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Innovations in prenatal genetic testingbeyond the fetal karyotype

Sandra Founds, PhD, CNM, FNP*Department of Health Promotion and Development, University of Pittsburgh School of Nursing, Pittsburgh, PA

a r t i c l e i n f o

Article history:Received 4 October 2013Revised 31 December 2013Accepted 31 December 2013Available Online 26 February2014

Keywords:Whole genome sequencingNext-generation sequencingNoninvasive prenatal testingNoninvasive prenatal diagnosis

* Corresponding author: Sandra Founds, 3500E-mail address: safounds@comcast.net (S

0029-6554/$ - see front matter � 2014 Elsevihttp://dx.doi.org/10.1016/j.outlook.2013.12.01

a b s t r a c t

Current trends in prenatal genetic testing will affect nursing practice, education,research,andpolicymaking.Althoughfetal genetic testinghasbeenthe traditionalfocus, new technologies open the possibility of acquiring genomic information forboth parents and offspring, revealing windows onto individuals’ lifelong health.Noninvasive prenatal testing of cell-free fetalDNAalsohasbecomea reality. Someof the recent advances indetecting cytogenetic andheritablemolecular variants inpregnancy are overviewed. Exemplars of prenatal tests are presented and relatedethical, legal, and social implications are considered. Educating clinicians withupdated genomic knowledge has been outpaced by new technologies and direct-to-consumer marketing of prenatal tests. Implications for nursing are discussed.

Cite this article: Founds, S. (2014, JUNE). Innovations in prenatal genetic testing

beyond the fetal karyotype. Nursing Outlook, 62(3), 212-218. http://dx.doi.org/10.1016/

j.outlook.2013.12.010.

Introduction

Nurses are at the forefront of advocacy for health careconsumers. Interactions ranging from informal contactsto those in health care settings to national policy devel-opment forums require knowledge of the rapid changesoccurring in prenatal genetic testing. Advances ingenomic technologies for prenatal genetic testing holdfar-reaching implications forchildbearingfamilies.At thesame time, these technologies and direct-to-consumermarketing have outpaced many clinicians’ preparationto effectively incorporate current and emerging prenatalscreening and diagnostics into practice. Prenatal genetictesting raises a perfect storm of issues holding implica-tions for nursing practice, education, and policy.

Current Methods

“Prenatal genetic testing” is used variably to referto both screening and diagnostic procedures for

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evaluating fetal genetic status. Screening is conductedto identify those at highest risk followed by diagnostictests to verify fetal genetic abnormality in pregnanciesat highest risk. Family history, first and secondtrimester ultrasonography, and maternal blood bio-markers are obtained for screening purposes. Tests fordiagnosis include chorionic villus sampling (CVS),amniocentesis, and preimplantation genetic analysis.These procedures taken together support decisionmaking for parents and health care providers todetermine plans of pregnancy care. A commonassumption is that findings indicating genetic abnor-mality necessarily lead to pregnancy termination;however, it is imperative during consent proceduresthat parents receive information to understand thedistinction between screening and diagnosis, and in-formation that results allows choices in managementas well as time to adapt to unanticipated findings.

Primary prevention of congenital anomalies is pro-moted by preconceptional screening for genetic riskfactors in women from puberty through menopause.Because nearly half of all pregnancies are unintended

Building, Pittsburgh, PA 15261.

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(Centers for Disease Control and Prevention [CDC],2013a), any nonemergent health care encounter withchildbearing-aged females can prepare for optimaloutcomes in planned and unplanned pregnancies bypreconceptional counseling and health management(Johnson et al., 2006; American College of Obstetriciansand Gynecologists [ACOG], 1995). Therefore, the scopeof preconceptional care extends beyond routine gyne-cologic visits. Preconceptional genetic screening sur-veys of individual, spouse/partner, and family riskswill become increasingly accessible through electronichealth records (Department of Health and HumanServices, 2013). The individual’s genetic risk factorsare reviewed, including but not limited to advancedparental age, ethnicity, teratogenic medications oroccupational exposures, and metabolic conditions. In-dividual and family histories and three-generationfamily pedigree reveal occurrences of congenital orchromosomal abnormality, inherited disease, consan-guinity, recurrent pregnancy loss, stillbirth, and earlyinfant death (Sackey, 2013). Screening tools to guidethese assessments are available through the March ofDimes (2013) and the National Human GenomeResearch Institute (NHGRI) (2012). Identified risk fac-tors indicate the need for referral to genetic counselingfor further assessment and possible testing.

