Correlation between sonographic follow-up of follicular growth, serum and salivary estradiol in women undergoing controlled ovarian stimulation (IVF/ICSI).

AIM OF THE STUDY: Investigation of the correlation between serum estradiol (E2), salivary E2 and sonographic measurements of follicles in women undergoing controlled ovarian stimulation (COS) for IVF/ICSI. METHODS: This is a prospective study performed at the Department of Reproductive Medicine of Ghent University Hospital (Belgium) between November 2016 and January 2017 over a total of 40 patients. During routine COS, two-dimensional measurements of the follicles were performed using transvaginal ultrasound (TVUS) and E2 was measured in saliva and serum. A linear Mixed-Effects model (MIXED) was built, using SPSS Statistics 24. RESULTS: Statistical analysis shows a strong linear correlation between serum and salivary E2. For every single unit increase in serum E2 (+ 1 ng/L) the estimated saliva E2 concentration is expected to increase with 0.011 pg/mL (95% CI [0.009 - 0.01]). Strong linear correlations between both saliva and serum E2 and follicular dimensions were also found. For every millimetre increase in follicle diameter the estimated serum E2 concentration is expected to increase with 8.32 ng/L (95% CI [7, 10-9, 54]). For every millimetre increase in follicle diameter the estimated saliva level of E2 is expected to increase with 0.11 pg/mL (95% CI [0.09 - 0.13]). CONCLUSIONS: A strong correlation between serum and salivary E2 concentrations was found. In addition, both are strongly correlated with the product of the number of follicles and their average diameter, measured by TVUS. More investigation needs to be done to find out if salivary E2 is an effective tool for monitoring IVF cycles.

No influence of the indication of freeze-all strategy on subsequent outcome to frozen-thawed embryo transfer cycle.

BACKGROUND: Freezing all embryos generated during an IVF/ICSI attempt is used increasingly as a strategy to optimize results. We investigated whether we could find differences in outcome between subpopulations of patients undergoing the so-called "freeze all" procedure. METHODS: Non-interventional, observational, retrospective study of 131 freeze-all cycles performed between July 2015 and December 2016 at the University Hospital of Ghent (Belgium). Freeze-all indications were categorized in 4 groups: group 1, high progesterone level (PE) on the day of hCG administration defined as >1.5 ng/ml (n= 50); group 2, risk of Ovarian Hyperstimulation Syndrome (OHSS) (n=38); group 3, partner donation in lesbian couples (n=23) and group 4, a miscellany of other reasons (n=20). Clinical pregnancy with fetal heart beat after the first thawed embryo transfer (ET) after ovum pick-up and cumulative clinical pregnancy rate per attempt were used as primary outcome variables. RESULTS: Clinical pregnancy rate (CPR) with fetal heart beat in the first thawed ET and cumulative clinical pregnancy rate per cycle (CCPR) were not statistically different between the four groups. In the group of PE a cumulative clinical pregnancy rate was observed of 40,5%, this in comparison to the 3 other groups involving risk of OHSS (66,7%), partner donation (61,1%) and other reasons (57,1%). More rFSH was used in the group with Progesterone elevation (PE) (P=0.04), as described earlier in the literature. CONCLUSION: Our findings indicate comparable (cumulative) clinical pregnancy rates per attempt between the four groups of freeze-all indications.

Correlation between saliva and serum concentrations of estradiol in women undergoing ovarian hyperstimulation with gonadotropins for IVF/ICSI.

