Comparison of perinatal outcomes following fresh and frozen-thawed blastocyst transfer

Comparison of perinatal outcomes following fresh and frozen-thawed blastocyst transfer

IJG-08732; No of Pages 5 International Journal of Gynecology and Obstetrics xxx (2016) xxx–xxx Contents lists available at ScienceDirect Internation...

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IJG-08732; No of Pages 5 International Journal of Gynecology and Obstetrics xxx (2016) xxx–xxx

Contents lists available at ScienceDirect

International Journal of Gynecology and Obstetrics journal homepage: www.elsevier.com/locate/ijgo

CLINICAL ARTICLE

Comparison of perinatal outcomes following fresh and frozen-thawed blastocyst transfer☆ Nigel Pereira a,⁎, Allison C. Petrini b, Jovana P. Lekovich a, Glenn L. Schattman a, Zev Rosenwaks a a b

Ronald O. Perelman and Claudia Cohen Center for Reproductive Medicine, Weill Cornell Medical Center, New York, NY, USA Department of Obstetrics and Gynecology, Weill Cornell Medical College, New York, NY, USA

a r t i c l e

i n f o

Article history: Received 22 January 2016 Received in revised form 12 April 2016 Accepted 8 June 2016 Keywords: Blastocyst Fresh embryo transfer Frozen embryo transfer In vitro fertilization Perinatal outcomes Pregnancy outcomes

a b s t r a c t Objective: To investigate the effect of ovarian stimulation on endometrial receptivity by comparing singleton pregnancy and perinatal outcomes following fresh or frozen-thawed blastocyst transfers. Methods: A retrospective cohort study enrolled patients undergoing fresh or frozen-thawed blastocyst transfers that resulted in live deliveries between January 1, 2010 and September 30, 2013 at a single academic center. Implantation, clinical pregnancy, spontaneous abortion, and live delivery rates were calculated. The incidence of term delivery, preterm delivery, low birth weight, term low birth weight, and very low birth weight were also recorded. To detect a 10% difference in the implantation rate, a minimum sample size of at least 415 transfer cycles in each group was estimated. Results: The study included data from 918 fresh and 1273 frozen-thawed cycles. Patients in both groups were of similar age and there was no difference in the grading of blastocysts. No differences were observed in the implantation (37.3% vs 37.7%), clinical pregnancy (50.2% vs 49.4%), spontaneous abortion (7.3% vs 9.3%), and live delivery (42.9% vs 40.6%) rates of the two groups. A sub-analysis of all live singleton and twin deliveries revealed no difference in perinatal outcomes between the two techniques. Conclusions: The present study demonstrated equivalent singleton pregnancy and perinatal outcomes when comparing frozenthawed and fresh blastocyst transfer procedures. © 2016 International Federation of Gynecology and Obstetrics. Published by Elsevier Ireland Ltd. All rights reserved.

1. Introduction During the past decade, frozen-thawed embryo transfers (FETs) have contributed to an increase in the proportion of live deliveries that occur following the use of assisted reproductive technology [1]. According to the Society for Assisted Reproductive Technology, the number of FETs has increased by 82.5% between 2006 and 2012, whereas there was an increase of only 3.1% in the number of fresh embryo transfers during the same period [2,3]. Although the increase in FETs can be attributed to factors including improved cryopreservation techniques, specifically vitrification [4], as well as banking of genetically screened embryos [3], there has also been a shift towards FETs in the name of improved endometrial receptivity and perinatal outcomes. Recent data have suggested a detrimental effect of ovarian stimulation on endometrial receptivity during fresh in vitro fertilization (IVF) cycles [5,6], leading to higher rates of low birth weight (LBW) [7], preterm delivery [8], and other adverse perinatal outcomes [5,8,9]. In the context of

