Beyond the American Society for Reproductive Medicine transfer guidelines: how many cleavage-stage embryos are safe to transfer in women ‡43 years old? Vinay Gunnala, M.D.,a David E. Reichman, M.D.,b Laura Meyer, M.D.,b Owen K. Davis, M.D.,b and Zev Rosenwaks, M.D.b a Weill Cornell Medical College and b The Ronald O. Perelman and Claudia Cohen Center for Reproductive Medicine, Weill Cornell Medical Center, New York, New York

Objective: To determine the number of cleavage-stage embryos that can be safely transferred in women R43 years old. Design: Retrospective cohort. Setting: Academic medical center. Patient(s): All patients R43 years old undergoing transfer of five or more cleavage-stage embryos during the period from January 2004 through April 2012. Intervention(s): In vitro fertilization. Main Outcome Measure(s): A total of 567 cycles in 464 patients aged 43–45 years, whose IVF cycles were characterized by transfer of five to eight cleavage-stage embryos were identified. Clinical outcomes and risk of multiples were analyzed, stratifying by age and number of embryos transferred. Result(s): Live birth rates per transfer were 14.4%, 9.4%, and 1.3% for women aged 43, 44, and 45 years, respectively. In 43-year-old women, 2.9% (2/69) of pregnancies were triplet gestations (one selective reduction and one spontaneous reduction). Twin birth rate was 16.3%, 6.7%, and 0 (of all live births) for ages 43, 44, and 45 years, respectively. There was no higher order multiple births. Women aged 43 and 44 years having five or more embryos transferred experienced higher clinical pregnancy rates (PRs) than those patients receiving a transfer of three or four embryos. Clinical outcomes for patients undergoing transfer with six or more embryos were not better than those undergoing transfer with five embryos. Conclusion(s): Transferring five or more day 3 embryos may be a safe option for patients R43 years of age, as it is associated with an overall low rate of multiple gestations. Having more than five embryos available for transfer on day 5 is associated with improved IVF outcomes. Whether this benefit is from the additional emUse your smartphone bryo(s) for transfer or the inherently better prognosis of such patients remains to be determined. to scan this QR code (Fertil SterilÒ 2014;102:1626–32. Ó2014 by American Society for Reproductive Medicine.) and connect to the Key Words: IVF, age >43 years, number of embryos, higher order multiples Discuss: You can discuss this article with its authors and with other ASRM members at http:// fertstertforum.com/gunnalav-how-many-embryos-safe-transfer-older-43/

B

ecause assisted reproductive technology (ART) implantation and pregnancy rates (PRs) have

increased during the past two decades, the American Society for Reproductive Medicine has successively revised

Received February 20, 2014; revised September 10, 2014; accepted September 11, 2014; published online October 22, 2014. V.G. has nothing to disclose. D.E.R. has nothing to disclose. L.M. has nothing to disclose. O.K.D. has nothing to disclose. Z.R. has nothing to disclose. Reprint requests: Owen K. Davis, M.D., The Ronald O. Perelman and Claudia Cohen Center for Reproductive Medicine, Weill Cornell Medical Center, 1305 York Avenue, New York, New York 10021 (E-mail: [email protected]). Fertility and Sterility® Vol. 102, No. 6, December 2014 0015-0282/$36.00 Copyright ©2014 American Society for Reproductive Medicine, Published by Elsevier Inc. http://dx.doi.org/10.1016/j.fertnstert.2014.09.015 1626

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guidelines for the number of embryos to be transferred (1). Although much data have accrued regarding the risks of multiple gestations with high ET number for most patients, less robust data exist regarding a transfer ceiling for patients at the higher extremes of reproductive aging. To this point, the American Society for Reproductive Medicine in their most recent iteration of the committee opinion entitled VOL. 102 NO. 6 / DECEMBER 2014