Similar comprehensive individual and family ge-netic risk assessments are conducted during historytaking in the first prenatal visit. Screening at this timepromotes secondary prevention through early detec-tion to reduce perinatal morbidity and mortality. Therate of birth defects in the United States is approxi-mately 3% (CDC, 2008), and these defects cause over20% of all infant deaths (Mathews & MacDorman,2012). Down syndrome is the most prevalent birthdefect in the United States (Parker et al., 2010).Maternal age at delivery had been a cardinal criterionfor genetic screening of fetal aneuploidies, that is, con-ditions with additional or missing chromosomes. Therisk of trisomy 21, Down syndrome, is 1 in 385 when themother is 35 years of age at delivery and 1 in 106 at40 years. The risk of all trisomies is 1 in 192 at 35 yearsand 1 in 66 at age 40 (Hook, Cross, & Schreinemachers,1983; Newberger, 2000).

Changes in clinical practices occurred with ad-vances in blood biomarkers and ultrasonography. In2007, the ACOG recommended that all clients beoffered aneuploidy screening before 20 weeks ofgestation regardless of maternal age (ACOG, 2007).Concentrations of maternal serum alpha-fetoprotein,human chorionic gonadotropin (hCG), and unconju-gated estriol are altered in trisomy pregnancies. Thethree markers are used in combination as a “triplescreen” to modify the maternal age-related risk ofDown syndrome. Adding inhibin A to these comprisesthe “quadruple screen,” which improves the detectionrate for Down syndrome to approximately 80%. Theaforementioned sets of markers are measured in thesecond trimester after 13 weeks’ gestation. Earlier

screening is conducted with first trimester mea-surement of fetal nuchal translucency on ultrasoundbefore 12 completed weeks of gestation combinedwith serum analytes hCG or free b-hCG and pregnancy-associated plasma protein A. The nuchal translucencyis a fluid collection at the back of the fetal neck inthe first trimester that, if increased, signals fetalchromosomal, genetic, and structural abnormalities;however, the requisite specialized ultrasound traininglimits the availability of this procedure in some regionsof the United States. (ACOG, 2007). At approximately18 weeks, an ultrasound to evaluate fetal growth anddevelopment is ordered to identify anatomic variationsrelated to genetic abnormalities.

Diagnostic genetic testing has been conductedusing CVS and amniocentesis. These invasive pro-cedures to acquire fetal cells for cytogenetic analysisare associated with a 0.25% to 0.5% risk of miscarriagefrom amniocentesis and a 0.5% to 1.0% risk from CVS(Olney et al., 1995; Tabor & Alfirevic, 2010). The con-ventional standard has been metaphase karyotypingfor fetal genetic analysis (Bianchi, 2012). Fetal cells aregrown in culture to capture and stain the full com-plement of 46 chromosomes. Large segments ofchromosomes that vary from normal in copy numberand structural arrangement, including aneuploidies,large deletions or duplications, and balanced trans-locations and inversions, can be detected with resultsin 7 to 12 days (Breman & Patel, 2012). Fluorescencein situ hybridization (FISH) is another chromosomeanalysis of large structural variations, which iscommonly used in clinical sites where the methodis available. This procedure provides results for an-euploidies in less than 2 days. An additional advan-tage is that FISH can detect microdeletions, smallermissing segments that would not be detected on akaryotype (Crawford & Dilks, 2011; Levy, Jobanputra, &Warburton, 2009).

