Objective
The purpose of this study was to use a validated prediction model to examine whether single embryo transfer (SET) over 2 cycles results in live birth rates (LBR) comparable with 2 embryos transferred (DET) in 1 cycle and reduces the probability of a multiple birth (ie, multiple birth rate [MBR]).
Study Design
Prediction models of LBR and MBR for a woman considering assisted reproductive technology developed from linked cycles from the Society for Assisted Reproductive Technology Clinic Outcome Reporting System for 2006-2012 were used to compare SET over 2 cycles with DET in 1 cycle. The prediction model was based on a woman’s age, body mass index (BMI), gravidity, previous full-term births, infertility diagnoses, embryo state, number of embryos transferred, and number of cycles.
Results
To demonstrate the effect of the number of embryos transferred (1 or 2), the LBRs and MBRs were estimated for women with a single infertility diagnosis (male factor, ovulation disorders, diminished ovarian reserve, and unexplained); nulligravid; BMI of 20, 25, 30, and 35 kg/m 2 ; and ages 25, 35, and 40 years old by cycle (first or second). The cumulative LBR over 2 cycles with SET was similar to or better than the LBR with DET in a single cycle (for example, for women with the diagnosis of ovulation disorders: 35 years old; BMI, 30 kg/m 2 ; 54.4% vs 46.5%; and for women who are 40 years old: BMI, 30 kg/m 2 ; 31.3% vs 28.9%). The MBR with DET in 1 cycle was 32.8% for women 35 years old and 20.9% for women 40 years old; with SET, the cumulative MBR was 2.7% and 1.6%, respectively.
Conclusion
The application of this validated predictive model demonstrated that the cumulative LBR is as good as or better with SET over 2 cycles than with DET in 1 cycle, while greatly reducing the probability of a multiple birth.
See related editorial, page 556
Since the birth of the first child from in vitro fertilization (IVF) >35 years ago, >5 million babies have been born from this technology. Worldwide, more than 1 million IVF cycles that result in the birth of >250,000 babies occur annually. In 2012 in the United States, there were >65,000 babies born from IVF, which accounted for 1.6% of all births, a proportion that has doubled over the past decade.
Multiple birth is one of the primary acknowledged adverse outcomes of IVF. In 2010 in the United States, multiple-birth deliveries accounted for nearly 30% of all IVF births and 44.5% of all IVF infants. On a national basis, IVF infants account for 0.8% of all singletons, but 43.4% of twins and 32.5% of all triplet and higher-order multiples. Although infants of multiple births comprise only 3% of all live births, they account for 13% of all preterm births (<37 weeks’ gestation), 15% of all early preterm births (<32 weeks’ gestation), 21% of all low birthweight infants (<2500 g), and 25% of all very low birthweight infants (<1500 g). The average birthweight and gestational age is 3296 g at 38.7 weeks for singletons, compared with 2336 g at 35.3 weeks for twins, 1660 g at 31.9 weeks for triplets, 1291 g at 29.5 weeks for quadruplets, and 1002 g at 26.6 weeks for quintuplets. The 2 most important factors that affect perinatal mortality rates are gestational age and relative birthweight ; with each additional fetus, both of these factors are compromised. As a consequence, the risk of dying before their first birthday is nearly 7 times greater for twins and almost 20 times greater for triplets and quadruplets; the survivors are at continued higher risk of perinatally related mental and physical handicaps. The estimate is that twin pregnancies produce a child with cerebral palsy 12 times more often than do singleton pregnancies and that one-fifth of all triplet pregnancies and one-half of all quadruplet pregnancies result in at least 1 child with a major handicap. Even when matched for gestational age, at 1 year of age, children of multifetal pregnancies have nearly 3 times the risk for cerebral palsy.
Historically, multiple embryos have been transferred to compensate for low implantation rates that, in turn, increased the likelihood of a multiple pregnancy, which is a known complication of IVF. In an effort to reduce the multiple birth rate (MBR) with IVF, the Society for Assisted Reproductive Technology issued the first clinical guidelines on the number of embryos to transfer in 1998; these guidelines have been revised downward in 1999, 2004, 2006, 2008, 2009, and most recently in 2013. The effect in clinical practice has been a reduction in the number of embryos transferred and a dramatic decrease in the higher-order multiple rate (triplets, quadruplets, and higher order) because of IVF. Analyses of IVF cycles in the United States from 1996-2002 indicated a progressive trend of the transfer of fewer embryos. Data from the Society for Assisted Reproductive Technology Clinic Outcome Reporting System (SART CORS) from 2004-2012 shows that the proportions of single embryo transfer (SET) and double embryo transfer (DET) have increased from 7.0-23.1%, and 32.9-49.8%, respectively; the transfer of ≥3 embryos has decreased from 60.1-27.1%. During this same time period, the proportion of singleton births from IVF increased from 67.9-73.8%; twin and triplet and higher-order births decreased from 29.7-25.4%, and 2.4-0.8%, respectively. SET is recommended in the most recent guidelines for women under 35 years old with a favorable prognosis (first cycle of IVF, good embryo quality, excess embryos available for cryopreservation, or previous successful IVF cycle).
