Burden of Treatments for Respiratory Complications in Extremely Premature Infants: Interviews with Caregivers

Infants born prematurely (<37 weeks gestation) have a high risk of respiratory complications, which are associated with a high rate of health care resource utilization [1‒3]. Globally, approximately 15 million births per year are premature [4, 5]; of these, an estimated 5% are extremely premature (EP), defined by the World Health Organization as born at <28 weeks gestational age. Although survival rates for EP infants have greatly improved in recent years [6‒8], the risk of developing health complications increases with decreasing gestational age [9, 10] and often results in long-term morbidities and disabilities [11‒14]. Upon discharge from the neonatal intensive care unit (NICU), EP infants with respiratory complications have a high rate of re-hospitalizations [2, 15, 16] and may need complex care regimens at home. This can create a heavy burden for caregivers who may be required to manage multiple medications, treatments, and medical equipment (including home oxygen, cardiopulmonary monitors, respiratory medications, and tube feedings) [17] and who rely on a variety of medical resources including visits to clinical specialists and emergency department (ED) services. As a result, caring for EP infants may have lasting negative financial, emotional, physical, and psychosocial impacts on caregivers [18‒20].

While there is a clear need for therapies and strategies to decrease respiratory morbidity associated with premature birth, there is a lack of established clinical trial endpoints to evaluate treatment benefit in respiratory morbidity in EP infants; thus, the most relevant outcomes may be overlooked. Furthermore, regulatory agencies increasingly require long-term measures of chronic respiratory morbidity, for example, through at least 1 year corrected age (CA) [21], as well as measures of how a patient feels, functions, or survives [22], to enable optimal assessment of interventions and the real-life impact on the patient [23, 24]. Traditionally, improvement or change in a clinical endpoint is assessed by statistical significance. More recently, however, with the increased emphasis on the perspective of the patient in disease management, regulatory agencies, particularly the US Food and Drug Administration [22], have started to request patient/caregiver/observer input on symptoms or impacts that they consider important to treat and improve and what specific amount or type of change they would consider meaningful or beneficial. The objective of the present study was to explore the impact of respiratory treatment on caregivers of EP infants after NICU discharge, the relative burden of various treatment modalities, and perceptions of what constitutes meaningful changes (i.e., improvement) in respiratory morbidity as measured by treatment use.

This study was initiated to inform the selection of the primary endpoint in a phase 2b clinical trial (NCT03253263). The endpoint was intended to capture the impact of treatments on respiratory complications in EP infants.

All researchers had experience in conducting qualitative interviews, with varying degrees of years of experience (online suppl. material S1; see www.karger.com/doi/10.1159/000527375 for all online suppl. material). All interviewers were provided with study-specific training on study objectives, study materials, and the interview guide.

The study targeted a sample size allowing for a balanced and diverse sample based on infant age and sociodemographic characteristics, on a best-efforts basis, and consistent with sample sizes of similar qualitative studies. Caregivers were recruited via patient advocacy organizations or clinical sites in four countries to provide a representative sample of the countries included in the global trial spanning the USA, Europe, and Japan, according to procedures outlined in an Institutional Review Board-approved protocol (including local site-based Institutional Review Boards in Japan). These were Preemie Parent Alliance (now NICU Parent Network), a caregiver advocacy organization in the USA; Das frühgeborene Kind, an organization with an extensive network supporting families of premature infants in Germany; TinyLife, a premature and vulnerable baby charitable organization dedicated to reducing premature birth, illness, disability, and death in babies born in Northern Ireland; and two clinical sites (Saitama Medical Center, Saitama Medical University, and Osaka Women’s and Children’s Hospital) in Japan. Recruitment in Japan occurred through clinical sites due to the limited resources of the small local parent association. Caregivers were selected by convenience sampling and were approached by telephone, email, and/or standard mail.

To be eligible for inclusion in the study, caregivers were required to be age ≥18 years (USA, Germany, and Northern Ireland) or ≥20 years (Japan), fluent in English (USA and Northern Ireland), German (Germany), or Japanese (Japan), and the primary caregiver of an infant between 3 and 14 months CA who had been discharged from the NICU at the time of interview. The infants were required to have experienced at least one of the following: ED visit or re-hospitalization due to respiratory diagnosis, home respiratory technology support (RTS; e.g., supplemental oxygen, breathing/heart rate monitor, feeding tube, pulse oximeter, ventilator, tracheostomy), and daily or occasional use of respiratory medications (e.g., nebulizers; inhalers; oral medications such as steroids, diuretics, and vasodilators). Caregivers were excluded from the study if the infant had a congenital malformation (e.g., cleft lip; cleft palate; ear, face, and neck anomalies), or a known or suspected chromosomal abnormality, genetic disorder, or syndrome.

