Avoiding multiple pregnancies in ART: consideration of new strategies

To maximize pregnancy rates, physicians who perform IVF, often transfer multiple embryos, which increases the multiple birth risk. Multiple birth infants are at significant risk for a number of adverse outcomes including preterm delivery, low birth weight, congenital malformations, fetal and infant deaths and long term morbidity and disability among survivors. Since the ultimate goal for an IVF treatment is the birth of a healthy infant, an important issue for all kinds of assisted reproductive technologies (ART) must be the reduction or elimination of multiple pregnancies. In this article, different strategies to avoid multiple births in ART are discussed.     

Number of embryos for transfer after IVF and ICSI: a Cochrane review

BACKGROUND: The most common complication of IVF is multiple pregnancy, which occurs in 25% of pregnancies following the transfer of two embryos. Single embryo transfer can minimize twin pregnancies but could also lower live birth rates. Our aim was to perform a systematic review of randomized trials to determine the effectiveness of single versus double embryo transfer. METHODS: Cochrane Collaboration review methods were followed. Randomized controlled trials comparing single and double embryo transfers were identified by searching Medline, EMBASE and the Cochrane register of controlled trials. Contents of specialist journals and proceedings from meetings of relevant societies were hand searched. Data were pooled with Rev Man software using the Peto-modified Mantel-Hanzel method. RESULTS: Pooled results from four trials indicate that although double embryo transfer leads to a higher live birth rate per woman [odds ratio (OR) 1.94, 95% confidence interval (CI) 1.47-2.55] in a fresh IVF cycle, comparable results are obtained by subsequent transfer of a frozen embryo (OR 1.19, 95% CI 0.87-1.62). The multiple pregnancy rate is significantly higher (OR 62.83, 95% CI 8.52-463.57) after double embryo transfer. CONCLUSIONS: Single embryo transfer significantly reduces the risk of multiple pregnancy, but also decreases the chance of live birth in a fresh IVF cycle. Subsequent replacement of a single frozen embryo achieves a live birth rate comparable with double embryo transfer.     

Avoiding multiple pregnancies in ART: multiple pregnancies: a test case for the moral quality of medically assisted reproduction

Although most professional societies have issued guidelines to diminish the number of embryos to be transferred during assisted reproduction techniques, the incidence of multiple pregnancies remains unacceptably high. The negative psychological, social and medical consequences for the patients and their offspring easily outweigh the benefits in terms of increased success rates. Multiple pregnancies would never be tolerated if the 'best interest of the child' standard was applied as strictly to these consequences, as it is to controversial family forms. The persistence of high multiple pregnancy rates is largely due to the pressure brought to bear on the physicians to increase the overall success rate. The fertility specialist should inform the patients about the risks and benefits of a multiple transfer but ultimately the specialist should decide how many embryos to transfer. Multifetal reduction is an ethically acceptable solution if, and only if, the physician has taken all reasonable steps to prevent the occurrence of a multiple pregnancy. Finally, an additional strategy to decrease the incidence of multiple pregnancies is proposed, i.e. to extend the professional responsibility of the fertility specialist to all steps of procreation including pregnancy, birth and neonatal care.     

Prevention of twin pregnancies after IVF/ICSI by single embryo transfer. ESHRE Campus Course Report

Twin pregnancies constitute the most serious complication for both mother and children after IVF/ICSI treatment, but transfer of at least two 'best looking' embryos remains the standard policy. This is due to our inability and reluctance to identify both the 'twin prone' patient and the top quality embryo. Some centres now electively transfer a single embryo (eSET) when particular embryo quality and patient criteria are met. Results from several centres were presented during an ESHRE Campus Course, held on May 6(th) 2000. Sound clinical trials are needed to clarify several points of discussion. What is the clinical profile of patients in whom eSET should be considered? Will the overall (ongoing) pregnancy rate of the IVF/ICSI programme decrease if eSET is performed in these patients? What is the twinning rate when eSET is a routine policy? Will the financial gain by avoiding perinatal hospitalization costs of prevented twins be balanced by the likely need to perform a number of extra IVF/ICSI cycles? What will be gained by freezing the extra number of high quality embryos? Should eSET be performed at the 2 pronuclear stage, the early cleaving embryo or the blastocyst stage? Common sense dictates that eSET as a concept should be applied from now onwards.     

