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. Author manuscript; available in PMC: 2017 Jul 1.
Published in final edited form as: Fertil Steril. 2016 Mar 18;106(1):80–89. doi: 10.1016/j.fertnstert.2016.02.034

Factors Associated with the Use of Elective Single Embryo Transfer And Pregnancy Outcomes in the United States, 2004–2012

Aaron K Styer a,*, Barbara Luke b, Wendy Vitek c, Mindy S Christianson d, Valerie L Baker e, Alicia Y Christy f, Alex J Polotsky g
PMCID: PMC5451272  NIHMSID: NIHMS767172  PMID: 26997248

Abstract

Objective

To evaluate factors associated with elective single embryo transfer (eSET) utilization and its effect on assisted reproductive technology (ART) outcomes in the United States.

Design

Historical cohort

Setting

Not applicable

Patient(s)

Fresh IVF cycles of women 18–37 years using autologous oocytes with either one (SET) or two (DET) embryos transferred and reported to the Society for Assisted Reproductive Technology Clinic Outcome Reporting System between 2004 and 2012. Cycles were categorized into four groups with[+] or without[−] supernumerary embryos cryopreserved. The SET group with embryos cryopreserved was designated as eSET.

Interventions

None

Main Outcomes Measure(s)

The likelihood of eSET utilization, live birth, and singleton non-low birthweight term live birth, modeled using logistic regression. Presented as adjusted odds ratios (aORs) and 95% confidence intervals (CIs).

Result(s)

The study included 263,375 cycles (21,917 SET[−]cryopreservation, 20,996 SET [+]cryopreservation, 103,371 DET[−]cryopreservation, and 117,091 DET[+]cryopreservation). The utilization of eSET (SET[+]cryopreservation) increased from 1.8% in 2004 to 14.9% in 2012 (aOR 7.66, 95% CI 6.87, 8.53), and was more likely with ART insurance coverage (1.60, 1.54–1.66), Asian race (1.26, 1.20–1.33), uterine factor diagnosis (1.48, 1.37–1.59), retrieval of ≥ 16 oocytes (2.85, 2.55–3.19), and the transfer of day 5–6 embryos (4.23, 4.06–4.40); eSET was less likely in women ages 35–37 years (0.76, 0.73–0.80). Compared to DET cycles, the likelihood of the ideal outcome, term non-low birthweight singleton live birth, was increased 45–52% with eSET.

Conclusions

Expanding insurance coverage for IVF would facilitate the broader use of eSET, and reduce the morbidity and healthcare costs associated with multiple pregnancies.

Keywords: Elective single embryo transfer, assisted reproductive technology, in vitro fertilization, multiple pregnancy

Introduction

Historically, the transfer of multiple embryos with in vitro fertilization (IVF) was performed to maximize pregnancy rates, but frequently resulted in multiple gestations (twins, triplets, and higher order multiples gestations) (1). Transferring more than one embryo has been shown to have a harmful effect on intrauterine growth and length of gestation even when only one embryo implants (2). Complications of prematurity associated with multiple gestation have been the most persistent adverse outcome of assisted reproductive technology (ART) and confer significant neonatal morbidity and health care expenditures.(3). Refinements of controlled ovarian hyperstimulation protocols, extended embryo culture, and embryo selection criteria have resulted in fewer embryos transferred per cycle and improved ART pregnancy rates (4, 5). As a result, the rate of triplets and higher order multiple gestation has been significantly reduced, but the incidence of ART twins has remained as high as 25–40% per embryo transfer.(6–11). It is desirable to modify current embryo transfer practices to increase term singleton live birth rates.(12, 13).

Elective single embryo transfer (eSET) was first utilized in Europe to reduce the rate of multiple gestation pregnancy and increase the rate of singleton pregnancy.(14). With national ART insurance coverage legislation, several European nations have successfully implemented mandatory eSET policies while maintaining acceptable pregnancy rates.(14, 15). An increase in eSET use in the U.S. has been observed since the first embryo transfer guidelines to recommend this practice in 2004 (16, 17). However, the use of eSET has been inconsistent (18, 19). Since eSET practice continues to evolve in the US, it is timely to investigate the factors associated with this practice and its associated pregnancy outcomes. The objective of this study was to evaluate factors associated with eSET utilization and pregnancy outcomes using the Society for Assisted Reproductive Technology Clinic Online Reporting System from 2004 through 2012. This study encompassed analyses of cycle outcomes in women less than 38 years of age since this favorable prognosis age group is most consistently considered for eSET.

This study was designed by the Clinical Research/Reproductive Scientist Training (CREST) program, in collaboration with the Society for Assisted Reproductive Technology (SART) (20). Its goal is to provide clinicians in academic or private practice with training and networking opportunities that enable them to better contribute to clinical research in reproductive medicine. The CREST scholars chose to evaluate factors associated with the use of eSET because the topic is of immediate relevance for practicing clinicians and patients. We hope that this report will help to inform the ongoing discussion regarding optimal ART treatments.

Materials and Methods

The data for this study was obtained from the Society for Assisted Reproductive Technology Clinic Outcome Reporting System (SART CORS), which contains comprehensive data from more than 90% of all clinics performing ART in the US. Data were collected and verified by SART and reported to the Centers for Disease Control and Prevention in compliance with the Fertility Clinic Success Rate and Certification Act of 1992 (Public Law 102–493). SART maintains HIPAA-compliant business associates agreements with reporting clinics. In 2004, following a contract change with CDC, SART gained access to the SART CORS data system for the purposes of conducting research. The national SART CORS database for 2004–12 contains 1,250,545 cycles among 642,715 women, resulting in 196,912 live births. The database includes information on demographic factors (age, race/ethnicity); ART factors (infertility diagnoses, oocyte source and state, use of micromanipulation, number of embryos transferred); treatment outcomes (number of fetal heart beats on early ultrasound, early pregnancy loss); and pregnancy outcomes (live born, stillborn, length of gestation, plurality, and genders). The data in the SART CORS are validated annually (21) with some clinics having on-site visits for chart review based on an algorithm for clinic selection. During each visit, data reported by the clinic were compared with information recorded in patients’ charts. In 2012, records for 2,045 cycles at 35 clinics were randomly selected for full validation, along with 238 egg/embryo banking cycles (21). The full validation included review of 1,318 cycles for which a pregnancy was reported. Among the non-donor cycles, 331 were multiple-fetus pregnancies. Ten out of 11 data fields selected for validation were found to have discrepancy rates of ≤5%. The exception was the diagnosis field, which, depending on the diagnosis, had a discrepancy rate between 2.1% and 9.2%.

