RESUMO
Chromosome testing strategies, such as preimplantation genetic testing for aneuploidy (PGT-A), improve initial IVF outcomes by avoiding unwitting transfer of aneuploid embryos in morphology-based selection practices. Newer technologies have revealed that some embryos may appear to have intermediate whole chromosome (or parts of a chromosome termed segmental) copy number results suggesting trophectoderm mosaicism. An embryo with a trophectoderm mosaic-range result may be the only option for transfer for some patients. Recent data suggest that such mosaic embryos can be transferred without added risk of abnormal birth outcomes but may be associated with increased implantation failure and miscarriage rates, with higher values of mosaicism appearing to be less favourable for producing good outcomes. In this Position Statement, we provide guidance to laboratories, clinics, clinicians and counsellors to assist in discussions on the utility and transfer of mosaic embryos.
Assuntos
Diagnóstico Pré-Implantação , Aneuploidia , Blastocisto , Transferência Embrionária , Feminino , Testes Genéticos/métodos , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Humanos , Mosaicismo , Gravidez , Diagnóstico Pré-Implantação/métodosAssuntos
Quimera/embriologia , Transferência Embrionária/normas , Mosaicismo , Diagnóstico Pré-Implantação/normas , Transferência Embrionária/métodos , Feminino , Humanos , Internacionalidade , Gravidez , Resultado da Gravidez/genética , Diagnóstico Pré-Implantação/métodos , Técnicas de Reprodução Assistida/normas , Sociedades Médicas/normasRESUMO
Economic appraisal of genetics services is important, but, in this sensitive area, analyses limited to financial aspects understandably cause public concern. Evaluation of these services must take account of their aim of helping everyone with a genetic disadvantage to live and reproduce as normally as possible, and must apply equally to patients and to couples at risk of having affected children. Here we propose that the classical concept of genetic fitness can be useful in evaluating genetics services, because it is measurable, and truly represents their underlying aim.
Assuntos
Análise Custo-Benefício , Aconselhamento Genético/economia , Testes Genéticos/economia , Diagnóstico Pré-Natal/economia , Aborto Terapêutico , Algoritmos , Eugenia (Ciência) , Europa (Continente) , Feminino , Doenças Genéticas Inatas , Política de Saúde , Humanos , Recém-Nascido , Gravidez , Alocação de Recursos , Medicina Estatal/economia , Reino Unido , Organização Mundial da Saúde , Talassemia beta/genética , Talassemia beta/prevenção & controleRESUMO
The only proven cure for Shwachman-Diamond syndrome (SDS) bone marrow failure is allogeneic hematopoietic stem cell transplantation (HSCT). However HSCT with donors other than HLA-identical siblings is associated with high mortality and unfavorable prognosis. This paper presents the first experience of HSCT treatment of SDS using an unaffected HLA-identical sibling produced through preimplantation genetic diagnosis (PGD). The patient was a 6-year-old blood transfusion-dependent SDS baby girl with secondary myelodysplastic syndrome, for whom no HLA-identical donor was available. As a result of PGD, two unaffected HLA matched embryos were identified; one of them was randomly selected for transfer, resulting in a clinical pregnancy and birth of an apparently healthy child. The patient underwent allogeneic transplantation of cord blood hematopoietic stem cells, together with bone marrow from this sibling, resulting in complete hemopoietic recovery. The patient was no longer transfusion-dependent and had normal blood values 160 days after transplantation.
Assuntos
Doenças da Medula Óssea/terapia , Insuficiência Pancreática Exócrina/terapia , Lipomatose/terapia , Diagnóstico Pré-Implantação/métodos , Condicionamento Pré-Transplante/métodos , Transplante Homólogo/métodos , Criança , Feminino , Transplante de Células-Tronco Hematopoéticas/métodos , Teste de Histocompatibilidade/métodos , Humanos , Síndrome de Shwachman-Diamond , Irmãos , Doadores de TecidosRESUMO
The activity of ATP-dependent phosphofructokinase (PFK) from subepidermal tissue of apple fruits was studied. The enzyme extracted under optimal conditions was stable for 14 h at room temperature. The enzyme was partially purified by ammonium sulfate fractionation and dialysis. PFK from apple fruits was found to be ATP-, UTP-, and CTP-specific. It was inhibited by PEP, Gly-2-P, Gly-1,3-DP, and ADP. The effect of the listed inhibitors was diminished by the presence of phosphate. The activity of PFK was stimulated by magnesium cations. The activity of the enzyme in fruits of an Antonovka cultivar was higher than in the Simirenko rennet cultivar by a factor of 1.3.