Practitioners and policy makers need to be aware ofthe Prenatally and Postnatally Diagnosed ConditionsAwareness Act (Public Law 110e374, 2008). The lawmandates that clinicians provide evidence-based in-formation and referral services for women who havereceived a positive diagnosis for congenital abnormal-ities such as Down syndrome. This legislation camein the wake of the 2007 ACOG prenatal screeningpractice recommendations and has been proposedto be linked with current sociopolitical controversiesregarding abortion (Reilly, 2009). Clinicians may offerfamilies resources accessed through the NationalCenter on Birth Defects and Developmental Disabilities(CDC, 2013b).

New Developments

Carrier screening may be ordered to evaluate an in-dividual’s status for passing Mendelian (single-gene)

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autosomal recessive disorders to offspring. The screencould target one disorder or a panel of 100 or moredisorders. Controversy exists about whether to screenbased on history or to screen all adults before or duringpregnancy. Because it is not specific to ethnicity orfamily history, universal carrier screening avoidsinaccuracies inherent to self-reported history and re-duces potential for stigmatization based on biologicalrace/ethnicity. Clinically oriented professional orga-nizations such as the American College of MedicalGenetics and ACOG recommend carrier screeningbased on history; however, businesses are conductingdirect-to-consumer marketing of genetic tests, raisingissues of adequacy of informed consent and accurateinterpretation of results through consultation withtrained clinicians. Furthermore, issues of cost and in-surance coverage create disparities in the accessibilityof these screening procedures (Borry et al., 2011; Ram&Klugman, 2010).

Molecular genetic testing methods are beingdeveloped to acquire higher-resolution details of thefetal genome. In contrast to the large segments ofchromosomes analyzed by the cytogenetic methodsof karyotyping and FISH, submicroscopic elements ofDNA such as single nucleic acids or extremely shortsegments of DNA sequences can be detected(Wapner et al., 2012). For example, cytogeneticmethods identify chromosome deletions and dupli-cations in the range of 5 to 10 million base pairs(megabases), whereas molecular methods can iden-tify changes as small as 50 to 100 thousand base pairs(kilobases) (Bianchi, 2012). Array comparativegenomic hybridization (aCGH) uses a microarrayplatform with uncultured cells or cell-free fetal DNAto compare client’s DNA with normal individuals’control DNA to detect mutations and variations inthe entire fetal genome or in targeted regions ofchromosomes (Brady, Devriendt, Deprest, &Vermeesch, 2012). A review of microarray technol-ogy is available in the nursing literature (Founds,Dorman, & Conley, 2008). Results can be obtainedwith aCGH in as little as 1 day (Miller, 2013). A recentmulticenter trial in the U.S. concluded that aCHGproduced additional clinically meaningful molecularcytogenetic information compared with karyotyping,identified aneuploidies and unbalanced rearrange-ments, but could not identify balanced translocationsand triploidies. The study also encountered thecommon challenge of how to interpret variants ofunknown significance (Wapner et al., 2012). Thesefindings are consistent with and corroborate theACOG recommendations for fetal karyotyping as thefirst-line prenatal cytogenetic test followed up withtargeted aCGH in certain situations, such ascongenital anomalies with a normal karyotype orfetal demise with congenital anomalies and theinability to conduct karyotyping (ACOG, 2009).

The small but real risk of pregnancy loss associ-ated with CVS and amniocentesis has motivated thesearch for noninvasive methods of genetic diagnosis.

Two major strands of research developmentsconverged over the past decade into the clinicalavailability of noninvasive prenatal testing (NIPT).Cell-free DNA in maternal plasma is composed of 3-20% of cell-free fetal DNA (cffDNA) derived from theplacenta (Nygren at al., 2010). Optimized methods toobtain these fetal fragments from maternal circula-tion have allowed for analysis by massively parallelsequencing technologies, which are also referred toas next-generation sequencing. These platforms pro-duce millions of very short 50 to 400 base pairsequence segments of client DNA; these segments arethen aligned in comparison with control DNA tem-plates, leading to rapid and even more submicro-scopic reads of genetic variations in the wholegenome or targeted chromosome regions (Tucker,Marra, & Friedman, 2009). Despite the lack of largeprospective clinical trials, the ACOG has recom-mended the use of NIPT for fetal aneuploidies usingmassively parallel sequencing and cffDNA in high-risk women’s blood based on several large valida-tion studies that showed over 98% detection rateswith low false-positive rates below 0.5% (ACOG, 2012).The recommendation is focused on trisomies 21, 18,and 13 in singleton pregnancies, does not includelow-risk women or other genetic information, andmaintains the recommendation for confirmatoryinvasive diagnostic testing.

