Siladitya Bhattacharya

Assisted reproductive technology in Europe, 2004: results generated from European registers by ESHRE

BACKGROUND European results of assisted reproductive techniques from treatments initiated during 2004 are presented in this eighth report. METHODS Data were mainly collected from existing national registers. From 29 countries, 785 clinics reported 367,066 treatment cycles including: IVF (114,672), ICSI (167,192), frozen embryo replacement (FER, 71,997), egg donation (ED, 10 334), preimplantation genetic diagnosis/screening (PGD/PGS, 2701) and in vitro maturation (IVM, 170). Overall, this represents only a marginal increase since 2003, due to a huge reduction in treatments in Germany. European data on intrauterine insemination using husband/partners semen (IUI-H) and donor semen (IUI-D) were reported from 20 countries. A total of 115,980 cycles (IUI-H, 98,388; IUI-D, 17,592) were included. RESULTS In 14 countries where all clinics reported to the IVF register, a total of 248,937 ART cycles were performed in a population of 261.6 million, corresponding to 1095 cycles per million inhabitants. For IVF, the clinical pregnancy rates per aspiration and per transfer were 26.6% and 30.1%, respectively. For ICSI, the corresponding rates were 27.1% and 29.8%. After IUI-H, the clinical pregnancy rate was 12.6% in women below 40. After IVF and ICSI, the distribution of transfer of 1, 2, 3 and 4 or more embryos was 19.2%, 55.3%, 22.1% and 3.3%, respectively. Compared with 2003, fewer embryos were transferred, but huge differences still existed between countries. The distribution of singleton, twin and triplet deliveries after IVF and ICSI combined was 77.2%, 21.7% and 1.0%, respectively. This gives a total multiple delivery rate of 22.7% compared with 23.1% in 2003 and 24.5% in 2002. After IUI-H in women below 40 years of age, 11.9% were twin and 1.3% triplet gestations. CONCLUSIONS Compared with earlier years, the reported number of ART cycles in Europe increased and the pregnancy rates increased marginally, even though fewer embryos were transferred and the multiple delivery rates were reduced.

Effect of Body Mass Index on pregnancy outcomes in nulliparous women delivering singleton babies

BackgroundThe increasing prevalence of obesity in young women is a major public health concern. These trends have a major impact on pregnancy outcomes in these women, which have been documented by several researchers. In a population based cohort study, using routinely collected data, this paper examines the effect of increasing Body Mass Index (BMI) on pregnancy outcomes in nulliparous women delivering singleton babies.MethodsThis was a retrospective cohort study, based on all nulliparous women delivering singleton babies in Aberdeen between 1976 and 2005. Women were categorized into five groups – underweight (BMI < 20 Kg/m2), normal (BMI 20 – 24.9 Kg/m2) overweight (BMI 25 – 29.9 Kg/m2), obese (BMI 30 – 34.9 Kg/m2) and morbidly obese (BMI > 35 Kg/m2). Obstetric and perinatal outcomes were compared by univariate and multivariate analyses.ResultsIn comparison with women of BMI 20 – 24.9, morbidly obese women faced the highest risk of pre-eclampsia {OR 7.2 (95% CI 4.7, 11.2)} and underweight women the lowest {OR 0.6 (95% CI 0.5, 0.7)}. Induced labour was highest in the morbidly obese {OR 1.8 (95% CI 1.3, 2.5)} and lowest in underweight women {OR 0.8 (95% CI 0.8, 0.9)}. Emergency Caesarean section rates were highest in the morbidly obese {OR 2.8 (95% CI 2.0, 3.9)}, and comparable in women with normal and low BMI. Obese women were more likely to have postpartum haemorrhage {OR 1.5 (95% CI 1.3, 1.7)} and preterm delivery (< 33 weeks) {OR 2.0 (95% CI 1.3, 2.9)}. Birthweights less than 2,500 g were more common in underweight women {OR 1.7 (95% OR 1.2, 2.0)}. The highest risk of birth weights > 4,000 g was in the morbidly obese {OR 2.1 (95% CI 1.3, 3.2)} and the lowest in underweight women {OR 0.5 (95% CI 0.4, 0.6)}.ConclusionIncreasing BMI is associated with increased incidence of pre-eclampsia, gestational hypertension, macrosomia, induction of labour and caesarean delivery; while underweight women had better pregnancy outcomes than women with normal BMI.

