Reproductive technologies, female infertility, and the risk of imprinting-related disorders (original) (raw)
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Imprinting disorders after assisted reproductive technologies
Current Opinion in Obstetrics and Gynecology, 2006
Purpose of review To assess the evidence of an increased risk of imprinting diseases in children born after use of assisted reproductive technologies. Recent findings Imprinting disorders occur when the epigenetic programming during gametogenesis is disturbed, or when this programming is not sufficiently sustained during the process of fertilization and early embryonic development. Ten case or case-reference reports have been published suggesting that compared with reference populations, a higher proportion of children with imprinting diseases were conceived by assisted reproductive technologies. These reports are inconsistent in linking the risk to a specific assisted reproductive technology, and a cytogenetic examination assessing the exact genetic imprinting mechanism was not always provided. Two national systematic follow-up studies on 6052 Danish and 16,280 Swedish in-vitro fertilization children found none and two children with imprinting diseases, respectively. These figures correspond approximately to the expected number of children with imprinting disease from the general population. Summary The evidence of an increased risk of imprinting diseases in children conceived by assisted reproductive technologies is limited. The published case reports, however, call for a systematic multinational long-term follow-up of children born after assisted reproductive technologies.
European Journal of Medical Genetics, 2018
Introduction: Assisted Reproductive Technologies (ART) is increasingly used to help infertile couples to have children around the world. A number of studies have been published reporting an increased risk of major malformations in children born following ART, especially an increased incidence of epigenetic diseases (ED). This study aimed to assess the incidence of epigenetic diseases with affected imprinting genes in infants or children from pregnancies obtained through IVF/ICSI compared to infants or children from pregnancies obtained spontaneously. Patient data: This is a monocentric retrospective epidemiological study based on data from a French congenital malformations registry called REMERA (Registre des Malformations en Rhône-Alpes) which exhaustively monitors all pregnancies in Rhone-Alpes region, whatever their nature of onset (spontaneous pregnancies or pregnancies from ART). This registry collects all malformations, except minor malformations (EUROCAT), and all polymalformative syndromes concerning all fetuses and children born alive or not, from 20 weeks of pregnancy (or 22 weeks of amenorrhea) and all medical termination of pregnancy whatever the term. Inclusion criteria are all diagnoses of epigenetic diseases (ED) related to parental imprinting recorded in the period January 2006 to December 2015. Methods: For each year, the total number of births (including stillbirths) was collected from the annual activity reports of the registry. The exhaustive number of cases of epigenetic diseases was known in the registry. Were collected the number of births resulting from ART pregnancies in the study population. This incidence of ED was compared between births from spontaneous pregnancies and those obtained through ART (IVF/ICSI) with a generalized linear model (GLM: binomial regression). Results: In total, 46 cases of epigenetic diseases were analyzed on the REMERA registry files from 2006 to 2015. 4 cases from the 46 analyzed cases were from pregnancies induced by ART. ART was a risk factor for epigenetic disease (OR = 2.9 [1.06-8.22] (p = .039)). In ART-pregnancies there were 2 diagnoses: Beckwith-Wiedemann syndrome (BWS) (3 cases out of 4) and Silver-Russell syndrome (SRS) (1 out of 4). Discussion: Infants and children obtained through IVF/ICSI appear to be related to a higher risk of epigenetic diseases compared to naturally conceived children. The perspectives of this study are to raise awareness about the creation of registries of congenital malformations and genetic and epigenetic syndromes with systematic and strict reports of all the cases on all the French territory and thus to widen this study with a bigger cohort.
