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Multiple births following in vitro fertilization treatment: redefining success
European Journal of Obstetrics & Gynecology and Reproductive Biology 170 (2013) 299–304
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European Journal of Obstetrics & Gynecology and Reproductive Biology journal homepage: www.elsevier.com/locate/ejogrb
Review
Multiple births following in vitro fertilization treatment: redefining success A. Umranikar a,*, D. Parmar b, S. Davies a, S. Fountain a a b
Salisbury NHS Foundation Trust, Salisbury, UK Peninsula College of Medicine and Dentistry, Plymouth, UK
A R T I C L E I N F O
A B S T R A C T
Article history: Received 5 November 2012 Received in revised form 13 March 2013 Accepted 24 June 2013
The focus of this article is to review the definition of success following in vitro fertilization (IVF) treatment. Pregnancy rates after IVF have been increasing, but the problem of multiple births with its associated morbidity and mortality has been considerable. This has led to rethinking of assisted reproductive technology (ART) success not only in terms of live birth rates, but also in terms of reduction of multiple births to singleton babies. Single embryo transfer using blastocysts and such other measures are being encouraged. Financial factors and patient satisfaction are key issues. IVF success is thus being redefined. ß 2013 Elsevier Ireland Ltd. All rights reserved.
Keywords: In vitro fertilization Assisted reproductive technologies Multiple births Embryo transfer
Contents 1. 2. 3.
4.
5.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Prevalence of multiple births: scope of the problem . . . . . . . . . . Problems associated with multiple births . . . . . . . . . . . . . 2.1. Strategies to reduce multiple births . . . . . . . . . . . . . . . . . . . . . . . Acceptance of eSET so far . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1. Blastocyst transfer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2. Challenges faced in the transition period prior to implementing Financial challenges . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1. Patients’ expectations and attitudes . . . . . . . . . . . . . . . . . 4.2. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
............. ............. ............. ............. ............. ............. the SET policy . ............. ............. ............. .............
1. Introduction Infertility affects 1 in approximately 6 couples. Growing awareness and increased availability of fertility services have resulted in many couples opting for in vitro fertilization (IVF) treatment. Since the first successful IVF in humans in 1978, IVF has become a standard treatment for subfertility [1]. There have been remarkable achievements over the years in pregnancy success rates following IVF. This has been due to continuous improvement in ovarian stimulation protocols, and refinements and advances in
* Corresponding author. Tel.: +44 2380262392. E-mail addresses: [email protected], [email protected] (A. Umranikar). 0301-2115/$ – see front matter ß 2013 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.ejogrb.2013.06.031
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IVF laboratories resulting in improved embryo quality. In addition to the success rates achieved through IVF and intracytoplasmic sperm injection (ICSI) treatment, there has been an intense effort to reduce the incidence of multiple births in recent years. IVF success has been defined as a live birth after an assisted reproductive technology (ART) cycle, regardless of the number of live-born infants per delivery [2]. This definition needs to change as we take into consideration problems related to multiple births including costs and other constraints. In the reporting of ART success rates, commercially competitive settings may maximize numerators and minimize denominators [3]. One may measure success rates in terms of clinical pregnancy (evidence of sac, detection of fetal heartbeat) or more ideally live birth rates, but the problem is complex. Multiple pregnancies can be associated with detrimental outcome. It is time that success is defined in terms of
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not only live birth rates but also the rate of multiple births. This review attempts to address some of these relevant issues, with special reference to the UK and Europe. 2. Prevalence of multiple births: scope of the problem There have been growing concerns over the incidence of multiple births following IVF. IVF is often a costly decision for patients financially, medically and emotionally and this is especially so when it is associated with multiple births [4]. The overall incidence of multiple births has been on the rise over the past 30 years. This is mainly attributable not just to the increasing use of IVF treatment by subfertile couples, but also to the increasing age of women seeking fertility treatment and to delayed childbearing [5,6]. The majority of the multiple births are twins, as the rate of triplet pregnancies has reduced over the last decade. While the incidence of multiple births is just over 1% (1.25%) following natural conception, the figure rises to 24% with IVF treatment. In the UK around 11,000 babies are born every year through ART, contributing to around 2% of live births [7]. In the UK the Human Fertilization and Embryology Authority (HFEA) [7] collects records of approximately 50,000 fertility treatments performed every year. Around 1 in 4 twins born in the UK are as a result of IVF treatment [7,8]. Around 50% of these are born before 37 weeks and contribute to nearly 10–20% of all low birth weight babies [9]. Until 2008, the rate of multiple births related to IVF was 26.7%. This reduced to 22% in 2009 following an increase in uptake of elective single embryo transfer (eSET) policy. The highest proportion (31.2%) of multiple births was seen in women between 18 and 34 years. There has been a similar increase in twin pregnancies following IVF treatment in most countries in Europe, Scandinavia, United States, Canada and Asia. In Denmark, the twin birth rate increased from 17.8 to 22 per 1000 births between 1996 and 2003. In Sweden, twin births increased 1.9-fold from 1973 to 2000 and in Norway the increase was 2.2-fold from 1974 to 2002 [10]. Studies from Australia have shown a greater than 20% risk of twins or higher order multiple pregnancy [11]. Multiple births comprised 9% of the infertility group compared with 1.3% in the general population of Victoria, Australia, and 23.7% of IVF and GIFT births [12]. Thus, studies from all over the world have shown a very high rate of multiple births following IVF. 2.1. Problems associated with multiple births Multiple pregnancy can pose a significant risk to both the mother and the baby, and is the single biggest health risk following IVF treatment. Women with multiple pregnancies have higher risks of miscarriage, anaemia, hypertensive disorders like preeclampsia, diabetes, operative deliveries and related postnatal illnesses. Although the mortality is low, morbidity figures are higher in these women than in women with singleton pregnancies. The risk of preeclampsia and gestational diabetes is 2–3 times higher in women with twins than in singleton pregnancies and 9 times higher with triplet pregnancy [13]. Advanced maternal age is a known risk factor and is associated with higher perinatal complications. Several studies worldwide have reported that around 10% women with twins experience parenting stress, depression and marital problems [14]. In first-time mothers, twins with low birth weight have a particularly high impact on their personal, social and emotional wellbeing. Most twins conceived as a result of IVF treatment happen to be dichorionic as a result of transfer of two or more embryos. Although the risk of chromosomal anomalies and cerebral palsy (CP) is seen more often in monochorionic twins, the risk of
prematurity and low birth weight is seen in both mono- and dichorionic twins equally. IVF twins are born approximately 3 weeks earlier than singletons and weigh 800–1000 gm less than their singleton counterparts [15]. The risk of CP increases from 1.7/1000 live births in singleton pregnancies to 6.2/1000 live births in twins [16]. Twins have at least a 6 times higher risk of developing CP and triplets have an 18 times higher risk. Most problems associated with twins appear to be related to prematurity and crucially the gestational age at birth. The risk of babies dying due to prematurity and low birth weight in the first month of life increases from 3 per 1000 for singletons to 19 per 1000 for multiple births. Low birth weight (<2500 gm), very low birth weight (<1500 gm) and extremely low birth weight (<1000 gm) are all mostly related to preterm deliveries in twins. Three out of 4 babies born under 26 weeks’ gestation are at risk of dying soon after birth or may require several months of care in the neonatal unit. Over 60% of survivors are likely to have significant brain and eye damage resulting in physical and mental impairment. These children end up having attention deficit hyperactive disorders and behavioural problems that are likely to persist into adult life [17]. Compared to singleton births, fetal, neonatal and perinatal mortality rates are 3–6 times higher in twins and 5–15 times in higher order multiple births in Australia [18]. CP rates among survivors are 6 times higher in twins and twenty times higher in triplets. In a study from Western Australia [19], the incidence of major birth defects was 7.1% in twins born after ART and 5.9% of non-ART twins of unlike sex. Studies by Venn and Lumley [12] showed that perinatal mortality between 1982 and 1990 was 11.1 per 1000 in general population and 34.9 per 1000 in the IVF group. Thus, for nearly three decades problems due to multiple births have been identified, underlining the crucial fact that birth of a singleton term baby carries the optimum outcome for both mother and baby. 3. Strategies to reduce multiple