Elective Single Embryo Transfer
Dr Gautam Khastgir
Elgin, Kolkata May 28, 2019
The first successful in-vitro fertilization and embryo transfer (IVF-ET) treatment was done in a natural cycle, where only one egg was collected and a single embryo was transferred.1 However, in order to improve the success rate of IVF-ET, controlled ovarian hyperstimulation (COH) has been practiced to develop multiple oocytes. This has resulted in multiple embryos available for transfer, leading to higher incidence of iatrogenic twins and higher-order multiple pregnancies. Over the period of years, it has been well accepted that the price one pays for higher success of any assisted reproductive treatment (ART) are increased maternal risk and poor perinatal outcome, mainly due to complications of twins and triplets. To avoid the problems of higher-order multiple pregnancies, clinicians often had no option other than to perform an invasive procedure like selective fetal reduction and accept its associated complications of pregnancy loss.
In spite of the fact that many twins are delivered healthy and the advances in neonatal medicine have decreased mortality and morbidity of premature babies, there still remains a significantly poor perinatal outcome with multiple pregnancies following ART. The risks related to multiple pregnancies include pregnancy induced hypertension, gestational diabetes, preterm delivery, low birth weight, higher incidence of birth defects and increase in the relative risk of neurological problems like cerebral palsy.2 These complications lead to significant rise in the average healthcare cost of pregnancy, delivery and neonatal care. It has been estimated that overall expenditure of multiple pregnancy is increased by 3 to 15 folds as compared to that of singleton pregnancies.3-5 In addition, there are reports of severe stress experienced by the parents of multiples and lifelong support needed for mildly or severely disabled children. 6-9 As a result there has been raving criticisms questioning the justification of entrusting the responsibility of our children’s health in the hands of those involved with ART.10-11 Hence, many reproductive scientists and clinicians from different parts of the world have voiced their opinions and convictions on elective single embryo transfer (eSET), in order to eliminate the problem of iatrogenic twin and higher order multiple pregnancies.
Risks of multiple pregnancies for children
The main cause of morbidity and mortality in children born after ART is the higher incidence of premature births in twin pregnancies, not to mention the higher-order multiples. The data analysis of all children born with ART and a comparison with the general population in Sweden
during the period between 1982 and 1995, showed that the incidence of multiple births after ART was much higher (27%) in contrast to the control population (1%). There were also a significantly higher incidence of preterm births (30.3% vs. 6.3%), low birth weight (<2.5 kg) babies (27.4% vs. 4.6%) and perinatal mortality (1.9% vs. 1.1%) among ART babies in contrast to that in the controls. The higher frequency of multiple births as well as maternal characteristics such as advanced age, associated medical problems and obesity were regarded as the main factors for adverse outcome, and not the ART treatment itself.12 Further analysis of this data showed that abnormalities detected in ART children in contrast to the control population were ever more alarming. The risk of neurological diagnosis was much higher among twins in comparison to the singletons born after ART, but interestingly, the risk did not differ from that of control non-ART twins. The commonest neurological problem detected was cerebral palsy, for which all ART babies including twins had a risk ratio of 3.7 (95% CI 2.0 - 6.6) whereas in the singletons it was 2.8 (95% CI 1.3 - 5.8). In addition, the risk of developmental delay was four times higher among ART children in contrast to that in the controls.13
A similar population based study in Denmark compared the risks between twins and singletons born after ART. The risk of prematurity was 10 times higher before 37 weeks and 7.4 times higher before 32 weeks in twins as opposed to that in singletons.14 In addition congenital anomalies are also more common in twin pregnancies. The total malformation rate (minor + major) in twins (73.7/1000) was significantly higher than that in singletons (55.0/1000).14 Other studies have also shown a higher prevalence of major malformations (9.3%) among ART infants when compared with the control infants. Of the ART infants with malformations, 70% were born from twin or triplet pregnancies.15, 16 Congenital heart disease is more common among twins than in singletons. Patent ductus arteriosus, typical of preterm births was found to be very common among twins.17, 18 An increased risk of anencephaly was also evident among twin infants born after ART.19 Other perinatal complications typical of a twin pregnancy also occur in ART twin pregnancies.