Patient attitudes towards twin pregnancies and single embryo transfer - a questionnaire study

BACKGROUND: The present trend towards selective single embryo transfer (SET) calls for evaluation of patient attitudes towards twins and how the patients balance advantages and disadvantages of one or two embryos in IVF/ICSI treatment. METHODS: The study was conducted in a Danish public fertility clinic, where the common practice was double embryo transfer (DET), and the number of reimbursed treatments was limited to three. Referred patients were given oral and written information about the IVF/ICSI treatment including twin probability following DET and the risk of preterm delivery and neonatal complications associated with twins. In order to evaluate patients and partners attitudes towards twins and SET, an anonymous survey was conducted, and 588 couples were invited to participate. RESULTS: Four hundred and fourteen women (70.4%) and 404 men (68.7%) answered the questionnaire adequately for analysis. About 58.7% preferred having twins to having one child at a time (37.9%). Primary reasons for preferring twins were desire for siblings (23.3%), a positive attitude towards twins (22.5%), and a wish to minimize physical and psychological stress through having as few IVF treatments as possible (19.3%). Economic considerations were not important. CONCLUSIONS: Obligatory single embryo policy would be in conflict with patient interests and wishes. More carefully prepared information seems to be needed. The challenge consists in balancing clinical considerations with unbiased information on twin pregnancy, respecting patient autonomy and enabling informed decision-making.     

Modelling the impact of single embryo transfer in a national health service IVF programme

BACKGROUND: Greater use of single embryo transfer (SET) to reduce twin ratesassociated with IVF requires good information on prognosticfactors and appropriate models of treatment outcomes. METHODS: Using data from a cohort of 1198 IVF cycles, we have developeda statistical model of live birth and twin outcomes in termsof routinely measured clinical parameters. From this model,we predict potential outcomes if those who had two embryos transferredhad actually received SET. RESULTS: Embryo quality, age, FSH level, idiopathic diagnosis, spermcount, smoking and alcohol consumption are all significant factorspredicting outcome. Couples with good embryos and good prognosishave a much greater risk of producing twins. In this cohort,to achieve a 10% twin rate would require 55% SET which, withoutselection of appropriate cycles, would lead to a reduction insuccess rate from ca. 21% to 17%. Selecting on the basis oftwin risk can partially mitigate this reduction to give a successrate of 18.5%. CONCLUSIONS: The use of SET to reduce twin rates will lead to a significantreduction in treatment success. Around half this reduction couldbe mitigated with careful selection of patients and cycles,including embryo quality.     

Single embryo transfer: a mini-review

This paper provides a concise review of single embryo transfer (SET) in cycles using fresh embryos as well as in cycles using frozen-thawed embryos. Relevant studies were identified by a computerized search in PubMed for the period 1995-2004. The pregnancy rates, delivery rates and multiple pregnancy/birth rates were evaluated after fresh or frozen embryo transfer as well as cumulative delivery rates after fresh and frozen SET. The results of four randomized controlled trials (RCT) and seven observational studies using fresh embryo transfers are analysed. No RCT with SET in freezing-thawing cycles was identified, while one observational study was identified. The effects of a change in the rules from the National Board of Health and Welfare in Sweden in 2003 regarding the implementation of SET in Sweden are summarized.     

Impact of patients' choice for single embryo transfer of a top quality embryo versus double embryo transfer in the first IVF/ICSI cycle

BACKGROUND: The aim of this study was to evaluate the impact of transferring a single top quality embryo in the first IVF/ICSI cycle of patients <38 years old who chose to have one or two embryos transferred. METHODS: A total of 262 patients participated in the study, and 243 transfers were performed: 156 (64%) patients chose the transfer of a single top quality embryo, if available, and two non-top quality embryos if not available; 87 (36%) patients chose to have a double embryo transfer regardless of embryo quality. RESULTS: In the first group an ongoing pregnancy rate of 40% (63/156) with a twin pregnancy rate of 2% (1/63) was achieved. In the second group the ongoing pregnancy rate was 44% (38/87) with 26% (10/38) twin pregnancies. In the patient group with only one embryo transferred, irrespective of the patient's choice, the ongoing pregnancy rate was 43% (54/127) with no twin pregnancies. For the study population as a whole, the ongoing pregnancy rate was 42% (101/243) with 11% (11/101) twins. CONCLUSION: We conclude that the introduction of single embryo transfer in the first IVF/ICSI cycle is highly acceptable in women <38 years old.     

