Hum. Reprod. Advance Access originally published online on June 19, 2006
Human Reproduction 2006 21(10):2633-2637; doi:10.1093/humrep/del247
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Birthweight of singletons after assisted reproduction is higher after single- than after double-embryo transfer
1 Department of Obstetrics and Gynaecology, University Hospital Gent 2 Department of Applied Mathematics and Informatics, Gent University, Gent, Belgium
3 To whom correspondence should be addressed at: Department of Obstetrics and Gynaecology, University Hospital Gent, De Pintelaan 185, B-9000 Gent, Belgium. E-mail: petra.desutter{at}ugent.be
* These authors contributed equally to this article.
 |
Abstract |
|---|
 Top Abstract IntroductionMaterials and methodsResultsDiscussionAcknowledgementReferences |
|---|
BACKGROUND: Single-embryo transfer (SET) has proven efficient in reducing multiple pregnancy rates after assisted reproduction technologies (ART). This study compares outcome of singletons after SET and double-embryo transfer (DET). METHODS: We studied 404 SET and 431 DET patients, who delivered a singleton child of >500 g after fresh embryo transfer in a first, second or third cycle. Preterm birth and low birthweight incidences and gestational age and birthweight were compared between both groups. Adjustments were made for maternal age, parity, cycle rank number, treatment indication, ART method, embryo characteristics and sex of the child. RESULTS: Singletons born after DET have a significantly lower birthweight than that after SET (3204.3 ± 617.5 g versus 3324.6 ± 509.7 g, P < 0.01). Also preterm birth (<37 weeks) [odds ratio (OR) 1.77, 95% confidence interval (CI) 1.06–2.94] and low birthweight (<2500 g) (OR 3.38, 95% CI 1.86–6.12) are significantly more common in DET singletons. CONCLUSIONS: Singleton birth after SET is advantageous compared with DET. This sheds new light on the reasons why singleton births following ART do worse than spontaneously conceived singletons in IVF programs, where double- or multiple-embryo transfer is standard.
Key words: assisted reproduction/pregnancy outcome/single-embryo transfer/singleton
|
Introduction |
|---|
|
TopAbstractIntroductionMaterials and methodsResultsDiscussionAcknowledgementReferences |
|---|
Elective transfer of one embryo in a selected population is the only effective way to reduce twin pregnancies, which is considered as the most important complication of ART (Luke and Keith, 1992
). Merely by their absolute numbers, twin pregnancies still constitute a serious medical problem (Blondel and Kaminski, 2002), leading to a high neonatal mortality and severe short- and long-term morbidity for the children (Bernasko et al., 1997; Elster, 2000).
The move from triple- to double-embryo transfer (DET), which was advocated in the late 1990s, had an impact on the reduction of triplets and children of a higher birth order but hardly affected the incidence of twin pregnancies (Staessen et al., 1993; Coetsier and Dhont, 1998; Vilska et al., 1999). The step towards single-embryo transfer (SET) was more difficult to take, because early articles studying pregnancy rates in SETs were discouraging (Elsner et al., 1997). These conclusions were biased, however, because these studies included solely patients who had only one embryo available for transfer. For this reason, a distinction should be made between elective and non-elective SET. When there is only one embryo available for transfer (non-elective), the pregnancy rate is indeed low (Dhont, 2001).
In Flanders, Belgium, the percentage of multiple pregnancies because of assisted reproduction dropped from 25% in 2002 to 11.9% in 2004 [Study Centre for Perinatal Epidemiology (SPE), 2004]. This substantial decrease in iatrogenic multiple pregnancies is because of the introduction of the Belgian law on 1 July 2003, which regulates the reimbursement of six IVF cycles up to a maternal age of 43 years (Royal Decree of 4 June 2003) under the condition that SET is performed in first cycles for all patients younger than 36 years. This unique project was the result of extensive research which showed that prevention of twin pregnancies with maintenance of a high overall pregnancy rate is possible, if one high-quality embryo is transferred to a patient with a twin-prone clinical profile, representing at least one-third of the patient population (Gerris et al., 1999; Vilska et al., 1999; Gerris et al., 2001; De Sutter et al., 2003; Tiitinen et al., 2003; Gardner et al., 2004; Martikainen et al., 2004). Reimbursement by the government was granted, because it was demonstrated that SET is a cost-effective alternative to DET, in terms of cost per live-child born (De Sutter et al., 2002; Ombelet et al., 2005).
