In Belgium, from July 1, 2003 onward, a reimbursement system for six IVF/ICSI cycles in a lifetime has been set up, based on the clinical experience of Belgian groups. Beneficiaries are patients who fall under the Belgian health insurance provisions up to <43 years of age. The crux is that savings from the reduction in twins and the disappearance of triplets make up for the money needed to cover six cycles, thus providing access to treatment to all who need it, while at the same time ensuring quality outcomes [15]. There is also compulsory online registration of all cycles. Depending on the woman’s age and the rank of the trial, the maximum number of embryos to transfer is regulated. All women <36 years of age in their first cycle receive one embryo, independent of its morphological assessment. In older women or in subsequent cycles, the number of embryos to transfer never exceeds two, except in women >39 years of age, where there is no imposed maximum. Figure 1.1 shows the impact of this new legislation in the rates of singleton and multiple deliveries from 1992 to 2011.

In Finland, SET has been applied widely for several years. At a national level, the incidence of IVF/ICSI twins has significantly decreased, and even the total national birth registry shows a decrease in the proportion of twins [83]. SET has been combined very successfully with cryopreservation [65] and was also shown to be very successful in oocyte donation [84, 85].

In the United Kingdom, SET has been introduced as a strategy for about five years now, following the introductory papers by El-Toukhy et al. [86] and Ledger et al. [87] The Royal College of Obstetricians and Gynaecologists issued guidelines in 2011 reinforcing the SET strategy [88]. Although individual clinics may have embraced the SET strategy, France and Southern European countries have until now not produced clear evidence of a substantial proportion of SET cycles, nor have they enacted any legislation that puts a maximum to the number of embryos transferred. Canada and Turkey have recently actively introduced the SET strategy [89–91].

One benefit of SET is an increase in the number of embryos available for cryopreservation [92]. Optimized cryopreservation of embryos after SET is part of the strategy to decrease multiple pregnancies [93–96]. It increases the cumulative pregnancy rate per oocyte retrieval and ideally allows patients who desire two children to have their “delayed” twin.

In a group of 127 Finnish patients who had a fresh SET, 49 became pregnant (38.6 %) and 34 delivered (26.8 %); those without on-going pregnancy had a total of 129 frozen embryo transfers resulting in another 32 pregnancies and 32 deliveries. This increased the pregnancy rate (PR) per patient to 62.4 % and the delivery rate to 52.8 % [65, 66]. In a Swedish study, the transfer of one frozen/thawed embryo after a failed fresh cycle was able to increase the cumulative PR (39.5 %) to the same as after the transfer of two embryos (43.5 %) [75].

In a Dutch study [97], the cumulative on-going pregnancy rate rose from 24 to 34 % in SET patients and from 34 to 38 % after DET, losing the significance between SET and DET.

An Australian group performed a fresh transfer of either a single blastocyst or two blastocysts (pregnancy rates of 44 and 59 %, respectively) followed by a frozen/thawed cycle of maximum two embryos, raising the PR per patient to 74 % in the SET group and 70 % in the DET group, respectively [80]. The twinning rates were 2 % versus 44 % for the fresh SET versus the fresh DET, and 5 % versus 28 % after cryoaugmentation. A small Japanese study of 66 patients [98] obtained a fresh pregnancy rate of 44.9 % in 66 fresh SET cycles and a cryoaugmented pregnancy rate of 72.4 % after 29 patients underwent a subsequent transfer of one frozen/thawed blastocyst. In this study embryos had been cryopreserved by vitrification. Vitrification and increasing application of frozen/thawed cycles is becoming an integral part of every IVF/ICSI program applying SET.

It has been shown that the outcome of singletons—but not of twins—after IVF/ICSI is worse than that of naturally conceived singletons or twins [28, 99]. These studies analysed pregnancies before the introduction of SET. Therefore, the groups were very heterogeneous and comprised both young good-prognosis patients, who conceived of a twin in a first treatment cycle, and on the other hand older women with poor prognosis who conceived of a singleton after multiple embryo transfer in high-rank trials. It has been shown that singletons after eSET do not compare unfavorably with spontaneously conceived singletons [100]. In another study, our own group found that on-going IVF/ICSI pregnancies showing first-trimester blood loss had a worse obstetrical and neonatal outcome than if no first-trimester blood loss occurred [101] and that there was an almost linear relationship between the number of embryos transferred and the incidence of first-trimester blood loss. First-trimester bleeding is frequent in ART pregnancies. It was not previously known whether first-trimester bleeding, if not ending in a spontaneous abortion, negatively influences further pregnancy outcome in ART in singletons. We found that significantly more singleton pregnancies resulted from a vanishing twin in the group with first-trimester bleeding (8.7 %) than in the controls (4.0 %). A correlation was found between the incidence of first-trimester bleeding and the number of embryos transferred. First-trimester bleeding led to increased second-trimester (OR = 4.56; 95 % CI = 2.76–7.56) and third-trimester bleeding rates (OR = 2.85; 95 % CI = 1.42–5.73), preterm premature rupture of membranes (OR = 2.44; 95 % CI = 1.38–4.31), preterm contractions (OR = 2.27; 95 % CI = 1.48–3.47) and neonatal intensive care unit admissions (OR = 1.75; 95 % CI = 1.21–2.54). First-trimester bleeding increased the risk for preterm birth (OR = 1.64; 95 % CI = 1.05–2.55) and extreme preterm birth (OR = 3.05; 95 % CI = 1.12–8.31). Therefore, we hold the opinion that first-trimester bleeding in an ongoing singleton pregnancy following ART increases the risk for pregnancy complications. The association between first-trimester bleeding, the number of embryos transferred, and adverse pregnancy outcome provides a further argument in favor of SET.

