Incidental Detection of Malignancies With Cell-Free DNA Screening.

Cell-free circulating DNA is an evolving technology with important clinical applications in both obstetric care and oncology. In the challenging patient with pregnancy and co-existing malignancy, the utility of cell-free DNA both for aneuploidy screening and cancer identification is an area of active research. Understanding the physiology associated with circulating cell-free DNA and subsequent laboratory evaluation is critical for clinicians caring for the obstetric patient with cell-free fetal DNA screening results suggestive of malignancy. Ongoing research is necessary to determine best practices for the evaluation and management of these patients with promising applications in the advancement of precision medicine.

Informed consent for expanded carrier screening: Past, present, and future.

History, law, bioethics, and geocultural influences all have impacted the modern application of informed consent. It is a complex, multilayered process to communicate information and obtain voluntary patient permission before a health care intervention. Lack of provider education about genetic disorders, complexities of advanced genomic technologies, limited time during patient encounters, and low health literacy within a population all represent challenges to effective communication. There is no consensus on how informed consent in reproductive genetics is optimally obtained. Expanded carrier screening (ECS) is purposed to simultaneously test for a large list of diseases in a pan-ethnic manner. The increased use of ECS is driven by advances in genomic technologies, decreased cost, an improved understanding of single gene disorders, and in support of reproductive autonomy. Academic organizations recommend pretest counseling when patients consider ECS, yet best practice is not established. Ongoing research is needed to determine how optimally implement informed consent given the increased complexity of ECS.

Incidental Detection of Maternal Malignancy by Fetal Cell-Free DNA Screening.

Cell-free DNA is an advancing technology with increasing applications in screening, diagnosis, and treatment for several disease processes. The shared physiologic, genetic, and epigenetic characteristics of placental physiology and tumor development have become apparent to both clinicians and researchers. Maternal malignancy has been reported as a cause of false-positive prenatal cell-free DNA screening results. The detection of multiple aneuploidies or a single autosomal monosomy increases the chance for an underlying maternal malignancy when the result is discordant with fetal diagnostic testing. There is currently no consensus guideline on counseling and evaluation of patients with concern for malignancy from cell-free DNA testing. Furthermore, laboratories differ significantly in reporting policies, terminology, and in reporting strategies and methods used for unexpected or incidental findings. The ordering practitioner is therefore tasked to understand the policies of their laboratory of choice to provide adequate pretest and posttest genetic counseling. In pretest counseling, the potential for incidental or unexpected findings or nonreportable results should be explained. With an abnormal, unanticipated, or nonreportable result, posttest counseling should include a description of possible fetal or maternal diagnoses, including malignancy. Health care professionals should explain options for further evaluation and management, including a recommendation for fetal diagnostic testing. The medical workup recommended by various authors to evaluate cancer risk is based on consensus, experience, and expert opinion. These strategies should incorporate the patient's desire for information, cost, and family and personal medical history. Ongoing research and multi-disciplinary collaboration in this area is critical to identify best practices in management of complex results from this increasingly common screening test.

What are the required components of pre- and post-test counseling?

Prenatal care providers are faced with a myriad of decisions about how to offer genetic screening and testing in ways that are appropriate to their patient population and their workflow. Among the critical issues brought to the forefront of rapidly advancing genetic and genomic technologies is the importance of pre- and post-test counseling. This document is a synthesis of proceedings of a workshop sponsored by the American College of Obstetricians and Gynecologists, the American College of Medical Genetics and Genomics, and the Society for Maternal-Fetal Medicine, on January 24-25, 2017, during which invited experts discussed required components of pre- and post-test counseling and associated concerns in the provision of prenatal care.

Screening for fetal aneuploidy.

Screening is currently recommended in pregnancy for a number of genetic disorders, chromosomal aneuploidy, and structural birth defects in the fetus regardless of maternal age or family history. There is an overwhelming array of sonographic and maternal serum-based options available for carrying out aneuploidy risk assessment in the first and/or second trimester. As with any screening test, the patient should be made aware that a "negative" test or "normal" ultrasound does not guarantee a healthy baby and a "positive" test does not mean the fetus has the condition. The woman should have both pre- and post-test counseling to discuss the benefits, limitations, and options for additional testing. Rapid advancements of genetic technologies have made it possible to screen for the common aneuploidies traditionally associated with advanced maternal age with improved levels of accuracy beyond serum and ultrasound based testing. Prenatal screening for fetal genetic disorders with cell-free DNA has transformed prenatal care with yet unanswered questions related to the financial, ethical, and appropriate application in the provision of prenatal risk assessment.

Changing indications for invasive testing in an era of improved screening.