Unfavourable outcomes of pregnancies after assisted reproduction are generally assigned to the higher incidence of twin pregnancies (Bergh et al., 1999). The implementation of an elective SET strategy and thus a reduction in twin pregnancies are expected to have a positive effect on overall pregnancy outcomes, such as preterm birth and low birthweights (Gerris and Van Royen, 2000). In their recent review, Helmerhorst et al. (2004) nevertheless showed outcomes to be worse also in singleton pregnancies after assisted reproduction, compared with spontaneous pregnancies, and this confirmed the findings in many other earlier studies (Tanbo et al., 1995; Dhont et al., 1999; Koudstaal et al., 2000; Schieve et al., 2004; Bower and Hansen, 2005). It is not clear whether this results from unfavourable patient characteristics and the infertility per se or is associated with the ART methodology. Recently, our group has shown that the perinatal outcome is not different after IVF than after intrauterine insemination, indicating that patient characteristics certainly play a role (De Sutter et al., 2005). On the contrary, we noted already in 2003 on a small series that singletons after SET had a higher birthweight than those after DET (De Sutter et al., 2003), and other authors have confirmed this finding since (De Neubourg et al., 2006; Thurin Kjellberg et al., 2006). The aim of the present study was to analyse on a larger series whether pregnancy outcome of singletons after SET is more favourable than singletons after DET.
|
Materials and methods |
|---|
|
TopAbstractIntroductionMaterials and methodsResultsDiscussionAcknowledgementReferences |
|---|
Study population
The database of the Gent University Hospital Infertility Centre was used for the present study. There are no restrictions for patients to enter the IVF/ICSI programme in this centre, except for HIV-positive patients. Patients older than 43 years are strongly advised against entering the programme. In the period 2000–2004, 5509 IVF/ICSI cycles were performed in our centre, resulting in 1386 ongoing pregnancies and 943 births of a singleton child. All patients undergoing a first, second or third IVF or ICSI cycle between 2000 and 2004 and having obtained a singleton pregnancy after fresh SET or DET, resulting in the live birth of a child of >500 g, were included. Thus, we entered 835 patients, representing 88.5% of the total patient-population who delivered a singleton child following IVF/ICSI. All patients included enjoyed equal obstetric care, irrespective of assisted reproductive method or number of embryos transferred.
Clinical and laboratory protocols
IVF and ICSI were performed according to accepted standard protocols of pituitary suppression, ovarian stimulation, oocyte retrieval, gamete handling, embryo culture techniques, embryo transfer and luteal supplementation, as was described in previous studies from our group (Laverge et al., 2001; De Sutter et al., 2003). All embryo transfers occurred at day 2 or 3 after oocyte retrieval. Patients younger than 36 years, who entered the program before 1 July 2003, were given the choice between the transfer of one (SET) or two (DET) embryos. Before that date, SET was mainly performed when the transferred embryo was of good quality, which is defined as an embryo with four or five blastomeres on day 2, seven or more blastomeres on day 7 and <20% of fragments and total absence of multinucleated blastomeres at any stage of cleavage (Van Royen et al., 1999). If no high-quality embryo was available, two embryos were transferred, if available. After 1 July 2003, legal prescriptions were followed, meaning that SET was applied at the first IVF/ ICSI attempt in patients younger than 36 years. In the second and third cycle, young patients were encouraged to undergo SET, but DET was also an option if only embryos of moderate or poor quality were available. Patients aged 36–39 years had the option to choose DET from the first and second attempt, and only exceptionally, three embryos were transferred from the third cycle on. In patients older than 39 years, no legal limit to the number of transferred embryos was imposed, but most patients received a maximum of two embryos in their first two cycles.
Data collection
Since 1992, data of each treatment cycle in our centre have been entered into a database. Numerous variables are entered, but for this study, we analysed the following: number of embryos transferred, embryo quality (scored as good, moderate or poor), cycle rank number, indication for assisted reproduction (female, male, combined or unexplained infertility), type of assisted reproductive technology (IVF or ICSI), maternal age, parity, sex of the child, gestational age and birthweight. The gestational duration was determined by subtraction of the oocyte retrieval from the date of birth and the addition of 14 days.