Kitzman et al. (2012) pushed the frontier of the po-tential of NIPT further by noninvasively predicting afull fetal genome at midgestation. This research groupused maternal blood to acquire maternal DNA andcffDNA and obtained paternal DNA from saliva sam-ples. The parents’ genomes were used to predict thewhole fetal genome with 98.1% accuracy at 2.8 millionparental heterozygous sites, that is, sites where oneparent has a different nucleic acid at the same locationon each of two chromosomes. The fetal genomesequenced from cffDNA and predicted from theparental DNA was validated by comparison with theinfant’s cord blood obtained after birth (Kitzman et al.,2012).

A virtual tsunami of ethical, legal, and social issuesreverberates from this discovery. Whole genome se-quences of both parents to noninvasively predict fetalhealth would provide much more information forreproductive decision making without the risk ofpregnancy loss; however, scientific validation re-mains to be accomplished, and many social andethical questions of pregnancy norms and expecta-tions arise. For example, variants of unknownsignificance are genetic variations whose associationswith disease are not yet fully understood by thescientific community, and these pose anxieties forclients and uncertainties for providers in post-testcounseling (Donley, Hull, & Berkman, 2012). Clini-cally, providers are unlikely to be prepared formeaningful interpretation of the volume and scope ofdata resulting from these methods for clients.Although the target is fetal information, both parents

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stand to gain detailed personalized genomic infor-mation as well for their own susceptibility to andprotection from illness. Ethicists appropriately ask,“Just because we can, should we?” (Donley et al.,2012).

Implications for Nursing

Nursing practice is being affected by the Patient Pro-tection and Affordable Care Act (ACA) (Public Law111e148, 2010), which specifies genetics withinseveral areas of health care reform. Individuals cannotbe excluded from insurance coverage based on geneticinformation. Health care is to be improved by applyingcomparative effectiveness research that elucidatesindividuals’ genetic and molecular subtypes. The lawalso affects practice by a call for education of healthcare providers about when to refer clients to providerswith genetics expertise. The Genetic InformationNondiscrimination Act of 2008 prohibits discrimina-tion against individuals on the basis of genetic infor-mation in relation to health insurance andemployment, and contains strong privacy protections.The ACA complements and does not conflict withGenetic Information Nondiscrimination Act becausethe ACA strengthens consumer protections in theprivate health insurance market (Sarata, DeBergh &Staman, 2011). More insured citizens will be able toseek care.

Therefore, “genetic/genomic nursing” needs toapply broadly to all nursing practice, rather than beinginterpreted only as a specialty area for some nurses.Expanding genetic and genomic knowledge needs to betranslated by nurses for clients so that the content isapproachable, understandable, and meaningful to in-dividuals and families. In order to encourage thisdevelopment, the American Nurses Association (ANA)Scope and Standards of Practice (2010) could berevised to explicate genetics/genomics in assessmentand management. Interestingly, the current ANAwebsite categorizes scope and standards of geneticsand genomics practice (ANA, 2007) under the “Ethics”menu (ANA, 2013). Nurses who access this excellentonline resource may need to see genetic/genomiccompetencies located under “Practice” in order toperceive that the content applies to them as practicingclinicians.

Prevention is a cornerstone of the ACA. TheAmerican Academy of Nursing (AAN) Expert Panels(2013) could consider collaboration among the genetichealth care, maternal and infant health, and women’shealth groups to strengthen the synthesis of geneticsand genomics into prevention strategies in nursingpractice. In response to national initiatives, theWomen’s Health Expert Panel proactively publishedrecommendations for improving clinical services forwomen by incorporating primary and secondary

prevention competencies into primary care practicesettings (AAN, 2012). Adding a brief mention, such as“including genetics/genomics competencies,” couldreinforce the importance of nurses incorporating thiscontent into practice. More opportunities will arise forthe use of genetics and genomics in screening, earlydetection and treatment such as pharmacogenomics,and preconceptional and primary care throughoutchildbearing women’s health care in various clinicalsettings.

