Reproductive Biology Associates in Sandy Springs, GA, USA. Cycles included in this study were those in which all oocytes from an oocyte donor were cryopreserved via vitrification for use in an oocyte bank and later warmed in separate cohorts for recipients’ use. We excluded cycles in which gestational carriers were used or no embryos were transferred. This resulted in a sample size of 350 oocyte donors who underwent 553 ovarian stimulation cycles. The cryopreserved oocytes from these donor stimulation cycles were used by 989 unique recipients who underwent a total of 1745 embryo transfer cycles.
Data collection and analysis were organized by the Division of Reproductive Endocrinology and Infertility at the Emory University School of Medicine.
Ethical approval
This study was approved by the Emory Institutional Review Board prior to study initiation (IRB #80463). Study data were collected using a REDCap electronic database hosted at Emory University as previously described (Capelouto et al., 2018).
Donor characteristics and stimulation
The oocyte donors were screened according to clinic protocol per ASRM recommendations (Practice Committee of American Society for Reproductive Medicine et al., 2013). Donors with polycystic ovary syndrome were excluded. The donors all underwent conventional ovarian stimulation using antagonist protocols. Following oocyte retrieval, mature oocytes were vitrified 39–40 h after the trigger injection, using the ‘minimum volume’ method (Nagy et al., 2009b). Via chart abstraction, we collected data about the donors at the time of their first retrieval, including demographics and reproductive history (e.g. age, race/ethnicity, BMI and gravidity/parity). For each retrieval, we collected ovarian reserve data (e.g. bilateral antral follicle count and anti-Müllerian hormone) and ovarian stimulation data (e.g. gonadotrophin dose, number of days of stimulation, number of large follicles (>14 mm) at trigger shot, peak estradiol levels, and trigger type). We described whether the estradiol levels were increasing (>20% change), were decreasing (<−10% change) or demonstrated a plateau (−10 –20% change) in the 24 h prior to trigger.
Recipient preparation and outcome assessment
Recipients were given a standard endometrial preparation of leuprolide acetate, estrogen and progesterone administered i.m. At time of oocyte warming, they were given a cohort of vitrified oocytes, most commonly six to eight. Two to three hours after oocyte warming, the oocytes were fertilized via ICSI with sperm from a male partner or a sperm donor (Nagy et al., 1995), and the embryos cultured in the laboratory until cleavage (Day 3) or blastocyst stage (Day 5/6). None of the embryos underwent pre-implantation genetic testing.
Embryo transfer was performed in standard fashion, with the highest quality embryo(s) transferred first, and the remaining embryos were cryopreserved for potential future use. Some of the recipients had multiple frozen embryo transfers from a single cohort of oocytes warmed (Chang et al., 2008).
Our primary outcome was live birth delivery rate, defined as the number of deliveries that resulted in at least one live birth per embryo transfer cycle. Secondary outcomes included proportion of warmed oocytes that resulted in the birth of a baby; the proportion of warmed oocytes that survived the warming; the proportion of warmed oocytes that fertilized; and the proportion of warmed oocytes that developed into usable embryos, which was calculated by adding the number of embryos transferred and the number cryopreserved. We also collected information on gestational age and birthweight among live born infants. Preterm delivery was defined as a birth prior to 37 weeks gestation, and low birthweight was defined as the birth of a neonate <2500 g.
Statistical analysis
We compared demographic, reproductive history and ovarian stimulation parameters of the oocyte donors at the time of their first retrieval according to the number of oocytes retrieved using the following categories: ≤15, 16–30, 31–50 and >50. These groups were chosen based on prior studies in autologous IVF cycles that showed live birth rate plateau after 15–30 oocytes (Steward et al., 2014; Baker et al., 2015). We also compared characteristics of the donor oocyte recipients at the time of their first embryo transfer by categories of number of oocytes retrieved during the donor’s stimulation cycle. For categorical variables, differences across categories were tested using chi-square tests or Fisher’s exact test where appropriate.
We analyzed the association between number of oocytes retrieved during the donor’s stimulation cycle and probability of live birth among all embryo transfer cycles using cluster weighted generalized estimating equations (GEE) with binomial distribution and log link function. These models account for the correlation between multiple embryo transfer cycles within a woman and non-ignorable cluster size. For example, women with more severe infertility will likely undergo a greater number of embryo transfers before achieving a live birth, compared to women with less severe infertility. When cluster size is informative, using an unweighted approach in marginal analyses will over-weigh couples with the most severe infertility, leading to biased estimates. A weighted GEE approach, in which the weight is equal to the inverse of the cluster size, is not subject to this bias (Williamson et al., 2003; Huang et al., 2011). For the primary analysis, we examined the relation between the continuous measure of number of oocytes retrieved and risk of live birth non-parametrically with restricted cubic splines (Durrleman et al., 1989). We also calculated risk ratios (RRs) comparing the risk of live birth in a specific category of number of oocytes retrieved (e.g. ≤15, 31–50 and >50) compared with the risk in the reference category (e.g. 16–30 oocytes retrieved). Sensitivity analyses were conducted stratifying the association by number of embryos transferred (e.g. 1 versus 2–3) and restricting the analysis to only blastocyst transfers and only first embryo transfers.
