Neonatal Encephalopathy in Low and Middle Income Countries

Isabel Li

Introduction

Neonatal encephalopathy (NE) is one of the leading causes of newborn death and disability in low-income and middle-income countries (LMICs).¹ Although NE accounts for 23% of global neonatal mortality, its burden is not equally distributed, with 99% of these deaths occur in low-resource settings.²

In accordance with Target 3.2 of the United Nations’ Sustainable Development Goals—a collection of objectives to reach global peace and prosperity—battling NE is an utmost priority for nations around the world.³ As a condition that undeniably preys along socioeconomic and geographic lines, it is critical to understand the relationship between LMICs and NE fatality in order to effectively address the crisis.

There are two primary aspects that contribute to NE fatality in LMICs: one, issues with birth conditions and neonatal care and two, a problematic treatment regimen for infants with the disease. Not only is immediate diagnosis and treatment generally inaccessible, the gold standard of treatment—therapeutic hypothermia—is impossible with the available healthcare services in many LMICs.

What is NE?

Neonatal encephalopathy refers to disturbed brain function in newborns. While it is commonly the result of birth asphyxia—that is, a lack of blood flow and oxygen to the brain during delivery—NE can also result from a variety of other conditions such as infections and metabolic disturbances.⁴ Since the mechanisms behind neonatal brain conditions continue to elude full understanding, NE is the preferred term to describe neonatal brain dysfunction given its lack of connection with a specific medical cause.⁵

Common symptoms of NE include respiratory issues, decreased levels of consciousness, slow reflexes, and seizures. Although survivors have a high risk of cerebral palsy, deafness, blindness, and cognitive impairment, immediate treatment can improve NE outcomes.⁶

Occurrence, Morbidity, and Mortality - A Knowledge Disparity

As NE is an umbrella term, the standards for NE diagnosis remain relatively variable; with this in mind, studies estimate an incidence rate of around 8.5 cases in 1,000 live births, with nearly all of the global one million deaths occurring in LMICs on a yearly basis.⁷ However, since most NE research is confined to the top 1% of citizens in high-income countries, the mortality and morbidity rates associated with NE for LMICs are not only high but under-researched. Indeed, NE in LMICs is both a threatening and insufficiently understood force.

This disparity in NE research can be attributed to the severe lack of neurological research and healthcare funding in LMICs.⁸ While it can be argued that neurological research is expensive, investigation into NE in LMICs is the first step into mitigating this problem—the severity and lifelong impact of NE demands attention, regardless of costs and challenges.

Challenges with NE Diagnosis and Treatment

Immediate treatment of NE is critical to reducing the risk of mortality and lifelong impairment for diagnosed patients; however, not only are healthcare facilities not optimized to treat NE, but diagnosis and treatment itself is inaccessible to a huge amount of home births.

The diagnostic process for NE tends to rely more heavily on apgar scores in LMICs than in high-income countries, since neuroimaging and EEGs are not commonly available for use in LMICs.⁹ Regardless, NE is typically diagnosed shortly after birth, particularly moderate and severe NE; given the severity, an earlier diagnosis is instrumental in combating the effects of NE.¹⁰

Once diagnosed, infants are supposed to immediately be given some form of breathing assistance—such as intubation and ventilator-assisted respiration—and fluids/medicine through an IV. The effects of NE are systemic, so other parts of the body—like the kidneys and liver—also require assessment after NE diagnosis.⁵ If the baby has moderate or severe NE, the standard treatment—as established by the 2010 International Consensus Conference on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science with Treatment Recommendations—is therapeutic hypothermia: purposefully exposing the infant to cold temperatures. When attached to some sort of cooling system (ex. a cooling blanket), the colder temperature helps the baby’s brain heal by reducing the brain’s metabolic rate and inflammation.^{11, 12}

In accordance with the aforementioned Sustainable Development Goals, there have been many recent interventions to improve maternal and neonatal health services in LMICs. Access and utilization of healthcare facilities has increased in these past two decades: the number of births in facilities increased 15% between 1990 and 2010.¹³ While births in facilities are generally safer, mothers and infants still face poor quality of care, which could impair NE treatments or even worsen related symptoms.⁷ With unsanitary conditions and a lack of quality obstetric care (which contributes to infection and birth asphyxia), many hospitals are not inherently optimized to reduce the number of NE cases in LMICs. Furthermore, these hospitals typically lack the resources and staff to treat this neonatal condition. In short, many NE cases from LMICs can be associated with preventable intrapartum complications.

Nevertheless, unattended home births continue to remain common even when facilities are within reach. A 2011 study revealed that around 80-90% of poor women in sub-Saharan Africa, South Asia, and Southeast Asia give birth at home, with many of these births occurring without an experienced assistant or professional.¹⁴ Without the needed medical supplies and experience provided at facilities and hospitals, unattended home births are directly associated with higher neonatal mortality rates, with increased complication risks and the lack of immediate diagnosis and treatment being key factors affecting mortality.

Effectively treating NE given its time-dependent prognosis remains out of reach for the people who need it most—the result is increased mortality and lifelong impairment, regardless of having a home or healthcare-facilitated birth. The mainstream solutions to bettering treatment in LMICs are not specific to NE, but rather targeted towards the broader idea of increasing medical facility usage and boosting standards of care. However, current methods should be revised to incorporate supporting home births as well. While increasing facility usage is indeed critical, the huge reliance on home births will not significantly decrease anytime soon. Supporting this population with knowledge and materials—such as portable maternal and neonatal health kits—holds major potential to better health outcomes for patients with NE.

Issues with Therapeutic Hypothermia

Not only is the diagnosis and treatment of NE inaccessible, but the standard treatment—therapeutic hypothermia—itself is deeply problematic in LMICs.