Data on outcome variables were collected by sending questionnaires to the patients and gynaecologists. If no reply was received, gynaecologists were approached by telephone. In this manner, a follow-up of 99% was reached.
Statistical analysis
We compared outcomes between SET and DET pregnancies, using the 
2-test for the univariate analysis of categorical outcomes (preterm birth and low birthweight) and logistic regression for the multivariate analysis. Linear regression was applied for the univariate and multivariate analysis of continuous outcomes (gestational age and birthweight). We used a forward stepwise selection method to build the multivariate models and considered adjustment for maternal age, primiparity, number of cycles, indication for assisted reproduction, type of assisted reproductive treatment, time of embryo transfer, embryo quality, compulsion to apply SET/DET and gender of the child. Two-sided P < 0.05 for differences was considered significant. The statistical package SPSS 12.0 (SPSS Inc., Chicago, IL, USA) was used to perform the analyses.
|
Results |
|---|
|
TopAbstractIntroductionMaterials and methodsResultsDiscussionAcknowledgementReferences |
|---|
Patient characteristics
Patient characteristics are described in Table I. A total of 835 women were included in the analysis; 404 patients in the SET group and 431 patients in the DET group. Women who received DET were significantly older than women who received SET (33.2 ± 4.3 versus 31.6 ± 3.5 years respectively, P < 0.001). Correspondingly, the DET group contained a significantly higher proportion of women of 35 years or older (38.1 versus 20.8%, P < 0.001). The SET group was characterized by significantly more first cycles compared with the DET group (94.3 versus 77.3%, P < 0.001). Male pathology occurred more frequently in patients with DET (P < 0.01). Consequently, ICSI was applied more often in this group, whereas IVF was more common in the SET group (P < 0.05). Transfer of the embryo on day 3 occurred significantly more frequent in the SET group (P < 0.001). Although not frequent overall, transferred embryos of poor quality were more common in the DET group (P < 0.01). The 14 DET cases with a poor average embryo score imply three cases where both embryos were of poor quality and 11 cases where one embryo was of intermediate quality and one embryo of poor quality. SET was elective in 95% of the cases, and in the other 5%, there was only one good-quality embryo available for transfer. The DET group represented a bigger proportion of compulsory DET: in 15% of the cases, only two embryos were considered appropriate for transfer (P < 0.001). No significant differences were found between both the groups for parity, Caesarean section rate, female or combined pathology as indication for treatment nor sex of the child.
|
Mean gestational age and mean birthweight
As the SET and DET groups were different for variables which are known to influence both gestational age and birthweight, we performed a multivariate analysis to compare gestational age and birthweight after adjusting for possible confounding variables. After DET, duration of gestation was on average 3 days shorter compared with SET (273.4 ± 15.0 versus 276.2 ± 10.5 days, P < 0.01) (Table II). In both the groups, patients delivered on average in the 39th gestational week. Singletons in the DET group, however, weigh on average 120 g less at birth compared with singletons in the SET group (P < 0.01). Significant interactions between variables were not found.
|
Prevalence of preterm birth and low birthweight
Table II summarizes that preterm birth [odds ratio (OR) 1.77, 95% confidence intervals (CI) 1.06–2.94] and low birthweight (OR 3.38, 95% CI 1.86–6.12) were significantly more common in singleton children conceived with DET than with SET, again after adjustment for maternal age, primiparity, cycle rank number, indication for treatment, type of assisted reproductive treatment, embryo quality and gender of the child. We found no significant interaction between variables for preterm birth and low birthweight.
|
Discussion |
|---|
|
TopAbstractIntroductionMaterials and methodsResultsDiscussionAcknowledgementReferences |
|---|
Belgian law has imposed SET in young patients since 1 July 2003. Hence, it is no longer possible to perform randomized trials comparing SET with DET in this patient group. Our study therefore is necessarily non-randomized, and this explains the clinical differences between both the groups. Indeed, logically SET patients are more often in their first treatment cycle, they are younger and have more often good-quality embryos. For some unknown reason, but because of bias inherent to non-randomized studies, there was more male infertility, and also, ICSI was more often performed in the DET than in the SET group. On the contrary, parity and sex of the child, two parameters known to influence obstetrical and perinatal outcome, were not different between the SET and DET groups. Also, we pooled first, second and third treatment cycles, because we have previously shown that pregnancy rates are not different for the first three cycles (De Vries et al., 1999
). Unfortunately, our data did not allow us to adjust for other important factors that could affect the outcome, such as BMI, smoking habits, bad obstetric history or chronic diseases of the mother.