Fertility and Sterility® ‘‘Criteria for number of embryos to transfer’’ stated that although it is not recommended to transfer more than 5 cleavage-stage embryos in women aged 41–42 years, ‘‘there are insufficient data to recommend a limit on the number of embryos to transfer in women R43 years of age’’ (1). At present, there is great variability in the number of day 3 embryos that individual programs feel comfortable transferring within this demographic, with limited data on a national scale to guide decision-making. Although evolving laboratory techniques have led to an increasing focus on blastocyst transfer, many women of P43 years of age do not have embryos that reach the blastocyst stage, or have had multiple prior failed attempts after day 5 ETs. Although such patients may benefit from day 3 transfer, it is difficult to counsel patients on the risk of multiple gestations given the paucity of cycles in patients aged P43 years with five or more embryos available for transfer. Given the increased risks of pregnancy in women of advanced reproductive age, minimizing multiple births in this demographic is of great importance. To address this question, we assessed our center's experience with transfer of five or more embryos in patients R43 years old to evaluate the likelihood of cycle success versus the incidence of multiple gestations, with the goal of creating data-driven parameters for safe transfer number.

follicles reached R17 mm. Embryo retrieval was performed in the standard fashion under monitored anesthesia care 35–37 hours after hCG administration. One day after oocyte retrieval, luteal P supplementation was initiated using 50 mg of IM P. Patients' oocytes were subjected to either conventional insemination or intracytoplasmic sperm injection (ICSI) according to infertility diagnosis and prior ART history. Oocytes undergoing ICSI were enzymatically and mechanically denuded to assess nuclear maturity before injection. The study period comprised a time period before our switching to reduced oxygen tension culture, during which all fertilized oocytes were incubated in in-house proprietary culture media (C1) at ambient oxygen and 5% CO2. Core laboratory personnel, media, physical facilities, and laboratory protocols were stable during this time period. Day 3 embryos with six to eight symmetric blastomeres and low fragmentation were favored for transfer in cases in which embryo selection was possible. Number of embryos to be transferred in this older demographic was a highly individual decision based on prior IVF performance, physician practice patterns, statement of the patient regarding comfort with multifetal reduction, day 3 cell number/embryo morphology, and availability of embryos for transfer. All identified patients meeting inclusion criteria underwent day 3 ET, which was performed with a Wallace catheter (Marlow/Cooper Surgical).

MATERIALS AND METHODS Cycle Inclusion and Exclusion Criteria

Outcome Variables Assessed

This study was approved by the Weill Cornell Medical College Institutional Review Board. All IVF cycles performed at the Ronald O. Perelman and Claudia Cohen Center for Reproductive Medicine from January 2004 through April 2012 were reviewed. A total of 20,745 IVF cycles occurring at our center during the study period were screened for inclusion. Inclusion criteria were any fresh IVF cycles in women aged 43–45 years at the time of oocyte retrieval in whom a minimum of five day 3 embryos were transferred. The study was designed as a retrospective cohort to compare the outcomes for patients having five or more embryos transferred compared with similarly aged patients undergoing transfer of three or four cleavage-stage embryos. Patients who underwent prenatal genetic screening or diagnosis before ET were excluded, as were donor egg recipients and patients pursuing gestational surrogacy.

Demographic characteristics of patients meeting inclusion criteria were collected. Implantation rate, clinical PR, live birth rate, rate of twins, and rate of higher order multiples were analyzed, stratifying by age and number of embryos transferred. Implantation rate was defined as the number of sacs detected by ultrasound at 6 weeks divided by the number of embryos transferred. Clinical PR was defined as the number of cycles with at least one viable fetus (as evidenced by fetal cardiac activity by ultrasound at 7 weeks) per transfer. Live birth rate was defined as the number of cycles resulting in at least one live born child delivered at R28 weeks gestation divided by of all transfers performed. Rate of twin clinical pregnancy was defined as the number of pregnancies with two fetal hearts divided by all clinical pregnancies. Rate of twin live birth was similarly defined, with all live births as the denominator. Rate of higher order multiples was defined in the same fashion.

