Call to Action for Advancing Equitable Genomic Newborn Screening Open Access

Newborn screening (NBS) facilitates early detection and treatment of infants with rare, treatable conditions, improving their health and longevity, limiting diagnostic odysseys, reducing healthcare expenditures, and advancing health equity among underrepresented or economically underserved populations [1, 2]. For decades, it has fulfilled the mandate set forth by the World Health Organization (WHO) to ensure that every child in the world “survives and thrives to reach their full potential” [3]. Recent technological advancements have led to the detection of more complex inherited disorders [4, 5]. Genomic NBS (gNBS), which incorporates genomic sequencing, could extend these benefits to more children [6], identify health conditions or carrier status in biological family members, and facilitate informed reproductive decision-making.

Yet, despite the potential for benefit to newborns and others, gNBS presents substantial challenges, which take on even greater significance as gNBS is scaled up to the population level. For example, gNBS can identify variants for which early detection offers no health benefits (i.e., late-onset conditions and diagnoses with no effective treatments), creating ethical dilemmas. Parents often retain little information about NBS, are confused about test results, and experience excessive worry about infant health [7‒9]. When parental consent is not required, NBS results may come as a shock to parents during a vulnerable time when they are likely fatigued and overwhelmed [10]. Obtaining genomic data on newborns and, by proxy, their family members, raises significant concerns about privacy and government interference, particularly since data and privacy protections can vary substantially between jurisdictions [11, 12]. Concerns also remain regarding the impact of genetic information from NBS on parents’ relationships with their children, particularly children identified as heterozygote carriers [13]. Differences within and between countries also create challenges for equitable development and implementation of gNBS programs [14, 15]. Even if countries can implement gNBS, equity in detection does not necessarily lead to equity in health outcomes for underserved populations, which have limited financial resources and find it difficult to access treatment [16]. Genomic NBS is also more expensive, has a longer turnaround time than traditional NBS, and cannot identify all conditions currently screened for using traditional NBS [15]. While many high-income nations have well-established, expansive NBS programs and plan to add genome sequencing, comprehensive NBS programs are less common in many low- and middle-income countries (LMICs).

Although weighing individual and societal risks and benefits has always been central to decisions about NBS, introducing gNBS amplifies the complexities surrounding these issues. In this perspective paper, we discuss four issues that we believe to be the most pressing challenges to the equitable implementation of gNBS at a population scale: selecting conditions for gNBS, respecting self-determination through informed consent and parent education, protecting privacy and confidentiality, and mitigating adverse psychosocial sequelae. We present calls to action for clinical practice, research, and public policies to advance the equitable use of gNBS worldwide.

Given the wealth of information generated from genomic sequencing, we consider the judicious selection of conditions for gNBS programs to be of paramount importance. Scaling up gNBS to the population level requires examining condition prevalence within populations, the benefits and challenges of different genomic technologies, and the type of information obtained. Selecting appropriate variants is particularly challenging in the constantly evolving genomic landscape, as empirical knowledge about variants and their health implications changes over time [17]. Genomic NBS can also identify variants of uncertain significance (VUS), variants associated with adult-onset conditions, and carrier status in individuals for whom early detection offers no health benefits but may affect reproductive choices. Findings have implications for biological family members beyond the newborn’s biological parents [18].

Another important consideration is whether to report previously selected variants or all identified variants and then determine their effects [18]. The latter approach will identify many VUS, creating prognostic uncertainty [17, 18]. Additionally, limited clinical phenotype data may be available when gNBS is scaled up to the population level, creating difficulties in determining the clinical relevance of results [19]. Not restricting screening to conditions for which there are clear data on genotype-phenotype correlations also creates challenges for public health and governmental ethics [14], but including such variants can increase knowledge about their clinical relevance. High sensitivity and specificity for gNBS are particularly important, in order to ensure low false-positive rates at population levels, which reduces the burden on healthcare systems [19].