Prior to the interview, an interviewer reached out to the participant to confirm that the participant had read the study information sheet, to provide the participant with an opportunity to ask any outstanding questions, and to provide the study materials in advance of the interview. During the interview, the interviewer provided additional details about the goals/objectives of the research. All caregivers provided verbal informed consent prior to participating in the study.

Interviews were semi-structured and followed an interview guide (online suppl. material S2) with open-ended questions as well as targeted probes designed to explore the following: infants’ experiences with lung- and breathing-related issues post-discharge from the NICU, caregivers’ experiences with respiratory treatments and associated impacts, and meaningful changes representing improvement when considering various respiratory treatments. The semi-structured interview approach is widely used in patient-focused qualitative research and was the preferred approach in this study because while the interviewer follows a preset guideline to help achieve the research objective, open-ended questions are also included to allow flexibility for new themes to emerge 25‒28. Within each treatment modality, meaningful change was explored using both open-ended questions and targeted probes. Meaningful change was defined as a change in treatment needs perceived as a meaningful improvement by the caregivers, for example, less frequent administration, shorter duration or discontinuation of treatment, or less invasive route of administration. “Meaningful change” and “most burdensome” treatment were not explicitly defined for the participant; however, the interviewer could have provided examples or scenarios that could illustrate meaningful changes. If the participant had difficulty answering, the interviewer could have probed further with additional follow-up questions.

Interviews were conducted remotely in the USA between February and March 2018 and in Germany, Northern Ireland, and Japan between July 2018 and August 2019. Interviews lasted approximately 60–90 min and were audio recorded and transcribed verbatim; transcripts were reviewed by interviewers and study team members for accuracy prior to analysis. The interviewers also recorded field notes during the interviews.

The study used grounded theory and content/thematic analysis. Interviews were translated into English if needed, and interview data were analyzed qualitatively by MAXQDA qualitative analysis software (version 11, copyright Udo Kuckartz 1995–2013). A content and thematic analysis involving the coding of the transcripts was conducted using a structured codebook to identify relevant concepts and themes related to respiratory treatment impacts (online suppl. material S3). Key domains were identified prior to the interviews; however, granular concepts and themes were derived from the data. Coding was performed by two data coders. Caregiver and infant sociodemographic information were summarized using descriptive statistics. To target a balanced and diverse sample on a best-efforts basis, caregivers were stratified in three groups according to the following CA ranges of their infant: 3–6 months CA, 6 months plus 1 day to 9 months CA, 9 months plus 1 day to 14 months CA.

Concept elicitation interviews were conducted with 45 caregivers: 21 from the USA, 14 from Germany, 5 from Northern Ireland, and 5 from Japan. Overall, 95.6% of caregivers were female, with a mean (standard deviation) age of 32.1 (5.1) years. Of the 45 infants, 12 (26.7%) had a CA of 3–6 months, 16 (35.6%) had a CA >6–9 months, and 17 (37.8%) had a CA >9–14 months. Caregivers (USA and EU only; n = 40) reported 33 (82.5%) infants with diagnosis of bronchopulmonary dysplasia/chronic lung disease of prematurity and 3 (7.5%) with reactive airway disease. Characteristics of the caregivers and their infants are presented in Table 1.

Caregivers reported that their infants had experienced a range of respiratory morbidities following discharge from the NICU, the most common of which were coughing (77.8%), breathing difficulties (e.g., dyspnea, tachypnea, heavy or noisy breathing, oxygen desaturations, fatigue during exercise, gasping for breath, retractions, 75.6%), wheezing (57.8%), bronchopulmonary dysplasia/chronic lung disease of prematurity (55.6%), respiratory infection (55.6%), and apnea (28.9%). Pulmonary hypertension, stridor, and cyanosis were each reported in 8 (17.8%) patients, acute respiratory distress syndrome in 7 (15.6%) patients, and hypoxemia in 5 (11.1%) patients.

