Materials and Methods

We performed a retrospective cohort study evaluating SET performed from December 2008 (the installation of our computerized fertility database system at the clinic) through December 2012 at the reproductive unit of the McGill University Health Center in Montreal, Quebec, Canada. Only women ≤40 years old who underwent the first fresh SET using nondonor oocytes were included. Women were included in the study only once. The institutional research and ethics board approved the study (code 12-283-SDR).

Following our standard practice, pregnancy outcome and placental pathology reports of the patients are continuously updated in our obstetric and neonatal database. We obtained missing information (if any) by detailed telephone survey conducted by trained personnel at our center.

We compared singleton live births resulting from transfer of a fresh cleavage embryo (day 2 or 3 after oocyte retrieval) and those of a fresh blastocyst transfer (day 5 after oocyte retrieval). Only 12 cases of SET occurred prior to August 2010. The practice of SET at our clinic was facilitated by the change in the Quebec policy for public funding of assisted reproductive technology in August 2010 where SET is the rule other than in exceptional cases.

Cycle outcome was analyzed as biochemical pregnancies and clinical pregnancies (intrauterine gestational sac seen) resulting in miscarriage, stillbirth, or live birth.

The primary outcomes of interest were: SGA (defined as birthweight <10th percentile for gestational age using the Canadian population-based live born infant birthweight curves), LBW (<2500 g), very LBW (<1500 g), PTD (<37 weeks), early PTD (<32 weeks), large for gestational age (birthweight >90th percentile), hospitalization in the neonatal intensive care unit, respiratory or gastrointestinal complications, and congenital malformations. Maternal complications included preeclampsia ( International Statistical Classification of Diseases, 10th Revision [ ICD-10 ] codes O.14, O.15), placenta previa ( ICD-10 code O.44), placental abruption ( ICD-10 code O.45), chorioamnionitis (according to placental pathology reports), or gestational diabetes ( ICD-10 code O.24.4).

Confounding variables were maternal and paternal age, body mass index (BMI) during infertility treatment, gravidity and parity, and use of a microdose flare, a fixed antagonist, and a midluteal long agonist protocol or a natural-cycle IVF with no gonadotropin stimulation. Etiology of infertility was divided into 6 major categories: polycystic ovarian syndrome, male infertility, tubal factor infertility, endometriosis (diagnosis by laparoscopy or ultrasound diagnosis of ovarian endometrioma), poor ovarian response or reserve, or unexplained infertility.

Embryo transfer day was determined based on the quantity and quality of embryos on days 2, 3, or 5. All embryos were cultured in cleavage medium (Cook Medical, Sydney, Australia) until day 3, then transferred to blastocyst medium (Cook Medical) for further culture to the blastocyst stage. All embryo cultures were performed under low-oxygen conditions (5% oxygen, 6% carbon dioxide, 89% nitrogen). Cleavage embryos were graded as good quality if they had 4 cells on day 2 or 7-8 cells on day 3, <20% fragmentation, and exhibited no apparent morphological abnormalities. Embryo transfer on day 2 or 3 was performed using embryos with the highest number of blastomeres or the highest embryo grading score.

When needed, assisted hatching with laser zona drilling (20 μm) was first performed under an inverted microscope in a microdrop (40 μL) using an infrared laser optical system (ZILOS-tk, version 3.29; Hamilton Thorne Instruments Biosciences, Beverly, MA). On day 5, embryos were scored for blastocyst formation. Blastocysts were graded according to the level of expansion, the presence and the quality of inner cell mass, and quality of trophectoderm. Good-quality blastocysts were defined as those ≥3 full blastocyst with inner cell mass loosely grouped with several cells and few trophectoderm cells forming a loose epithelium based on the Gardner and Schoolcraft scoring system. When there were ≥2 blastocysts, we transferred only the best embryo. Embryo transfer was defined as elective when there were >1 (high-quality) available embryos and only 1 embryo was transferred. Embryo transfer was performed under ultrasound guidance and a serum beta-human chorionic gonadotropin pregnancy test was performed 16 days after collection.

Statistical analysis was performed using SAS 9.2 (SAS Institute, Cary, NC). Patient characteristics and clinical outcomes were tabulated by day of transfer (cleavage or blastocyst). We performed χ ² or Fisher exact test for categorical variables and Wilcoxon rank sum tests for continuous variables. The correlation between day of transfer and a specific clinical outcome was assessed using multivariable logistic analysis. Covariates were regarded as known risk factors for adverse outcomes including maternal age, BMI, smoking, parity, cause of infertility, and sex of the baby.