AIM OF THE STUDY: To examine saliva- and serum concentrations correlation of estradiol (E2) in women undergoing ovarian hyperstimulation for IVF/ICSI. Saliva measurements could simplify stimulation follow up. A 'home' test for E2 could be useful. METHODS: Prospective interventional academic monocentric study at the Centre for Reproductive Medicine of the University Hospital of Ghent, Belgium. Between November 2014 and August 2015 thirty-one patients were included after random selection (inclusion criteria: < 41 years of age, any rank of IVF/ICSI cycle, serum anti- Müllerian hormone concentration ≥ 1 µg/L, treatment completely at the University Hospital.) Measurements took place using immunoassay serum measurements. Estradiol was determined in saliva and serum by LC-MS/MS. At every control, E2 was measured in saliva and serum. Equilibrium analysis on a part of the serum samples took place. Statistic method used is a linear Mixed- Effects model (MIXED) in SPSS. RESULTS: Statistical analysis shows a strong linear relation between serum and salivary E2, (R2 of 0.75). E2 in equilibrium dialysis and E2 in serum were also strong correlated (R2 of 0.85). CONCLUSIONS: Strong correlation between serum and salivary E2 concentrations was found. Equilibrium dialysis showed good correlation with salivary E2. Saliva can be a good surrogate for free E2 in women undergoing ovarian hyperstimulation. This may create an opportunity to develop a point of care test for measuring E2, in purpose to simplify screening for OHSS risk.

Correlation between follicle dimensions recorded by patients at home (SOET) versus ultrasound performed by professional care providers.

INTRODUCTION: Serial measurements of the number of follicles and their growth by ultrasound is a standard way of monitoring fertility treatments using controlled ovarian stimulation. This is stressful for both the patient and the professional. Self-operated endovaginal telemonitoring (SOET) is more patient friendly and less time-consuming. AIM OF THE STUDY: The goal of the study is to see if there's a correlation in the number of follicles and in two- dimensional growth between recordings made using SOET versus measurements performed by a professional sonographer. RESULTS: Three different ultrasound moments were recorded and compared in a total of 15 women. At time A an ultrasound was performed by the patient at home using SOET at the decision time of triggering. At time B an ultrasound was also recorded by the patient, 24 hours later. At time C an ultrasound was performed by a physician using a high end ultrasound device immediately prior to oocyte retrieval, 12 hours later than time B. The correlation in number and two-dimensional size between the different measurement moments was calculated. There is an excellent correlation in follicle count between time B and C. The difference in mean two-dimensional size between different measurement moments was not statistically significant. CONCLUSION: SOET ultrasound correlates well with ultrasound performed by a professional in number of follicles. SOET is a good alternative for monitoring controlled ovarian stimulation in a well-defined population group of normal responders, especially near the end of the ovarian stimulation.

Patients' ideas, expectations and experience with self operated endovaginal telemonitoring: a prospective pilot study.

OBJECTIVE: To examine advantages and disadvantages as perceived by patients and their partners using home sonography for monitoring ovarian stimulation prior to artificial fertility treatment. METHOD: We interviewed 25 patients and their partners and took 44 online questionnaires. All interviews were written out and the transcripts were coded, based on words patients used to describe their experience. The query consisted mostly of statements, of which the participant had to ascertain whether or not they agreed (1= I absolutely don't agree and 5 = I absolutely agree). The median and mean of agreement scores was calculated. RESULTS: The time saving and practical aspect of self-operated endo-vaginal tele-monitoring (SOET) was the most important argument to choose SOET. In addition, the following aspects were considered advantages: more autonomy, no need for leave from work, a better doctor-patient relationship and sometimes more involvement of the partner. The most important disadvantage is a sense of initial insecurity couples experience during the first ultrasound. Almost all couples experience this, but they accept it as part of the process. CONCLUSION: Using SOET was a pleasant experience for all couples. All patients and partners had positive expectations about SOET. The initial insecurity can be minimized, by improving teaching measures. It would be positive if a legal framework is set up allowing reimbursement of home sonography.

Outcome of one hundred consecutive ICSI attempts using patient operated home sonography for monitoring follicular growth.