Clinical and Laboratory Protocols Protocols for controlled ovarian hyperstimulation (COH) and egg retrieval were performed as was described previously (2). In brief, patients were administered either a GnRH agonist (lupron, Abbott Pharmaceuticals) followed by gonadotropin stimulation (follistim, Merck; gonal-F, EMD-Serono; and/or menopur, Ferring) or alternatively suppressed using a flexible GnRH antagonist protocol (ganirelix acetate: 0.25 mg Organon; Cetrotide 0.25 mg: EMD-Serono). Human chorionic gonadotropin (profasi, EMD-Serono; novarel, Ferring Pharmaceuticals; or pregnyl, ScheringPlough) was generally administered when two or more VOL. 102 NO. 6 / DECEMBER 2014

Statistical Analysis All data analyses were performed with STATA Statistical Software, version 11 (StataCorp LP). Differences in continuous variables according to age were determined using analysis of variance (ANOVA) with Bonferroni adjustment for multiple comparisons. The IVF outcomes according to age and number of embryos transferred were compared using the c2 test. Differences in demographic characteristics and implantation between patients having three to four embryos transferred versus five or more were calculated by t test. In all cases, P< .05 was considered to be statistically significant. 1627

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RESULTS Of the 20,745 cycles performed during the study period, 2.7 % (567 cycles) met inclusion criteria. In total 298, 192, and 77 cycles in patients aged 43 (250 patients), 44 (152 patients), and 45 (62 patients) years, respectively, underwent transfer of five or more cleavage-stage embryos. No patient had more than eight embryos transferred. The demographic characteristics of the study population are shown in Table 1. There were no differences in demographic characteristics between groups. Similarly, there were no differences observed in number of oocytes harvested, mature oocytes, or fertilization across age groups. These 567 cycles represented 23% of all cycles in patients aged 43–45 years undergoing IVF at our institution during the same time period. Table 2 demonstrates the primary clinical outcomes assessed in this study. There were no statistically significant differences in implantation, clinical pregnancy or live birth according to number of embryos transferred within any of the three age groups. The overall live birth rates were 14.4%, 9.4%, and 1.3% for women aged 43, 44, and 45 years, respectively (Supplemental Table 1, available online). In terms of risk for multiple gestations, 43-year-old patients had an overall 16.3% chance of having a twin live birth in their pregnancy cycle, with no difference in risk with increasing transfer number. Two transfers in this age group (0.7% of all cycles in this group, 2.9% of clinical pregnancies achieved) resulted in pregnancies with three fetuses. One of these patients had five embryos transferred and elected to selectively reduce the pregnancy to twins; in the other patient, in whom six embryos were transferred, the third fetus spontaneously reduced. In both circumstances, a twin birth occurred. Of note, transfer of more than five embryos did not result in significantly higher clinical PR or live birth rate than transfer of five embryos alone, although statistical power was limited for this comparison given the paucity of cases with seven or eight embryos transferred.

For patients aged 44 years, 6.7% of pregnancy cycles were twin gestations, with no difference in risk with increasing transfer number (see Table 2). No triplet gestations occurred. There were no multiple gestations in the 45-year-old age group despite a maximum of eight embryos transferred. On the whole, 43- and 44-year-old patients with five or more embryos for transfer had significantly better IVF outcomes compared with all 43- and 44-year olds undergoing transfer after IVF. Live birth rate was 14.4% for 43-year olds undergoing transfer of five or more embryos as opposed to 6.4% for 43-year olds undergoing transfer of one to four day 3 embryos (P¼ .0001). The 44-year olds similarly experienced higher live birth rates (9.4% vs. 1.9%; P¼ .0001). No differences, however, were evident among 45-year olds. Table 3 shows the demographic characteristics of patients aged 43–45 years undergoing day 3 transfer with three or four embryos, compared with the study cohort undergoing transfer with five or more embryos. As shown, patients with five or more embryos for transfer tended to have higher antral follicle counts and better response to stimulation, with more mature oocytes harvested. In addition, 43-year olds had lower day 3 FSH levels and slightly higher average day 3 blastomere numbers within the transferred cohort. Number of blastocysts frozen also varied significantly; 43- and 44-year old patients were unlikely to have any embryos frozen, but those experiencing transfer of five or more embryos (compared with 3 or 4 embryos) had significantly more frozen (0.10 vs. 0.02 embryos, aged 43 years; 0.09 vs. 0.01 embryos, aged 44 years). As shown in Table 4, transfer of five or more embryos as opposed to three or four embryos was associated with a statistically significant increase in clinical PRs for patients aged 43 and 44 years, and a statistically significant increase in live birth rate in 44-year olds. Differences in live birth rate for 43-year olds just missed the threshold for significance (P¼ .05). There was a small but not statistically significant increase in the risk of multiples with transfer of five or more