births The best way to reduce multiple births is to reduce the number of embryos transferred into the uterus. For the past two decades, the HFEA has encouraged clinics in the UK to take steps to reduce the risks of multiple births. In 1991, clinics were discouraged from transferring more than three embryos at one time in a treatment cycle. In 2001, the HFEA introduced a two-embryo transfer policy. In 2004, this was tightened further to allow a maximum of two embryos to be transferred in women under 40 years: for women aged 40 years and over, a maximum of three embryos could be transferred under exceptional circumstances. These early measures halved the number of triplet pregnancies in the UK but the twin pregnancy rate continued to rise. In 2007/2008, HFEA introduced an elective single embryo transfer (e SET) policy in a selected group of patients less than 37 years of age. 3.1. Acceptance of eSET so far Based on national data, if 50% of women are offered and agree to eSET, the multiple birth rate would fall to less than 10%. In order to maintain the pregnancy rate using eSET, it is important to ensure that effective cryopreservation programmes are available to patients so that good quality embryos are available for another cycle. The first study of single embryo transfer (SET) was conducted in Finland [20] and showed that pregnancy rates were not significantly different (14.7%) with SET and double embryo transfer (DET) in a specific population group. The rate of multiple births dropped to 5% in the SET group from 38% in the DET group. In 2003, Tiitinen et al. [21] reported a dramatic reduction in twin rates in
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Finland from 25% in 1997 to 5% in 2001 following implementation of SET. At the same time, Swedish IVF centres adopted the SET policy widely in all women under 36 years of age. The mean number of embryos transferred reduced from 2.7 to 1.3 between 1992 and 2004, and by 2004 SET was adopted nationally in Sweden (67.4%). The policy resulted in a dramatic reduction in multiple births while maintaining success rates from a SET cycle. The multiple birth rate reduced from 35% in 1991 to 5.7% in 2004. The live birth rate was stable around 25% per transfer. Saldeen and Sundstrom [22] compared three different embryo transfer policies between 2002 and 2004: a two embryo transfer policy adopted in 2001 to early 2002, a transitional period of DET for private patients and SET for public patients in 2002, and a SET policy for all implemented in 2003.The clinical pregnancy rates in all three groups remained stable (33.3%, 32.8%, 37.4% respectively), while the twin rate was significantly lower in the SET group (22.6%, 16.3%, 6.2% respectively). The expected decline of twinning was accompanied by an unchanged clinical pregnancy rate, and thus the SET legislation had no negative consequences for the couples [22]. A randomized multicenter trial in Sweden in 2004 [23] compared pregnancy rates and multiple gestation rates between SET and DET. Women with two good-quality embryos were randomly assigned either to undergo transfer of a single fresh embryo and if there was no live birth, subsequent transfer of a single frozen and thawed embryo, or to undergo single transfer of two fresh embryos. The results showed a live birth rate of 42.9% in the DET group versus 38.8% in the SET group. The rate of multiple births was significantly lower in the SET group (0.8%) than in the DET group (33.1%). A similar study in 2009 [24] which compared cumulative live births after SET versus DET showed a cumulative live birth rate of 43.9% in the SET group versus 51.1% in the DET group. The multiple birth rate was significantly lower in the SET group (2.3%) than in the DET group (27.5%). The rate of preterm births (<37 weeks) was higher in the DET group than in the SET group (25.5% versus 11.8%). Around the same period, other countries like Denmark, Belgium and the Netherlands adopted a SET policy and found similar results with their pregnancy rates with a dramatic reduction in multiple births. A randomized controlled trial in the Netherlands [25] studied the clinical outcomes and cost effectiveness of two cycles of eSET versus one cycle of DET in women less than 35 years of age. The results showed a comparable cumulative live birth rate of 41% with SET versus 36% with DET. The multiple birth rates were significantly higher in the DET group (37%) as compared to 0% in the SET group. Cost analysis also confirmed a comparable medical cost per live birth up to 6 weeks after delivery with 2 cycles of SET and one cycle of DET. If lifetime costs due to handicaps in multiple births were considered, however, a SET policy would clearly be a more cost effective strategy than DET. Despite the favourable results following SET implementation, other countries in Europe and USA have been slow to adopt the policy. This could be partly because couples who are self-funding were worried about lowering the results following SET. Most couples would prefer to optimize their success in the first attempt. In a study by Roberts et al. [26], many patients perceived moving from DE to SET as unfair. Additional treatment cycles are seen by patients as physically and emotionally burdensome. It therefore appears that in countries where IVF treatment is provided by the state, SET policy is implemented earlier than in countries where IVF treatment is largely available to couples who self-fund. A similar strategy was introduced in many European countries to reduce risks of multiple births. While a two-embryo transfer policy effectively reduced the triplet rates, the twin pregnancy rates in most countries in Europe including UK remained high at 24%. In the UK, HFEA data between 2005 and 2007 revealed multiple birth rates of 22–24% and live birth rate around 23% per
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cycle. The transition period from 2008 showed a growing uptake of eSET in the UK (4.8%) and this increased to 14.7% in 2010.The vast majority of women (87.3%) were 37 years or younger. Two thirds had SET in their first cycle with most having 2 or more embryos to freeze. Several studies have compared the live birth and multiple pregnancy rates between SET and DET. Khalaf et al. [27] examined outcomes after introducing SET using blastocyst in a selected group of patients, and demonstrated an increase in the clinical pregnancy rates from 27% to 32% with a reduction in multiple births from 32 to 17%. Bhattacharya and Templeton [28] reviewed data from randomized controlled trials which indicate that SET results in lower live birth rates per fresh IVF cycle (odds ratio 0.53, 95% confidence interval 0.31–0.89, p = 0.02) in comparison with DET, but they also concluded that the perceived effectiveness of SET is influenced by the way evidence is interpreted. Other factors are laboratory techniques, individual preferences and funding issues. A Cochrane review in 2005 [29] compared success rates and multiple birth rates of SET as compared to DET. It included 4 randomized controlled trials between 1999 and 2004 and concluded that although a SET policy reduced the rate of multiple births, the live birth rate and clinical pregnancy rates were also reduced. On the other hand, adopting a policy of SET in a fresh cycle and a frozen cycle showed comparable cumulative birth rates as seen with DET, and reduced the risk of multiples. The review also redefined success as cumulative live birth rates per oocyte retrievals which include utilization of fresh and frozen cycles using a SET policy for the fresh cycle. The study also suggested that for a SET policy to be implemented effectively, the age group of women should be less than 35 years and should include women undergoing their first or second IVF/ICSI cycles using their own eggs with good quality embryos in cryo storage. In a more recent meta-analysis [30] of the clinical effectiveness of SET versus DET, the overall live birth rate following SET in a fresh cycle (27%) was lower than DET (42%), but addition of a single embryo frozen cycle gave a cumulative birth rate (38%) which was comparable to that of DET. The odds of a singleton term live birth were almost 5 times higher after a SET than after a DET and the cumulative risk of multiple births was 1% (SET) versus 32% in DET. Studies from Australia found that replacement of one single embryo is just as successful as two-embryo transfer without the risk of multiple pregnancy [31] and that transfer of one or two embryos decreases the risk of a multiple pregnancy, preterm birth and low birth weight [32]. Reynolds and Schieve [33] studied trends in embryo transfer policies and multiple births in USA from 1996 to 2002 involving a population-based sample of 506,072 transfers. In 2002, 15% of all twin births and 43% of all triplets were due to assisted reproductive techniques. Amongst women under 35 years, the proportion of 2 embryos being transferred increased from 8% in 1996 to 43% in 2002, while the proportion of 3 embryos being transferred declined from 87% to 52%. This reduced the proportion of triplet pregnancies from 15% to 7.5%. Although this practice contributed to reducing the triplet rate, the overall rate of multiple births showed only a smaller decline due to widespread use of DET policy in most clinics, with a low uptake of SET policy. These studies are summarized in Table 1. 3.2. Blastocyst transfer The HFEA adopted a ‘‘one at a time’’ policy setting its target of multiple pregnancies to less than 20% in 2011 and less than 15% by 2012. Most clinics in the UK are increasingly adopting a SET policy using blastocyst transfers for patients less than 35 years old. Blastocysts are embryos incubated in a laboratory for 5–6 days
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Table 1 Studies comparing DET and SET. Name of study
Type of study
Martikainen et al. [20] Tiitinen et al. [21] Saldeen and Sundstrom [22] Thurin et al. [23] Lukassen et al. [25]
Randomized control Retrospective Study Randomized control Randomized control Randomized control
McLernon et al. [30]