Association between the number of eggs and live birth in IVF treatment: an analysis of 400 135 treatment cycles

BACKGROUND While live birth is the principal clinical outcome following in vitro fertilization (IVF) treatment, the number of eggs retrieved following ovarian stimulation is often used as a surrogate outcome in clinical practice and research. The aim of this study was to explore the association between egg number and live birth following IVF treatment and identify the number of eggs that would optimize the IVF outcome. METHODS Anonymized data on all IVF cycles performed in the UK from April 1991 to June 2008 were obtained from the Human Fertilization and Embryology Authority (HFEA). We analysed data from 400 135 IVF cycles. A logistic model was fitted to predict live birth using fractional polynomials to handle the number of eggs as a continuous independent variable. The prediction model, which was validated on a separate HFEA data set, allowed the estimation of the probability of live birth for a given number of eggs, stratified by age group. We produced a nomogram to predict the live birth rate (LBR) following IVF based on the number of eggs and the age of the female. RESULTS The median number of eggs retrieved per cycle was 9 [inter-quartile range (IQR) 6-13]. The overall LBR was 21.3% per fresh IVF cycle. There was a strong association between the number of eggs and LBR; LBR rose with an increasing number of eggs up to ∼15, plateaued between 15 and 20 eggs and steadily declined beyond 20 eggs. During 2006-2007, the predicted LBR for women with 15 eggs retrieved in age groups 18-34, 35-37, 38-39 and 40 years and over was 40, 36, 27 and 16%, respectively. There was a steady increase in the LBR per egg retrieved over time since 1991. CONCLUSION The relationship between the number of eggs and live birth, across all female age groups, suggests that the number of eggs in IVF is a robust surrogate outcome for clinical success. The results showed a non-linear relationship between the number of eggs and LBR following IVF treatment. The number of eggs to maximize the LBR is ∼15.

Assisted reproductive technology in Europe, 2006: results generated from European registers by ESHRE

BACKGROUND In this 10th European IVF-monitoring (EIM) report, the results of assisted reproductive techniques from treatments initiated in Europe during 2006 are presented. Data were mainly collected from existing national registers. METHODS From 32 countries, 998 clinics reported 458 759 treatment cycles including: IVF (117 318), ICSI (232 844), frozen embryo replacement (FER, 86 059), egg donation (ED, 12 685), preimplantation genetic diagnosis/screening (6561), in vitro maturation (247) and frozen oocytes replacements (3498). Overall this represents a 9.7% increase in activity since 2005, which is partly due to an increase in registers (seven more countries with complete coverage). European data on intrauterine insemination using husband/partners (IUI-H) and donor (IUI-D) semen were reported from 22 countries. A total of 134 261 IUI-H and 24 339 IUI-D cycles were included. RESULTS In 20 countries, where all clinics reported to the IVF register, a total of 359 110 assisted reproductive technology (ART) cycles were performed in a population of 422.5 million, corresponding to 850 cycles per million inhabitants. For IVF, the clinical pregnancy rates per aspiration and per transfer were 29.0 and 32.4%, respectively. For ICSI, the corresponding rates were 29.9 and 33.0%. After IUI-H the delivery rate was 9.2% in women below 40. After IVF and ICSI the distribution of transfer of one, two, three and four or more embryos was 22.1, 57.3, 19.0 and 1.6%, respectively. Compared with 2005, fewer embryos were replaced per transfer, but significant national differences in practice were apparent. The proportion of singleton, twin and triplet deliveries after IVF and ICSI combined was 79.2, 19.9 and 0.9%, respectively. This gives a total multiple delivery rates of 20.8% compared with 21.8% in 2005 and 22.7% in 2004. IUI-H in women below 40 years of age resulted in 10.6% twin and 0.6% triplet pregnancies. CONCLUSIONS Compared with previous years, the reported number of ART cycles in Europe has increased, pregnancy rates have increased marginally, even though fewer embryos were transferred and the multiple delivery rates have declined.