Assuntos
Frutas/enzimologia , Fosfofrutoquinases/isolamento & purificação , Proteínas de Plantas/isolamento & purificação , Pyrus/enzimologia , Inibidores Enzimáticos/química , Fosfofrutoquinases/química , Proteínas de Plantas/química , Pyrus/química , Ribonucleotídeos/química , Especificidade da EspécieRESUMO
It was previously shown that more than half of the human oocytes obtained from IVF patients of advanced reproductive age are aneuploid, due to meiosis I and meiosis II errors. The present paper further confirms that 61.8% of the oocytes tested by fluorescent probes specific for chromosomes 13, 16, 18, 21 and 22 are abnormal, representing predominantly chromatid errors, which are the major source of aneuploidy in the resulting embryos. Almost half of the oocytes with meiosis I errors (49.3%) are prone to sequential meiosis II errors, which may lead to aneuploidy rescue in 30.8% of the cases. Half of the detected aneuploidies (49.8%) are of complex nature with involvement of two or more chromosomes, or the same chromosome in both meiotic divisions. The aneuploidy rates for individual chromosomes are different, with a higher prevalence of chromosome 21 and 22 errors. The origin of aneuploidy for the individual chromosomes is also not random, with chromosome 16 and 22 errors originating more frequently in meiosis II, and chromosome 18, 13 and 21 errors in meiosis I. There is an age dependence not only for the overall frequency of aneuploidies, but also for each chromosome error, aneuploidies originating from meiosis I, meiosis II, and both meiosis I and meiosis II errors, as well as for different types of aneuploidies. The data further suggest the practical relevance of oocyte aneuploidy testing for detection and avoidance from transfer of the embryos deriving from aneuploid oocytes, which should contribute significantly to the pregnancy outcomes of IVF patients of advanced reproduction age.
Assuntos
Aberrações Cromossômicas/estatística & dados numéricos , Oócitos/fisiologia , Adulto , Envelhecimento , Deleção Cromossômica , Mapeamento Cromossômico , Feminino , Humanos , Hibridização in Situ Fluorescente , Idade Materna , Meiose , Ciclo Menstrual , Oócitos/citologiaRESUMO
Embryos found to be abnormal during preimplantation genetic diagnosis are discarded or analyzed to confirm the diagnosis. The destruction of affected embryos is ethically unacceptable to some couples. We developed a preembryonic genetic diagnosis, that uses sequential first and second polar body removal, followed by oocyte freezing at the pronuclear stage. This was applied in a patient at risk of having a child with sickle cell disease, who suffered hyper-stimulation syndrome. Fourteen oocytes were obtained and tested for the maternal sickle cell allele by PCR analysis of the first and second polar body. Immediately after procedure of polar body removal, the pronuclear-stage oocytes were frozen. Six mutation-free oocytes detected by polar body analysis were then thawed, allowed to cleave, and transferred in the two consecutive clinical cycles, both resulting in clinical pregnancies, one of which resulted in birth of a healthy child. The oocytes predicted to contain abnormal beta-globin gene were not further cultured, to avoid formation and discard of the affected embryos. The results demonstrate feasibility of preembryonic diagnosis for single gene disorders, avoiding the establishment and destruction of mutant embryos.
