Talk:Assisted Reproductive Technology
Association of In Vitro Fertilization With Childhood Cancer in the United States
Spector LG, Brown MB, Wantman E, et al. Association of In Vitro Fertilization With Childhood Cancer in the United States. JAMA Pediatr. Published online April 01, 2019. doi:10.1001/jamapediatrics.2019.0392
This study found a small association of IVF with overall cancers of early childhood, but it did observe an increased rate of embryonal cancers, particularly hepatic tumors, that could not be attributed to IVF rather than to underlying infertility. Continued follow-up for cancer occurrence among children conceived via IVF is warranted.
Conclusions We found, at most, a small, marginally significant association between IVF and overall cancer in childhood. We found no association of specific modes of IVF treatment or indication for IVF with overall cancer or embryonal tumors. Although we observed increased rates of embryonal cancers, particularly hepatic tumors, these cancers remained rare in absolute terms. We also could not attribute the increased rate to treatment per se rather than to underlying infertility. Despite the large size of the study, these results do not definitively establish an association between IVF and embryonal tumors. These results suggest that continued follow-up of children conceived via IVF for cancer occurrence is warranted, while other approaches to understanding potential mechanisms should also be pursued, for instance, by comparing the somatic epigenetic landscape of tumors in children conceived via IVF with children conceived naturally.
see also earlier paper 26908669
Mitochondrial replacement therapy and assisted reproductive technology: A paradigm shift toward treatment of genetic diseases in gametes or in early embryos
Reprod Med Biol. 2018 Sep 19;17(4):421-433. doi: 10.1002/rmb2.12230. eCollection 2018 Oct.
Tachibana M1, Kuno T1, Yaegashi N1.
BACKGROUND: Recent technological development allows nearly complete replacement of the cytoplasm of egg/embryo, eliminating the transmission of undesired defective mitochondria (mutated mitochondrial DNA: mtDNA) for patients with inherited mitochondrial diseases, which is called mitochondrial replacement therapy (MRT). METHODS: We review and summarize the mitochondrial biogenesis and mitochondrial diseases, the research milestones and future research agenda of MRT and also discuss MRT-derived potential application in common assisted reproductive technology (ART) treatment for subfertile patients. MAIN FINDINGS: Emerging techniques, involving maternal spindle transfer (MST) and pronuclear transfer (PNT), have demonstrated in preventing carryover of the unbidden (mutated) mtDNA in egg or in early embryos. The House of Parliament in the United Kingdom passed regulations permitting the use of MST and PNT in 2015. Furthermore, the Human Fertilization and Embryology Authority (HFEA) to granted licenses world first use of those techniques in March 2017. However, recent evidence demonstrated gradual loss of donor mtDNA and reversal to the nuclear DNA-matched haplotype in MRT derivatives. CONCLUSION: While further studies are needed to clarify mitochondrial biogenesis responsible for reversion, ruling in United Kingdom may shift the current worldwide consensus that prohibits gene modification in human gametes or embryos, toward allowing the correction of altered genes in germline. KEYWORDS: germ line gene therapy; maternal spindle transfer (MST); mitochondrial bottleneck effect; mitochondrial diseases; mitochondrial replacement therapy (MRT) PMID: 30377395 PMCID: PMC6194288 DOI: 10.1002/rmb2.12230
Severity of congenital heart defects associated with assisted reproductive technologies: Case series and review of the literature
Birth Defects Res. 2018 May 1;110(8):654-661. doi: 10.1002/bdr2.1228.
Patil AS1, Nguyen C2, Groff K2, Wu J2, Elliott J1, Gunatilake RP1.
OBJECTIVE: Assisted reproductive technology (ART) has been associated with a higher incidence of congenital anomalies, including a specific increase in the rate of congenital heart defects (CHD). In this study, the rate of CHD in pregnancies resulting from ART at a single high-risk pregnancy referral center are compared to the published literature. METHODS: Pregnancies were screened by fetal echocardiography for the indication of ART over a 2-year period. CHD were classified as either mild or severe based on the need for postnatal surgical intervention. Results were compared to findings from a literature review of studies examining CHD in pregnancies resulting from ART since 1980. RESULTS: Over the course of two years, 363 fetuses in 264 pregnancies from our cohort were screened for CHD. The incidence of mild CHD in fetuses from ART pregnancies was 2.75% (10 out of 363 fetuses). None of the affected fetuses had severe CHD. Review of the literature yielded 20 studies since 1980 that examined CHD in pregnancies resulting from ART. Composite data from the studies was described based on characterization of severity of the CHD anomalies. The incidence of mild CHD in ART pregnancies was 2.2%, compared to 1% in non-ART pregnancies (out of 332,157 infants). The incidence of severe CHD in ART pregnancies and naturally conceived pregnancies was 1.4% and 1.2%, respectively (out of 661,455 infants). The incidence of unspecified CHD in ART pregnancies was 1.8%, compared to 1% in naturally conceived pregnancies (out of 1,593,277 infants). CONCLUSION: The greatest increase in risk appears to be for mild CHD (nonsurgical), which may inform counseling of patients prior to use of assisted reproductive technologies. © 2018 Wiley Periodicals, Inc. KEYWORDS: IVF; atrial septal defects; coarctation of the aorta; congenital heart defects; hypoplastic left heart syndrome; tetralogy of fallot; ventricular septal defects PMID: 29714054 DOI: 10.1002/bdr2.1228
New national outcome data on fresh versus cryopreserved donor oocytes
J Ovarian Res. 2018 Jan 5;11(1):2. doi: 10.1186/s13048-017-0378-4.
Kushnir VA1,2, Darmon SK3, Barad DH3,4, Gleicher N3,4,5,6.
BACKGROUND: Improvements in oocyte cryopreservation techniques and establishment of cryopreserved donor oocyte banks have led to improved access to and lower cost of donor oocytes, upending the traditional practice of fresh oocyte donation. The objective of this study was to examine national trends in utilization and live birth rates with fresh versus cryopreserved donor oocytes. METHODS: A retrospective analysis of 2013 through 2015 aggregate U.S. national data reported by the Society for Assisted Reproductive Technology which included 30,160 IVF cycles with either fresh or cryopreserved donor oocytes was performed. RESULTS: During the study period utilization of fresh oocyte donations rapidly declined by 32.9%, while cryopreserved oocyte donation increased by 44.4%. Fresh donor oocytes produced significantly higher live birth rates per recipient cycle start than cryopreserved donor oocytes (51.1% vs. 39.7%). Over the three-year study period fresh donor oocytes produced stable live birth rates per recipient cycle start while those with cryopreserved oocytes significantly declined year-by-year. CONCLUSION: Despite rising popularity of cryopreserved donor oocytes, prospective patients should be counselled that fresh donor oocytes still represent standard of care due to higher live birth rates. KEYWORDS: Cryopreservation; In vitro fertilization; Oocyte donation; Vitrification PMID: 29304839 PMCID: PMC5755289 DOI: 10.1186/s13048-017-0378-4
Inter-laboratory agreement on embryo classification and clinical decision: Conventional morphological assessment vs. time lapse
PLoS One. 2017 Aug 25;12(8):e0183328. doi: 10.1371/journal.pone.0183328. eCollection 2017.
Martínez-Granados L1, Serrano M2, González-Utor A3, Ortíz N4, Badajoz V5, Olaya E6, Prados N7, Boada M8, Castilla JA1,9,10; Special Interest Group in Quality of ASEBIR (Spanish Society for the Study of Reproductive Biology). Author information Abstract The aim of this study is to determine inter-laboratory variability on embryo assessment using time-lapse platform and conventional morphological assessment. This study compares the data obtained from a pilot study of external quality control (EQC) of time lapse, performed in 2014, with the classical EQC of the Spanish Society for the Study of Reproductive Biology (ASEBIR) performed in 2013 and 2014. In total, 24 laboratories (8 using EmbryoScope™, 15 using Primo Vision™ and one with both platforms) took part in the pilot study. The clinics that used EmbryoScope™ analysed 31 embryos and those using Primo Vision™ analysed 35. The classical EQC was implemented by 39 clinics, based on an analysis of 25 embryos per year. Both groups were required to evaluate various qualitative morphological variables (cell fragmentation, the presence of vacuoles, blastomere asymmetry and multinucleation), to classify the embryos in accordance with ASEBIR criteria and to stipulate the clinical decision taken. In the EQC time-lapse pilot study, the groups were asked to determine, as well as the above characteristics, the embryo development times, the number, opposition and size of pronuclei, the direct division of 1 into 3 cells and/or of 3 into 5 cells and false divisions. The degree of agreement was determined by calculating the intra-class correlation coefficients and the coefficient of variation for the quantitative variables and the Gwet index for the qualitative variables. For both EmbryoScope™ and Primo Vision™, two periods of greater inter-laboratory variability were observed in the times of embryo development events. One peak of variability was recorded among the laboratories addressing the first embryo events (extrusion of the second polar body and the appearance of pronuclei); the second peak took place between the times corresponding to the 8-cell and morula stages. In most of the qualitative variables analysed regarding embryo development, there was almost-perfect inter-laboratory agreement among conventional morphological assessment (CMA), EmbryoScope™ and Primo Vision™, except for false divisions, vacuoles and asymmetry (users of all methods) and multinucleation (users of Primo Vision™), where the degree of agreement was lower. The inter-laboratory agreement on embryo classification according to the ASEBIR criteria was moderate-substantial (Gwet 0.41-0.80) for the laboratories using CMA and EmbryoScope™, and fair-moderate (Gwet 0.21-0.60) for those using Primo Vision™. The inter-laboratory agreement for clinical decision was moderate (Gwet 0.41-0.60) on day 5 for CMA users and almost perfect (Gwet 0.81-1) for time-lapse users. In conclusion, time-lapse technology does not improve inter-laboratory agreement on embryo classification or the analysis of each morphological variable. Moreover, depending on the time-lapse platform used, inter-laboratory agreement may be lower than that obtained by CMA. However, inter-laboratory agreement on clinical decisions is improved with the use of time lapse, regardless of the platform used. PMID: 28841654 PMCID: PMC5571938 DOI: 10.1371/journal.pone.0183328
Does Embryo Culture Medium Influence the Health and Development of Children Born after In Vitro Fertilisation?
PLoS One. 2016 Mar 23;11(3):e0150857. doi: 10.1371/journal.pone.0150857. eCollection 2016.
Bouillon C1, Léandri R2, Desch L3, Ernst A4, Bruno C3, Cerf C4, Chiron A5, Souchay C4, Burguet A6, Jimenez C7, Sagot P8, Fauque P3.
In animal studies, extensive data revealed the influence of culture medium on embryonic development, foetal growth and the behaviour of offspring. However, this impact has never been investigated in humans. For the first time, we investigated in depth the effects of embryo culture media on health, growth and development of infants conceived by In Vitro Fertilization until the age of 5 years old. This single-centre cohort study was based on an earlier randomized study. During six months, in vitro fertilization attempts (No. 371) were randomized according to two media (Single Step Medium-SSM group) or Global medium (Global group). This randomized study was stopped prematurely as significantly lower pregnancy and implantation rates were observed in the SSM group. Singletons (No. 73) conceived in the randomized study were included (42 for Global and 31 for SSM). The medical data for gestational, neonatal and early childhood periods were extracted from medical records and parental interviews (256 variables recorded). The developmental profiles of the children in eight domains (social, self-help, gross motor, fine motor, expressive language, language comprehension, letter knowledge and number knowledge - 270 items) were compared in relation to the culture medium. The delivery rate was significantly lower in the SSM group than in the Global group (p<0.05). The culture medium had no significant effect on birthweight, risk of malformation (minor and major), growth and the frequency of medical concerns. However, the children of the Global group were less likely than those of the SSM group to show developmental problems (p = 0.002), irrespective of the different domains. In conclusion, our findings showed that the embryo culture medium may have an impact on further development.