This study included cycles reported to the SART CORS from January 1, 2004 through December 31, 2012. Cycles were limited to women who were US residents, between the ages of 18–37 years at cycle start, who used their own fresh oocytes, and their partner’s semen. The study was limited to cycles initiated in women age less 38 years since these patients are most consistently considered eSET candidates. Cycles were additionally limited to those with either one (single embryo transfer, SET) or two embryos transferred (double embryo transfer, DET), and were categorized into four groups if additional embryos were or were not cryopreserved (i.e. SET without cryopreservation, SET with cryopreservation, DET without cryopreservation, DET with cryopreservation) during the same cycle. Excluded were all cycles that used gestational carriers, were designated as research cycles, or which had preimplantation genetic diagnosis or screening (PGD/PGS) analysis.

Independent variables included reporting year of the cycle (2004–2012); insurance coverage in the woman’s State of residence (mandated coverage [inclusive of ART (IVF)] or some coverage [not inclusive of ART (IVF)]); region of country of the infertility clinic (Northeast [subregions: New England, Mid-Atlantic], Midwest [subregions: East-North-Central, West-North-Central] South [subregions: South Atlantic, East-South-Central, West-South-Central], and West [Mountain, Pacific]); woman’s age (continuous, and as 18–29, 30–34, and 35–37 at cycle start), race/ethnicity (white, Asian, black, Hispanic, other, and unknown), BMI (14.0–18.4, 18.5–24.9, 25.0–29.9, 30.0–34.9, ≥40.0, and not stated), smoking status (current, prior three months, and nonsmoker), gravidity (0, 1, ≥2), infertility diagnoses; number of oocytes retrieved (mean and 1–5, 6–10, 11–15, and ≥16); micromanipulation (ICSI and assisted hatching; some or all embryos), additional embryos cryopreserved (0, 1, 2–5, 6–10, ≥11); day of embryo transfer (2–3, 4, or 5–6). The dependent variables included treatment outcome of clinical intrauterine gestation; number of fetal heartbeats at six week ultrasound; pregnancy outcome (live birth, stillbirth, fetal loss, unknown); plurality at birth; mean length of gestation and birthweight for all singleton and twin live births (≥154 days gestation and ≥300 grams birthweight), and live born non-low birthweight term singleton.

Statistical Analysis

ART treatment year, insurance coverage, region of infertility clinic, maternal age, race and ethnicity, body mass index, gravidity, infertility diagnoses, and infertility treatment and outcomes were compared across the study groups using χ2 and analysis of variance; logistic regression was used for dichotomized outcomes. Models of factors associated with elective single embryo transfer were adjusted for reporting year (2004 [reference group), 2005, 2006, 2007, 2008, 2009, 2010, 2011, 2012), insurance coverage (none [reference group]), insurance ART (IVF) mandate (no [reference group], yes), maternal age at cycle start (18–29 years [reference group], 30–34, 35–37), maternal race and ethnicity (white [reference group], Asian, black, Hispanic, other, unknown), infertility diagnosis (male factor, endometriosis, ovulation disorders, diminished ovarian reserve, tubal factor, uterine factor, unexplained, other factor, other non-infertile factor), number of oocytes retrieved (1–5 [reference group], 6–10, 11–15, ≥16), and day of embryo transfer (day 2–3 [reference group], day 4, day 5–6).

Models of clinical intrauterine gestation and live birth outcomes with SET with cryopreservation versus SET without cryopreservation, DET with and without cryopreservation were adjusted for maternal age at cycle start, maternal race and ethnicity, infertility diagnoses, number of oocytes retrieved, day of embryo transfer, and year of ART treatment. Five outcomes were modeled: 1) treatment outcome of clinical intrauterine pregnancy; 2) pregnancy outcome of a live birth (≥154 days gestation and birthweight ≥300 grams); 3) live birth outcome of a singleton; and 4) singleton live birth outcome at term (≥259 days gestation); and 5) non low birth weight term singleton outcome (birth weight ≥2,500 g and gestation ≥259 days). Models were generated based on all cycles, and on cycles resulting in a clinical intrauterine gestation (treatment outcomes 2–5). Results were considered significant when the 95% confidence intervals did not include 1. All analyses were performed using the Statistical Package for the Social Sciences, version 19.0 (IBM SPSS, Inc., Chicago, IL, USA, 2010). The study was reviewed and approved by the Society for Assisted Reproductive Technology Research Committee prior to provision of data. The study was reviewed by the Partners Healthcare Institutional Review Board and considered exempt.

Results

The study included 263,375 cycles (SET without cryopreservation, 21,917 cycles; SET with cryopreservation [eSET], 20,996 cycles; DET without cryopreservation, 103,371 cycles; and DET with cryopreservation, 117,091 cycles). A description of the study groups is shown in Table 1. There was an increase in all four study groups during the study period, with the largest increase in the eSET group (from 1.8% in 2004 to 25.2% in 2012). More than 30% of cycles in each study group were performed in States with some (noninclusive of ART) fertility treatment insurance coverage, and nearly half of all study cycles were performed in the six States (CA, NY, IL, MA, NJ, and TX) with the largest number of ART cycles.

Table 1.