The risk of premature birth with multiple pregnancies is further enhanced in conditions associated with prematurity such as uterine malformations, cervical incompetence, hypoplastic uterus as in Turner’s syndrome and previous history of premature delivery. Therefore multiple pregnancies should not be induced among individual who has any increased risk factor of premature delivery. It has been confirmed that pregnancy complications like intra uterine growth retardation and prematurity even in singleton pregnancies are caused by the condition called vanishing twin syndrome, which is actually a consequence of an ART twin pregnancy.20, 21
Risks of multiple pregnancies for mother
Multiple pregnancy is a very high risk factor for mother too, since it is associated with many obstetric complications. The risks of pregnancy induced hypertension, pre-eclampsia, ecalmpsia, impaired glucose tolerance, pregnancy induced diabetes, placental abruption and placenta praevia are much higher in twins than among the singletons.22-24 All these conditions have adverse effects on maternal health in addition to increasing chances of operative delivery resulting in infection and blood loss leading to higher incidence of maternal morbidity and mortality.14 Women who are already suffering from essential hypertension, heart disease, kidney problem and diabetes are more likely to develop complications in pregnancy and therefore should avoid multiples by all means in order to prevent an alarmingly high risk situation. Obesity further increases the risk of pregnancy induced hypertension and gestational diabetes.25Therefore, increasing the risk of complications with a twin pregnancy by transferring more than one embryo, is not desirable in these high-risk individuals.
Women with Turner’s syndrome suffer from primary ovarian failure and need ART with donor oocytes.26-28 These women often have associated cardiac anomaly and suffer from essential hypertension. The most dangerous complication in Turner’s syndrome is aortic dissection and several such cases have been reported in pregnancy.29 It is therefore justified not to increase the risk in pregnancy by transferring more than one embryo at a time. Women requiring ART with donor oocytes for other indications are likely to be of advanced age and have a higher risk of all medical complications in pregnancy. Since oocyte donation ART gives a much higher pregnancy rate it is prudent to transfer only one embryo to avoid the additional risks of multiple pregnancy in these relatively elderly women.30-32
Outcome of Elective Single Embryo Transfer (eSET)
Several prospective randomized trials have been published to identify the difference in the pregnancy rates between one or two embryos of high implantation potential in a homogenous group of ideal patients i.e. younger than 35 years, first or second IVF/ICSI cycle. The embryos were transferred on day 2 in two studies,33, 34 on day 3 in two other studies35, 36 and on day 5 in blastocyst stage in only one study.37 In these studies taken together, the mean pregnancy rate after elective single embryo transfer (eSET) was 31.3% with 1.58% twins, whereas that after double embryo transfer (DET) the rates was 47.6% with 29.8% twins (Table I). A formal Cochrane meta-analysis came to similar conclusion.38 Out of these randomized trials, in two studies, patients were randomized to receive one excellent fresh embryo followed by one frozen/thawed embryo (1+1), just in case the fresh attempt proved unsuccessful, versus two fresh embryos (2). With the strategy of fresh plus frozen transfer, the cumulative pregnancy rate of 39.7% did not differ when compared to 43.5% when two embryos were transferred together. However, with only fresh embryo transfer, the pregnancy rate of 27.6% with eSET was significantly lower than 43.5% with DET but most importantly, twinning rate after eSET (0.8%) was significantly lower when compared to that after DET (36.1%).33 In the other study
the cumulative pregnancy rates after fresh and frozen embryo transfers were 47.3% after SET and 58.6% after DET but in the latter group there was alarge number (39%) of twins.36
However, in cohort studies,39-44 the mean pregnancy rate after eSET was 33.9% with 1% twin versus 35% after DET with 32.6% multiple pregnancies. (Table I) In most of these studies, SET was elective, which means that it was performed when an excellent quality embryo was available from a cohort of several embryos. Thus, taken together, these data suggest that eSET yields the same pregnancy rate as non-elective DET. The differences in the outcome of SET versus DET between randomized and cohort studies could be anticipated. In the randomized trials all embryos were of good-quality, transferred in selected cases with good prognosis and cryopreserved for future use; obviously two good quality embryos yielded more pregnancies with an increased risk of twining than the “best” embryo. However, in the real-life cohort studies, there were no differences in the outcome because SET meant elective transfer of a highly selected embryo of predictable implantation potential, whereas DET resulted in transfer of a mixture of embryos of excellent, intermediate or poor implantation potential. In addition, the significant difference found in the randomized trials disappears when one cryopreservation cycle is added to the fresh eSET cycle.33 An effective and active cryopreservation policy along with eSET protocol increases pregnancy rates per oocyte retrieval.45 The policy of eSET even in the frozen thawed treatment cycles obviously reduces the incidence of multiple pregnancies without affecting the pregnancy rates.46 One of the benefits of eSET is an increase in the number of embryos available for cryopreservation that increases the cumulative pregnancy rate per oocyte harvest. It also gives an option of a second baby which is actually a “delayed twin” after the success in the first attempt.47, 48 (Table II)
