Hum. Reprod. Update [JOURNAL]
Sun
200 papers
The missing role of diagnosis of confined placental mosaicism in the management of fetal growth restriction.
Hantoushzadeh S, Saleh M, Nouri B … +2 more , Nazari F, Salmani T
Hum Reprod Update · 2021 Dec · PMID 34642745 · Publisher ↗
Abstract loading — click title to view on PubMed.
Asthma and allergies in offspring conceived by ART: a systematic review and meta-analysis.
Wijs LA, Fusco MR, Doherty DA … +2 more , Keelan JA, Hart RJ
Hum Reprod Update · 2021 Dec · PMID 34642743 · Publisher ↗
BACKGROUND: Currently, 1 in 25 children born in Australia are conceived through ARTs such as IVF and ICSI. Worldwide over 8 million children have been born after ART. There is evidence that these children are at an incre...
BACKGROUND: Currently, 1 in 25 children born in Australia are conceived through ARTs such as IVF and ICSI. Worldwide over 8 million children have been born after ART. There is evidence that these children are at an increased risk of congenital malformations, preterm birth, low birth weight and neonatal morbidity. However, studies on long-term health outcomes of offspring conceived after ART are lacking. Atopic disorders, such as asthma, atopic dermatitis and various allergies are increasingly common within society, and concerns have been raised that ART increases the risk of atopy amongst offspring. OBJECTIVE AND RATIONALE: The aim of this study was to systematically summarise and quantify the risk of atopic disorders in offspring conceived with ART compared to those conceived without ART. SEARCH METHODS: A systematic review was conducted according to the PRISMA guidelines. Several systematic searches were performed in the following international databases: Medline, Embase, Cinahl, PsychINFO, AMED, Global Health and ISI Web of Science. Search terms utilised were all terms pertaining to ART, IVF, ICSI, asthma, atopic dermatitis and allergies. The search period was 1978-2021. Included observational studies stated a primary outcome of asthma or allergies in offspring conceived after ART, with a comparison group conceived without ART. Individual studies were scored on quality and risk of bias, using the Newcastle-Ottawa scale (NOS). OUTCOMES: There were 26 studies which met the inclusion criteria; of these, 24 studies investigated asthma in offspring conceived after ART. While 10 studies, including the two largest population-based studies, reported a significantly increased risk of asthma in offspring conceived after ART (adjusted odds ratio (aOR) range: 1.20-2.38), 14 smaller cohort studies found no difference (aOR range 0.70-1.27). In the meta-analysis of the 14 highest-quality studies (NOS ≥ 7), a modest yet significantly increased risk of asthma was demonstrated in offspring conceived after ART [risk ratio (RR) 1.28 (1.08-1.51)]. Although heterogeneity in these 14 studies was high (I2 = 85%), the removal of outliers and high weight studies significantly reduced heterogeneity (I2 = 0% and I2 = 34% respectively) while still demonstrating a significantly increased risk [RR 1.19 (1.10-1.28) and RR 1.31 (1.03-1.65), respectively]. The increased asthma risk was also observed in most subgroup and sensitivity analyses. The allergy rates were not increased in offspring conceived after ART in 9 of 12 studies (aOR range 0.60-1.30). In summary, the findings of this systematic review and meta-analysis suggest a trend towards a significantly increased risk of asthma, but not allergies, in offspring conceived after ART. There was no evidence of publication bias in the asthma studies and minimal evidence of publication bias in the allergy studies (both P > 0.05). WIDER IMPLICATIONS: Asthma brings considerable burden to the quality of life of individuals and to society. Hence, it is of great importance to untangle potential causal pathways. Although ART use is common, knowledge about its long-term health effects is required to provide evidence-based advice to couples considering ART, and to be vigilant for any potential adverse health effects on offspring conceived after ART.
All you need to know about sperm RNAs.
Santiago J, Silva JV, Howl J … +2 more , Santos MAS, Fardilha M
Hum Reprod Update · 2021 Dec · PMID 34624094 · Publisher ↗
BACKGROUND: Spermatogenesis generates a small and highly specialised type of cell that is apparently incapable of transcription and translation. For many years, this dogma was supported by the assumption that (i) the com...
BACKGROUND: Spermatogenesis generates a small and highly specialised type of cell that is apparently incapable of transcription and translation. For many years, this dogma was supported by the assumption that (i) the compact sperm nucleus, resulting from the substitution of histones by protamine during spermatogenesis, renders the genome inaccessible to the transcriptional machinery; and (ii) the loss of most organelles, including endoplasmic reticulum and ribosomes, limits or prevents translational activity. Despite these observations, several types of coding and non-coding RNAs have been identified in human sperm. Their functional roles, particularly during fertilisation and embryonic development, are only now becoming apparent. OBJECTIVE AND RATIONALE: This review aimed to summarise current knowledge of the origin, types and functional roles of sperm RNAs, and to evaluate the clinical benefits of employing these transcripts as biomarkers of male fertility and reproductive outcomes. The possible contribution of sperm RNAs to intergenerational or transgenerational phenotypic inheritance is also addressed. SEARCH METHODS: A comprehensive literature search on PubMed was conducted using the search terms 'sperm' AND 'RNA'. Searches focussed upon articles written in English and published prior to August 2020. OUTCOMES: The development of more sensitive and accurate RNA technologies, including RNA sequencing, has enabled the identification and characterisation of numerous transcripts in human sperm. Though a majority of these RNAs likely arise during spermatogenesis, other data support an epididymal origin of RNA transmitted to maturing sperm by extracellular vesicles. A minority may also be synthesised by de novo transcription in mature sperm, since a small portion of the sperm genome remains packed by histones. This complex RNA population has important roles in paternal chromatin packaging, sperm maturation and capacitation, fertilisation, early embryogenesis and developmental maintenance. In recent years, additional lines of evidence from animal models support a role for sperm RNAs in intergenerational or transgenerational inheritance, modulating both the genotype and phenotype of progeny. Importantly, several reports indicate that the sperm RNA content of fertile and infertile men differs considerably and is strongly modulated by the environment, lifestyle and pathological states. WIDER IMPLICATIONS: Transcriptional profiling has considerable potential for the discovery of fertility biomarkers. Understanding the role of sperm transcripts and comparing the sperm RNA fingerprint of fertile and infertile men could help to elucidate the regulatory pathways contributing to male factor infertility. Such data might also provide a molecular explanation for several causes of idiopathic male fertility. Ultimately, transcriptional profiling may be employed to optimise ART procedures and overcome some of the underlying causes of male infertility, ensuring the birth of healthy children.