We described number of total live births and total number of babies in our cohort and also calculated the total number of babies per 100 warmed oocytes in total and in specific categories by number of oocytes retrieved. Since many embryos from the oocytes are still cryopreserved, we also calculated the estimated number of babies per 100 warmed oocytes if all the embryos in the cohort were transferred (assuming implantation rate and delivery rate held constant).
The association between number of oocytes retrieved during the donor’s stimulation cycle and secondary outcomes following oocyte warming (e.g. % survived, % fertilized, % usable embryos) were analyzed using GEE with binomial distribution and log (% survived and % fertilized) or logit (% usable embryos) link function. Data are presented as back transformed marginal percentages at the mean level of continuous covariates and most common level of categorical covariates. The analyses for birth outcomes (e.g. gestational age and birthweight) were restricted to singleton live births with known gestational age at delivery (n = 701). The association between number of oocytes retrieved during the donor’s stimulation cycle and gestational length was conducted using a cluster weighted Cox proportional hazard model and a robust sandwich covariance estimate. Analyses for birthweight were conducted using cluster weighted GEE with normal distribution and identity link function. For the outcomes of pre-term birth and low birthweight, we used cluster weighted GEE with binomial distribution and logit link function to calculate the odds ratios (ORs) and 95% CI. All of these models account for the multiple live births a woman could contribute to the analysis and the presence of non-ignorable cluster size by weighting each recipient inversely according to the number of live births they achieved.
Confounding was evaluated using prior knowledge and descriptive statistics from our cohort through the use of directed acyclic graphs (Weng et al., 2009). Variables retained in the final multivariable models were donor age, BMI and race (Northern European, African-American, Hispanic or Latino, Asian or Other, Missing), retrieval year (2008–2009, 2010–2011, 2012–2013, 2014–2015) and recipient age (for analyses of live birth, gestational age, and birthweight). All tests of statistical significance were two-sided, and a significance-level of P < 0.05 was used. All data were analyzed using SAS 9.4 (SAS Institute Inc, Cary, NC, USA).
Results
The characteristics of the oocyte donors (n = 350 women) at time of their first oocyte retrieval, stratified by number of oocytes retrieved, are presented in Table I. The donors were all 21 to 32 years of age. Per cycle, the median number of oocytes retrieved was 30 (range: 9–95). The majority of the donors were of Northern European race/ethnicity, had normal BMI and were nulliparous. There was a trend of increasing oocyte yield during the study years (P < 0.001). Women with higher measures of ovarian reserve (anti-Müllerian hormone and antral follicle count), number of follicles >14 mm at maturation trigger and higher peak estradiol levels had higher number of oocytes retrieved. There were no cases of severe ovarian hyperstimulation syndrome, as defined by the American Society for Reproductive Medicine 2016 guidelines (Practice Committee of the American Society for Reproductive Medicine. Electronic address et al., 2016).
Table I. Characteristics of oocyte donors at time of first ovarian stimulation, stratified by number of oocytes retrieved, 2008–2015.
| Number of oocytes retrieved | ||||||
|---|---|---|---|---|---|---|
| Total | ≤15 | 16–30 | 31–50 | >50 | P valuea | |
| Number of women | 350 | 18 | 174 | 125 | 33 | |
| n (%) | n (%) | n (%) | n (%) | n (%) | ||
| Age at first retrieval (years) | 0.92 | |||||
| 21–23 | 108 (30.9) | 4 (22.2) | 58 (33.3) | 37 (29.6) | 9 (27.3) | |
| 24–26 | 107 (30.6) | 5 (27.8) | 55 (31.6) | 37 (29.6) | 10 (30.3) | |
| 27–29 | 107 (30.6) | 7 (38.9) | 46 (26.4) | 43 (34.4) | 11 (33.3) | |
| 30–32 | 28 (8.0) | 2 (11.1) | 15 (8.6) | 8 (6.4) | 3 (9.1) | |