Results

Of a total of 1543 fresh IVF-SET cycles using nondonor oocytes, we encountered 693 cleavage transfers and 850 blastocyst transfers resulting in 564 pregnancies and 381 singleton births. Eight monozygotic twins, 6 resulting from single blastocyst transfers and 2 from single cleavage transfers, were excluded from the analysis.

Patient demography of the entire study group including all cycles is presented in Table 1 . Maternal and paternal ages were approximately a year younger in the blastocyst transfer group. Compared to those of cleavage transfers, there were significantly more primary IVF cycles, high-quality embryos, and elective embryo transfers in the blastocyst transfer group. Treatment characteristics of the entire study groups are demonstrated in Table 2 . The groups differed in treatment characteristics with a higher gonadotropin dose, number of mature oocytes, and fertilization and implantation rates in the blastocyst transfer group. The biochemical pregnancy rate (calculated from all positive beta-human chorionic gonadotropin results) was 14.1% (70/496) in the blastocyst transfer group and 13.2% (21/159) in the cleavage transfer group ( P = .89). Cycle outcome was significantly associated with day of transfer. Transfer of blastocyst resulted in a clinical pregnancy rate of 50.1% and live birth rate of 33.5% per embryo transfer. These were significantly higher than the clinical pregnancy rate of 19.9% and live birth rate of 13.8% after transfer of cleavage embryos ( P < .001). Calculated from all clinical pregnancies, the singleton live birth rates were similar: 69.6% in the cleavage transfer group and 66.9% in the blastocyst transfer group.

Table 3 demonstrates the frequencies of maternal characteristics for singleton births derived from single blastocyst transfers and from single cleavage transfers. The blastocyst group had a different distribution of infertility diagnosis (more couples with male infertility and less with poor ovarian reserve, P = .037) and had more primary IVF cycles ( P = .011).

Pregnancy outcomes of the pregnancies resulting in live births from blastocyst and cleavage embryo transfers are shown in Table 4 . There were no differences in any of the perinatal outcomes between the 2 groups. Maternal and neonatal pregnancy complications in live births from blastocyst and cleavage embryo transfers are shown in Tables 5 and 6 . No significant differences in pregnancy-related complications were found after adjustment for known risk factors including maternal age, BMI, smoking, parity, infertility diagnosis, and sex of the baby. In addition, in a logistic regression analysis there was no correlation between the incidence of grouped maternal complications and grouped neonatal complications with extended embryo culture ( Table 7 ).

Table 6

Pregnancy complications after transfer of cleavage or blastocyst embryo

Adverse outcome	OR (95% CI)	P value	Adjusted OR (95% CI)	Adjusted P value
Single cleavage transfer	1.0		1.0
Single blastocyst transfer
SGA, %	1.30 (0.53–3.21)	0.57	1.04 (0.41–2.68)	.93
LBW, %	0.82 (0.37–1.82)	0.63	0.79 (0.32–1.95)	.62
VLBW, %	0.50 (0.13–1.96)	0.32	1.30 (0.27–6.32)	.74
PTD, %	1.49 (0.74–2.99)	0.26	1.57 (0.72–3.43)	.26
Early PTD, %	0.50 (0.13–1.97)	0.32	1.10 (0.22–5.40)	.90
Preeclampsia, %	0.71 (0.15–3.24)	0.66	0.59 (0.16–2.09)	.41
Placental abruption, %	0.45 (0.09–2.33)	0.34	0.49 (0.12–1.92)	.30
LGA, %	1.18 (0.57–2.47)	0.65	1.25 (0.54–2.92)	.60
Gestational diabetes, %	0.75 (0.11–5.23)	0.77	0.93 (0.19–4.44)	.92
Chorioamnionitis, %	0.06 (0.003–1.34)	0.07	0.19 (0.03–1.15)	.09
Genetic disorder/malformations, %	1.63 (0.07–34.8)	0.75	1.52 (0.21–10.9)	.68
Maternal complications, %	0.72 (0.31–1.69)	0.46	0.82 (0.33–2.05)	.69
Neonatal complications, %	1.29 (0.76–2.18)	0.34	1.27 (0.70–2.30)	.43
Maternal or neonatal complication, %	1.24 (0.75–2.06)	0.40	1.26 (0.71–2.23)	.43

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