The impact of assisted reproductive technologies on genomic imprinting and imprinting disorders
Current Opinion in Obstetrics & Gynecology, 2014
Intrauterine growth is usually estimated using gestational age and weight at birth, which are routinely recorded on all births in most countries where assisted reproductive technologies (ART) have been introduced. It is therefore not surprising that the possible effects of ART on these two measures were reported soon after the first ART birth in 1978. For example, in 1985, the Australian In Vitro Fertilisation Collaborative Group [1] reported that 19% of 108 ART singletons in Australia were born before 37 weeks of gestation and 19% had a birth weight <2500 g, about three times the population rates at that time of preterm birth (PTB) and low birth weight (LBW). Although there were also early reports on birth defects following ART, they were based on small numbers of affected children, as birth defects are relatively rare. Hence, risk estimates were imprecise and often interpreted as showing no increase because the difference was not statistically significant. It took until the mid-2000s for the increased risk of birth defects in ART-conceived infants to be generally acknowledged [2,3]. ART has changed greatly since those early days. Techniques have altered, advanced and multiplied, pregnancy success rates have increased considerably, and more couples are using ART and for an increasing list of indicationsthere are now estimated to be more than five million ART children worldwide. This article surveys the systematic reviews and meta-analyses on intrauterine growth and birth defects in ART compared with non-ART singletons and discusses the possible reasons for the differences found, again using evidence from systematic reviews and meta-analyses where available. We report on recent reductions in risk of these outcomes and discuss two emerging issues: (i) the shift towards frozen-thawed embryos, and (ii) the risk of excessive intrauterine growth. 2 Systematic reviews and meta-analyses 2.1 Intrauterine growth Poor intrauterine growth is a predictor of adverse perinatal (and later) outcomes and is usually estimated using infant weight and gestation at the time of birth. Whereas the advent of prenatal ultrasound scanning has allowed serial measurement of growth during pregnancy, all the population studies included in the systematic reviews have used weight and gestation at birth to assess intrauterine growth.
Imprinting Disorders and Assisted Reproductive Technology
Seminars in Reproductive Medicine, 2009
Worldwide use of assisted reproductive technology (ART) accounts for an estimated 1 to 3% of births. Since 2002, a series of reports have suggested an increased risk of imprinting disorders (Beckwith-Wiedemann syndrome and Angelman syndrome) in children conceived by ART. Definitive conclusions are difficult to substantiate due to the rarity of imprinting disorders and the variability in ART protocols. Despite these limitations, there is biological plausibility for alteration in nongenomic inheritance caused by ART. Animal studies have shown that ART procedures can alter normal imprinting, specifically DNA methylation patterns. Collectively, studies suggest an association between ART and loss of maternal methylation. More recent reports examined a possible association between ART and global hypomethylation of DNA. Three other imprinting disorders (Silver-Russell syndrome, maternal hypomethylation syndrome, and retinoblastoma) have also been implicated, but there is insufficient evidence to establish an association of these syndromes with ART. Based on current evidence, the absolute risk of imprinting disorders after ART remains small and does not warrant routine screening. Large prospective studies are needed to better understand the risks associated with imprinting disorders, imprinting defects, and ART.
A survey of assisted reproductive technology births and imprinting disorders
Human Reproduction, 2007
BACKGROUND: Genomic imprinting is an epigenetic process in which allele-specific gene expression is dependent on the parental inheritance. Although only a minority of human genes are imprinted, those that have been identified to date have been preferentially implicated in prenatal growth and neurodevelopment. Mutations or epimutations in imprinted genes or imprinting control centres are associated with imprinting disorders such as Angelman syndrome (AS) and Beckwith-Wiedemann syndrome (BWS). Recently, an increased frequency of assisted reproductive technology (ART) conceptions has been reported in children with BWS and AS. However, the risk of imprinting disorders in ART children is unknown. METHODS: We undertook a survey of 2492 children born after ART in the Republic of Ireland and Central England with the aim of detecting cases (both clinically diagnosed and previously unrecognized) of BWS and AS in this cohort. The response rate to an initial questionnaire was 61%, corresponding to data for 1524 children. After evaluation of the questionnaire, 70 children were invited for a detailed clinical assessment, and 47 accepted (response rate of 67%). RESULTS: In this entire cohort, we detected one case of BWS and no cases of AS. We did not find evidence that there exists a significant group of ART children with unrecognized milder forms of AS or BWS. CONCLUSIONS: Although previous studies have suggested an increased relative risk of BWS and AS after ART, our findings suggest that the absolute risk of imprinting disorders in children conceived by ART is small (<1%). Precise risk estimates of risk are difficult to define because of the rarity of the conditions and incomplete response rates to the questionnaire and clinical examination invitations. Hence further investigations are indicated to (i) refine the absolute and relative risks of imprinting disorders after ART and (ii) ensure that changes in ART protocols are not associated with increased frequencies of epigenetic changes and imprinting disorders in children born after ART.