☆ Presented at the American Society of Reproductive Medicine 2015 Annual Meeting; October 17–21, 2015; Baltimore, Maryland, USA. ⁎ Corresponding author at: Weill Cornell Medical Center, The Ronald O. Perelman and Claudia Cohen Center for Reproductive Medicine, 1305 York Ave., New York, NY 10021, USA. Tel.: +1 646 962 3745; fax: +1 646 962 0395. E-mail address: [email protected] (N. Pereira).

these epidemiologic findings, preferentially electing to transfer frozenthawed embryos into a more receptive uterine environment over transferring fresh embryos immediately following ovarian stimulation has been proposed as the new gold standard of care for assisted reproductive technology [5,10]. In an attempt to mimic the natural stimulation process, a physiologic approach to ovarian stimulation has been utilized by the authors, with a step-down protocol and combinations of folliclestimulating hormone and luteinizing hormone activity. To investigate the effect of ovarian stimulation on endometrial receptivity, the aim of the present study was to compare the singleton pregnancy and perinatal outcomes between fresh and frozen-thawed blastocyst transfers at the study institution. 2. Materials and methods All patients who began IVF cycles at the Ronald O. Perelman and Claudia Cohen Center for Reproductive Medicine, New York, USA, that resulted in live deliveries between January 1, 2010 and September 30, 2013 were analyzed for potential inclusion in the present study. Only fresh and frozen-thawed blastocyst transfers were included. Any live deliveries occurring earlier than 37 weeks of pregnancy were defined as preterm deliveries. Preterm delivery earlier than 34 weeks of pregnancy was defined as early preterm delivery, while preterm delivery between 34 and 37 weeks of pregnancy was defined as late preterm

http://dx.doi.org/10.1016/j.ijgo.2016.04.007 0020-7292/© 2016 International Federation of Gynecology and Obstetrics. Published by Elsevier Ireland Ltd. All rights reserved.

Please cite this article as: Pereira N, et al, Comparison of perinatal outcomes following fresh and frozen-thawed blastocyst transfer, Int J Gynecol Obstet (2016), http://dx.doi.org/10.1016/j.ijgo.2016.04.007