| Year of retrieval | <0.001 | |||||
| 2008–2009 | 88 (25.0) | 5 (27.8) | 60 (34.5) | 27 (20.9) | 4 (12.1) | |
| 2010–2011 | 108 (30.9) | 9 (50.0) | 56 (32.2) | 28 (21.7) | 10 (30.3) | |
| 2012–2013 | 106 (30.3) | 4 (22.2) | 39 (22.4) | 49 (38.0) | 16 (48.5) | |
| 2014–2015 | 48 (13.7) | 0 (0.0) | 19 (10.9) | 25 (19.4) | 3 (9.1) | |
| Race/ethnicity | 0.94 | |||||
| Northern European | 255 (72.9) | 13 (72.2) | 126 (72.4) | 89 (71.2) | 27 (81.8) | |
| African-American | 36 (10.3) | 2 (11.1) | 16 (9.0) | 16 (12.8) | 2 (6.1) | |
| Hispanic or Latino | 14 (4.0) | 1 (5.6) | 9 (5.2) | 4 (3.2) | 0 (0.0) | |
| Other | 34 (9.7) | 2 (11.1) | 16 (9.2) | 13 (10.4) | 3 (9.1) | |
| Missing | 11 (3.0) | 0 (0.0) | 7 (4.0) | 3 (2.4) | 1 (3.0) | |
| BMI (kg/m 2 ) b | 0.78 | |||||
| ≤21.0 | 102 (29.1) | 4 (22.2) | 48 (27.8) | 37 (29.6) | 12 (36.4) | |
| 21.1–24.9 | 186 (53.1) | 12 (66.7) | 90 (52.0) | 68 (54.4) | 16 (48.5) | |
| ≥25.0 | 62 (17.7) | 2 (11.1) | 35 (20.2) | 20 (16.0) | 5 (15.2) | |
| Number of prior births | 0.21 | |||||
| 0 | 274 (78.3) | 12 (66.7) | 146 (83.9) | 93 (74.4) | 23 (69.7) | |
| 1 | 37 (10.6) | 4 (22.2) | 14 (8.1) | 15 (12.0) | 4 (12.1) | |
| 2 | 32 (9.1) | 2 (11.1) | 11 (6.3) | 13 (10.4) | 6 (18.2) | |
| ≥3 | 7 (2.0) | 0 (0.0) | 3 (1.7) | 4 (3.2) | 0 (0.0) | |
| Anti-Müllerian hormone (ng/mL) b | <0.001 | |||||
| <2 | 10 (6.9) | 2 (40.0) | 6 (11.8) | 3 (4.4) | 0 (0.0) | |
| 2–4.0 | 53 (36.6) | 3 (60.0) | 24 (47.1) | 20 (29.0) | 3 (15.0) | |
| 4.1–8.0 | 56 (38.6) | 0 (0.0) | 18 (33.3) | 33 (47.8) | 6 (30.0) | |
| 8.1–12.0 | 21 (14.5) | 0 (0.0) | 3 (5.9) | 13 (18.8) | 6 (30.0) | |
| ≥12.0 | 5 (3.5) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 5 (25.0) | |
| Antral follicle count b | <0.001 | |||||
| ≤15 | 8 (2.3) | 0 (0.0) | 6 (3.5) | 2 (1.6) | 0 (0.0) | |
| 16–30 | 138 (39.7) | 7 (38.9) | 88 (51.5) | 34 (26.6) | 5 (15.2) | |
| 31–45 | 139 (39.9) | 8 (44.4) | 58 (33.9) | 60 (46.9) | 14 (42.2) | |
| 46–60 | 47 (13.5) | 3 (16.7) | 19 (11.1) | 19 (14.8) | 11 (33.3) | |
| >60 | 16 (4.6) | 0 (0.0) | 0 (0.0) | 13 (10.2) | 3 (9.1) | |
| Gonadotrophin total dose (IU) | 0.01 | |||||
| ≤1500 | 15 (4.3) | 0 (0.0) | 4 (2.3) | 8 (6.4) | 3 (9.1) | |
| 1501–2500 | 194 (55.4) | 7 (38.9) | 86 (49.4) | 80 (64.0) | 21 (63.6) | |
| 2501–3500 | 129 (36.9) | 11 (61.1) | 76 (43.7) | 33 (26.4) | 9 (27.3) | |
| 3501–5000 | 12 (3.4) | 0 (0.0) | 8 (4.6) | 4 (3.2) | 0 (0.0) | |
| Days of stimulation | 0.42 | |||||
| 8–9 | 96 (27.4) | 5 (27.8) | 41 (23.6) | 41 (32.8) | 9 (27.3) | |
| 10–11 | 212 (60.6) | 12 (66.7) | 107 (61.5) | 71 (56.8) | 22 (66.7) | |
| 12–13 | 42 (12.0) | 1 (5.6) | 26 (14.9) | 13 (10.4) | 2 (6.1) | |
| Number of follicles >14 mm at trigger | <0.001 | |||||
| ≤12 | 29 (8.3) | 7 (38.9) | 20 (11.5) | 2 (1.6) | 0 (0.0) | |
| 13–24 | 231 (66.0) | 11 (61.1) | 135 (77.6) | 75 (60.0) | 10 (30.0) | |
| 25–40 | 84 (24.0) | 0 (0.0) | 19 (10.9) | 45 (36.0) | 20 (60.6) | |
| 41–55 | 6 (1.7) | 0 (0.0) | 0 (0.0) | 3 (2.4) | 3 (9.1) | |
| Peak estradiol (pg/mL) | <0.001 | |||||
| <2000 | 98 (28.0) | 9 (50.0) | 52 (29.9) | 29 (23.2) | 8 (24.2) | |
| 2001–4500 | 159 (45.4) | 9 (50.0) | 88 (50.6) | 51 (40.8) | 11 (33.3) | |
| 4501–6000 | 55 (15.7) | 0 (0.0) | 27 (15.5) | 22 (17.6) | 6 (18.2) | |
| >6000 | 38 (10.9) | 0 (0.0) | 7 (4.0) | 23 (18.4) | 8 (24.2) | |
| Change in estradiol prior to peak | 0.96 | |||||
| Drop (<−10% change) | 39 (11.1) | 2 (11.1) | 19 (10.9) | 13 (10.4) | 5 (15.2) | |
| Plateau (−10–20% change) | 112 (32.0) | 6 (33.3) | 52 (29.9) | 43 (34.4) | 11 (33.3) | |
| Rise (>20% change) | 199 (56.9) | 10 (55.6) | 103 (59.2) | 69 (55.2) | 17 (51.5) | |
| Maturation trigger type b | <0.001 | |||||
| hCG | 132 (37.8) | 14 (77.8) | 85 (49.1) | 30 (24.0) | 3 (9.1) | |
| GnRH agonist (Lupron) | 217 (62.2) | 4 (22.2) | 88 (50.9) | 95 (76.0) | 30 (90.9) | |
a P values were calculated using chi-square or Fisher’s exact tests where appropriate.
bAmount of women with missing data: 1 for BMI, 205 for anti-Mullerian hormone (not routinely measured before 2012), 2 for antral follicle count, and 1 for trigger type.