Assuntos
Anemia Falciforme/diagnóstico , Anemia Falciforme/genética , Globinas/genética , Oócitos/fisiologia , Diagnóstico Pré-Implantação , Adulto , Alelos , Feminino , Marcadores Genéticos , Genótipo , Humanos , Recém-Nascido , Oócitos/ultraestrutura , Reação em Cadeia da Polimerase/métodos , Gravidez , Resultado da Gravidez , Gravidez de Alto Risco , Diagnóstico Pré-NatalRESUMO
Aneuploidy free oocytes may be pre-selected by testing the first and second polar bodies removed from oocytes following their maturation and fertilization. We present here our experience on the application of the method in IVF cycles from patients of advanced maternal age. Overall, 5590 oocytes were obtained from 917 cycles and tested by polar body sampling and fluorescent in situ hybridization (FISH) analysis using specific probes for chromosomes 13,16,18,21 and 22. FISH results were available in 4599 (82.2%) of 5590 oocytes studied, from which 2077(45.2%) were with aneuploidies. Thirty six point one percent of aneuploidies were of the first meiotic origin, and 29.3% of the second meiotic origin. Most errors in the first meiotic division were represented by chromatid errors. The transfer of embryos deriving from 2014 of 2520 aneuploidy free oocytes in 821 treatment cycles resulted in 182 (22.2%) clinical pregnancies and 140 healthy children born after confirmation of the polar body diagnosis. Polar body testing of oocytes provides an approach for pre-selection of aneuploidy free embryos, improving pregnancy rate in IVF patents of advanced maternal age.
Assuntos
Aneuploidia , Oócitos/ultraestrutura , Diagnóstico Pré-Implantação/métodos , Adulto , Cromossomos Humanos , Sondas de DNA/genética , Transferência Embrionária , Feminino , Fertilização in vitro , Humanos , Hibridização in Situ Fluorescente , Recém-Nascido , Cariotipagem , Idade Materna , Oócitos/fisiologia , Gravidez , Taxa de Gravidez , Gravidez de Alto RiscoRESUMO
OBJECTIVE: To use preimplantation genetic diagnosis to achieve a phenylketonuria-free pregnancy in a couple at 50% risk for producing an affected child. DESIGN: DNA analysis of the first and second polar bodies (PB1 and PB2) obtained from oocytes of a heterozygous mother in IVF-ET, with the goal of identifying and transferring back to the patient the embryos resulting from mutation-free oocytes. SETTING: IVF program of Reproductive Genetics Institute, Chicago, Illinois. PATIENT(S): A mother carrying the R408W mutation and a father with compound heterozygosity for R408 and Y414C mutations in phenylalanine hydroxylase (PAH) gene. INTERVENTION(S): Removal and testing for maternal mutation in PB1 and PB2 from each oocyte after standard IVF. MAIN OUTCOME MEASURE(S): DNA analysis of PB1 and PB2 indicating whether corresponding oocytes were mutation-free, for the purposes of transferring only unaffected embryos resulting from these oocytes. RESULT(S): Of 11 zygotes with both PB1 and PB2, 6 were predicted to be free of phenylketonuria. Of these, 4 were transferred, resulting in an unaffected twin pregnancy and birth of two healthy children. CONCLUSION(S): Preimplantation genetic diagnosis of phenylketonuria resulted in the birth of phenylketonuria-free children. Preimplantation genetic diagnosis by PB analysis in couples with a compound heterozygous male partner is clinically useful.
Assuntos
Desenvolvimento Embrionário , Fenilcetonúrias/diagnóstico , Diagnóstico Pré-Natal/métodos , Adulto , Transferência Embrionária , Feminino , Fertilização in vitro , Genótipo , Haplótipos , Humanos , Masculino , Mutação , Fenilalanina Hidroxilase/genética , Gravidez , Mapeamento por RestriçãoRESUMO
OBJECTIVE: To perform preimplantation diagnosis of common aneuploidies by polar body analysis and fluorescent in situ hybridization technique using probes specific for chromosomes X, 18, and 13/21. DESIGN: The first and/or second polar bodies were removed and studied by fluorescent in situ hybridization to detect and avoid fertilization and transfer of oocytes with common aneuploidies. SETTING: The Reproductive Genetics Institute's IVF program at Illinois Masonic Medical Center. PATIENTS: One hundred ninety-three couples of advanced maternal age (34 to 46 years) under-going IVF treatment volunteered to be part of a clinical trial on preimplantation polar body diagnosis of common aneuploidies. INTERVENTIONS: Using micromanipulation procedures, the first and second polar bodies were removed after their extrusion from the oocytes. MAIN OUTCOME MEASURE: Fluorescent in situ hybridization signals specific for chromosomes X, 18, and 13/21. RESULTS: In 235 IVF cycles performed in 193 couples, 1,293 oocytes were biopsied and subjected to fluorescent in situ hybridization analysis, with fluorescent in situ hybridization results available in 993 oocytes (76.8%). Of 993 oocytes with fluorescent in situ hybridization results, 665 (67%) were predicted to be normal based on the chromosomes studied; 460 embryos resulting from these oocytes were transferred in 187 treatment cycles, resulting in 12 births of healthy children and 18 ongoing pregnancies after confirmation of the polar body diagnosis by chorionic villus sampling or amniocentesis. CONCLUSION: Polar body fluorescent in situ hybridization analysis may be used for preimplantation diagnosis of common aneuploidies in IVF patients of advanced maternal age.