Impact of elective single embryo transfer on the twin pregnancy rate

BACKGROUND: It is unclear how the implementation of elective single embryo transfer in clinical practice would affect clinical pregnancy and delivery rates and multiple birth rates. METHODS: This retrospective study analysed 1871 IVF/ICSI cycles carried out from 1997 to 2001 in the IVF programme of a single university infertility clinic. RESULTS: The number of elective single embryo transfers increased from 11 to 56%. At the same time the clinical pregnancy rate was relatively stable; mean 34.0% (range 28-42). The number of embryos per embryo transfer decreased from 1.8 to 1.3. The multiple pregnancy and delivery rates dropped markedly from 25 to 7.5% and from 25 to 5% respectively. CONCLUSIONS: An elective single embryo transfer programme can be adopted in daily practice that decreases the twinning rate to <10% and does not affect the overall pregnancy rate.     

Randomized single versus double embryo transfer: obstetric and paediatric outcome and a cost-effectiveness analysis

BACKGROUND: Transfer of several embryos after IVF results in a high multiple birth rate associated with increased morbidity and high costs for the neonatal care. In a previous randomized trial we demonstrated that a single embryo transfer (SET) strategy, including one fresh single embryo transfer and, if no live birth, one additional frozen-thawed SET, resulted in a live-birth rate that was not substantially lower than after double embryo transfer (DET) but markedly reduced the multiple birth rate. METHODS: We compared costs for maternal health care and productivity losses and paediatric costs for the SET and DET strategies. In addition, maternal and paediatric outcomes between the two groups were compared. RESULTS: The SET strategy resulted in lower average total costs from treatment until 6 months after delivery. There were a few more deliveries with at least one live-born child in the DET group. The incremental cost per extra delivery in the DET alternative was high, 71 940. The rates of prematurely born and low birthweight children were significantly lower with the SET strategy. There were also markedly fewer maternal and paediatric complications in the SET group. CONCLUSIONS: The SET strategy is superior to the DET strategy, when number of deliveries with at least one live-born child, incremental cost-effectiveness ratio and maternal and paediatric complications are taken into consideration. The findings do not support continuing transfers of two embryos in this group of patients.     

Single embryo transfer is an option in frozen embryo transfer

BACKGROUND: A good strategy to decrease multiple pregnancy rate in assisted reproduction technology (ART) is the use of single embryo transfer (SET). METHODS: This retrospective study analysed 1647 frozen embryo transfers carried out during 1998-2003 in Helsinki University Central Hospital; of these, 872 were double embryo transfers (DETs) and 775 SETs. The SET group included 140 (18.1%) elective SETs (eSETs). RESULTS: The yearly rate of SETs in frozen cycles increased from 28 to 66%. Overall, the clinical pregnancy rate per frozen embryo transfer was 30.7% and the delivery rate 22.6%. The delivery rate was significantly higher in DET cryocycles than in SET cryocycles (25.7 versus 19.2%, respectively; P < 0.01). In DET cryocycles, the multiple delivery rate was 21.9%, 10 times higher than that observed in cryocycles with SET (2.0%) (P < 0.0001). When eSET was applied, no difference in delivery rate was observed when compared with cryocycles with DET (28.6 and 25.7%, respectively). CONCLUSIONS: SET can be used in frozen cycles to reduce multiple delivery rates.     