Contribution of epididymal epithelial cell functions to sperm epigenetic changes and the health of progeny.
Chen H, Alves MBR, Belleannée C
Hum Reprod Update · 2021 Dec · PMID 34618012 · Publisher ↗
BACKGROUND: Spermatozoa acquire their motility and fertilizing abilities during their maturation through the epididymis. This process is controlled by epididymal epithelial cells that possess features adapted to sense an...
BACKGROUND: Spermatozoa acquire their motility and fertilizing abilities during their maturation through the epididymis. This process is controlled by epididymal epithelial cells that possess features adapted to sense and respond to their surrounding environment and to communicate with spermatozoa. During the past decade, new intercellular communication processes have been discovered, including the secretion and transport of molecules from the epithelium to spermatozoa via extracellular vesicles (EVs), as well as sensing of the intraluminal milieu by cellular extensions. OBJECTIVE AND RATIONALE: This review addresses recent findings regarding epididymal epithelial cell features and interactions between spermatozoa and the epididymal epithelium as well as epigenetic modifications undergone by spermatozoa during transit through the epididymal microenvironment. SEARCH METHODS: A systematic search was conducted in Pubmed with the keyword 'epididymis'. Results were filtered on original research articles published from 2009 to 2021 and written in the English language. One hundred fifteen original articles presenting recent advancements on the epididymis contribution to sperm maturation were selected. Some additional papers cited in the primary reference were also included. A special focus was given to higher mammalian species, particularly rodents, bovines and humans, that are the most studied in this field. OUTCOMES: This review provides novel insights into the contribution of epididymal epithelium and EVs to post-testicular sperm maturation. First, new immune cell populations have been described in the epididymis, where they are proposed to play a role in protecting the environment surrounding sperm against infections or autoimmune responses. Second, novel epididymal cell extensions, including dendrites, axopodia and primary cilia, have been identified as sensors of the environment surrounding sperm. Third, new functions have been outlined for epididymal EVs, which modify the sperm epigenetic profile and participate in transgenerational epigenetic inheritance of paternal traits. WIDER IMPLICATIONS: Although the majority of these findings result from studies in rodents, this fundamental research will ultimately improve our knowledge of human reproductive physiopathologies. Recent discoveries linking sperm epigenetic modifications with paternal environmental exposure and progeny outcome further stress the importance of advancing fundamental research on the epididymis. From this, new therapeutic options for infertile couples and better counseling strategies may arise to increase positive health outcomes in children conceived either naturally or with ART.
A systematic review of the validated monogenic causes of human male infertility: 2020 update and a discussion of emerging gene-disease relationships.
Houston BJ, Riera-Escamilla A, Wyrwoll MJ … +11 more , Salas-Huetos A, Xavier MJ, Nagirnaja L, Friedrich C, Conrad DF, Aston KI, Krausz C, Tüttelmann F, O'Bryan MK, Veltman JA, Oud MS
Hum Reprod Update · 2021 Dec · PMID 34498060 · Full text
BACKGROUND: Human male infertility has a notable genetic component, including well-established diagnoses such as Klinefelter syndrome, Y-chromosome microdeletions and monogenic causes. Approximately 4% of all infertile m...
BACKGROUND: Human male infertility has a notable genetic component, including well-established diagnoses such as Klinefelter syndrome, Y-chromosome microdeletions and monogenic causes. Approximately 4% of all infertile men are now diagnosed with a genetic cause, but a majority (60-70%) remain without a clear diagnosis and are classified as unexplained. This is likely in large part due to a delay in the field adopting next-generation sequencing (NGS) technologies, and the absence of clear statements from field leaders as to what constitutes a validated cause of human male infertility (the current paper aims to address this). Fortunately, there has been a significant increase in the number of male infertility NGS studies. These have revealed a considerable number of novel gene-disease relationships (GDRs), which each require stringent assessment to validate the strength of genotype-phenotype associations. To definitively assess which of these GDRs are clinically relevant, the International Male Infertility Genomics Consortium (IMIGC) has identified the need for a systematic review and a comprehensive overview of known male infertility genes and an assessment of the evidence for reported GDRs. OBJECTIVE AND RATIONALE: In 2019, the first standardised clinical validity assessment of monogenic causes of male infertility was published. Here, we provide a comprehensive update of the subsequent 1.5 years, employing the joint expertise of the IMIGC to systematically evaluate all available evidence (as of 1 July 2020) for monogenic causes of isolated or syndromic male infertility, endocrine disorders or reproductive system abnormalities affecting the male sex organs. In addition, we systematically assessed the evidence for all previously reported possible monogenic causes of male infertility, using a framework designed for a more appropriate clinical interpretation of disease genes. SEARCH METHODS: We performed a literature search according to the PRISMA guidelines up until 1 July 2020 for publications in English, using search terms related to 'male infertility' in combination with the word 'genetics' in PubMed. Next, the quality and the extent of all evidence supporting selected genes were assessed using an established and standardised scoring method. We assessed the experimental quality, patient phenotype assessment and functional evidence based on gene expression, mutant in-vitro cell and in-vivo animal model phenotypes. A final score was used to determine the clinical validity of each GDR, across the following five categories: no evidence, limited, moderate, strong or definitive. Variants were also reclassified according to the American College of Medical Genetics and Genomics-Association for Molecular Pathology (ACMG-AMP) guidelines and were recorded in spreadsheets for each GDR, which are available at imigc.org. OUTCOMES: The primary outcome of this review was an overview of all known GDRs for monogenic causes of human male infertility and their clinical validity. We identified a total of 120 genes that were moderately, strongly or definitively linked to 104 infertility phenotypes. WIDER IMPLICATIONS: Our systematic review curates all currently available evidence to reveal the strength of GDRs in male infertility. The existing guidelines for genetic testing in male infertility cases are based on studies published 25 years ago, and an update is far overdue. The identification of 104 high-probability 'human male infertility genes' is a 33% increase from the number identified in 2019. The insights generated in the current review will provide the impetus for an update of existing guidelines, will inform novel evidence-based genetic testing strategies used in clinics, and will identify gaps in our knowledge of male infertility genetics. We discuss the relevant international guidelines regarding research related to gene discovery and provide specific recommendations to the field of male infertility. Based on our findings, the IMIGC consortium recommend several updates to the genetic testing standards currently employed in the field of human male infertility, most important being the adoption of exome sequencing, or at least sequencing of the genes validated in this study, and expanding the patient groups for which genetic testing is recommended.