OBJECTIVE: cohort study describing clinical and laboratory outcomes in ICSI patients using self-operated endovaginal tele-monitoring (SOET). SETTING: University department of reproductive medicine. PATIENTS: 78 patients undergoing 100 consecutive ICSI attempts. INTERVENTIONS: patients' recorded vaginal sonograms and sent recordings using the cloud based Sonaura device to the care provider who procured responses, avoiding hospital visits. MAIN OUTCOME MEASURES: Number of cycles without hospital visit, laboratory and clinical variables, transportation avoided. RESULTS: In 100 attempts, only one patient missed her follicles, 9 hospital visits occurred for circumstantial reasons and 90 attempts were completed without any hospital visit between initiation and puncture. Mean number ± 2SD was for oocytes 11.7±6.6, metaphase-II oocytes 8.5±5.4, 2PN zygotes 5.5±3.7, good day-5 blastocysts 2.4±2.4, embryos transferred 1.0±0.7 and embryos frozen 1.3±2.2. Percentages of total (+HCG), clinical (cardiac activity) and on-going pregnancies (>20 weeks) were 40%, 35% and 29% per started cycle and 48.8%, 42.7% and 35.4% per embryo transfer. CONCLUSIONS: Using SOET, 90% of ICSI (and IVF) patients can avoid visits to care providers for making sonograms. Results were similar as in patients with a similar profile using traditional monitoring. In appropriate patients, SOET is an efficient, safe and patient-friendly alternative for ovarian stimulation monitoring in IVF/ICSI programmes.

What does a clinically-scientific professional society stand for?

Originated as a mainly social group of befriended colleagues, the VVOG has evolved over the past 55 years to become a truly professional society facing successfully such diverse challenges as organizing scientific congresses, postgraduate training, ethical debates, hands-on training courses, social events, interactions with national and international sister societies but also with the industry, insurers, the government, politicians and patient organisations.

Seasons in the sun: the impact on IVF results one month later.

BACKGROUND: Several retrospective studies have evaluated seasonal variations in the outcome of IVF treatment. Some also included weather conditions, mostly temperature and hours of daylight. The results were conflicting. METHODS: In a retrospective study we analysed all fresh cycles (N = 9865) that were started between January 1, 2007 and December 31, 2012. Because some patients were included more than once, correction for duplicate patients was performed. We focused on individual variables provided as monthly results by our national meteorological institute. We evaluated if weather conditions determined by temperature, rain and sunshine at the start of ovarian stimulation had an effect on the outcome of IVF in terms of number of mature and fertilized oocytes, pregnancy and live birth rates. We shifted the results in IVF outcome to the weather results of one month earlier, as we supposed that the selection of good quality oocytes might start in the weeks before ovarian stimulation is initiated. RESULTS: There was a clear trend towards better results when the "early" weather conditions (one month before the treatment cycle) were good. There was a statistically significant correlation between the number of rainy days (Pearson Correlation -0.326; p < 0.01) and the rain flow (Pearson Correlation -0.262; p < 0.05) on the one hand and the live birth rate per cycle on the other. The live birth rate per cycle was statistically different between cohorts of patients that were stratified into quartiles of sunshine hours (p < 0.01) and of number of rainy days (p < 0.05) during the month before the start of ovarian stimulation. CONCLUSIONS: Weather conditions during the month before IVF treatment have an impact on live birth rate.

A retrospective study of the pregnancy, delivery and neonatal outcome in overweight versus normal weight women with polycystic ovary syndrome.