Table II includes information about the recipients (n = 989 women) at time of first embryo transfer, stratified by the number of oocytes retrieved in the oocyte donor. The majority of recipients were ≥40 years of age (n = 675; 68.2%), normal BMI, of Northern European race/ethnicity and nulliparous. In regards to fertility diagnoses besides diminished ovarian reserve/advanced reproductive age, 152 (15.4%) had uterine factor infertility, 62 (6.3%) had recurrent pregnancy loss, and 27 (2.7%) had ovulatory dysfunction. Recipients underwent 1 (n = 509, 51.5%), 2 (n = 302, 30.5%), 3 (n = 111, 11.2%) or 4+ (n = 69, 6.8%) embryo transfer cycles. Most embryo transfers were performed at the blastocyst stage (n = 888; 89.8%). Among the 1745 embryo transfer cycles, 856 of the cycles resulted in a live birth (49.1%). The remainder included negative pregnancy tests (n = 520; 29.8%), biochemical pregnancies (n = 155; 8.9%), ectopic pregnancies (n = 8; <1%), spontaneous abortions (n = 198; 11.3%), elective terminations (n = 5, <1%) and stillbirths (n = 3; <1%). Of the infants born, 707 (82.6%) were singletons, 144 (16.8%) were twins and 5 (0.6%) were triplets.
Table II. Characteristics of female donor oocyte recipients by total number of oocytes retrieved during donor’s stimulation cycle, 2008–2015.
| Number of oocytes retrieved | ||||||
|---|---|---|---|---|---|---|
| Total | ≤15 | 16–30 | 31–50 | >50 | P valuea | |
| Number of women | 989 | 34 | 409 | 429 | 117 | |
| n (%) | n (%) | n (%) | n (%) | n (%) | ||
| Age (years) b | 0.05 | |||||
| ≤35 | 129 (13.0) | 3 (8.8) | 47 (11.5) | 64 (14.9) | 15 (12.8) | |
| 35–39 | 185 (18.7) | 3 (8.8) | 70 (17.1) | 89 (20.8) | 22 (18.8) | |
| 40–45 | 547 (55.3) | 19 (55.9) | 231 (56.5) | 236 (55.0) | 62 (53.0) | |
| ≥46 | 128 (12.9) | 9 (26.5) | 61 (14.9) | 40 (9.3) | 18 (15.4) | |
| Year of embryo transfer | 0.001 | |||||
| 2008–2009 | 265 (26.8) | 7 (20.6) | 130 (31.8) | 106 (24.7) | 22 (18.8) | |
| 2010–2011 | 313 (31.7) | 17 (50.0) | 138 (33.7) | 123 (28.7) | 35 (29.9) | |
| 2012–2013 | 311 (31.5) | 9 (26.5) | 106 (25.9) | 147 (34.3) | 49 (41.9) | |
| 2014–2015 | 100 (10.1) | 1 (2.9) | 35 (8.6) | 53 (12.4) | 11 (9.4) | |
| BMI (kg/m 2 ) b | 0.37 | |||||
| <18.5 | 15 (1.6) | 1 (3.2) | 5 (1.3) | 9 (2.2) | 0 (0.0) | |
| 18.5–24.9 | 578 (58.4) | 16 (51.6) | 240 (62.3) | 250 (61.6) | 72 (64.3) | |
| 25.0–29.9 | 218 (22.0) | 12 (38.7) | 90 (23.4) | 86 (21.2) | 30 (26.8) | |
| 30.0–34.9 | 83 (8.4) | 2 (6.5) | 34 (8.8) | 41 (10.1) | 6 (5.4) | |
| ≥35.0 | 40 (4.0) | 0 (0.0) | 16 (4.2) | 20 (4.9) | 4 (3.6) | |
| Race/ethnicitiy | 0.22 | |||||
| Northern European | 686 (69.4) | 23 (67.7) | 271 (66.3) | 300 (69.9) | 92 (78.6) | |
| African-American | 121 (12.2) | 5 (14.7) | 54 (13.2) | 59 (13.8) | 3 (2.6) | |
| Hispanic or Latino | 33 (3.3) | 1 (2.9) | 17 (4.2) | 12 (2.8) | 3 (2.6) | |
| Asian | 72 (7.3) | 2 (8.1) | 33 (8.1) | 25 (5.8) | 12 (10.3) | |
| Other | 19 (1.9) | 0 (0.0) | 8 (2.0) | 9 (2.1) | 2 (1.7) | |
| Missing | 58 (5.9) | 3 (8.8) | 26 (6.4) | 24 (5.6) | 5 (4.3) | |
| Number of prior births b | 0.80 | |||||