Assuntos
Aneuploidia , Aberrações Cromossômicas/diagnóstico , Implantação do Embrião , Oócitos/ultraestrutura , Adulto , Transtornos Cromossômicos , Cromossomos Humanos Par 13 , Cromossomos Humanos Par 18 , Cromossomos Humanos Par 21 , Transferência Embrionária , Feminino , Fertilização in vitro , Humanos , Hibridização in Situ Fluorescente , Recém-Nascido , Idade Materna , Micromanipulação , Pessoa de Meia-Idade , Gravidez , Resultado da Gravidez , Taxa de Gravidez , Gravidez de Alto Risco , Cromossomo XRESUMO
Current practice for prevention of chromosomal aneuploidies involves prenatal screening and termination of pregnancy, a procedure that is not universally acceptable. We introduced prepregnancy genetic testing by sampling and fluorescence in situ hybridization (FISH) analysis of the first and second polar body (PB), to avoid fertilization and transfer of embryos resulting from aneuploid oocytes. In 395 in vitro fertilization (IVF) patients of advanced maternal age, the first and second PBs were removed following their extrusion from oocytes and studied by FISH, using probes specific for chromosomes 13, 18, and 21, to detect and avoid the transfer of oocytes with common aneuploidies. Overall, 3,651 oocytes obtained from 598 IVF cycles were available for FISH analysis, with 2,952 showing interpretable FISH results (80.9%). The analysis revealed 1,271 (43.1%) oocytes with aneuploidy, which were excluded from transfer and subjected to follow-up FISH analysis to confirm PB diagnosis in the cleavage or blastocyst stage embryos. Only embryos originating from 1,681 aneuploidy-free oocytes were transferred back to patients, resulting in 119 pregnancies overall, from which 78 healthy children have already been born, 35 were spontaneously aborted, and 16 are ongoing, after confirming PB diagnosis by prenatal diagnosis. The results demonstrate that PB-based preimplantation diagnosis may be used for prepregnancy screening in women with age-related risk for common aneuploidies.
Assuntos
Aneuploidia , Testes Genéticos , Hibridização in Situ Fluorescente , Idade Materna , Meiose , Cuidado Pré-Concepcional , Blastocisto , Transferência Embrionária , Feminino , Fertilização in vitro , Humanos , Recém-Nascido , Oócitos/citologia , Gravidez , Resultado da GravidezRESUMO
Preventive measures for single-gene disorders are currently based on carrier screening in pregnancy and prenatal diagnosis. Although this has been extremely effective for preventing new cases of common inherited conditions, the major limitation is still termination of 25% of wanted pregnancies following detection of affected fetuses. To overcome this important problem, we developed a method for prepregnancy genetic testing that involves DNA analysis of the first and second polar bodies, which are extruded during maturation and fertilization of oocytes. We offered this option to 28 couples at risk for having children with single-gene disorders. Fifty clinical cycles were performed from these patients for the following conditions: 20 for cystic fibrosis, 18 for thalassemia, 6 for sickle cell disease, 2 each for Gaucher disease and LCHAD (long-chain 3-hydroxyacyl-COA dehydrogenase deficiency), and 1 each for hemophilia B and phenylketonuria. Oocytes obtained from these patients using in vitro fertilization procedures (IVF) were tested by a sequential multiplex nested PCR analysis of the first and second polar body to detect the gene involved simultaneously with linked polymorphic markers. A total of 191 of 399 oocytes with predicted genotype were mutation free and preselected for fertilization and transfer. In all but three cycles, one to three unaffected embryos with predicted unaffected genotypes were transferred, resulting in 20 pregnancies, from which 19 healthy children have been born. The follow-up analysis of embryos resulting from oocytes with predicted affected genotype, confirmed the diagnosis in 97% of cases, demonstrating the reliability of prepregnancy diagnosis of single-gene defects by polar body analysis.