Meta-analysis
trial trial trial trial
Amount of data
Multiple birth rate in DET group
Multiple birth rates in SET group
Difference in live birth rate
144 participants 1871 participants 1362 participants 661 participants 107 participants
38% 25% 22.6% 33.1% 37%
5% 5% 6.2% 0.8% 0%
1367 participants from 8 trials
32%
1%
14.7% 0.3% 4.1% 4.1% 5% (higher in SET group due to 2 cycles) 4%higher cumulative live birth in DET group
after fertilization, and blastocyst transfer allows a self-selection process enabling the best embryo to be available for transfer, thereby achieving good pregnancy rates. Although long-term data on the outcome of embryos placed in extended laboratory culture are unknown, transfer of a blastocyst is considered to increase pregnancy rates as compared to the currently used day 2 or 3 cleavage staged embryos, due to a better implantation potential. Several studies have reported the advantages and disadvantages of blastocyst and cleavage stage embryo transfer. A prospective RCT by Papanikolaou et al. in 2006 [34] comparing pregnancy and delivery rates between day 5 (blastocyst) and day 3 (cleavage stage) transfer was terminated early as a significantly higher pregnancy and delivery rate was seen in patients having a blastocyst transfer. A systematic review by Papanikolaou et al. in 2008 [35] included 8 randomized controlled trials: the live birth rate was significantly higher using blastocyst, and the implantation potential of a blastocyst was found to be superior to a cleavage stage embryo. Zander-Fox et al. [36] compared pregnancy rates with single blastocyst transfer versus double cleavage stage embryos and showed a live birth rate of 27% following a single blastocyst transfer which was comparable to that obtained following a double embryo transfer (24%). There was a significant reduction in multiple birth rates in the former group. Since 2008, there has been a steady increase of blastocyst transfers in the UK from 8.4% in 2008 to 27.6% in 2010 (HFEA). Pregnancy rates in UK using SET policy with blastocysts have remained steady between 2008 and 2010 (29–31%). Notably, the rate of multiple pregnancies has reduced from 26.7% in 2008 to 22% in 2010. Much of this success has been seen in women aged less than 35 years. 4. Challenges faced in the transition period prior to implementing the SET policy 4.1. Financial challenges Funding policies for IVF/ICSI treatment vary between countries. In countries where IVF is a state-funded treatment the uptake of SET has been higher than in countries where patients have to fund their own treatment. The policy of adopting SET so widely in Sweden may be due to the fact that majority of cycles in Sweden are state funded. In the UK, IVF is not uniformly funded by the NHS and many desperate couples end up financing their own treatment. These couples are powerful drivers to opt for DET than SET to maximize their chances of pregnancy in the first attempt. The bigger picture of risks associated with multiple births due to prematurity resulting in long-term neurodevelopment problems seldom gets considered. Gleicher et al. [37] observed significant differences in ART practices between European countries and the USA. Of note was the difference in the number of embryos transferred. Only 33% of
women in the US had 1 or 2 embryos transferred, compared with 63% of women in Europe. In addition 3 or 4 embryos were routinely transferred in the US, while that practice was observed in 36% women in Europe. These practices contributed to higher multiple births in US (38.6%) than in European countries (25.5%). The difference between Scandinavian countries and the US could be due to the fact that ART is a state-funded treatment in the former, whereas in the latter ART is a treatment available to the financially advantaged section of society. Several differences in policies and practices were therefore noted between the two continents as patient preferences and acceptance differed considerably. A review of the economic impact of ART [38] showed that the cost per live birth was highest in the U.S.A. and U.K. (41,132 and 40,364 dollars respectively) and lowest in Scandinavia and Japan (24,485 and 24,329 dollars respectively). The cost of an IVF cycle after government subsidization ranged from 50% of annual disposable income in the U.S.A. to 6% in Australia [38]. Thus, ART may be expensive from a patient perspective, but not from a societal perspective. Countries with funding arrangements that minimize out of pocket expenses met expected demand. Whether through Government or insurance, funding should maximize efficiency and equity of access while minimizing the potential harm from multiple births [38]. Models from various countries with different funding sources have shown that the cheaper the cost to patients, the more acceptable is SET. 4.2. Patients’ expectations and attitudes The key component of patient expectations is a successful outcome of the treatment. This is more so for patients funding their own treatment. An important factor in increasing uptake of SET involves understanding the expectations and attitudes of patients undergoing IVF/ICSI. There also appear to be differences in perceptions among clinicians and patients towards multiple pregnancies. This was evident from the study conducted by Hartshorne and Lilford [39] which showed that nearly 80% of patients preferred options that increased their chances of a pregnancy, with nearly half of these accepting the additional risks of multiple pregnancies. In contrast, less than 5% of healthcare professionals accepted the risks of multiple births. Patient preferences were also seen to shift between SET and DET depending on the success from a given cycle: in a study by Fiddelers et al. [40] 62% of patients showed a preference shift from singleton to twins in order to fulfil their desire to have a child. A national questionnaire survey in Denmark in 2003 [41] showed that mothers in general had a positive preference towards twins: 84% of mothers with IVF/ICSI twins and 62% of mothers with IVF/ICSI singletons would have preferred twins. Acceptance of SET in these women was reported as 17–24%. Following extensive counselling regarding the potential risks to babies due to prematurity, another 20% women accepted SET policy provided they were offered more treatment cycles. This was also confirmed
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by Rai et al. [42], who compared patients and clinicians’ perceptions and attitudes towards SET. Effective counselling was suggested to be a reliable intervention in increasing the uptake of SET. Several studies have been conducted worldwide to study patient attitudes and preferences towards a SET policy. Decisionmaking can be a difficult process if SET reduces the success rates of treatment, thereby necessitating more treatment cycles. Blennborn et al. [43] demonstrated the factors involved: younger women with no history of previous IVF treatment failures who had good quality embryos for transfer and for cryopreservation were likely to accept SET, while couples who were older and had experienced previous unsuccessful cycle outcome were more likely to opt for DET to optimize their success in achieving a baby. For these women the success from treatment was far more important than the risks of multiple births with a DET. A recent review [44] of attitudes of patients towards SET confirmed that as success rates were improving and as women were being counselled regarding potential risks of multiple births, there was an increasing acceptance of 2 rather than 3 embryos. A further step would be to achieve a greater uptake of SET policy. In addition, increasing state funding would enable a more uniform availability of ART, all making a significant contribution towards an increase in the uptake of SET resulting in a reduction of multiple births. An analysis of the problems of multiple births, issues related to decreasing them, financial constraints and patients’ attitudes make one rethink how success following ART should be measured. Min et al. [45] have summarized success exquisitely. Success must reflect delivery of healthy babies and the burden of treatment to couples. They suggest that delivery of a singleton, term gestation and live baby per cycle is the most relevant standard of success and they encourage programmes to report the BESST outcome (Birth Emphasizing a Successful Singleton at Term) [45]. 5. Conclusion It has been documented that the safest outcome of in vitro fertilization treatment, both for the mother and the baby, is to achieve a singleton pregnancy. Professional bodies have recommended various strategies like single embryo transfer policy using blastocysts for women under 37 years. International experience is encouraging and the increased implementation of a SET policy has reduced the rate of multiple births significantly. Further success from these practices would be achievable with wider availability of state funding for these patients, and better availability of embryos for cryopreservation through better laboratory standards. Success from assisted reproductive technologies is thus being redefined. Success is not just based on the live birth rates reported from centres. More crucially, it includes the number of multiple births, as the best outcome would be to achieve good clinical success rates with low multiple births. Finally, patient satisfaction is often a key reflection of good clinical practice. Conflict of interest The authors state no conflicts of interests. References [1] Jones CA, Christensen AL, Salihu H, et al. Prediction of individual probabilities of live birth and multiple birth events following in vitro fertilisation (IVF): a new outcomes counselling tool for IVF providers and patients using HFEA metrics. J Exp Clin Assist Reprod 2011;8:3. [2] Hogue CJ. Successful assisted reproductive technology: the beauty of one. Obstet Gynecol 2002;100:1017–9. [3] Barlow DH. A time for consensus and consistency of reporting in clinical studies and the importance of new basic research. Human Reprod 2004;19:1–2.