Assisted reproductive technology and the risk of preterm birth among primiparas
Fertil Steril. 2015 Apr;103(4):974-979.e1. doi: 10.1016/j.fertnstert.2015.01.015. Epub 2015 Feb 20.
Dunietz GL1, Holzman C2, McKane P3, Li C2, Boulet SL4, Todem D2, Kissin DM4, Copeland G5, Bernson D6, Sappenfield WM7, Diamond MP8.
OBJECTIVE: To investigate the risk of preterm birth among liveborn singletons to primiparas who conceived with assisted reproductive technology (ART) using four mutually exclusive categories of infertility (female infertility only, male infertility only, female and male infertility, and unexplained infertility) and to examine preterm birth risk along the gestational age continuum. DESIGN: Retrospective cohort study. SETTING: Not applicable. PATIENT(S): Singletons born to primiparas who conceived with or without ART. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Preterm (<37 weeks' gestation) and preterm/early term birth <39 weeks' gestation). RESULT(S): For the male infertility only, female infertility only, combined male and female infertility, and unexplained infertility groups, ART-conceived singletons were significantly more likely than non-ART singletons to be born preterm: adjusted odds ratio (aOR) 1.24 (95% CI, 1.13, 1.37), aOR 1.60 (95% CI, 1.50, 1.70), aOR 1.49 (95% CI, 1.35, 1.64), and aOR 1.26 (1.12, 1.43) respectively. Among infants whose mothers were diagnosed with infertility, the odds of preterm birth were highest between 28-30 weeks [female infertility only, aOR 1.95 (95% CI, 1.59, 2.39); male and female infertility: 2.21 (95% CI, 1.62, 3.00)] compared with infants in the general population. Within the ART population, singletons of couples with female infertility only were more likely to be born preterm than singletons born to couples with other infertility diagnoses. CONCLUSION(S): Among singleton births to primiparas, those conceived with ART had an increased risk for preterm birth, even when only the male partner had been diagnosed with infertility. The risk of preterm birth for ART-conceived infants whose mothers were diagnosed with infertility included the earliest deliveries. Copyright © 2015 American Society for ReproductiveMedicine. All rights reserved. KEYWORDS: Assisted reproductive technology (ART); infertility; preterm birth
In vitro fertilization with preimplantation genetic screening improves implantation and live birth in women age 40 through 43
J Assist Reprod Genet. 2015 Mar;32(3):435-44. doi: 10.1007/s10815-014-0417-7. Epub 2015 Jan 13.
Lee HL1, McCulloh DH, Hodes-Wertz B, Adler A, McCaffrey C, Grifo JA.
PURPOSE: In Vitro Fertilization is an effective treatment for infertility; however, it has relatively low success in women of advanced maternal age (>37) who have a high risk of producing aneuploid embryos, resulting in implantation failure, a higher rate of miscarriage or birth of a child with chromosome abnormalities. The purpose of this study was to compare the implantation, miscarriage and live birth rates with and without preimplantation genetic screening (PGS) of embryos from patients aged 40 through 43 years. METHODS: This is a retrospective cohort study, comparing embryos screened for ploidy using trophectoderm biopsy and array comparative genomic hybridization to embryos that were not screened. We compared pregnancy outcomes for traditional fresh IVF cycles with day 5 embryo transfers, Frozen Embryo Transfer (FET) cycles without PGS and PGS-FET (FET of only euploid embryos) cycles of patients with maternal ages ranging from 40 to 43 years, undergoing oocyte retrievals during the period between 1/1/2011 and 12/31/2012. RESULTS: The implantation rate of euploid embryos transferred in FET cycles (50.9 %) was significantly greater than for unscreened embryos transferred in either fresh (23.8 %) or FET (25.4 %) cycles. The incidence of live birth per transferred embryo for PGS-FET (45.5 %) was significantly greater than for No PGS fresh (15.8 %) or No PGS FET (19.0 %) cycles. The incidences of live birth per implanted sac for PGS FET cycles (89.3 %), No PGS fresh cycles (66.7 %) and No PGS FET cycles (75.0 %) were not significantly different. CONCLUSIONS: The present data provides evidence of the benefits of PGS with regard to improved implantation and live birth rate per embryo transferred.
Applying metabolomic analyses to the practice of embryology: physiology, development and assisted reproductive technology
Reprod Fertil Dev. 2015 Mar 13. doi: 10.1071/RD14359.
Krisher RL, Heuberger AL, Paczkowski M, Stevens J, Pospisil C, Prather RS, Sturmey RG, Herrick JR, Schoolcraft WB.
The advent of metabolomics technology and its application to small samples has allowed us to non-invasively monitor the metabolic activity of embryos in a complex culture environment. The aim of this study was to apply metabolomics technology to the analysis of individual embryos from several species during in vitro development to gain an insight into the metabolomics pathways used by embryos and their relationship with embryo quality. Alanine is produced by both in vivo- and in vitro-derived human, murine, bovine and porcine embryos. Glutamine is also produced by the embryos of these four species, but only those produced in vitro. Across species, blastocysts significantly consumed amino acids from the culture medium, whereas glucose was not significantly taken up. There are significant differences in the metabolic profile of in vivo- compared with in vitro-produced embryos at the blastocyst stage. For example, in vitro-produced murine embryos consume arginine, asparagine, glutamate and proline, whereas in vivo-produced embryos do not. Human embryos produce more alanine, glutamate and glutamine, and consume less pyruvate, at the blastocyst compared with cleavage stages. Glucose was consumed by human blastocysts, but not at a high enough level to reach significance. Consumption of tyrosine by cleavage stage human embryos is indicative of blastocyst development, although tyrosine consumption is not predictive of blastocyst quality. Similarly, although in vivo-produced murine blastocysts consumed less aspartate, lactate, taurine and tyrosine than those produced in vitro, consumption of these four amino acids by in vitro-derived embryos with high octamer-binding transcription factor 4 (Oct4) expression, indicative of high quality, did not differ from those with low Oct4 expression. Further application of metabolomic technologies to studies of the consumption and/or production of metabolites from individual embryos in a complete culture medium could transform our understanding of embryo physiology and improve our ability to produce developmentally competent embryos in vitro. PMID 25763765
Surveillance of congenital malformations in infants conceived through assisted reproductive technology or other fertility treatments
Birth Defects Res A Clin Mol Teratol. 2015 Feb 12. doi: 10.1002/bdra.23355. [Epub ahead of print]
Heisey AS1, Bell EM, Herdt-Losavio ML, Druschel C.
BACKGROUND: As assisted reproductive technology (ART) becomes more common, it is important to understand the associated risks. The objective of this study was to determine if congenital malformations are associated with ART or other fertility treatments in New York. METHODS: In a retrospective cohort study of all live births in upstate New York from 1997 to 2005, exposure was defined using ART or other fertility treatments as noted on birth certificates. Outcomes were assessed from the New York State Congenital Malformations Registry. Specific malformations were examined to determine if there is elevated risk for exposed singleton infants compared with infants conceived naturally. RESULTS: The study included 7120 in the ART group, 11,890 in the other fertility treatments group and 1,118,162 in the comparison group. The relative risk for a congenital malformation was 1.43 (95% CI 1.19-1.72) for singleton infants conceived through ART compared with singleton infants conceived naturally. The specific defects associated with ART were patent ductus arteriosus, hypospadias, and obstructive defect in the renal pelvis and ureter, while spina bifida, other specific anomalies of the spinal cord, atresia or stenosis of the pulmonary valve, hypospadias, and obstructive defects of the renal pelvis and ureter were associated with other fertility treatment. CONCLUSION: Assisted reproductive technology is associated with a slight excess risk of birth defects. The specific congenital malformations with elevated risks for singleton infants vary depending on the exposure. Further research is necessary to understand the mechanism related to the increase in risk. Birth Defects Research (Part A), 2015. © 2015 Wiley Periodicals, Inc. © 2015 Wiley Periodicals, Inc. KEYWORDS: IVF; assisted reproductive technology (ART); birth defects; congenital malformations; reproductive epidemiology
Comparison of Genome-Wide and Gene-Specific DNA Methylation between ART and Naturally Conceived Pregnancies
Epigenetics. 2015 Jan 12:0. [Epub ahead of print]
Melamed N1, Choufani S, Wilkins-Haug LE, Koren G, Weksberg R.
ABSTRACT Data linking assisted reproductive technologies (ART) with aberrant DNA methylation is limited and inconclusive. In addition, most studies to date have analyzed only a small number of CpG sites and focused on methylation changes in placentas, while data on cord blood are scarce. Our aim was to compare DNA methylation in cord blood samples from ART (N = 10) and control pregnancies (N = 8) using a genome-wide approach with the Illumina® Infinium Human Methylation27 array, which interrogates 27,578 CpG sites. A total of 733 (2.7%) of the CpG sites were significantly differentially methylated between the two groups (P < 0.05), with an overall relative hypomethylation in the ART group (P < 0.001). Differences in DNA methylation were more pronounced for CpG sites in certain types of genomic locations and were related to baseline methylation levels and distance from CpG islands and transcription start sites. ART was associated with significantly higher variation in DNA methylation, suggesting that differences in DNA methylation between cases and controls may result from a stochastic increase in genome-wide DNA methylation in IVF pregnancies. We identified 24 candidate genes with 2 or more CpG sites that were significantly different between the IVF and control groups. The current study provides support for the hypothesis that ART-associated subfertility may be associated with genome-wide changes in DNA methylation, and these changes appear to be, at least in part, due to epigenetic instability in ART pregnancies. Further studies are required in order to determine the extent to which such ART-related epigenetic instability may have phenotypic consequences.
Live birth after artificial oocyte activation using a ready-to-use ionophore: a prospective multi centre study
Reprod Biomed Online. 2014 Dec 9. pii: S1472-6483(14)00642-7. doi: 10.1016/j.rbmo.2014.11.012. [Epub ahead of print]
Ebner T1, Montag M2; Oocyte Activation Study Group, Montag M2, Van der Ven K2, Van der Ven H2, Ebner T3, Shebl O3, Oppelt P3, Hirchenhain J4, Krüssel J4, Maxrath B5, Gnoth C5, Friol K5, Tigges J5, Wünsch E6, Luckhaus J6, Beerkotte A6, Weiss D7, Grunwald K7, Struller D8, Etien C8.
Artificial oocyte activation has been proposed as a suitable means to overcome the problem of failed or impaired fertilization after intracytoplasmic sperm injection (ICSI). In a multicentre setting artificial oocyte activation was applied to 101 patients who were diagnosed with fertilization abnormalities (e.g. less than 50% fertilized oocytes) in a previous conventional ICSI cycle. Female gametes were activated for 15 min immediately after ICSI using a ready-to-use Ca2+-ionophore solution (A23187). Fertilization, pregnancy and live birth rates were compared with the preceding cycle without activation. The fertilization rate of 48% in the study cycles was significantly higher compared with the 25% in the control cycles (P < 0.001). Further splitting of the historical control group into failed (0%), low (1-30%) and moderate fertilization rate (31-50%) showed that all groups significantly benefitted (P < 0.001) in the ionophore cycle. Fewer patients had their embryo transfer cancelled compared with their previous treatments (1/101 versus 15/101). In total, 99% of the patients had an improved outcome with A23187 application resulting in a 28% live birth rate (35 babies). These data suggest that artificial oocyte activation using a ready-to-use compound is an efficient method. Copyright © 2014 Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved. KEYWORDS: activation failure; calcium; fertilization; ionophore A23187; oocyte; sperm
Births Resulting From Assisted Reproductive Technology: Comparing Birth Certificate and National ART Surveillance System Data, 2011
Natl Vital Stat Rep. 2014 Dec;63(8):1-12.
