Best Practice & Research Clinical Obstetrics & Gynaecology最新文献

Conclusion

Advances in ultrasound and prenatal diagnosis are leading an expansion in the options for parents whose fetus is identified with a congenital disease. Obstetric diseases such as pre-eclampsia and fetal growth restriction may also be amenable to intervention to improve maternal and neonatal outcomes. Advanced Medicinal Therapeutic Products such as stem cell, gene, enzyme and protein therapies are most commonly being investigated as the trajectory of treatment for severe genetic diseases moves toward earlier intervention. Theoretical benefits include prevention of in utero damage, smaller treatment doses compared to postnatal intervention, use of fetal circulatory shunts and induction of immune tolerance. New systematic terminology can capture adverse maternal and fetal adverse events to improve safe trial conduct. First-in-human clinical trials are now beginning to generate results with a focus on safety first and efficacy second. If successful, these trials will transform the care of fetuses with severe early-onset congenital disease.

Prenatal detection of copy number variants (CNVs) plays an important role in the diagnosis of fetal genetic abnormalities. Understanding the methods used for prenatal CNV detection and their clinical significance contributes to the implementation of advanced genetic screening techniques in prenatal care; facilitating early identification and management of genetic disorders in fetuses. Some CNVs impose significant genetic counselling challenges; especially those which are associated with uncertain clinical significance, in the context of variable penetrance and/or expressivity or when identified incidentally.

This chapter focuses on the different techniques used for detecting CNVs, including Single Nucleotide Polymorphism (SNP) arrays, comparative genomic hybridization (CGH) arrays, Non-Invasive Prenatal Testing (NIPT), Whole Exome Sequencing (WES) and Whole Genome Sequencing (WGS) as well as their advantages and limitations. The tools needed for the classification of CNVs and their clinical relevance are also explored, emphasising the importance of accurate interpretation for appropriate clinical management and genetic counselling.

This paper discusses ethical issues arising in the context of prenatal genomic testing. While genomic information in the prenatal context might increase reproductive choice, e.g. to better understand a phenotype detected during screening, the availability of ever broader screens, even in the absence of a suspicion of abnormality, will generate increasingly complex and uncertain information. This raises questions of how much and what information should be provided prior to testing and what information should be returned (and to whom) once testing has been performed. As prenatal genomic testing becomes broader and more routine, the information generated will have more often implications not only for the fetus, but also for the parents, siblings and the wider family, raising questions about professionals' responsibilities. Further challenges discussed in this paper include access to genomic testing and justice, as well as ongoing management and post-pregnancy follow-up. The paper highlights the importance of taking into account the particular difficulties that arise in the context of prenatal genomic testing: the uncertainty of the information while choices are binary (to continue with or to terminate pregnancy); the time pressure due to the statutory limits on the availability of termination; and the impact the testing of the fetus has on the woman's body and life.

Genetic testing for prenatal diagnosis in the pre-genomic era primarily focused on detecting common fetal aneuploidies, using methods that combine maternal factors and imaging findings. The genomic era, ushered in by the emergence of new technologies like chromosomal microarray analysis and next-generation sequencing, has transformed prenatal diagnosis. These new tools enable screening and testing for a broad spectrum of genetic conditions, from chromosomal to monogenic disorders, and significantly enhance diagnostic precision and efficacy. This chapter reviews the transition from traditional karyotyping to comprehensive sequencing-based genomic analyses. We discuss both the clinical utility and the challenges of integrating prenatal exome and genome sequencing into prenatal care and underscore the need for ethical frameworks, improved prenatal phenotypic characterization, and global collaboration to further advance the field.