Obstetric and neonatal outcomes of pregnancies resulting from preimplantation genetic testing: a systematic review and meta-analysis.
Zheng W, Yang C, Yang S … +8 more , Sun S, Mu M, Rao M, Zu R, Yan J, Ren B, Yang R, Guan Y
Hum Reprod Update · 2021 Oct · PMID 34473268 · Publisher ↗
BACKGROUND: Preimplantation genetic testing (PGT) includes methods that allow embryos to be tested for severe inherited diseases or chromosomal abnormalities. In addition to IVF/ICSI and repeated freezing and thawing of...
BACKGROUND: Preimplantation genetic testing (PGT) includes methods that allow embryos to be tested for severe inherited diseases or chromosomal abnormalities. In addition to IVF/ICSI and repeated freezing and thawing of the embryos, PGT requires a biopsy to obtain embryonic genetic material for analysis. However, the potential effects of PGT on obstetric and neonatal outcomes are currently uncertain. OBJECTIVE AND RATIONALE: This study aimed to investigate whether pregnancies conceived after PGT were associated with a higher risk of adverse obstetric and neonatal outcomes compared with spontaneously conceived (SC) pregnancies or pregnancies conceived after IVF/ICSI. SEARCH METHODS: PubMed, EMBASE, MEDLINE, Web of Science and The Cochrane Library entries from January 1990 to January 2021 were searched. The primary outcomes in this study were low birth weight (LBW) and congenital malformations (CMs), and the secondary outcomes included gestational age, preterm delivery (PTD), very preterm delivery (VPTD), birth weight (BW), very low birth weight (VLBW), neonatal intensive care unit (NICU) admission, hypertensive disorders of pregnancy (HDP), gestational diabetes, placenta previa and preterm premature rupture of membranes (PROM). We further pooled the results of PGT singleton pregnancies. Subgroup analyses included preimplantation genetic diagnosis (PGD), preimplantation genetic screening (PGS), cleavage-stage biopsy combined with fresh embryo transfer (CB-ET) and blastocyst biopsy combined with frozen-thawed embryo transfer (BB-FET). OUTCOMES: This meta-analysis included 15 studies involving 3682 babies born from PGT pregnancies, 127 719 babies born from IVF/ICSI pregnancies and 915 222 babies born from SC pregnancies. The relative risk (RR) of LBW was higher in PGT pregnancies compared with SC pregnancies (RR = 3.95, 95% confidence interval [CI]: 2.32-6.72), but the risk of CMs was not different between the two groups. The pooled results for the risks of LBW and CMs were similar in PGT and IVF/ICSI pregnancies. The risks of PTD (RR = 3.12, 95% CI: 2.67-3.64) and HDP (RR = 3.12, 95% CI: 2.18-4.47) were significantly higher in PGT pregnancies compared with SC pregnancies. Lower gestational age (mean difference [MD] = -0.76 weeks, 95% CI -1.17 to -0.34) and BW (MD = -163.80 g, 95% CI: -299.35 to -28.24) were also noted for PGT pregnancies compared with SC pregnancies. Nevertheless, compared with IVF/ICSI pregnancies, the risks of VPTD and VLBW in PGT pregnancies were significantly decreased by 41% and 30%, respectively, although the risk of HDP was still significantly increased by 50% in PGT pregnancies compared with IVF/ICSI pregnancies. The combined results of obstetric and neonatal outcomes of PGT and IVF/ICSI singleton pregnancies were consistent with the overall results. Further subgroup analyses indicated that both PGD and PGS pregnancies were associated with a higher risk of PTD and a lower gestational age compared with SC pregnancies. WIDER IMPLICATIONS: This meta-analysis showed that PGT pregnancies may be associated with increased risks of LBW, PTD and HDP compared with SC pregnancies. The overall obstetric and neonatal outcomes of PGT pregnancies are favourable compared with those of IVF/ICSI pregnancies, although PGT pregnancies were associated with a higher risk of HDP. However, because the number of studies that could be included was limited, more randomised controlled trials and prospective cohort studies are needed to confirm these conclusions.
Stanniocalcin-1 in the female reproductive system and pregnancy.
Bishop A, Cartwright JE, Whitley GS
Hum Reprod Update · 2021 Oct · PMID 34432025 · Full text
BACKGROUND: Stanniocalcin-1 (STC-1) is a widely expressed glycoprotein hormone involved in a diverse spectrum of physiological and pathophysiological processes including angiogenesis, mineral homeostasis, cell proliferat...
BACKGROUND: Stanniocalcin-1 (STC-1) is a widely expressed glycoprotein hormone involved in a diverse spectrum of physiological and pathophysiological processes including angiogenesis, mineral homeostasis, cell proliferation, inflammation and apoptosis. Over the last 20 years, numerous studies have reported STC-1 expression within female reproductive tissues including the uterus, ovaries and placenta and implicated STC-1 in processes such as ovarian follicular development, blastocyst implantation, vascular remodelling in early pregnancy and placental development. Notably, dysregulation of STC-1 within reproductive tissues has been linked to the onset of severe reproductive disorders including endometriosis, polycystic ovary syndrome, poor trophoblast invasion and placental perfusion in early pregnancy. Furthermore, significant changes in tissue expression and in maternal systemic concentration take place throughout pregnancy and further substantiate the vital role of this protein in reproductive health and disease. OBJECTIVE AND RATIONALE: Our aim is to provide a comprehensive overview of the existing literature, to summarise the expression profile and roles of STC-1 within the female reproductive system and its associated pathologies. We highlight the gaps in the current knowledge and suggest potential avenues for future research. SEARCH METHODS: Relevant studies were identified through searching the PubMed database using the following search terms: 'stanniocalcin-1', 'placenta', 'ovary', 'endometrium', 'pregnancy', 'reproduction', 'early gestation'. Only English language papers published between 1995 and 2020 were included. OUTCOMES: This review provides compelling evidence of the vital function that STC-1 plays within the female reproductive system. The literature presented summarise the wide expression profile of STC-1 within female reproductive organs, as well as highlighting the putative roles of STC-1 in various functions in the reproductive system. Moreover, the observed link between altered STC-1 expression and the onset of various reproductive pathologies is presented, including those in pregnancy whose aetiology occurs in the first trimester. This summary emphasises the requirement for further studies on the mechanisms underlying the regulation of STC-1 expression and function. WIDER IMPLICATIONS: STC-1 is a pleiotropic hormone involved in the regulation of a number of important biological functions needed to maintain female reproductive health. There is also growing evidence that dysregulation of STC-1 is implicated in common reproductive and obstetric disorders. Greater understanding of the physiology and biochemistry of STC-1 within the field may therefore identify possible targets for therapeutic intervention and/or diagnosis.