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[4] Jones HW. Multiple births: how are we doing. Fertil Steril 2003;79:17–21. [5] Bensdorp AJ, Slappendel E, Koks C, Van Wely M. The INeS study: prevention of multiple pregnancies. BMC Womens Health 2009;9:35. [6] Hur YM, Song TB. A recent rise in twin birth rates and demographic changes in mothers of twins in South Korea 2003–2007. Twin Res Hum Genet 2009;12:118–22. [7] H.F.E.A.. A statistical report. Improving outcomes of fertility patients: Multiple births; 2011. [8] Office for National Statistics. Live births in England and Wales by characteristics of birth; 2010. [9] Blondel B, Kogan MD, Alexander DR, et al. The impact of the increasing number of multiple births on the rates of preterm birth and low birth weight: an international study. Am J Pub Health 2002;92:1323–30. [10] Pinborg A. IVF/ICSI twin pregnancies: risks and prevention. Hum Reprod Update 2005;11:575–93. [11] Jansen RP. Benefits and challenges brought by improved results from in vitro fertilization. Intern Med J 2005;35:108–17. [12] Venn A, Lumley J. Births after a period of infertility in Victorian women 1982– 1990. Aust NZ J Obstet Gynaecol 1993;33:379–84. [13] Cook R, Bradley S, Golombok S. A preliminary study of parental stress and child behaviour in families with twins conceived by in-vitro fertilization. Hum Reprod 1998;13:3244–6. [14] Oliveness F, Golombok S, Ramogida C, Rust J. Behavioural and cognitive development as well as family functioning of twins conceived by assisted reproduction: findings from a large population study. Fertil Steril 2005;84:725–33. [15] Pinborg A, Loft A, Schmidt L, Andersen AN. Morbidity in a Danish national cohort of IVF/ICSI twins: health related and social implications for the children and their families. Hum Reprod 2003;18:1234–43. [16] Surman G, Newdick H, King A, Gallagher M, Kurinczuk JJ. Four counties database of cerebral palsy, vision loss and hearing loss in children: annual report. University of Oxford; 2006. [17] Costeloe K, Hennessy E, Gibson AT, Marlow N, The EPICURE study. Outcomes to discharge from hospital for infants born at the threshold of viability. Pediatrics 2000;106:659–71. [18] Yu VY. Assisted reproduction technology. Multiple births and adverse perinatal outcome. Croat Med J 1998;39:208–11. [19] Hansen M, Kurinczuk JJ, Deklerk N, Burton P, Bower C. Assisted reproductive technology and major birth defects in Western Australia. Obstet Gynecol 2012;120:852–63. [20] Martikainen H, Tiitinen A, Tomas C, Tapanainen J, Finnish ET study group. One versus two embryo transfer after IVF and ICSI: a randomised study. Hum Reprod 2001;16:1900–3. [21] Tiitinen A, Unkila-Kallio L, Haltuunen M, Hyden-Granskog C. Impact of elective selective embryo transfer on twin pregnancy rate. Hum Reprod 2003;18:1449–53. [22] Saldeen P, Sundstrom P. Would legislation imposing single embryo transfer be a feasible way to reduce the rate of multiple pregnancies after IVF treatment. Hum Reprod 2005;20:4–8. [23] Thurin A, Hausken J, Hillensio T, et al. Elective single embryo transfer versus double embryo transfer in vitro fertilization. N Eng J Med 2004;351:2392–402. [24] Thurin-Kjellberg A, Olivius C, Bergh C. Cumulative live birth rates in a trial of single embryo or double embryo transfer. N Eng J Med 2009;361:1812–3. [25] Lukassen HGM, Braat DD, Wetzel AMM, Zielhuis G. Two cycles with single embryo transfer versus one cycle with double embryo transfer. A randomised controlled trial. Hum Reprod 2004;20:702–8. [26] Roberts SA, McGowan L, Vail A, Brison DR. The use of single embryo transfer to reduce the incidence of twins. Hum Fertil 2011;14:89–96. [27] Khalaf Y, El-Toukhy T, Coomarasamy A, Kamal A, Bolton V, Braude P. Selective single blastocyst transfer reduces the multiple pregnancy rate and increases the pregnancy rates: a pre and post intervention study. BJOG 2008;115:385– 90. [28] Bhattacharya S, Templeton A. What is the most relevant standard of success in assisted reproduction? Redefining success in the context of single embryo transfer: evidence intuition and financial reality. Hum Reprod 2004;19:1939– 42. [29] Pandian Z, Templeton A, Serour G, Bhattacharya S. Number of embryos for transfer after IVF and ICSI: a Cochrane review. Hum Reprod 2005;20:2681–7. [30] McLernon DJ, Harrild K, Bergh C, et al. Clinical effectiveness of single versus embryo transfer: meta-analysis of individual patient data from randomised trials. BMJ 2010;341:c6945. [31] Kovacs G, MacLachlan V, Rombauts L, Healy D, Howlett D. Replacement of one selected embryo is just as successful as two embryo transfer, without the risk of twin pregnancy. Aust NZ J Obstet Gynaecol 2003;43:369–71. [32] Dare MR, Crowther CA, Dodd JM, Norman RJ. Single or multiple embryo transfer following in vitro fertilization for improved neonatal outcome: a systematic review of the literature. Aust NZ J Obstet Gynaecol 2004;44:283–91. [33] Reynolds MA, Schieve LA. Trends in embryo transfer practices and multiple gestation for IVF procedures in the USA, 1996–2002. Hum Reprod 2006;21:694–700. [34] Papanikolaou EG, Camus M, Kolibianakis EM, VanLandyut L, Van Steirteghem A, Devroey P. In vitro fertilization with single blastocyst-stage versus cleavage stage embryos. N Eng J Med 2006;354:1139–46. [35] Papanikolaou EG, Kolibianakis E, Tournaye H, Venetis C, Fatemi H. Live birth rates after transfer of equal number of blastocysts or cleavage stage embryos in IVF. A systematic review and meta-analysis. Hum Reprod 2008;23:91–9.
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[36] Zander-Fox DL, Tremellen K, Lane M. Single blastocyst embryo transfer maintains comparable pregnancy rates to double cleavage stage embryo transfer but results in healthier pregnancy outcomes. J Obstet Gynaecol 2011;51:406–10. [37] Gleicher N, Weghofer A, Barad D. A formal comparison of the practice of assisted reproductive technologies between Europe and the USA. Hum Reprod 2006;21:1945–50. [38] Chambers GM, Sullivan EA, Ishihara O, Chapman MG, Adamson GD. The economic impact of assisted reproductive technology: a review of selected developed counties. Fertil Steril 2009;91:2281–94. [39] Hartshorne GM, Lilford RJ. Different perspectives of patients and health care professionals on the potential benefits and risks of blastocyst culture and multiple embryo transfer. Hum Reprod 2002;17:1023–30. [40] Fiddelers A, Nieman FH, Dumoulin JC, et al. During IVF treatment patient preference shifts from singletons towards twins but only a few patients show an actual reversal of preference. Hum Reprod 2011;26:2092–100.
[41] Pinborg A, Loft A, Schmidt L, Nyboe Andersen A. Attitudes of IVF/ICSI-twin mothers towards twins and single embryo transfer. Hum Reprod 2003;18:621–7. [42] Rai V, Betsworth A, Beer C, Dukwe G, Glazebrook C. Comparing patients’ and clinicians perceptions of elective single embryo transfer using the attitudes to a twin IVF pregnancy scale. Assist Reprod Genet 2011;28:65–72. [43] Blennborn M, Nilsson S, Hillervik C, Hellberg D. The couple’s decision making in IVF: one or two embryos at transfer. Hum Reprod 2005;20:1292–7. [44] Leese B, Denton J. Attitudes towards single embryo transfer, twin and higher order pregnancies in patients undergoing infertility treatment: a review. Hum Fertil 2010;13:28–34. [45] Min JK, Breheny SA, MacLachlan V, Healy DL. What is the most relevant standard of success in assisted reproduction? The singleton, term gestation, live birth rate per cycle initiated: the BESST end point for assisted reproduction. Hum Reprod 2004;19:3–7.