Non-invasive prenatal diagnosis of monogenic disorders is becoming integrated into routine clinical care for many indications. This is carried out by testing cell-free DNA extracted from the plasma portion of a maternal blood sample. The cell-free DNA is low in concentration, and consists of a mixture of maternal and fetally-derived DNA which are not easy to separate. Methods used therefore need to be rapid, sensitive and specific, including real-time PCR, digital PCR and next generation sequencing with complex algorithms. Testing may be required for pregnancies with an increased chance of a monogenic disorder due to family history or carrier status, or where there are specific abnormalities identified by ultrasound scan. In these situations, testing is considered to be diagnostic and therefore does not require confirmation by invasive testing. With increased access to genomic technologies, and more diagnoses for rare disease patients, future demand for NIPD and possibilities during pregnancy will continue.

Genome-wide sequencing, which includes exome sequencing and genome sequencing, has revolutionized the diagnostics of genetic disorders in both postnatal and prenatal settings. Compared to exome sequencing, genome sequencing enables the detection of many additional types of genomic variants, although this depends on the bioinformatics pipelines used. Variant classification might vary among laboratories. In the prenatal setting, variant classification may change if new fetal phenotypic features emerge as the pregnancy progresses. There is still a need to evaluate the incremental diagnostic yield of genome sequencing compared to exome sequencing in the prenatal setting. This article reviews the advantages and limitations of genome sequencing, with an emphasis on fetal diagnostics.

The role of genetic testing within maternal medicine is expanding. Advancing technology and the increasing availability of genetic testing have seen more patients receiving a genetic diagnosis than ever before. Improved healthcare and understanding of these rare diseases means that many patients are living well into their reproductive years and starting families.

Individual diseases are considered by their patterns of inheritance i.e. autosomal recessive, autosomal dominant and chromosomal diseases. This chapter specifically addresses the following examples and outlines an approach to pre-conceptual and pregnancy management; autosomal recessive (cystic fibrosis, phenylketonuria), autosomal dominant (osteogenesis imperfecta, vascular Ehlers-Danlos syndrome) and chromosomal (Turner syndrome).

For many rare and ultrarare genetic diseases, there may be no clear guidelines or consensus on the correct management in pregnancy. This chapter seeks to provide a framework for the clinician to use to address the unique needs and risk profile of these patients in pregnancy and pre-conceptually and plan accordingly. The role of pharmacogenetics in maternal medicine, the future of education in genetics for patients and clinicians and the important role of genetic counselling are all considered in this chapter.

This overview highlights the important role of genetics in maternal medicine and how this can inform management and planning for the safe care of mother and baby.

The World Health Organization includes oral emergency contraception (EC) in the list of essential medicines. Ulipristal acetate (UPA) and levonorgestrel (LNG) are the recommended oral methods. UPA has superior efficacy and a comparable side effect profile compared with LNG. Both work by inhibiting or delaying ovulation, so that sperm present in the reproductive tract will have lost their fertilising ability by the time the oocyte is eventually released. Neither LNG nor UPA at the EC doses have significant effects on the endometrium and are unable to prevent implantation. Mifepristone can also be used for EC but its availability is limited to few countries. LNG is less effective in women with a body mass index over 26 kg/m² or weight over 70 kg. Hormonal contraception can be quickstarted immediately following LNG, or five days following UPA. LNG-releasing intrauterine devices and cyclo-oxygenase inhibitors are promising options for EC to be further studied.

Routine antenatal care includes history, examination, and several standard laboratory tests. Other than the original objectives, the generated data is seldom utilised for screening for adverse obstetric and perinatal outcomes. Although new approaches and sophisticated tests improve prediction of complications such as pre-eclampsia, these may not be available globally. Maternal age, race/ethnicity, anthropometry, and method of conception can influence the occurrence of pregnancy complications. The importance of medical and obstetric history is well documented but often ignored. Routine test results including blood picture, hepatitis B and rubella serology, and sexually transmitted diseases, have additional health implications. The awareness of, and the ability to utilise, available antenatal data and tests in obstetric management will enhance individualised obstetric risk assessment thus facilitating the targeting of high-risk gravidae for further management, including the use of specific and technology-driven tests where available, and close monitoring and treatment, in a cost-effective manner.