| 0 | 706 (72.6) | 23 (67.7) | 293 (73.1) | 309 (73.4) | 81 (69.8) | |
| 1 | 188 (19.3) | 6 (17.7) | 75 (18.7) | 82 (19.5) | 25 (21.6) | |
| ≥2 | 78 (8.0) | 5 (14.7) | 33 (8.2) | 30 (7.1) | 10 (8.6) | |
| Prior autologous IVF transfers b | 0.12 | |||||
| 0 | 495 (52.3) | 15 (46.9) | 197 (50.5) | 215 (52.2) | 68 (60.2) | |
| 1 | 176 (18.6) | 5 (15.6) | 76 (19.5) | 79 (19.2) | 16 (14.2) | |
| 2 | 115 (12.1) | 8 (25.0) | 56 (14.4) | 39 (9.5) | 12 (10.6) | |
| ≥3 | 161 (17.0) | 4 (12.5) | 61 (15.6) | 79 (19.2) | 17 (15.0) | |
| Prior donor IVF transfers b | 0.01 | |||||
| 0 | 794 (83.7) | 27 (84.4) | 315 (81.2) | 346 (83.4) | 105 (92.1) | |
| 1 | 97 (10.2) | 3 (9.4) | 37 (9.5) | 50 (12.1) | 8 (7.0) | |
| ≥2 | 58 (6.1) | 2 (6.3) | 36 (9.3) | 19 (4.6) | 1 (0.9) | |
| Uterine factor infertility | 152 (15.4) | 5 (14.7) | 71 (17.4) | 63 (14.7) | 13 (11.1) | 0.39 |
| Recurrent pregnancy loss | 62 (6.3) | 4 (11.8) | 21 (5.1) | 27 (6.3) | 10 (8.6) | 0.30 |
| PCOS or other ovulatory dysfunction | 27 (2.7) | 0 (0.0) | 9 (2.2) | 14 (3.3) | 4 (3.4) | 0.56 |
| Number of oocytes thawed | <0.001 | |||||
| ≤5 | 167 (16.9) | 12 (35.3) | 84 (20.5) | 59 (13.8) | 12 (10.3) | |
| 6 | 592 (59.9) | 12 (35.3) | 249 (60.9) | 260 (60.6) | 70 (59.8) | |
| ≥7 | 230 (23.3) | 10 (29.4) | 76 (18.6) | 110 (25.6) | 35 (29.9) | |
| Embryo stage at transfer | 0.71 | |||||
| Day 3 | 101 (10.2) | 3 (8.8) | 47 (11.5) | 39 (9.1) | 13 (11.1) | |
| Day 5 | 888 (89.8) | 31 (91.2) | 362 (88.5) | 390 (90.9) | 104 (88.9) | |
| Number of embryos transferred | 0.12 | |||||
| 1 | 607 (61.4) | 22 (64.7) | 236 (57.7) | 270 (62.9) | 79 (67.5) | |
| 2 | 372 (37.6) | 12 (35.3) | 165 (40.3) | 157 (36.6) | 38 (32.5) | |
| 3 | 10 (1.0) | 0 (0.0) | 8 (2.0) | 2 (0.5) | 0 (0.0) | |
| Pregnancy outcome | 0.22 | |||||
| Negative pregnancy test | 245 (24.8) | 3 (8.8) | 105 (25.7) | 113 (26.3) | 24 (20.5) | |
| Biochemical pregnancy | 67 (6.8) | 7 (20.6) | 27 (6.6) | 24 (5.6) | 9 (7.7) | |
| Ectopic pregnancy | 5 (0.5) | 1 (2.9) | 2 (0.5) | 2 (0.5) | 0 (0.0) | |
| Elective termination | 3 (0.3) | 0 (0.0) | 2 (0.5) | 1 (0.2) | 0 (0.0) | |
| 1st or 2nd trimester SAB | 108 (10.9) | 5 (14.7) | 41 (10.0) | 48 (11.2) | 14 (12.0) | |
| 3rd trimester SAB | 2 (0.2) | 0 (0.0) | 1 (0.2) | 1 (0.2) | 0 (0.0) | |
| Live birth | 559 (56.5) | 18 (52.9) | 231 (55.9) | 240 (55.9) | 70 (59.8) | |
| Number of infants born | 0.90 | |||||
| 1 | 454 (81.2) | 15 (83.3) | 187 (81.0) | 104 (80.8) | 58 (82.9) | |
| 2 | 101 (18.1) | 3 (16.7) | 41 (17.8) | 45 (18.8) | 12 (17.1) | |
| 3 | 4 (0.7) | 0 (0.0) | 3 (1.3) | 1 (0.4) | 0 (0.0) | |
PCOS: polycystic ovary syndrome, SAB: spontaneous abortion
a P values were calculated using chi-square or Fisher’s exact tests where appropriate.
bAmount of women with missing data: 2 for age, 55 for BMI, 17 for parity, 42 for prior autologous IVF cycles and 40 for prior donor IVF cycles
There were 1010 babies born in the cohort from a total of 7382 oocytes, translating to 13.7 babies per 100 warmed oocytes (Table III). This was similar regardless of the number of oocytes retrieved in the donor.