Thoma ME, Boulet S, Martin JA, Kissin D.
Objectives-This report compares data on births resulting from assisted reproductive technology (ART) procedures from 2011 birth certificates with data from the 2011 National ART Surveillance System (NASS) among the subset of jurisdictions that adopted the 2003 revised birth certificate as of January 1, 2011, with information on ART. Methods-Birth certificate data are based on 100% of births registered in 27 states and the District of Columbia. NASS data included all ART cycles initiated in 2010 or 2011 for which a live birth in 2011 was reported. The same reporting area was used for both data sources and represents 67% of all births in the United States in 2011. A ratio was computed by dividing the percentage of births resulting from ART procedures for NASS data by the percentage for birth certificate data. A ratio of 1.0 represents equivalent levels of reporting. Because this reporting area is not a random sample of births, the results are not generalizable to the United States as a whole. Results-Overall, the percentage of births resulting from ART procedures was 2.06 times higher for NASS data (1.44%) compared with birth certificate data (0.70%). The ratio for each jurisdiction varied from 1.04 for Utah and Wisconsin to 7.50 for Florida. Higher-risk groups had more consistent reporting between data sources [e.g., triplet or higher-order multiples (1.36) compared with singletons (2.11)]. Conclusions-Births resulting from ART procedures appear to be underreported on the birth certificate; however, the magnitude of underreporting varied by jurisdiction and maternal-infant health characteristics. All material appearing in this report is in the public domain and may be reproduced or copied without permission; citation as to source, however, is appreciated.
Birthweight percentiles by gestational age for births following assisted reproductive technology in Australia and New Zealand, 2002-2010
Hum Reprod. 2014 Jun 7. pii: deu120. [Epub ahead of print]
Li Z1, Wang YA1, Ledger W2, Sullivan EA3.
STUDY QUESTION: What is the standard of birthweight for gestational age for babies following assisted reproductive technology (ART) treatment? SUMMARY ANSWER: Birthweight for gestational age percentile charts were developed for singleton births following ART treatment using population-based data. WHAT IS KNOWN ALREADY: Small for gestational age (SGA) and large for gestational age (LGA) births are at increased risks of perinatal morbidity and mortality. A birthweight percentile chart allows the detection of neonates at high risk, and can help inform the need for special care if required. STUDY DESIGN, SIZE, DURATION: This population study used data from the Australian and New Zealand Assisted Reproduction Database (ANZARD) for 72 694 live born singletons following ART treatment between January 2002 and December 2010 in Australia and New Zealand. PARTICIPANTS/MATERIALS, SETTING, METHODS: A total of 69 315 births (35 580 males and 33 735 females) following ART treatment were analysed for the birthweight percentile. Exact percentiles of birthweight in grams were calculated for each gestational week between Week 25 and 42 for fresh and thaw cycles by infant sex. Univariate analysis was used to determine the exact birthweight percentile values. Student t-test was used to examine the mean birthweight difference between male and female infants, between single embryo transfer (SET) and double embryo transfer (DET) and between fresh and thaw cycles. MAIN RESULTS AND THE ROLE OF CHANCE: Preterm births (birth before 37 completed weeks of gestation) and low birthweight (<2500 g) were reported for 9.7 and 7.0% of live born singletons following ART treatment. The mean birthweight was 3280 g for live born singletons following fresh cycles (3338 g for male infants and 3217 for female infants) and 3413 g for live born singletons following thaw cycles (3475 g for male infants and 3349 for female infants). The proportion of SGA for male ART births following thaw cycles at 35-41 weeks gestation was significantly lower than for the Australian general population, ranging from 3.8% (95% confidence interval (CI): 1.3%, 6.2%) at 35 weeks gestation to 7.9% (95% CI: 6.3%, 9.5%) at 41 weeks gestation. The proportion of LGA for male ART births following thaw cycles was significantly higher than for the Australian general population between 33 weeks (17.1%, 95% CI: 8.9%, 25.2%) and 41 weeks (14.4%, 95% CI: 12.3%, 16.5%). A similar trend was shown for female infants following thaw cycles. The live born singletons following SET were, on average, 45 g heavier than live born singletons following DET (P< 0.001). Overall, SGA was reported for 8.9% (95% CI: 8.6%, 9.1%) of live born singletons following SET and for 9.9% (95% CI: 9.5%, 10.3%) of live born singletons following DET. LIMITATIONS, REASONS FOR CAUTION: Birthweight percentile charts do not represent fetal growth standards but only the weight of live born infants at birth. WIDER IMPLICATIONS OF THE FINDINGS: The comparison of birthweight percentile charts for ART births and general population births provide evidence that the proportion of SGA births following ART treatment was comparable to the general population for SET fresh cycles and significantly lower for thaw cycles. Both fresh and thaw cycles showed better outcomes for singleton births following SET compared with DET. Policies to promote single embryo transfer should be considered in order to minimize the adverse perinatal outcomes associated with ART treatment. STUDY FUNDING/COMPETING INTERESTS: No specific funding was obtained. The authors have no conflicts of interest to declare. © The Author 2014. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: firstname.lastname@example.org. KEYWORDS: assisted reproductive technology; birthweight; gestational age; single embryo transfer; small for gestational age
Congenital anomalies identified at birth among infants born following assisted reproductive technology in Colorado
Birth Defects Res A Clin Mol Teratol. 2014 Feb 14. doi: 10.1002/bdra.23222. [Epub ahead of print]
Moses XJ, Torres T, Rasmussen A, George C. Author information
BACKGROUND: Assisted reproductive technology (ART) has assisted many infertile couples in conceiving. Despite increasing use in the United States, the association between ART and congenital anomalies remains a highly contested subject. We conducted a study to examine the risk of congenital anomalies among infants conceived using ART. METHODS: A retrospective cohort study of 344,567 infants born in Colorado from 2007 to 2011 was conducted using data obtained from the Colorado Birth Certificate Database. The incidence of congenital anomalies identified at birth following conception with ART was assessed and compared with all naturally conceived infants born during the same time period. The odds ratio was calculated using multiple logistic regression after adjusting for multiple confounders. RESULTS: Of 2071 infants, 23 (1.11%) conceived using ART had a congenital anomaly identified at birth compared with 3826 (1.12%) of 342,496 infants conceived naturally. The adjusted odds ratio of a congenital anomaly among infants born following conception with ART was 1.01 (95% confidence interval, 0.67-1.52). The proportion of infants born following usage of ART in Colorado has not changed significantly (p = 0.20) from 2007 to 2011 with an overall proportion of 0.60% (range 0.52-0.64%), while the incidence of congenital anomalies has decreased significantly (p = 0.002) during the study years with an average of 1.12% (range, 0.92-1.25%). CONCLUSION: This study suggests that conception by means of ART is not associated with an increased risk of congenital abnormalities identified by birth certificate data in Colorado when compared with births following natural conception. Birth Defects Research (Part A), 2014. © 2014 Wiley Periodicals, Inc. Copyright © 2014 Wiley Periodicals, Inc. KEYWORDS: Colorado, assisted reproductive technology, birth defects, congenital anomalies, in vitro fertilization, incidence, malformations, prevalence
Pregnancy outcomes after assisted human reproduction J Obstet Gynaecol Can. 2014 Jan;36(1):64-83.
Society of Obstetricians annd Gynaecologists of Canada, Okun N1, Sierra S1. Collaborators (14)
OBJECTIVE: To review the effect of assisted human reproduction (AHR) on perinatal outcomes, to identify areas requiring further research with regard to birth outcomes and AHR, and to provide guidelines to optimize obstetrical management and counselling of prospective Canadian parents. OUTCOMES: This document compares perinatal outcomes of different types of AHR pregnancies with each other and with those of spontaneously conceived pregnancies. Clinicians will be better informed about the adverse outcomes that have been documented in association with AHR, including obstetrical complications, adverse perinatal outcomes, multiple gestations, structural congenital abnormalities, chromosomal abnormalities, and imprinting disorders. EVIDENCE: Published literature was retrieved through searches of MEDLINE and the Cochrane Library from January 2005 to December 2012 using appropriate controlled vocabulary and key words (assisted reproduction, assisted reproductive technology, ovulation induction, intracytoplasmic sperm injection, embryo transfer, and in vitro fertilization). Results were not restricted to systematic reviews, randomized control trials/controlled clinical trials, and observational studies; studies of all designs published in English from January 2005 to December 2012 were reviewed, and additional publications were identified from the bibliographies of these articles. Searches were updated on a regular basis and incorporated in the guideline to August 2013. Grey (unpublished) literature was identified through searching the websites of health technology assessment and health technology assessment-related agencies, clinical practice guideline collections, clinical trial registries, and national and international medical specialty societies. VALUES: The quality of evidence in this document was rated using the criteria described in the Report of the Canadian Task Force on Preventive Health Care (Table 1). Summary Statements 1. There is increasing evidence that infertility or subfertility is an independent risk factor for obstetrical complications and adverse perinatal outcomes, even without the addition of assisted human reproduction. (II-2) 2. The relative risk for an imprinting phenotype such as Silver-Russell syndrome, Beckwith-Wiedemann syndrome, or Angelman syndrome is increased in the assisted reproduction population, but the actual risk for one of these phenotypes to occur in an assisted pregnancy is estimated to be low, at less than 1 in 5000. The exact biological etiology for this increased imprinting risk is likely heterogeneous and requires more research. (II-2) Recommendations 1. All men with severe oligozoospermia or azoospermia (sperm count < 5 million/hpf) should be offered genetic/clinical counselling, karyotype assessment for chromosomal abnormalities, and Y-chromosome microdeletion testing prior to in vitro fertilization with intracytoplasmic sperm injection. (II-2A) 2. All men with unexplained obstructive azoospermia should be offered genetic/clinical counselling and genetic testing for cystic fibrosis prior to in vitro fertilization with intracytoplasmic sperm injection. (II-2A) 3. Multiple pregnancy is the most powerful predictive factor for adverse maternal, obstetrical, and perinatal outcomes. Couples should be thoroughly counselled about the significant risks of multiple pregnancies associated with all assisted human reproductive treatments. (II-2A) 4. The benefits and cumulative pregnancy rates of elective single embryo transfer support a policy of using this protocol in couples with good prognosis for success, and elective single embryo transfer should be strongly encouraged in this population. (II-2A) 5. To reduce the incidence of multiple pregnancy, health care policies that support public funding for assisted human reproduction, with regulations promoting best practice regarding elective single embryo transfer, should be strongly encouraged. (II-2A) 6. Among singleton pregnancies, assisted reproductive technology is associated with increased risks of preterm birth and low birth weight infants, and ovulation induction is associated with an increased risk of low birth weight infants. Until sufficient research has clarified the independent roles of infertility and treatment for infertility, couples should be counselled about the risks associated with treatment. (II-2B) There is a role for closer obstetric surveillance of women who conceive with assisted human reproduction. (III-L) 7. There is growing evidence that pregnancy outcomes are better for cryopreserved embryos fertilized in vitro than for fresh embryo transfers. This finding supports a policy of elective single embryo transfer for women with a good prognosis (with subsequent use of cryopreserved embryos as necessary), and may reassure women who are considering in vitro fertilization. (II-2A) 8. Women and couples considering assisted human reproduction and concerned about perinatal outcomes in singleton pregnancies should be advised that (1) intracytoplasmic sperm injection does not appear to confer increased adverse perinatal or maternal risk over standard in vitro fertilization, and (2) the use of donor oocytes increases successful pregnancy rates in selected women, but even when accounting for maternal age, can increase the risks of low birth weight and preeclampsia. (II-2B) 9. Any assisted reproductive technology procedure should be prefaced by a discussion of fetal outcomes and the slight increase in the risk of congenital structural abnormalities, with emphasis on known confounding factors such as infertility and body mass index. (II-2B) 10. In pregnancies achieved by artificial reproductive technology, routine anatomic ultrasound for congenital structural abnormalities is recommended between 18 and 22 weeks. (II-2A) 11. Pregnancies conceived by intracytoplasmic sperm injection may be at increased risk of chromosomal aberrations, including sex chromosome abnormalities. Diagnostic testing should be offered after appropriate counselling. (II-2A) 12. The possible increased risk for late onset cancer due to gene dysregulation for tumour suppression requires more long-term follow-up before the true risk can be determined. (III-A) 13. The clinical application of preimplantation genetic testing in fertile couples must balance the benefits of avoiding disease transmission with the medical risks and financial burden of in vitro fertilization. (III-B) 14. Preimplantation screening for aneuploidy is associated with inconsistent findings for improving pregnancy outcomes. Any discussion of preimplantation genetic screening with patients should clarify that there is no adequate information on the long-term effect of embryo single cell biopsy. (I-C). KEYWORDS: assisted human reproduction; assisted reproductive technology; congenital anomalies; imprinting; imprinting disorders; multiple gestation; pregnancy outcomes
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Assisted reproductive technology surveillance -- United States, 2010
MMWR Surveill Summ. 2013 Dec 6;62(9):1-24.