Because of the differences in group characteristics, however, we chose to compare gestational age and birthweight using a multivariate analysis and adjusting for the aforementioned confounders. Still, a significant difference in birthweight of 120 g was found. This perfectly matches with the difference we observed in a preliminary study (De Sutter et al., 2003), although the latter did not use a multivariate method of analysis. In that study, the birthweight of the SET singletons was 3303 ± 481 g and of the DET singletons 3175 ± 641 g (statistically significant difference of 128 g). In a recent study by De Neubourg et al. (2006), the birthweight of 251 SET singletons was 3322 ± 538 g and not statistically different from the birthweight of population-based spontaneous singletons (3330 ± 531 g). It is striking that, in the present study, birthweight of SET singletons was 3324.6 ± 509.7 g, thus almost exactly the same weight as found by De Neubourg et al. (2006). The randomised study of Thurin Kjellberg et al. (2006) on 129 neonates born after SET versus 189 neonates born after DET also found mean gestational age and birthweight to be higher in the SET group.
Patient characteristics may play a role in this matter. Support for this hypothesis can be deduced from an earlier study of our group (De Sutter et al., 2005), where it is found that the perinatal outcome after IVF was not different than that after intrauterine insemination. Furthermore, previous publications have discussed the increased obstetric risk associated with the long time to pregnancy inherent to subfecundity (Henriksen et al., 1997; Draper et al., 1999; Pandian et al., 2001; Basso and Baird, 2003; Basso and Olsen, 2005).
The difference in mean birthweight between SET and DET may be related to a difference in mean gestational age, but this difference is only 3 days. Therefore, there must be some other intrinsic pregnancy-related factors, such as placental growth and foetal nourishment in certain pregnancies. We have previously shown that embryos with maximum implantation potential (twins after DET as well as singletons after SET) have a lower miscarriage risk than singletons after DET (Tummers et al., 2003). In the latter group, as per definition 50% of the embryos were wasted, and this could mean that implantation possibilities are less favourable in singleton birth after DET. Consequently, this could imply a higher miscarriage risk, less ideal placental development, less optimal foetal growth and lower birthweight.
A possible mechanism that could influence the incidence of lower birthweight in DET singletons is the likely higher incidence of vanishing twins in this group. First trimester ultrasound showed two fetal sacs to be present in 7.0% of our DET cases that resulted in a singleton birth. This rate is comparable to the findings of Pinborg et al. (2005) who found 10.4% of vanishing twins in a similar population and observed low birthweights to be more common in singleton survivors of a vanishing twin versus singletons from single gestations in IVF/ICSI pregnancies (OR 1.7, 95% CI 1.2–2.2). The presence of a second foetal sac could impact on the implantation process of the ongoing ‘twin’ and can thus be at the origin of pregnancy complications with possibly long-term effects, such as cerebral palsy (Hvidtjørn et al., 2005). Recently, our group has found not only that first trimester bleeding is more frequent after DET than that after SET (pointing to the vanishing twin hypothesis) but also that this is associated with an adverse pregnancy outcome (De Sutter et al., 2006). Taken together, these facts indicate that the adverse outcome of singleton pregnancies as reported in the literature (Tanbo et al., 1995; Dhont et al., 1999; Koudstaal et al., 2000; Helmerhorst et al., 2004; Schieve et al., 2004; Bower and Hansen, 2005) may well be associated with the fact that all these pregnancies resulted from the transfer of more than one embryo, with early vanishing twins as the sole and independent factor leading to lower birthweight of the surviving singleton. Indeed, these studies were performed in a period when SET was not yet implemented in most infertility clinics. For instance, in the Koudstaal et al. study (2000), the mean birthweight of IVF singletons was 3112 ± 759 g and of spontaneously conceived singletons 3326 ± 639 g (difference of 214 g, P < 0.001). The latter weight is almost exactly the weight of the SET singletons in the present study (3324.6 ± 509.7 g). The incidence of preterm birth (6.2%) and low birthweight (4.2%) in our SET population is similar to the incidence of preterm birth (6.2%) and low birthweight (4.8%) in the general Flemish spontaneously conceived and live-born singleton population (SPE, 2004). The lower birthweight of IVF singletons in previous studies may thus be accounted for by the fact that two embryos were transferred and not to the IVF procedure per se.