Obstetric, gynecologic, and neonatal nurses willcontinue to routinely participate in genetic/genomiccare with increasing availability of noninvasivescreening and test options. They are poised to lead inenhancing genetic and genomic nursing. Clinicalspecialty organizations, such as the Association ofWomen’s Health, Obstetric and Neonatal Nurses(2000) and the American College of Nurse Midwivesmay consider updating or creating position state-ments to encourage ongoing development andapplication of genetic/genomic competencies in thecare of women and childbearing families. Clientteaching materials can be created or may need to beupdated, such as the American College of NurseMidwives [2005] information on prenatal testing forDown syndrome could incorporate NIPT. Lewis(2011) compiled a list of priority genetic/genomicresources for perinatal and neonatal nurses, whichcontinues to be applicable for the primary care ofwomen as well. Based on research evidence at thistime, some groups of high-risk women may beappropriately offered NIPT, but the adoption ofpopulation screening requires provider education,further research, and public discussion at the policylevel to address ethical, legal, and social implica-tions. Providing a period of time between informa-tion giving and consent signature is necessary tosupport informed choices about NIPT. Culturallyappropriate NIPT care also remains to be developedthrough research and policy activities (Skirton &Patch, 2013).

Nursing advocacy and anticipatory guidance areneeded for women in the current controversies sur-rounding direct-to-consumer marketing of prenatalgenetic tests. Clinicians can access information abouthow to evaluate genetic tests and about the dearth ofregulation in the United States for tests marketeddirectly to consumers without a health care pro-vider’s counsel and orders (NHGRI, 2013). The AAN(2008) previously urged the Department of Healthand Human Services Secretary’s Advisory Committeeto promote analytic validity, proficiency testing, andclinical validity assurances for all genetic tests. Atthis time, the evidence base indicates key points fornursing practice. Two systematic reviews on direct-to-consumer genomic testing integrated primaryresearch and prior systematic reviews, indexed in thehealth care literature databases and written in En-glish, from 2001 to 2011 regarding consumers and

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from 2001 to 2012 regarding health care providers(Goldsmith, Jackson, O’Connor, & Skirton, 2012;Goldsmith, Jackson, O’Connor, & Skirton, 2013). Thelimited data about users indicated a low level ofawareness about direct-to-consumer genomictesting. Potential users were interested in informa-tion about their risks of developing common dis-eases; however, they were concerned about thereliability of these tests and privacy for personal ge-netic risk information. There was anxiety about re-sults and a preference to access genomic teststhrough a provider or to discuss results and advicefrom a health professional (Goldsmith et al., 2012).Health professionals also have a low level of aware-ness of and experience with direct-to-consumertesting. Inconsistent levels of knowledge and under-standing and concerns about clinical usefulness, lackof counseling, and increased post-testing workloadwere identified (Goldsmith et al., 2013). Nurses in theUnited States can use the lead time to becomeknowledgeable critical thinkers concerning issuesand controversies surrounding direct-to-consumertesting in order to guide clients, conduct research,and inform policy makers.

Although there is currently no evidence that largenumbers of individuals will use direct-to-consumertests, concerns for the ethical use of NIPT for diag-nostic or susceptibility tests for the fetus may beexacerbated by direct-to-consumer marketing. Usersand potential users of NIPT most highly valued thesafety of the fetus and accuracy of NIPT results,whereas knowing fetal status early and ease oftesting were also important to them; however, healthprofessionals and users were concerned about theinappropriate use of NIPT, such as eugenics and fetalsex selection (Skirton & Patch, 2013). Direct-to-consumer prenatal testing and the ease of NIPTcould dramatically increase the numbers of testsperformed, which would create demand for inter-pretation and support by health professionals andfeasibly could change the management of pregnancy(Skirton et al., 2013).