Hormone therapy in the postmenopausal years: considering benefits and risks in clinical practice.
Genazzani AR, Monteleone P, Giannini A … +1 more , Simoncini T
Hum Reprod Update · 2021 Oct · PMID 34432008 · Publisher ↗
BACKGROUND: Menopausal symptoms can be very distressing and considerably affect a woman's personal and social life. It is becoming more and more evident that leaving bothersome symptoms untreated in midlife may lead to a...
BACKGROUND: Menopausal symptoms can be very distressing and considerably affect a woman's personal and social life. It is becoming more and more evident that leaving bothersome symptoms untreated in midlife may lead to altered quality of life, reduced work productivity and, possibly, overall impaired health. Hormone therapy (HT) for the relief of menopausal symptoms has been the object of much controversy over the past two decades. At the beginning of the century, a shadow was cast on the use of HT owing to the concern for cardiovascular and cerebrovascular risks, and breast cancer, arising following publication of a large randomized placebo-controlled trial. Findings of a subanalysis of the trial data and extended follow-up studies, along with other more modern clinical trials and observational studies, have provided new evidence on the effects of HT. OBJECTIVE AND RATIONALE: The goal of the following paper is to appraise the most significant clinical literature on the effects of hormones in postmenopausal women, and to report the benefits and risks of HT for the relief of menopausal symptoms. SEARCH METHODS: A Pubmed search of clinical trials was performed using the following terms: estrogens, progestogens, bazedoxifene, tibolone, selective estrogen receptor modulators, tissue-selective estrogen complex, androgens, and menopause. OUTCOMES: HT is an effective treatment for bothersome menopausal vasomotor symptoms, genitourinary syndrome, and prevention of osteoporotic fractures. Women should be made aware that there is a small increased risk of stroke that tends to persist over the years as well as breast cancer risk with long-term estrogen-progestin use. However, healthy women who begin HT soon after menopause will probably earn more benefit than harm from the treatment. HT can improve bothersome symptoms, all the while conferring offset benefits such as cardiovascular risk reduction, an increase in bone mineral density and a reduction in bone fracture risk. Moreover, a decrease in colorectal cancer risk is obtainable in women treated with estrogen-progestin therapy, and an overall but nonsignificant reduction in mortality has been observed in women treated with conjugated equine estrogens alone or combined with estrogen-progestin therapy. Where possible, transdermal routes of HT administration should be preferred as they have the least impact on coagulation. With combined treatment, natural progesterone should be favored as it is devoid of the antiapoptotic properties of other progestogens on breast cells. When beginning HT, low doses should be used and increased gradually until effective control of symptoms is achieved. Unless contraindications develop, patients may choose to continue HT as long as the benefits outweigh the risks. Regular reassessment of the woman's health status is mandatory. Women with premature menopause who begin HT before 50 years of age seem to have the most significant advantage in terms of longevity. WIDER IMPLICATIONS: In women with bothersome menopausal symptoms, HT should be considered one of the mainstays of treatment. Clinical practitioners should tailor HT based on patient history, physical characteristics, and current health status so that benefits outweigh the risks.
The effects of bariatric surgery on periconception maternal health: a systematic review and meta-analysis.
Snoek KM, Steegers-Theunissen RPM, Hazebroek EJ … +4 more , Willemsen SP, Galjaard S, Laven JSE, Schoenmakers S
Hum Reprod Update · 2021 Oct · PMID 34387675 · Full text
BACKGROUND: Worldwide, the prevalence of obesity in women of reproductive age is increasing. Bariatric surgery is currently viewed as the most effective, long-term solution for this problem. Preconception bariatric surge...
BACKGROUND: Worldwide, the prevalence of obesity in women of reproductive age is increasing. Bariatric surgery is currently viewed as the most effective, long-term solution for this problem. Preconception bariatric surgery can reduce the prevalence of obesity-related subfertility and adverse maternal, pregnancy and birth outcomes. Maternal health during the periconception period is crucial for optimal gametogenesis and for embryonic and fetal development which also affects health in the later lives of both mother and offspring. Although preconception bariatric surgery improves several pregnancy outcomes, it can also increase the prevalence of pregnancy complications due to excessive and rapid weight loss. This can lead to iatrogenic malnutrition with vitamin deficiencies and derangements in metabolic and endocrine homeostasis. Thus, bariatric surgery can greatly influence periconception maternal health with consequences for reproduction, pregnancy and health in later life. However, its influence on periconception maternal health itself has never been reviewed systematically. OBJECTIVE AND RATIONALE: The aim of this review was to investigate associations between bariatric surgery and determinants of periconception maternal health such as endocrine changes, fertility, vitamin status, irregular menstrual cycles, miscarriages and congenital malformations. SEARCH METHODS: Medline, Embase, PubMed, Web of Science, Google Scholar and the Cochrane databases were used for the literature search until 1 November 2020. The search strategy terms included, among others, bariatric surgery, hormones, fertility, malformations, miscarriages and vitamin status. We searched for human studies that were written in English. Abstracts, reviews, meta-analyses and conference papers were excluded. The ErasmusAGE score was used to assess the quality of the included studies. OUTCOMES: A total of 51 articles were analysed. The mean quality score was 5 (range 2-8). After bariatric surgery, hormonal axes normalized and menstrual cycle regularity was restored, resulting in increased fertility. Overall, there were no short-term risks for reproductive outcomes such as the increased risk of miscarriages or congenital malformations. However, the risk of vitamin deficiencies was generally increased after bariatric surgery. A meta-analysis of 20 studies showed a significant decrease in infertility (risk difference (RD) -0.24, 95% confidence interval (CI) -0.42, -0.05) and menstrual cycle irregularities (RD -0.24, 95% CI -0.34, -0.15) with no difference in rates of miscarriage (RD 0.00, 95% CI -0.09, 0.10) and congenital malformations (RD 0.01, 95% CI -0.02, 0.03). WIDER IMPLICATIONS: The current systematic review and meta-analysis show associations between bariatric surgery and periconception maternal health and underlines the need for providing and personalizing preconception care for women after bariatric surgery. We recommend preconception care including the recommendation of postponing pregnancy until weight loss has stabilized, irrespective of the surgery-to-pregnancy interval, and until vitamin status is normalized. Therefore, regular monitoring of vitamin status and vitamin supplementation to restore deficiencies is recommended. Furthermore, this systematic review emphasizes the need for a long-term follow-up research of these women from the periconception period onwards as well as their pregnancies and offspring, to further improve care and outcomes of these mothers and children.
