Scaling Up Caffeine Citrate Use for Prevention and Management of Apnoea of Prematurity in Kenya

Background:

The first month of life is the most vulnerable period for child survival, with 2.4 million new-borns dying globally in 2020. Sub-Saharan Africa has the highest neonatal mortality rate in the world, and contributes to 43% of global newborn deaths. In Kenya, neonatal mortality accounts for approximately 51% of all under-5 deaths. Unfortunately, most of these children die as a result of conditions and diseases associated with the lack of quality care at or immediately after birth and in the first few days of life such as prematurity, birth asphyxia and neonatal sepsis. Pre-term birth (i.e. babies born <37 weeks gestational age (AG)) is one of the leading causes of death, disability and non-communicable diseases. In Kenya, pre-term birth rate is ~12%, translating to an estimated 193,000 pre-term babies born every year. Of note, 80% of newborn deaths have solutions to address them and prevent life-long disability.

 Apnoea of Prematurity (AOP) is the cessation of breathing lasting more than 20 seconds or less when accompanied by bradycardia and hypoxaemia. AOP can result in failure to thrive, respiratory failure or death. The incidence of AOP is inversely proportional to gestational age, affecting almost ALL extreme pre- terms (i.e. <28 weeks GA), 85% of very pre-term cases (i.e. >28-32 weeks GA) and 20% of the moderate to late pre-term cases (i.e. >32-37 weeks GA).

 The treatment of AOP includes methylxanthines therapy e.g. Aminophylline or Caffeine Citrate (CC), Nasal Continuous Positive Airway Pressure therapy (CPAP) and blood transfusion. Caffeine citrate's efficacy, tolerability, longer half-life, wide therapeutic index and safety margin makes it one of the most widely prescribed drugs in high-income settings. In Kenya, it is listed in the EML and was recently adopted in clinical guidelines.

Problem:

Only ~6% of all pre-term infants are currently treated with CC in the public sector. The low uptake of CC for the management of Apnoea of Prematurity is mainly due to the following access barriers: 

•  Awareness – Notable capacity gaps contribute to high use of suboptimal methylxanthines i.e. Aminophylline. Unfortunately, the management of AOP is not included in key new-born trainings and updated guidelines have not yet been disseminated. Hence, demand for CC is generally low.

Figure 1: Caffeine Citrate drug available in Kenya (only one supplier)

• Availability & utilization– There is Limited availability of CC, fragmented demand and low visibility on utilization. Unfortunately, the commodity is not procured by KEMSA. From a rapid spot-check conducted in 21 referral hospitals in Kenya, CHAI found that 52% of referral hospitals use aminophylline only, 19% use caffeine citrate, while 29% of them have intermittent supply of either caffeine citrate or aminophylline.
• Affordability – The current CC product from Martindale costs $20.00- $40.00 for the loading dose & $10.00- $20.00 for the daily maintenance dose, for to up to 6 weeks. Of note, aminophylline is way cheaper, however it has a lower therapeutic window and a daily requirement of serum aminophylline concentration test, which is expensive & rarely done in the public sector. Hence, there is a high risk of drug toxicity for patients on aminophylline.

 Areas of Focus:

Kenya is relatively unique across sub-Sahara African countries in terms of the level of progress already made by the Government towards the adoption of CC in KEML and in clinical guidelines. Through the support of in-country neonatologists and paeditricians, the MOH incorporated the “prevention and management of AOP algorithms using CC” in the basic paediatric protocols, ahead of the 2022 WHO recommendations launch. As such, a series of low hanging fruit and priority areas of focus are a priority in 2023:

o  Service delivery

• Support the MOH in engaging the KPFP neonatologists, paeditricians, neonatal nurses and referral institutions such as MRTH etc. to disseminate guidelines, roll out of onsite mentorship, CMEs and OJT sessions. Leverage on existing programs to scale up key interventions such as the use of CPAP and pulse oximetry and improved access to quality oxygen.
• Sensitization and monitoring of health care workers in lower level facilities on the provision of essential ANC services, timely identification of danger signs & structured support for high risk pregnancies, timely pre-referral care and clear linkages will ensure high uptake of life-saving measures.
• Scaling up prevention practices through health talks to promote healthy practices during the antenatal and delivery period, early identification of danger signs and care-seeking, and compliance in essential newborn care is key in preventing still births and neonatal deaths.
• Pre-service training on the management of AOP will be key in ensuring sustainable roll out of technical skills in key cadres. Immediate collaboration with training institutions, KPFP program etc. will strengthen the availability of competent HCWs and the provision of quality health services for newborns.

o  Supply Chain

• Ensuring a holistic assessment of full CC market potential by conducting a market sizing exercise will provide visibility on volumes and key areas to address in mitigating drop-offs though the health system.
• Intensive supplier engagement will aim at: securing affordable product(s), accelerating the registration of new products, supporting KEMSA procurement process and accelerating the uptake of CC through catalytic donation.
• The sensitization of county pharmacists will be critical in ensuring sustainable allocation of funds, procurement of CC and monitoring of stock levels.

o  Data

• Credible data will inform prioritization of needs, which informs strategic purchasing of necessary infrastructure, equipment, supplies and essential commodities for new-born care. Close coordination at facility level to strengthen the use of informative tools that aid in decision making, proper documentation and reporting practice will be critical in providing key data on areas of need/improvement.
• Activating neonatal audits by equipping HCWs in key departments with necessary tools/structure is will enable timely course correction and mitigating health system failures through the application of local solutions.

o  Health Financing

• Linda mama services highly favor a well mother and child. Hence engagement with county and facility leadership has been prioritized to enable allocation of resources in support of cost-effective newborn interventions, availability of essential commodities and supplies such as thermal care, KMC for all stable neonates <2,000g, assisted feeding, iv fluids, safe administration of oxygen, early detection and management of neonatal sepsis, detection and management of neonatal jaundice with phototherapy are some of the essential services that can be scaled up at secondary care level.
• In Kenya we only have 3 functional NICU facilities. Scaling up the number of NICUs in tertiary hospitals is key in ensuring complications after birth such as the management of AOP, mechanical ventilation, advanced feeding support, screening for complications etc. is effectively done. With the support of the MOH and recently deployed neonatologists, the development of NICU standards and simplified checklist is underway for immediate dissemination. Kwale county has spearheaded the process and the county government is keen on establishing NICU facility at Msambweni Referral Hospital.

 ANNEX: THEORY OF CHANGE & MARKET SIZING ESTIMATES FOR CC USE IN KENYA