Sunderam S, Kissin DM, Crawford S, Anderson JE, Folger SG, Jamieson DJ, Barfield WD; Division of Reproductive Health, National Center for Chronic Disease Prevention and Health Promotion, CDC.
PROBLEM/CONDITION: Since the first U.S. infant conceived with Assisted Reproductive Technology (ART) was born in 1981, both the use of advanced technologies to overcome infertility and the number of fertility clinics providing ART services have increased steadily in the United States. ART includes fertility treatments in which both eggs and sperm are handled in the laboratory (i.e., in vitro fertilization [IVF] and related procedures). Women who undergo ART procedures are more likely to deliver multiple-birth infants than those who conceive naturally because more than one embryo might be transferred during a procedure. Multiple births pose substantial risks to both mothers and infants, including pregnancy complications, preterm delivery, and low birthweight infants. This report provides state-specific information on U.S. ART procedures performed in 2010 and compares infant outcomes that occurred in 2010 (resulting from procedures performed in 2009 and 2010) with outcomes for all infants born in the United States in 2010. REPORTING PERIOD COVERED: 2010. DESCRIPTION OF SYSTEM: In 1996, CDC began collecting data on all ART procedures performed in fertility clinics in the United States and U.S. territories, as mandated by the Fertility Clinic Success Rate and Certification Act of 1992 (FCSRCA) (Public Law 102-493). Data are collected through the National ART Surveillance System (NASS), a web-based data collecting system developed by CDC. RESULTS: In 2010, a total of 147,260 ART procedures performed in 443 U.S. fertility clinics were reported to CDC. These procedures resulted in 47,090 live-birth deliveries and 61,564 infants. The largest numbers of ART procedures were performed among residents of six states: California (18,524), New York (excluding New York City) (14,212), Illinois (10,110), Massachusetts (9,854), New Jersey (8,783), and Texas (8,754). These six states also had the highest number of live-birth deliveries as a result of ART procedures and together accounted for 48.0% of all ART procedures performed, 45.0% of all infants born from ART, and 45.0% of all multiple live-birth deliveries but only 34.0% of all infants born in the United States and U.S. territories. Nationally, the average number of ART procedures performed per 1 million women of reproductive age (15-44 years), which is a proxy indicator of ART use, was 2,331. In 13 states (California, Connecticut, Delaware, Hawaii, Illinois, Maryland, Massachusetts, New Hampshire, New Jersey, New York, Pennsylvania, Rhode Island, and Virginia), this proxy measure was higher than the national rate, and in four states (Connecticut, Massachusetts, New Jersey, and New York) and the District of Columbia, it exceeded twice the national rate. Nationally, among cycles in which at least one embryo was transferred, the average number of embryos transferred increased with increasing age (2.0 among women aged <35 years, 2.4 among women aged 35-40 years, and 3.0 among women aged >40 years). Elective single-embryo transfer (eSET) rates decreased with increasing age (10.0% among women aged <35 years, 3.8% among women aged 35-40 years, and 0.6% among women aged >40 years). ESET rates also varied substantially between states (range: 0 to 45.0% among women aged <35 years). The number of ART births as a percentage of total infants born in the state or territory is considered as another measure of ART use. Overall, ART contributed to 1.5% of U.S. births (range: 0.1% in Guam to 4.8% in Massachusetts) with the highest rates (>3.5% of all infants born) observed in four states (Connecticut, Massachusetts, New Jersey, and New York), and the District of Columbia. The proportion of ART births was ≤2.5% in the remaining states and territories. Infants conceived with ART comprised 20.0% of all multiple-birth infants (range: 0 in Guam to 40.5% in Massachusetts), 19.0% of all twin infants (range: 0 in Guam to 40.0% in Massachusetts), and 33.0% of triplet or higher order infants (range: 0 in several states to 60.0% in Arizona). Among infants conceived with ART, 46.0% were born in multiple deliveries (range: 0 in Guam to 55.4% in Utah), compared with only 3.0% of infants among all births in the general population (range: 1.3% in Guam to 4.7% in Connecticut). A substantial proportion (43.4%) of ART-conceived infants were twin infants, and a smaller proportion (3.0%) were triplets and higher order infants. Nationally, infants conceived with ART comprised 5.6% of all low birthweight (<2,500 grams) infants (range: 0 in Guam to 16.0% in Massachusetts) and 5.6% of all very low birthweight (<1,500 grams) infants (range: 0 in Guam to 15.8% in Massachusetts). Overall, among ART-conceived infants, 31.6% were low birthweight (range: 22.6% in New Hampshire to 48.2% in Puerto Rico), compared with 8.0% among all infants (range: 5.7% in Alaska to 12.6% in Puerto Rico); 5.6% of ART infants were very low birthweight (range: 1.9% in Maine to 14.3% in Montana), compared with 1.4% among all infants (range: 0.9% in Alaska to 2.3% in the District of Columbia). Finally, ART-conceived infants comprised 4.4% of all infants born preterm (<37 weeks; range: 0 in Guam to 13.3% in Massachusetts) and 4.9% of all infants born very preterm (<32 weeks; range: 0 in Guam to 16.2% in Massachusetts). Overall, among infants conceived with ART, 36.6% were born preterm (range: 23.6% in New Hampshire to 56.8% in Wyoming), compared with 12.0% among all infants born in the general population (range: 8.4% in Vermont to 17.9% in Guam); 6.6% of ART infants were born very preterm (range: 0 in Maine to 14.5% in Puerto Rico), compared with 2.0% among all infants born in the general population (range: 1.3% in Alaska to 3.0% in the District of Columbia). INTERPRETATION: The percentage of infants conceived with ART varied considerably by state and territory (range: 0.1% to 4.8%). In most states, multiples from ART comprised a substantial proportion of all twin, triplet, and higher-order infants born in the state, and the rates of low birthweight and preterm infants were disproportionately higher among ART infants than in the birth population overall. Even among women aged <35 years, for whom single embryo transfers should be considered (particularly in patients with a favorable prognosis) according to American Society of Reproductive Medicine (ASRM) guidelines, on average, two embryos were transferred per cycle in ART procedures, influencing the overall multiple infant rates in the United States. ART use per population unit was distributed disproportionately in the United States, with only 13 states showing ART use above the national rate, which might suggest barriers to ART services in the remaining states. Of the four states (Illinois, Massachusetts, New Jersey, and Rhode Island) with comprehensive statewide-mandated health insurance coverage for ART procedures (e.g., coverage for at least four cycles of IVF), three states (Illinois, Massachusetts, and New Jersey) also had rates of ART use >1.5 times the national level. This type of mandated insurance has been associated with greater use of ART and might account for the differences observed in other states. PUBLIC HEALTH ACTIONS: Reducing the number of embryos transferred per ART procedure among all age groups and promotion of eSET procedures, when clinically appropriate, is needed to reduce multiple births, including twin births, and related adverse consequences of ART. Improved patient education and counseling on the risks of twins might be useful in reducing twin births because twins account for the majority of multiples. Although ART contributes to increasing rates of multiple births, it does not explain all of the increases, and therefore the possible role of non-ART fertility treatments warrants further study.
Ongoing Pregnancy Rates in Women with Low and Extremely Low AMH Levels. A Multivariate Analysis of 769 Cycles
Kedem A, Haas J, Geva LL, Yerushalmi G, Gilboa Y, et al. (2013) Ongoing Pregnancy Rates in Women with Low and Extremely Low AMH Levels. A Multivariate Analysis of 769 Cycles. PLoS ONE 8(12): e81629. doi:10.1371/journal.pone.0081629
Patients with extremely low AMH measurements have reasonable and similar pregnancy rates as patients with low AMH. Therefore, AMH should not be used as the criterion to exclude couples from performing additional IVF treatments.
Comparison of the clinical outcomes of day 4 and 5 embryo transfer cycles
Clin Exp Reprod Med. 2013 Sep;40(3):122-5. doi: 10.5653/cerm.2013.40.3.122. Epub 2013 Sep 30.
Lee SH, Lee HS, Lim CK, Park YS, Yang KM, Park DW. Source Laboratory of Reproductive Biology and Infertility, Cheil General Hospital and Women's Healthcare Center, Kwandong University College of Medicine, Seoul, Korea.
OBJECTIVE: The majority of embryo transfers (ETs) to date have been performed on day 3 to reduce the potential risk of developmental arrest of in vitro cultured embryos before ET. Development of sequential media has significantly improved culture conditions and allowed blastocyst transfer on day 5. While day 5 ET provides higher clinical pregnancy outcomes with reduced risks of multiple pregnancies, it still has potential risks of developmental arrest of IVF embryos. The aim of this study was to evaluate the clinical outcomes of day 4 ETs and compare the efficacy of day 4 ET with day 5 ET. METHODS: From 2006 to 2009, a total of 747 fresh IVF-ET cycles were retrospectively analyzed (day 4, n=440 or and day 5, n=307). The cycles with any genetic factors were excluded. The rates of matured oocytes, fertilization, good embryos, and clinical pregnancy of the two groups were compared. The chi-square test and t-test were used for statistical analysis. RESULTS: There were no significant differences between the two groups with respect to the mean age of the females and rates of matured oocytes. The pregnancy outcomes of day 4 ET (40.7%) were similar to those of day 5 ET (44.6%). The implantation rate of day 5 ET (24.2%) was significantly higher than that of day 4 ET (18.4%) (p=0.003). CONCLUSION: Day 4 ET can be chosen to avoid ET cancellation in day 5 ET resulting from suboptimal circumstances in the IVF laboratory, but the decremented quality of embryos for transfer and the decreased pregnancy rate must be taken into consideration. KEYWORDS: Blastocyst, Embryo culture, Embryo selection, Embryo transfer, Embryo-uterine synchrony, Embryonic grading, Pregnancy outcome
Biomarkers of ovarian response: current and future applications
Fertil Steril. 2013 Mar 15;99(4):963-9. doi: 10.1016/j.fertnstert.2012.11.051. Epub 2013 Jan 8.