STUDY QUESTION: Do overweight women with polycystic ovary syndrome (PCOS) have a higher risk of perinatal complications than normal weight women with PCOS? SUMMARY ANSWER: Overweight women with PCOS with an ongoing singleton pregnancy have an increased risk of preterm birth as well as an increased risk of giving birth to a baby with a higher birthweight than normal weight women with PCOS. WHAT IS KNOWN ALREADY: There is evidence that overweight (BMI > 25 kg/m²) has a negative influence on the prevalence of gestational diabetes mellitus and fetal macrosomia in women with PCOS. STUDY DESIGN, SIZE, DURATION: We set up a retrospective comparative cohort study of 93 overweight (BMI ≥ 25 kg/m²) and 107 normal weight (BMI < 25 kg/m²) women with PCOS who were scheduled for fertility treatment between January 2000 and December 2009 and achieved a pregnancy as a result of a treatment cycle, or spontaneously before or between treatment cycles. PARTICIPANTS/MATERIALS, SETTING, METHODS: All data (patient characteristics, medical information, pregnancy, delivery and neonatal outcome) were retrieved from patient medical files. All pregnancy, delivery and neonatal outcome parameters were adjusted for age and pre-pregnancy smoking behaviour. The neonatal outcome parameters were additionally adjusted for gestational age. MAIN RESULTS AND THE ROLE OF CHANCE: The median BMI in the overweight and normal weight women was, respectively, 30.8 kg/m² [interquartile quartile range (IQR) 5.8] and 20.9 kg/m² (IQR 2.3) (P < 0.001). Baseline characteristics did not differ between groups, except for free testosterone and fasting insulin levels, which were higher, and sex hormone-binding globulin, which was lower, in overweight versus normal weight women (all P < 0.001). The time-to-pregnancy was significantly higher in the overweight group (P = 0.01). Multivariate analyses of the ongoing singleton pregnancies showed significantly more preterm births in overweight (10/61) versus normal weight (2/71) women [adjusted odds ratio 0.1, 95% confidence interval (CI) 0-0.6, P = 0.01]. The mean birthweight of newborns was significantly higher in overweight (3386 ± 663 g) than in normal weight (3251 ± 528 g) women (adjusted mean difference 259.4, 95% CI 83.4-435.4, P = 0.004). LIMITATIONS, REASON FOR CAUTION: Our results only represent the pregnancy, delivery and neonatal outcome of ongoing singleton pregnancies. The rather small sample size and observational nature of the study are further limitations. WIDER IMPLICATIONS OF THE FINDINGS: Our results suggest the importance of pre-pregnancy weight loss in overweight women with PCOS in order to reduce the risk of adverse perinatal outcomes. STUDY FUNDING/COMPETING INTERESTS: Veerle De Frène is holder of a Special PhD Fellowship by the Flemish Foundation for Scientific Research (FWO-Vlaanderen). Petra De Sutter is holder of a fundamental clinical research mandate by the Flemish Foundation for Scientific Research (FWO-Vlaanderen). There are no competing interests.

Effect of small molecule supplements during in vitro culture of mouse zygotes and parthenogenetic embryos on hypoblast formation and stem cell derivation.

BACKGROUND: Small molecule inhibitors are organic components that modulate signalling pathways and have the ability to change the differentiation state of cells. They have been used to increase the efficiency of induced pluripotent stem cell generation and to support stem cell derivation and culture. In this study, we aimed to evaluate the effects of small molecules on the development of mouse zygotes and parthenogenetic embryos. METHODS AND RESULTS: Three inhibitors (SC-1, PD0325901 and BIO) were added to the culture medium from the 2-cell stage onwards. We have observed that addition of an inhibitor of the fibroblast growth factor (FGF) pathway (SC-1 or PD0325901) compromises the segregation of hypoblast from the inner cell mass (ICM). Given no difference was observed in size of the ICM, but more epiblast cells were found in these embryos, we can conclude that this is caused by redirection of all ICM cells to the epiblast. We also determined the consequences of reduced hypoblast and increased epiblast formation on stem cell derivation efficiency. No significant difference was found between derivation rates from treated embryos as compared to controls. However, only under 2i + ROCKi conditions, stem cells could be derived with an efficiency of more than 90%. Addition of BIO, an activator of the WNT pathway, did not have any effects on hypoblast development or stem cell derivation. CONCLUSION: We have demonstrated that FGF signalling is crucial for hypoblast generation and small molecules can be efficiently used to inhibit this process both in zygotes and parthenogenetic embryos.

Assisted oocyte activation is not beneficial for all patients with a suspected oocyte-related activation deficiency.