Table III. Association between the number of oocytes retrieved during donor stimulation and oocyte to baby rate (among 350 donors who underwent 553 stimulations and 989 recipients who had a total of 1745 embryo transfer cycles).
| No. of donation cycles | No. of thawed oocytes | No. of useable embryos | No. of embryos transferred | No. of embryos remaining | No. of live birth deliveries | No. of babies | No. of babies per 100 warmed oocytes | Estimated No. of babies per 100 warmed oocytes if all embryos used a | |
|---|---|---|---|---|---|---|---|---|---|
| Total cohort | 1189 | 7382 | 3782 | 2429 | 1330 | 856 | 1010 | 13.7 | 21.2 |
| Number of Oocytes Retrieved | |||||||||
| ≤15 | 39 | 232 | 140 | 77 | 60 | 26 | 30 | 12.9 | 23.0 |
| 16–30 | 492 | 2963 | 1598 | 1030 | 559 | 356 | 426 | 14.4 | 22.2 |
| 31–50 | 512 | 3212 | 1592 | 1029 | 553 | 371 | 438 | 13.6 | 21.0 |
| >50 | 146 | 975 | 452 | 293 | 158 | 103 | 116 | 11.9 | 18.3 |
aFormula: {[(no. of babies/no. of embryos transferred)*no. of embryos remaining] + no. of babies}/no. thawed oocytes * 100. This calculation assumes that all remaining cryopreserved embryos will have the same delivery rate as the previous transfers.
Mean (SD) percentage of oocytes that survived the warming was 93.6% (11.5%), successfully fertilized was 79.8% (18.2%) and developed into usable embryos was 53.9% (21.8%). As the number of oocytes retrieved in a donor increased, there were decreasing proportions of oocytes that survived being warmed, fertilized and developed into usable embryos (Fig. 1). These were statistically significant for the group with >50 oocytes for survival and fertilization and for the groups >30 oocytes for usable embryos. This is also illustrated in Supplementary Table SI. Adjusting for donor age, BMI, race/ethnicity and retrieval year, donors with more oocytes retrieved had a relatively lower percentage of usable embryos per oocyte warmed (≤15: 65.9% (95% CI 57.4–73.4), 16–30: 59.3% (95% CI 55.2–63.3), 31–50: 54.3% (95% CI 49.9–58.7), >50: 52.1% (95% CI 45.2–58.8%)). For example, for the average donor in the dataset, holding all other variables in the model constant, each additional five oocytes that were retrieved was associated with 4% lower odds of fertilization and 5% lower odds of having a usable embryo from an individual oocyte. The inverse association between number of oocytes retrieved and fertilization and usable embryo rates remained (although was slightly attenuated) when the denominator was changed to number of oocytes surviving warming (data not shown). Analyzing by number of mature oocytes (versus total number of oocytes) showed similar results (data not shown). We did not find any correlation between peak estradiol and length of stimulation (days) and laboratory outcomes (data not shown).
Figure 1. Association between the number of oocytes retrieved during donor stimulation and early outcomes following oocyte warming. The association between number of oocytes retrieved during the donor’s stimulation cycle and % oocytes surviving warm, % fertilized oocytes and % usable embryos were analyzed among the 350 donors and 989 recipients using generalized estimating equations with binomial distribution and log (% surviving warm surviving warm and % fertilized surviving warm) or logit (% usable embryos) link function. The solid lines represent the adjusted percentage for each outcome and the dotted lines represent the lower and upper 95% CI. All data are presented at the mean level of continuous covariates (donor age and donor BMI) and most common level of categorical covariates (donor race and retrieval year).
Figure 2 illustrates the impact of higher number of oocytes retrieved in a donor on risk of live birth in recipients. All donor stimulations (n = 553) and embryo transfers (n = 1745) were included. There was not a significant effect of oocyte yield in the analysis adjusted for donor age, donor BMI, donor race/ethnicity, recipient age and retrieval year. RR comparing the categories of number of oocytes retrieved are presented in Supplementary Table SII. Compared against a reference range of 16–30 oocytes, having an oocyte donor who had ≤15, 31 to 50 oocytes or >50 oocytes retrieved did not affect live birth delivery rates in recipients (e.g. >50 oocytes, adjusted RR 1.02, 95% CI 0.89, 1.16). In order to determine whether the outcomes were affected by number of embryos transferred or stage of embryo transfer, we also assessed live birth delivery rates by stratifying the analysis by number of embryos transferred (1 versus 2–3 embryos), restricting the analysis to only blastocyst transfers and restricting the analysis to only first embryo transfers. Across all of these sensitivity analyses, results were similar suggesting no relationship between number of oocytes retrieved during donor stimulation and risk of live birth among the recipient (Supplementary Table SIII).
Figure 2. Association between the number of oocytes retrieved during donor stimulation and risk of live birth. Data are for 350 donors who underwent 553 stimulations and 989 recipients who had a total of 1745 embryo transfer cycles. The association between number of oocytes retrieved during the donor’s stimulation cycle and probability of live birth among was analyzed using cluster weighted generalized estimating equations with binomial distribution and log link function. The analysis was adjusted for donor age, BMI and race, retrieval year and recipient age. In the top panel, the solid black line represents the adjusted RR of live birth and the dotted black lines represent the lower and upper 95% CIs. The horizontal gray dotted line represents the null value. The bottom panel is a smoothed histogram of the exposure (number of oocytes retrieved during the donor’s stimulation cycle).