We recognize that gNBS poses substantial challenges to decisions about sharing results with parents, particularly for clinicians. Their decisions must consider the needs of all stakeholders, including the parents, the child, and healthcare professionals [20]. For example, clinicians might prefer to only share actionable information relevant to the child’s immediate health needs, while parents might also want information about variants associated with adult-onset diseases [21]. Clinicians will need to balance their moral obligation to the health and well-being of the child with respect for parents’ rights to their child’s genetic information [20].

Genomic NBS can also identify variants in individuals from minoritized and underrepresented populations whose genomes do not align with the current reference genome, rendering results of questionable utility [17, 19] and creating greater inequities in who benefits from NBS [6]. Although knowledge of diverse genomes is expanding rapidly, developing comprehensive understanding of these genomes will take time, further limiting the applicability of gNBS results for individuals from minoritized and underrepresented populations [19].

We assert that global gNBS implementation must align with the health policies, medical infrastructure, technical and human resources, and national priorities of each jurisdiction and country where it is applied. We also acknowledge that such individualization may lead to substantial variability in conditions selected and technologies used for gNBS, potentially increasing inequities between high-income nations and LMICs [22‒24]. To address these issues, we support efforts to ensure that geography of birth does not create inequity in access to gNBS.

We propose the following calls to action to support the ethical and equitable selection of variants and conditions for gNBS:

• Identify and communicate the purpose of and approach to gNBS in each jurisdiction;

• Ensure that the perspectives of parents, community leaders, researchers, and healthcare providers inform recommendations and guidelines for best practices;

• Consider the influence of social determinants of health, system-level factors, and individual-level factors, including access to healthcare and health insurance, race, and ethnicity, on gNBS implementation;

• Use flexible, evidence-based approaches to select variants and/or conditions that accommodate rapidly changing knowledge of genomics; and

• Conduct research in LMICs to identify relevant, cost-effective, and equitable approaches to gNBS and ensure that implementation, if pursued, aligns with community values and national priorities.

The American Nurses Association (ANA) Code of Ethics for Nurses [22] emphasizes patients’ rights to self-determination in healthcare decision-making. True self-determination requires an accurate understanding of the risks and benefits of the health procedure in question and is supported by informed consent. This may be particularly difficult in the context of gNBS, given limited knowledge and low genetic literacy in the general public [25]. We believe that supporting patient and parent self-determination is inextricably linked to informed consent and is only achievable when parents have sufficient knowledge and understanding of gNBS.

Parents are recognized as the most appropriate proxy decision-makers for their minor children, as they are considered to have the child’s best interests at heart. Implementing gNBS that supports public health ethics requires effective parental education that ensures genuine consent [14]. Truly informed consent also requires that those obtaining informed consent have a comprehensive understanding of the implications of the health procedure; thus, healthcare providers who are not specialists in genomics may require more education to obtain truly informed consent from parents [20]. It is also critical to consider the wide global variability in approaches to informed consent for NBS, which may influence whether and how our calls to action can be implemented.

We also assert that the timing of and approach to parental education are critical to improving parents’ knowledge of NBS. One challenge is limited knowledge of genomics and NBS in the general population, which further adds to the need for comprehensive education about gNBS. In addition, parents who are single, members of minoritized groups, and economically or educationally disadvantaged, and those who live in rural areas or have limited or no health insurance, experience further disparities in knowledge of NBS [9, 24].

We support parents’ preferences for receiving information about NBS before delivery [26], when they may be more likely to assimilate the information than after the infant’s birth. We also recognize that current approaches to parental education about NBS, which often rely on printed information to convey relevant facts [27], may be inadequate. Evidence shows that parents are often uninformed about NBS [26], suggesting that these approaches do not ensure that parents are truly knowledgeable. As a result, parents lack agency in their decisions about NBS, thwarting their right to self-determination. These difficulties will only become more prominent with population-level implementation of gNBS.

We believe that the rapid evolution of genomic science, limited size of the genetic counseling workforce, and implementation of population-wide gNBS require flexible and innovative approaches to education and counseling. One proposed approach is online education, potentially combined with artificial intelligence (AI), to augment education provided by genetic counselors [17, 28, 29]. However, exclusively online education may not be appropriate in all countries and for all populations [6]. Thus, we advocate for research to determine what approaches to parent education work best, for whom, and where.