Contents lists available at SciVerse ScienceDirect
European Journal of Obstetrics & Gynecology and Reproductive Biology journal homepage: www.elsevier.com/locate/ejogrb
Review
Multiple births following in vitro fertilization treatment: redefining success A. Umranikar a,*, D. Parmar b, S. Davies a, S. Fountain a a b
Salisbury NHS Foundation Trust, Salisbury, UK Peninsula College of Medicine and Dentistry, Plymouth, UK
A R T I C L E I N F O
A B S T R A C T
Article history: Received 5 November 2012 Received in revised form 13 March 2013 Accepted 24 June 2013
The focus of this article is to review the definition of success following in vitro fertilization (IVF) treatment. Pregnancy rates after IVF have been increasing, but the problem of multiple births with its associated morbidity and mortality has been considerable. This has led to rethinking of assisted reproductive technology (ART) success not only in terms of live birth rates, but also in terms of reduction of multiple births to singleton babies. Single embryo transfer using blastocysts and such other measures are being encouraged. Financial factors and patient satisfaction are key issues. IVF success is thus being redefined. ß 2013 Elsevier Ireland Ltd. All rights reserved.
Keywords: In vitro fertilization Assisted reproductive technologies Multiple births Embryo transfer
Contents 1. 2. 3.
4.
5.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Prevalence of multiple births: scope of the problem . . . . . . . . . . Problems associated with multiple births . . . . . . . . . . . . . 2.1. Strategies to reduce multiple births . . . . . . . . . . . . . . . . . . . . . . . Acceptance of eSET so far . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1. Blastocyst transfer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2. Challenges faced in the transition period prior to implementing Financial challenges . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1. Patients’ expectations and attitudes . . . . . . . . . . . . . . . . . 4.2. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
............. ............. ............. ............. ............. ............. the SET policy . ............. ............. ............. .............
1. Introduction Infertility affects 1 in approximately 6 couples. Growing awareness and increased availability of fertility services have resulted in many couples opting for in vitro fertilization (IVF) treatment. Since the first successful IVF in humans in 1978, IVF has become a standard treatment for subfertility [1]. There have been remarkable achievements over the years in pregnancy success rates following IVF. This has been due to continuous improvement in ovarian stimulation protocols, and refinements and advances in
* Corresponding author. Tel.: +44 2380262392. E-mail addresses: [email protected], [email protected] (A. Umranikar). 0301-2115/$ – see front matter ß 2013 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.ejogrb.2013.06.031
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IVF laboratories resulting in improved embryo quality. In addition to the success rates achieved through IVF and intracytoplasmic sperm injection (ICSI) treatment, there has been an intense effort to reduce the incidence of multiple births in recent years. IVF success has been defined as a live birth after an assisted reproductive technology (ART) cycle, regardless of the number of live-born infants per delivery [2]. This definition needs to change as we take into consideration problems related to multiple births including costs and other constraints. In the reporting of ART success rates, commercially competitive settings may maximize numerators and minimize denominators [3]. One may measure success rates in terms of clinical pregnancy (evidence of sac, detection of fetal heartbeat) or more ideally live birth rates, but the problem is complex. Multiple pregnancies can be associated with detrimental outcome. It is time that success is defined in terms of
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not only live birth rates but also the rate of multiple births. This review attempts to address some of these relevant issues, with special reference to the UK and Europe. 2. Prevalence of multiple births: scope of the problem There have been growing concerns over the incidence of multiple births following IVF. IVF is often a costly decision for patients financially, medically and emotionally and this is especially so when it is associated with multiple births [4]. The overall incidence of multiple births has been on the rise over the past 30 years. This is mainly attributable not just to the increasing use of IVF treatment by subfertile couples, but also to the increasing age of women seeking fertility treatment and to delayed childbearing [5,6]. The majority of the multiple births are twins, as the rate of triplet pregnancies has reduced over the last decade. While the incidence of multiple births is just over 1% (1.25%) following natural conception, the figure rises to 24% with IVF treatment. In the UK around 11,000 babies are born every year through ART, contributing to around 2% of live births [7]. In the UK the Human Fertilization and Embryology Authority (HFEA) [7] collects records of approximately 50,000 fertility treatments performed every year. Around 1 in 4 twins born in the UK are as a result of IVF treatment [7,8]. Around 50% of these are born before 37 weeks and contribute to nearly 10–20% of all low birth weight babies [9]. Until 2008, the rate of multiple births related to IVF was 26.7%. This reduced to 22% in 2009 following an increase in uptake of elective single embryo transfer (eSET) policy. The highest proportion (31.2%) of multiple births was seen in women between 18 and 34 years. There has been a similar increase in twin pregnancies following IVF treatment in most countries in Europe, Scandinavia, United States, Canada and Asia. In Denmark, the twin birth rate increased from 17.8 to 22 per 1000 births between 1996 and 2003. In Sweden, twin births increased 1.9-fold from 1973 to 2000 and in Norway the increase was 2.2-fold from 1974 to 2002 [10]. Studies from Australia have shown a greater than 20% risk of twins or higher order multiple pregnancy [11]. Multiple births comprised 9% of the infertility group compared with 1.3% in the general population of Victoria, Australia, and 23.7% of IVF and GIFT births [12]. Thus, studies from all over the world have shown a very high rate of multiple births following IVF. 2.1. Problems associated with multiple births Multiple pregnancy can pose a significant risk to both the mother and the baby, and is the single biggest health risk following IVF treatment. Women with multiple pregnancies have higher risks of miscarriage, anaemia, hypertensive disorders like preeclampsia, diabetes, operative deliveries and related postnatal illnesses. Although the mortality is low, morbidity figures are higher in these women than in women with singleton pregnancies. The risk of preeclampsia and gestational diabetes is 2–3 times higher in women with twins than in singleton pregnancies and 9 times higher with triplet pregnancy [13]. Advanced maternal age is a known risk factor and is associated with higher perinatal complications. Several studies worldwide have reported that around 10% women with twins experience parenting stress, depression and marital problems [14]. In first-time mothers, twins with low birth weight have a particularly high impact on their personal, social and emotional wellbeing. Most twins conceived as a result of IVF treatment happen to be dichorionic as a result of transfer of two or more embryos. Although the risk of chromosomal anomalies and cerebral palsy (CP) is seen more often in monochorionic twins, the risk of
prematurity and low birth weight is seen in both mono- and dichorionic twins equally. IVF twins are born approximately 3 weeks earlier than singletons and weigh 800–1000 gm less than their singleton counterparts [15]. The risk of CP increases from 1.7/1000 live births in singleton pregnancies to 6.2/1000 live births in twins [16]. Twins have at least a 6 times higher risk of developing CP and triplets have an 18 times higher risk. Most problems associated with twins appear to be related to prematurity and crucially the gestational age at birth. The risk of babies dying due to prematurity and low birth weight in the first month of life increases from 3 per 1000 for singletons to 19 per 1000 for multiple births. Low birth weight (<2500 gm), very low birth weight (<1500 gm) and extremely low birth weight (<1000 gm) are all mostly related to preterm deliveries in twins. Three out of 4 babies born under 26 weeks’ gestation are at risk of dying soon after birth or may require several months of care in the neonatal unit. Over 60% of survivors are likely to have significant brain and eye damage resulting in physical and mental impairment. These children end up having attention deficit hyperactive disorders and behavioural problems that are likely to persist into adult life [17]. Compared to singleton births, fetal, neonatal and perinatal mortality rates are 3–6 times higher in twins and 5–15 times in higher order multiple births in Australia [18]. CP rates among survivors are 6 times higher in twins and twenty times higher in triplets. In a study from Western Australia [19], the incidence of major birth defects was 7.1% in twins born after ART and 5.9% of non-ART twins of unlike sex. Studies by Venn and Lumley [12] showed that perinatal mortality between 1982 and 1990 was 11.1 per 1000 in general population and 34.9 per 1000 in the IVF group. Thus, for nearly three decades problems due to multiple births have been identified, underlining the crucial fact that birth of a singleton term baby carries the optimum outcome for both mother and baby. 3. Strategies to reduce multiple births The best way to reduce multiple births is to reduce the number of embryos transferred into the uterus. For the past two decades, the HFEA has encouraged clinics in the UK to take steps to reduce the risks of multiple births. In 1991, clinics were discouraged from transferring more than three embryos at one time in a treatment cycle. In 2001, the HFEA introduced a two-embryo transfer policy. In 2004, this was tightened further to allow a maximum of two embryos to be transferred in women under 40 years: for women aged 40 years and over, a maximum of three embryos could be transferred under exceptional circumstances. These early measures halved the number of triplet pregnancies in the UK but the twin pregnancy rate continued to rise. In 2007/2008, HFEA introduced an elective single embryo transfer (e SET) policy in a selected group of patients less than 37 years of age. 3.1. Acceptance of eSET so far Based on national data, if 50% of women are offered and agree to eSET, the multiple birth rate would fall to less than 10%. In order to maintain the pregnancy rate using eSET, it is important to ensure that effective cryopreservation programmes are available to patients so that good quality embryos are available for another cycle. The first study of single embryo transfer (SET) was conducted in Finland [20] and showed that pregnancy rates were not significantly different (14.7%) with SET and double embryo transfer (DET) in a specific population group. The rate of multiple births dropped to 5% in the SET group from 38% in the DET group. In 2003, Tiitinen et al. [21] reported a dramatic reduction in twin rates in