We developed validated prediction models for live birth rate (LBR) and multiple birth rate (MBR) using the SART CORS data from 2004-2011. We subsequently have revised the model to include data from 2006-2012; this revised model is implemented on the Society for Assisted Reproductive Technology website ( www.sart.org ). The goal of this analysis was to compare the estimates of LBR and MBR when 2 embryos are transferred: either (1) both in 1 cycle (DET, DET) or (2) in 2 successive cycles, each with a single embryo (ie, SET).
Materials and Methods
Development and validation of the original model has been described previously. This analysis was based on deidentified data and therefore was deemed exempt by institutional review board review at Michigan State University (as defined in 45 Code of Federal Regulations 46.l02[f]). We describe only changes between the current and original model. Data for this model used cycles reported from 2006-2012. Instead of categorizing age and body mass index (BMI) and fitting the model to the categoric data, we included both a linear and quadratic term for both age and BMI in the model. In addition, we included an indicator variable for reporting year. We developed separate models for LBRs when 1 and 2 embryos are transferred. Because the rate of multiple births is very low when 1 embryo is transferred, we modeled MBRs simultaneously for both 1 and 2 embryos transferred with an indicator variable to denote the number of embryos transferred. The other variables included in the modeling were number of previous full term births (0, 1, ≥2), number of infertility diagnoses (1, >1), infertility diagnosis (male factor, endometriosis, ovulation disorders, diminished ovarian reserve, tubal ligation, tubal hydrosalpinx, tubal other, uterine factor, other factor, and unexplained).
Logistic regression modeling was performed, using a backward-stepping algorithm, eliminating variables until those remaining were all significant at P < .05. In this application of the prediction model, we estimated the LBRs and MBRs for women with: (1) a single infertility diagnosis of male factor, ovulation disorders, diminished ovarian reserve, or unexplained; (2) no previous conceptions or live births (nulligravid); (3) cycles using only autologous oocytes; (4) cycle 1 used only fresh embryos. The model for SET at cycle 1 included data from 33,065 cycles; for DET at cycle 1 it included 126,921 cycles, and for fresh SET at cycle 2 it included 8682 cycles and thawed SET at cycle 2 it included 6747 cycles. Estimates are reported for ages 25, 35, and 40 years and for BMIs of 20, 25, 30, and 35. Because the LBR improved with reporting year, all estimates are calibrated to 2012 (the most recent year with data).
The cumulative LBR at cycle 2 is equal to LBR at cycle 1 + LBR at cycle 2 × (1 – LBR at cycle 1). This assumes that there is no contraindication during cycle 1 to continuing into cycle 2. The cumulative MBR at cycle 2 is equal to MBR at cycle 1 + MBR at cycle 2 × (1 – LBR at cycle 1).
Results
The LBRs and MBRs at cycle 1 and the cumulative LBRs and MBRs over 2 cycles when 1 embryo is transferred are presented in the Table for combinations of 4 infertility diagnoses (male factor, ovulation disorders, diminished ovarian reserve, and unexplained), 3 ages (25, 35, and 40 years), and 4 BMI levels (20, 25, 30, and 35 kg/m 2 ) for women without a previous birth, a single infertility diagnosis, with fresh autologous oocytes in cycle 1 and separately for fresh SET in cycle 2 and thawed SET in cycle 2. The cumulative LBR at cycle 2 with fresh SET in both cycles is greater or equal to the LBR at cycle 1 with DET, ranging from 23.0–63.9%, compared with 21.8–53.4%. The cumulative MBR at cycle 2 with SET is 1.4-3.0% compared with 18.3-39.8% with DET in cycle 1. The largest difference in LBR is among the women with the youngest ages: 17-20% improvement in LBR when 2 cycles with SET are used compared with 1 cycle with DET. This reduces the improvement to a 4-6% at age 40 years. The MBR with 2 cycles of SET is reduced by 92-94% from the MBR with DET.