Description of the Study Groups

SET, no cryo SET, yes cryo DET, no cryo DET, yes cryo P Values
N, cycles 21,917 20,996 103,371 117,091 Across SET DET
Factor (%) Categories All Groups Groups Groups
Reporting Year 2004 8.1 1.8 8.5 8.4 <0.0001 <0.0001 <0.0001
2005 8.6 3.5 9.2 9.5
2006 9.6 5.4 10.2 10.2
2007 10.7 7.4 11.1 10.9
2008 10.9 9.0 11.8 11.6
2009 12.2 12.4 12.5 12.2
2010 13.2 16.2 12.6 12.3
2011 12.8 19.2 12.1 12.4
2012 13.9 25.2 12.0 12.6
Insurance Coverage Some1 32.8 34.2 31.9 35.8 <0.0001 .001 <0.0001
Mandated2 28.2 27.3 25.8 20.0 <0.0001 .06 <0.0001
Regions: Northeast New England3 15.5 17.9 12.0 8.7 <0.0001 <0.0001 <0.0001
Mid-Atlantic4 24.3 15.6 21.6 19.4
Midwest East-North-Central5 13.8 11.6 14.7 16.2
West-North-Central6 6.6 6.2 7.7 6.6
South South Atlantic7 19.9 23.8 19.8 16.9
East-South-Central8 1.9 1.6 2.8 2.5
West-South-Central9 6.2 6.2 9.3 9.9
West Mountain10 3.5 3.6 4.3 6.1
Pacific11 8.3 13.4 7.7 13.7
ART Cycles Top 6 ART States12 48.9 47.8 45.1 44.5 <0.0001 .02 .004
Age (years, %) 18–29 16.7 25.9 21.3 26.1 <0.0001 <0.0001 <0.0001
30–34 51.5 57.0 54.2 54.2
35–37 31.8 17.1 24.4 19.7
Race and Ethnicity (%) White 72.2 73.4 75.4 75.9 <0.0001 <0.0001 <0.0001
Asian 13.1 14.1 10.9 9.8
Black 6.8 6.1 6.1 6.2
Hispanic 7.3 5.8 7.0 7.4
Other 0.7 0.7 0.7 0.
Unknown 33.1 32.3 33.0 32.0
Body Mass Index (%) 14.0 – 18.4 3.4 4.0 3.0 3.0 <0.0001 <0.0001 <0.0001
18.5 – 24.9 56.7 60.6 55.2 56.4
25.0–29.9 22.0 21.6 22.9 23.1
30.0–34.9 10.4 8.5 10.9 10.3
35.0–39.9 5.1 3.9 5.4 4.8
≥40.0 2.5 1.4 2.6 2.4
Missing 42.4 27.1 43.5 43.7
Gravidity (%) 0 53.6 54.4 54.4 55.0 <0.0001 .04 .001
1 25.9 26.1 25.5 24.9
≥2 20.5 19.5 20.1 20.1
Infertility Diagnosis (%) Male Factor 42.5 38.8 43.6 42.4 <0.0001 <0.0001 <0.0001
Endometriosis 14.2 10.1 14.4 13.3 <0.0001 <0.0001 <0.0001
Ovulation Disorders 15.0 24.6 18.1 22.5 <0.0001 <0.0001 <0.0001
Dim. Ovarian Res. 19.3 4.1 11.0 5.1 <0.0001 <0.0001 <0.0001
Tubal Ligation 2.0 1.9 2.3 2.5 <0.0001 .40 <0.0001
Tubal Hydrosalpinx 1.5 1.8 1.6 1.7 0.02 .02 .03
Tubal Other 13.5 12.8 14.0 14.5 <0.0001 .04 <0.0001
Uterine Factor 4.4 4.9 3.4 3.4 <0.0001 .01 .88
Unexplained 13.2 17.7 14.3 14.5 <0.0001 <0.0001 .38
Other 9.4 8.4 8.4 8.3 <0.0001 <0.0001 .23
Other Non-Infertile 0.2 0.2 0.1 0.2 0.14 .74 .70
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SET: single embryo transfer; DET: double embryo transfer; yes cryo: cryopreservation of supernumerary embryo(s); no cryo: No cryopreservation of supernumerary embryos

1

AR, CA, HI, LA, MD, MT, NY, OH, TX, WV

2

CT, IL, MA, NJ, RI

3

CT, ME, MA, NH, RI, VT

4

NJ, NY, PA

5

IL, IN, MI, OH, WI

6

IA, KS, MN, MO, NE, ND, SD

7

DC, DE, FL, GA, MD, NC, SC, VA, WV

8

AL, KY, MS, TN

9

AR, LA, OK, TX

10

AZ, CO, ID, MT, NV, NM, UT, WY

11

AK, CA, HI, OR, WA

12

The six States with the highest number of ART cycles: CA, NY, IL, MA, NJ, TX

More than half of all cycles were among women ages 30–34 years, but women in the SET without cryopreservation group were more likely to be older. About 75% of each study group was white; Asian women were less likely to be in either of the DET groups. More than half of women in each study group were normal weight; more than 20% were overweight, and 3–4% underweight. The study groups were comparable in terms of gravidity, with more than half of women in each group being nulligravid, and about 25% were primigravid. Fewer women with endometriosis were in the eSET group (SET with cryopreservation); more women with ovulation disorders were in the eSET and DET with cryopreservation groups; and more women with diminished ovarian reserve were in the SET and DET groups without cryopreservation.

Infertility treatment and outcome by study group is shown in Table 2. Women in the SET and DET groups without cryopreservation had the lowest average and proportion of oocytes retrieved. Women in the eSET group (SET with cryopreservation) were less likely than women in the other three groups to have micromanipulation performed (intracytoplasmic sperm injection, 66.3%, or assisted hatching, 14.1%), and were more likely to have day 5–6 embryos transferred (83.4%). Clinical intrauterine gestation was more likely in the SET and DET groups with cryopreservation (57.6% and 62.5%, respectively) compared to the two study groups without cryopreservation. The presence of a single fetal heartbeat at six weeks gestation was more likely in the SET groups (91.1% and 93.0%, without and with cryopreservation, respectively), compared to the two DET groups. More than 80% of cycles in each of the study groups resulted in a live birth; in the two SET groups more than 98% of the live births were singletons, and more than 80% were born at term. The term singleton outcomes were comparable across the four study groups, with gestation averaging 272–273 days, and birthweights over 3,300 grams. Statistically significant differences in demographic, reproductive, and insurance characteristics were observed between groups within the SET and DET groups respectively in Tables 1 and 2.

Table 2.