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Finland from 25% in 1997 to 5% in 2001 following implementation of SET. At the same time, Swedish IVF centres adopted the SET policy widely in all women under 36 years of age. The mean number of embryos transferred reduced from 2.7 to 1.3 between 1992 and 2004, and by 2004 SET was adopted nationally in Sweden (67.4%). The policy resulted in a dramatic reduction in multiple births while maintaining success rates from a SET cycle. The multiple birth rate reduced from 35% in 1991 to 5.7% in 2004. The live birth rate was stable around 25% per transfer. Saldeen and Sundstrom [22] compared three different embryo transfer policies between 2002 and 2004: a two embryo transfer policy adopted in 2001 to early 2002, a transitional period of DET for private patients and SET for public patients in 2002, and a SET policy for all implemented in 2003.The clinical pregnancy rates in all three groups remained stable (33.3%, 32.8%, 37.4% respectively), while the twin rate was significantly lower in the SET group (22.6%, 16.3%, 6.2% respectively). The expected decline of twinning was accompanied by an unchanged clinical pregnancy rate, and thus the SET legislation had no negative consequences for the couples [22]. A randomized multicenter trial in Sweden in 2004 [23] compared pregnancy rates and multiple gestation rates between SET and DET. Women with two good-quality embryos were randomly assigned either to undergo transfer of a single fresh embryo and if there was no live birth, subsequent transfer of a single frozen and thawed embryo, or to undergo single transfer of two fresh embryos. The results showed a live birth rate of 42.9% in the DET group versus 38.8% in the SET group. The rate of multiple births was significantly lower in the SET group (0.8%) than in the DET group (33.1%). A similar study in 2009 [24] which compared cumulative live births after SET versus DET showed a cumulative live birth rate of 43.9% in the SET group versus 51.1% in the DET group. The multiple birth rate was significantly lower in the SET group (2.3%) than in the DET group (27.5%). The rate of preterm births (<37 weeks) was higher in the DET group than in the SET group (25.5% versus 11.8%). Around the same period, other countries like Denmark, Belgium and the Netherlands adopted a SET policy and found similar results with their pregnancy rates with a dramatic reduction in multiple births. A randomized controlled trial in the Netherlands [25] studied the clinical outcomes and cost effectiveness of two cycles of eSET versus one cycle of DET in women less than 35 years of age. The results showed a comparable cumulative live birth rate of 41% with SET versus 36% with DET. The multiple birth rates were significantly higher in the DET group (37%) as compared to 0% in the SET group. Cost analysis also confirmed a comparable medical cost per live birth up to 6 weeks after delivery with 2 cycles of SET and one cycle of DET. If lifetime costs due to handicaps in multiple births were considered, however, a SET policy would clearly be a more cost effective strategy than DET. Despite the favourable results following SET implementation, other countries in Europe and USA have been slow to adopt the policy. This could be partly because couples who are self-funding were worried about lowering the results following SET. Most couples would prefer to optimize their success in the first attempt. In a study by Roberts et al. [26], many patients perceived moving from DE to SET as unfair. Additional treatment cycles are seen by patients as physically and emotionally burdensome. It therefore appears that in countries where IVF treatment is provided by the state, SET policy is implemented earlier than in countries where IVF treatment is largely available to couples who self-fund. A similar strategy was introduced in many European countries to reduce risks of multiple births. While a two-embryo transfer policy effectively reduced the triplet rates, the twin pregnancy rates in most countries in Europe including UK remained high at 24%. In the UK, HFEA data between 2005 and 2007 revealed multiple birth rates of 22–24% and live birth rate around 23% per
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cycle. The transition period from 2008 showed a growing uptake of eSET in the UK (4.8%) and this increased to 14.7% in 2010.The vast majority of women (87.3%) were 37 years or younger. Two thirds had SET in their first cycle with most having 2 or more embryos to freeze. Several studies have compared the live birth and multiple pregnancy rates between SET and DET. Khalaf et al. [27] examined outcomes after introducing SET using blastocyst in a selected group of patients, and demonstrated an increase in the clinical pregnancy rates from 27% to 32% with a reduction in multiple births from 32 to 17%. Bhattacharya and Templeton [28] reviewed data from randomized controlled trials which indicate that SET results in lower live birth rates per fresh IVF cycle (odds ratio 0.53, 95% confidence interval 0.31–0.89, p = 0.02) in comparison with DET, but they also concluded that the perceived effectiveness of SET is influenced by the way evidence is interpreted. Other factors are laboratory techniques, individual preferences and funding issues. A Cochrane review in 2005 [29] compared success rates and multiple birth rates of SET as compared to DET. It included 4 randomized controlled trials between 1999 and 2004 and concluded that although a SET policy reduced the rate of multiple births, the live birth rate and clinical pregnancy rates were also reduced. On the other hand, adopting a policy of SET in a fresh cycle and a frozen cycle showed comparable cumulative birth rates as seen with DET, and reduced the risk of multiples. The review also redefined success as cumulative live birth rates per oocyte retrievals which include utilization of fresh and frozen cycles using a SET policy for the fresh cycle. The study also suggested that for a SET policy to be implemented effectively, the age group of women should be less than 35 years and should include women undergoing their first or second IVF/ICSI cycles using their own eggs with good quality embryos in cryo storage. In a more recent meta-analysis [30] of the clinical effectiveness of SET versus DET, the overall live birth rate following SET in a fresh cycle (27%) was lower than DET (42%), but addition of a single embryo frozen cycle gave a cumulative birth rate (38%) which was comparable to that of DET. The odds of a singleton term live birth were almost 5 times higher after a SET than after a DET and the cumulative risk of multiple births was 1% (SET) versus 32% in DET. Studies from Australia found that replacement of one single embryo is just as successful as two-embryo transfer without the risk of multiple pregnancy [31] and that transfer of one or two embryos decreases the risk of a multiple pregnancy, preterm birth and low birth weight [32]. Reynolds and Schieve [33] studied trends in embryo transfer policies and multiple births in USA from 1996 to 2002 involving a population-based sample of 506,072 transfers. In 2002, 15% of all twin births and 43% of all triplets were due to assisted reproductive techniques. Amongst women under 35 years, the proportion of 2 embryos being transferred increased from 8% in 1996 to 43% in 2002, while the proportion of 3 embryos being transferred declined from 87% to 52%. This reduced the proportion of triplet pregnancies from 15% to 7.5%. Although this practice contributed to reducing the triplet rate, the overall rate of multiple births showed only a smaller decline due to widespread use of DET policy in most clinics, with a low uptake of SET policy. These studies are summarized in Table 1. 3.2. Blastocyst transfer The HFEA adopted a ‘‘one at a time’’ policy setting its target of multiple pregnancies to less than 20% in 2011 and less than 15% by 2012. Most clinics in the UK are increasingly adopting a SET policy using blastocyst transfers for patients less than 35 years old. Blastocysts are embryos incubated in a laboratory for 5–6 days
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Table 1 Studies comparing DET and SET. Name of study
Type of study
Martikainen et al. [20] Tiitinen et al. [21] Saldeen and Sundstrom [22] Thurin et al. [23] Lukassen et al. [25]
Randomized control Retrospective Study Randomized control Randomized control Randomized control
McLernon et al. [30]
Meta-analysis
trial trial trial trial
Amount of data
Multiple birth rate in DET group