Preparedness of clinicians to understand andinterpret data from the new technologies, such aswhole genome sequencing and genome-wide associ-ation studies, and to translate the information andrelated issues into meaningful health implications forclients is of wide concern (Bianchi, 2012; Goldsmithet al., 2013; Skirton et al., 2013). Colleges andschools of nursing in the United States may directtheir curricula according to the American Associationof Colleges of Nursing (AACN) guidelines in the Es-sentials documents for undergraduate and graduateeducation (AACN, 2006; AACN, 2008; AACN, 2011;AACN, 2012). The Essentials for baccalaureate(AACN, 2008) and master’s education (AACN, 2011)contain conceptual integration of “genetics and ge-nomics” and consistently include this topic in sug-gestions for sample content. In contrast, theEssentials for the Doctor of Nursing Practice (DNP)

refers to “genomics” one time only in relation to sci-ences foundational to nursing practice and does notcontain “genetics.” The specification of genetics/ge-nomics is needed in several DNP Essentials: QualityImprovement and Systems Thinking, Policy forAdvocacy, Improving Patient and Population Health,and Advanced Nursing Practice within AdvancedHealth/Physical Assessment, Advanced Physiology/Pathophysiology, and Advanced Pharmacology.Because DNP is a practice-based degree, the DNP Es-sentials need to be updated conceptually and mayrefer to specific competencies delineated in theEssential Genetic and Genomic Competencies forNurses with Graduate Degrees (AACN, 2012).Including task force members with expertise in thisarea would keep genetics/genomics in the foregroundas the DNP Essentials are revised.

Nurses may need to be reminded that theyalready apply genetics and genomics in routinecare, such as family history taking, pedigreedevelopment, prenatal care, and newborn care.Building on this foundation could enhance theapproachability of advanced molecular geneticstopics. Nurses need to become educated appraisersof genomic research to develop evidence-basedprotocols incorporating valid genetic tests.Continuing education will be needed to update theknowledge of these applications. Nurse leadershiporganizations such as the ANA and AAN shouldcontinue to advocate for funding to implement theACA legislation to prepare health care providers ingenetics/genomics care throughout higher educa-tion and continuing education programs, as exem-plified by the AAN (2008). Numerous resources foreducation and outcome indicators can be found ineach Essentials document for genetic and genomiccompetencies (AACN, 2009; AACN, 2012). TheNHGRI maintains current online educational re-sources.

Conclusions

Burgeoning genomic technologies and direct-to-consumer marketing of genetic tests without pre-scription compel the need for nurses to familiarizethemselves with current and upcoming prenatal ge-netic testing modalities. Understanding the variety ofscreening methods available, the validity and reli-ability of tests, and the associated ethical, legal, andsocial implications is critical to incorporate intonursing education so that advocacy for clients andfamilies can be supported through nursing practice,research, and policy making. Policy implications hav-ing been suggested in this article are summarized inBox 1. The impact on the translation of disease sus-ceptibility and protection extends far beyond the fetalkaryotype to the lifelong health of mother, father, andoffspring.

POLICY IMPLICATIONS OF DEVELOPMENTSIN PRENATAL GENETIC TESTING

Practice

Integrate preconceptional genetic screening intoprimary care visits

Provide aneuploidy screening before 20 weeks’gestation regardless of maternal age

Promote well-informed, accurate prenatal ge-netic testing to allow choices in management andclient adaptation

Education

Apply genetics/genomics competencies in evidence-based practice for women and families

Promote ethical application of new genetics/genomics technologies in nursing care

Policy

Explicate genetics and genomics in all nursingmanagement and services

Synthesize genetics and genomics into pre-vention strategies

Safeguard genetics privacy and nondiscri-mination

Advocate for analytic validity, proficiencytesting, and clinical validity in genetic tests

Develop guidelines for ethical implementationand insurance coverage for noninvasive prenatalgenetic/genomic testing

Advocate for ethical use of fetal, parental, andfamilial genomics resulting from prenatal testing

Prepare for the potential impact of direct-to-consumer marketing on health care services

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