Infertility Treatment and Outcome by Study Group

SET, no cryo SET, yes cryo DET, no cryo DET, yes cryo P Values
N, cycles 21,917 20,996 103,371 117,091 Across SET DET
Factor (%) Categories All Groups Groups Groups
Number of Oocytes (mean, SD) 7.7 ± 6.2 17.9 ± 8.4 11.7 ± 6.6 17.0 ± 7.6 <0.0001 <0.0001 <0.0001
Retrieved (%) 1–5 37.7 1.7 9.8 0.6 <0.0001 <0.0001 <0.0001
6–10 28.6 15.6 34.3 17.8
11–15 14.2 26.1 26.0 29.3
≥16 10.9 55.4 23.9 51.2
Not Stated 8.5 1.1 5.9 1.1
Micromanipulation ICSI-Some or All 74.2 66.3 71.9 72.7 <0.0001 <0.0001 <0.0001
AZH-Some or All 40.4 14.1 31.6 23.5 <0.0001 <0.0001 <0.0001
Additional Embryos 0 100.0 0.0 100.0 0.0 <0.0001 – –
Cryopreserved 1 – 12.5 – 15.4
2–5 – 54.6 – 58.4
6–10 – 25.7 – 20.6
≥11 – 7.2 – 5.6
Day of 2–3 70.5 16.0 60.3 40.3 <0.0001 <0.0001 <0.0001
Transfer 4 2.4 0.6 1.9 1.6
5–6 27.2 83.4 37.9 58.1
Treatment Not Pregnant 66.1 33.1 43.3 28.6 <0.0001 <0.0001 <0.0001
Outcome Biochemical 6.8 8.5 8.0 7.8 <0.0001 <0.0001 .07
Clinical Gestation 26.6 57.6 47.8 62.5 <0.0001 <0.0001 <0.0001
Ectopic 0.5 0.8 0.8 1.0 <0.0001 <0.0001 <0.0001
Heterotopic 0.0 0.0 0.0 0.1 <0.0001 1.00 <0.0001
N, pregnancies 5,787 12,046 49,180 72,956
Number of Fetal 0 6.9 4.7 5.2 3.8 <0.0001 <0.0001 <0.0001
Heartbeats 1 91.1 93.0 63.3 53.1
≥2 1.9 2.2 31.5 43.1
Pregnancy Live Birth 81.7 85.6 85.5 88.0 <0.0001 <0.0001 <0.0001
Outcome1 Stillbirth 0.6 0.5 0.6 0.7 <0.0001 .002 <0.0001
Loss (<22 weeks) 17.1 13.6 13.3 11.0 <0.0001 <0.0001 <0.0001
Unknown 0.6 0.3 0.5 0.4 <0.0001 <0.0001 <0.0001
N, deliveries 4,780 10,407 42,391 64,447
Number2 1 98.2 98.1 70.4 59.9 <0.0001 .01 <0.0001
Liveborn >1 1.8 1.9 29.6 40.1
Term (≥259 days) 82.4 81.1 65.0 58.1 <0.0001 .07 <0.0001
Preterm (154–258 days) 17.6 18.9 35.0 41.9
Term-Singleton 82.6 81.4 58.1 48.8 <0.0001 .09 <0.0001
Singletons2 N, pregnancies 4,623 10,101 29,370 37,998
Gestation (days, SD) 268 ± 15 267 ± 15 267 ± 16 266 ± 16 <0.0001 <0.0001 <0.0001
Birthweight (grams, SD) 3,265 ± 588 3,243 ± 585 3,243 ± 607 3,209 ± 617 <0.0001 .03 <0.0001
Term N, pregnancies 3,889 8,378 24,234 30,961
Singletons Gestation (days, SD) 273 ± 7 272 ± 7 273 ± 7 272 ± 7 <0.0001 <0.0001 <0.0001
Birthweight (grams, SD) 3,395 ± 453 3,380 ± 446 3,393 ± 455 3,369 ± 455 <0.0001 .08 <0.0001
Twins2 N, pregnancies 82 182 12,077 24,835
Gestation (days, SD) 245 ± 17 239 ± 23 245 ± 21 244 ± 21 0.001 .21 .001
Birthweight (grams, SD) 2,279 ± 494 2,166 ± 584 2,350 ± 567 2,338 ± 573 <0.0001 .42 .02
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SET: single embryo transfer; DET: double embryo transfer; yes cryo: cryopreservation of supernumerary embryo(s); no cryo: No cryopreservation of supernumerary embryos

1

Pregnancy outcome of cycles in which treatment outcome was clinical intrauterine pregnancy

2

Live births of ≥154 days gestation (≥22 weeks) and birthweights of ≥300 grams

Results of the logistic regression models of factors associated with elective single embryo transfer are shown in Table 3. The use of eSET increased progressively from 2004 to 2012, resulting in an AOR of 7.66 (95% CI 6.87–8.53) by the end of the study period. Notably, the use of eSET was more likely with some (not inclusive of ART) insurance coverage for infertility treatment and with ART insurance mandates (AOR 1.08, 95% CI 1.05–1.12, and 1.60, 1.54–1.66, respectively). The use of eSET was also more likely among women who were Asian (1.26, 1.20–1.33), with the diagnosis of uterine factor (1.48, 1.37–1.59), and increasing number of oocytes retrieved (≥16, 2.85, 2.55–3.19), and day 5–6 embryo transfer (4.23, 4.06–4.40). The use of eSET was less likely among women ages 35–37 years (0.76, 0.73–0.80), among women who were black or Hispanic (0.91, 0.84–0.98, and 0.75, 0.70–0.81, respectively), with the diagnoses of male factor (0.80, 0.77–0.83), endometriosis (0.78, 0.74–0.82), diminished ovarian reserve (0.62, 0.58–0.67), or tubal factors (0.92, 0.88–0.97).

Table 3.

Factors Associated with Elective Single Embryo Transfer (SET with cryopreservation)*†

Factor Categories % eSET aOR 95% CI
Reporting year 2004 1.8 1.00 Reference
2005 3.1 1.71 1.50, 1.94
2006 4.4 2.37 2.10, 2.67
2007 5.5 2.82 2.51, 3.17
2008 6.2 3.01 2.69, 3.38
2009 8.1 4.01 3.59, 4.49
2010 10.1 5.14 4.61, 5.74
2011 11.9 5.99 5.37, 6.69
2012 14.9 7.66 6.87, 8.53
Insurance Coverage None 7.9 1.00 Reference
Some 8.1 1.08 1.05, 1.12
Insurance Mandate No 7.6 1.00 Reference
Yes 9.3 1.60 1.54, 1.66
Age 18–29 8.8 1.00 Reference
30–34 8.4 0.99 0.96, 1.03
35–37 6.1 0.76 0.73, 0.80
Race & Ethnicity White 7.8 1.00 Reference
Asian 10.4 1.26 1.20, 1.33
Black 7.8 0.91 0.84, 0.98
Hispanic 6.5 0.75 0.70, 0.81
Other 8.2 0.94 0.75, 1.18
Infertility Diagnosis Male Factor 7.3 0.80 0.77, 0.83
Endometriosis 5.9 0.78 0.74, 0.82
Ovulation Disorders 9.7 0.97 0.93, 1.01
Diminished Ovarian Reserve 3.9 0.62 0.58, 0.67
Tubal Factor 7.3 0.92 0.88, 0.97
Uterine Factor 11.0 1.48 1.37, 1.59
Unexplained 9.7 1.01 0.96, 1.07
Other Factor 7.9 0.96 0.91, 1.02
Other-Non-infertile 10.4 0.94 0.68, 1.31
Number of 1–5 1.8 1.00 Reference
Oocytes retrieved 6–10 5.0 1.60 1.43, 1.80
11–15 7.9 2.04 1.82, 2.28
≥16 11.8 2.85 2.55, 3.19
Day of 2–3 2.6 1.00 Reference
Transfer 4 2.8 1.00 0.83, 1.21
5–6 13.4 4.23 4.06, 4.40
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*

Elective single embryo transfer (single embryo transfer [SET] with additional embryos cryopreserved) is reference compared to SET without cryopreservation, and double embryo transfer with or without cryopreservation.