BACKGROUND: Despite the success of ICSI, total fertilization failure (TFF) still occurs in 1-3% of all ICSI cycles. ICSI followed by assisted oocyte activation (ICSI-AOA) can restore fertilization, most efficiently in cases of sperm-related fertilization deficiency. The indication for ICSI-AOA is less obvious when the capacity of the sperm to activate oocytes is considered normal, as proved by a heterologous ICSI model, such as the mouse oocyte activation test (MOAT). In this study, we verified whether ICSI-AOA is beneficial for patients in whom an oocyte-related activation deficiency is suspected. METHODS: A prospective study was conducted including patients presenting with a history of TFF or low fertilization (LF) following conventional ICSI in our centre (in-house cases, n= 2) or elsewhere (out-house cases, n= 12). In all cases a sperm deficiency was refuted by the MOAT. In a next treatment cycle, ICSI-AOA was performed on half of the sibling metaphase II oocytes and conventional ICSI on the rest ('split ICSI-AOA cycle'). The main outcome parameters were fertilization, pregnancy and live birth rates. RESULTS: Overall, ICSI-AOA was able to improve fertilization rates in couples with a suspected oocyte-related fertilization problem, with a mean fertilization rate of 74.2% following ICSI-AOA compared with 43.5% following conventional ICSI (P< 0.001). Cumulative pregnancy rate and live birth rate per cycle were 35.7 and 14.3%, respectively. Considering the out-house patients only, fertilization rates with ICSI-AOA were higher in couples with previous TFF than with conventional ICSI (P< 0.001). Interestingly, for out-house patients who had experienced low, but not zero, fertilization elsewhere, ICSI-AOA could not enhance the fertilization rate. For the two in-house patients, both suffering from previous LF following conventional ICSI, the ICSI-AOA procedure enhanced the mean fertilization rate (25 versus 75%, respectively). CONCLUSIONS: For patients with a suspected oocyte-related activation deficiency, as diagnosed by a heterologuous ICSI model, the indication for ICSI-AOA still remains debatable. Our data show that ICSI-AOA is very efficient in patients with a suspected oocyte-related activation deficiency and previous TFF after conventional ICSI. In contrast, when there was a history of LF in another centre, one should be careful and test the efficiency of ICSI-AOA on half of the sibling oocytes, because ICSI-AOA is not always beneficial for patients with previous LF and a suspected oocyte-related activation deficiency. For these patients, a split ICSI-AOA cycle using sibling oocytes can help to distinguish between a molecular oocyte-related activation deficiency and a previous technical or other biological failure. Moreover, this split ICSI-AOA strategy enables us to set the appropriate strategy for future treatment cycles. Further research with larger groups of patients is now required.

Does transferring three or more embryos make sense for a well-defined population of infertility patients undergoing IVF/ICSI?

Recently, there has been a marked increase in the use of Single Embryo Transfer (SET) subsequent to In Vitro Fertili-zation (IVF) and Intracytoplasmic Sperm Injection (ICSI), with the aim of reducing the risk of multiple gestations. However, critics have stated that by reducing the number of embryos transferred, a group of women with an a priori reduced chance of pregnancy are at particular greater risk of undertreatment. This group includes women who are of a certain age (≥ 40 years) or have already received a number of - failed - IVF attempts. We wanted to study whether the practice of three or more embryos being transferred would be of added value to these patients and whether the strategy of Heavy Load Transfer (HLT) is likely to boost the pregnancy rates to an acceptable level. We performed both a literature study and a retrospective cohort analysis of 7,850 IVF/ICSI cycles of early cleavage stage embryo transfer. Notwithstanding the limitations associated with this approach, we contend that HLT in the group of patients with poor prognosis should be recommended. This article outlines a suggested protocol within the legal framework relevant to Belgium.

Prevalence of chromosomal abnormalities and timing of karyotype analysis in patients with recurrent implantation failure (RIF) following assisted reproduction.

AIMS: To analyze the prevalence and type of karyotype abnormalities in RIF patients and to evaluate the adequate timing for analysis and the presence of possible risk factors. METHODS: 615 patients (317 women and 298 men) with RIF, having undergone at least 3 sequential failed IVF/ICSI cycles prior to karyotype analysis, were included in this study. Anomaly rates found were compared with published series. RESULTS: Chromosomal abnormalities were diagnosed in 2.1% of patients (13/615): 8 females (2.5%) and 5 males (1.7%) which is significantly higher for the females than in unselected newborns (0.8%) and normo-ovulatory women (0.6%) but lower than in women with high-order implantation failure (10.8%). No significant differences were found with couples at the start of IVF/ICSI (2.0%). Karyotyping all patients prior to IVF/ICSI results in a higher cost than selecting RIF patients. Two subgroups showed an increased prevalence of abnormalities: secondary infertile women with a history of only miscarriages (9.1%) and women with female infertility (6.0%). CONCLUSION: A karyotype analysis is indicated in all women with RIF. Nulliparous women with a history of mis-carriage and women with documented infertility are at greater risk of CA and are to be advised to undergo -karyotyping.