| Diagnosis | Age | BMI, kg/m 2 | Live birth rates, % | Multiple birth rates, % | ||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Single embryo transfer | Double embryo transfer | Single embryo transfer | Double embryo transfer | |||||||
| Cycle 1 | Cycle 2, cumulative | Cycle 1 | Cycle 1 | Cycle 2, cumulative | Cycle 1 | |||||
| Fresh cycle 1 | Fresh cycle 1, fresh cycle 2 | Fresh cycle 1, thawed cycle 2 | Fresh cycle 1 | Fresh cycle 1 | Fresh cycle 1, fresh cycle 2 | Fresh cycle 1, thawed cycle 2 | Fresh cycle 1 | |||
| Male factor | ||||||||||
| 25 | 20 | 45.9 | 62.7 | 63.4 | 53.4 | 2.1 | 3.0 | 3.2 | 39.8 | |
| 25 | 45.2 | 61.4 | 62.0 | 52.3 | 2.1 | 3.0 | 3.2 | 39.8 | ||
| 30 | 43.2 | 59.2 | 59.8 | 50.3 | 2.1 | 3.0 | 3.3 | 39.8 | ||
| 35 | 40.0 | 56.0 | 56.8 | 47.1 | 2.1 | 3.1 | 3.4 | 39.8 | ||
| 35 | 20 | 39.7 | 56.7 | 59.3 | 49.6 | 1.5 | 2.5 | 2.5 | 32.8 | |
| 25 | 39.0 | 55.4 | 57.8 | 48.6 | 1.5 | 2.5 | 2.5 | 32.8 | ||
| 30 | 37.0 | 53.1 | 55.3 | 46.5 | 1.5 | 2.5 | 2.6 | 32.8 | ||
| 35 | 34.0 | 50.0 | 51.8 | 43.4 | 1.5 | 2.6 | 2.6 | 32.8 | ||
| 40 | 20 | 22.3 | 33.1 | 40.0 | 31.5 | 0.8 | 1.4 | 1.6 | 20.9 | |
| 25 | 21.8 | 32.0 | 38.3 | 30.6 | 0.8 | 1.4 | 1.6 | 20.9 | ||
| 30 | 20.4 | 30.2 | 36.0 | 28.9 | 0.8 | 1.5 | 1.6 | 20.9 | ||
| 35 | 18.3 | 27.7 | 33.1 | 26.4 | 0.8 | 1.5 | 1.6 | 20.9 | ||
| Ovulation disorders | ||||||||||
| 25 | 20 | 47.8 | 63.9 | 64.1 | 53.4 | 2.1 | 3.1 | 3.1 | 39.8 | |
| 25 | 47.0 | 62.7 | 62.8 | 52.3 | 2.1 | 3.1 | 3.2 | 39.8 | ||
| 30 | 45.0 | 60.5 | 60.6 | 50.3 | 2.1 | 3.2 | 3.2 | 39.8 | ||
| 35 | 41.8 | 57.3 | 57.6 | 47.1 | 2.1 | 3.2 | 3.3 | 39.8 | ||
| 35 | 20 | 41.5 | 58.0 | 60.1 | 49.6 | 1.5 | 2.6 | 2.5 | 32.8 | |
| 25 | 40.7 | 56.7 | 58.6 | 48.6 | 1.5 | 2.6 | 2.5 | 32.8 | ||
| 30 | 38.8 | 54.4 | 56.4 | 46.5 | 1.5 | 2.7 | 2.5 | 32.8 | ||
| 35 | 35.7 | 51.3 | 53.2 | 43.4 | 1.5 | 2.7 | 2.6 | 32.8 | ||
| 40 | 20 | 23.7 | 34.2 | 41.3 | 31.5 | 0.8 | 1.5 | 1.6 | 20.9 | |
| 25 | 23.1 | 33.1 | 39.6 | 30.6 | 0.8 | 1.5 | 1.6 | 20.9 | ||
| 30 | 21.7 | 31.3 | 37.3 | 28.9 | 0.8 | 1.6 | 1.6 | 20.9 | ||
| 35 | 19.5 | 28.8 | 34.3 | 26.4 | 0.8 | 1.6 | 1.6 | 20.9 | ||
| Diminished ovarian reserve | ||||||||||
| 25 | 20 | 40.4 | 56.0 | 60.5 | 47.2 | 1.8 | 2.8 | 3.1 | 36.0 | |
| 25 | 39.7 | 54.7 | 58.8 | 46.2 | 1.8 | 2.8 | 3.1 | 36.0 | ||
| 30 | 37.7 | 52.5 | 56.2 | 44.1 | 1.8 | 2.8 | 3.1 | 36.0 | ||
| 35 | 34.7 | 49.3 | 52.7 | 41.0 | 1.8 | 2.9 | 3.2 | 36.0 | ||
| 35 | 20 | 34.4 | 50.0 | 54.9 | 43.5 | 1.3 | 2.3 | 2.3 | 29.4 | |
| 25 | 33.7 | 48.7 | 53.1 | 42.5 | 1.3 | 2.3 | 2.3 | 29.4 | ||