Day 2 elective single embryo transfer in clinical practice: better outcome in ICSI cycles

BACKGROUND: Single embryo transfer (SET) after IVF/ICSI has been shown to result in an acceptable pregnancy rate in selected subjects. In our unit, SET is routinely carried out among women under the age of 36 in the first or second treatment cycle when a top-quality embryo is available. In order to define further the selection criteria for SET, we have analysed the outcome of elective SET (eSET), including the cumulative pregnancy rate after frozen embryo transfers, performed in the years 2000-2002 in the Oulu Fertility Center. METHODS: During the study period, a total of 1271 transfers were performed, and in 468 cycles SET (39% of all transfers) was carried out. Of the SET cycles, in 308 cases a top-quality embryo was transferred on day 2 and extra embryos were frozen. Of these eSET cycles, ICSI was carried out in 87 cycles (28%). RESULTS: The overall clinical pregnancy rate per transfer was 34.7% in the eSET cycles. In the eSET ICSI cycles, the clinical pregnancy rate was significantly higher than in the corresponding IVF cycles (50.6 versus 28.5%, P < 0.001). The cumulative pregnancy rate per patient after fresh and frozen embryo transfers was also significantly higher after ICSI (71.2 versus 53.4%, P < 0.01). CONCLUSIONS: A high cumulative pregnancy rate per oocyte retrieval can be achieved after eSET in daily clinical practice. The implantation rate of fresh top-quality embryos in the ICSI cycles was significantly higher than in the IVF cycles, possibly due to more successful selection of the embryo for embryo transfer on day 2 after ICSI. In addition, our data suggest that embryo quality is a more important determinant of outcome than the age of the woman.     

Babies born after ART treatment cost more than non-ART babies: a cost analysis of inpatient birth-admission costs of singleton and multiple gestation pregnancies

BACKGROUND: Currently, about one-third of infants born after assisted reproductive technology (ART) worldwide are twins or triplets. This study compared the inpatient birth-admission costs of singleton and multiple gestation ART deliveries to non-ART deliveries. METHODS: A cohort of 5005 mothers and 5886 infants conceived following ART treatment were compared to 245 249 mothers and 248 539 infants in the general population. Birth-admission costs were calculated using Australian Refined Diagnosis Related Groups and weighted national average costs (2003-2004 euro). RESULTS: ART infants were 4.4 times more likely to be low birthweight (LBW) compared with non-ART infants, translating into 89% higher birth-admission costs (euro2,832 and euro1,502, respectively). ART singletons were also more likely to be LBW compared with non-ART singletons, translating into 31% higher birth-admission costs (euro1,849 and euro1,415, respectively). After combining infant and maternal admission costs, the average cost of an ART singleton delivery was euro4,818 compared with euro13 890 for ART twins and euro54 294 for ART higher order multiples. Findings were not sensitive to changes in casemix. CONCLUSIONS: The poorer neonatal outcomes of ART singletons compared with non-ART singletons are significant enough to impact healthcare resource consumption. The high costs associated with ART multiple births add to the overwhelming clinical and economic evidence in support of single embryo transfer.     

In unselected patients, elective single embryo transfer prevents all multiples, but results in significantly lower pregnancy rates compared with double embryo transfer: a randomized controlled trial

BACKGROUND: Elective single embryo transfer (eSET) in a selected group of patients (i.e. young patients with at least one good quality embryo) reduces the number of multiple pregnancies in an IVF programme. However, the reduced overall multiple pregnancy rate (PR) is still unacceptably high. Therefore, a randomized controlled trial (RCT) was conducted comparing eSET and double embryo transfer (DET) in an unselected group of patients (i.e. irrespective of the woman's age or embryo quality). METHODS: Consenting unselected patients were randomized between eSET (RCT-eSET) (n = 154) or DET (RCT-DET) (n = 154). Randomization was performed just prior to the first embryo transfer, provided that at least two 2PN zygotes were available. Non-participants received our standard transfer policy [SP-eSET in a selected group of patients (n = 100), otherwise SP-DET (n = 122)]. RESULTS: The ongoing PR after RCT-eSET was significantly lower as compared with RCT-DET (21.4 versus 40.3%) and the twin PR was reduced from 21.0% after RCT-DET to 0% after RCT-eSET. The ongoing PRs after SP-eSET and SP-DET did not differ significantly (33.0 versus 30.3%), with an overall twin PR of 12.9%. CONCLUSION: To avoid twin pregnancies resulting from an IVF treatment, eSET should be applied in all patients. The consequence would be a halving of the ongoing PR as compared with applying a DET policy in all patients. The transfer of one embryo in a selected group of good prognosis patients leads to a less drastic reduction in PR but maintains a twin PR of 12.9%.     

