Ethical practice is an integral part of medical professionalism. Physicians have a duty to promote the highest quality patient care, and particular attention must be given to the pediatric patient population, which ranges in physical and cognitive maturity. Medical decision-making can be challenged by unique ethical circumstances, particularly for cases of diseases that impact quality or longevity of life. This article explores various ethical considerations in pediatric retina through a case-based discussion.

REFUSAL OF TREATMENT

Case 1: Leukocoria

A 2-year-old child is taken to the pediatrician for a well-child visit. The patient’s last visit was more than 1 year ago. On examination, the pediatrician notices loss of the red reflex in the right eye and is concerned for leukocoria. An urgent referral is made for evaluation by an ophthalmologist. At the ophthalmologist’s office, the mother is reluctant to allow dilation of the eyes for a fundus examination. Ultimately, the ophthalmologist is able to complete the examination, and workup demonstrates high clinical suspicion for retinoblastoma. The ophthalmologist has a long discussion with the mother about the natural history of the disease, management options, and prognosis. The ophthalmologist emphasizes that there is over a 95% chance of survival if the cancer does not spread outside of the right eye.¹ However, the mother refuses any form of focal therapy or surgical treatment for the child.

Failure to treat retinoblastoma is associated with subsequent metastasis and mortality. Parental refusal of treatment that has been scientifically proven to be effective for life-threatening disease poses a complex situation and highlights Beauchamp’s principles of biomedical ethics that are at the core of medical training and practice.² Beneficence, or the act of doing good, has additional implications when applied to the realm of pediatrics. The physician has the responsibility to advocate for their pediatric patients and ensure that medical decision-making is conducted in the child’s best interest. This mission may be hindered by the inability to obtain informed consent for treatment from the parent or legal guardian of a child. In the case described above, this would be due to parent refusal of treatment. The first step is to fully educate the parents about the circumstances and to address their concerns, ensuring that there are no communication barriers (eg, language interpretation services may be warranted) and that the information is discussed clearly in lay terms. In the case of retinoblastoma, interventions, such as enucleation or chemotherapy, are not without their associated morbidity, pharmacologic side effects, and psychosocial implications.

This may raise the issue of nonmaleficence, the second principle of biomedical ethics, that no harm is to be done to the patient.² Communicating to parents that the benefits of a known effective treatment outweigh the risks is paramount, particularly if parents are conducting their own online searches and may not have all the information they require to make a decision. If the parents are a married couple, the consent of one parent may be sufficient to proceed with medical care.³ If the parents disagree over providing consent for treatment, or neither parent would like to treat the child and there is concern for medical neglect, an ethics consultation is warranted and the case may be escalated to a legal court.³ Legal involvement due to parents denying a child oncologic treatment has been cited, and parents’ decisions have been overruled.⁴ In legal cases where lack of treatment is not associated with significant morbidity, or where parental decision not to treat is due to religious beliefs, then the parents’ wishes may be upheld.⁴

RESEARCH IN MINORS

Case 2: Clinical Trial for Retinopathy of Prematurity

An infant is born at 30 weeks gestational age with a birth weight of 1,500 grams. While in the neonatal intensive care unit, the infant is screened for retinopathy of prematurity and is found to have treatment-requiring disease. The retina specialist discusses with the parents the need for therapeutic intervention. It is explained that laser photocoagulation or intravitreal anti-vascular endothelial growth factor (anti-VEGF) may be used for treatment. The risks, benefits, and alternatives for both options are discussed at length with the family. The physician also discusses clinical trials that the patient may be enrolled in that assess the efficacy and potential adverse events of intravitreal anti-VEGF therapy.