Imprinting diseases and IVF: Danish National IVF cohort study
Human Reproduction, 2004
were stratified into children born without and after IVF, and were followed from birth until the end of 2002 in the National Register of Patients and the Central Register of Psychiatric Diseases, which include all discharge diagnoses from somatic and psychiatric hospitals/clinics, respectively. Included in the study were malignancies, mental, behavioural and neurological diseases, congenital syndromes, and developmental disturbances. Only diagnosis codes potentially relevant for imprinting diseases were included. RESULTS: During the 7-year study period, 442 349 singleton non-IVF and 6052 IVF children were born. Mean follow-up time was 4.5 and 4.1 years for the two groups, respectively, corresponding to 2 million and 25 000 followup years. In the IVF/non-IVF cohort, we detected 0/72 children with cancer, 47/3766 with mental diseases, 72/3654 neurological diseases, 4/287 congenital syndromes and 96/6727 developmental disturbances, in a total of 219/14 506 clinical outcomes. The number of children with specific imprinting diseases in the non-IVF group was 54: 44 kidney cancers, five retinoblastoma, three Prader-Willi syndrome and two Russel -Silver syndrome. Anticipating the same occurrence in IVF children, the total expected number was calculated to be 0.74. The observed number in the IVF group was 0. We found a significantly increased risk of cerebral palsy in the IVF group, with a rate ratio (RR) (IVF:non-IVF) of 1.8 [95% confidence interval (CI) 1.2-2.8; P < 0.01], and of sleeping disturbances, with an RR 2.0 (95% CI 1.2-3.3). The incidence rate of childhood cancers, mental diseases, congenital syndromes and developmental disturbances was equal in the two groups. CONCLUSIONS: We found no indication of an increased risk of imprinting diseases after IVF, but an 80% increased risk of cerebral palsy. We observed equal frequencies of childhood cancers, mental diseases, congenital syndromes and developmental disturbances in the two groups. Danish register data do not support reports of an increased risk of imprinting diseases after IVF.
Infertility, assisted reproduction technologies and imprinting disturbances: a Dutch study
Human Reproduction, 2007
BACKGROUND: Evaluation of relationships between assisted reproduction technologies (ART), fertility problems and disorders caused by disturbed genetic imprinting such as Angelman syndrome (AS) and Beckwith-Wiedemann syndrome (BWS). METHODS: A nation-wide questionnaire survey was performed regarding ART in families with a child with AS, BWS or Prader-Willi syndrome (PWS) including questions on fertility. Molecular data on the genetic disorder in affected children were gathered. RESULTS: Of the 220 affected children in this study, 14 (6.4%) were born following any form of ART compared with 83 818 (2.1%) in the Dutch population. Of AS, PWS or BWS children 15 (6.8%) were born after a fertility problem (Time To Pregnancy >12 months, no forms of ART) compared to 141,340 (3.5%) in the Dutch population. Maternal age in the individual syndromes was higher than in the Dutch population. Families with affected children were three times more likely to experience fertility problems than the general population. All three syndromes were also individually associated with increased fertility problems in the families. CONCULSIONS: After correction for the increased fertility problems of the parents, there is no increased incidence of ART related birth of AS, PWS or BWS children. ART does not seem to have a direct effect on the increase of imprinted diseases.
Assessing the epigenetic risks of assisted reproductive technologies: a way forward
The International Journal of Developmental Biology, 2019
Since the birth of the first baby conceived by in vitro fertilization (IVF), assisted reproductive technologies (ART) have been constantly evolving to accomodate needs of a growing number of infertile couples. Rapidly developing ART procedures are directly applied for human infertility treatment without prior long-term safety evaluation. Although the majority of ART babies are healthy at birth, a comprehensive assessment of the long-term risks associated with ART is still lacking. An increased risk of epigenetic errors has been associated with the use of ART, which may contribute to the onset of civilization disease later in adolescence/adulthood and/or in subsequent generations. Therefore, our investigations should not focus on (or be limited to) the occurrence of a few very rare imprinting disorders in ART children, which might be associated with parental age and/or the use of ART, but on the possibly increased disease susceptibilities later in life and their potential transmissio...