Apnea of prematurity (AOP) is a common complication among preterm infants (<37 weeks gestation), globally. However, access to caffeine citrate (CC) that is a proven safe and effective treatment in high income countries is largely unavailable in low-and-middle income countries, where most preterm infants are born. Therefore, the overall aim of this study was to describe the demand, policies, and supply factors affecting the availability and clinical use of CC in LMICs.

A mixed methods approach was used to collect data from diverse settings in LMICs including Ethiopia, Kenya, Nigeria, South Africa, and India. Qualitative semi-structured interviews and focus group discussions were conducted with different health care providers, policymakers, and stakeholders from industry. Additional data was collected using standard questionnaires. A thematic framework approach was used to analyze the qualitative data and descriptive statistics were used to summarize the quantitative data. The findings indicate that there is variation in in-country policies on the use of CC in the prevention and treatment of AOP and its availability across the LMICs. As a result, the knowledge and experience of using CC also varied with clinicians on Ethiopia having no experience of using it while those in India have greater knowledge and experience of using it. The in turn influenced the demand and our findings show that only 29% of eligible preterm infants are receiving CC in these countries.

There is an urgent need to address the multilevel barriers to accessing CC for management of AOP in Africa. These include cost, lack of national policies and therefore lack of demand stemming from its clinical equivalency with aminophylline.  Practical ways to reduce the cost of CC in LMICs could potentially increase its availability and use.

Study design, setting, population, sampling

We conducted a landscape evaluation involving stakeholders in Africa (Ethiopia, Kenya, Nigeria, South Africa) and South Asia (India – five states of Delhi; Bihar, Uttar Pradesh, Telangana and Madhya Pradesh) on CC availability and use from 1 July 2022 to 31 December 2022. We used a mixed methods study design to understand the complexity of CC availability and use across these LMICs. We selected a geographically and culturally diverse countries with high annual preterm births (~200,000). The selection of stakeholders within each focus country was by convenience and/or purposive sampling. We selected health facilities providing care for preterm infants and were able to provide the data required to achieve the study’s objectives. Proximity and ease of data collection was also factored into selection by research teams.

Data collection

Qualitative

The research teams conducted key informant interviews and focus group discussions (FGD’s) with stakeholders in newborn health. The interviews with healthcare providers sought to explore their experience of using CC as a treatment for AOP. Interviews with WHO and Ministry of Health officials sought to understand current global and national health policies and CC’s inclusion in the essential drug list for using CC to treat AOP. 

Interviews with major drug suppliers and distributors of CC aimed to determine the current local market pricing of CC and its alternatives within and between countries. Also, to evaluate the factors determining the end-customer price of CC. The available average end-customer price per country was used to determine the daily cost of managing AOP for aminophylline and CC. We compared the average daily cost between aminophylline and cc for both public and private hospitals in each country. The dosing regimen for CC was a loading dose of 20 mg/kg/dose and a daily maintenance dose of between 5 to 10 mg/kg/day. The dosing regimen for aminophylline was a loading dose of 6 mg/kg administered intravenously (IV), followed by a maintenance dose of 2.5 mg/kg/dose/IV administered every 8 hours. 

Interviews and FGD’s were done in person or virtually over video or audio teleconferencing based on the preferences of the participants. All interviews were conducted in English. teams were situated in each country of focus and had previous training and experience conducting qualitative interviews and FGDs and in qualitative data analysis. The interviews and FGDs were semi structured using guide with a set of open-ended questions, in a set order and allowing for in-depth insights into the subject area. These guides were pilot tested across the 3 countries prior to data collection.

Quantitative

Additional interviews were conducted using standard questionnaires and had been piloted and refined in these settings prior to being used for data collection.The research team surveyed 107 providers: 20 from Ethiopia, 18 from India, 23 from Kenya, 28 from Nigeria, and 18 from South Africa. Providers were from 45 private or public health facilities across the five study countries. Of these, 12 (27%) were primary or secondary public, 7 (16%) were primary or secondary private, 25 (56%) were tertiary public, and 1 (2%) tertiary private

Demand forecast for caffeine citrate.

A demand forecast was conducted to determine the amount of CC needed per country. Using data from demographic health survey data from each country, we estimated the proportion of infants who would be eligible for CC treatment. Given AOP risk can be as high as 80% in preterm infants with birthweight ≤1500g (very low birth weight (VLBW)), we estimated that all VLBW infants met eligibility criteria for treatment with CC. We limited this forecast to public facilities where limited government funding constrains drug availability. We applied country-specific policies and assumptions to determine the percentage of VLBW infants who received or had a missed opportunity for CC treatment. These assumptions included, availability of CC, VLBW infants born in secondary facilities will be transferred to a tertiary center capable of providing AOP treat; some transfers will be unsuccessful and even when successful, AOP treatment will be unavailable.

Data management and analysis

All interviews were transcribed verbatim by an experienced transcriber. Authors reviewed the interview transcripts for errors. A coding framework was generated, and an emergent thematic analysis approach was used to analyze the data, to identify patterns and themes. Descriptive statistics were used to summarize the quantitative data.