Multiple birth rates in SET group
Difference in live birth rate
144 participants 1871 participants 1362 participants 661 participants 107 participants
38% 25% 22.6% 33.1% 37%
5% 5% 6.2% 0.8% 0%
1367 participants from 8 trials
32%
1%
14.7% 0.3% 4.1% 4.1% 5% (higher in SET group due to 2 cycles) 4%higher cumulative live birth in DET group
after fertilization, and blastocyst transfer allows a self-selection process enabling the best embryo to be available for transfer, thereby achieving good pregnancy rates. Although long-term data on the outcome of embryos placed in extended laboratory culture are unknown, transfer of a blastocyst is considered to increase pregnancy rates as compared to the currently used day 2 or 3 cleavage staged embryos, due to a better implantation potential. Several studies have reported the advantages and disadvantages of blastocyst and cleavage stage embryo transfer. A prospective RCT by Papanikolaou et al. in 2006 [34] comparing pregnancy and delivery rates between day 5 (blastocyst) and day 3 (cleavage stage) transfer was terminated early as a significantly higher pregnancy and delivery rate was seen in patients having a blastocyst transfer. A systematic review by Papanikolaou et al. in 2008 [35] included 8 randomized controlled trials: the live birth rate was significantly higher using blastocyst, and the implantation potential of a blastocyst was found to be superior to a cleavage stage embryo. Zander-Fox et al. [36] compared pregnancy rates with single blastocyst transfer versus double cleavage stage embryos and showed a live birth rate of 27% following a single blastocyst transfer which was comparable to that obtained following a double embryo transfer (24%). There was a significant reduction in multiple birth rates in the former group. Since 2008, there has been a steady increase of blastocyst transfers in the UK from 8.4% in 2008 to 27.6% in 2010 (HFEA). Pregnancy rates in UK using SET policy with blastocysts have remained steady between 2008 and 2010 (29–31%). Notably, the rate of multiple pregnancies has reduced from 26.7% in 2008 to 22% in 2010. Much of this success has been seen in women aged less than 35 years. 4. Challenges faced in the transition period prior to implementing the SET policy 4.1. Financial challenges Funding policies for IVF/ICSI treatment vary between countries. In countries where IVF is a state-funded treatment the uptake of SET has been higher than in countries where patients have to fund their own treatment. The policy of adopting SET so widely in Sweden may be due to the fact that majority of cycles in Sweden are state funded. In the UK, IVF is not uniformly funded by the NHS and many desperate couples end up financing their own treatment. These couples are powerful drivers to opt for DET than SET to maximize their chances of pregnancy in the first attempt. The bigger picture of risks associated with multiple births due to prematurity resulting in long-term neurodevelopment problems seldom gets considered. Gleicher et al. [37] observed significant differences in ART practices between European countries and the USA. Of note was the difference in the number of embryos transferred. Only 33% of
women in the US had 1 or 2 embryos transferred, compared with 63% of women in Europe. In addition 3 or 4 embryos were routinely transferred in the US, while that practice was observed in 36% women in Europe. These practices contributed to higher multiple births in US (38.6%) than in European countries (25.5%). The difference between Scandinavian countries and the US could be due to the fact that ART is a state-funded treatment in the former, whereas in the latter ART is a treatment available to the financially advantaged section of society. Several differences in policies and practices were therefore noted between the two continents as patient preferences and acceptance differed considerably. A review of the economic impact of ART [38] showed that the cost per live birth was highest in the U.S.A. and U.K. (41,132 and 40,364 dollars respectively) and lowest in Scandinavia and Japan (24,485 and 24,329 dollars respectively). The cost of an IVF cycle after government subsidization ranged from 50% of annual disposable income in the U.S.A. to 6% in Australia [38]. Thus, ART may be expensive from a patient perspective, but not from a societal perspective. Countries with funding arrangements that minimize out of pocket expenses met expected demand. Whether through Government or insurance, funding should maximize efficiency and equity of access while minimizing the potential harm from multiple births [38]. Models from various countries with different funding sources have shown that the cheaper the cost to patients, the more acceptable is SET. 4.2. Patients’ expectations and attitudes The key component of patient expectations is a successful outcome of the treatment. This is more so for patients funding their own treatment. An important factor in increasing uptake of SET involves understanding the expectations and attitudes of patients undergoing IVF/ICSI. There also appear to be differences in perceptions among clinicians and patients towards multiple pregnancies. This was evident from the study conducted by Hartshorne and Lilford [39] which showed that nearly 80% of patients preferred options that increased their chances of a pregnancy, with nearly half of these accepting the additional risks of multiple pregnancies. In contrast, less than 5% of healthcare professionals accepted the risks of multiple births. Patient preferences were also seen to shift between SET and DET depending on the success from a given cycle: in a study by Fiddelers et al. [40] 62% of patients showed a preference shift from singleton to twins in order to fulfil their desire to have a child. A national questionnaire survey in Denmark in 2003 [41] showed that mothers in general had a positive preference towards twins: 84% of mothers with IVF/ICSI twins and 62% of mothers with IVF/ICSI singletons would have preferred twins. Acceptance of SET in these women was reported as 17–24%. Following extensive counselling regarding the potential risks to babies due to prematurity, another 20% women accepted SET policy provided they were offered more treatment cycles. This was also confirmed
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by Rai et al. [42], who compared patients and clinicians’ perceptions and attitudes towards SET. Effective counselling was suggested to be a reliable intervention in increasing the uptake of SET. Several studies have been conducted worldwide to study patient attitudes and preferences towards a SET policy. Decisionmaking can be a difficult process if SET reduces the success rates of treatment, thereby necessitating more treatment cycles. Blennborn et al. [43] demonstrated the factors involved: younger women with no history of previous IVF treatment failures who had good quality embryos for transfer and for cryopreservation were likely to accept SET, while couples who were older and had experienced previous unsuccessful cycle outcome were more likely to opt for DET to optimize their success in achieving a baby. For these women the success from treatment was far more important than the risks of multiple births with a DET. A recent review [44] of attitudes of patients towards SET confirmed that as success rates were improving and as women were being counselled regarding potential risks of multiple births, there was an increasing acceptance of 2 rather than 3 embryos. A further step would be to achieve a greater uptake of SET policy. In addition, increasing state funding would enable a more uniform availability of ART, all making a significant contribution towards an increase in the uptake of SET resulting in a reduction of multiple births. An analysis of the problems of multiple births, issues related to decreasing them, financial constraints and patients’ attitudes make one rethink how success following ART should be measured. Min et al. [45] have summarized success exquisitely. Success must reflect delivery of healthy babies and the burden of treatment to couples. They suggest that delivery of a singleton, term gestation and live baby per cycle is the most relevant standard of success and they encourage programmes to report the BESST outcome (Birth Emphasizing a Successful Singleton at Term) [45]. 5. Conclusion It has been documented that the safest outcome of in vitro fertilization treatment, both for the mother and the baby, is to achieve a singleton pregnancy. Professional bodies have recommended various strategies like single embryo transfer policy using blastocysts for women under 37 years. International experience is encouraging and the increased implementation of a SET policy has reduced the rate of multiple births significantly. Further success from these practices would be achievable with wider availability of state funding for these patients, and better availability of embryos for cryopreservation through better laboratory standards. Success from assisted reproductive technologies is thus being redefined. Success is not just based on the live birth rates reported from centres. More crucially, it includes the number of multiple births, as the best outcome would be to achieve good clinical success rates with low multiple births. Finally, patient satisfaction is often a key reflection of good clinical practice. Conflict of interest The authors state no conflicts of interests. References [1] Jones CA, Christensen AL, Salihu H, et al. Prediction of individual probabilities of live birth and multiple birth events following in vitro fertilisation (IVF): a new outcomes counselling tool for IVF providers and patients using HFEA metrics. J Exp Clin Assist Reprod 2011;8:3. [2] Hogue CJ. Successful assisted reproductive technology: the beauty of one. Obstet Gynecol 2002;100:1017–9. [3] Barlow DH. A time for consensus and consistency of reporting in clinical studies and the importance of new basic research. Human Reprod 2004;19:1–2.
