Would legislation imposing single embryo transfer be a feasible way to reduce the rate of multiple pregnancies after IVF treatment?

Pia Saldeen1,2 and Per Sundström1

1 IVF Clinic CURA, Malmö, Sweden

2 To whom correspondence should be addressed at: IVF Clinic CURA, Box 237, S-200 74 Malmö, Sweden. or Email: pia.saldeen{at}curakliniken.se


    Abstract
 Top
 Abstract
 Introduction
 Discussion
 References
 
Due to increased maternal and fetal risks, there is a strong opinion in favor of single embryo transfer (SET) in order to reduce the high multiple pregnancy rate after IVF. We have evaluated the effects on pregnancy rate and twinning of recent Swedish legislation on SET. The study comprised three embryo transfer (ET) periods: period I, autumn 2001–spring 2002 (n=609), with a double embryo transfer (DET) policy; period II, autumn 2002 (n=320), a transitional period; and period III, January–September 2003 (n=433), with a SET policy. During the three periods, the SET rates were 25.1, 55.5 and 72.7%, respectively (Kruskal–Wallis test P<0.0001). There was no difference in clinical pregnancy rates (33.3, 32.8 and 37.4%, respectively) (P=0.4), but the twinning rate was significantly lower in the third period (6.2 versus 22.6% in period I and 16.3% in period II) (P<0.005). After introducing a SET policy, the expected decline of twinning was met at an unchanged clinical pregnancy rate. Thus, the SET legislation had no negative consequences for the couples. On the contrary, the lower rate of twinning is expected to reduce the severity and rate of pregnancy complications after IVF. Whether legislation or voluntary SET is the most feasible way to proceed, in order to reduce the multiple pregnancy rates after IVF, can be debated.

Key words: elective single embryo transfer/IVF/pregnancy rate/twin pregnancy rate


    Introduction
 Top
 Abstract
 Introduction
 Discussion
 References
 
Traditionally, IVF treatment is associated with a high incidence of multiple pregnancies. The obvious reason for this is the common practice of transferring more than one embryo. On a worldwide perspective, almost 50% of IVF children are the outcome of multiple pregnancies (ESHRE Task Force on Ethics and Law, 2003Go). In Europe, the overall rate of multiple pregnancies in 1999 was 26.3%, the majority being twins (Nygren and Andersen, 2002Go). In Sweden, with a double embryo transfer (DET) policy, the corresponding figure since 1994 has been ~24%.

Multiple pregnancies are considered to be the major problem after IVF treatment, with increased risks for both mother and child compared with singleton pregnancy. Due to an increased risk of hypertensive disorders, tocolytic therapy, anaemia, complicated delivery and postpartum haemorrhage in multiple pregancy (Blickstein, 1997Go; Senat et al., 1998Go; ESHRE Capri Workshop Group, 2000Go; Gurewitsch, 2001Go; Wennerholm, 2003Go), the maternal mortality and morbidity are increased. The main neonatal risks are associated with preterm birth and low birth weight (Tallo et al., 1995Go; Moise et al., 1998Go; Bergh et al., 1999Go; Wennerholm and Bergh, 2000Go; Koivurova et al., 2002aGo; Schieve et al., 2002Go).

The high incidence of multiple births and the maternal characteristics, but not the IVF technique per se, are the main factors influencing the adverse outcome after IVF treatment (Bergh et al., 1999Go; Koivurova et al., 2002bGo). Logically, combating the high multiple pregnancy rate would then result in a lower rate of perinatal complications. The DET technique has long been a general policy in Sweden. However, after encouraging reports on the success rate with elective single embryo transfer (eSET) (Gerris et al., 1999Go, 2002Go; Vilksa et al., 1999Go; De Neubourg et al., 2002Go; De Sutter et al., 2003Go; Tiitinen et al., 2003Go), and after demands from neonatologists and also for economical reasons (Wölner-Hanssen and Rydhström, 1998Go), the Board of Chairmen in the South Swedish Health Care Region, in 2002, decided that all IVF treatments offered by public health care should be performed as SETs, unless special circumstances (i.e. poor embryo quality) would justify DET. Moreover, on January 1, 2003, the Swedish National Board of Health and Welfare, for the same reasons as above, released a general decree that all IVF treatments should be SETs, with the exception that two embryos may be transferred if the risk for twinning is considered to be low.