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delivery [11]. Neonatal weight below 2500 g at delivery, irrespective of gestational age, was defined as LBW [12] and neonatal weight below 1500 g at delivery, irrespective of gestational age, was defined as very low birth weight (VLBW) [12]. The Weill Cornell Medical College institutional review board approved the study design (protocol# 1503016064) and, as the protocol involved the retrospective review of patient charts, the need for individual consent from patients was waived. Controlled ovarian stimulation was performed to maximize ovarian follicular response while minimizing the overall risk of ovarian hyperstimulation syndrome. Controlled ovarian stimulation, human chorionic gonadotropin (hCG) trigger, oocyte retrieval, embryo culture, and embryo transfer were performed per the standard protocols at the study institution [13]. Patients were downregulated in the preceding luteal phase using either oral contraceptive pills or 0.1 mg (estradiol) E2 patches. Controlled ovarian stimulation was initiated with gonadotropins (Follistim; Merck, Kenilworth, NJ, USA; Gonal-F; EMDSerono Inc, Rockland, MA, USA; and/or Menopur; Ferring Pharmaceuticals Inc, Parsippany, NJ, USA). Patients were initially treated with a gonadotropin-releasing hormone antagonist (Ganirelix acetate 0.25 mg; Merck, Kenilworth, NJ, USA) based on a previously described flexible protocol to suppress ovulation [13]. hCG was used to trigger ovulation and was administered according to a sliding scale dosage (10 000 IU for E2 ≤ 1500 pg/mL; 5000 IU for E2 1501–2500 pg/mL; 4000 IU for E2 2501–3000 pg/mL; and 3300 IU for E2 ≥3001 pg/mL). In general, the hCG trigger was administered when two lead follicles attained a mean diameter larger than 17 mm. Oocyte retrieval was performed under conscious sedation using transvaginal ultrasonography guidance approximately 35–37 hours after hCG administration. Luteal support was initiated the day after retrieval using 50 mg of intramuscular progesterone daily. IVF was performed using conventional insemination or intracytoplasmic sperm injection based on each patient’s partner's semen analysis and the couple’s history. All embryos were cultured using a two-step culture media manufactured in the study institution’s embryology laboratory. Embryos cultured until the blastocyst stage were then graded based on their degree of expansion, development of the inner cell mass and trophectoderm [14]. Patients underwent fresh blastocyst transfers on day five. Embryo transfers were performed using catheters (Smiths Medical Inc, Norwell, MA, USA) at approximately 1 cm below the uterine depth identified at prior trial transfer. Ultrasonography guidance was only utilized when the transfers were deemed difficult based on the prior trial transfer. Cryopreservation of day-five blastocysts from fresh IVF cycles was generally performed for either the cryopreservation of supernumerary top-quality blastocysts during the fresh IVF cycle, or the prevention of ovarian hyperstimulation syndrome. All blastocysts were cryopreserved using a previously described protocol [15]. Briefly, embryos were transferred through vitrification solutions containing ethylene glycol, dimethyl sulfoxide and sucrose before being loaded to a vitrification device (Cryolock; Biotech Inc, Cumming, GA, USA) and immersed in liquid nitrogen [15]. Patients underwent either natural or programmed FETs based on menstrual history or prior FET success. Patients with ovulatory menstrual cycles underwent natural FET comprising ultrasonographic and hormonal monitoring for ovulation. Vaginal progesterone supplementation (Endometrin 100 mg twice daily; Ferring Pharmaceuticals Inc, Parsippany, NJ, USA) was started one day after luteinizing hormone surge in some patients based on clinical history and physician preference. Patients with anovulatory menstrual cycles underwent programmed FET, in which patients received 0.1-mg E2 patches with or without prior downregulation using gonadotropin-releasing hormone antagonist. After confirming the presence of a trilaminar endometrial pattern via ultrasonography, intramuscular progesterone supplementation was initiated. FET was performed in these patients 5 days after the detection of luteinizing hormone surge. Embryo transfers were performed using the same procedure as fresh IVF cycles. The demographic characteristics included in the analyses were age, parity, body mass index, and the number of previous IVF attempts;

patient baseline variables included total days of stimulation, total gonadotropin dose administered, endometrial stripe thickness on day of hCG or peak thickness prior to progesterone administration, number of oocytes retrieved, the number of mature oocytes, and the grade of the transferred blastocyst. The implantation rate was defined as the mean number of sacs observed on ultrasonography divided by the number of embryos transferred for each patient. Clinical pregnancy rate was defined as the number of intrauterine gestations with fetal cardiac activity per cycle. A biochemical pregnancy was defined by positive hCG levels without a gestational sac. Pregnancy loss after visualization of an intrauterine gestation was considered a spontaneous abortion. Any delivery after 24 weeks of pregnancy was considered a live delivery. The perinatal outcomes analyzed included mode of delivery, incidence of term deliveries, incidence of preterm deliveries (including early and late preterm delivery), overall birth weight, LBW, VLBW, and term LBW. Continuous variables were expressed as mean ± SD, categorical variables were expressed as absolute numbers and percentages, and non-parametric variables were expressed as medians and interquartile ranges. The Student t test was utilized to analyze differences between groups for continuous variables, the χ2 and Fisher exact tests were used for categorical variables, and the Wilcoxon rank-sum test was used for non-parametric variables. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated for the incidence of preterm delivery, overall LBW, and term LBW, and adjusted ORs (aOR) were calculated incorporating the Mantzel– Haenszel correction. Statistical significance was set at Pb 0.05 and statistical analyses were performed using STATA version 13 (StataCorp LP; College Station, TX, USA). Assuming an α error of 5% and power of 80%, a minimum sample size of at least 415 transfer cycles in each group was deemed necessary to detect a 10% difference in implantation rates [3]. 3. Results A total of 2191 blastocyst transfer cycles met the inclusion criteria during the study period; 918 were fresh embryo transfers and 1273 were frozen-thawed transfers. Demographic and baseline characteristics of patients who underwent fresh IVF cycles are detailed in Table 1. When the demographic characteristics and blastocyst grading were compared between patients who underwent fresh or frozen-thawed blastocyst transfers, no significant differences were observed in age, body mass index, specific infertility diagnoses, endometrial stripe thickness, grading of blastocele expansion, inner cell mass, or trophectoderm of the blastocysts transferred (Table 2). No differences were noted in the implantation, clinical pregnancy, biochemical pregnancy, spontaneous abortion, and live delivery rates between the two groups (Table 3). The rates of singleton and twin deliveries were also comparable. No triplets or other higher-order gestations were recorded in the present study. Table 4 summarizes the perinatal Table 1 Demographic and baseline characteristics of patients who underwent fresh blastocyst cycles (n=918). a Variable