Prenatal diagnostic testing is available for a growing number of disorders. The goal of prenatal diagnosis was initially focused on the identification of Down syndrome in women aged 35 years and older, but invasive prenatal genetic techniques can now detect a far broader array of conditions. The risks of invasive procedures have also decreased over time. Advances in genomic medicine allow testing for smaller but significant chromosomal abnormalities known as copy number variants, in addition to major aneuploidies and structural rearrangements. Molecular DNA techniques can detect many single-gene conditions. In the future, it is likely that whole-exome and whole-genome sequencing will be applied to prenatal genetic testing to allow identification of yet more genetic disorders. With advances in technology, the indications for testing have likewise evolved far beyond recommendations based solely on maternal age to include a more patient-centered view of the goals of prenatal testing.

Noninvasive prenatal screening by next-generation sequencing.

Noninvasive prenatal screening (NIPS) has emerged as a highly accurate method of screening for fetal Down syndrome, with a detection rate and specificity approaching 100%. Challenging the widespread use of this technology are cost and the paradigm shift in counseling that accompanies any emerging technology. The expense of the test is expected to decrease with increased utilization, and well beyond the current NIPS technology, its components (fetal genome measurements, sequencing technology, and bioinformatics) will be utilized alone or in combinations to interrogate the fetal genome. The end goal is simple: to offer patients information early in pregnancy about fetal genomes without incurring procedural risks. This will allow patients an opportunity to make informed reproductive and pregnancy management decisions based on precise fetal genomic information.

Maternal hemolysis after intravenous immunoglobulin treatment in fetal and neonatal alloimmune thrombocytopenia.

BACKGROUND: Intravenous immunoglobulin (IVIG) is a therapeutic agent used to prevent fetal thrombocytopenia in those pregnancies identified to be at risk for fetal and neonatal alloimmune thrombocytopenia. Although generally considered a safe medication, hemolytic anemia is a known side effect of IVIG treatment that may result in maternal medical complications. CASES: We present three cases of IVIG-induced maternal anemia from separate institutions that occurred during treatment for fetal and neonatal alloimmune thrombocytopenia and resolved after discontinuation or alteration of therapy. None of the treated fetuses had thrombocytopenia at birth. CONCLUSION: There is a potential for hemolysis when prescribing IVIG. We recommend laboratory monitoring for hemolytic anemia and suggest options for management including drug modification or cessation of therapy.

Arthrogryposis: a review and approach to prenatal diagnosis.

UNLABELLED: Congenital contractures are a common ultrasound finding. Arthrogryposis, defined as multiple contractures involving more than one area of the body, is not a specific diagnosis but rather a description of clinical findings. It is associated with more than 300 different disorders, many of which have other associated malformations and/or neurocognitive delay. Lack of fetal movement or akinesia commonly accompanies the contractures. The underlying diagnosis may be the result of a neurogenic or myopathic process, a connective tissue disorder, intrauterine compression, a teratogenic exposure or vascular insult. When a patient presents with arthrogryposis, the challenge for obstetricians is to assess the fetal condition, associated abnormalities and family history to offer the most accurate counseling and diagnosis. A multidisciplinary approach incorporating obstetrics, genetics, pediatric neurology, and fetopathology is warranted. Prenatal diagnostic testing options are available. Postnatal evaluation by pediatric specialists is important and offers enhanced diagnostic capabilities and recurrence risk counseling. We present an organized approach to the prenatal assessment of arthrogryposis as well as recommendations for intrapartum and postpartum care. TARGET AUDIENCE: Obstetricians & Gynecologists, Family Physicians LEARNING OBJECTIVES: After completing this CME activity, physicians should be better able to define arthrogryposis and identify a classification framework to approach prenatal diagnosis, develop a differential diagnosis for a fetus who demonstrates arthrogryposis, formulate an action plan for prenatal diagnosis and assess the importance of a multidisciplinary approach to counseling and care when a fetus is identified to have arthrogryposis.

Newborn and carrier screening for spinal muscular atrophy.

Spinal muscular atrophy (SMA) is a common autosomal recessive neuromuscular disorder caused by mutations in the survival motor neuron (SMN1) gene, affecting approximately 1 in 10,000 live births. The homozygous absence of SMN1 exon 7 has been observed in the majority of patients and is being utilized as a reliable and sensitive SMA diagnostic test. Treatment and prevention of SMA are complementary responses to the challenges presented by SMA. Even though a specific therapy for SMA is not currently available, a newborn screening test may allow the child to be enrolled in a clinical trial before irreversible neuronal loss occurs and enable patients to obtain more proactive treatments. Until an effective treatment is found to cure or arrest the progression of the disease, prevention of new cases through accurate diagnosis and carrier and prenatal diagnosis is of the utmost importance. The goal of population-based SMA carrier screening is to identify couples at risk for having a child with SMA, thus allowing carriers to make informed reproductive choices. During this study we performed two pilot projects addressing the clinical applicability of testing in the newborn period and carrier screening in the general population. We have demonstrated that an effective technology does exist for newborn screening of SMA. We also provide an estimate of the carrier frequency among individuals who accepted carrier screening, and report on patient's knowledge and attitudes toward SMA testing.