SET by legislation is a drastic act to be taken but was regarded necessary by the community since no voluntary agreement had been reached. It was expected that the multiple pregnancy rates would be reduced, but the question was whether or not the overall pregnancy rate would be negatively affected after introduction of SET on a non-voluntary basis. In this report, we have analysed the outcome in terms of pregnancy rate and twinning rate from the first 14 months of SET policy by legislation. Since it was not possible to perform randomization, the data are compared with historical controls from the 12 months preceding initiation of the SET policy.

Comparative study periods
Approximately three-fifths of the IVF cycles at the IVF Clinic CURA are performed on public patients and two-fifths on private patients. Only couples with the female partner under the age of 38 years at initiation of the first treatment cycle and who had no children together are accepted for public treatment.

A consecutive series of fresh embryo transfers (ETs) was divided into three time periods, depending on which ET policy was in force. During the study period, a total of 1362 fresh ETs (from 1641 ovum pick-ups and 1728 started cycles) were performed. All women undergoing transfer of fresh embryo(s) were included in the analysis. During period I (August 2001–June 2002), 609 ETs were performed and the DET policy was in force. Period II (August–December 2002) was a transitional period when two embryos were transferred to most private patients while all new public patients received only one embryo. A total of 320 ETs were performed during this period. During period III (January–September 2003), the eSET transfer policy was in force and 433 ETs were performed. SET was performed either as an elective or non-elective procedure: eSET was defined as an SET when two or more transferable embryos were available for transfer but only one was transferred. Non-eSET was defined as when no more than one embryo was available for ET. During the last study period, SET was in force. However, under certain circumstances (poor embryo quality, female age >39 years, ≥3 previously failed ET cycles), DET was also allowed during 2003.

IVF/ICSI procedures
For the initiation of the IVF treatment, all women with no contraindication to estrogen were given oral contraceptive pills (Follimin®, containing 30 µg of ethinylestradiol and 150 µg of levonorgestrel). For downregulation, buserelin (Suprecur® nasal spray; Hoechst AG, Frankfurt, Germany, 0.3 mg four times daily) was started on day 21 in the contraceptive pill cycle. A minority were treated with Cetrorelix (Cetrotide®; 0.25 mg). For ovarian stimulation, recombinant FSH (Gonal F®; Laboratories Serono, Geneva, Switzerland or in a few patients Puregon®; Organon, The Netherlands) in daily doses ranging from 75 to 450 IU was used. Oocyte maturation was induced with recombinant or urinary HCG (250 µg Ovitrelle® s.c. or 10 000 IU Profasi® s.c.; Laboratories Serono, Geneva, Switzerland) when the leading follicles were 18–20 mm in diameter and ovum pick-up was scheduled 36 h later. Oocyte retrieval was performed vaginally under ultrasound guidance under general anaesthesia (fentanyl 1 µg/kg and propofol 2–3 mg/kg i.v.).

Medicult®, Jyllinge, Denmark, or Vitrolife®, Gothenburg, Sweden was used for culture.

For standard IVF, groups of a maximum of five oocytes were inseminated with 200 000 motile swim-up sperm in individual 500 µl volume droplets of medium under mineral oil and incubated overnight. ICSI was performed using an Eppendorf ICSI apparatus and oocytes were incubated further as above. Inclusion criteria for ICSI were low sperm count (<1 x 106 sperm/ml after preparation) or low motility (<3 on a subjective scale of 1–4) or previously failed fertilization after standard IVF.

Embryo grading and transfer
ET in 80% of patients was performed on day 2 and in 20% on day 3 (on Monday when ovum pick-up was performed on a Friday). Selection and grading of pre-embryos for transfer was based on a morphological evaluation of pre-embryos under a light microscope (Olympus CK 2) at x200 magnification and performed by either of the authors throughout the study period. Pre-embryos were graded according to the total number of blastomeres, degree of cytoplasmatic fragmentation (0=0%, 1=10–19%, 22–30%, 3≥30%), visible nucleus/nuclei in each blastomere, equal sized blastomeres or not and symmetric cleavage or not. A pre-embryo was regarded to be of top quality if, on day 2, the following criteria were fulfilled: four cells, <20% fragmentation, equally sized and symmetrically arranged blastomeres, and no signs of multinucleation. Pre-embryos cultured to day 3 were scored as of top quality when eight equal sized and symmetrical blastomeres with <20% fragmentation were present.

ET was performed with a Sydney IVF catheter (K-JETS-7019-SIVF, COOK® Australia) or Edwards-Wallace replacement catheter (Smiths Medical, Hythe, Kent, UK).