†

Models include adjustments all factors in the table aOR: adjusted odds ratio

Results of the logistic regression models of the number of embryos transferred and clinical and live birth outcomes are presented in Table 4. Compared to eSET cycles, the likelihood of clinical pregnancy (AOR 1.38, 95% CI 1.34, 1.42) and live birth (AOR 1.40, 95 % CI, 1.36, 1.44) respectively was greater with DET with cryopreservation, and less with SET without cryopreservation (0.39, 0.37–0.41 and 0.41, 0.39–0.43, respectively) and DET without cryopreservation (0.86, 0.83–0.89 and 0.89, 0.86–0.91, respectively). Compared to cycles with eSET, the likelihood of a singleton live birth outcome was reduced by one-half to two-thirds in the other three groups (0.34, 0.32–0.36 SET without cryopreservation; 0.46, 0.44–0.47 DET without cryopreservation; and 0.53, 0.51–0.55 DET with cryopreservation). A similar pattern was observed with singleton term live birth and singleton term non-low birthweight outcomes in the models of Table 4 and within models of each adjusted variable.

Table 4.

Clinical and Live birth Pregnancy Outcomes With Fresh Single Embryo Transfer (SET) and Double Embryo Transfer (DET) With and Without Supernumerary Embryos Cryopreserved*

Treatment Outcome: Pregnancy Outcome: Live Birth Outcome: Singleton Live Birth Outcome: Singleton Live Birth Outcome:
Clinical Intrauterine Gestation Live birth Singleton Term Gestation Non-LBW, Term Gestation
N, Cycles 140,544 120,237 81,843 67,511 66,016
ALL CYCLES 263,375 % aOR 95% CI % aOR 95% CI % aOR 95% CI % aOR 95% CI % aOR 95% CI
SET, with cryopreservation 20,996 57.6 1.00 Reference 49.3 1.00 Reference 48.1 1.00 Reference 39.9 1.00 Reference 39.1 1.00 Reference
SET, without cryopreservation 21,917 26.6 0.39 0.37, 0.41 21.7 0.41 0.39, 0.43 21.1 0.34 0.32, 0.36 17.7 0.36 0.34, 0.38 17.3 0.36 0.34, 0.36
DET, without cryopreservation 103,371 47.8 0.86 0.83, 0.89 40.9 0.89 0.86, 0.91 28.3 0.46 0.44, 0.47 23.5 0.47 0.46, 0.49 23.0 0.48 0.46, 0.49
DET, with cryopreservation 117,091 62.5 1.38 1.34, 1.42 55.0 1.40 1.36, 1.44 32.3 0.53 0.51, 0.55 26.5 0.55 0.53, 0.56 25.8 0.55 0.53, 0.57
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*

Models adjusted for age, race and ethnicity, infertility diagnosis, number of oocytes retrieved, day of transfer, and year of treatment

aOR: adjusted odds ratio

Discussion

These analyses, based on nearly a decade of national data, show that the use of eSET has increased dramatically, is more likely with infertility treatment insurance coverage and specific demographic and reproductive characteristics, and results in the ideal ART pregnancy outcome, a term singleton non-low birth weight live birth infant. This study identifies factors that influence eSET practice, and provides national evidence that eSET is an effective approach to reducing the likelihood of ART twin gestation pregnancy.

The first legislative mandate for eSET was instituted in Belgium in 2003 and required eSET for the first two ART attempts in women < 36 years of age. The multiple pregnancy rate was reduced from 29.1% to 9.5% in all patients and from 28.9 to 6.2% in patient less than 36 years, while the overall pregnancy rate was not affected (15). In the U.S., the rate of increase in DET continued to be greater than SET following the first U.S. embryo transfer guidelines to recommend eSET (16, 17, 22). The inconsistent use of eSET has been attributed to the absence of a financial subsidy for ART, lack of obligatory policies for eSET, and patient/provider perception of reduced pregnancy rates with eSET (18, 23).

An increased likelihood of eSET was observed in States with insurance coverage for infertility treatment (with and without inclusion of ART treatment). Approximately 48% of all eSET cycles occurred in the six States with the greatest number of ART cycles (CA, NY, IL, MA, NJ, TX) performed; three of these States (IL, MA, and NJ) have the most comprehensive insurance mandates inclusive of ART (IVF). An association between the number of embryos transferred and insurance coverage has been reported, with an increased rate of adverse perinatal outcomes in States without insurance mandated coverage (10, 24). Our results indicate that the likelihood of eSET was greater in States with an insurance mandate inclusive of ART coverage compared to States with fertility insurance non inclusive of ART. These findings suggest that in circumstances with less financial risk (i.e. out of pocket expense), patients and their clinicians may be more willing to utilize eSET. More importantly, this observation demonstrates the possible large-scale influence of healthcare costs on medical practice. Since infertility treatment is elective, the likelihood of eSET may involve more than financial factors and requires further investigation (24).

An insurance mandate for eSET, similar to that in Belgium, was initiated in Massachusetts by insurers over the past 12 months. The Massachusetts eSET mandate has been applied to the first two ART cycles in patients younger than 35 years of age and the first ART cycle in patients 35–37 years of age using fresh embryos. On a fiscal level, it represents a standardized approach by insurers to reduce the significant costs associated with multiple gestation and its adverse sequelae on perinatal and childhood health (12, 25, 26). Investigators have reported that pregnancies with the delivery of twins are approximately five times as costly as singleton pregnancies (3). Short-term cost benefits of eSET have been previously demonstrated in Canada. (27). However, the possible long-term healthcare cost reduction of eSET in the U.S. has not been evaluated. This study’s finding of an increased likelihood of eSET with ART insurance mandate is noteworthy and warrants further attention by policymakers to delineate the role of expanded ART insurance coverage to reduce the cost per live birth.

The demographic and reproductive characteristics associated with eSET in this study provide further insight into potential selection criteria for this practice. Prior studies have shown that factors associated with transferring a higher number of embryos reflect suboptimal maternal conditions (older age and the use of autologous oocytes), less favorable oocyte or embryo quality, less favorable prognosis, or unsuccessful prior cycles (the use of micromanipulation, embryos that were thawed or cleavage-stage) (28). Current criteria for eSET include good embryo quality, supernumerary embryos available for cryopreservation, and women undergoing their first or second fresh IVF cycle (22, 28). However, the decision to proceed with eSET is not always straightforward. Age is typically the primary criterion when considering a patient’s candidacy for eSET (22, 23). In this study, eSET cycles were more likely in women < 35 years of age. Patients undergoing DET with cryopreservation had a similar age distribution, in line with previous reports (14, 23). Some clinicians may be hesitant to use eSET in patients 35–37 year of age. However, DET in this age group will also yield twins rates greater than 25% (9, 10). Notably, favorable outcomes have been reported in patients 35–37 years of age with day 5 eSET (13). The number, quality, and stage of embryos available for transfer are also important factors influencing the decision to use eSET versus DET, with a greater likelihood of implantation and live birth reported with eSET on day 5 versus day 3 embryos (23, 29). Our findings indicate that patients less than 38 years of age with good quality embryos on day 5–6 and supernumerary embryos available for cryopreservation represent the ideal candidates for eSET.