Assisted reproductive technology and intrauterine inseminations in Europe, 2005: results generated from European registers by ESHRE ESHRE. The European IVF Monitoring Programme (EIM), for the European Society of Human Reproduction and Embryology (ESHRE)

BACKGROUND Results of assisted reproductive techniques from treatments initiated in Europe during 2005 are presented in this ninth report. Data were mainly collected from existing national registers. METHODS From 30 countries, 923 clinics reported 418 111 treatment cycles including: IVF (118 074), ICSI (203 329), frozen embryo replacement (79 140), oocyte donation (ED, 11 475), preimplantation genetic diagnosis/screening (5846) and in vitro maturation (247). Overall, this represents a 13.6% increase since 2004, partly due to inclusion of 28 417 cycles from Turkey. European data on intrauterine insemination using husband/partners semen (IUI-H) and donor semen (IUI-D) were reported from 21 countries and included 128 908 IUI-H and 20 568 IUI-D cycles. RESULTS In 16 countries where all clinics reported to the IVF register, 1115 cycles were performed per million inhabitants. For IVF, the clinical pregnancy rates per aspiration and per transfer were 26.9% and 30.3%, respectively. For ICSI, the corresponding rates were 28.5% and 30.9%. After IUI-H, the clinical pregnancy rate was 12.6% per insemination in women <40. After IVF and ICSI, the distribution of transfer of one, two, three and four or more embryos was 20.0%, 56.1%, 21.5% and 2.3%, respectively. Huge differences exist between countries. The distribution of singleton, twin and triplet deliveries after IVF and ICSI was 78.2%, 21.0% and 0.8%, respectively. This gives a total multiple delivery rate of 21.8% compared with 22.7% in 2004 and 23.1% in 2003. In women <40 years of age, IUI-H was associated with a twin and triplet pregnancy rate of 11.0% and 1.1%, respectively. CONCLUSIONS Compared with earlier years, there was an increase in the reported number of ART cycles in Europe. Although fewer embryos were transferred per treatment, there was a marginal increase in pregnancy rates and a reduction in multiple deliveries.

Obstetric and perinatal outcomes in singleton pregnancies resulting from IVF/ICSI: a systematic review and meta-analysis

BACKGROUND Earlier reviews have suggested that IVF/ICSI pregnancies are associated with higher risks. However, there have been recent advances in the way IVF/ICSI is done, leading to some controversy as to whether IVF/ICSI singletons are associated with higher perinatal risks. The objective of this systematic review was to provide an up-to-date comparison of obstetric and perinatal outcomes of the singletons born after IVF/ICSI and compare them with those of spontaneous conceptions. METHODS Extensive searches were done by two authors. The protocol was agreed a priori. PRISMA guidance was followed. The data were extracted in 2 × 2 tables. Risk ratio and risk difference were calculated on pooled data using Rev Man 5.1. Quality assessment of studies was performed using Critical Appraisal Skills programme. Sensitivity analysis was performed when the heterogeneity was high (I(2) > 50%). RESULTS There were 20 matched cohort studies and 10 unmatched cohort studies included in this review. IVF/ICSI singleton pregnancies were associated with a higher risk (95% confidence interval) of ante-partum haemorrhage (2.49, 2.30-2.69), congenital anomalies (1.67, 1.33-2.09), hypertensive disorders of pregnancy (1.49, 1.39-1.59), preterm rupture of membranes (1.16, 1.07-1.26), Caesarean section (1.56, 1.51-1.60), low birthweight (1.65, 1.56-1.75), perinatal mortality (1.87, 1.48-2.37), preterm delivery (1.54, 1.47-1.62), gestational diabetes (1.48, 1.33-1.66), induction of labour (1.18, 1.10-1.28) and small for gestational age (1.39, 1.27-1.53). CONCLUSIONS Singletons pregnancies after IVF/ICSI are associated with higher risks of obstetric and perinatal complications when compared with spontaneous conception. Further research is needed to determine which aspect of assisted reproduction technology poses most risk and how this risk can be minimized.