Elective single embryo transfer (eSET) policy in the first three IVF/ICSI treatment cycles

BACKGROUND: Elective single embryo transfer (eSET), applied in the first or second IVF cycle in young patients with good quality embryos, has been demonstrated to lower the twin pregnancy rate, while the overall pregnancy rate is not compromised. It is as yet unclear whether eSET could be the preferred transfer policy in all treatment cycles, or that it should be restricted to the first or first two cycles. METHODS: eSET policy (when two or more embryos were available, at least one of them being of good quality) was offered to patients younger than 38 years in the first three treatment cycles. Retrospectively, treatment cycle outcome was studied. RESULTS: In 326 patients, 586 treatment cycles were performed (326 first, 168 second and 92 third treatment cycles). In 65 cycles (11%), eSET could not be applied because there was either no fertilization, or only one embryo available. In the remaining 521 cycles, eSET was performed in 111 cycles (19%), while in 410 cycles, no good quality embryo was available resulting in the transfer of two embryos (double embryo transfer, DET). No significant differences in ongoing pregnancy rates after transfer of fresh embryos were observed between eSET and DET in the first (both 33%), second (36 and 23%, respectively) and third treatment cycles (20 and 24%, respectively). In significantly more eSET cycles compared to DET cycles, could embryos be frozen. This resulted in a significantly higher cumulative pregnancy rate after eSET compared to DET. CONCLUSIONS: In patients younger than 38 years with at least one top quality embryo, eSET can be the transfer policy of choice in at least the first three treatment cycles, since the pregnancy rates obtained in each treatment cycle are comparable to those after DET.     

Two cycles with single embryo transfer versus one cycle with double embryo transfer: a randomized controlled trial

BACKGROUND: With the aim of reducing the number of multiple pregnancies after IVF we investigated the effectiveness of two cycles with single embryo transfer (SET) and one cycle with double embryo transfer (DET) after IVF and calculated the cost-effectiveness of both strategies. Methods: A randomized controlled trial was performed in 107 women, aged <35 years, in their first IVF cycle, with at least one good quality embryo. They were randomized to the SET (n = 54) or DET (n = 53) group using a computer-generated random block number table, stratified for primary or secondary infertility. RESULTS: The cumulative live birth rates per woman randomized of two consecutive cycles of SET [41%; 95% confidence interval (CI) 27-54] versus one cycle of DET (36%; 95% CI 23-49) were comparable, whereas the multiple pregnancy rate was significantly higher: 37% (95% CI 15-59) in the DET and 0% in the in the SET group (P = 0.002). Combining the medical costs of the IVF treatments (where 1.5 more SET cycles were required to achieve each live birth) and of pregnancies up to 6 weeks after delivery, the total medical costs of DET per live birth were 13,680 and 13,438 for SET. CONCLUSIONS: Two cycles with SET were equally effective as one cycle with DET, and the medical costs per live birth up to 6 weeks after delivery were the same. However, if lifetime costs for severe handicaps are included, more than 7000 per live birth will be saved after implementing SET. Because of the high probability of multiple pregnancies in this group of IVF patients, only SET should be performed.     

The relative myth of elective single embryo transfer

The option of single embryo transfer (SET) has recently dominated the pages of this and other medical journals. Opinions, in regards to the utility of such an approach, appear to differ between Europe and the US. While US guidelines promote a more individualized approach, European opinions, at times, even advocate mandated practice patterns. The European approach, however, fails to recognize the rather significant differences in supportive arguments between the historical switch from multiple embryo transfers to 2-embryo transfers and the current discussion, favouring a switch from 2-embryo transfer to elective (e)-SET. In the former, a significant risk of (at times, high-order) multiple pregnancies was reduced without loss of pregnancy potential. In the latter, a comparably relatively low twinning risk is reduced at the expense of declining pregnancy rates, a need for more treatment cycles, a potential delay in treatment success and, potentially, higher treatment costs. These consequences of e-SET, together with the preference of some infertility patients to actually conceive twins, raise serious questions about the wide utilization of e-SET, as has been propagated by many authorities. According to US guidelines, e-SET, therefore, appears to represent an appropriate transfer option for only a small minority of IVF patients. Argument in favour of indiscriminate SET appears unrealistic and should be reconsidered.     