In conclusion, next to a very effective reduction in multiple pregnancy rates, SET also seems to be beneficial in terms of pregnancy outcome characteristics in singleton pregnancies as well. Mean birthweight was found to be significantly higher in SET singletons compared with DET singletons. Also the incidence of preterm birth and low birthweight is clearly reduced when SET is compared with DET. A possible explanation for this outcome can be the ‘avoidance’ of vanishing twins in IVF/ICSI procedures when SET is applied, but this hypothesis needs further investigation. A more frequent application of SET in assisted reproductive technologies clinics could be an essential step to reduce differences in outcome between spontaneous and assisted reproduction children.
|
Acknowledgement |
|---|
|
TopAbstractIntroductionMaterials and methodsResultsDiscussionAcknowledgementReferences |
|---|
The first author is holder of a fundamental clinical research mandate by the Flemish foundation of scientific research (FWO-Vlaanderen).
|
References |
|---|
|
TopAbstractIntroductionMaterials and methodsResultsDiscussionAcknowledgementReferences |
|---|
Basso O and Baird DD. (2003) Infertility and preterm delivery, birthweight, and Caesarean section: a study within the Danish National Birth Cohort. Human Reprod 18:2478–2484.
Basso O and Olsen J. (2005) Subfecundity and neonatal mortality: longitudinal study within the Danish national birth cohort. BMJ 330:393–394.
Bergh T, Ericson A, Hillensjö T, Nygren K-G, Wennerholm U-B. (1999) Deliveries and children born after in – vitro fertilization in Sweden 1982–95: a retrospective cohort study. Lancet 354:1579–1585.[CrossRef][Web of Science][Medline]
Bernasko J, Lynch L, Lapinski R, Berkowitz R. (1997) Twin pregnancies conceived by assisted reproductive techniques: maternal neonatal outcomes. Obstet Gynecol 89:368–372.[CrossRef][Web of Science][Medline]
Blondel B and Kaminski M. (2002) Trends in the occurrence, double embryo transfer determinants, and consequences of multiple births. Semin Perinat 26:239–249.
Bower C and Hansen M. (2005) Assisted reproductive technologies and birth outcomes: overview of recent systematic reviews. Rep Fert Dev 17:329–333.[CrossRef]
Coetsier T and Dhont M. (1998) Avoiding multiple pregnancies in in-vitro fertilization: who’s afraid of single embryo transfer? Hum Reprod 13:2663–2664.
De Neubourg D, Gerris J, Mangelschots K, Royen EV, Vercruyssen M, Steylemans A, Elseviers M. (2006) The obstetrical and neonatal outcome of babies born after single-embryo transfer in IVF/ICSI compares favourably to spontaneously conceived babies. Hum Reprod 21:1041–1046.
De Sutter P, Gerris J, Dhont M. (2002) A health-economic decision-analytic model comparing double with single embryo transfer in IVF/ICSI. Hum Reprod 17:2891–2896.
De Sutter P, Van der Elst J, Coetsier T, Dhont M. (2003) Single embryo transfer and multiple pregnancy rate reduction in IVF/ICSI: a 5-year appraisal. Reprod Biomed Online 6:464–469.[Medline]
De Sutter P, Veldeman L, Kok P, Szymczak N, Van der Elst J, Dhont M. (2005) Comparison of outcome of pregnancy after intra-uterine insemination (IUI) and IVF. Hum Reprod 20:1642–1646.
De Sutter P, Bontinck J, Schutyser V, Gerris J, Van der Elst J, Dhont M. ( Feb 24, 2006) First trimester bleeding and pregnancy outcome after assisted reproduction. Hum Reprod [Epub ahead of print](http://humrep.oxfordjournals.org/cgi/reprint/del054v1).
