ONE, TWO, OR MORE EMBRYOS: THE RIGHT DECISION by Dr. Sonya Kashyap (Fall 2011)

ONE, TWO, OR MORE EMBRYOS: THE RIGHT DECISION
by Dr. Sonya Kashyap

The leading cause of infant morbidity and mortality among women who become pregnant through assisted reproductive technologies (ART) is multiple pregnancy (twins or triplets). In the US, 35% of ART live births are multiple pregnancies, and in Canada anywhere from 30-40% of ART pregnancies are multiple pregnancies. Sixty-one percent of women with multiple gestations deliver preterm and 13% deliver very early at less than 28 weeks.1,2Eight percent of children born from such deliveries experience serious long-term morbidity. Preterm delivery may be associated with many newborn complications, including lung disease, cerebral palsy, severe bowel infections, and eye problems. The most effective way to reduce infant morbidity and mortality associated with ART is to prevent multiple pregnancies.

The strongest predictor of multiple pregnancy among women using ART is the number of embryos transferred per cycle.3 Live birth rates with good quality, single embryo transfer are only slightly lower than with double embryo transfer, but the marginal improvement in pregnancy rate is associated with a marked increase in multiple pregnancies.4 Despite the increased risks brought about by multiple pregnancies, the average number of embryos transferred in women under the age of 35 years in the US in 2007 was 2.2, and only 4.5% of women under 35 years old had elective single embryo transfer.2 A woman’s decision regarding the number of embryos to transfer might be influenced by her knowledge of the adverse effects associated with multiple gestation and her desire to avoid such complications.

A little history
Since the birth of Louise Brown, the first “test tube baby”, in 1978, both success rates and the number of women using ART have increased exponentially. Currently, the ART-related pregnancy rate among women under 35 years of age in the US who use ART is 45% per cycle.2Unfortunately, this remarkable success in helping infertile women/couples become pregnant is often associated with multiple pregnancies. Multiple pregnancy occurs in only 2-3% of spontaneous pregnancies, but, overall, 33% of women who become pregnant using ART have twins and 2% have triplets or higher order pregnancies.6,7

In addition to the social, emotional and financial burdens that twins or triplets may impose, multiple pregnancies are associated with high infant morbidity and mortality. The most common complication of multiple gestation is preterm delivery and its related neonatal complications, including lung disease, cerebral palsy, severe bowel infection and injury, and eye problems.- Preterm delivery occurs in 61.4% and very preterm delivery in 13.2% of multiple pregnancies.1 Preterm delivery is responsible for at least 1.2 infant deaths of every 1000 live births.(1 Multiple gestations and preterm delivery are associated with other excess morbidity; for example, cerebral palsy occurs 17 times more frequently in triplet gestations and 4 times more frequently in twin gestations than in singleton gestations.(- Up to 25% of twins and 60% of triplets experience intrauterine growth restriction and approximately 50% of multiples require neonatal intensive care unit admission. Infant and child health issues after extreme prematurity are compounded adversely by low birth weight and multiple pregnancy.8 Compared to singleton pregnancy, multiple pregnancy is also associated with higher maternal risk for heart disease, blood clots, high blood pressure, gestational diabetes, bleeding complications, hysterectomy, blood transfusion, operative delivery, and prolonged hospital stay.9,10

The rate of multiple pregnancies directly correlates with the number of embryos transferred.11 One very good study evaluated elective single (eSET) versus double embryo transfer (DET) in women younger than 36 years old. Thirty-nine percent achieved pregnancy with single embryo transfer compared to 43% of cycles with double embryo transfer.(4 Although pregnancy rates with double embryo transfers were slightly better, this small increase in pregnancy rates came with a marked increase in multiple pregnancies. Single embryo transfer resulted in twins in 0.8% of cycles, while double embryo transfer resulted in twins in 33% of cycles.(4) This small change in overall pregnancy rates are of course important to patients who have a long history of infertility and for whom the costs of infertility treatment are high. However, the exponential increased financial and emotional costs of both uncomplicated and complicated multiple pregnancy far exceed those costs.

