IVF: fewer complications with single-embryo transfer, but what about the live birth rates?

In the first decades of IVF the routine practice was to transfer three, or sometimes even four or five, embryos if available. The reason for this was poor live birth rates when transferring fewer embryos, and also the fact that multiple births were not seen as an adverse outcome. Later research has shown that IVF children are at increased risk of adverse obstetric outcome, and that most of that risk increase is caused by the high incidence of multiple births. Double-embryo transfer (DET), which was the predominant choice in many countries 10 years ago, has now been replaced in Northern Europe to a large extent by single-embryo transfer (SET), at least in patients with a good prognosis. The SET rates greatly differ between different industrialized countries, being highest in Northern Europe where the introduction of SET has been most rapid. In 2005, the SET rate in fresh transfers was 69% in Sweden, 20% in Europe and 9% in the USA [1,2,101].

The main factor behind the increased risks for IVF children is the high multiple birth rate

The incidence of preterm birth, low birth weight and perinatal mortality is higher in IVF children than in spontaneously conceived children [3–5]. Secondary to preterm birth, IVF children are also at greater risk of cerebral palsy and mental retardation [6]. The single most important factor behind these increased risks is the high multiple birth rate.

The higher incidence of adverse obstetric outcome in multiple births was illustrated in a Danish study including over 3000 IVF twins and 5000 IVF singletons [7]. The rates for IVF singletons compared with IVF twins were: low birth weight in 4 versus 30%; very low birth weight in 1.5 versus 8%; preterm birth in 6 versus 35%; very preterm birth in 1.3 versus 9%; stillbirth in 0.7 versus 1.3%; and mortality within the first year of life in 1.4 versus 2.3% [7]. In the 2005 national statistics from the USA, the preterm birth rate was 15% in IVF singletons, 66% in IVF twins and 97% in IVF triplets or higher order multiples [2]. The risk of cerebral palsy was 3.7-times higher in IVF children compared with controls in a Swedish study, which could mainly be explained by the higher multiple birth risk [6]. A total of 2% of the IVF children in that study were in contact with a childhood disability center, compared with 1% of the controls [6]. A systematic review concluded that IVF/intracytoplasmic sperm injection (ICSI) per se does not lead to increased risks for cerebral palsy or mental retardation; the risk increase is explained by other risk factors such as preterm birth [8]. Small size at birth is also related to cardiovascular morbidity and mortality in adult life [9]. An investigation of IVF children of approximately 12 years of age showed that they had significantly higher fasting glucose levels and higher blood pressure compared with controls [10].

SET policy reduces risks for IVF children

Single-embryo transfer decreases the multiple birth rate to a similar level to that in the normal population. In a randomized controlled trial with 661 patients assigned either to fresh SET and a frozen–thawed SET if the fresh cycle was unsuccessful, or one fresh DET, the multiple birth rates were 1% in the SET group and 33% in the DET group [11]. The rates of preterm and very preterm birth were 12 and 2% in the SET group versus 29 and 7% in the DET group. The rates of low and very low birth weight were 8 and 4% in the SET group versus 28 and 7% in the DET group [11]. De Sutter et al. compared rates in singletons born after DET or SET, and found higher risks for low birth weight and preterm birth in the DET group [12].

Live birth rates after SET

The evidence is clear that SET leads to better obstetric outcome for the children born after IVF. The question is, can we combine a broad implementation of SET with satisfying live birth rates?

In Sweden, national guidelines were introduced in 2003 declaring that SET should be the choice except in cases where the risk of a twin pregnancy is very small. A study of Swedish national data from 1994 to 2004 reveals that the birth rate after IVF remained about the same during that time period (26% per transfer), despite the fact that the SET rate increased from 10 to nearly 70% and the multiple birth rate fell from 25 to 5% [13]. The reason for the stable delivery rate is probably improvements in the IVF technique, and possibly also the fact that with a SET policy only the best embryos are chosen and transferred, allowing for a higher implantation rate. Northern Europe has pioneered strategies to reduce the number of embryos used per transfer, and in 2005 the SET rate was 69% in Sweden, 50% in Finland, 48% in Belgium, 43% in Norway and 33% in Denmark [1,101]. The birth rate per fresh IVF/ICSI transfer was 26% in Sweden, 21% in Finland, 20% in Belgium, 25% in Norway and 21% in Denmark [1]. The multiple birth rate was 7% in Sweden and 22% in Europe [1,101]. In the USA the live birth rate was 34% per fresh transfer, higher than in Europe; however, SET was used in only 9% of fresh transfers and the multiple birth rate was 31% [2].

Per transfer, DET leads to higher live birth rates than SET. In the randomized controlled study by Thurin et al., the live birth rate was 43% after one fresh DET compared with 28% after one fresh SET [14]. However, when including one frozen–thawed SET in the SET group when the fresh cycle had been unsuccessful, the live birth rate reached 39% [14]. When including all frozen–thawed transfers with embryos from the study cycles, the cumulative live birth rates reached 51% in the DET group and 44% in the SET group (p = 0.08) [15]. The multiple birth rate was dramatically lower in the SET group. One explanation as to why the live birth rates ended up on a similar level in the two groups is that there will be more good-quality embryos to cryopreserve after fresh SET than DET, which enables a higher number of frozen–thawed transfers. Well-functioning cryopreservation programs are vital when using the SET strategy, since the cryopreservation cycles contribute significantly to the live birth rates.

Obstacles to SET implementation

Despite the availability of SET for more than a decade, implementation has been limited outside the Scandinavian countries, The Netherlands and Belgium. The SET strategy is based on choosing better long-term consequences for the IVF children over the short-term satisfaction of higher pregnancy and live birth rates. The biggest obstacle is probably the health economy system. In countries where IVF clinics are mainly private, strong competition between clinics leads to a more pronounced emphasis on high pregnancy and live birth rates than on preventing complications, which hampers the introduction of SET. It is probably possible to alter this condition by providing physicians and patients with more information about SET. The doctor’s attitude toward SET has been shown to be an important predictive factor for choosing SET among IVF patients [16,17]. An official clinic policy to promote SET is another influencing factor [16]. Van Peperstraten et al. showed that lack of a SET protocol, uncertainty about essential SET aspects, absence of reimbursement systems that favor SET, inferior success rates in cryopreservation cycles and not seeing twin pregnancy as a complication were factors behind not implementing SET more often [18,19]. Professionals with a university hospital background were more positive towards SET [19].

The dropout rates in IVF treatment are high, and the main factor behind discontinuing treatment is that the treatment is psychologically stressful [20], especially with the SET strategy. Since the live birth rates per transfer are somewhat lower, it is important to take care of the patients’ psychological well-being to make it possible to stay in treatment [20].

Conclusion

A wide implementation of SET is beneficial, since it leads to decreased rates of preterm birth, low birth weight and perinatal mortality. Lower prematurity rates lead to decreased risks of cerebral palsy and mental retardation.

Double-embryo transfer leads to higher live birth rates than SET; however, data from countries where SET is used in a majority of transfers are promising. When including results from all cryopreservation cycles, the cumulative live birth rates after SET and DET end up on a similar level, at least in patients with a good prognosis.

Well-functioning cryopreservation programs and taking good care of the patients’ psychological well-being to reduce high dropout rates are essential to optimize the cumulative live birth rates.

In countries where multiple birth rates are still high, the use of SET could probably be increased by providing more information to physicians and patients about this method of IVF.

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.