Value

Age, y Parity BMI Previous IVF attempts Total stimulation days Total gonadotropins administered, IU Peak endometrial stripe thickness, mm E2 level on day of trigger, pg/mL No. of oocytes retrieved No. of mature oocytes

35.8±5.09 0.73±0.26 23.2±4.72 1.64±0.69 9.52±1.72 2378.5±1304.9 10.7±3.73 2042.4±802.6 15 (11–17) 12 (9–14)

Abbreviations: BMI, body mass index (calculated as weight in kilograms divided by the square of height in meters); IVF, in vitro fertilization; E2, estradiol. a Values are given as mean±SD or median (interquartile range).

Please cite this article as: Pereira N, et al, Comparison of perinatal outcomes following fresh and frozen-thawed blastocyst transfer, Int J Gynecol Obstet (2016), http://dx.doi.org/10.1016/j.ijgo.2016.04.007

N. Pereira et al. / International Journal of Gynecology and Obstetrics xxx (2016) xxx–xxx Table 2 Demographics and embryo parameters in patients who underwent fresh or frozenthawed blastocyst transfer (n=2191). a Variable

Patients who underwent fresh blastocyst transfer (n=918)

Patients who underwent frozen-thawed blastocyst transfer (n=1273)

P value

Age, y BMI Infertility diagnosis Ovulatory Tubal Endometriosis Male factor Idiopathic Other Peak endometrial stripe thickness, mm Blastocele grading 1 or 2 3 ICM grading A B C Trophectoderm grading A B C

35.8 ±5.1 23.2 ±4.7

36.1±5.3 23.4±4.2

0.18 0.60 0.86

217 (23.6) 114 (12.4) 55 (6.0) 251 (27.3) 158 (17.2) 123 (13.4) 10.7 ±3.7

330 (25.9) 180 (14.1) 98 (7.7) 324 (25.5) 161 (12.6) 180 (14.1) 10.5±3.8

151 (16.4) 767 (83.6)

220 (17.3) 1053 (82.7)

61 (6.6) 709 (77.2) 148 (16.1)

60 (4.7) 1098 (86.3) 115 (9.0)

73 (8.0) 701 (76.4) 144 (15.7)

62 (4.9) 1111 (87.3) 120 (9.4)

0.19 0.61

0.25

0.22

Abbreviations: BMI, body mass index (calculated as weight in kilograms divided by the square of height in meters); ICM, inner cell mass. a Values are given as mean±SD or number (percentage, unless indicated otherwise.

outcomes of singleton births in the fresh and frozen-thawed blastocyst transfer groups. The rates of vaginal and cesarean deliveries were comparable, and no differences were recorded in the rates of term delivery, late preterm delivery, or early preterm delivery. The mean overall neonatal weight at delivery was similar when comparing the two groups and there was no significant difference in the incidence of overall LBW, overall VLBW, and term LBW between the two groups. These findings remained unchanged even after controlling for age and the fresh-transfer group exhibited no increase in the odds of overall preterm delivery (aOR 0.85, 95% CI 0.33–2.41; P = 0.83), overall LBW (aOR 0.97, 95% CI 0.23–4.89; P=0.93), and overall term LBW (aOR 0.78, 95% CI 0.06–7.91; P=0.56). The perinatal outcomes of twin deliveries in the fresh and frozenthawed blastocyst transfer groups are detailed in Table 5. All twins in the study cohort were di-chorionic gestations. Similar to the observations made for the singleton deliveries resulting from fresh or frozenthawed blastocyst transfers, no differences were noted between twin deliveries in the two groups in terms of the rate of cesarean deliveries, term deliveries, late preterm deliveries, early preterm deliveries, overall