In spite of the evidence supporting eSET, some authors have conveyed their reservation about this approach arguing that the benefits are limited to only good prognosis patients, which actually constitutes only a small minority of ART patients in clinical practice. They suggested that the argument in favor of indiscriminate eSET is unrealistic and should be reconsidered.51, 52 Others have stressed the importance of counseling and educating patients as well as members of the staff, since both are hankering after a higher success of ART for obvious reasons.53 It is true that overzealous and indiscriminate use of eSET, without any option of embryo and patient selection, would damage the interest of the patients by significantly lowering the success rate of ART. Therefore, judicious application of eSET should be adopted with a balanced view about the benefits and limitations. Several reviews have given balanced arguments to optimize, not maximize, ART results by selective use of eSET.54, 55
Many early studies demonstrated the difference in the pregnancy rates between non-elective and elective SET. If only one embryo was available for transfer, the pregnancy rate was 20% per transfer, but if an elective SET was carried out in a non-selected population, a pregnancy rate of
29.7% was achieved, which was similar to that in a non-selective two-embryo transfer (29.4%).56 However, recent prospective randomized trials and cohort studies have confirmed that in a selected population of patients when top or good quality embryos are available, elective SETs result in much better pregnancy rates than non-selective SETs and that such pregnancy rates are similar to those achieved by the transfer of two embryos.57, 58 Similarly, pregnancy outcome was not affected when blastocyst-stage embryos were transferred resulting in a life birth rate of 53.8% after eSET and 54.4% after DET with a twin rate of 3.1% and 51% respectively.59
The practice of eSET has proved to be a successful method by which the incidence of multiple pregnancies can be reduced without affecting the overall pregnancy rates.41 In real life, it has not only been equally affective but also, economically, substantially cheaper than DET with all its complications.43, 60 However, in order to be as effective as DET, there has to be some criteria to select the patients suitably for eSET because in a non-selected population eSET resulted in a lower pregnancy rate.61 There are now data from Sweden and Belgium, which have laws and guidelines for regular SET, to support the fact that pregnancy rates have remained similar, while the rates of multiple pregnancies has dropped significantly when compared before and after adopting the practice of eSET.62, 63
Criteria for elective single embryo transfer
The essential prerequisites of introducing eSET in an ART center are reasonably good ongoing pregnancy rate of the existing treatment protocol along with a compellingly high multiple pregnancy rate, and presence of an efficient cryopreservation program. In order to achieve similar pregnancy rates between single and double embryo transfers, some kind of selection process must be there to balance the likelihood of pregnancy and minimize the risk of twins.61 The criteria used in the majority of the studies include age of the female partner, absence of tubal pathology, endometriosis and severe male factor subfertility, fewer number of earlier unsuccessful cycles, non-ongoing pregnancy in the first cycle, good ovarian response with lower dose of FSH stimulation, adequate number of oocytes collected, fertilized 2 PN stage zygotes available and embryo quality.64-67 Different authors have taken different values for some of these parameters but currently recommended criteria for eSET are 1) age of the female partner between 35 to 39 years or less, 2) the number of previous unsuccessful ART cycles up to 2 - 3 and 3) most importantly, selection from at least two good quality embryos. By strictly following these criteria, there has been reports of unchanged pregnancy rates along with a twin pregnancy rate of <5%.63
By definition, eSET suggests that there is a choice of selection from among two or more good-quality embryos, with the purpose of transferring only one embryo. However, if only one embryo is available, obviously that is not elective but compulsory single embryo transfer. Since
the majority of these cycles occur in poor prognosis patients i.e. older women, poor responders to ovarian stimulation, severe male factor subfertility and intrinsic fertilization defects, the only available embryo may be of poor quality resulting in low implantation and live birth rates of 10-19% and 9-15% respectively.40, 41 Therefore,in such patients, if two or more embryos of sub-optimal quality are available, then eSET should be avoided to improve the pregnancy rate as much as possible.