Overall, most (86.7%) caregivers reported usage of respiratory medications during the post-NICU period, the most common being nebulizers (18 [40.0%] infants), bronchodilators (14 [31.1%]), and diuretics or steroid inhalers (12 [26.7%] for each). A majority of caregivers (80.0%) also reported use of home RTS, with 26 (57.8%) using supplemental oxygen, 25 (55.6%) using a breathing or heart rate monitor, and 14 (31.1%) using a feeding tube. Respiratory-related re-hospitalizations and ED visits were reported by 17 (37.8%) and 15 (33.3%) caregivers, respectively (Table 2).

To assess the burden associated with caring for or living with an infant with chronic respiratory or breathing issues, caregivers were initially asked the open-ended question “what is it like to [give medication, be on home technology, go to the emergency room, be hospitalized, etc]?” Caregivers described numerous negative impacts associated with use of respiratory treatment modalities (Fig. 1). The highest number of impacts reported (n = 41) was associated with RTS; some of these were also the most frequently reported impacts overall, such as the effect on infant mobility and development (reported by 19/36 [52.8%] caregivers with RTS experience), sleep (15 [41.7%]), false alarms from monitoring devices (14 [38.9%]), and limitations on social/recreational activities (13 [36.1%]). RTS use was commonly described as inconvenient and time consuming, caused disruption to work and daily life, and caused emotional distress. Examples of comments from caregivers included the following: “The oxygen, the oximeter, and the inhaler… They just affect every aspect of daily life;” “[Respiratory medications are] most difficult…The monitoring is the most nerve-wracking, I would say;”and “…the high flow [oxygen] was somewhat impractical, and that gave us a lot of problems…”

Notably, although the rate of respiratory medication use was higher than that of RTS use, fewer negative impacts were reported (n = 20). Difficulty with administration of medication was the most frequent impact (14/39 caregivers [35.9%]), and inconvenience associated with dosing schedules was also frequently mentioned by caregivers. For each treatment modality, frustration and stress were reported by at least two caregivers, and the impact on relationships and caring for other children was also reported. The most burdensome respiratory treatments, based on actual experience (excluding treatments experienced by a single caregiver only), were ED visits (71.4%), supplemental oxygen (65.2%), and feeding tube (64.3%) (Table 3).

Elimination of, or reduced need for, the use of home RTS, along with less frequent dosing of respiratory medications, was reported by most caregivers as changes in treatment use that would be considered meaningful. The most frequently mentioned changes related to the use of home RTS were reduced need for oxygen, including periods of stability without oxygen and weaning off oxygen, reported by 24 (53.3%) caregivers, and reducing the time using breathing/heart rate monitors, reported by 17 (37.8%) caregivers (Table 4). Caregivers commented, for example, that “…it would be nice if we were able to like wean her down in the amount [of oxygen] that she’s using, but that still requires like having her being on it all the time, so that would be nice. I would love for them to say like that we can just have her on it when she’s sleeping, but I think we’re a little far from there, but that would be my ultimate like… that would be so much easier;” and “It was most definitely an improvement that I didn’t connect her during the daytime, but only at nights.”

Less frequent administration of medications and no longer requiring/weaning off medications were the most frequently reported changes related to respiratory medication use that would be meaningful, reported by 26 (57.8%) and 20 (44.4%) caregivers, respectively. A reduction in the number of ED visits was reported as a meaningful change by 12 (26.7%) caregivers (Table 4). For example, caregivers described that “…generally a dose reduction is always desirable…or, of course, discontinuing the medication, or, for example, if there was a medication that has to be given only once daily…,” and “…it would be definitely a progress if you don’t have to go there [ED] all the time…If there was a way to resolve it differently.”

Although this study focused on treatment impacts and meaningful changes related to use of home RTS, other concepts and themes elicited from caregivers were also identified, including general caregiver challenges, family impacts, and difficulties encountered during the NICU stay (online suppl. material S3).

This study aimed to explore caregiver perspectives on the impact of respiratory treatment after NICU discharge for EP infants, the relative burden of various treatment modalities, and what constitutes meaningful change (i.e., reduction) in the burden associated with use of treatment modalities. While previous studies have reported the high medical and economic burden of complications of prematurity [1‒3], few have evaluated the impact on primary caregivers of continuing care of premature infants with respiratory comorbidities after discharge from the NICU.

In this study, caregivers reported that more than 80% of EP infants received respiratory medications and/or RTS for respiratory treatment after discharge, and approximately one-third of infants were re-hospitalized or visited the ED as a result of their respiratory morbidities. As such, the caregivers in this study were experienced in caring for infants with significant respiratory morbidities and were well positioned to provide insights on caregiver burden.