Obstetric and perinatal outcomes in singleton pregnancies resulting from the transfer of frozen thawed versus fresh embryos generated through in vitro fertilization treatment: a systematic review and meta-analysis

OBJECTIVE To perform a systematic review and meta-analysis of obstetric and perinatal complications in singleton pregnancies after the transfer of frozen thawed and fresh embryos generated through IVF. DESIGN Systematic review. SETTING Observational studies, comparing obstetric and perinatal outcomes in singleton pregnancies subsequent to frozen thawed ET versus fresh embryo transfer, were included from Medline, EMBASE, Cochrane Central Register of Clinical Trials, DARE, and CINAHL (1984-2012). PATIENT(S) Women undergoing IVF/intracytoplasmic sperm injection (ICSI). INTERVENTION(S) Two independent reviewers extracted data and assessed the methodological quality of the relevant studies using critical appraisal skills program scoring. Risk ratios and risk differences were calculated in Rev Man 5.1. Subgroup analysis was performed on matched cohort studies. MAIN OUTCOME MEASURE(S) Antepartum hemorrhage, very preterm birth, preterm birth, small for gestational age, low birth weight, very low birth weight, cesarean section, congenital anomalies, perinatal mortality, and admission to neonatal intensive care unit. RESULT(S) Eleven studies met the inclusion criteria. Singleton pregnancies after the transfer of frozen thawed embryos were associated with better perinatal outcomes compared with those after fresh IVF embryos. The relative risks (RR) and 95% confidence intervals (CI) of antepartum hemorrhage (RR = 0.67, 95% CI 0.55-0.81), preterm birth (RR = 0.84, 95% CI 0.78-0.90), small for gestational age (RR = 0.45, 95% CI 0.30-0.66), low birth weight (RR = 0.69, 95% CI 0.62-0.76), and perinatal mortality (RR = 0.68, 95% CI 0.48-0.96) were lower in women who received frozen embryos. CONCLUSION(S) Although fresh ET is the norm in IVF, results of this systematic review of observational studies suggest that pregnancies arising from the transfer of frozen thawed IVF embryos seem to have better obstetric and perinatal outcomes.

Maternal obesity during pregnancy and premature mortality from cardiovascular event in adult offspring: follow-up of 1 323 275 person years

Objectives To determine whether maternal obesity during pregnancy is associated with increased mortality from cardiovascular events in adult offspring. Design Record linkage cohort analysis. Setting Birth records from the Aberdeen Maternity and Neonatal databank linked to the General Register of Deaths, Scotland, and the Scottish Morbidity Record systems. Population 37 709 people with birth records from 1950 to present day. Main outcome measures Death and hospital admissions for cardiovascular events up to 1 January 2012 in offspring aged 34-61. Maternal body mass index (BMI) was calculated from height and weight measured at the first antenatal visit. The effect of maternal obesity on outcomes in offspring was tested with time to event analysis with Cox proportional hazard regression to compare outcomes in offspring of mothers in underweight, overweight, or obese categories of BMI compared with offspring of women with normal BMI. Results All cause mortality was increased in offspring of obese mothers (BMI >30) compared with mothers with normal BMI after adjustment for maternal age at delivery, socioeconomic status, sex of offspring, current age, birth weight, gestation at delivery, and gestation at measurement of BMI (hazard ratio 1.35, 95% confidence interval 1.17 to 1.55). In adjusted models, offspring of obese mothers also had an increased risk of hospital admission for a cardiovascular event (1.29, 1.06 to 1.57) compared with offspring of mothers with normal BMI. The offspring of overweight mothers also had a higher risk of adverse outcomes. Conclusions Maternal obesity is associated with an increased risk of premature death in adult offspring. As one in five women in the United Kingdom is obese at antenatal booking, strategies to optimise weight before pregnancy are urgently required.