In a subpopulation of women multiple pregnancies substantially increases the risk of premature delivery. Congenital uterine anomaly, previous mid-trimester miscarriage due to cervical incompetence, past history of severe prematurity even with singleton pregnancy, previous loss of twin pregnancy, bad obstetrical history and severe systemic disease i.e. essential hypertension, heart disease, kidney problems and insulin dependent diabetes constitute absolute contraindication against more than one embryo transfer. This is referred to medically indicated single embryo transfer. Such contraindications are more relevant both in young women with Turner’s syndrome as well as in elderly women, since both groups of patients are at a greater risk of medical complications and also require oocyte donation which has much higher success rate of ART with an increased rate of pregnancy as well as multiples.
Embryo quality for elective single embryo transfer
A major issue in limiting the number of embryos transferred is the apparent inability to accurately estimate the reproductive potential of an individual embryo. The existing selection techniques, which largely encompass morphological evaluation, are not so accurate. Hence, in selecting only one or two embryos for transfer, we will be compelled to make certain changes in our ART practice. One of the steps may be to rely on less aggressive ovarian stimulation protocol, thus generating fewer numbers of oocytes at collection so that there is a natural selection process. Interestingly, the generation of a smaller number of oocytes actually leads to a greater percentage of viable embryos of good quality within a given cohort.68, 69 The other very important issue is to improve the selection process in defining the quality of individual embryos so that the ones that are selected for transfer are more likely to implant. The strategies in selection criteria have been defined objectively towards making the process accurate and further studies are continuing to identify noninvasive novel tests of embryo function.
Morphology as an assessment tool has been the mainstay in the embryo selection process before transfer in ART cycles. It is well known that embryos cleaving faster and those of better morphological appearance are more likely to result in a pregnancy.70, 71 The top-quality embryos have been described as those with less than 20% fragmentation, 4 or 5 blastomeres on day 2, 7 or more blastomere on day 3 after insemination, and no multinucleation in any of the blastomere. Such embryos have shown to have an implantation potential of about 40%.72 The
system of morphological assessment of embryos has improved over the period of years and in addition to classical parameters of cell number and fragmentation, the other characteristics including pronuclear morphology, nuclear membrane breakdown and early cleavage to 2-cellstage have been found to be of predictive value.73-75 The ability to culture and assess blastocyst stage embryos has also significantly improved the ability to select embryos on the basis of their morphology.37 The implantation rate of embryo on the basis of day 2 morphology is 14-28%, day 3 morphology is 35%, and day 5 blastocyst is 60%.37, 57, 76, 77 No single static information gives all the information regarding embryo quality. It is more logical to suggest that a combination of different observation, preferably reflecting different aspects of implantation potential, should be used. (Figure 1)
The ideal features shared by the pronuclear oocytes that have high viability are 1) the number of nucleolar precursor bodies (NPBs) in both pronuclei do not differ by more than three, 2) the NPBs are always polarized or non-polarized in both pronuclei but never polarized in one pronucleus and not in the other one, and 3) the angle between a line drawn through the axis of the pronuclei and the furthest polar body is less than 50 degree.78, 79 It has been postulated that the misalignment of the polar body might be linked to cytoplasmic turbulence resulting in poor embryo quality. An embryo score has been developed which is estimated on day one on the basis of alignment of pronuclei and nucleoli, cytoplasmic appearance, nuclear membrane breakdown and cleavage to 2-cell stage. Patients with an overall high embryo score had a much higher pregnancy and implantation rate of 71% and 28% respectively, compared to only 8% and 2% in the lower embryo score group.80, 81
The finding of cleavage to 2-cell stage at 25 hours post insemination or microinjection has been considered as one of the most important criteria for selecting embryos which have significantly higher implantation and pregnancy rates.82-84 In the embryo scoring system this feature has been given the highest individual point of 10.80 When single embryos are transferred, a significantly higher clinical pregnancy rate was noted after transfer of early-cleaving (50%) rather than non-early cleaving (26.4%) embryos.76 It has also been reported that embryos that cleave early lead to a significantly higher blastocyst formation rate.85, 86 Interestingly, early cleavage and cell number on day 2 are the most powerful parameters to predict the development of a good-morphology blastocyst on day 5.86
The most widely used criteria for selecting the best embryos for transfer has been based on number and symmetry of blastomereas well as embryo appearance or morphology.68 The characteristics top-quality embryos are 1) at least 4 to 5 blastomeres on day 2 after insemination, 2) at least 7 blastomeres on day 3 after insemination, 3) absence of multinucleated blastomere, and 4) less than 20% fragmentation on day 2 or 3 after insemination.35, 72 In a prospective randomized trial comparing single and double embryo