| 30 | 31.9 | 46.5 | 50.5 | 40.4 | 1.3 | 2.4 | 2.4 | 29.4 | ||
| 35 | 29.1 | 43.4 | 47.2 | 37.5 | 1.3 | 2.4 | 2.4 | 29.4 | ||
| 40 | 20 | 18.6 | 27.8 | 35.2 | 26.4 | 0.7 | 1.4 | 1.4 | 18.3 | |
| 25 | 18.1 | 26.8 | 33.6 | 25.6 | 0.7 | 1.4 | 1.4 | 18.3 | ||
| 30 | 16.9 | 25.2 | 31.5 | 24.1 | 0.7 | 1.4 | 1.4 | 18.3 | ||
| 35 | 15.1 | 23.0 | 28.9 | 21.8 | 0.7 | 1.4 | 1.4 | 18.3 | ||
| Unexplained | ||||||||||
| 25 | 20 | 46.3 | 62.9 | 63.6 | 53.4 | 2.1 | 3.0 | 3.2 | 39.8 | |
| 25 | 45.5 | 61.6 | 62.2 | 52.3 | 2.1 | 3.0 | 3.2 | 39.8 | ||
| 30 | 43.5 | 59.4 | 60.1 | 50.3 | 2.1 | 3.0 | 3.3 | 39.8 | ||
| 35 | 40.3 | 56.3 | 57.0 | 47.1 | 2.1 | 3.1 | 3.4 | 39.8 | ||
| 35 | 20 | 40.0 | 57.0 | 59.5 | 49.6 | 1.5 | 2.5 | 2.5 | 32.8 | |
| 25 | 39.3 | 55.6 | 58.0 | 48.6 | 1.5 | 2.5 | 2.5 | 32.8 | ||
| 30 | 37.3 | 53.4 | 55.5 | 46.5 | 1.5 | 2.5 | 2.6 | 32.8 | ||
| 35 | 34.3 | 50.3 | 52.1 | 43.4 | 1.5 | 2.6 | 2.6 | 32.8 | ||
| 40 | 20 | 22.6 | 33.3 | 40.2 | 31.5 | 0.8 | 1.4 | 1.6 | 20.9 | |
| 25 | 22.0 | 32.2 | 38.5 | 30.6 | 0.8 | 1.4 | 1.6 | 20.9 | ||
| 30 | 20.6 | 30.4 | 36.2 | 28.9 | 0.8 | 1.5 | 1.6 | 20.9 | ||
| 35 | 18.5 | 27.9 | 33.2 | 26.4 | 0.8 | 1.5 | 1.6 | 20.9 | ||
a Models were adjusted for all of the factors included in the Table, with the assumption of no previous births, a single infertility diagnosis, and the use of autologous oocytes.
Among women with the same diagnosis and age, an increase in BMI from 20-35 kg/m 2 is associated with a reduction in LBRs by approximately 6-7 percentage points for women 25 years old, approximately 5-6 percentage points for women 35 years old, and approximately 3-4 percentage points for women 40 years old. Among women with the same diagnosis and BMI, an increase in age from 25-35 years is associated with a reduction in LBRs by approximately 4-6 percentage points; an increase in age from 35-40 years is associated with a reduction in LBRs by approximately 18-24 percentage points.
We also developed a model in which the second cycle used a thawed embryo. These models were based on the assumption that there were additional embryos of adequate quality to freeze in cycle 1. The cumulative LBRs and MBRs did not differ significantly from those reported in the Table for women 20-30 years old with fresh SET in both cycle 1 and cycle 2. However, because there were relatively few cases of SET with thawed embryos in cycle 2 for older women, the LBRs for women over 30 years old should be viewed with caution.
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