The larger reduction from twins to singletons may be more important to patients who understand the ramifications of a twin pregnancy. Several studies have shown that education improves patients’ understanding of the complications of multiple pregnancies and decreases their desire for such. Satisfaction with the decision regarding the number of embryos to transfer relates to how involved a patient feels with the decision making. This appears to be more important for female rather than male partners. Factors that have consistently been associated with a desire for multiple pregnancy include: 1) older maternal age 2) longer duration of infertility 3) previous failed treatment cycles. In a study of patients carefully selected for eSET versus DET the pregnancy rates were 33.0 and 30.3% with an overall twin rate of 12.9 %.12(12)

Evidence shows that women feel that shared decision-making with their partner about the number of embryos to transfer is extremely important.The opportunity for patients to share information with their partners was at least as important as the information that was received. Several studies show that women are less risk-averse than their partners with regards to the number of embryos to transfer. Studies also that show that small increments in the probability of pregnancy are important factors in patients’ decisions. However, there is also evidence that a change in knowledge about the risk of multiple pregnancy can modify the patients’ predisposition about the number of embryos to transfer.22,31

Interestingly, the cost of IVF treatment has often been blamed for multiple pregnancies following the procedure. In an unpublished survey that we conducted, while many patients said avoiding multiple pregnancies was not important, they all agreed that avoiding the complications of multiple pregnancies was important. Even more interesting is the fact that no participant identified lower cost as a significant reason for selecting more embryos, only success rates. Other studies have demonstrated consistently that, in fact, it is not the majority of patients who desire multiple pregnancies but the minority ( ~ 20%), and that the uptake of intended single embryo transfer improves with patient education and with the time spent counseling these patients.

Patients said they were concerned about decreased pregnancy rates but admitted they felt “ inadequately prepared to make a decision about the number of embryos to transfer”. Blennborn and colleagues showed that patients felt this was a “hard decision” and that they were influenced by the following factors: the number of spare embryos available for cryopreservation, their age, previous ART failures, and their pre-existing concern about twins. Blennborn also showed that patients’ decisions about the number of embryos to transfer were strongly influenced by their partners and also by information provided about risks.21 Ryan combined an educational program with a mandated eSET program in 110 patients with good prognosis. She showed improved patient knowledge about the risks of multiple gestation and increased patient preference for singletons compared to prior to the educational program.22 However, since single embryo transfer was mandated in best prognoses patients, she did not measure the patient choice/acceptance for elective single embryo transfer as the driving force for eSET.

Physicians’ attitudes towards multiple pregnancies and the number of embryos to transfer are also important.20 In semi-structured interviews, providers cited the following reasons for not using eSET: lower pregnancy rates requiring more cycles; lack of prognostic models; lack of protocol and even the fact that having twins helped patients achieve their family goals more quickly. Jain et al. showed that states with mandated insurance coverage for IVF have a lower incidence of higher order multiple pregnancies than uninsured states but that the rate of twins is similar in insured versus uninsured states.19 Swedish practitioners are perhaps among the best educated about the complications of multiple pregnancy since much of the literature was published there and there was a resulting campaign to reduce the multiple pregnancy rate after ART. In the early part of this decade Swedish IVF physicans voluntarily agreed to single embryo transfer in eligible cases. The pregnancy rates did not drop but the multiple pregnancy rates decreased significantly. In 2003, national guidelines in Sweden were published stating that single embryo transfer should be the norm. In Canada, efforts to decrease the multiple pregnancy rates have been stagnant despite the introduction of the Healthy Singleton Birth Committee with the respectable goal of lowering the multiple pregnancy rate through patient education. However, an interesting experiment in the province of Quebec has occurred where mandated insurance coverage for IVF treatment now exists. The program is linked to single embryo transfer and it funds the transfer of frozen embryos in later cycles. Programs which have higher than acceptable multiple pregnancy rates will have their funding reassessed. The multiple pregnancy rates had dropped from 27.2% to 3.8% three months after the program was implemented

Despite evidence that single embryo transfer achieves pregnancy at almost the same rate as double embryo transfer and prevents multiple gestations, less than 5% of U.S. women under 35 years old underwent elective single embryo transfer in 2007.