The Belmont Report and the Declaration of Helsinki have delineated the principles research investigators should follow when recruiting subjects for studies.^5,6 Although the subject, or the parent or guardian, has provided consent, this does not alleviate the investigators from the responsibility of protecting their subjects with regard to safety and privacy.⁵ Clinical trials occur at a much lower rate in children because investigators are likely more cautious with this age group. Trials involving neonates comprise approximately 7% of clinical investigations in children.⁷ In addition, the frequency of trials involving pediatric populations in low-income countries is notably low; however, in these settings, there may be limited resources and additional environmental factors impacting health care that warrant further investigation.⁷

Clinical trials conducted in the pediatric population may subject the participants to various risks; however, research in minors is particularly important given that children vary from adults from a developmental and psychological standpoint. Results from clinical studies in adults cannot be directly applied to children without first undergoing further investigation. In the second case described above, the infant and the family participated in the trial for anti-VEGF therapy. Although anti-VEGF has been studied in adult populations affected by other retinopathies, the systemic and neurodevelopmental effects of anti-VEGF in children are not fully understood.^7,8 In the general realm of medicine, adverse outcomes have been reported in the literature when medications deemed safe in adults led to serious complications in children.⁷

There are various aspects of clinical research in minors that must be considered. For example, the inclusion of children in a phase 1 trial is typically only permitted under the notion that there are no alternative treatments for a disease associated with significant morbidity or mortality. Moreover, a clinical trial must be must be approved by appropriate review mechanisms (such as an Institutional Review Board) and must comply with all requirements of the approved study protocol.⁹ Providing the public and colleagues with accurate and reproducible data surrounding the research is paramount.⁷ Regardless of whether the results support the hypothesis of the research group or if there are adverse outcomes, it is important that the findings be published.⁹ This either prevents the replication of futile efforts or allows for the modification of hypotheses in the attempt to generate more favorable outcomes. Ultimately, the research should be longitudinal in nature. As children age into adulthood, it is critical to assess the long-term outcomes of the interventions that were tested, even if the short-term findings were promising.⁷ In this case of anti-VEGF for ROP, the subjects are neonates; however, for other studies where adolescents are recruited, they must be involved in the consent process if they have the capacity to make decisions even though they cannot give consent. If a minor has sound reason not to participate in the study, this wish should be respected.¹⁰ Furthermore, research investigators should be careful about financially incentivizing subjects into joining a study.⁷ It may, however, be appropriate to cover modest portions of the expenses if patients choose to enroll in the trial.⁷

GENETIC TESTING

Case 3: Juvenile Macular Degeneration

A 16-year-old female presents with her parents to the ophthalmologist’s office after she started experiencing blurriness in her central vision. Workup revealed a best-corrected visual acuity of 20/80 in the right eye and 20/60 in the left eye. Dilated fundus examination showed atrophy of the macula with scattered yellow flecks in both eyes. The patient’s mother and father both report family history of blindness at a young age in other relatives. The patient has 2 younger siblings who have no vision problems. After completing additional workup, the ophthalmologist is concerned for Stargardt disease and notes that genetic testing is available.

Botkin et al differentiates between “clinical” and “personal” utility of genetic testing.¹¹ The former suggests that a confirmed diagnosis will assist in medical decision-making, especially with regard to treatment.¹¹ The latter indicates that clinical management will likely be unaltered, particularly in the setting of diseases that lack a definitive therapy.¹¹ Examples of “personal” utility include general awareness about the underlying genetic disorder, family planning considerations, and carrier testing of relatives.¹¹ There has been a limited number of studies among adolescents that have demonstrated that clarity surrounding carrier status alleviates trepidation regardless of the test result.¹² In a pediatric case with concern for an inheritable disease, parents may be inclined to request genetic testing because they may feel more assured if questions are answered, or at minimum, pursued.¹¹ For genetic diseases with no known treatments, such as in this case of Stargardt disease, the American Society of Human Genetics recommends that capable adolescents should be included in the discussion to undergo testing.¹²

It is important to educate the family about the possibility of genetic testing yielding inconclusive results.¹³ In the case of Stargardt disease, the ABCA4 gene is most commonly associated with the condition; however, other genes have been implicated, and at times, the testing is negative.^13,14 Identifying the exact gene involved may facilitate a family discussion regarding prognosis and allow the adolescent patient, as in the case described above, to enroll in a clinical trial that explores treatment options for patients with the same mutation.¹³