Nelson SM. Author information
Abstract With our increasing appreciation that simply maximizing oocyte yield for all patients is no longer an appropriate stimulation strategy and that age alone cannot accurately predict ovarian response, there has been an explosion in the literature regarding the utility of biomarkers to predict and individualize treatment strategies. Antral follicle count (AFC) and antimüllerian hormone (AMH) have begun to dominate the clinical scene, and although frequently pitted against each other as alternatives, both may contribute and indeed be synergistic. Their underlying technologies are continuing to develop rapidly and overcome the standardization issues that have limited their development to date. In the context of in vitro fertilization (IVF), their linear relationship with oocyte yield and thereby extremes of ovarian response has led to improved pretreatment patient counseling, individualization of stimulation strategies, increased cost effectiveness, and enhanced safety. This review highlights that although biomarkers of ovarian response started in the IVF clinic, their future extends well beyond the boundaries of assisted reproduction. The automation of AMH and its introduction into the routine repertoire of clinical biochemistry has tremendous potential. A future where primary care physicians, endocrinologists, and oncologists can rapidly assess ovarian dysfunction and the ovarian reserve more accurately than with the current standard of follicle-stimulating hormone (FSH) is an exciting possibility. For women, the ability to know the duration of their own reproductive life span will be empowering and allow them to redefine the meaning of family planning. Copyright © 2013 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.
Cumulus and granulosa cell markers of oocyte and embryo quality
Fertil Steril. 2013 Mar 15;99(4):979-97. doi: 10.1016/j.fertnstert.2013.01.129.
Uyar A, Torrealday S, Seli E. Source Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, New Haven, Connecticut. Abstract Lack of an objective, accurate, and noninvasive embryo assessment strategy remains one of the major challenges encountered in in vitro fertilization. Cumulus and mural granulosa cells reflect the characteristics of the oocyte, providing a noninvasive means to assess oocyte quality. Specifically, transcriptomic profiling of follicular cells may help identify biomarkers of oocyte and embryo competence. Current transcriptomics technologies include quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR) for analysis of individual genes and microarrays and high-throughput deep sequencing for whole genome expression profiling. Recently, using qRT-PCR and microarray technologies, a multitude of studies correlated changes in cumulus or granulosa cell gene expression with clinically relevant outcome parameters, including in vitro embryo development and pregnancy. While the initial findings are promising, a clinical benefit from the use of identified biomarker genes remains to be demonstrated in randomized controlled trials. Copyright © 2013 American Society for Reproductive Medicine. All rights reserved.
The predictive value of anti-mullerian hormone on embryo quality, blastocyst development, and pregnancy rate following in vitro fertilization-embryo transfer (IVF-ET)
J Assist Reprod Genet. 2013 Mar 17. [Epub ahead of print]
Lin WQ, Yao LN, Zhang DX, Zhang W, Yang XJ, Yu R. Source Reproductive Medcine Center, the First Affiliated Hospital of Zhejiang University, School of Medicine, Qingchun Road 79, Hangzhou, 310003, China, email@example.com. Abstract PURPOSE: The objective of this study was to investigate the predictive value of anti-Mullerian hormone (AMH) on fertilization rate (FR), blastocyst development, embryo quality, the outcome of the pregnancy and the live birth rate (LBR) following in vitro fertilization-embryo transfer (IVF-ET)/intracytoplasmic sperm injection (ICSI). METHOD: In this prospective study outcomes were followed in 83 women undergoing cycles of IVF/ICSI within a university hospital. Basal serum AMH, follicle stimulating hormone (FSH), luteinizing hormone (LH) and antral follicle count (AFC) were measured on Day 3. Serum AMH (Gn6 AMH ) level was measured on Day 6 after the administration of gonadotrophin (Gn). AMH was measured in follicle fluid (FF AMH) on the day of ovum pick-up (dOPU). The numbers of retrieved and fertilized oocytes, good quality embryos and blastocysts were counted. Secondary outcome variables included clinical pregnancy rate (CPR) and LBR. RESULTS: Spearman correlation analysis indicated that the numbers of oocytes, good quality embryos and blastocysts were associated with AMH (P < 0.05) and that LBR was correlated with FF AMH (r = 0.495, P < 0.05). No associations were found between FR and AMH (P > 0.05). Receiver operating characteristic analysis showed that the sensitivity of FF AMH at predicting CPR was 91.2 %; the specificity was 86.5 % and ROCAUC was 0.893 (P < 0.0001). CONCLUSION: AMH parameters were correlated with good quality embryos and blastocysts, but only FF AMH showed a significant correlation with LBR and CPR.
Singleton preterm birth: risk factors and association with assisted reproductive technology
Matern Child Health J. 2012 May;16(4):807-13. doi: 10.1007/s10995-011-0787-8.
Tepper NK, Farr SL, Cohen BB, Nannini A, Zhang Z, Anderson JE, Jamieson DJ, Macaluso M. Source National Center for Chronic Disease Prevention and Health Promotion, Centers for Disease Control and Prevention, Atlanta, GA 30341, USA. firstname.lastname@example.org
The objectives of this study were to determine risk factors for early (less than 34 weeks gestation) and late (34-36 weeks gestation) preterm singleton birth, by assisted reproductive technology (ART) status. We linked data from Massachusetts birth records and ART records representing singleton live births from 1997 through 2004. Using multinomial regression models, we assessed risk factors for early and late preterm birth by ART status. From 1997 to 2004 in Massachusetts, among non-ART births, risk factors for early and late preterm birth were similar and included women <15 and ≥ 35 years of age, those of non-white race or Hispanic ethnicity, those with ≤ 12 years of education, those with chronic diabetes, those with gestational diabetes, those with gestational hypertension, those who smoked during pregnancy, those who used fertility medications, and those who had not had a previous live birth. Among ART births, risk factors for early and late preterm birth differed and odds of early preterm birth were increased among women with ≤ 12 years of education while odds of late preterm birth were increased among women with gestational diabetes. Odds of both early and late preterm birth were increased among women of non-white race or Hispanic ethnicity and among women with gestational hypertension. Among non-ART births, increased risk for preterm birth was more strongly related to socioeconomic factors than among ART births. Medical conditions were associated with an increased risk for preterm birth regardless of women's ART status. Efforts to prevent preterm births should focus on reducing modifiable risk factors.
Preliminary results of the first human uterus transplantation from a multiorgan donor
Fertil Steril. 2012 Oct 18. pii: S0015-0282(12)02254-6. doi: 10.1016/j.fertnstert.2012.09.035.
Ozkan O, Erman Akar M, Ozkan O, Erdogan O, Hadimioglu N, Yilmaz M, Gunseren F, Cincik M, Pestereli E, Kocak H, Mutlu D, Dinckan A, Gecici O, Bektas G, Suleymanlar G. Source Department of Plastic Surgery, Akdeniz University, Antalya, Turkey.
OBJECTIVE: To describe the first-year results of the first human uterus transplantation case from a multiorgan donor. DESIGN: Case study. SETTING: University hospital. PATIENT(S): A 21-year-old woman with complete müllerian agenesis who had been previously operated on for vaginal reconstruction. INTERVENTION(S): Uterus transplantation procedure consisting of orthotopic replacement and fixation of the retrieved uterus, revascularization, end to site anastomoses of bilateral hypogastric arteries and veins to bilateral external iliac arteries and veins was performed. MAIN OUTCOME MEASURE(S): Resumption of menstrual cycles. RESULT(S): The patient had menarche 20 days after transplant surgery. She has had 12 menstrual cycles since the operation. CONCLUSION(S): We have described the longest-lived transplanted human uterus to date with acquirement of menstrual cycles. Copyright © 2012 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.
DONATION OF 'SPARE' FRESH OR FROZEN EMBRYOS TO RESEARCH: WHO DECIDES THAT AN EMBRYO IS 'SPARE' AND HOW CAN WE ENHANCE THE QUALITY AND PROTECT THE VALIDITY OF CONSENT?
Med Law Rev. 2012 May 30. [Epub ahead of print]
Scott R, Williams C, Ehrich K, Farsides B. Source 1 Centre of Medical Law and Ethics and School of Law, King's College London.
This paper analyses elements of the legal process of consent to the donation of 'spare' embryos to research, including stem-cell research, and makes a recommendation intended to enhance the quality of that process, including on occasion by guarding against the invalidity of such consent. This is important in its own right and also so as to maximise the reproductive treatment options of couples engaged in in vitro fertilisation (IVF) treatment and to avoid possible harms to them. In Part 1, with reference to qualitative data from three UK IVF clinics, we explore the often delicate and contingent nature of what comes to be, for legal purposes, a 'spare' embryo. The way in which an embryo becomes 'spare', with its implications for the process of consent to donation to research, is not addressed in the relevant reports relating to or codes of practice governing the donation of embryos to research, which assume an unproblematic notion of the 'spare' embryo. Significantly, our analysis demonstrates that there is an important and previously unrecognised first stage in the donation of a 'spare' embryo to research, namely: consent to an embryo being 'spare' and so, at the same time, to its disuse in treatment. This is not explicitly covered by the Human Fertilisation and Embryology (HFE) Act 1990, as amended by the HFE Act 2008. Having identified this important initial stage in the process of consent to the donation of a 'spare' embryo to research in conclusion to Part 1, in Part 2 we analyse the idea of consent to an embryo's disuse in treatment on the basis that it is 'spare' with reference to the legal elements of consent, namely information as to nature and purpose, capacity, and voluntariness. We argue that there are in fact three related consent processes in play, of which the principal one concerns consent to an embryo's disuse in treatment. If the quality of this first consent is compromised, in turn this will impact on the quality of the consent to the donation of that 'spare' embryo to research, followed by the quality of consent to future cycles of assisted reproduction treatment in the event that these are needed as a result of a donation decision. The analysis overall is of central relevance to the debate as to whether, and if so when, it should be permissible to request the donation of fresh embryos for research, as opposed to those that have been frozen and, for instance, have reached the end of their statutory storage term. This has a particular bearing on the donation of embryos to stem-cell research since there is a debate as to whether fresh embryos are most useful for this.
A novel isolator-based system promotes viability of human embryos during laboratory processing
PLoS One. 2012;7(2):e31010. Epub 2012 Feb 29.
Hyslop L, Prathalingam N, Nowak L, Fenwick J, Harbottle S, Byerley S, Rhodes J, Watson B, Henderson R, Murdoch A, Herbert M. Source Newcastle Fertility Centre, Newcastle upon Tyne, England, United Kingdom.
In vitro fertilisation (IVF) and related technologies are arguably the most challenging of all cell culture applications. The starting material is a single cell from which one aims to produce an embryo capable of establishing a pregnancy eventually leading to a live birth. Laboratory processing during IVF treatment requires open manipulations of gametes and embryos, which typically involves exposure to ambient conditions. To reduce the risk of cellular stress, we have developed a totally enclosed system of interlinked isolator-based workstations designed to maintain oocytes and embryos in a physiological environment throughout the IVF process. Comparison of clinical and laboratory data before and after the introduction of the new system revealed that significantly more embryos developed to the blastocyst stage in the enclosed isolator-based system compared with conventional open-fronted laminar flow hoods. Moreover, blastocysts produced in the isolator-based system contained significantly more cells and their development was accelerated. Consistent with this, the introduction of the enclosed system was accompanied by a significant increase in the clinical pregnancy rate and in the proportion of embryos implanting following transfer to the uterus. The data indicate that protection from ambient conditions promotes improved development of human embryos. Importantly, we found that it was entirely feasible to conduct all IVF-related procedures in the isolator-based workstations.