In another study, we found that the birth weight of singletons born after eSET (3,324.6 ± 509.7 g) was significantly higher than of singletons born after DET (3,204.3 ± 617.5) (p < 0.01) [102]; that the incidence of prematurity <37 weeks was 6.2 % for singletons after SET versus 10.4 % after DET (adjusted odds 1.77; 95 % CI = 1.06–2.94); and that the incidence of low birth weight (<2,500 g) was lower for singletons after SET (4.2 %) versus DET (11.6 %) (adjusted odds = 3.38; 95 % CI = 1.86–6.12).

These observations are in line with the fact that there appear to be more vanishing twins after IVF than previously suspected [103, 104] and that in utero competition for implantation may play a role in the final outcome of these pregnancies. Hence, eSET not only prevents the well-known and documented complications of twin pregnancies, but actually improves the outcome of singleton pregnancies [105].

Although the main reason to apply SET is the health of the children at their start of life, financial considerations are paramount. The increased utilisation of hospital care in ART children is the consequence of multiple pregnancies [106]. The estimated cost for an IVF singleton after IVF was calculated to be three times that of a twin [54]; an American group found a twin twice as expensive, and a triplet 15 times as expensive, as a singleton [107]. We have used a health–economic model to establish that SET and DET are financially equivalent per live-born child. SET needs more cycles and yields less children per cycle but DET yields higher obstetrical, and mainly neonatal, costs per child [108, 109] and these effects balance out each other. From these studies we concluded SET to be preferred because most of the extra cost and care starts only after birth. A recent modelling study in the UK confirmed that SET is the preferred option for young women [110]. In a real-life prospective comparison between elective SET versus DET in women <38 years of age in their first IVF/ICSI cycle, our group further showed that elective SET was as efficient as DET (40 % pregnancy rate in both groups), but the cost per child was only approximately half after elective SET [111]. In all studies, as in the models, the major cost driver was the higher neonatal cost for premature children.

In Belgium, it was calculated that the money saved by avoiding half of the multiple pregnancies would suffice to finance all IVF/ICSI cycles in a year [15]. This is the basis for the Belgian reimbursement system, which has shown to be successful in reducing by 50 % multiple pregnancy rates in the last 10 years (Figure 1.1) [112].

One of the most important challenges for a future toward a safe IVF/ICSI treatment resides in the proper counseling of patients. Patients need proper and complete information [113, 114] about the fact that prevention is possible without a decrease in the chances for pregnancy, especially if combined with cryopreservation and if results are expressed (and patients or health insurers charged) per oocyte harvest and not per cycle or per transfer. There are differences among patients, embryologists, and clinicians in their perceptions of the desirability of multiple pregnancies [115]. These have different origins and are determined by a mix of objective elements (statistics of chances for success versus risks for complications) and subjective factors (hope versus bad obstetrical experience). Decisions imply a trade-off between the informed patients’ autonomy and the physicians’ clinical judgement, increasingly including medico–legal considerations. This takes time, patience, commitment, and personal conviction from those who treat and counsel. It also takes insight in how patients think, or feel, about their chances and about risks they do not always understand [116].

A British study investigated whether patients’ willingness to accept a hypothetical policy of SET changed with the method of providing information. The information that their chance for a pregnancy would not decrease due to SET and that fresh and frozen transfers would imply a fixed charge led to acceptance in a similar proportion of respondents who received a standard information pack (82 %), an additional information leaflet (83 %), or a personal discussion session (87 %) [117]. It thus did not seem that counseling could easily change patients’ views. A Danish group analysed attitudes of IVF/ICSI-twin mothers toward twins and embryo transfers and found that only a quarter of these mothers agreed to SET [118]. They also found that the delivery of a child with very low birth weight, and hence morbidity, was predictive of high acceptance of SET. It is noteworthy that not much was known about ~20 % of women who did not respond to the questionnaire and who may have been the ones with a bad obstetrical outcome. They conclude that SET requires extensive counseling. It also illustrates that mothers of twins, even with some degree of disability, always love their children and would go through the same efforts and risks again to have them. As long as they are under the erroneous conviction that their twin was the result of a choice between either twins versus no children, they will not easily agree with SET.

Multiple pregnancies are an avoidable complication of assisted reproduction, just like ovarian hyperstimulation syndrome, and should be considered iatrogenic mishaps. Elective SET, combined with subsequent transfer of frozen/thawed embryos, can maintain a high pregnancy rate with a dramatic decrease in multiple pregnancy rates. The medical complications, human suffering, and expense that can thus be avoided should be sufficiently strong arguments to reinforce a strict embryo transfer policy to avoid multiple pregnancies [119]. Single-embryo transfer should be the strategy of choice in IVF, maybe for all patients in the future, especially since vitrification has been shown to lead to very high embryo survival rates.