TABLE 1 Demographic characteristics in patients aged 43–45 years undergoing fresh IVF with five or more embryos transferred. Age (y) Characteristic No. of cycles Gravidity (median) Parity (median) Day 3 FSH level (mIU/mL) AFC BMI No. of prior IVF attempts Starting dose (IU) Total gonadotropins (IU) E2 at hCG administration (pg/mL) No. of embryos harvested No. of embryos mature 2PN Days of stimulation Day 3 cell number

43

44

45

P value

298 1 0 8.6  3.7 7.5  3.2 24.6  4.4 2.8  2.3 472.6  122.9 3,936.0  1,545.1 1,781.9  690.5 12.1  4.5 10.2  3.7 7.9  3.2 9.6  1.8 7.2  1.2

192 2 0 8.9  3.4 7.8  3.4 24.4  4.9 2.9  2.4 489.8  117.5 4,046.4  1,570.1 1,809.1  686.7 12.1  4.7 10.2  3.6 7.6  2.6 9.9  2.0 7.4  1.0

77 2 1 9.6  3.6 7.4  3.7 23.7  4.0 3.6  2.6 489.9  131.7 3,964.0  1,707.7 1,629.3  761.1 11.5  5.1 9.8  4.2 7.5  3.1 9.4  1.7 7.4  0.9

.91 .29 .05 .56 .28 .06 .24 .75 .15 .53 .73 .46 .14 .58

Note: AFC ¼ antral follicle count; BMI ¼ body mass index; PN ¼ pronuclei. Gunnala. Transfer of R5 embryos in women R43 years old. Fertil Steril 2014.

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TABLE 2 Primary clinical outcomes stratified by age and number of embryos transferred for five or more embryos transferred. Clinical outcome Age, 43 y No. of cycles Implantation (%) Clinical pregnancy (%) Live birth (%) % twin FH % triplet FH % twin birth % HOM birth Age, 44 y No. of cycles Implantation (%) Clinical pregnancy (%) Live birth (%) % twin FH % triplet FH % twin birth % HOM birth Age, 45 y No. of cycles Implantation (%) Clinical pregnancy (%) Live birth (%) % twin FH % triplet FH % twin birth % HOM birth

5 embryos

6 embryos

7 embryos

8 embryos

P value

151 7.9  13.7 22.5 11.9 23.5 2.9 22.2 0

129 7.0  12.5 23.3 16.3 23.3 3.3 9.5 0

12 7.0  12.5 25.0 16.7 0 0 0 0

6 6.3  10.5 33.3 33.3 50.0 0 50.0 0

.83 .94 .30 .65 1.0 .32 NA

92 4.4  9.3 14.1 10.9 0 0 0 0

78 5.6  9.9 17.9 7.7 14.3 0 16.7 0

16 0.9  3.6 6.3 6.3 0 0 0 0

6 4.2  6.5 33.3 16.7 0 0 0 0

.32 .40 .71 .58 NA .47 NA

35 1.1  4.7 0 0 0 0 0 0

27 1.2  4.4 3.7 0 0 0 0 0

5 5.0  6.9 20.0 20.0 0 0 0 0

.24 .06 .07 NA NA NA NA

10 0 0 0 0 0 0 0

Note: FH ¼ fetal heart beat; HOM ¼ higher order multiples; NA ¼ not available. Gunnala. Transfer of R5 embryos in women R43 years old. Fertil Steril 2014.

embryos as opposed to three or four embryos. The 43-year olds had a 64.7% increased likelihood of conception with five or more embryos transferred as opposed to patients with three or four embryos transferred (odds ratio [OR] 1.647, 95% confidence interval [CI] 1.086–2.498). Live birth rate was similarly increased, although was just shy of statistical significance (OR 1.649, 95% CI 0.989–2.749; P¼ .053). The 44-year olds were 2.4 times as likely to achieve clinical pregnancy with transfer of five or more embryos as opposed to three or four embryos (OR 2.365, 95% CI 1.191–4.695), with a corresponding increase in live birth (OR 3.6, 95% CI 1.308–9.912). For patients aged 45 years, there were no differences in chance of pregnancy according to number of embryos transferred.