From late fatherhood to prenatal screening of monogenic disorders: evidence and ethical concerns.
Zhytnik L, Peters M, Tilk K … +7 more , Simm K, Tõnisson N, Reimand T, Maasalu K, Acharya G, Krjutškov K, Salumets A
Hum Reprod Update · 2021 Oct · PMID 34329448 · Publisher ↗
BACKGROUND: With the help of ART, an advanced parental age is not considered to be a serious obstacle for reproduction anymore. However, significant health risks for future offspring hide behind the success of reproducti...
BACKGROUND: With the help of ART, an advanced parental age is not considered to be a serious obstacle for reproduction anymore. However, significant health risks for future offspring hide behind the success of reproductive medicine for the treatment of reduced fertility associated with late parenthood. Although an advanced maternal age is a well-known risk factor for poor reproductive outcomes, understanding the impact of an advanced paternal age on offspring is yet to be elucidated. De novo monogenic disorders (MDs) are highly associated with late fatherhood. MDs are one of the major sources of paediatric morbidity and mortality, causing significant socioeconomic and psychological burdens to society. Although individually rare, the combined prevalence of these disorders is as high as that of chromosomal aneuploidies, indicating the increasing need for prenatal screening. With the help of advanced reproductive technologies, families with late paternity have the option of non-invasive prenatal testing (NIPT) for multiple MDs (MD-NIPT), which has a sensitivity and specificity of almost 100%. OBJECTIVE AND RATIONALE: The main aims of the current review were to examine the effect of late paternity on the origin and nature of MDs, to highlight the role of NIPT for the detection of a variety of paternal age-associated MDs, to describe clinical experiences and to reflect on the ethical concerns surrounding the topic of late paternity and MD-NIPT. SEARCH METHODS: An extensive search of peer-reviewed publications (1980-2021) in English from the PubMed and Google Scholar databases was based on key words in different combinations: late paternity, paternal age, spermatogenesis, selfish spermatogonial selection, paternal age effect, de novo mutations (DNMs), MDs, NIPT, ethics of late fatherhood, prenatal testing and paternal rights. OUTCOMES: An advanced paternal age provokes the accumulation of DNMs, which arise in continuously dividing germline cells. A subset of DNMs, owing to their effect on the rat sarcoma virus protein-mitogen-activated protein kinase signalling pathway, becomes beneficial for spermatogonia, causing selfish spermatogonial selection and outgrowth, and in some rare cases may lead to spermatocytic seminoma later in life. In the offspring, these selfish DNMs cause paternal age effect (PAE) disorders with a severe and even life-threatening phenotype. The increasing tendency for late paternity and the subsequent high risk of PAE disorders indicate an increased need for a safe and reliable detection procedure, such as MD-NIPT. The MD-NIPT approach has the capacity to provide safe screening for pregnancies at risk of PAE disorders and MDs, which constitute up to 20% of all pregnancies. The primary risks include pregnancies with a paternal age over 40 years, a previous history of an affected pregnancy/child, and/or congenital anomalies detected by routine ultrasonography. The implementation of NIPT-based screening would support the early diagnosis and management needed in cases of affected pregnancy. However, the benefits of MD-NIPT need to be balanced with the ethical challenges associated with the introduction of such an approach into routine clinical practice, namely concerns regarding reproductive autonomy, informed consent, potential disability discrimination, paternal rights and PAE-associated issues, equity and justice in accessing services, and counselling. WIDER IMPLICATIONS: Considering the increasing parental age and risks of MDs, combined NIPT for chromosomal aneuploidies and microdeletion syndromes as well as tests for MDs might become a part of routine pregnancy management in the near future. Moreover, the ethical challenges associated with the introduction of MD-NIPT into routine clinical practice need to be carefully evaluated. Furthermore, more focus and attention should be directed towards the ethics of late paternity, paternal rights and paternal genetic guilt associated with pregnancies affected with PAE MDs.
Reply: Spermatogonia stem cell technology: a new avenue for all age Klinefelter patients.
Deebel NA, Galdon G, Zarandi NP … +7 more , Stogner-Underwood K, Howards S, Lovato J, Kogan S, Atala A, Lue Y, Sadri-Ardekani H
Hum Reprod Update · 2021 Aug · PMID 34323999 · Publisher ↗
Abstract loading — click title to view on PubMed.
False hope for patients with Klinefelter syndrome on cryopreservation of spermatogonia at younger ages.
Winge SB, Almstrup K
Hum Reprod Update · 2021 Aug · PMID 34323963 · Publisher ↗
Abstract loading — click title to view on PubMed.
Is diminished ovarian reserve a risk factor for miscarriage? Results of a systematic review and meta-analysis.
Busnelli A, Somigliana E, Cirillo F … +1 more , Levi-Setti PE
Hum Reprod Update · 2021 Oct · PMID 34254138 · Publisher ↗
BACKGROUND: Anti-Müllerian hormone (AMH) serum concentration and antral follicle count (AFC), as measured by transvaginal ultrasonography, accurately reflect the antral follicle pool. However, AMH and AFC association wit...