There was a total of 701 singleton infants born with a known gestational age from all of the embryo transfer cycles. The overall rates of preterm delivery (<37 weeks gestation) and low birthweight (<2500 g) were 15.1 and 9.9%, respectively. Table IV presents obstetric outcomes of these infants according to categories of number of oocytes retrieved. Overall, there was no association between number of oocytes retrieved during donor stimulation and gestational age or birthweight among singleton, live born infants. There was also no difference in the risk of preterm delivery or risk of low birthweight across categories of number of eggs retrieved. The results were similar when vanishing twin pregnancies (n = 32) were excluded as well as pregnancies resulting from multiple embryo transfer (n = 218).
Table IV. Association between number of oocytes retrieved during donor stimulation and length of gestation and birthweight among 701 donor-egg recipient singleton live births.
| Length of gestation | Birthweight | ||||||
|---|---|---|---|---|---|---|---|
| Number of singleton live births | Mean weeks/% < 37 weeks |
Adjusted
HR (95% CI) a |
Adjusted
OR of pre-term (95% CI) b |
Mean grams/% < 2500 g | Adjusted β (95% CI) c | Adjusted OR of low birthweight (95% CI) b | |
| Number of oocytes retrieved | |||||||
| ≤15 | 22 | 38.0/13.6% | 1.01 (0.75, 1.37) | 0.63 (0.14, 2.92) | 3215/13.6% | 57.2 (−222.7, 337.0) | 0.90 (0.20, 4.12) |
| 16–30 | 286 | 38.3/15.0% | REF | REF | 3261/10.6% | REF | REF |
| 31–50 | 304 | 38.4/15.8% | 0.97 (0.81, 1.16) | 1.26 (0.79, 2.02) | 3266/10.2% | 9.5 (−111.1, 130.2) | 1.02 (0.59, 1.78) |
| >50 | 89 | 38.6/13.5% | 1.02 (0.83, 1.25) | 0.85 (0.41, 1.78) | 3296/5.6% | 40.4 (−92.2, 173.0) | 0.39 (0.12, 1.30) |
HR: hazard ratio, OR: odds ratio
aAnalyses for gestational length were conducted using cluster weighted Cox proportional hazard and a robust sandwich covariance estimate to account for the multiple live births per woman in the presence of non-ignorable cluster size. Each observation was weighted inversely to the number of live births they contributed to the analysis. Models were adjusted for donor age, BMI and race (Northern European, African-American, Hispanic or Latino, Asian or Other, Missing), recipient age, retrieval year (2008–2009, 2010–2011, 2012–2013, 2014–2015).
bAnalyses for pre-term birth and low birthweight were conducted using cluster weighted generalized estimating equations with binomial distribution and logit link function to account for within-person correlations in the presence of non-ignorable cluster size. Each observation was weighted inversely to the number of live births they contributed to the analysis. Models were adjusted for donor age, BMI and race (Northern European, African-American, Hispanic or Latino, Asian or Other, Missing), recipient age, retrieval year (2008–2009, 2010–2011, 2012–2013, 2014–2015).
cAnalyses for birthweight were conducted using cluster weighted generalized estimating equations with normal distribution and identity link function to account for within-person correlations in the presence of non-ignorable cluster size. Each observation was weighted inversely to the number of live births they contributed to the analysis. Models were adjusted for donor age, BMI and race (Northern European, African-American, Hispanic or Latino, Asian or Other, Missing), recipient age and retrieval year (2008–2009, 2010–2011, 2012–2013, 2014–2015).
Discussion
In this large cohort of oocytes vitrified for use in an oocyte bank, we found an impact of high oocyte yield on laboratory parameters. As compared to oocytes from donors who had 16 to 30 oocytes retrieved, oocytes from higher yield retrievals had lower rates of developing into a usable embryo for recipients. Per embryo transfer, however, live birth delivery rates in recipients were unaffected by the oocyte donor stimulation. Similarly, we did not find any effects of high donor oocyte recruitment on adverse obstetric outcomes in singleton infants, including preterm delivery and low birthweight.
In autologous oocyte IVF, there is a known detriment of aggressive ovarian stimulation in fresh cycles, presumed to be due to the negative effect on the endometrium. In addition, there is the potential risk of ovarian hyperstimulation that often acts as a deterrent. Prior studies in autologous oocyte IVF in Europe and the USA have found live birth delivery rates to plateau at 15–20 oocytes and then diminish with increasing number retrieved (Sunkara et al., 2011; Steward et al., 2014). These studies were limited in that they only included fresh cycles. When taking both fresh and frozen-thawed cycles into account, however, there is an increase in cumulative live birth delivery rates in autologous IVF with increasing number of oocytes retrieved (Magnusson et al., 2018). Polyzos et al. reported cumulative live birth rates of 70% with more than 25 oocytes retrieved and no plateau was identified (Polyzos et al., 2018). In their study, however, the median number of oocytes retrieved was 10 (interquartile range 7–14), with less ability to study very high egg yields (e.g. >30).