Live birth after ovarian tissue autotransplantation following overnight transportation before cryopreservation
Fertil Steril. 2012 Feb;97(2):387-90. Epub 2011 Dec 16.
Dittrich R, Lotz L, Keck G, Hoffmann I, Mueller A, Beckmann MW, van der Ven H, Montag M. Source Department of Obstetrics and Gynecology, Erlangen University Hospital, Erlangen, Germany. email@example.com
OBJECTIVE: To describe the first live birth after transplantation of ovarian tissue following overnight transportation of the tissue before freezing. DESIGN: Technical note. SETTING: University department of obstetrics and gynecology. PATIENT(S): A 25-year-old cancer survivor with previous Hodgkin disease and relapse. INTERVENTION(S): The ovarian tissue was kept cool for >20 hours in a special transport medium and a special cooling device before it was cryopreserved. After premature ovarian failure due to preconditioning chemotherapy for bone marrow transplantation, the cryopreserved ovarian tissue was transplanted orthotopically. MAIN OUTCOME MEASURE(S): Resumption of ovarian function after transplantation, recovery of fertility, and pregnancy. RESULT(S): Ovarian function returned in the patient 3 months after transplantation, as shown by follicle development and estrogen production. During the fifth menstrual cycle, mild stimulation with FSH was initiated in accordance with a low-dose protocol. When ultrasonography revealed a follicle 18-20 mm in size in the ovarian graft, hCG was added and the patient had sexual intercourse at the optimal time point. On day 14 of the luteal phase, hCG concentration and vaginal echography confirmed a viable intrauterine pregnancy, which resulted in a healthy live birth. CONCLUSION(S): Overnight transportation of ovarian tissue appears to be possible in combination with appropriate transportation logistics. However, further investigations are needed before this procedure can be offered as a chance for women to preserve fertility independently of direct access to a tissue-processing bank. Copyright © 2012 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.
The role of melatonin as an antioxidant in the follicle
J Ovarian Res. 2012 Jan 26;5:5.
Tamura H, Takasaki A, Taketani T, Tanabe M, Kizuka F, Lee L, Tamura I, Maekawa R, Aasada H, Yamagata Y, Sugino N. Source Department of Obstetrics and Gynecology, Yamaguchi University Graduate School of Medicine, Minamikogushi 1-1-1, Ube, 755-8505 Japan. firstname.lastname@example.org.
ABSTRACT: Melatonin (N-acetyl-5-methoxytryptamine) is secreted during the dark hours at night by pineal gland, and it regulates a variety of important central and peripheral actions related to circadian rhythms and reproduction. It has been believed that melatonin regulates ovarian function by the regulation of gonadotropin release in the hypothalamus-pituitary gland axis via its specific receptors. In addition to the receptor mediated action, the discovery of melatonin as a direct free radical scavenger has greatly broadened the understanding of melatonin's mechanisms which benefit reproductive physiology. Higher concentrations of melatonin have been found in human preovulatory follicular fluid compared to serum, and there is growing evidence of the direct effects of melatonin on ovarian function especially oocyte maturation and embryo development. Many scientists have focused on the direct role of melatonin on oocyte maturation and embryo development as an anti-oxidant to reduce oxidative stress induced by reactive oxygen species, which are produced during ovulation process. The beneficial effects of melatonin administration on oocyte maturation and embryo development have been confirmed by in vitro and in vivo experiments in animals. This review also discusses the first application of melatonin to the clinical treatment of infertile women and confirms that melatonin administration reduces intrafollicular oxidative damage and increase fertilization rates. This review summarizes our recent works and new findings related to the reported beneficial effects of melatonin on reproductive physiology in its role as a reducer of oxidative stress, especially on oocyte maturation and embryo development.
PMID 22277103 [PubMed - in process] PMCID: PMC3296634
Retransplantation of cryopreserved ovarian tissue: the first live birth in Germany
Dtsch Arztebl Int. 2012 Jan;109(1-2):8-13. Epub 2012 Jan 9.
Müller A, Keller K, Wacker J, Dittrich R, Keck G, Montag M, Van der Ven H, Wachter D, Beckmann MW, Distler W. Source Frauenklinik, Universitätsklinikum Erlangen.
BACKGROUND: Cryopreserved ovarian tissue can be retransplanted to restore fertility after radiation or chemotherapy. To date, 15 live births after retransplantation have been reported worldwide. We report the first pregnancy and the first live birth after retransplantation in Germany. CASE REPORT: A 25-year-old female patient received initial chemotherapy and radiation of the mediastinum for Hodgkin's lymphoma in 2003 and suffered a relapse two years later. Ovarian tissue was laparoscopically removed and cryopreserved, and she was then treated with high-dose chemotherapy and stem cell transplantation. She remained in remission for 5 years and she could not conceive during this time. The cryopreserved ovarian tissue was thawed and laparoscopically retransplanted into a peritoneal pouch in the ovarian fossa of the right pelvic wall. Three months later, her menopausal symptoms resolved, and she had her first spontaneous menstruation. Six months after retransplantation, after two normal menstrual cycles, low-dose follicle stimulating hormone (FSH) treatment induced the appearance of a dominant follicle in the tissue graft. Ovulation was then induced with human chorionic gonadotropin (HCG), whereupon the patient conceived naturally. After an uncomplicated pregnancy, she bore a healthy child by Caesarean section on 10 October 2011. Histological examination of biopsy specimens revealed that the ovarian tissue of the graft contained follicles in various stages of development, while the original ovaries contained only structures without any reproductive potential. CONCLUSION: This was the first live birth after retransplantation of cryopreserved ovarian tissue in Germany and also the first case with histological confirmation that the oocyte from which the patient conceived could only have come from the retransplanted tissue. In general, young women who will be undergoing chemotherapy and/or radiotherapy for cancer must be informed and counseled about the available options for fertility preservation.
Assisted reproductive technology in Europe, 2007: results generated from European registers by ESHRE
Hum Reprod. 2012 Apr;27(4):954-966. Epub 2012 Feb 17.
de Mouzon J, Goossens V, Bhattacharya S, Castilla JA, Ferraretti AP, Korsak V, Kupka M, Nygren KG, Andersen AN; The European IVF-Monitoring (EIM); Consortium for the European Society on Human Reproduction and Embryology (ESHRE). Source ESHRE Central Office, Meerstraat 60, B-1852 Grimbergen, Belgium.
BACKGROUND This 11th European IVF-monitoring report presents the results of assisted reproductive technology (ART) treatments initiated in Europe during 2007. METHODS From 33 countries, 1029 clinics reported 493 184 treatment cycles: IVF (120 761), ICSI (256 642), frozen embryo replacement (91 145), egg donation (15 731), preimplantation genetic diagnosis/preimplantation genetic screening (4638), in vitro maturation (660) and frozen oocytes replacements (3607). Overall, this represents a 7.6% increase since 2006, mostly related to an increase in all registers. IUI using husband/partner's (IUI-H) and donor (IUI-D) semen was reported from 23 countries: 142 609 IUI-H (+6.2%) and 26 088 IUI-D (+7.2%). RESULTS In 18 countries where all clinics reported, 376 971 ART cycles were performed in a population of 425.6million (886 cycles per million). The clinical pregnancy rates per aspiration and per transfer were 29.1 and 32.8% for IVF, and 28.6 and 33.0% for ICSI. Delivery rate after IUI-H was 10.2% in women aged < 40 years. In IVF/ICSI cycles, 1, 2, 3 and ≥4 embryos were transferred in 21.4, 53.4, 22.7 and 2.5% of cycles, with no decline in the number of embryos per transfer since 2006. The proportion of multiple deliveries (22.3: 21.3% twin and 1.0% triplet), did not decrease compared with 2006 (20.8%) and 2005 (21.8%). In women < 40 years undergoing IUI-H, twin deliveries occurred in 11.7% and triplets in 0.5%. CONCLUSIONS In comparison with previous years, the reported number of ART cycles in Europe increased in 2007; pregnancy rates increased marginally, but the earlier decline in the number of embryos transferred and multiple births did not continue.
Results after ART in 2007
|Country||Cycles IVF + ICSI||IVF||ICSI||FER||ART infantsa||ART infants per national births (%)|
|Aspirations||Pregnancies per aspiration (%)||Deliveries per aspiration (%)||Aspirations||Pregnancies per aspiration (%)||Deliveries per aspiration (%)||Thawings FER||Pregnancies per thawing (%)||Deliveries per thawing (%)|
|France||20 211||24.6||19.2||31 635||25.9||20.5||14 710||1.8|
|Germany||45 182||10 995||29.4||16.0||32 124||28.2||16.1||17 140||18.3||9.9||10 483||1.5|
|Italy||40 005||7570||22.0||15.2||28 075||22.0||14.3||709||14.7||8.3||6575||1.2|
|Russia||21 837||12 171||35.2||24.1||9002||33.1||20.4||3084||23.9||14.9||7197|
|Spain||34 499||3041||34.6||27 905||33.6||9089||23.1||12 647|
|The Netherlands||16 163||8399||27.6||20.5||6659||31.8||25.1||4616||2.5|
|United Kingdom||35 922||15944||30.1||26.4||17 615||31.1||27.5||8549||20.9||18.1||13 838||1.8|
|Allb||264 022||108 390||29.1||21.1||199 950||28.6||20.2||72493||20.1||13.5||96 690||1.5|
Number of embryos transferred and deliveries after ART in 2007
|Country||In vitro Fertilisation + Intracytoplasmic Sperm Injection||Frozen Embryo Replacement|
|Transfers||1 embryo (%)||2 embryos (%)||3 embryos (% )||4 + embryos (%)||Deliveries||Twin (%)||Triplet (%)||Deliveries||Twin (%)||Triplet (%)|
|France||44 453||23.2||62.3||13.2||1.3||10 359||18.9||0.4||1913||11.3||0.2|
|The Netherlands||13 375||3396||15.1||0.1||629||11.0||0.0|
|United Kingdom||31 114||12.8||82.3||4.9||0.0||9094||24.1||0.3||1548||17.6||0.3|
Istanbul consensus workshop on embryo assessment: proceedings of an expert meeting
Reprod Biomed Online. 2011 Jun;22(6):632-46. doi: 10.1016/j.rbmo.2011.02.001. Epub 2011 Apr 11.
ALPHA Scientists In Reproductive Medicine; ESHRE Special Interest Group Embryology.
This paper reports the proceedings of an international consensus meeting on oocyte and embryo morphology assessment. Following background presentations about current practice, the expert panel developed a set of consensus points to define the minimum criteria for oocyte and embryo morphology assessment. It is expected that the definition of common terminology and standardization of laboratory practice related to embryo morphology assessment will result in more effective comparisons of treatment outcomes. This document is intended to be referenced as a global consensus to allow standardized reporting of the minimum dataset required for the accurate description of embryo development. This paper reports the proceedings and outcomes of an international consensus meeting on human oocyte and embryo morphology assessment. An expert panel developed a series of consensus points to define the minimum criteria for such assessments. The definition of common terminology, and standardization of laboratory practices related to these morphological assessments, will permit more effective comparisons of treatment outcomes around the world. This report is intended to be referenced as a global consensus to allow standardized reporting of the minimum descriptive criteria required for routine clinical evaluations of human embryo development in vitro. Copyright © 2011 Elsevier Limited and ALPHA Scientists in Reproductive Medicine and the European Society of Human Reproduction and Embryology. Published by Elsevier Ltd.. All rights reserved.
Sperm storage for cancer patients in the UK: a review of current practice
Hum Reprod. 2011 Nov;26(11):2935-43. Epub 2011 Aug 26.