Since eSET is a shared decision between physician and patient, additional obstacles to its use may include patient preference for twins and a limited understanding of the risks of multiples, the belief that a live birth (regardless of plurality and length of gestational) is the ultimate desired outcome of ART (30–33). Numerous studies have shown that pregnancy rates are comparable with eSET and DET in favorable prognosis women (14, 34–37). Although the likelihood of clinical pregnancy and livebirth was greatest with DET, it should be noted that this observation includes preterm twin livebirths and their associated complications. Twin livebirth following DET poses a significantly increased risk of obstetrical complications such as preeclampsia and gestational diabetes and perinatal morbidity and mortality associated with extreme prematurity, low birth weight, and impaired behavioral development during the neonatal and infant stages (38, 39). Since maximizing the safety of ART involves minimizing the most common ART complication, preterm birth associated with multiple gestation, the ideal pregnancy outcome of ART is a non-low birth weight singleton born at term (13, 35, 40, 41). Prior studies have shown that the cumulative term live birth rate is as good as or better with SET over two cycles than with DET in one cycle, while greatly reducing the probability of a multiple birth (42, 43). Although DET was associated with a greater likelihood of a live birth, our study demonstrates that eSET was most strongly associated with the ideal ART pregnancy outcome.

There are several limitations in the present study. The SART CORS is primarily surveillance data, and its use for research is secondary. Although the data is validated annually, several variables are known to be unreliable or have high rates of missing data or misclassification. Race and ethnicity is self-reported, with no objective criteria. Inconsistent use of infertility definitions by individual clinics could lead to misclassification. The decision to proceed with eSET is influenced by an institution’s criteria for extended culture to fresh day 5–6 transfer or day 5–6 cryopreservation, and prior experience with eSET. In general, poor prognosis patients are less likely to be offered and select eSET compared to DET. However, these data are not available in the SART CORS and residual confounding is possible. Recently, embryo morphology and quality have been included in SART CORS (44). However, embryo grading is subjective and varies significantly among institutions (45). This variable was not collected in SART CORS during the period of this study. It will be useful to investigate its association with eSET use and pregnancy outcome in the future. Since cycles analyzed in this study were not linked over time, women who underwent more than one cycle have likely been included. The observation of increased eSET during the study period may be the result of an increase in the number of cycles utilizing eSET and/or an increase in women using eSET in their first several attempts prior to success. This study’s primary strength is a large sample size of cycles in this database which allowed us to observe trends and outcomes which may not have been evident in smaller studies. This study’s selection of patients less than 38 years of age who underwent either SET or DET provides the most contemporary and realistic analysis of subjects who are consistently considered eSET candidates in the U.S.

Several emerging areas of practice, insurance coverage policies, and long term neonatal and family outcome data may facilitate the broader use and acceptance of eSET. Preimplantation genetic diagnosis/screening (PGD/PGS) was initially used to detect heritable genetic disorders or aneuploidy in embryos prior to transfer. Refinement of PGS aneuploidy screening methods has allowed selection of a single euploid embryo for eSET (46). Future studies to investigate the general application of this technique are warranted. It will also be important to evaluate the effect of the Massachusetts eSET mandate on pregnancy rates, time to conception, cost per cycle, and cost per live birth. Future analysis of the effect of this policy may provide justification for increased eSET use and expanded ART insurance coverage to improve ART safety and reduce healthcare costs. Additional insight into the effect of multiple gestation pregnancy on families is also needed. Investigators have shown that twins have lower levels of cognitive functioning compared to singletons (47). Greater difficulties in parenting and child development were experienced by IVF/ICSI families with twins (47). Concerns for several quality of life issues for families with multiple gestation have been raised (48). Expansion of our understanding of the downstream medical, economic, and social consequences of ART multiple births may serve to introduce eSET into mainstream ART practice in the U.S.

Conclusions

In the United States between 2004 and 2012, there has been an increase in the use of eSET in women less than 38 years of age with specific demographic and reproductive factors and ART insurance coverage. Use of eSET is most strongly associated with the ideal pregnancy outcome of ART: a non-low birthweight singleton born at term. Expansion of insurance coverage for ART would facilitate the wider use of eSET and reduce iatrogenic multiple gestations.

Capsule.

Elective single embryo transfer (eSET) is more likely with infertility treatment insurance coverage, and specific demographic and reproductive characteristics. Term non-low birthweight singleton live birth is most likely with eSET.

Acknowledgments

Barbara Luke ScD MPH had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Support

This study was supported (design and conduct of study) by Clinical Research Scientist Training Program, Eunice Kennedy Shriver National Institute of Child Health and Human Development (R25HD075737, Nanette Santoro, MD, PI), National Institutes of Health, Clinical Research Training Program at Duke University, The American Society for Reproductive Medicine and The Society for Assisted Reproductive Technology.

We would like to express our gratitude to Nanette Santoro MD for critical review of this manuscript.

Footnotes

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Presented at the 71st Annual Meeting of the American Society for Reproductive Medicine, Baltimore, Maryland, October 17–21, 2015