Previously published studies in oocyte donor IVF have similarly not found a ‘ceiling’ in live birth delivery rates with higher oocyte yields, with more oocytes equating to more embryos available from which to pick to transfer. These studies, however, utilized fresh oocytes with matched recipients and the majority of the donors had 10–20 oocytes retrieved (Cohen et al., 1999; Letterie et al., 2005; Baker et al., 2015; Hariton et al., 2017). Our study, in contrast, used vitrified oocytes, a modality with growing prevalence. In addition, we were able to include donor ovarian stimulations with a much higher number of oocytes retrieved (218 ovarian stimulations with 31–50 oocytes; 47 ovarian stimulations with >50 oocytes).
This study provides reassuring data for oocyte donor recipients, as live birth delivery rates remain high with varying amounts of oocytes retrieved, though there may be slightly less usable embryos per oocyte. It is also helpful information to know in an oocyte bank setting, where oocytes are typically sent as a limited number cohort, that recipients are not helped or harmed by oocyte yields. In addition, our findings may have implications for women who are undergoing ovarian stimulation for autologous use, especially planned oocyte cryopreservation to preserve future fertility (Ethics Committee of the American Society for Reproductive Medicine. Electronic address et al., 2018) or a planned frozen transfer, wherein having more oocytes or embryos is often preferred.
As ovarian hyperstimulation is becoming less common with the advent of GnRH-agonist triggers and ‘freeze-all’ cycles (Iliodromiti et al., 2013), physicians and patients may have less concern about aggressive ovarian stimulation in order to maximize a cycle and the inherent financial costs involved. Importantly, however, there are limits identified in women pursuing fresh autologous transfers and safety concerns regarding aggressive ovarian stimulation (Steward et al., 2014), including side effects of bloating, abdominal pain, and cramping and risks of ovarian hyperstimulation and ovarian torsion. In addition, data on long-term health outcomes of aggressive ovarian stimulation are lacking both for oocyte donors or women pursuing autologous oocyte treatment (Soderstrom-Anttila et al., 2016). In the absence of data on long-term health outcomes and the profound short-term risks that ovarian hyperstimulation carries, it is appropriate to err on the side of caution in ovarian stimulation of donors, an especially vulnerable healthcare population.
There has been a focus in recent years on obstetric outcomes in IVF, especially in how aggressive ovarian stimulation may affect placentation and accompanying risks of preterm delivery, hypertensive disorders of pregnancy, and birthweight (Maheshwari et al., 2018). Similar to others (Baker et al., 2015), we did not find a correlation between oocyte yields and higher risk of either preterm delivery or low birthweight infants using donor oocytes. We did not have obstetric information beyond gestational age and birthweight, so we could not analyze the impact of stimulation on other obstetric issues such as hypertensive disorders of pregnancy and other placentation defects. These complications are a known higher risk in pregnancies conceived via donor oocytes, thought to be secondary to an immunologic response (Levron et al., 2014).
This study is among the first to analyze the effects of ovarian stimulation in a large cohort of cycles using oocytes that underwent a standard process of vitrification and later warming as a part of a donor oocyte bank. The use of these banks is growing in the USA; a 2013 survey identified seven different commercial egg banks in the USA (Quaas et al., 2013), but this number was updated to 16 in a 2018 review (Quaas et al., 2018). Donor oocyte IVF is an ideal model in which to study the individual influence of stimulation on the oocyte versus the endometrium (Provost et al., 2016). By transferring the embryos to recipients in frozen-warmed cycles, we were able to separate out the influence of the stimulation on the endometrium to determine the specific impact on oocyte quality and subsequent embryo quality. In addition, we were able to adjust for a large number of potential covariates in this analysis, with detailed data about both the donor and recipient. Lastly, with detailed laboratory information, we were able to study how ovarian stimulation affected in vitro outcomes.
Limitations include the fact that ovarian stimulation was exclusively performed in oocyte donors, the majority of whom were young, of a normal BMI, healthy and with a normal/high ovarian reserve. These findings may not generalizable to older or less healthy women who may be vitrifying oocytes for planned fertility delay. Lastly, we did not have progesterone levels to evaluate the impact of rising progesterone on outcomes.
In conclusion, this is an important update in a changing field regarding how ovarian stimulation affects IVF outcomes in a vitrified donor oocyte model. We found that higher donor oocyte recruitment results in slightly less usable embryos per oocyte, but live birth delivery rates were not affected by the ovarian stimulation.
Supplementary Material
Acknowledgements
We would like to acknowledge the members of the clinical and administrative staff at Reproductive Biology Associates for their support. For additional aid in completing chart review, we would like to thank Hannah Marcovitch, Alexandrea Ramsey, Sydney Archer and Deandrea Ellis. We would like to thank Dr Michael Heard for financial support.
Authors’ roles
H.S.H., Z.P.N., D.B.S. and J.B.S. participated in study conception and design. H.H. and S.C. participated in data acquisition. A.J.G. did data analysis. H.S.H., A.J.G., Z.P.N., D.B.S. and J.B.S. interpreted the data. H.H. drafted the article. All authors participated in critical revision and final approval of the article.
Funding
Additional REDCap grant support at Emory was provided through UL1 TR000424. Dr. Audrey Gaskins was supported in part by a career development award from the NIEHS (R00ES026648).
Conflict of interest
Drs Shapiro and Nagy are members of Origio/Cooper-Surgical Scientific Advisory Board and are stock owners of Prelude Fertility, Inc.
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