transfer, when top-quality embryos were transferred, implantation and pregnancy rates were 42.3% and 38.5% respectively with eSET whereas, 48.1% and 74% respectively with DET.35 Another study showed that the pregnancy rates after single top-quality embryo transfer was 51.9%.87
As with the scoring of embryos during the cleavage stage, time and morphology play an important part in selecting the best blastocyst. The scoring assessment for blastocyst is based on the expansion state of the blastocyst, as well as on the consistency of the inner cell mass and trophectoderm cells.88 When two high scoring blastocysts with expanded blastocoel, compacted inner cell mass and cohesive trophectoderm epithelium are transferred the implantation and pregnancy rates are 69% and 80% respectively. However, when two blastocysts not achieving such high scores are transferred, the implantation and pregnancy rates are significantly lower at 33% and 50% respectively, but early blastocyst on day 5 still have a high development potential than a cleaved stage embryo.89, 90 The time of blastocyst formation is also crucial. In comparison to day 5 or 6 blastocysts when those on or after day 7 are transferred, the pregnancy rates are 38.9% and 6.2% respectively. Therefore the best blastocyst would be those that develop by day 5.91 Although day 5 blastocystculture remains one of the strongest indicators of all morphological parameters, in reality, most practicing ART centers still chose to perform the majority of transfers at an earlier stage of embryo development.92 Although single blastocyst transfer has given excellent result in some centers 37, 57, 77, others have found no difference in the pregnancy rates between blastocyst and cleavage stage embryo transfer.93-95
Improved outcome even in singletons with eSET
It is interesting to note that eSET gives not only less twins but also better singletons. The outcome of singletons in a standard two-embryo transfer ART program is worse than naturally conceived singletons but such difference is not seen between ART and natural twins.96, 97 However, singletons after eSET do not compare unfavorably with spontaneously conceived singletons.98 It has also been reported that ongoing ART pregnancies showing first-trimester blood loss had an inferior obstetrical and neonatal outcome than when no first-trimester blood loss occurred. The complications included antepartum haemorrhage, intrauterine growth retardation, preterm delivery, low birth weight, preterm pre-labor rupture of membranes, increased caesarean sections, greater need for neonatal intensive care units (NICU) admission, respiratory distress syndrome, necrotizing enterocolitis and higher perinatal mortality. Interestingly, there was almost a linear relationship between the number of embryos transferred and the incidence of first-trimester blood loss.40 Many of these singleton pregnancies after ART resulted in a vanishing twin manifested with first trimester bleeding.99 The association between the number of embryos transferred, first-trimester bleeding and
adverse pregnancy outcome provide a further argument in favor of eSET. In yet another study, the birth weight of singletons born after eSET (3,324.6 + 509.7 gm) was significantly lower than that after two-embryo transfer (3,204.3 + 617.5 gm). The incidence of low birth weight (<2,500 gm) was lower for singletons after SET (4.2%) versus DET (11.6%), and the incidence of prematurity less than 37 weeks was 6.2% for singleton after SET versus 10.4% after DET.100 Hence, eSET does not only prevent the well-known and documented complications of twin pregnancies, but actually improves the outcome of singleton pregnancies.
Health Economic Aspects of Single Embryo Transfer
Although the main reason for adopting the practice of eSET is the good health of children at the beginning of their life, it is also true that the financial considerations are of great significance. The increased cost for the babies born after ART are mainly due to higher utilization of hospital care as a consequence of multiple pregnancies.7 It has been calculated that the estimated cost for a twin pregnancy was 3 times and that of a triplet pregnancy was 15 times as expensive as a singleton pregnancy after ART.4, 5 However, health economic models have shown that eSET and DET are financially equivalent per live born child since eSET needs more cycles for successful outcome and yields less child per cycle but DET requires less number of cycles in achieving pregnancy with higher obstetrics plus neonatal costs per child and these effects balance out each other.101, 102 In a state funding system, it has been shown that the money saved by avoiding half of the multiple pregnancies with eSET would suffice to finance all ART services in a year in spite of the fact that more treatment cycles would be necessary to achieve pregnancy.103 Similarly, another study confirmed that multiple pregnancies after ART are associated with higher cost to the National Health System (NHS) and utilization of money saved by implementation of a mandatory two-embryo transfer policy could double the number of NHS funded ART cycles at no extra cost; further saving could be made if selective SET policy were to be adopted.3 In countries where patients self-fund their ART cycles, proper counseling is needed to convince them that the pregnancy rate would not decline with eSET if combined with cryopreservation. The acceptance of eSET would be higher if results are expressed and patients are charges per oocyte harvest and not per cycle or transfer. Patients are often happy with the prospect of twins and are keen to have more embryo transfer without any idea of higher obstetric and perinatal risks. As regards the higher cost of neonatal care with multiple pregnancies, the patient awareness can be increased by arranging group discussions for prospective parents with those who have already had such experiences.