For luteal phase support, natural micronized progesterone pessaries 400 mg TID (Apoteksbolaget, Stockholm, Sweden) were used. A urinary pregnancy test (HCG urine test, Abbot Laboratories, Diagnostics Division, Abbot Park, IL) was performed 18 days after oocyte retrieval. Clinical pregnancy was defined as vaginal ultrasound verification of gestational sac/sacs at 7 weeks of gestation. Viable pregnancy was defined as ultrasonographically visible embryonic heartbeats at 7 weeks of gestation.

Statistical analysis
Statistical analyses were performed with the {chi}2 test and the Kruskal–Wallis test. The odds ratio (OR) with 95% confidence interval (CI) was calculated for risk estimation. A two-tailed P of <0.05 was considered statistically significant. The statistical analyses were performed with the aid of StatView® (SAS Institute, Cary, NC) and MedCalc® (MedCalc Software, Mariakerke, Belgium) computer software.

Demographic characteristics in the three study periods
The three study periods were similar regarding demographic characteristics (Table I). ICSI was performed in 50% of the cycles, which is the same as the average ICSI rate in the country, and there was no difference regarding the ICSI/IVF ratio between the periods.


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Table I. Maternal demographic characteristics

 
Embryo transfer and pregnancy rates in the three study periods
No difference was found in the average embryo morphological scores of the embryo chosen for ET between the study periods. For day 2 transfers, the embryos that were transferred had a mean number of 3.96 (2–6) blastomeres in period I and 3.93 (2–7) and 3.97 (2–7) in periods II and III, respectively. For day 3 transfers, the mean numbers of blastomeres were 6.88 (4–10), 7.18 (5–9) and 7.5 (4–10), respectively, in the three periods. The number of oocytes retrieved per patient was higher during period I than during period III, 11.0 (1.0–44.0) versus 9.0 (1.0–36.0) P<0.0001. Also, the proportion of first treatment cycles was higher during period I (46%) than during periods II and III (24 and 34%, respectively).

The SET rate, the clinical pregnancy rate, the ongoing pregnancy rate and the multiple pregnancies rate are shown in Table II. The overall clinical and viable pregnancy rates were constant during the periods, with a viable pregnancy rate of ~30%/ET. The SET rate was 25.1% during period I, with the majority of the transfers being non-eSETs (54.8%). eSET constituted 11.5% of all ET cycles during this period. The SET rate increased to 72.7% during period III, and the majority of these were eSETs (222 out of 315=70.5%) (Table III). eSET constituted 51% (222 out of 433) of all ETs during period III.


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Table II. Details on embryo transfer and pregnancy

 

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Table III. Single embryo transfers during the three periods

 
The clinical and the viable pregnancy rate among elective SETs during period III was 45.0% (100 out of 222) and 41.0% (91 out of 222), respectively. The corresponding figures among those with non-eSET during the same period were 22.6% (21 out of 93) and 20.4% (19 out of 93). The mean number of embryos transferred decreased from 1.85 (SD 0.69) in period I to 1.45 (SD 0.50) in period II and 1.27 (SD 0.45) in period III. The implantation rate increased from 22.6 to 25.8 and 30.3% during the three periods. The viable multiple pregnancy rate decreased from 22.6% (41 out of 181) in period I to 6.2% (nine out of 146) in period III (OR 0.21, 95% CI 0.10–0.47).

Ongoing pregnancy related to embryo morphology
in period III

The scoring of the embryo quality in relation to cycle outcome during period III was analysed separately and is illustrated in Table IV. There was no difference in viable pregnancy rate (40%) when one top quality embryo was transferred compared with that when two top quality embryos were transferred. However, the viable multiple pregnancy rate in the latter group was 35%. In ET cycles where embryos were classified as of not top quality, the pregnancy rate in the SET group was 18% and in the DET group 15%. In a subgroup of patients, who on day 2 had transfer of a 4-cell embryo, in which each blastomere showed a single nucleus, the clinical pregnancy rate was 51% (71 out of 139).


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Table IV. Clinical and ongoing pregnancy at 7 weeks of gestation related to embryo morphology and to number of embryos transferred during period III

 
The effects of legislation
By the introduction of a mandatory SET policy, the SET rate increased from 25 to 73% over a period of 14 months, and the multiple pregnancy rate decreased from 23 to 6%. Meanwhile, the clinical pregnancy rate per embryo transfer remained unchanged at 33–37%. For obvious reasons, we had no other option but to accommodate the imposed legislation. Therefore, no other study design other than retrospective with historical controls was possible.