Sharma V. Source The Leeds Centre for Reproductive Medicine, Seacroft Hospital, Leeds LS146UH, UK. email@example.com Abstract An increasing number of cancer patients can now hope to have a full and normal life due to significant improvements in treatment outcomes and survival rates. The application of cryobiology to store fertile gametes before sterilizing treatments has been a natural progression. Greater awareness has markedly increased the worldwide demand for long-term storage of sperm, and has prompted the UK Human Fertilization and Embryology Authority to extend the period of storage permitted by their regulations to 55 years. Other patients undergoing sterilizing chemotherapy and/or radiotherapy such as haemoglobinopathies requiring bone marrow transplantation and autoimmune disorders such as rheumatoid arthritis may further increase the indications for sperm storage. Most adult and adolescent patients and their relatives/spouses/parents/guardians value this service even though very few eventually use the sperm. There is an urgent need to develop national and international guidelines for the provision, organization, maintenance and management of the cryopreservation services.
Bivariate analysis of basal serum anti-Müllerian hormone measurements and human blastocyst development after IVF
Reprod Biol Endocrinol. 2011 Dec 2;9:153.
Sills ES, Collins GS, Brady AC, Walsh DJ, Marron KD, Peck AC, Walsh AP, Salem RD. Source Division of Reproductive Endocrinology, Pacific Reproductive Center, Irvine, California, USA. firstname.lastname@example.org
BACKGROUND: To report on relationships among baseline serum anti-Müllerian hormone (AMH) measurements, blastocyst development and other selected embryology parameters observed in non-donor oocyte IVF cycles. METHODS: Pre-treatment AMH was measured in patients undergoing IVF (n = 79) and retrospectively correlated to in vitro embryo development noted during culture. RESULTS: Mean (+/- SD) age for study patients in this study group was 36.3 ± 4.0 (range = 28-45) yrs, and mean (+/- SD) terminal serum estradiol during IVF was 5929 +/- 4056 pmol/l. A moderate positive correlation (0.49; 95% CI 0.31 to 0.65) was noted between basal serum AMH and number of MII oocytes retrieved. Similarly, a moderate positive correlation (0.44) was observed between serum AMH and number of early cleavage-stage embryos (95% CI 0.24 to 0.61), suggesting a relationship between serum AMH and embryo development in IVF. Of note, serum AMH levels at baseline were significantly different for patients who did and did not undergo blastocyst transfer (15.6 vs. 10.9 pmol/l; p = 0.029). CONCLUSIONS: While serum AMH has found increasing application as a predictor of ovarian reserve for patients prior to IVF, its roles to estimate in vitro embryo morphology and potential to advance to blastocyst stage have not been extensively investigated. These data suggest that baseline serum AMH determinations can help forecast blastocyst developmental during IVF. Serum AMH measured before treatment may assist patients, clinicians and embryologists as scheduling of embryo transfer is outlined. Additional studies are needed to confirm these correlations and to better define the role of baseline serum AMH level in the prediction of blastocyst formation. PMID 22136508
Relationship of Follicular Size to the Development of Intracytoplasmic Sperm Injection-derived Human Embryos
Taiwan J Obstet Gynecol. 2010 Sep;49(3):302-5.
Lee TF, Lee RK, Hwu YM, Chih YF, Tsai YC, Su JT.
Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, Mackay Memorial Hospital, Taitung, Taiwan. Abstract OBJECTIVE: To compare the embryonic development of oocytes obtained from follicles of different sizes.
MATERIALS AND METHODS: Oocytes (n = 819) were retrieved from women at 40 years of age or younger during 86 in vitro fertilization cycles and categorized as small, medium, or large based on the estimated volume of follicular fluid at the time of retrieval.
RESULTS: The rates of good quality embryos from the large, medium, and small groups on days 2 and 3 were 76.85% and 66.20%, 74.00% and 61.33%, and 69.81% and 58.49%, respectively. There were no significant differences in the rates of good quality embryos between the three follicular volume groups.
CONCLUSION: Even though fewer oocytes completed maturation in the small follicle group than in the other two groups, the quality of the embryos in all three groups was the same on days 2 and 3. These findings suggest that follicles of all sizes should be aspirated during the intracytoplasmic sperm injection cycle as follicles of every size were a good source of embryos.
Non-invasive imaging of human embryos before embryonic genome activation predicts development to the blastocyst stage
Nat Biotechnol. 2010 Oct 3. [Epub ahead of print]
Wong CC, Loewke KE, Bossert NL, Behr B, De Jonge CJ, Baer TM, Pera RA.
 Institute for Stem Cell Biology and Regenerative Medicine, School of Medicine, Stanford University, Stanford, California, USA.  Department of Obstetrics and Gynecology, School of Medicine, Stanford University, Stanford, California, USA.  These authors contributed equally to this work. Abstract We report studies of preimplantation human embryo development that correlate time-lapse image analysis and gene expression profiling. By examining a large set of zygotes from in vitro fertilization (IVF), we find that success in progression to the blastocyst stage can be predicted with >93% sensitivity and specificity by measuring three dynamic, noninvasive imaging parameters by day 2 after fertilization, before embryonic genome activation (EGA). These parameters can be reliably monitored by automated image analysis, confirming that successful development follows a set of carefully orchestrated and predictable events. Moreover, we show that imaging phenotypes reflect molecular programs of the embryo and of individual blastomeres. Single-cell gene expression analysis reveals that blastomeres develop cell autonomously, with some cells advancing to EGA and others arresting. These studies indicate that success and failure in human embryo development is largely determined before EGA. Our methods and algorithms may provide an approach for early diagnosis of embryo potential in assisted reproduction.
Biomarkers of human oocyte developmental competence expressed in cumulus cells before ICSI: a preliminary study
Assidi M, Montag M, Van Der Ven K, Sirard MA.
J Assist Reprod Genet. 2010 Oct 16.
Centre de recherche en biologie de la reproduction, Département des Sciences Animales, Laval University, Ste-Foy, Québec, Canada, G1K 7P4. Abstract PURPOSE: To identify reliable genomic biomarkers expressed in cumulus cells that accurately and non-invasively predict the oocyte developmental competence and reinforce the already used morphological criteria.
METHODS: Eight consenting patients were selected for ovarian stimulation and ICSI procedures. Cumulus-oocyte complexes were transvaginally punctured and individually selected based on both good morphological criteria and high zona pellucida birefringence. Following ICSI, two 3-day embryos per patient were transferred. Pregnancy outcome was recorded and proven implantation was thereafter confirmed. Differential gene expression was assessed using two microarray platforms. Further real-time PCR validation, Ingenuity pathways analysis and intra-patient analysis were performed on 17 selected candidates.
RESULTS: Seven genes were differentially (p ≤ 0.05) associated to successful pregnancy and implantation. These biomarkers could be used to predict the oocyte developmental competence.
CONCLUSIONS: These genomic markers are a powerful reinforcement of morphological approaches of oocyte selection. Their large-scale validation could increase pregnancy outcome and single embryo transfer efficiency.
- 1959 Min Chueh Chang, working in the United States, had managed to carry out IVF in rabbits.
- 1960s, and now based at Cambridge University, that he read of Patrick Steptoe’s experience in using the then novel technique of laparoscopy.
(The first 100 or so attempts ended in failure, with the embryo dying early on in the pregnancy.)
- Sheep (ovine) http://www.ncbi.nlm.nih.gov/pubmed/20615540
- Horse (equine) http://www.ncbi.nlm.nih.gov/pubmed/20591059
SMH 2004 article - http://www.smh.com.au/articles/2004/09/13/1094927508626.html
Preimplantation mouse embryo selection guided by light-induced dielectrophoresis
PLoS One. 2010 Apr 13;5(4):e10160.
Valley JK, Swinton P, Boscardin WJ, Lue TF, Rinaudo PF, Wu MC, Garcia MM.
Berkeley Sensor & Actuator Center, Electrical Engineering and Computer Sciences, University of California, Berkeley, California, United States of America. Abstract Selection of optimal quality embryos for in vitro fertilization (IVF) transfer is critical to successful live birth outcomes. Currently, embryos are chosen based on subjective assessment of morphologic developmental maturity. A non-invasive means to quantitatively measure an embryo's developmental maturity would reduce the variability introduced by the current standard. We present a method that exploits the scaling electrical properties of pre-transfer embryos to quantitatively discern embryo developmental maturity using light-induced dielectrophoresis (DEP). We show that an embryo's DEP response is highly correlated with its developmental stage. Uniquely, this technique allows one to select, in sequence and under blinded conditions, the most developmentally mature embryos among a mixed cohort of morphologically indistinguishable embryos cultured in optimized and sub-optimal culture media. Following assay, embryos continue to develop normally in vitro. Light-induced dielectrophoresis provides a non-invasive, quantitative, and reproducible means to select embryos for applications including IVF transfer and embryonic stem cell harvest.
Blastocyst versus cleavage stage transfer in in vitro fertilization: differences in neonatal outcome?
Fertil Steril. 2010 Oct;94(5):1680-3. Epub 2010 Feb 4.
Källén B, Finnström O, Lindam A, Nilsson E, Nygren KG, Olausson PO.
Tornblad Institute, University of Lund, Lund, Sweden. Bengt.Kallen@med.lu.se Abstract OBJECTIVE: To compare neonatal outcome of blastocyst and cleavage stage embryo transfers after IVF.
DESIGN: Register study.
SETTING: Births recorded in the Swedish Medical Birth Register after IVF performed, 2002-2006.
PATIENT(S): Treatments reported from all Swedish IVF clinics.
MAIN OUTCOME MEASURE(S): Some neonatal characteristics were compared in 1,311 infants born after blastocyst-stage transfer and 12,562 infants born after cleavage-stage transfer. Comparisons were also made with all births, 2002-2007 (n = 598,687).
RESULT(S): After adjusting for year of birth, maternal age, parity, smoking habits, and body mass index, the risk of preterm birth among singletons was significantly greater after blastocyst-stage transfer than after cleavage-stage transfer. The risk of congenital malformations was also significantly higher. When the analysis was restricted to clinics where blastocyst transfers were made, the risk estimates increased for preterm birth, low birth weight, low APGAR score, and respiratory diagnoses, but did not change for congenital malformations.
CONCLUSION(S): The results indicate a small increase in risk associated with blastocyst transfer, perhaps owing to the longer period of in vitro culture. There is a possibility that this effect is due, at least in part, to a selection of women for blastocyst transfers. Further studies are needed either to verify or to refute the found associations.
Comparison of the major malformation rate of children conceived from cryopreserved embryos and fresh embryos
Chin Med J (Engl). 2010 Jul;123(14):1893-7.
Li HZ, Qiao J, Chi HB, Chen XN, Liu P, Ma CH.
Medical Center for Human Reproduction, Department of Obstetrics and Gynecology, Peking University Third Hospital, Beijing 100191, China. Abstract BACKGROUND: Cryopreserved embryo transfer has become indispensable in reproductive technology. More and more children are conceived from frozen-thawed embryo transfer (FET). The risk of birth defects associated with frozen-thawed embryo transfer has been evaluated and conflict results are obtained. The aim of this study was to compare the rate of major malformations in children conceived from cryopreserved embryos with that of children from fresh embryos.
METHODS: A retrospective analysis was performed on children conceived from frozen-thawed embryos and fresh embryos between January 2005 and December 2008 at the Reproduction Center of the Third Hospital, Peking University. The major malformation rates were compared between two groups for all children, as well as singletons or twins, separately. The frequencies of different subtypes of malformations classified according to different organ system were also compared.