Disclosure Statement: The authors have nothing to disclose

References

  • 1.Schieve LA, Peterson HB, Meikle SF, Jeng G, Danel I, Burnett NM, Wilcox LS. Live-birth rates and multiple-birth risk using in vitro fertilization. JAMA. 1999;282:1832–1838. doi: 10.1001/jama.282.19.1832. [DOI] [PubMed] [Google Scholar]
  • 2.Luke B, Brown MB, Stern JE, Grainger DA, Klein N, Cedars M. Effect of embryo transfer number on singleton and twin implantation pregnancy outcomes after assisted reproductive technology. J Reprod Med. 2010;55:387–394. [PubMed] [Google Scholar]
  • 3.Lemos EV, Zhang D, Van Voorhis BJ, Hu XH. Healthcare expenses associated with multiple vs singleton pregnancies in the United States. Am J Obstet Gynecol. 2013;209:586, e581–586, e511. doi: 10.1016/j.ajog.2013.10.005. [DOI] [PubMed] [Google Scholar]
  • 4.Raymond CA. Fertility specialists seeking better recipe for in vitro fertilization. JAMA. 1988;259:2060, 2063. doi: 10.1001/jama.259.14.2060. [DOI] [PubMed] [Google Scholar]
  • 5.Jain T, Harlow BL, Hornstein MD. Insurance coverage and outcomes of in vitro fertilization. N Engl J Med. 2002;347:661–666. doi: 10.1056/NEJMsa013491. [DOI] [PubMed] [Google Scholar]
  • 6.Reynolds MA, Schieve LA, Martin JA, Jeng G, Macaluso M. Trends in multiple births conceived using assisted reproductive technology, United States, 1997–2000. Pediatrics. 2003;111:1159–1162. [PubMed] [Google Scholar]
  • 7.Tiitinen A, Halttunen M, Harkki P, Vuoristo P, Hyden-Granskog C. Elective single embryo transfer: the value of cryopreservation. Hum Reprod. 2001;16:1140–1144. doi: 10.1093/humrep/16.6.1140. [DOI] [PubMed] [Google Scholar]
  • 8.Sunderam S, Kissin DM, Crawford S, Anderson JE, Folger SG, Jamieson DJ, Barfield WD, et al. Assisted reproductive technology surveillance – United States, 2010. MMWR Surveill Summ. 2013;62:1–24. [PubMed] [Google Scholar]
  • 9.Sunderam S, Kissin DM, Crawford SB, Folger SG, Jamieson DJ, Barfield WD, Centers for Disease C et al. Assisted reproductive technology surveillance–United States, 2011. MMWR Surveill Summ. 2014;63:1–28. [PubMed] [Google Scholar]
  • 10.Sunderam S, Kissin DM, Crawford SB, Folger SG, Jamieson DJ, Warner L, Barfield WD, et al. Assisted Reproductive Technology Surveillance - United States, 2012. MMWR Surveill Summ. 2015;64:1–29. [PubMed] [Google Scholar]
  • 11.Sunderam S, Kissin DM, Flowers L, Anderson JE, Folger SG, Jamieson DJ, Barfield WD, et al. Assisted reproductive technology surveillance–United States, 2009. MMWR Surveill Summ. 2012;61:1–23. [PubMed] [Google Scholar]
  • 12.Murray SR, Norman JE. Multiple pregnancies following assisted reproductive technologies–a happy consequence or double trouble? Semin Fetal Neonatal Med. 2014;19:222–227. doi: 10.1016/j.siny.2014.03.001. [DOI] [PubMed] [Google Scholar]
  • 13.Kissin DM, Kulkarni AD, Kushnir VA, Jamieson DJ, National ARTSSG Number of embryos transferred after in vitro fertilization and good perinatal outcome. Obstet Gynecol. 2014;123:239–247. doi: 10.1097/AOG.0000000000000106. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 14.Thurin A, Hausken J, Hillensjo T, Jablonowska B, Pinborg A, Strandell A, Bergh C. Elective single-embryo transfer versus double-embryo transfer in in vitro fertilization. N Engl J Med. 2004;351:2392–2402. doi: 10.1056/NEJMoa041032. [DOI] [PubMed] [Google Scholar]
  • 15.Van Landuyt L, Verheyen G, Tournaye H, Camus M, Devroey P, Van Steirteghem A. New Belgian embryo transfer policy leads to sharp decrease in multiple pregnancy rate. Reprod Biomed Online. 2006;13:765–771. doi: 10.1016/s1472-6483(10)61022-x. [DOI] [PubMed] [Google Scholar]
  • 16.Guidelines on the number of embryos transferred. Fertil Steril. 2004;82(Suppl 1):S1–2. doi: 10.1016/j.fertnstert.2004.07.937. [DOI] [PubMed] [Google Scholar]
  • 17.Kulkarni AD, Kissin DM, Adashi EY. Fertility treatments and multiple births in the United States. N Engl J Med. 2014;370:1070–1071. doi: 10.1056/NEJMc1400242. [DOI] [PubMed] [Google Scholar]
  • 18.Davis OK. Elective single-embryo transfer–has its time arrived? N Engl J Med. 2004;351:2440–2442. doi: 10.1056/NEJMe048268. [DOI] [PubMed] [Google Scholar]
  • 19.Gleicher N. The irrational attraction of elective single-embryo transfer (eSET) Hum Reprod. 2013;28:294–297. doi: 10.1093/humrep/des401. [DOI] [PubMed] [Google Scholar]
  • 20.Armstrong AY, Decherney A, Leppert P, Rebar R, Maddox YT. Keeping clinicians in clinical research: the Clinical Research/Reproductive Scientist Training Program. Fertil Steril. 2009;91:664–666. doi: 10.1016/j.fertnstert.2008.10.029. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 21.Center for Disease Control and Prevention ASfRM, and Society for Assisted Reproductive Technology. 2012 Assisted Reproductive Technology Success Rates: National Summary and Fertility Clinic Reports. Washington, DC: US Dept. of Health and Human Services; 2014. [Google Scholar]
  • 22.Practice Committee of Society for Assisted Reproductive T, Practice Committee of American Society for Reproductive M. Elective single-embryo transfer. Fertil Steril. 2012;97:835–842. doi: 10.1016/j.fertnstert.2011.11.050. [DOI] [PubMed] [Google Scholar]
  • 23.Styer AK, Wright DL, Wolkovich AM, Veiga C, Toth TL. Single-blastocyst transfer decreases twin gestation without affecting pregnancy outcome. Fertil Steril. 2008;89:1702–1708. doi: 10.1016/j.fertnstert.2007.05.036. [DOI] [PubMed] [Google Scholar]
  • 24.Boulet SL, Crawford S, Zhang Y, Sunderam S, Cohen B, Bernson D, McKane P, et al. Embryo transfer practices and perinatal outcomes by insurance mandate status. Fertil Steril. 2015;104:403–409. e401. doi: 10.1016/j.fertnstert.2015.05.015. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 25.Bromer JG, Ata B, Seli M, Lockwood CJ, Seli E. Preterm deliveries that result from multiple pregnancies associated with assisted reproductive technologies in the USA: a cost analysis. Curr Opin Obstet Gynecol. 2011;23:168–173. doi: 10.1097/GCO.0b013e32834551cd. [DOI] [PubMed] [Google Scholar]
  • 26.Scotland GS, McLernon D, Kurinczuk JJ, McNamee P, Harrild K, Lyall H, Rajkhowa M, et al. Minimising twins in in vitro fertilisation: a modelling study assessing the costs, consequences and costutility of elective single versus double embryo transfer over a 20-year time horizon. BJOG. 2011;118:1073–1083. doi: 10.1111/j.1471-0528.2011.02966.x. [DOI] [PubMed] [Google Scholar]