There was no change in handling techniques or equipment at ovum pick-up during the study period. Neither was the ovarian stimulation protocol altered over the study periods, and therefore there was no deliberate aim towards a softer stimulation policy when the SET policy was introduced. For an unknown reason, the number of oocytes at retrieval was decreased during periods II and III. Further, the proportion of first treatment cycles was higher during period I than during periods II and III. However, there is no reason to believe that these differences had a negative impact on the pregnancy rates during periods II and III.


    Discussion
 Top
 Abstract
 Introduction
 Discussion
 References
 
The most reasonable way to solve the problem of the high incidence of multiples after IVF is to shift from a policy with multiple embryos for transfer to a policy with the majority of transfers performed as SETs. However, the physicians', and thereby also the patients' fear of a less successful pregnancy rate with SET may then be an obstacle. This fear seems not to be justified, since reports from Finland and Belgium have shown unchanged pregnancy rates after transfer of only one embryo (Gerris et al., 1999Go, 2002Go; Vilska et al., 1999Go; Martikainen et al., 2001Go; De Neubourg et al., 2002Go; De Sutter et al., 2003Go). Furthermore, Tiitinen et al. (2003)Go recently reported on the successful implementation and adaptation of a SET policy where eSET gradually was adopted on a voluntary basis into the programme over a period of 5 years, and where eSET represented 56% of the cycles at the end of the period. The overall clinical pregnancy rate in their eSET group was 34.5%. Our analysis confirms their results, with a total SET rate of 73%, an eSET rate of 51% of all ETs, and a clinical pregnancy rate of 45% in the eSET group during period III even though our SET design was on a non-voluntary basis.

Currently, the rate of SET is 80% of all fresh ETs at our clinic, with the majority of them being eSET. However, the mean female age during the study period was 33 years and only 5% were 40 years or older. At IVF clinics with a larger proportion of ‘elderly’ women, the proportion of SETs would most probably be lower.

Future prospects for reducing multiple pregnancies
Initially, we experienced resistance from the couples to the SET policy. However, over a few months after the SET legislation came into force, an increasing compliance was obtained. This was probably not due to the decree as such, but rather to more thorough and careful counselling regarding the increased risks with multiple pregnancies. Furthermore, additional treatments from frozen–thawed cycles can motivate the couples to freeze additional embryos rather than risk a twin pregnancy after DET. Results from freezing–thawing from the periods in our report can, however, not be presented yet since there is an agreement for public patients to have three consecutive fresh IVF cycles before considering frozen–thawed embryos (paid for privately) and only a few of the patients from period III could therefore be included in a presentation of results.

In an attempt to promote SET, Hazekamp et al. (2000)Go have suggested the use of a new IVF treatment outcome measure, namely the ‘birth per embryo transferred’ rate. We cannot yet report this figure, since many pregnancies are still ongoing. However, the rate for viable pregnancies per embryo transferred was 17% during period I with a DET policy and 26% during period III with an SET policy. Recently, an even more strict formula for calculating the ‘true’ success rate was suggested by Min et al. (2004)Go. The authors propose that delivery of a live baby in a single, term gestation per started IVF cycle (BESST) is the most relevant standard of success, in order to emphasize that multiples should be regarded as failures of IVF. Thus, with these new outcome measures, multiples will not contribute to success but rather to failure.

Intuitively, by reducing the proportion of multiple pregnancies, the overall neonatal morbidity in children conceived with IVF technology will most probably be reduced, but this remains to be demonstrated. However, in an attempt to achieve this goal, the first step is to apply SET on a broad scale. In this study, we add to other studies showing that it is possible, even in a non-voluntary SET design, to reduce the twinning rate substantially and at the same time to maintain a high pregnancy rate by applying SET in the vast majority of patients in an ordinary IVF programme. It is therefore our belief that comparable results can also be achieved in other IVF centres with a similar population of patients.

There seems to be a consensus within the IVF community on an urgent need for a reduction in the number of multiple pregnancies after IVF, and a growing number of debate articles have been published on the subject in recent years. The only solution to reduce the number of multiple gestations is by a substantial increase in SETs. Whether a change in transfer policy can be achieved on a voluntary basis or if legislative measures, as in Sweden, will be needed remains to be debated.


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 Abstract
 Introduction
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Submitted on March 1, 2004; resubmitted on June 28, 2004; accepted on October 15, 2004.





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