Assisted reproductive technology in Europe, 2009: results generated from European registers by ESHRE

STUDY QUESTION The 13th European in vitro fertilization (IVF)-monitoring (EIM) report presents the results of treatments involving assisted reproductive technology (ART) initiated in Europe during 2009: are there any changes in the trends compared with previous years? SUMMARY ANSWER Despite some fluctuations in the number of countries reporting data, the overall number of ART cycles has continued to increase year by year and, while pregnancy rates in 2009 remained similar to those reported in 2008, the number of transfers with multiple embryos (3+) and the multiple delivery rates declined. WHAT IS KNOWN ALREADY Since 1997, ART data in Europe have been collected and reported in 12 manuscripts, published in Human Reproduction. STUDY DESIGN, SIZE, DURATION Retrospective data collection of European ART data by the EIM Consortium for the European Society of Human Reproduction and Embryology (ESHRE); cycles started between 1st January and 31st December are collected on a yearly basis; the data are collected by the National Registers, when existing, or on a voluntary basis. PARTICIPANTS/MATERIALS SETTING, METHODS From 34 countries (-2 compared with 2008), 1005 clinics reported 537 463 treatment cycles including: IVF (135 621), intracytoplasmic sperm injection (ICSI, 266 084), frozen embryo replacement (FER, 104 153), egg donation (ED, 21 604), in vitro maturation (IVM, 1334), preimplantation genetic diagnosis/screening (PGD/PGS, 4389) and frozen oocyte replacements (FOR, 4278). European data on intrauterine insemination using husband/partners semen (IUI-H) and donor (IUI-D) semen were reported from 21 and 18 countries, respectively. A total of 162 843 IUI-H (+12.7%) and 29 235 IUI-D (+17.3%) cycles were included. Data available from each country are presented in the tables; total values (as numbers and percentages) refer to those countries where all data have been reported. MAIN RESULTS AND THE ROLE OF CHANCE In 21 countries where all clinics reported to the ART register, a total of 399 020 ART cycles were performed in a population of 373.8 million, corresponding to 1067 cycles per million inhabitants. For IVF, the clinical pregnancy rates per aspiration and per transfer were 28.9 and 32.9%, respectively and for ICSI, the corresponding rates were 28.7 and 32.0%. In FER cycles, the pregnancy rate per thawing was 20.9%; in ED cycles, the pregnancy rate per transfer was 42.3%. The delivery rate after IUI-H was 8.3 and 13.4% after IUI-D. In IVF and ICSI cycles, 1, 2, 3 and 4+ embryos were transferred in 24.2, 57.7, 16.9 and 1.2%, respectively. The proportions of singleton, twin and triplet deliveries after IVF and ICSI (combined) were 79.8, 19.4 and 0.8%, respectively, resulting in a total multiple delivery rate of 20.2%, compared with 21.7% in 2008, 22.3% in 2007, 20.8% in 2006 and 21.8% in 2005. In FER cycles, the multiple delivery rate was 13.0% (12.7% twins and 0.3% triplets). Twin and triplet delivery rates associated with IUI cycles were 10.4/0.7% and 10.3/0.5%, following treatment with husband and donor semen, respectively. LIMITATIONS, REASONS FOR CAUTION The method of reporting varies among countries, and registers from a number of countries have been unable to provide some of the relevant data such as initiated cycles and deliveries. As long as data are incomplete and generated through different methods of collection, results should be interpreted with caution. WIDER IMPLICATIONS OF THE FINDINGS The 13th ESHRE report on ART shows a continuing expansion of the number of treatment cycles in Europe, with more than half a million of cycles reported in 2009. The use of ICSI has reached a plateau. Pregnancy and delivery rates after IVF and ICSI remained relatively stable compared with 2008 and 2007. The number of multiple embryo transfers (3+ embryos) and the multiple delivery rate have shown a clear decline.

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.