BACKGROUND: Anti-Müllerian hormone (AMH) serum concentration and antral follicle count (AFC), as measured by transvaginal ultrasonography, accurately reflect the antral follicle pool. However, AMH and AFC association with fertility surrogates (i.e. age at menopause, probability of conceiving naturally and ART success rate) is questioned. Miscarriage is often considered an alternative measure of reproductive capacity. Nonetheless, the impact of diminished ovarian reserve (DOR) on miscarriage incidence remains an understudied and unresolved issue. OBJECTIVE AND RATIONALE: The aim of this systematic review and meta-analysis was to elucidate associations between DOR and miscarriage risk, both in women who conceived naturally and in those who achieved pregnancy through ART. SEARCH METHODS: Relevant studies were identified by a systematic search in PubMed, MEDLINE, Embase and Scopus, from database inception to 1 March 2021. Studies were included only if all the following conditions were met: DOR was defined using serum AMH concentration or AFC; miscarriage rate was reported separately for different groups of women categorized according to the AMH and/or AFC level; authors reported either the rate of intrauterine pregnancy loss before 22 weeks of gestation or enough data were available to calculate it. OUTCOMES: From a total of 347 publications initially identified, 16 studies were included. Pooled results from 13 retrospective studies focusing on ART pregnancies showed a significantly higher rate of miscarriage in women with a low AMH, as compared to women with a medium or high serum AMH concentration (12 042 women, random effects model, odds ratio (OR) 1.35; 95% CI, 1.10-1.66; P = 0.004; I2=50%). The only prospective study on ART pregnancies failed to show any association (61 women, risk ratio (RR) 2.95; 95% CI, 0.66-3.18; P = 0.16). Data from two prospective studies, which included naturally conceived pregnancies, showed a significantly increased miscarriage risk for women with low serum AMH. However, these data could not undergo meta-analysis owing to differing study designs. Using three retrospective studies, we observed an association between low AFC and miscarriage incidence (three retrospective studies on ART pregnancies, random effects model, OR 1.81; 95% CI, 1.02-3.21; P = 0.04; I2=64%). WIDER IMPLICATIONS: Our meta-analysis findings suggest that within the DOR patient subgroup, serum AMH and AFC biomarker levels may correlate with both the quantitative and qualitative aspects of ovarian reserve. However, owing to study limitations, the aetiology of this effect remains unclear and we are unable to define a causal relationship between DOR and increased miscarriage or to provide clinical recommendations based on this information. However, if confirmed by future well-designed studies, these findings would be profoundly informative for guiding women in family planning decisions.
The multiple roles of RAB GTPases in female and male meiosis.
Shan MM, Sun SC
Hum Reprod Update · 2021 Oct · PMID 34227671 · Publisher ↗
BACKGROUND: RAB GTPases constitute the largest family of small GTPases and are found in all eukaryotes. RAB GTPases regulate components of the endomembrane system, the nucleus and the plasma membrane, and are involved in...
BACKGROUND: RAB GTPases constitute the largest family of small GTPases and are found in all eukaryotes. RAB GTPases regulate components of the endomembrane system, the nucleus and the plasma membrane, and are involved in intracellular actin/tubulin-dependent vesicle movement, membrane fusion and cell growth in mitosis. OBJECTIVE AND RATIONALE: RAB GTPases play multiple critical roles during both female and male meiosis. This review summarizes the progress made in our understanding of the role of RAB GTPases in female and male meiosis in different species. We also discuss the potential relationship between RAB GTPases and oocyte/sperm quality, which may help in understanding the mechanisms underlying oogenesis and spermatogenesis and potential genetic causes of infertility. SEARCH METHODS: The PubMed database was searched for articles published between 1991 and 2020 using the following terms: 'RAB', 'RAB oocyte', 'RAB sperm' and 'RAB meiosis'. OUTCOMES: An analysis of 126 relevant articles indicated that RAB GTPases are present in all eukaryotes, and ten subfamilies (almost 70 members) are expressed in human cells. The roles of 25 RAB proteins and orthologues in female meiosis and 12 in male meiosis have been reported. RAB proteins are essential for the accurate continuity of genetic material, successful fertilization and the normal growth of offspring. Distinct and crucial functions of RAB GTPases in meiosis have been reported. In oocytes, RAB GTPases are involved in spindle organization, kinetochore-microtubule attachment, chromosome alignment, actin filament-mediated spindle migration, cytokinesis, cell cycle and oocyte-embryo transition. RAB GTPases function in mitochondrial processes and Golgi-mediated vesicular transport during female meiosis, and are critical for cortical granule transport during fertilization and oocyte-embryo transition. In sperm, RAB GTPases are vital for cytoskeletal organization and successful cytokinesis, and are associated with Golgi-mediated acrosome formation, membrane trafficking and morphological changes of sperm cells, as well as the exocytosis-related acrosome reaction and zona reaction during fertilization. WIDER IMPLICATIONS: Abnormal expression of RAB GTPases disrupts intracellular systems, which may induce diverse diseases. The roles of RAB proteins in female and male reproductive systems, thus, need to be considered. The mechanisms underlying the function of RAB GTPases and the binding specificity of their effectors during oogenesis, spermatogenesis and fertilization remain to be studied. This review should contribute to our understanding of the molecular mechanisms of oogenesis and spermatogenesis and potential genetic causes of infertility.
Plasticity of the human preimplantation embryo: developmental dogmas, variations on themes and self-correction.
Coticchio G, Barrie A, Lagalla C … +4 more , Borini A, Fishel S, Griffin D, Campbell A
Hum Reprod Update · 2021 Aug · PMID 34131722 · Publisher ↗
BACKGROUND: IVF for the treatment of infertility offers unique opportunities to observe human preimplantation development. Progress in time-lapse technology (TLT) and preimplantation genetic testing (PGT) has greatly exp...