To improve the success rates in ART, the clinicians have induced controlled ovarian hyper-stimulation (COH) towards multi-follicular development leading to in-vitro fertilization of several oocytes and transfer of multiple embryos per cycle. This has resulted in an undesirable but expected side-effect of twin and higher order multiple pregnancies which increases the health risk of bothmothers and their children. The problems are largely due to the higher chance of premature births and are also caused by the increased incidence of congenital anomalies among multiple pregnancies. With evolving embryo culture techniques even transfer of a single embryo of good quality now results in a pregnancy rate comparable to that of natural conception. Although the pregnancy rates of ART can be improved tremendously by increasing the number of embryos transferred, but sadly enough, the prices to be paid are the maternal and neonatal sufferings due to multiple pregnancies. Hence, it is prudent not to transfer more than one embryo to eliminate the possibilities of multiple pregnancies. Therefore, decreasing the prevalence of multiple pregnancies, while maintaining or improving overall success rates of ART, remains the most significant contemporary goal of infertility research.
In order to obtain equal pregnancy rates between single and double embryo transfer, certain criteria have been used for patient selection for ART. In women under the age of 40 years, during her first three ART cycles, and with good quality embryos, a reasonable success rate with a twin rate of less than 5% can be achieved. However, two embryos need to be transferred in women who do not fulfill these criteria. If the embryo is intact after thawing, only a single frozen-thawed embryo should be transferred. Irrespective of women’s age, the number of earlier cycles or the embryo quality, single embryo should be transferred in women known to have a high risk of premature birth such as congenital uterine anomaly, cervical incompetence or hypoplastic uterus. The same is true as regards the maternal contraindications for multiple pregnancies, such as hypertension, cardiac problem, diabetes and obesity. With increasing maternal age or Turner’s syndrome, in addition to maternal contraindication, a better success rate with ART using oocyte donation, single embryo transfer is considered more suitable.
The mainstay of elective single embryo transfer depends upon selection of the most appropriate embryo to be transferred to achieve pregnancy. Analysis of embryo morphology and development of suitable grading systems have helped in identification of most suitable embryo for transfer. As regards the criteria of good quality embryos, the features are early cleavage by 25 hours, four cells on day 2, eight cells on day 3, no multinucleated blastomere, less than 20% fragmentation, embryo within an even zonapellucida. An exception of one of these parameters still counts a good-quality embryo. In the blastocyst stage, an expanded blastocyst with compacted inner cell mass and cohesive trophectoderm epithelium on day 5 indicate good quality. The introduction of eSET compels the embryologists to optimize their embryo selection procedure. It appears that the decision may be made in the cleavage-stage selection, and in certain circumstances blastocyst culture may facilitate identification of the most suitable embryo to maximize results without increasing the risk of twin pregnancy. In frozen embryo transfer cycles, an intact embryo after thawing is indicative for eSET suitability.
In a number of developed countries, the problems associated with multiple pregnancies have been eliminated by legal restrictions on the number of embryos that can be transferred in one ART cycle. In other parts of the world, where no legal bindings exists, the onus is on the individual clinician as well as the patient to limit the number of embryos transferred, so that an acceptable balance can be achieved between the risks associated with multiple pregnancies and a reasonable pregnancy rate with ART. It is expected that the clinics in countries lacking legislation, will be compelled by medico-legal, financial and moral obligations to restrict the number of embryos transferred in order to minimize the risks of multiple pregnancy.
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Table I: Randomized and cohort studies comparing the pregnancy rates (PR) and twins with SET & DET.
Table II: Pregnancy rates (PR) with fresh and frozen ART cycles with SET & DET.