Characterization of a top quality embryo, a step towards single-embryo transfer.

In most in-vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI) programmes approximately one ongoing pregnancy in three is multiple. The need to characterize embryos with optimal implantation potential is obvious. We retrospectively examined all of 23 double transfers resulting in ongoing twins, occurring between January 1, 1996 and May 19, 1997. Characteristics of these top quality embryos were absence of multinucleated blastomeres, four or five blastomeres on day 2, seven or more cells on day 3, and 2 embryos, 11/31 (35%) were multiple. We applied our top quality criteria to the 221 double transfers: 106 transfers with two top embryos resulted in 65 (63%) ongoing pregnancies with 37 (57%) twins, 65 transfers with one top embryo in 38 (58%) ongoing pregnancies with eight (21%) twins. In the group without top embryos, 12/52 (23%) ongoing singletons occurred, with no twins. The corresponding ongoing implantation rates were 49, 35 and 12%. This analysis suggests that single embryo transfer with an acceptable pregnancy rate might be considered if a top quality embryo is available.     

Trends in embryo transfer practices and multiple gestation for IVF procedures in the USA, 1996-2002

BACKGROUND: Increasing use of IVF in the USA has been a major contributor to the rising national multiple birth rate. Many have advocated that reducing the number of embryos transferred is essential for addressing the IVF-associated multiple birth problem. METHODS: A population-based sample of 506 072 IVF transfers performed in the USA in 1996-2002 was used to investigate trends in embryo transfer practices and to determine whether any changes in practice patterns have impacted the multiple gestation risk associated with IVF. RESULTS: The proportion of procedures in which >or=3 embryos were transferred declined significantly for most patient groups between 1996 and 2002. However, declines for some groups were not sizeable (from 79 to 73% and from 76 to 71% for fresh, non-donor procedures among women aged 38-40 and 41-42 years respectively) and transferring >or=3 embryos remained the norm for all groups. As of 2002, single embryo transfer had not increased for most groups and remained uncommon. Some declines in overall multiple gestation rates were observed, although multiple gestation risk associated with 2 embryos transferred increased significantly for all groups. CONCLUSIONS: Despite changes in embryo transfer practices, multiple gestation risk remains high, in part due to increased multiple gestation rates associated with the transfer of two embryos.     

Obstetric and neonatal outcome after single embryo transfer

BACKGROUND: Single embryo transfer (SET) pregnancies practically lack vanishing twins and may be associated with improved neonatal outcome. Our objective was to compare the obstetric and neonatal outcome of SET singletons with the outcome of singletons following double embryo transfer (DET) and spontaneous conception. METHODS: A 7-year (1997-2003) cohort of fresh SET (n = 269) and DET (n = 230, including 25 vanishing twins) cycles resulting in singleton birth at Helsinki University Central Hospital, Finland, was linked to the Finnish Medical Birth Register and the obstetric and neonatal outcome data compared with that from 15 037 spontaneously conceived singleton pregnancies. RESULTS: The obstetric and neonatal outcome of the SET group was comparable to that in the DET group. Compared with the comparison cohort, gestational hypertension (P = 0.005), placenta praevia (P < 0.001), preterm contractions (P = 0.01) and maternal hospitalization (P < 0.001) was more typical of women in the SET group. After adjusting for age, parity and socio-economic status the SET pregnancies showed increased risks of Caesarean section [odds ratio (OR) 1.54 with 95% confidence interval (CI) 1.18-2.00], preterm birth (OR 2.85; 95% CI 1.96-4.16) and low birthweight (OR 2.01; 95% CI 1.19-3.99) compared with the comparison cohort. CONCLUSIONS: Our results indicate that subject- and infertility-related mechanisms other than the number of transferred embryos influence the neonatal outcome of singleton IVF pregnancies.