De Vries MJ, De Sutter P, Dhont M. (1999) Prognostic factors in patients continuing in vitro fertilization or intracytoplasmic sperm injection treatment and dropouts. Fertil Steril 72:674–678.[CrossRef][Web of Science][Medline]
Dhont M. (2001) Single-embryo transfer. Semin Reprod Med 19:251–258.[CrossRef][Web of Science][Medline]
Dhont M, De Sutter P, Ruyssinck G, Martens G, Bekaert A. (1999) Perinatal outcome of pregnancies after assisted reproduction: a case – control study. Am J Obstet Gynecol 181:688–695.[CrossRef][Web of Science][Medline]
Draper ES, Kurinczuk JJ, Abrams KR, Clarke M. (1999) Assessment of separate contributions to perinatal mortality of infertility history and treatment: a case-control analysis. Lancet 353:1746–1749.[CrossRef][Web of Science][Medline]
Elsner CW, Tucker MJ, Sweitzer CL, Brockman WD, Morton PC, Wright G, Toledo AA. (1997) Multiple pregnancy rate and embryo number transferred during in vitro fertilization. Am J Obstet Gynecol 177:350–355.[CrossRef][Web of Science][Medline]
Elster N. (2000) Less is more: the risk of multiple births. Fertil Steril 74:617–623.[CrossRef][Web of Science][Medline]
Gardner DK, Surrey E, Minjarez D, Leitz A, Stevens J, Schoolcraft WB. (2004) Single blastocyst transfer: a prospective randomized trial. Fertil Steril 81:551–555.[CrossRef][Web of Science][Medline]
Gerris J and Van Royen E. (2000) Avoiding multiple pregnancies in assisted reproductive technologies. A plea for single embryo transfer. Hum Reprod 15:1884–1888.
Gerris J, De Neubourg D, Mangelschots K, Van Royen E, Van de Meerssche M, Valkenburg M. (1999) Prevention of twin pregnancy after in-vitro fertilization or intracytoplasmic sperm injection based on strict embryo criteria: a prospective randomized clinical trial. Hum Reprod 14:2581–2587.
Gerris J, Van Royen E, De Neubourg D, Mangelschots K, Valkenburg M, Ryckaert G. (2001) Impact of single embryo transfer on the overall and twin-pregnancy rates of an IVF/ICSI programme. Reprod Biomed Online 2:172–177.
Helmerhorst FM, Perquin DAM, Donker D, Keirse MJNC. (2004) Perinatal outcome of singleton and twins after assisted conception: a systematic review of controlled studies. BMJ 328:7434.
Henriksen TB, Baird DD, Olsen J, Hedegaard M, Secher NJ, Wilcox AJ. (1997) Time to pregnancy and preterm delivery. Obstet Gynecol 89:594–599.[CrossRef][Web of Science][Medline]
Hvidtjørn D, Grove J, Schendel D, Væth M, Ernst E, Nielsen L, Thorsen P. (2005) Short communication: ‘Vanishing embryo syndrome’ in IVF/ICSI. Human Reprod 20:2550–2551.
Koudstaal J, Bruinse HW, Helmerhorst FM, Vermeiden JPW, Willemsen WNP, Visser GHA. (2000) Obstetric outcome of twin pregnancies after in-vitro fertilization: a matched control study in four Dutch University hospitals. Hum Reprod 15:935–940.
Laverge H, De Sutter P, Van der Elst J, Dhont M. (2001) A prospective, randomized study comparing day 2 and day 3 embryo transfer in human IVF. Hum Reprod 16:476–480.
Luke B and Keith L. (1992) The contribution of singletons, twins and triplets to low birthweight, infant mortality and handicaps in the United States. J Reprod Med 37:661–666.[Web of Science][Medline]
Martikainen H, Orava M, Lakkakorpi J, Tuomivaara L. (2004) Day 2 elective single embryo transfer in clinical practice: better outcome in ICSI cycles. Hum Reprod 19:1364–1366.
Ombelet W, De Sutter P, Van der Elst J, Martens G. (2005) Multiple gestation and infertility treatment: registration, reflection and reaction – the Belgian project. Hum Reprod Update 11:3–14.
Pandian Z, Bhattacharya S, Templeton A. (2001) Review of unexplained infertility and obstetric outcome: a 10 year review. Human Reprod 16:2593–2597.