BACKGROUND: IVF for the treatment of infertility offers unique opportunities to observe human preimplantation development. Progress in time-lapse technology (TLT) and preimplantation genetic testing (PGT) has greatly expanded our knowledge of developmental patterns leading to a healthy pregnancy or developmental failure. These technologies have also revealed unsuspected plastic properties of the preimplantation embryo, at macromolecular, cellular and multicellular levels. OBJECTIVE AND RATIONALE: This review focuses on the emerging concept of plasticity of the human embryo as revealed by recent evidence derived from TLT and PGT, calling for an updated and more precise redefinition of the boundaries between normal and abnormal development. SEARCH METHODS: PubMed was used to search the MEDLINE database for peer-reviewed English-language original articles and reviews concerning human preimplantation development. Cross-searches were performed by adopting 'fertilisation', 'pronucleus', 'cleavage', 'multinucleation', 'compaction', 'embryo', 'preimplantation genetic testing', 'aneuploidy', mosaicism', 'micromanipulation', 'time-lapse microscopy' and 'IVF/assisted reproduction' as main terms. The most relevant publications, i.e. those concerning major phenomena occurring during normal and abnormal development-with a focus on the human species-were assessed and discussed critically. OUTCOMES: Advances in TLT and PGT have revealed an astonishing plasticity and self-correction ability of the human preimplantation embryo in vitro. At fertilisation, an abnormal number of pronuclei do not always result in the formation of an aneuploid blastocyst. Animal studies and preliminary human observations indicate that combining of parental genomes may occur at the early cleavage stage, if not at fertilisation. Multinucleation occurs with much higher prevalence than previously thought and may be corrected at later cleavage stages. Irregular cleavage (multichotomous, direct, rapid and reverse cleavages) can generate chromosome segregation abnormalities that often lead to developmental arrest, but that sporadically may be confined to cells excluded from the blastocyst, and may sometimes result in viable pregnancy. Mitotic errors can generate mosaic blastocysts, but alternatively normal embryos may form from selective death or clonal depletion of aneuploid cells. WIDER IMPLICATIONS: Deviations from developmental dogmas and the increasing evidence of plasticity of the human embryo challenge current embryological notions and suggest the need to write new rules governing cell cycle, cell determination and chromosome segregation during preimplantation development.
Adenomyosis pathogenesis: insights from next-generation sequencing.
Bulun SE, Yildiz S, Adli M … +1 more , Wei JJ
Hum Reprod Update · 2021 Oct · PMID 34131719 · Full text
BACKGROUND: Adenomyosis, characterized by the presence of islands of endometrial tissue surrounded by hypertrophic smooth muscle cells within the myometrium, is one of the most challenging uterine disorders in terms of d...
BACKGROUND: Adenomyosis, characterized by the presence of islands of endometrial tissue surrounded by hypertrophic smooth muscle cells within the myometrium, is one of the most challenging uterine disorders in terms of diagnosis and management. Adenomyosis presents with pelvic pain, excessive uterine bleeding, anemia and infertility. The relative contributions of abnormal endometrial tissue and myometrial smooth muscle cells to the development and growth of adenomyosis are not well understood. Moreover, there is continuing debate on the origins of adenomyosis; two competing theories describe the invagination of basal endometrium into the myometrium or the metaplastic differentiation of remnant endometrial stem/progenitor cells within the myometrium. OBJECTIVE AND RATIONALE: A recent series of next-generation sequencing (NGS) studies have provided the best scientific evidence thus far regarding the cellular origins of adenomyosis and the contributions of new signaling pathways to its pathogenesis, survival, and growth. These seminal studies on endometrium, adenomyosis and endometriosis demonstrate or support the following key points. (i) Mutations of KRAS map to both intracavitary endometrial tissue and proximally located adenomyotic samples, supporting the invagination theory of pathogenesis. Driver mutations found in smooth muscle cells of uterine fibroids are absent in adenomyosis. (ii) KRAS and other less frequent mutations are limited to endometrial-type epithelial cells. They are also observed in endometriosis, indicating that the disease process in adenomyosis is similar to that in endometriosis and distinct from that of uterine fibroids. (iii) Activating mutations of KRAS stimulate specific pathways to increase cell survival and proliferation and are associated with progesterone resistance in adenomyosis. Together, these findings suggest that distinct cell populations in eutopic endometrial tissue play key roles in the etiology of adenomyosis. Dependence on ovarian steroids and ovulatory cycles for disease severity is a unique feature of adenomyosis. In this context, common patterns of aberrant gene expression have been reported both in adenomyosis and endometriosis. These include pathways that favor increased estrogen biosynthesis, decreased estradiol metabolism, a unique estrogen receptor beta (ESR2)-driven inflammatory process, and progesterone resistance due to decreased progesterone receptor expression. Since adenomyosis exhibits a uniquely estrogen-driven inflammatory process and progesterone resistance, we discuss the interactions between these molecular characteristics and signaling pathways induced by the newly discovered KRAS mutations. SEARCH METHODS: We conducted a comprehensive search using PubMed for human and animal studies published until 2020 in the following areas: adenomyosis, endometriosis, endometrium, NGS, whole-exome sequencing, whole-genome sequencing, RNA sequencing, targeted deep sequencing, epigenetics, driver mutation, KRAS, progesterone resistance, estrogen action and steroid production. OUTCOMES: Targeted deep sequencing analyses of epithelial cells in adenomyosis and adjacent basalis endometrial glands demonstrated recurring KRAS mutations in both cell types. This finding suggests that adenomyosis originates from basalis endometrium. Epithelial cells of the endometrium, adjacent adenomyosis and co-occurring endometriosis also share identical KRAS mutations. These findings suggest both adenomyosis and endometriosis are oligoclonal tissues that arise from endometrial cell populations carrying a specific driver mutation that most commonly affects the KRAS gene. WIDER IMPLICATIONS: Adenomyosis usually follows an event such as pregnancy that has disrupted the integrity of the endometrial-myometrial junction followed by repetitious menstrual episodes that increase the likelihood of the entrapment of the basalis endometrium within the myometrium. Glandular epithelial cells carrying KRAS mutations and located within the deep crypts of basalis endometrium may become entrapped and invade myometrial tissue to give rise to adenomyosis. Evidence suggests that KRAS mutations may be responsible, in part, for previously observed phenomena such as prolonged cell survival and progesterone resistance in adenomyosis.
Cell dynamics in human villous trophoblast.
Aplin JD, Jones CJP
Hum Reprod Update · 2021 Aug · PMID 34125187 · Publisher ↗
BACKGROUND: Villous cytotrophoblast (vCTB) is a precursor cell population that supports the development of syncytiotrophoblast (vSTB), the high surface area barrier epithelium of the placental villus, and the primary int...