The American Society for Reproductive Medicine has also identified reduction in the incidence of ART-related multiple gestation as “an essential goal for ART programs and their patients”. 13,14 Practice guidelines of the Society suggest that eSET should be considered for women less than 35 years old and that more than two embryos should not be transferred except in extraordinary circumstances in this age group.14 ASRM guidelines have resulted in a decrease in the incidence of triplets and higher order gestations from 14% in 1996 to 2% in 2007, but the incidence of twin gestations has remained stable at 33%.14-17(14-17) Despite evidence that single embryo transfer achieves pregnancy at almost the same rate as double embryo transfer and prevents multiple pregnancy, and despite strong practice guidelines, the average number of embryos transferred in the US in 2007 in women under the age of 35 was 2.2 and in Canada it is 1.8.18 Reasons for the high number of embryos transferred in the US are complex. Success rates vary among ART clinics and depend on patient prognostic factors; single embryo transfer may not be appropriate for all women. Clinic pregnancy rates are very important in an increasingly competitive environment where small differences in success rates may determine which clinic a woman/couple chooses to use. The high direct patient costs associated with ART ($5,000 – $10,000 per cycle) also influence a woman’s desire to transfer more embryos to maximize success rates. Cost does not increase if additional embryos are transferred, and the cost per cycle is not reduced for subsequent cycles if the initial cycle fails.

The optimal number of embryos to transfer depends on several determinants, including an individual woman’s age, her pregnancy history and medical conditions, as well as the ART clinic’s age-specific pregnancy rates and the viability of potential frozen embryos. While these factors are generally not modifiable, an individual woman/couple’s knowledge of and attitude toward pregnancy rates associated with the number of embryos transferred, risk for multiple gestation and associated complications might impact her decision regarding the number of embryos to transfer.

Decision-making is generally influenced both by a person’s knowledge of the alternatives and by their values regarding the possible outcomes of the decision.23 Decision aids are designed to improve decision-making by improving knowledge and explicitly incorporating an individual’s values.23 Women using ART generally place high value on avoiding neonatal and maternal morbidity and mortality. Education about the small increase in pregnancy rate per cycle associated with double embryo transfer and the marked increase in multiple gestation and associated complications will increase the proportion of women who choose single embryo transfer. In fact, lack of knowledge about the potential adverse outcomes of multiple gestation has been shown to be a major predictor of the desire for twins.13

We hypothesize that improvement in decision satisfaction and quality in this clinical scenario concerning the number of embryos to transfer after ART will result in better clinical outcomes – more eSET uptake and therefore more singleton pregnancies. We have developed and tested a decision aid to help women/couples decide how many embryos to transfer. If you would like more information about this tool please contact us.

All references are listed on the IAAC website at iaac.ca/content/library.

About the author
Dr Sonya Kashyap is a co-director at Genesis Fertility Center. She completed her medical school, residency and Masters in Epidemiology at the University of Ottawa. She then completed her fellowship in Reproductive Endocrinology and Infertility at the world-reknowned Center for Reproductive Medicine and Infertility at Cornell University Medical College in NYC, under the mentorship of Dr Zev Rosenwaks. She returned to Canada to practice from 2004-2007 during which time she received both national and international awards, research funding for projects in fertility preservation, patient decision-making in IVF, as well as maternal and fetal outcomes after IVF. She was recruited by the NIH Center for Excellence in Women’s Health at the University of California at San Francisco where she practiced from 2007-2010 before returning home to Vancouver. Her motivation is to provide compassionate, cutting-edge and evidence-based care to help couples and individuals who suffer from infertility achieve their goal of having a family.