  • 27.Velez MP, Connolly MP, Kadoch IJ, Phillips S, Bissonnette F. Universal coverage of IVF pays off. Hum Reprod. 2014;29:1313–1319. doi: 10.1093/humrep/deu067. [DOI] [PubMed] [Google Scholar]
  • 28.Gleicher N, Barad D. The relative myth of elective single embryo transfer. Hum Reprod. 2006;21:1337–1344. doi: 10.1093/humrep/del026. [DOI] [PubMed] [Google Scholar]
  • 29.Papanikolaou EG, Camus M, Kolibianakis EM, Van Landuyt L, Van Steirteghem A, Devroey P. In vitro fertilization with single blastocyst-stage versus single cleavage-stage embryos. N Engl J Med. 2006;354:1139–1146. doi: 10.1056/NEJMoa053524. [DOI] [PubMed] [Google Scholar]
  • 30.Ryan GL, Sparks AE, Sipe CS, Syrop CH, Dokras A, Van Voorhis BJ. A mandatory single blastocyst transfer policy with educational campaign in a United States IVF program reduces multiple gestation rates without sacrificing pregnancy rates. Fertil Steril. 2007;88:354–360. doi: 10.1016/j.fertnstert.2007.03.001. [DOI] [PubMed] [Google Scholar]
  • 31.Ryan GL, Zhang SH, Dokras A, Syrop CH, Van Voorhis BJ. The desire of infertile patients for multiple births. Fertil Steril. 2004;81:500–504. doi: 10.1016/j.fertnstert.2003.05.035. [DOI] [PubMed] [Google Scholar]
  • 32.Van Peperstraten AM, Kreuwel IA, Hermens RP, Nelen WL, Van Dop PA, Grol RP, Kremer JA. Determinants of the choice for single or double embryo transfer in twin prone couples. Acta Obstet Gynecol Scand. 2008;87:226–231. doi: 10.1080/00016340701855670. [DOI] [PubMed] [Google Scholar]
  • 33.van Peperstraten AM, Hermens RP, Nelen WL, Stalmeier PF, Scheffer GJ, Grol RP, Kremer JA. Perceived barriers to elective single embryo transfer among IVF professionals: a national survey. Hum Reprod. 2008;23:2718–2723. doi: 10.1093/humrep/den327. [DOI] [PubMed] [Google Scholar]
  • 34.Thompson SM, Onwubalili N, Brown K, Jindal SK, McGovern PG. Blastocyst expansion score and trophectoderm morphology strongly predict successful clinical pregnancy and live birth following elective single embryo blastocyst transfer (eSET): a national study. J Assist Reprod Genet. 2013;30:1577–1581. doi: 10.1007/s10815-013-0100-4. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 35.Steinberg ML, Boulet S, Kissin D, Warner L, Jamieson DJ. Elective single embryo transfer trends and predictors of a good perinatal outcome–United States, 1999 to 2010. Fertil Steril. 2013;99:1937–1943. doi: 10.1016/j.fertnstert.2013.01.134. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 36.Veleva Z, Karinen P, Tomas C, Tapanainen JS, Martikainen H. Elective single embryo transfer with cryopreservation improves the outcome and diminishes the costs of IVF/ICSI. Hum Reprod. 2009;24:1632–1639. doi: 10.1093/humrep/dep042. [DOI] [PubMed] [Google Scholar]
  • 37.Rodriguez Barredo DB, Tur Padro R, Mancini F, Parriego Garcia M, Rodriguez Garcia I, Coroleu Lletget B, Barri Rague PN. Elective single embryo transfer and cumulative pregnancy rate: five-year experience in a Southern European Country. Gynecol Endocrinol. 2012;28:425–428. doi: 10.3109/09513590.2011.633662. [DOI] [PubMed] [Google Scholar]
  • 38.Boulet SL, Schieve LA, Nannini A, Ferre C, Devine O, Cohen B, Zhang Z, et al. Perinatal outcomes of twin births conceived using assisted reproduction technology: a population-based study. Hum Reprod. 2008;23:1941–1948. doi: 10.1093/humrep/den169. [DOI] [PubMed] [Google Scholar]
  • 39.Geisler ME, O’Mahony A, Meaney S, Waterstone JJ, O’Donoghue K. Obstetric and perinatal outcomes of twin pregnancies conceived following IVF/ICSI treatment compared with spontaneously conceived twin pregnancies. Eur J Obstet Gynecol Reprod Biol. 2014;181:78–83. doi: 10.1016/j.ejogrb.2014.07.033. [DOI] [PubMed] [Google Scholar]
  • 40.Umranikar A, Parmar D, Davies S, Fountain S. Multiple births following in vitro fertilization treatment: redefining success. Eur J Obstet Gynecol Reprod Biol. 2013;170:299–304. doi: 10.1016/j.ejogrb.2013.06.031. [DOI] [PubMed] [Google Scholar]
  • 41.Grunfeld L, Luna M, Mukherjee T, Sandler B, Nagashima Y, Copperman AB. Redefining in vitro fertilization success: should triplets be considered failures? Fertil Steril. 2008;90:1064–1068. doi: 10.1016/j.fertnstert.2007.07.1360. [DOI] [PubMed] [Google Scholar]
  • 42.Luke B, Stern JE, Kotelchuck M, Declercq ER, Hornstein MD, Gopal D, Hoang L, et al. Adverse pregnancy outcomes after in vitro fertilization: effect of number of embryos transferred and plurality at conception. Fertil Steril. 2015;104:79–86. doi: 10.1016/j.fertnstert.2015.04.006. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 43.Pandian Z, Marjoribanks J, Ozturk O, Serour G, Bhattacharya S. Number of embryos for transfer following in vitro fertilisation or intra-cytoplasmic sperm injection. Cochrane Database Syst Rev. 2013;7:CD003416. doi: 10.1002/14651858.CD003416.pub4. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 44.Luke B, Brown MB, Stern JE, Jindal SK, Racowsky C, Ball GD. Using the Society for Assisted Reproductive Technology Clinic Outcome System morphological measures to predict live birth after assisted reproductive technology. Fertil Steril. 2014;102:1338–1344. doi: 10.1016/j.fertnstert.2014.07.1242. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 45.Baxter Bendus AE, Mayer JF, Shipley SK, Catherino WH. Interobserver and intraobserver variation in day 3 embryo grading. Fertil Steril. 2006;86:1608–1615. doi: 10.1016/j.fertnstert.2006.05.037. [DOI] [PubMed] [Google Scholar]
  • 46.Forman EJ, Tao X, Ferry KM, Taylor D, Treff NR, Scott RT., Jr Single embryo transfer with comprehensive chromosome screening results in improved ongoing pregnancy rates and decreased miscarriage rates. Hum Reprod. 2012;27:1217–1222. doi: 10.1093/humrep/des020. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 47.Olivennes F, Golombok S, Ramogida C, Rust J, Follow-Up T. Behavioral and cognitive development as well as family functioning of twins conceived by assisted reproduction: findings from a large population study. Fertil Steril. 2005;84:725–733. doi: 10.1016/j.fertnstert.2005.03.039. [DOI] [PubMed] [Google Scholar]
  • 48.Ellison MA, Hall JE. Social stigma and compounded losses: quality-of-life issues for multiple-birth families. Fertil Steril. 2003;80:405–414. doi: 10.1016/s0015-0282(03)00659-9. [DOI] [PubMed] [Google Scholar]

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