Table 3 Outcomes of fresh and frozen-thawed blastocyst transfers (n=2191). a Outcome

Embryos transferred Single embryo transfer Implantation rate Clinical pregnancy Biochemical pregnancy Spontaneous abortion Live delivery Singleton Twin

Patients who underwent fresh blastocyst transfer (n=918)

Patients who underwent frozen-thawed blastocyst transfer (n=1273)

P value

1.49±0.58 424 (46.2) 469/1258 (37.3) 520 (56.6) 121 (13.2) 67 (7.3) 394 (42.9) 334 (36.4) 60 (6.5)

1.52±0.47 b 611 (48.0) 643/1706 (37.7) 635 (49.8) 193 (15.2) 118 (9.3) 517 (40.6) 427 (33.5) 90 (7.1)

0.18 0.43 0.95 0.91 0.70 0.61 0.74

a Values are given as mean±SD, number (percentage), or number/maximum possible (percentage), unless indicated otherwise. b The thaw-survival rate was 98.7%.

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Table 4 Perinatal outcomes of singleton deliveries (n=761). a Outcome

Mode of Delivery Vaginal Cesarean Term delivery b Preterm delivery c Late preterm delivery d Early preterm delivery e Overall neonatal weight at delivery, g Overall LBW Overall VLBW Term LBW

Patients who underwent fresh blastocyst transfer (n=334)

Patients who underwent P value frozen-thawed blastocyst transfer (n=427)

203 (60.8) 131 (39.2) 306 (91.6)

253 (59.3) 174 (40.7) 387 (90.6)

19 (5.7) 9 (2.7) 3391.8±561.2

26 (6.1) 14 (3.3) 3329.4±581.3

0.50

11 (3.3) 0 6 (1.8)

15 (3.5) 0 9 (2.1)

0.93 NA 0.78

0.67

0.64 0.81

Abbreviations: LBW, low birth weight (b2500 g at delivery irrespective of gestational age); VLBW, very low birth weight (b1500 g at delivery irrespective of gestational age); NA, not applicable. a Values are given as number (percentage) or mean±SD, unless indicated otherwise. b N37 weeks of pregnancy. c b37 weeks of pregnancy. d 34–37 weeks of pregnancy. e b34 weeks of pregnancy.

neonatal weight at delivery, overall LBW, or overall VLBW. Finally, a sub-analysis of all patients undergoing either natural or programmed frozen-thawed blastocyst transfers revealed no difference in the aforementioned pregnancy or perinatal outcomes (Table 6). 4. Discussion The present study demonstrated equivalence in singleton pregnancy and perinatal outcomes between fresh and frozen-thawed blastocyst transfer cycles. Specifically, no difference was observed in the incidence of term delivery, preterm delivery, LBW, term LBW, and VLBW. Initially, the cryopreservation of supernumerary top-quality embryos with subsequent FET was considered supplemental to fresh IVF cycles [1]. However, there has been a clear recent trend towards increasing use of FET [3]. In fact, the number of live deliveries following FET cycles in the USA has risen from 5797 in 2006 to 15 408 in 2012, and FET cycles are now routine at many clinics [1,4]. In addition to the improved survival rates of thawed embryos due to the wide adoption of vitrification, the use of FET has increased, in part, owing to the rationale

Table 5 Perinatal outcomes of twin deliveries (n=150). a Parameter

Mode of Delivery Vaginal Cesarean Term delivery b Preterm delivery c Late preterm delivery d Early preterm delivery e Overall neonatal weight at delivery, g Overall LBW Overall VLBW