DISCUSSION The current study was undertaken to evaluate the risk of multiple gestations with transfer of five or more cleavage-stage embryos in older women undergoing IVF. Our study demonstrates an overall acceptable safety profile of such transfers in women older than 42 years with regard to multiple gestations, with no higher order multiple births occurring within the cohort studied (although two triplet gestations did occur, with one spontaneous reduction and one reduction procedure performed). Transfer of five or more embryos was associated with a higher chance of pregnancy (and live birth in 44-year olds) compared with patients experiencing transfer with three or four day 3 embryos, albeit with a small (but not statistically VOL. 102 NO. 6 / DECEMBER 2014

significant) increase in the risk of multiple pregnancy as opposed to transferring three or four cleavage-stage embryos. Of note, increasing the number of embryos transferred beyond five did not statistically improve clinical outcomes for any of the age groups studied. Studies have demonstrated a lower reproductive efficiency in women older than 40 years and therefore a relatively low probability of multiple gestations despite transferring increasing number of embryos (3–5). For instance, in a study analyzing 455 IVF cycles in women aged 40–44 years old, there were only three multiple births (all twins), despite transferring up to 10 embryos; average transfer number was not defined in that study (4). Conversely, in a larger study analyzing IVF outcomes in 5,016 women aged 40–44 years, the multiple birth rate was 24.6%, 24.1%, and 38.6% respectively, when five, six, or seven or more embryos were transferred. That study (5), however, did not delineate the age distribution of patients, and presumably was composed of patients closer to age 40 years based on the PRs reported. Higher order multiple births in this group were 2.1%, 0.9%, and 5.3%, respectively. The importance of preventing multiple gestations cannot be overstated. Even in singleton gestations, women older than 40 years experience an increased incidence of gestational diabetes, prematurity, low birth weight, low Apgar scores, and cesarean section (6–8). Such risks are compounded in the setting of multiples. Single blastocyst transfer, with or without preimplantation genetic screening, is an excellent means of avoiding multiple gestations. However, blastocyst 1629

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TABLE 3 Demographic comparison of patients having transfer of three to four embryos versus five or more embryos according to age. 3–4 embryos

‡5 embryos

P value

291 1 0 9.8  4.8 6.6  2.9 24.6  5.0 2.9  3.0 501.3  114.6 4,602.1  1,662.4 1,337.2  626.2 7.4  3.2 5.9  2.6 4.0  1.5 10.2  2.1 6.9  1.3 0.02  0.18

298 1 0 8.5  3.7 7.5  3.2 24.6  4.4 2.8  2.3 472.6  122.9 3,935.9  1,545.1 1,781.9  690.5 12.1  4.5 10.2  3.7 7.9  3.2 9.6  1.8 7.2  1.2 0.10  0.65

.98 .67 .0008 .0003 .93 .89 .004 .00001 .00001 .00001 .00001 .00001 .0003 .01 .034

179 1 0 9.3  4.0 6.3  2.9 24.9  5.6 2.8  2.9 502.6  113.6 4,671.9  1,680.4 1,321.6  712.9 7.2  3.4 5.7  2.6 4.0  1.6 10.3  2.2 7.3  1.1 0.01  0.15

192 2 0 8.9  3.4 7.8  3.4 24.2  4.9 2.9  2.4 489.8  117.5 4,046.4  1,570.1 1,809.1  686.7 12.1  4.7 10.2  3.6 7.6  2.6 9.9  2.0 7.4  1.0 0.09  0.5

.59 .72 .19 .00001 .24 .68 .29 .0002 .00001 .00001 .00001 .00001 .07 .88 .047

73 2 1 10.3  3.7 6.7  2.7 24.3  4.8 3.3  3.1 514.4  104.6 4,650.9  1,545.3 1,186.9  466.9 6.4  2.5 5.3  2.0 3.9  1.4 9.8  2.3 7.5  0.8 00