Efficiency of polarized microscopy as a predictive tool for human oocyte quality.

BACKGROUND: Conflicting results have been reported regarding the use of polarized microscopy as a predictive tool for human oocyte quality. METHODS: Oocytes from 121 ICSI cycles were analysed with polarized microscopy. Both qualitative (spindle presence) and quantitative (retardance) data were correlated to the key assisted reproduction technology outcome parameters. Second, polarized microscopy was applied on in vitro matured (IVM) oocytes from germinal vesicle oocytes that matured after 24 or 48 h and from metaphase I oocytes matured after 3 or 24 h. These data were correlated with confocal analysis of spindle-chromosome complex. RESULTS: Spindles were detected in 82% of in vivo matured oocytes and in 64% adjacent to the first polar body (PB). Fertilization rate was higher in oocytes with a visible spindle (P = 0.0002). In patients aged over 35 years, the percentage of a visible spindle and mean spindle retardance was lower than in younger patients (P < 0.03). A higher number of spindles were located adjacent to the first PB in IVM matured oocytes (94%) versus in vivo matured oocytes (P < 0.0001). Confocal imaging revealed that spindle absent IVM metaphase II (MII) oocytes had a higher degree of aberrant spindle and chromosomal configurations versus IVM MII oocytes with a visible spindle (P = 0.002). CONCLUSIONS: Oocytes with absent spindles were associated with lower fertilization rates and advanced female age. Other important outcome parameters (embryo quality, pregnancy rates) were not correlated to spindle nor zona inner layer analysis. Interestingly, confocal imaging showed that polarized microscopy might be used as a qualitative predictive tool of human oocyte quality but no correlation could be demonstrated with quantitative polarized microscopy.

To continue or discontinue storage of cryopreserved embryos? Patients' decisions in view of their child wish.

OBJECTIVE Cryopreservation of supernumerary embryos resulting from IVF treatment offers extra chances to conceive. The objective of this study is to describe patients' decisions to continue or discontinue storage of their embryos after a minimum storage period of 2 years. METHODS Female patients who had embryos stored at the Infertility Centre of the Ghent University Hospital (Belgium) were sent a mail questionnaire to be completed anonymously. RESULTS The questionnaire had a response rate of 79% (326/412). After an embryo storage period of at least 2 years, 40% of the couples who were still together wished to continue storage of their embryos. Half of these had no concrete plans for a transfer and wanted to postpone the decision or keep all options open. For those who decided to discontinue storage (60%), the main reason was the completion of their families. Despite the fact that the patients' child wish was the main factor in their storage decision, two groups of patients with distinct profiles made decisions that were inconsistent with their child wish: those who wanted to continue storage while not wanting a(nother) child (7% of those with no child wish), and those who wanted a(nother) child but decided to discontinue storage (25% of those with a child wish). Overall, these patients more often expressed emotional difficulties regarding this decision. CONCLUSIONS This study demonstrates the importance of gaining more insight into patients' embryo storage decisions (along with their embryo disposition decisions) and into the emotional factors playing a role in patients' decision-making.

Aberrant spindle structures responsible for recurrent human metaphase I oocyte arrest with attempts to induce meiosis artificially.