Assuntos
Análise Mutacional de DNA/métodos , Doenças Genéticas Inatas/genética , Doenças Genéticas Inatas/prevenção & controle , 3-Hidroxiacil-CoA Desidrogenases/deficiência , 3-Hidroxiacil-CoA Desidrogenases/genética , Anemia Falciforme/diagnóstico , Anemia Falciforme/genética , Anemia Falciforme/prevenção & controle , Sequência de Bases , Fibrose Cística/diagnóstico , Fibrose Cística/genética , Fibrose Cística/prevenção & controle , Primers do DNA/genética , Transferência Embrionária , Feminino , Fertilização in vitro , Doença de Gaucher/diagnóstico , Doença de Gaucher/genética , Doença de Gaucher/prevenção & controle , Doenças Genéticas Inatas/diagnóstico , Técnicas Genéticas , Testes Genéticos , Genótipo , Hemofilia B/diagnóstico , Hemofilia B/genética , Hemofilia B/prevenção & controle , Humanos , 3-Hidroxiacil-CoA Desidrogenase de Cadeia Longa , Masculino , Mutação , Oócitos/metabolismo , Fenilcetonúrias/diagnóstico , Fenilcetonúrias/genética , Fenilcetonúrias/prevenção & controle , Reação em Cadeia da Polimerase/métodos , Gravidez , Resultado da Gravidez , Diagnóstico Pré-Natal , Reprodutibilidade dos Testes , Talassemia/diagnóstico , Talassemia/genética , Talassemia/prevenção & controleRESUMO
At least one half of oocytes and preimplantation embryos are aneuploid and have to be avoided from transfer in in vitro fertilization (IVF) patients of advanced reproductive age. This can now be done by preimplantation genetic diagnosis, which has recently become an integral part of assisted reproduction technologies and was shown to improve implantation rate and reduce spontaneous abortions after implantation. The experience of approximately 5000 preimplantation genetic diagnosis (PGD) cycles performed for poor prognosis IVF patients have already resulted in birth of approximately 1000 apparently healthy children, suggesting that this novel technique is safe and reliable, and may in future replace the current IVF practice of preselection of embryos for transfer based on morphological parameters.
Assuntos
Aneuploidia , Fertilização in vitro , Diagnóstico Pré-Implantação , Técnicas de Reprodução Assistida , Embrião de Mamíferos , Feminino , Humanos , Hibridização in Situ Fluorescente , Recém-Nascido , Masculino , Oócitos , Gravidez , Gravidez MúltiplaRESUMO
Antisera to diploid, trisomic and triploid embryonic fibroblast-like cells were obtained after hyperimmunization of rabbits. Immunoelectrophoretic analysis with these antisera revealed up to 9 water-soluble antigens in embryonic cells, which were present in skin fibroblasts from adult donors as well. Trisomic and triploid strains did not differ from the diploid ones by the spectrum of water-soluble antigens. The content of the number of antigens (especially of cathode fractions) in trisomic cells was significantly low as compared with those in control diploid cells, whereas in triploid ones it differed slightly. All the strains were characterized by the presence of proteins immunologically identical to alpha-globulin of human serum.
Assuntos
Aneuploidia , Antígenos , Embrião de Mamíferos/imunologia , Trissomia , Humanos , ImunoeletroforeseRESUMO
Determination of parameters of the mitotic cycles in 5 human diploid embryonic strains and in 4 human strains from donor skin biopsies was conducted in termal room (37 degrees C). Diploid strains of postnatal origin have a longer duration both of the whole mitotic cycle (P less than 0.001) and of particular stages G1 (P less than 0.001), G2 (P less than 0.001) (duration of S-phase was not deviated) as well as lower values for the proliferative pool during the whole cultivation to the embryonic diploid strains.
Assuntos
Fibroblastos/citologia , Mitose , Linhagem Celular , Diploide , HumanosRESUMO
A case of triploidy identified in second trimester fetal diagnosis is presented. Cytogenetic study was undertaken in chorionic willi obtained by transabdominal placentocentesis. The diagnosis was confirmed by cytogenetic analysis of cultured amniotic fluid cells. The observation was revealed within a programme of combined ultrasound and cytogenetic prenatal monitoring, in association with maternal age. The fetus aborted at 23 weeks of pregnancy was abnormal, including congenital malformations and hypoplasia of internal organs and placenta.