Patients who underwent fresh blastocyst transfer (n=60)

Patients who underwent P value frozen-thawed blastocyst transfer (n=90)

13 (21.7) 47 (78.3) 43 (71.7)

16 (17.8) 74 (82.2) 69 (76.7)

12 (20.0) 5 (8.3) 2692.8±385.9

14 (15.6) 7 (7.8) 2642.6±339.4

0.42

16 (26.7) 1 (1.7)

22 (24.4) 1 (1.1)

0.90 0.77

0.56

0.62 0.93

Abbreviations: LBW, low birth weight (b2500 g at delivery irrespective of gestational age); VLBW, very low birth weight (b1500 g at delivery irrespective of gestational age). a Values are given as number (percentage) or mean±SD, unless indicated otherwise. b N37 weeks of pregnancy. c b37 weeks of pregnancy. d 34–37 weeks of pregnancy. e b34 weeks of pregnancy.

Please cite this article as: Pereira N, et al, Comparison of perinatal outcomes following fresh and frozen-thawed blastocyst transfer, Int J Gynecol Obstet (2016), http://dx.doi.org/10.1016/j.ijgo.2016.04.007

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N. Pereira et al. / International Journal of Gynecology and Obstetrics xxx (2016) xxx–xxx

Table 6 Outcomes of natural and programmed frozen-thawed blastocyst transfers (n=1273). a Variable

Patients who underwent natural frozen embryo transfer (n=521)

Patients who P value underwent programmed frozen-thawed blastocyst transfer (n=752)

Age, y BMI Peak endometrial stripe thickness, mm Blastocele grading 1 or 2 3 ICM grading A B C Trophectoderm grading A B C Implantation rate Clinical pregnancy rate Live delivery rate Singleton Twin Mode of delivery among singleton pregnancies Vaginal Cesarean Mode of delivery among twin pregnancies Vaginal Cesarean Term deliveries b Singleton Twin Preterm deliveries among singleton pregnancies Late preterm c Early preterm d Preterm deliveries among twin pregnancies Late preterm c Early preterm d Overall neonatal weight at delivery, g Among singleton pregnancies Among twin pregnancies Overall LBW Among singleton pregnancies Among twin pregnancies Overall VLBW Among singleton pregnancies Among twin pregnancies

35.7±4.79 23.5±4.35 10.4±3.71

36.2±5.42 23.1±4.06 10.7±3.96

90/521 (17.3) 431/521 (82.7)

130/752 (17.3) 622/752 (82.7)

21/521 (4.0) 457/521 (87.7) 43/521 (8.3)

39/752 (5.2) 641/752 (85.2) 72/752 (9.6)

22/521 (4.2) 458/521 (87.9) 41/521 (7.9) 258/698 (37.0) 263/521 (50.5) 218/521 (41.8) 186/521 (35.7) 32/521 (6.1)

40/752 (5.3) 633/752 (84.2) 79/752 (10.5) 353/1008 (35.0) 372/752 (49.5) 299/752 (39.8) 241/752 (32.0) 58/752 (7.7)

116/186 (62.4) 70/186 (37.6)

137/241 (56.8) 104/241 (43.2)

6/32 (18.8) 26/32 (81.3)

10/58 (17.2) 48/58 (82.8)

169/186 (90.9) 23/32 (71.9)

217/241 (90.0) 46/58 (79.3)

12/186 (6.5) 5/186 (2.7)

14/241 (5.8) 9/241 (3.7)

6/32 (18.8) 3/32 (9.4)

8/58 (13.8) 5/58 (8.6)

3327.9±626.1 2638.9±426.8

3333.2±497.8 2647.2±418.4

7/186 (3.8) 8/32 (25.0)

8/241 (3.3) 14/58 (24.1)

0 0

0 1/58 (1.7)