Genomic NBS raises additional questions about mandatory screening and whether parental informed consent should be required [30]. Traditional NBS focuses on conditions that have severe consequences for the child early in life and can be treated; however, this is not the case for all conditions that could be included in gNBS [14]. This contradicts one of the foundational principles of NBS as a public health program [14]. For example, gNBS can identify variants associated with early-onset severe forms of a condition as well as variants associated with later-onset, less severe forms. If parental consent is not obtained, parents whose children have variants for later-onset forms of a condition may question whether gNBS provides an immediate health benefit to their child, which could lead to a backlash against NBS [14]. Therefore, we support the use of comprehensive and effective informed consent for gNBS.

When NBS identifies a potential condition, parents experience emotional distress, which can compromise their ability to understand complicated genetic information, leading to misconceptions about the health of their child(ren) and exacerbating their concerns [9]. Of particular concern is the risk that such scenarios, in conjunction with limited education on and communication about NBS, could intensify mistrust among disenfranchised people who suffer continuing discrimination and racism within healthcare systems and medical research [23]. Approaches to parental consent for NBS also vary substantially. In some countries, NBS is mandatory, with “opt-out” provisions in some jurisdictions, while in other countries, explicit written consent is required. Regardless of the location or the approach, ensuring truly informed consent in gNBS requires that parents are adequately informed about gNBS, are cognizant of the consequences of screening and not screening, and that their participation is voluntary. We contend that truly informed consent should be aligned with local values, culture, and preferences. However, the literature does not provide adequate guidance about consent processes in non-Western countries, making this an urgent area for future research.

We propose the following calls to action to ensure true self-determination regarding gNBS:

• Increase awareness and knowledge of NBS and gNBS through national public health educational initiatives, ensuring access to credible information sources, and incorporating information on genomics and NBS into primary and secondary education;

• Design and implement comprehensive NBS and gNBS education to improve knowledge of all parents, including those with low health literacy and members of marginalized populations;

• Ensure that parents receive sufficient and clear information on the NBS program, understand the information provided, and have access to confirmatory diagnostic, counseling and treatment services;

• Establish comprehensive and flexible informed consent policies and procedures for gNBS; and

• Prepare a culturally diverse genomics workforce to ensure that parents receive comprehensive, accurate information from experts who understand their cultural backgrounds.

Individual genomes are unique identifiers, containing extensive information on health and other characteristics. Therefore, we believe that it is crucial to develop procedures that protect the privacy and confidentiality of genomic data obtained through gNBS. We also appreciate the potential individual, familial, and societal benefits of long-term storage of genomic information. The ANA Code of Ethics defines privacy as “the right to control access to, and disclosure or non-disclosure of, information pertaining to oneself, and to control the circumstances, timing, and extent to which information may be disclosed.” [22]. Confidentiality requires that NBS programs protect private information [31].

We recognize that providing information on gNBS results to parents who may then share them with extended family members creates challenges to ensuring the security and confidentiality of genomic data. Genomic NBS results may identify multiple generations of family members who are at risk for genetic conditions and/or who may transmit clinically significant mutations to their progeny. Parents who receive information about their child from gNBS must decide whether to share this information and with whom. This can affect relationships with family members, including the potential for stigmatization or assigning blame among family members [32].

Many NBS programs store dried blood spots (DBS) for quality control and future research [33], creating additional risks for ensuring the security and confidentiality of genomic data. The consequences of a breach could be substantial [34]. Limited legal protections for genomic information exist in some countries, such as the Genetic Information Nondiscrimination Act (GINA) in the USA. Designed to prevent discrimination based on genetic information in health insurance coverage and employment [35], GINA does not apply to life or long-term care insurance, or businesses with fewer than 15 employees. Even more concerning is the wide variability in policies on use of DBS and other aspects of genomic privacy. This could lead to further inequities and loss of public trust in gNBS, particularly if they are used for law enforcement activities [12].