Assuntos
Amostra da Vilosidade Coriônica , Poliploidia , Adulto , Feminino , Humanos , Gravidez , Segundo Trimestre da GravidezRESUMO
Complex investigation of 5 enzymes was carried out in a cell strain with triploidy 69, XXY, derived from a human spontaneous abortus. The activity of 3 enzymes (acid phosphatase, lactate and malate dehydrogenases) in triploid cells proved to be significantly increased as compared to those of 3 diploid strains, whereas the activity of alkaline phosphatase was decreased. The activity of glutamate-oxalacetate transaminase did not change. The absence of the pronounced genetic dose effect and different alteration of the activities of the enzymes studied may be considered as an expression of a disbalance of enzymes in cytogenetically defective cells.
Assuntos
Fibroblastos/enzimologia , Poliploidia , Fosfatase Ácida/metabolismo , Fosfatase Alcalina/metabolismo , Aspartato Aminotransferases/metabolismo , Humanos , L-Lactato Desidrogenase/metabolismo , Malato Desidrogenase/metabolismoRESUMO
The activity of five enzymes (AIP, AcP, GOT, LDH, MDH) was investigated in four cell strains derived from spontaneous abortuses with C-trisomy (three cell strains with trisomy 7, one--with trisomy 9). Significant differences in the activity of three enzymes were revealed. In all the strains AIP activity was lower and GOT activity--higher than in diploid strains. Lowering of AcP level was found in three strains (two cell strains with trisomy 7, one--with trisomy 9). The data obtained are evaluated as a result of disturbed regulatory interrelations in an abnormal genome.
Assuntos
Cromossomos Humanos 6-12 e X , Fibroblastos/enzimologia , Trissomia , Fosfatase Ácida/metabolismo , Fosfatase Alcalina/metabolismo , Aspartato Aminotransferases/metabolismo , Linhagem Celular , Humanos , L-Lactato Desidrogenase/metabolismo , Malato Desidrogenase/metabolismoRESUMO
The object of this investigation were the parameters of the mitotic cycle in 14 fibroblasts-like cell strains with chromosome aberrations obtained from skin biopsies of patients and from spontaneous human abortuses. In two strains of embryonal origin (trisomic for chromosome and monosomic for chromosome 21) increased duration of stage G2 of the cell cycle accompanied by a shorter period of DNA synthesis was observed. In the other 5 strains of embryonal origin (two strains trisomic for chromosome 7, strains trisomic for chromosome 9, trisomic for chromosome 14 and triploid strains) no deviations from the normal duration of the stages of the cell cycle were observed. Two types of changes of the mitotic cycle parameters were observed in the cell strains obtained from patients with chromosome aberrations. A considerably prolonged G2 stage was observed in two strains obtained from patients affected by Down's syndrome. Three strains with the karyotypes 47, XXX, 47 XY+18 and 46, XX, 5p-were characterized by a complex of features typical of the strains of embryonal origin. A considerable decrease of the stage G2 duration was observed in these strains. In the strains obtained from a proband with Kleinfelter's syndrome and from a patient with the karyotype 46XX no deviations in the parameters of the cell cycle were observed.
Assuntos
Aberrações Cromossômicas/patologia , Mitose , Transtornos Cromossômicos , Cromossomos Humanos 13-15 , Cromossomos Humanos 6-12 e X , Síndrome de Down/patologia , Humanos , Síndrome de Klinefelter/patologia , TrissomiaRESUMO
Preimplantation diagnosis of inherited and chromosomal diseases provides an option for couples at risk for conceiving genetically abnormal fetus to avoid a birth of an affected child without the need for a prenatal diagnosis and selective abortion of affected fetus (1-3). In some countries this might be the only way to the prevention of genetic disease, as abortion is not acceptable procedure. Even in those countries where prenatal diagnosis is practiced for many years, there is also concern that existing genetic programs based on prenatal screening will lead to increasing number of abortions. On the other hand, the possibilities for genotyping oocytes and cleaving embryos open a new prospect for genetic diagnosis before pregnancy, making genetic programs more ethically acceptable in any social setting. This will make preimplantation diagnosis the method of choice in the community based programs for prevention of genetic disease in the future, as well as a useful addition to assisted reproduction technologies, at least for IVF patients of advanced maternal age.