Findings from this study indicate that all of the respiratory treatment modalities explored were associated with negative impacts on caregivers, with the most burdensome being ED visits, supplemental oxygen, and use of feeding tubes. The treatments were inconvenient, difficult to administer, and caused emotional distress. As such, caregivers indicated that the most meaningful changes in treatment use would involve weaning off medications and supplemental oxygen and reducing the amount of time using breathing or heart rate monitors. This is in line with previous observations that complex home care is associated with lower caregiver quality of life after NICU discharge [20]. It follows that a reduction in the use of these treatment modalities would be a benefit to pre-term infants and their caregivers. For example, Adams et al. [29] found that the need for a ventilator was ranked as the disability that would contribute the most to a poor quality of life for infants who had been in the NICU (63.9% of caregivers considered it related to “bad” quality of life), with need for a tracheostomy or g-tube also considered “bad” (35.1%). However, there is a balance in parents’ treatment preferences versus impairment in quality of life; Lau et al. [30] found that parents often preferred earlier discharge with home oxygen use over extended stays in the NICU, but parents were also willing to accept more disabilities than dependence on medical treatment [29]. This study highlights the benefits of partnering with caregivers of EP infants to explore the most valuable outcomes for assessment of treatment response.

As this study comprised a population drawn from four countries (the USA, Northern Ireland, Germany, and Japan), further analysis of the data might provide insight into how cultural and health care system differences may influence caregivers’ perspectives, with the limitation that the number of caregivers among the countries was unequal. For example, it was noted by the interviewer for this study in Japan that Japan does not use a primary care system. Furthermore, hospitals may tend to postpone discharge if patients require more than easy-to-manage treatment such as oral medications. Finally, Japanese females who were interviewed felt uncomfortable in answering open-ended questions. Additional limitations include that the recruitment of caregivers from the USA, Germany, and Northern Ireland was led by patient advocacy groups, which could lead to bias toward caregivers who experienced greater impacts. Similarly, recruitment from clinical sites, which have access to information regarding treatments administered, could select for participation of caregivers who experienced greater impacts. Study eligibility criteria include caregiver report of treatments, which could select for participation of caregivers who experienced greater impacts. While the sample size was small, this is in line with similar qualitative studies and recommendations that showed similar trends in caregiver-reported impacts and burdens related to respiratory comorbidities in EP infants.

While all respiratory treatment modalities evaluated among caregivers of EP infants were associated with negative impact, caregivers considered ED visits and administration of supplemental oxygen and feeding tubes to be the most burdensome treatments. Reduction in the need for such treatments and input from caregivers on their concerns and preferences should be considered when developing and evaluating new treatments for respiratory morbidities in EP infants.

The authors would like to thank Katarina Eglin, Das frühgeborene Kind, Germany, for her role in the study. Under direction of the authors, Lindsay Napier, PhD, CMPP, of Excel Medical Affairs provided writing assistance for this publication. Editorial assistance in formatting, proofreading, and copyediting was provided by Excel Scientific Solutions.

The study protocol and interview materials were reviewed and approved by Salus IRB (Austin, TX), a central IRB based in the USA (approved protocol number SHP607-15). As this was a minimal risk study, all caregivers provided verbal consent prior to initiation of interviews, which was deemed acceptable by the IRB.

S. Sarda, L. Han, and A. Mangili were employees of Takeda when the study took place. M. Vanya was an employee of ICON at the time of the study and is currently an employee of Takeda. E. Schwartz is an employee of ICON and has no other disclosures to declare. K. Sorrells is an employee of NICU Parent Network and has no other disclosures to declare. F. Namba and S. Hirano are involved in clinical trials sponsored by Takeda. A. McNulty is an employee of TinyLife and has no other disclosures to declare.

This study was funded by Shire, a member of the Takeda group of companies, who also provided funding to Excel Medical Affairs for support in writing and editing this manuscript.

Sujata P. Sarda and Alexandra Mangili contributed to the conception and design, interpretation of data, and drafting/revising the article critically for important intellectual content. Magdalena Vanya, Ethan J. Schwartz, Keira Sorrells, Fumihiko Namba, Shinya Hirano, and Alison McNulty contributed to the collection and interpretation of data and drafting/revising the article critically for important intellectual content. All authors provided approval of the final manuscript.

All data generated or analyzed during this study are included in this article and its online supplementary material files. Further inquiries can be directed to the corresponding author.