CONCLUSIONS AND FUTURE DIRECTIONS

An ophthalmologist may be faced with varying ethical scenarios, particularly in the management of pediatric patients. The American Academy of Ophthalmology code of ethics provides guiding principles for daily practice, in addition to descriptive rules of conduct for ophthalmologists in all areas of practice.⁹ These rules include conducting a thorough pretreatment assessment by evaluating the patient from a medical and psychosocial perspective, educating family through proper informed consent, ensuring that postoperative care is provided by competent practitioners agreed to in advance by the research subjects, avoiding ancillary testing that has no utility, and disclosing conflicts of interest that may unduly influence professional judgment.⁹ As we look toward the development of new diagnostic techniques and therapeutic interventions, the integrity of patients and of the physician–patient relationship should not be comprised by research efforts.⁹ Ultimately, early educational initiatives through case-based training during residency and fellowship may better prepare physicians for these challenges.¹⁵ RP

REFERENCES

1. St. Jude Children’s Research Hospital. Retinoblastoma. Accessed January 18, 2021. https://www.stjude.org/disease/retinoblastoma.html .
2. Ronen GM, Rosenbaum PL. Reflections on ethics and humanity in pediatric neurology: the value of recognizing ethical issues in common clinical practice. Curr Neurol Neurosci Rep. 2017;17(5):39. doi:10.1007/s11910-017-0749-7
3. Weber P. Informed consent for minor patients. Ophthalmic Mutual Insurance Company. Published 1999. Accessed January 18, 2021. https://www.omic.com/informed-consent-for-minor-patients/
4. Black L. Limiting parents’ rights in medical decision making. Virtual Mentor. 2006;8(10):676-680. doi:10.1001/virtualmentor.2006.8.10.hlaw1-0610
5. The Belmont Report. U.S.Department of Health & Human Services, Office for Human Research Protections. Published 1979. Accessed January 18, 2021. https://www.hhs.gov/ohrp/regulations-and-policy/belmont-report/read-the-belmont-report/index.html
6. World Medical Association. WMA declaration of Helsinki – ethical principles for medical research involving human subjects. Published 2018. Accessed January 18, 2021. https://www.wma.net/policies-post/wma-declaration-of-helsinki-ethical-principles-for-medical-research-involving-human-subjects/
7. Joseph PD, Craig JC, Caldwell PH. Clinical trials in children. Br J Clin Pharmacol. 2015;79(3):357-369. doi:10.1111/bcp.12305
8. VanderVeen DK, Cataltepe SU. Anti-vascular endothelial growth factor intravitreal therapy for retinopathy of prematurity. Semin Perinatol. 2019;43(6):375-380. doi:10.1053/j.semperi.2019.05.011
9. American Academy of Ophthalmology. Code of ethics. Published 2020. Accessed January 18, 2021. https://www.aao.org/ethics-detail/code-of-ethics
10. Davidson AJ, O’Brien M. Ethics and medical research in children. Paediatr Anaesth. 2009;19(10):994-1004. doi:10.1111/j.1460-9592.2009.03117.x
11. Botkin JR. Ethical issues in pediatric genetic testing and screening. Curr Opin Pediatr. 2016;28(6):700-704. doi:10.1097/mop.0000000000000418
12. Botkin JR, Belmont JW, Berg JS, et al. Points to consider: ethical, legal, and psychosocial implications of genetic testing in children and adolescents. Am J Hum Genet. 2015;97(1):6-21. doi:10.1016/j.ajhg.2015.05.022
13. Schlegel D, Branham KE, Heckenlively JR, Fahim AT, Jayaundera T. The journey from clinical to genetic diagnosis in Stargardt disease. Invest Ophthalmol Vis Sci. 2018;59(9):1433.
14. NIH, National Eye Institute. Stargardt disease. Accessed January 18, 2021. https://www.nei.nih.gov/learn-about-eye-health/eye-conditions-and-diseases/stargardt-disease
15. Martakis K, Czabanowska K, Schröder-Bäck P. Teaching ethics to pediatric residents: a literature analysis and synthesis. Klin Padiatr. 2016;228(5):263-269. doi:10.1055/s-0042-109709