0.10 0.09 0.17 0.61

0.87

0.81

0.89 0.92 0.61

0.29

0.91

0.14

0.76

0.84

0.87 0.73 0.76

0.99

Abbreviations: BMI, body mass index (calculated as the weight in kilograms divided by the square of height in meters); ICM, inner cell mass; LBW, low birth weight (b2500 g at delivery irrespective of gestational age); VLBW, very low birth weight (b1500 g at delivery irrespective of gestational age). a Values are given as mean±SD or number/denominator (percentage), unless indicated otherwise. b N37 weeks of pregnancy. c 34–37 weeks of pregnancy. d b34 weeks of pregnancy.

that FET facilitates the transfer of an embryo into a more physiologically welcoming uterine environment [3,10]. It has been postulated that widespread adoption of FET would potentially decrease perinatal morbidity [10]. By way of example, a Japanese registry study by Ishihara et al. [16] that included 277 042 single-embryo cycles demonstrated that FET was associated with a significantly reduced incidence of preterm delivery, LBW, and small-for-gestational-age neonates [16]. In another study that included 645 FET and 1157 fresh cycles, Roy et al. [17] reported better neonatal outcomes and equivalent live delivery rates when comparing FET with fresh cycle transfer [17]. Furthermore,

a systematic review and meta-analysis of 11 published studies by Maheshwari et al. [18] revealed that the relative risks of preterm delivery, LBW, and perinatal mortality were lower among individuals with live singletons after FET [18]. Contrary to these findings, the present study revealed no difference or improvement in the incidence of term delivery, preterm delivery, LBW, term LBW, and VLBW between frozen-thawed and fresh blastocyst transfers. The role of E2 could explain these differences. The proposed benefits of FET over fresh transfers are thought to be due to the differences in the peri-implantation environment; specifically, concern has been raised that the hyperestrogenic milieu resulting from controlled ovarian hyperstimulation creates a less-healthy environment for embryo implantation and development compared with that present during a normal menstrual cycle. Supraphysiologic E2 levels have been shown to impair embryonic adhesion and implantation potential in mice embryos [19–21]. Similarly, supraphysiologic E2 levels can modulate endometrial gene expression profiles in humans, leading to modifications in trophoblastic invasion and possible placental dysfunction [22,23]. Clinically, at least two studies have reported associations between supraphysiologic E2 levels during controlled ovarian hyperstimulation and adverse perinatal outcomes such as LBW [7,8]. In their analysis of neonatal delivery weight among 56 792 singletons, Kalra et al. [7] reported 1.73 times higher odds of LBW among term singletons from fresh autologous IVF in comparison with FET cycles [7]. In another retrospective study of 292 IVF singletons, Imudia et al [8] reported 9.4 times higher odds of LBW singletons in patients with E2 levels above 3450 pg/mL on the day of hCG administration [8]. It is important to note that while E2 levels are implicated in adverse perinatal outcomes, the supraphysiologic threshold for such an effect remains unknown [10]. Consequently, it could be argued that lower E2 levels resulting from conservative ovarian stimulation protocols during fresh IVF cycles do not have the same deleterious endometrial effects as vigorous stimulation. By way of example, mean ± SD E2 levels of 5263± 2832 pg/mL [24] and 2354±754 pg/mL [8] on the day of hCG administration have been shown to negatively impact clinical pregnancy rate and neonatal delivery weight, respectively; however, lower mean±SD E2 levels of 2042.4±802.6 pg/mL, as observed in the present study cohort, appear to have no clinically discernable impact on endometrial receptivity. The lack of difference in adverse perinatal outcomes in natural and programmed frozen-thawed blastocyst transfers compared to fresh transfers in the present study further strengthens the above argument. The novel strengths of the present study included the uniformity in fresh IVF and FET protocols utilized. Similar to previous studies, the present study was retrospective in nature; therefore, it is uncertain whether these findings would hold true in a prospective setting. In the absence of evidence from randomized controlled trials or robust prospective studies comparing perinatal outcomes between elective blastocyst cryopreservation after fresh IVF followed by FET and fresh embryo transfer, moves in clinical practice to the preferential transfer of frozenthawed embryos or “freeze-all strategies” must be challenged for important reasons. First, as with any new hypothesis-driven study, the possibilities of patient selection bias and publication bias in reporting only positive results must be taken into consideration [10]. Second, no consensus has been reached regarding embryo cryopreservation and FET protocols [4]. Most clinics performing FET cycles utilize protocols based on anecdote rather than evidence. Finally, the selection of embryo cryopreservation and FET protocols must be based not only on efficacy, but also on long-term clinical safety and overall technical costs [4]. The impact of the hyperestrogenic milieu during fresh IVF cycles on endometrial receptivity is an active area of investigation; however, it is also possible that an elevated E2 level could simply be a surrogate for some other uncharacterized molecular marker [10]. Although maximizing follicular response during controlled ovarian hyperstimulation is important, it is more important that the ovarian stimulation protocols utilized minimize the risks of ovarian hyperstimulation syndrome and