77 2 1 9.6  3.6 7.4  3.7 23.7  4.0 3.6  2.6 489.9  131.7 3,964  1,707.7 1,629.3  761.1 11.5  5.1 9.8  4.2 7.5  3.1 9.4  1.7 7.4  0.9 00

.71 .89 .33 .25 .41 .43 .21 .01 .00001 .00001 .00001 .00001 .28 .34

Demographic variable Age, 43 y No. of cycles Gravidity (median) Parity (median) Day 3 FSH level (mIU/mL) AFC BMI No. of prior IVF attempts Starting dose (IU) Total gonadotropins (IU) E2 at hCG administration (pg/mL) No. of harvested embryos No. of mature embryos 2 PN Days of stimulation No. of cells (transfer cohort) No. of frozen blastocysts Age, 44 y No. of cycles Gravidity (median) Parity (median) Day 3 FSH level (mIU/mL) AFC BMI No. of prior IVF attempts Starting dose (IU) Total gonadotropins (IU) E2 at hCG administration (pg/mL) No. of harvested embryos No. of mature embryos 2 PN Days of stimulation No. of cells (transfer cohort) No. of frozen blastocysts Age, 45 y No. of cycles Gravidity (median) Parity (median) Day 3 FSH level (mIU/mL) AFC BMI No. of prior IVF attempts Starting dose (IU) Total gonadotropins (IU) E2 at hCG administration (pg/mL) No. of harvested embryos No. of mature embryos 2 PN Days of stimulation No. of cells (transfer cohort) No. of frozen blastocysts

1

Note: AFC ¼ antral follicle count; BMI ¼ body mass index; PN ¼ pronuclei. Gunnala. Transfer of R5 embryos in women R43 years old. Fertil Steril 2014.

transfer may be less feasible in women at the latter extreme of reproductive aging, as culturing to blastocyst is associated with a significantly lower transfer rate in women more than 40 years as opposed to younger women (9). Day 3 transfer may be more appropriate in instances where in vitro attrition is a clinical concern. Many of our older patients have previously failed multiple attempts at blastocyst transfer, either from cycle cancellation due to lack of embryos for transfer on day 5 or failure to conceive despite 1630

having blastocysts transferred. For these patients day 3 transfer should be considered, and thus data regarding multiple gestation risk are needed. It should be noted that the population analyzed in this study represents a small proportion of patients undergoing IVF in this age group, as response to stimulation and embryo quality both diminish greatly with age (10, 11). Only recently has Society of Assisted Reproductive Technology (SART) begun reporting IVF outcomes and cycle VOL. 102 NO. 6 / DECEMBER 2014

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TABLE 4 Clinical outcomes for patients with five or more embryos transferred versus three or four embryos transferred. Clinical outcome Age, 43 y No. of cycles Implantation (%) Clinical pregnancy (%) Live birth (%) % twin FH % triplet FH % twin birth % HOM birth Age, 44 y No. of cycles Implantation (%) Clinical pregnancy (%) Live birth (%) % twin FH % triplet FH % twin birth % HOM birth Age, 45 y No. of cycles Implantation (%) Clinical pregnancy (%) Live birth (%) % twin FH % triplet FH % twin birth % HOM birth

3–4 embryos

5–8 embryos

P value

291 6.2  13.8 15.5 9.3 11.1 0 7.4 0

298 7.3  12.9 23.2 14.4 23.2 2.9 16.3 0

.31 .02 .05 .16 .73 .49 NA

179 4.6  12.3 7.3 2.8 0 0 0 0

192 4.5  9.2 15.6 9.4 6.7 0 5.6 0

.99 .01 .01 .96 NA 1.0 NA

73 2.9  8.9 9.5 5.5 0 0 0 0

77 1.3  4.5 2.6 1.3 0 0 0 0

.17 .15 .33 NA NA NA NA

Note: FH ¼ fetal heart beat; HOM ¼ higher order multiples; NA ¼ not available. Gunnala. Transfer of R5 embryos in women R43 years old. Fertil Steril 2014.