BACKGROUND In some couples, not all retrieved oocytes mature, even after prolonged in vitro culture. The underlying mechanisms are not known, although ionophore treatment may alleviate metaphase I (MI) arrest in some mouse strains. We attempted to induce first polar body (PB) extrusion and fertilization using assisted oocyte activation (AOA) after ICSI in maturation-resistant human MI oocytes. METHODS Four ICSI patients are described in this retrospective study. A pilot study tested the calcium ionophore ionomycin (10 µM) on donated MI oocytes from patients with a normal number of metaphase II (MII) oocytes. Subsequently, ionomycin was used to induce first PB extrusion in two patients showing maturation-resistant MI oocytes. AOA, by calcium injection and ionomycin exposure, was applied when mature oocytes were available. Oocytes were analysed by polarized microscopy and immunostaining. RESULTS Ionomycin induced the first PB extrusion in MI oocytes from patients with a normal number of retrieved MII oocytes, while extended in vitro culture failed to achieve the MII stage. Similarly, ionomycin induced first PB extrusion in one of two patients with recurrent maturation-resistant MI oocytes. Use of ICSI combined with AOA on MII oocytes matured in vitro or in vivo resulted in failed or abnormal fertilization with no further embryo cleavage potential. Highly abnormal spindle and chromosome configurations were observed in MI maturation-resistant oocytes, in contrast to control MI oocytes. CONCLUSIONS Ionophore induced first PB extrusion in MI oocytes from patients without maturation arrest but to a lower extent in maturation-resistant MI oocytes. Immunofluorescence staining and confocal analysis revealed, for the first time, highly abnormal spindle/chromosomal structures that may be responsible for this maturation arrest.

Clinical effectiveness of elective single versus double embryo transfer: meta-analysis of individual patient data from randomised trials.

OBJECTIVE: To compare the effectiveness of elective single embryo transfer versus double embryo transfer on the outcomes of live birth, multiple live birth, miscarriage, preterm birth, term singleton birth, and low birth weight after fresh embryo transfer, and on the outcomes of cumulative live birth and multiple live birth after fresh and frozen embryo transfers. DESIGN: One stage meta-analysis of individual patient data. DATA SOURCES: A systematic review of English and non-English articles from Medline, Embase, and the Cochrane Central Register of Controlled Trials (up to 2008). Additional studies were identified by contact with clinical experts and searches of bibliographies of all relevant primary articles. Search terms included embryo transfer, randomised controlled trial, controlled clinical trial, single embryo transfer, and double embryo transfer. Review methods Comparisons of the clinical effectiveness of cleavage stage (day 2 or 3) elective single versus double embryo transfer after fresh or frozen in vitro fertilisation (IVF) or intracytoplasmic sperm injection (ICSI) treatments were included. Trials were included if the intervention differed only in terms of the intended number of embryos to be transferred. Trials that involved only blastocyst (day five) transfers were excluded. RESULTS: Individual patient data were received for every patient recruited to all eight eligible trials (n=1367). A total of 683 and 684 women randomised to the single and double embryo transfer arms, respectively, were included in the analysis. Baseline characteristics in the two groups were comparable. The overall live birth rate in a fresh IVF cycle was lower after single (181/683, 27%) than double embryo transfer (285/683, 42%) (adjusted odds ratio 0.50, 95% confidence interval 0.39 to 0.63), as was the multiple birth rate (3/181 (2%) v 84/285 (29%)) (0.04, 0.01 to 0.12). An additional frozen single embryo transfer, however, resulted in a cumulative live birth rate not significantly lower than the rate after one fresh double embryo transfer (132/350 (38%) v 149/353 (42%) (0.85, 0.62 to 1.15), with a minimal cumulative risk of multiple birth (1/132 (1%) v 47/149 (32%)). The odds of a term singleton birth (that is, over 37 weeks) after elective single embryo transfer was almost five times higher than the odds after double embryo transfer (4.93, 2.98 to 8.18). CONCLUSIONS: Elective single embryo transfer results in a higher chance of delivering a term singleton live birth compared with double embryo transfer. Although this strategy yields a lower pregnancy rate than a double embryo transfer in a fresh IVF cycle, this difference is almost completely overcome by an additional frozen single embryo transfer cycle. The multiple pregnancy rate after elective single embryo transfer is comparable with that observed in spontaneous pregnancies.