Please cite this article as: Pereira N, et al, Comparison of perinatal outcomes following fresh and frozen-thawed blastocyst transfer, Int J Gynecol Obstet (2016), http://dx.doi.org/10.1016/j.ijgo.2016.04.007

N. Pereira et al. / International Journal of Gynecology and Obstetrics xxx (2016) xxx–xxx

supraphysiologic elevations of E2. Such an approach could be beneficial in optimizing the peri-implantation environment, especially given the correlation between early in-utero stress and adult cardiovascular disease, diabetes, and dyslipidemia [25]. Whereas there continues to be a shift towards FET cycles in the name of improved perinatal outcomes, it is possible that conservative stimulation protocols with fresh transfer offer equivalent benefits, provided serum E2 levels are carefully monitored. Conflicts of interest The authors have no conflicts of interest. References [1] Doody KJ. Cryopreservation and delayed embryo transfer-assisted reproductive technology registry and reporting implications. Fertil Steril 2014;102(1):27–31. [2] Center for Disease Control and Prevention. Assisted Reproductive Technology (ART). http://www.cdc.gov/art. Accessed November 4, 2014. [3] Shapiro BS, Daneshmand ST, Garner FC, Aguirre M, Hudson C. Clinical rationale for cryopreservation of entire embryo cohorts in lieu of fresh transfer. Fertil Steril 2014;102(1):3–9. [4] Wong KM, Mastenbroek S, Repping S. Cryopreservation of human embryos and its contribution to in vitro fertilization success rates. Fertil Steril 2014;102(1):19–26. [5] Weinerman R, Mainigi M. Why we should transfer frozen instead of fresh embryos: the translational rationale. Fertil Steril 2014;102(1):10–8. [6] Shapiro BS, Daneshmand ST, Restrepo H, Garner FC, Aguirre M, Hudson C. Matchedcohort comparison of single-embryo transfers in fresh and frozen-thawed embryo transfer cycles. Fertil Steril 2013;99(2):389–92. [7] Kalra SK, Ratcliffe SJ, Coutifaris C, Molinaro T, Barnhart KT. Ovarian stimulation and low birth weight in newborns conceived through in vitro fertilization. Obstet Gynecol 2011;118(4):863–71. [8] Imudia AN, Awonuga AO, Doyle JO, Kaimal AJ, Wright DL, Toth TL, et al. Peak serum estradiol level during controlled ovarian hyperstimulation is associated with increased risk of small for gestational age and preeclampsia in singleton pregnancies after in vitro fertilization. Fertil Steril 2012;97(6):1374–9. [9] Kalra SK. Adverse perinatal outcome and in vitro fertilization singleton pregnancies: what lies beneath? Further evidence to support an underlying role of the modifiable hormonal milieu in in vitro fertilization stimulation. Fertil Steril 2012;97(6):1295–6.

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Please cite this article as: Pereira N, et al, Comparison of perinatal outcomes following fresh and frozen-thawed blastocyst transfer, Int J Gynecol Obstet (2016), http://dx.doi.org/10.1016/j.ijgo.2016.04.007