characteristics on women aged 43–44 years. Existing studies examining IVF outcomes in older patients reveal reasonable success rates in women up to 44 years, but only limited success in women aged 45 years, even when several embryos are available for transfer (12–15). In a recent study (16) analyzing the outcomes of 108 fresh IVF transfers (n ¼ 99 cleavagestage embryos, n ¼ 9 blastocyst) in women aged 43–45 years, the mean number of embryos transferred was 2.2  2.1 and the live birth rate (per cycle) was 9.6%, 3.6%, and 0, respectively. Multiple PRs were not reported. In a larger study (17), analyzing the outcomes of 501 fresh IVF cycles in women 43–45 years old, the overall reported mean number of embryos transferred was 2.7  1.5, which resulted in an overall live birth rate of 2.8%. In contrast to these two studies, our data suggest a potential benefit of higher transfer number, albeit with a small risk of multiples in the 43-year-old demographic. Potential intrinsic differences between the two patient populations studied are a limitation of our data. It should be noted that older patients with five or more embryos available for transfer may be a more favorable demographic than those patients with only three or four embryos. The 43-year olds had embryos with slightly more blastomeres at transfer, perhaps underlying superior embryo quality. In addition, 43- and 44-year olds having transfer with five or more embryos also had a statistically significant higher chance of having blastocysts available for freezing. It is thus unclear whether transferring one additional embryo is truly a benefit, VOL. 102 NO. 6 / DECEMBER 2014

or whether the patient population studied is associated with a better prognosis that would still be manifest when only four embryos are transferred. Whether outcomes would differ for patients having four versus five day 3 embryos transferred when analysis is limited to only patients with excess embryos for transfer remains to be determined, and would be best answered by a randomized controlled trial. Our analysis provides insight into the chance of pregnancy and risk of multiples when transferring five or more embryos, questions with a dearth of answers in the existing literature. In addition, the fact that implantation rates were not different between the index and control populations of this study argues for a potential incremental benefit of the additional embryo(s) transferred. In conclusion, our study demonstrates that five or more cleavage-stage embryos can be transferred in women aged 43–45 years who are undergoing fresh autologous IVF cycles, and can be viewed as a clinical alternative to potential blastocyst transfer. Our study showed no higher order multiples births in any age group (albeit with a clinically induced reduction of one triplet gestation) and a low overall twin birth rate. It should be noted that patients undergoing transfer of six or more embryos did not do considerably better than patients undergoing transfer with five embryos, thus arguing that the benefit versus patients having four embryos transferred is potentially the incremental addition of one extra embryo. Our data, however, are insufficient in number to establish a maximum limit on the number of embryos that can be transferred within this age group, and indeed, transferring seven or eight embryos, at any age, requires a careful review of the patient's history, diagnosis, and ART performance. The reasonable live birth rates for 43- and 44-year olds with adequate ovarian reserve suggest that this age group should not be discouraged from attempting IVF after appropriate counseling. For patients in this age group with several embryos on day 3, we offer both options (cleavage stage vs. blastocyst transfer) based on their previous history of treatment success or failure, and according to their preferences after nuanced counseling. Given their low PRs regardless of the number of embryos transferred, 45-year olds should be offered the option of oocyte donation.

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SUPPLEMENTAL TABLE 1 Summary of clinical outcomes for five or more embryos transferred. Clinical outcome

Age, 43 y

Age, 44 y

Age, 45 y

No. of cycles Implantation (%) Clinical pregnancy (%) Live birth (%) % twin FH % triplet FH % twin birth % HOM birth

298 7.3  12.9 23.2 14.4 23.2 2.9 16.3 0

192 4.5  9.2 15.6 9.4 6.7 0 5.6 0

77 1.3  4.5 2.6 1.3 0 0 0 0

Note: FH ¼ fetal heart beat; HOM ¼ higher order multiples. Gunnala. Transfer of R5 embryos in women R43 years old. Fertil Steril 2014.

VOL. 102 NO. 6 / DECEMBER 2014

1632.e1

Beyond the American Society for Reproductive Medicine transfer guidelines: how many cleavage-stage embryos are safe to transfer in women ≥43 years old?

To determine the number of cleavage-stage embryos that can be safely transferred in women ≥43 years old...
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