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[4] Jones HW. Multiple births: how are we doing. Fertil Steril 2003;79:17–21. [5] Bensdorp AJ, Slappendel E, Koks C, Van Wely M. The INeS study: prevention of multiple pregnancies. BMC Womens Health 2009;9:35. [6] Hur YM, Song TB. A recent rise in twin birth rates and demographic changes in mothers of twins in South Korea 2003–2007. Twin Res Hum Genet 2009;12:118–22. [7] H.F.E.A.. A statistical report. Improving outcomes of fertility patients: Multiple births; 2011. [8] Office for National Statistics. Live births in England and Wales by characteristics of birth; 2010. [9] Blondel B, Kogan MD, Alexander DR, et al. The impact of the increasing number of multiple births on the rates of preterm birth and low birth weight: an international study. Am J Pub Health 2002;92:1323–30. [10] Pinborg A. IVF/ICSI twin pregnancies: risks and prevention. Hum Reprod Update 2005;11:575–93. [11] Jansen RP. Benefits and challenges brought by improved results from in vitro fertilization. Intern Med J 2005;35:108–17. [12] Venn A, Lumley J. Births after a period of infertility in Victorian women 1982– 1990. Aust NZ J Obstet Gynaecol 1993;33:379–84. [13] Cook R, Bradley S, Golombok S. A preliminary study of parental stress and child behaviour in families with twins conceived by in-vitro fertilization. Hum Reprod 1998;13:3244–6. [14] Oliveness F, Golombok S, Ramogida C, Rust J. Behavioural and cognitive development as well as family functioning of twins conceived by assisted reproduction: findings from a large population study. Fertil Steril 2005;84:725–33. [15] Pinborg A, Loft A, Schmidt L, Andersen AN. Morbidity in a Danish national cohort of IVF/ICSI twins: health related and social implications for the children and their families. Hum Reprod 2003;18:1234–43. [16] Surman G, Newdick H, King A, Gallagher M, Kurinczuk JJ. Four counties database of cerebral palsy, vision loss and hearing loss in children: annual report. University of Oxford; 2006. [17] Costeloe K, Hennessy E, Gibson AT, Marlow N, The EPICURE study. Outcomes to discharge from hospital for infants born at the threshold of viability. Pediatrics 2000;106:659–71. [18] Yu VY. Assisted reproduction technology. Multiple births and adverse perinatal outcome. Croat Med J 1998;39:208–11. [19] Hansen M, Kurinczuk JJ, Deklerk N, Burton P, Bower C. Assisted reproductive technology and major birth defects in Western Australia. Obstet Gynecol 2012;120:852–63. [20] Martikainen H, Tiitinen A, Tomas C, Tapanainen J, Finnish ET study group. One versus two embryo transfer after IVF and ICSI: a randomised study. Hum Reprod 2001;16:1900–3. [21] Tiitinen A, Unkila-Kallio L, Haltuunen M, Hyden-Granskog C. Impact of elective selective embryo transfer on twin pregnancy rate. Hum Reprod 2003;18:1449–53. [22] Saldeen P, Sundstrom P. Would legislation imposing single embryo transfer be a feasible way to reduce the rate of multiple pregnancies after IVF treatment. Hum Reprod 2005;20:4–8. [23] Thurin A, Hausken J, Hillensio T, et al. Elective single embryo transfer versus double embryo transfer in vitro fertilization. N Eng J Med 2004;351:2392–402. [24] Thurin-Kjellberg A, Olivius C, Bergh C. Cumulative live birth rates in a trial of single embryo or double embryo transfer. N Eng J Med 2009;361:1812–3. [25] Lukassen HGM, Braat DD, Wetzel AMM, Zielhuis G. Two cycles with single embryo transfer versus one cycle with double embryo transfer. A randomised controlled trial. Hum Reprod 2004;20:702–8. [26] Roberts SA, McGowan L, Vail A, Brison DR. The use of single embryo transfer to reduce the incidence of twins. Hum Fertil 2011;14:89–96. [27] Khalaf Y, El-Toukhy T, Coomarasamy A, Kamal A, Bolton V, Braude P. Selective single blastocyst transfer reduces the multiple pregnancy rate and increases the pregnancy rates: a pre and post intervention study. BJOG 2008;115:385– 90. [28] Bhattacharya S, Templeton A. What is the most relevant standard of success in assisted reproduction? Redefining success in the context of single embryo transfer: evidence intuition and financial reality. Hum Reprod 2004;19:1939– 42. [29] Pandian Z, Templeton A, Serour G, Bhattacharya S. Number of embryos for transfer after IVF and ICSI: a Cochrane review. Hum Reprod 2005;20:2681–7. [30] McLernon DJ, Harrild K, Bergh C, et al. Clinical effectiveness of single versus embryo transfer: meta-analysis of individual patient data from randomised trials. BMJ 2010;341:c6945. [31] Kovacs G, MacLachlan V, Rombauts L, Healy D, Howlett D. Replacement of one selected embryo is just as successful as two embryo transfer, without the risk of twin pregnancy. Aust NZ J Obstet Gynaecol 2003;43:369–71. [32] Dare MR, Crowther CA, Dodd JM, Norman RJ. Single or multiple embryo transfer following in vitro fertilization for improved neonatal outcome: a systematic review of the literature. Aust NZ J Obstet Gynaecol 2004;44:283–91. [33] Reynolds MA, Schieve LA. Trends in embryo transfer practices and multiple gestation for IVF procedures in the USA, 1996–2002. Hum Reprod 2006;21:694–700. [34] Papanikolaou EG, Camus M, Kolibianakis EM, VanLandyut L, Van Steirteghem A, Devroey P. In vitro fertilization with single blastocyst-stage versus cleavage stage embryos. N Eng J Med 2006;354:1139–46. [35] Papanikolaou EG, Kolibianakis E, Tournaye H, Venetis C, Fatemi H. Live birth rates after transfer of equal number of blastocysts or cleavage stage embryos in IVF. A systematic review and meta-analysis. Hum Reprod 2008;23:91–9.
304
A. Umranikar et al. / European Journal of Obstetrics & Gynecology and Reproductive Biology 170 (2013) 299–304
[36] Zander-Fox DL, Tremellen K, Lane M. Single blastocyst embryo transfer maintains comparable pregnancy rates to double cleavage stage embryo transfer but results in healthier pregnancy outcomes. J Obstet Gynaecol 2011;51:406–10. [37] Gleicher N, Weghofer A, Barad D. A formal comparison of the practice of assisted reproductive technologies between Europe and the USA. Hum Reprod 2006;21:1945–50. [38] Chambers GM, Sullivan EA, Ishihara O, Chapman MG, Adamson GD. The economic impact of assisted reproductive technology: a review of selected developed counties. Fertil Steril 2009;91:2281–94. [39] Hartshorne GM, Lilford RJ. Different perspectives of patients and health care professionals on the potential benefits and risks of blastocyst culture and multiple embryo transfer. Hum Reprod 2002;17:1023–30. [40] Fiddelers A, Nieman FH, Dumoulin JC, et al. During IVF treatment patient preference shifts from singletons towards twins but only a few patients show an actual reversal of preference. Hum Reprod 2011;26:2092–100.
[41] Pinborg A, Loft A, Schmidt L, Nyboe Andersen A. Attitudes of IVF/ICSI-twin mothers towards twins and single embryo transfer. Hum Reprod 2003;18:621–7. [42] Rai V, Betsworth A, Beer C, Dukwe G, Glazebrook C. Comparing patients’ and clinicians perceptions of elective single embryo transfer using the attitudes to a twin IVF pregnancy scale. Assist Reprod Genet 2011;28:65–72. [43] Blennborn M, Nilsson S, Hillervik C, Hellberg D. The couple’s decision making in IVF: one or two embryos at transfer. Hum Reprod 2005;20:1292–7. [44] Leese B, Denton J. Attitudes towards single embryo transfer, twin and higher order pregnancies in patients undergoing infertility treatment: a review. Hum Fertil 2010;13:28–34. [45] Min JK, Breheny SA, MacLachlan V, Healy DL. What is the most relevant standard of success in assisted reproduction? The singleton, term gestation, live birth rate per cycle initiated: the BESST end point for assisted reproduction. Hum Reprod 2004;19:3–7.