RESULTS: Thirty-four of 3125 children from cryopreserved embryos had a major malformation. The malformation rate was 1.09%, which was comparable to that for children after fresh embryos transfer (1.53% (55/3604), OR: 0.71, 95%CI; 0.46-1.09). The malformation rate was also similar when the analysis was limited to children from cryopreserved embryos resulted from in vitro fertilization (IVF) (1.39%) and fresh IVF (1.3%). However, children from cryopreserved embryos resulted from intracytoplasmic sperm injections (ICSI) had much lower malformation rate than from fresh ICSI (0.63% vs.1.83%, OR: 0.34, 95%CI: 0.16-0.75). No difference was found in the incidence of major malformations in singletons from cryo ICSI (0.73%) and fresh ICSI (1.9%), or from cryo IVF (1.49%) and fresh IVF (1.67%). Similar malformation rate was found in multiples from cryo ICSI (0.52%) and fresh ICSI (1.76%), or cryo IVF (1.30%) and fresh IVF (0.90%). The distribution and risk of the subtype of malformations, such as cardiovascular, gastrointestinal, neural tube, urogenital, musculoskeletal and facial abnormalities was not different between the cryo group and fresh group.
CONCLUSIONS: The major malformation rate is similar between fetuses/children conceived from cryopreserved embryos and those from fresh embryos. Large prospective and long-term follow-up studies are needed to get exact results concerning the birth defects of the children born after cryopreserved embryos.
Trends in delivery and neonatal outcome after in vitro fertilization in Sweden: data for 25 years.
Hum Reprod. 2010 Apr;25(4):1026-34. Epub 2010 Feb 5.
Källén B, Finnström O, Lindam A, Nilsson E, Nygren KG, Otterblad Olausson P.
Tornblad Institute, University of Lund, Biskopsgatan 7, SE-223 62 Lund, Sweden. email@example.com Abstract
BACKGROUND: Marked changes have occurred in in vitro fertilization (IVF) methodology during the past 25 years but also in characteristics of couples undergoing treatment.
METHODS: This study was based on 27 386 women undergoing IVF treatment from 1982 to 2006 and giving birth to 31 850 infants. Outcomes of deliveries were studied using Swedish health registers. Comparisons were made with all deliveries in the population (n = 2 603 601). Adjusted odds ratios were calculated when important changes in background rates had occurred.
RESULTS: There was a substantial increase in the use of intracytoplasmatic sperm injection (ICSI) and the transfer of cryopreserved embryos. Among all ICSI cases, the proportion using epididymal or testicular sperm varied between 5 and 10%. Maternal characteristics changed during the observation period but the median age remained relatively constant in spite of the increasing maternal age in the population. There was a decline in the rate of some maternal pregnancy diagnoses (notably pre-eclampsia, premature rupture of membranes) and some neonatal diagnoses (notably preterm births, low birthweight, cerebral hemorrhage, respiratory diagnoses, use of continuous positive airway pressure and mechanical ventilation, sepsis/pneumonia). Up till 1992, the twinning rate increased to a maximum of about 30% and then declined to 5% towards the end of the period whereas higher order multiples nearly disappeared. The total rate of infants with congenital malformations changed only little.
CONCLUSIONS: The decrease in unwanted outcomes can, to a large extent, be explained by the reduced rate of multiple births but was seen also among singletons. Other explanations can be sought in changes in the characteristics of patients undergoing IVF.
PMID: 20139431 [PubMed - indexed for MEDLINE]
- Effects of In Vitro Maturation on Histone Acetylation in Metaphase II Oocytes and Early Cleavage Embryos. http://www.ncbi.nlm.nih.gov/pubmed/20613962
- Reorganization of the Endoplasmic Reticulum and Development of Ca2+ Release Mechanisms During Meiotic Maturation of Human Oocytes. http://www.ncbi.nlm.nih.gov/pubmed/20610804
- "Oocyte maturation in rodents is characterized by a dramatic reorganization of the endoplasmic reticulum (ER) and an increase in the ability of an oocyte to release Ca(2+) in response to fertilization or inositol 1,4,5-trisphosphate (IP(3)). We examined if human oocytes undergo similar changes during cytoplasmic meiotic maturation both in vivo and in vitro. Immature, germinal vesicle (GV)-stage oocytes had a fine network of ER throughout the cortex and interior, whereas the ER in in vivo-matured metaphase II (MII)-stage oocytes was organized in large (~2-3 microm) accumulations throughout the cortex and interior. Likewise, oocytes matured in vitro exhibited cortical and interior clusters with no apparent polarity with regard to the meiotic spindle. In vivo-matured oocytes contained approximately 1.5X the amount of IP3 receptor protein and released significantly more Ca(2+) in response to IP(3) than GV-stage oocytes; however, oocytes matured in vitro did not contain more IP(3) receptor protein or release more Ca(2+) in response to IP(3) than GV-stage oocytes. These results show that at least one cytoplasmic change occurs during in vitro maturation of human oocytes that might be important for fertilization and subsequent embryonic development but suggest that a low developmental competence of in vitro matured oocytes could be due to deficiencies in the ability to release Ca(2+) at fertilization."
In vitro fertilization and cleavage of human ovarian eggs
Am J Obstet Gynecol. 1948 Mar;55(3):440-52.
MENKIN MF, ROCK J.
- Miriam Menken and John Rock retrieved more than 800 oocytes from women during operations for various conditions.
- One hundred and thirty-eight of these oocytes were exposed to spermatozoa in vitro.
IN VITRO FERTILIZATION AND CLEAVAGE OF HUMAN OVARIAN EGGS
Science. 1944 Aug 4;100(2588):105-7.
Rock J, Menkin MF.
PMID 17788930 http://www.sciencemag.org/content/100/2588/105.long
Assisted Reproductive Technology Surveillance - United States, 2006
Assisted reproductive technology surveillance--United States, 2006. Sunderam S, Chang J, Flowers L, Kulkarni A, Sentelle G, Jeng G, Macaluso M; Centers for Disease Control and Prevention (CDC). MMWR Surveill Summ. 2009 Jun 12;58(5):1-25. PMID: 19521336 [PubMed - indexed for MEDLINE]Free Article Related citations
Assisted reproductive technology surveillance--United States, 2005. Wright VC, Chang J, Jeng G, Macaluso M; Centers for Disease Control and Prevention (CDC). MMWR Surveill Summ. 2008 Jun 20;57(5):1-23. Erratum in: MMWR Surveill Summ. 2009 Mar 6;58(8):203-4. MMWR Surveill Summ. 2008 Oct 10;57(40):1105. PMID: 18566567 [PubMed - indexed for MEDLINE]Free Article Related citations
Assisted reproductive technology surveillance - United States, 2004. Wright VC, Chang J, Jeng G, Chen M, Macaluso M; Centers for Disease Control and Prevention. MMWR Surveill Summ. 2007 Jun 8;56(6):1-22. Erratum in: MMWR Morb Mortal Wkly Rep. 2007 Jul 6;56(26):658. PMID: 17557073 [PubMed - indexed for MEDLINE]Free Article Related citations
Assisted reproductive technology surveillance--United States, 2000. Wright VC, Schieve LA, Reynolds MA, Jeng G. MMWR Surveill Summ. 2003 Aug 29;52(9):1-16. Erratum in: MMWR 2003 Oct 3; 52(39):942. PMID: 14532867 [PubMed - indexed for MEDLINE]Free Article Related citations
Assisted reproductive technology surveillance--United States, 2003. Wright VC, Chang J, Jeng G, Macaluso M. MMWR Surveill Summ. 2006 May 26;55(4):1-22. PMID: 16723970 [PubMed - indexed for MEDLINE]Free Article Related citations
Assisted reproductive technology surveillance--United States, 2001. Wright VC, Schieve LA, Reynolds MA, Jeng G, Kissin D. MMWR Surveill Summ. 2004 Apr 30;53(1):1-20. PMID: 15123982 [PubMed - indexed for MEDLINE]Free Article Related citations
Assisted reproductive technology surveillance--United States, 2002. Wright VC, Schieve LA, Reynolds MA, Jeng G; Division of Reproductive Health, National Center for Chronic Disease Prevention and Health Promotion, Centers for Disease Control and Prevention (CDC). MMWR Surveill Summ. 2005 Jun 3;54(2):1-24. PMID: 15931153 [PubMed - indexed for MEDLINE]Free Article Related citations
Pregnancy outcomes after assisted reproductive technology. Allen VM, Wilson RD, Cheung A; Genetics Committee of the Society of Obstetricians and Gynaecologists of Canada (SOGC); Reproductive Endocrinology Infertility Committee of the Society of Obstetricians and Gynaecologists of Canada (SOGC). J Obstet Gynaecol Can. 2006 Mar;28(3):220-50. English, French. PMID: 16650361 [PubMed - indexed for MEDLINE] Related citations
Preconception and interconception health status of women who recently gave birth to a live-born infant--Pregnancy Risk Assessment Monitoring System (PRAMS), United States, 26 reporting areas, 2004. D'Angelo D, Williams L, Morrow B, Cox S, Harris N, Harrison L, Posner SF, Hood JR, Zapata L; Centers for Disease Control and Prevention (CDC). MMWR Surveill Summ. 2007 Dec 14;56(10):1-35. Erratum in: MMWR Morb Mortal Wkly Rep. 2008 Apr 25;57(16):436. PMID: 18075488 [PubMed - indexed for MEDLINE]Free Article Related citations
From the Centers of Disease Control and Prevention. Use of assisted reproductive technology--United States, 1996 and 1998. Centers for Disease Control and Prevention (CDC). MMWR Morb Mortal Wkly Rep. 2002 Feb 8;51(5):97-101. PMID: 11892956 [PubMed - indexed for MEDLINE]Free Article Related citations
Single-embryo transfer reduces clinical pregnancy rates and live births in fresh IVF and Intracytoplasmic Sperm Injection (ICSI) cycles: a meta-analysis. Baruffi RL, Mauri AL, Petersen CG, Nicoletti A, Pontes A, Oliveira JB, Franco JG Jr. Reprod Biol Endocrinol. 2009 Apr 23;7:36. PMID: 19389258
- Use of zona pellucida-bound sperm for intracytoplasmic sperm injection produces higher embryo quality and implantation than conventional intracytoplasmic sperm injection "The proportion of high-quality embryos (grades 1 and 2) and implantation rate were significantly higher in the test group than in the control group, but the difference in fetal heart pregnancy rate was not significant despite seven more pregnancies being obtained in the test group (26 pregnancies) versus the control group (19 pregnancies) following fresh embryo transfers."
- Global variations in the uptake of single embryo transfer."Single embryo transfer (SET) is the most effective way of reducing multiple pregnancy rates associated with assisted reproductive technology (ART). Despite published evidence suggesting that the judicious use of elective SET can lead to near-elimination of multiples without compromising cumulative live birth rates, the uptake of this strategy has been variable. ...Data from 31 countries suggest that there has been a gradual increase in SET rates over a 3 year period (2003-2005) but major geographical differences were noted. SET rates are highest in Sweden (69.4%) but are as low as 2.8% in the USA."
- Assisted Reproductive Technologies (ART) With Baboons A Nonhuman Primate Model for ART and Reproductive Sciences "The first ART baboons produced by ICSI, a pair of male twins, were delivered naturally at 165 days postgestation. Genetic testing of these twins confirmed their ART parental origins and demonstrated that they are unrelated fraternal twins not identicals."
- Trends in delivery and neonatal outcome after in vitro fertilization in Sweden: data for 25 years. "The decrease in unwanted outcomes can, to a large extent, be explained by the reduced rate of multiple births but was seen also among singletons. Other explanations can be sought in changes in the characteristics of patients undergoing IVF."