BACKGROUND: Villous cytotrophoblast (vCTB) is a precursor cell population that supports the development of syncytiotrophoblast (vSTB), the high surface area barrier epithelium of the placental villus, and the primary interface between maternal and fetal tissue. In light of increasing evidence that the placenta can adapt to changing maternal environments or, under stress, can trigger maternal disease, we consider what properties of these cells empower them to exert a controlling influence on pregnancy progression and outcome. OBJECTIVE AND RATIONALE: How are cytotrophoblast proliferation and differentiation regulated in the human placental villus to allow for the increasing demands of the fetal and environmental challenges and stresses that may arise during pregnancy? SEARCH METHODS: PubMed was interrogated using relevant keywords and word roots combining trophoblast, villus/villous, syncytio/syncytium, placenta, stem, transcription factor (and the individual genes), signalling, apoptosis, autophagy (and the respective genes) from 1960 to the present. Since removal of trophoblast from its tissue environment is known to fundamentally change cell growth and differentiation kinetics, research that relied exclusively on cell culture has not been the main focus of this review, though it is mentioned where appropriate. Work on non-human placenta is not systematically covered, though mention is made where relevant hypotheses have emerged. OUTCOMES: The synthesis of data from the literature has led to a new hypothesis for vCTB dynamics. We propose that a reversible transition can occur from a reserve population in G0 to a mitotically active state. Cells from the in-cycle population can then differentiate irreversibly to intermediate cells that leave the cycle and turn on genes that confer the capacity to fuse with the overlying vSTB as well as other functions associated with syncytial barrier and transport function. We speculate that alterations in the rate of entry to the cell cycle, or return of cells in the mitotic fraction to G0, can occur in response to environmental challenge. We also review evidence on the life cycle of trophoblast from the time that fusion occurs, and point to gaps in knowledge of how large quantities of fetal DNA arrive in maternal circulation. We critique historical methodology and make a case for research to re-address questions about trophoblast lifecycle and dynamics in normal pregnancy and the common diseases of pre-eclampsia and fetal growth restriction, where altered trophoblast kinetics have long been postulated. WIDER IMPLICATIONS: The hypothesis requires experimental testing, moving research away from currently accepted methodology towards a new standard that includes representative cell and tissue sampling, assessment of cell cycle and differentiation parameters, and robust classification of cell subpopulations in villous trophoblast, with due attention to gestational age, maternal and fetal phenotype, disease and outcome.
Reply: Should women receive luteal support following natural cycle frozen embryo transfer? A systematic review and meta-analysis. Critical assessment of a review and meta-analysis.
Mizrachi Y, Weissman A
Hum Reprod Update · 2021 Jun · PMID 34086930 · Publisher ↗
Abstract loading — click title to view on PubMed.
Should women receive luteal support following natural cycle frozen embryo transfer? A systematic review and meta-analysis. Critical assessment of a review and meta-analysis.
Lawrenz B, Fatemi HM
Hum Reprod Update · 2021 Jun · PMID 34086890 · Publisher ↗
Abstract loading — click title to view on PubMed.
Confined placental mosaicism and the association with pregnancy outcome and fetal growth: a review of the literature.
Eggenhuizen GM, Go A, Koster MPH … +2 more , Baart EB, Galjaard RJ
Hum Reprod Update · 2021 Aug · PMID 33984128 · Full text
BACKGROUND: Chromosomal mosaicism can be detected in different stages of early life: in cleavage stage embryos, in blastocysts and biopsied cells from blastocysts during preimplantation genetic testing for aneuploidies (...
BACKGROUND: Chromosomal mosaicism can be detected in different stages of early life: in cleavage stage embryos, in blastocysts and biopsied cells from blastocysts during preimplantation genetic testing for aneuploidies (PGT-A) and later during prenatal testing, as well as after birth in cord blood. Mosaicism at all different stages can be associated with adverse pregnancy outcomes. There is an onward discussion about whether blastocysts diagnosed as chromosomally mosaic by PGT-A should be considered safe for transfer. An accurate diagnosis of mosaicism remains technically challenging and the fate of abnormal cells within an embryo remains largely unknown. However, if aneuploid cells persist in the extraembryonic tissues, they can give rise to confined placental mosaicism (CPM). Non-invasive prenatal testing (NIPT) uses cell-free (cf) DNA released from the placenta in maternal blood, facilitating the detection of CPM. In literature, conflicting evidence is found about whether CPM is associated with fetal growth restriction (FGR) and/or other pregnancy outcomes. This makes counselling for patients by clinicians challenging and more knowledge is needed for clinical decision and policy making. OBJECTIVE AND RATIONALE: The objective of this review is to evaluate the association between CPM and prenatal growth and adverse pregnancy outcomes. All relevant literature has been reviewed in order to achieve an overview on merged results exploring the relation between CPM and FGR and other adverse pregnancy outcomes. SEARCH METHODS: The following Medical Subject Headings (MESH) terms and all their synonyms were used: placental, trophoblast, cytotrophoblast, mosaicism, trisomy, fetal growth, birth weight, small for gestational age and fetal development. A search in Embase, PubMed, Medline Ovid, Web of Science, Cochrane Central Register of Controlled Trials (CENTRAL) and Google Scholar databases was conducted. Relevant articles published until 16 July 2020 were critically analyzed and discussed. OUTCOMES: There were 823 articles found and screened based on their title/abstract. From these, 213 articles were selected and full text versions were obtained for a second selection, after which 70 publications were included and 328 cases (fetuses) were analyzed. For CPM in eight different chromosomes (of the total 14 analyzed), there was sufficient evidence that birth weight was often below the 5th percentile of fetal growth standards. FGR was reported in 71.7% of CPM cases and preterm birth (<37 weeks of delivery) was reported in 31.0% of cases. A high rate of structural fetal anomalies, 24.2%, in cases with CPM was also identified. High levels of mosaicism in CVS and presence of uniparental disomy (UPD) were significantly associated with adverse pregnancy outcomes. WIDER IMPLICATIONS: Based on the literature, the advice to clinicians is to monitor fetal growth intensively from first trimester onwards in case of CPM, especially when chromosome 2, 3, 7, 13, 15, 16 and 22 are involved. In addition to this, it is advised to examine the fetuses thoroughly for structural fetal anomalies and raise awareness of a higher chance of (possibly extreme) premature birth. Despite prematurity in nearly a fifth of cases, the long-term follow-up of CPM life borns seems to be positive. More understanding of the biological mechanisms behind CPM will help in prioritizing embryos for transfer after the detection of mosaicism in embryos through PGT-A.
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