Pinborg A, Lidegaard O, Cour Freiesleben N, Andersen AN. (2005) Consequences of vanishing twins in IVF/ICSI pregnancies. Hum Reprod 20:2821–2829.
Royal Decree of 4 June. (2003) Belgisch staatsblad/Moniteur Belge 16 June 2003, 32127. (http://www.ejustice.just.fgov.be/cgi/assistedreproductivetechnologiesicle_body.pl?language=nl=summary=2003-0616=2003022627).
Schieve LA, Ferre C, Peterson HB, Macaluso M, Reynolds MA, Wright VC. (2004) Perinatal outcome among singleton infants conceived through assisted reproductive technology in the United States. Obstet Gynecol 103:1144–1153.[CrossRef][Web of Science][Medline]
Staessen C, Janssenswillen C, Van Den Abbeel E, Devroey P, Van Steirteghem A. (1993) Avoidance of triplet pregnancies by elective transfer of two good quality embryos. Hum Reprod 8:1650–1653.
Study Centre for Perinatal Epidemiology (SPE) Flanders. (2004) Annual report.
Tanbo T, Dale PO, Lunde O, Moe N, Abyholm T. (1995) Obstetric outcome in singleton pregnancies after assisted reproduction. Obstet Gynecol 86:188–192.[CrossRef][Web of Science][Medline]
Thurin Kjellberg A, Carlsson P, Bergh C. (2006) Randomized single versus double embryo transfer: obstetric and paediatric outcome and a cost-effectiveness analysis. Hum Reprod 21:210–216.
Tiitinen A, Unkila-Kallio L, Halttunen M, Hydén-Granskog C. (2003) Impact of elective single embryo transfer on the twin pregnancy rate. Hum Reprod 18:1449–1453.
Tummers P, De Sutter P, Dhont M. (2003) Risk of spontaneous abortion in singleton and twin pregnancies after IVF/ICSI. Hum Reprod 18:1720–1723.
Van Royen E, Mangelschots K, De Neubourg D, Valkenburg M, Van de Meerssche M, Ryckaert G, Eestermans W, Gerris J. (1999) Characterization of a top quality embryo, a step towards single-embryo transfer. Hum Reprod 14:2345–2349.
Vilska S, Tiitinen A, Hydén-Granskog C, Hovatta O. (1999) Elective transfer of one embryo results in an acceptable pregnancy rate and eliminates the risk of multiple birth. Hum Reprod 14:2392–2395.
Submitted on February 10, 2006; resubmitted on April 8, 2006; accepted on April 13, 2006.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  L. A. Schieve, O. Devine, C. A. Boyle, J. R. Petrini, and L. Warner Estimation of the Contribution of Non-Assisted Reproductive Technology Ovulation Stimulation Fertility Treatments to US Singleton and Multiple Births Am. J. Epidemiol., December 1, 2009; 170(11): 1396 - 1407. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 I. Delbaere, S. Vansteelandt, J. Gerris, P. De Sutter, D. De Bacquer, and M. Temmerman Human chorionic gonadotropin levels in early IVF/ICSI pregnancies are higher in singletons after single embryo transfer compared with singletons after double embryo transfer Hum. Reprod., November 1, 2008; 23(11): 2421 - 2426. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Bettegowda, O. V. Patel, K.-B. Lee, K.-E. Park, M. Salem, J. Yao, J. J. Ireland, and G. W. Smith Identification of Novel Bovine Cumulus Cell Molecular Markers Predictive of Oocyte Competence: Functional and Diagnostic Implications Biol Reprod, August 1, 2008; 79(2): 301 - 309. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. M. Chambers, M. G. Chapman, N. Grayson, M. Shanahan, and E. A. Sullivan 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 Hum. Reprod., December 1, 2007; 22(12): 3108 - 3115. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
I. Delbaere, S. Vansteelandt, D. De Bacquer, H. Verstraelen, J. Gerris, P. De Sutter, and M. Temmerman Should we adjust for gestational age when analysing birth weights? The use of z-scores revisited Hum. Reprod., August 1, 2007; 22(8): 2080 - 2083. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Poikkeus, M. Gissler, L. Unkila-Kallio, C. Hyden-Granskog, and A. Tiitinen Obstetric and neonatal outcome after single embryo transfer Hum. Reprod., April 1, 2007; 22(4): 1073 - 1079. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||