We propose the following calls to action to protect privacy and confidentiality:

• Implement strategies designed to protect privacy and security of genomic data and specimens worldwide, based on local resources and cultural values;

• Create data and specimen storage systems with multiple layers of security;

• Provide parents with guidance on disseminating genomic information, with particular attention to sharing information with their child(ren) in the future;

• Evaluate the effectiveness of informed consent regarding the retention and storage of DBS; and

• Include information about relevant laws and their limitations as part of informed consent for gNBS and the retention and storage of DBS.

We also recognize the significant impact of genomic information from gNBS on couples and extended families. Genomic NBS provides results that can lead to cascade testing in families. Information obtained through cascade testing can influence decisions about family planning, prenatal testing, and whether to complete or terminate future pregnancies [36, 37]. Results of gNBS can also cast doubts on assumed biological relationships, which can lead to discord between partners and among family members [32, 37]. Information obtained from NBS can adversely affect parents’ mental health, alter their self-concepts, engender concerns about their child’s vulnerability, influence whether they share NBS results with their child(ren), and impact family quality of life [9]. Psychosocial issues have the potential to become more widespread as NBS becomes ubiquitous globally and incorporates genomic technologies. Furthermore, there are important differences in approaches to patient autonomy and health-seeking behaviors in LMICs, with crucial implications for the psychosocial impact of NBS. Global variability in family structures and values makes this yet another area with an urgent need for additional research.

We propose the following calls to action to address psychosocial issues:

• Conduct research globally on family communication about gNBS and its psychosocial effects;

• Recognize that parents’ psychosocial responses to positive NBS results will vary and use discrete choice methods to tailor information and support, in keeping with familial and cultural values and norms;

• Identify best practices to limit psychosocial harm of parents and child(ren), recognizing that these will vary substantially in different countries;

• Educate clinicians to recognize persistent parental psychological distress, unfounded perceptions of child vulnerability, or overutilization of healthcare, and mitigate their effects; and

• Recognize that the psychosocial impact of gNBS results may extend beyond the child and parents to other family members and refer them to mental health professionals as needed.

In this perspective paper, we discussed four critical challenges for equitable implementation of gNBS at the population level. There is an urgent need to address the calls to action outlined for each challenge. In principle, global expansion of gNBS offers potential benefits including early diagnosis and access to treatment, limiting diagnostic odysseys, and supporting informed reproductive decision-making, yet it also raises substantial concerns. While high-income countries grapple with pragmatic and ethical dilemmas related to gNBS implementation, LMICs face challenges in implementing traditional NBS, in part due to important political and cultural differences. Biases driving the rapid expansion of gNBS programs in high-income countries further exacerbate inequities between high-income countries and LMICs [6]. Substantial gaps in empirical knowledge of gNBS remain, particularly at a global scale, and highlight opportunities for innovative research, particularly in LMICs. To ensure the benefits of genomic technology are available worldwide, we believe that these pressing challenges must be addressed, and that equitable and just implementation of gNBS must be pursued to avoid perpetuating and expanding global health inequities.

The authors have no conflicts of interest to declare.

The authors did not receive any funding for this work.

Dr. Ersig contributed to the overall conception of the project, acquisition of supporting evidence from the literature, writing, critically reviewing, and revising all drafts, and approval of the final version. She wrote the initial draft of several sections, took the lead on making revisions to all versions of the manuscript, and generated the final and final revised versions of the manuscript. Her contributions are incorporated into every section of this manuscript. Dr. Jaja contributed to the global perspective of genomic NBS with particular attention to the needs of low and middle-income countries and advancing issues of equity. His specific contributions included the acquisition of supporting evidence from the literature, writing, critically reviewing and revising multiple drafts, and approval of the final version. His contributions are incorporated into every section of this manuscript. Dr. Tluczek contributed to the overall conception of the project, acquisition of supporting evidence from the literature, writing, critically reviewing and revising all drafts, and approval of the final version. More specifically, she wrote the initial draft of several sections and contributed substantially to manuscript revisions for a revised submission. Her contributions are incorporated into every section of this manuscript. All authors agree to be accountable for all aspects of the work, ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.