Therapeutic hypothermia, as commonly used in high-income countries, has been established to decrease mortality rates and increase neurological recovery in neonates.¹⁵ This relatively expensive treatment is inaccessible in LMICs. Moreover, recent findings reveal a glaring issue with the efficacy of therapeutic hypothermia in LMICs beyond the accessibility of cooling devices.

Most therapeutic hypothermia efficacy studies in the past have been conducted in high-income countries. In contrast, a 2013 meta-analysis focused on LMICs revealed that therapeutic hypothermia not only failed to reduce morbidity and mortality in LMICs, but even increased the neonatal death rate.⁹ The study then discouraged the use of therapeutic hypothermia in LMICs even when intensive care units were available. There exists a multitude of potential reasons behind this discrepancy. Ineffective cooling devices, low quality of neonatal care, and conditions such as malnutrition that disproportionately affect the maternal/neonatal population are all possible contributing factors.

This inconsistency with the efficacy of therapeutic hypothermia reveals a fundamental misconception in combating medical conditions globally: treatments are not blindly translatable between different environments. Funding the flow of medical equipment (like cooling blankets) is insufficient in battling diseases such as NE. Instead, more research needs to be done to establish an effective way to combat NE that takes account of the environmental and logistical conditions of individual LMICs.

Conclusion

Every aspect of combating NE is hindered by the conditions in LMICS: not only are diagnosis and treatment generally inaccessible, the gold-standard treatment plan itself is flawed when used in low-resource settings. To relieve the problem, however, means to dig deeper into two fundamental concepts: one, the lack of immediate support for home births, and two, the misguided translation of treatments between diverse environments. There are also several nuances to address. While it’s easy to simplify the disease, it’s also important to acknowledge the complexity of medicine in turbulent or low-resource settings—solutions are always more complicated in reality. Nevertheless, to shine light on specific issues—and potential solutions—still remains a critical part of the process toward global health equity.

References

1. Kukka AJ, Waheddoost S, Brown N, Litorp H, Wrammert J, KC A. Incidence and outcomes of intrapartum-related neonatal encephalopathy in low-income and middle-income countries: a systematic review and meta-analysis. BMJ Global Health. 2022 Dec;7(12):e010294.
2. Lawn JE, Cousens S, Zupan J. 4 million neonatal deaths: When? Where? Why? The Lancet. 2005 Mar;365(9462):891–900.
3. United Nations. The 17 Sustainable Development Goals [Internet]. United Nations. United Nations; 2015. Available from: https://sdgs.un.org/goals
4. Sell E, Munoz FM, Soe A, Wiznitzer M, Heath PT, Clarke ED, et al. Neonatal encephalopathy: Case definition & guidelines for data collection, analysis, and presentation of maternal immunisation safety data. Vaccine. 2017 Dec;35(48):6501–5.
5. Aslam S, Strickland T, Molloy EJ. Neonatal Encephalopathy: Need for Recognition of Multiple Etiologies for Optimal Management. Frontiers in Pediatrics [Internet]. 2019 Apr 16;7. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6477286/
6. Neonatal Encephalopathy. Riley’s Children’s Health. Indiana University Health; Available from: https://www.rileychildrens.org/health-info/neonatal-encephalopathy
7. Lee AC, Kozuki N, Blencowe H, Vos T, Bahalim A, Darmstadt GL, et al. Intrapartum-related neonatal encephalopathy incidence and impairment at regional and global levels for 2010 with trends from 1990. Pediatric Research. 2013 Dec;74(S1):50–72.
8. Mohammadi D. Neurology in resource-poor countries: fighting for funding. The Lancet Neurology. 2011 Nov;10(11):953–4.
9. Pauliah SS, Shankaran S, Wade A, Cady EB, Thayyil S. Therapeutic Hypothermia for Neonatal Encephalopathy in Low- and Middle-Income Countries: A Systematic Review and Meta-Analysis. PLoS ONE [Internet]. 2013 Mar 19; 8(3). Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3602578/
10. Campellone J, Wojcik S, editors. Neonatal Hypoxic-Ischemic Encephalopathy [Internet]. Nationwide Children’s. Available from: https://www.nationwidechildrens.org/conditions/health-library/neonatal-hypoxic-ischemic-encephalopathy
11. Aoki Y, Kono T, Enokizono M, Okazaki K. Short‐term outcomes in infants with mild neonatal encephalopathy: a retrospective, observational study. BMC Pediatrics. 2021 May 7;21(1).
12. Juan Sahuquillo, Anna Vilalta. Cooling the Injured Brain: How Does Moderate Hypothermia Influence the Pathophysiology of Traumatic Brain Injury. Current Pharmaceutical Design. 2007 Aug 1;13(22):2310–22.
13. Narayanan I, Nsungwa-Sabiti J, Lusyati S, Rohsiswatmo R, Thomas N, Kamalarathnam CN, et al. Facility readiness in low and middle-income countries to address care of high risk/ small and sick newborns. Maternal Health, Neonatology and Perinatology. 2019 Jun 18;5(1).
14. Montagu D, Yamey G, Visconti A, Harding A, Yoong J. Where Do Poor Women in Developing Countries Give Birth? A Multi-Country Analysis of Demographic and Health Survey Data. PLoS ONE [Internet]. 2011 Feb 28;6(2):e17155. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3046115/
15. Shankaran S, Laptook AR, Ehrenkranz RA, Tyson JE, McDonald SA, Donovan EF, et al. Whole-body hypothermia for neonates with hypoxic-ischemic encephalopathy. The New England journal of medicine [Internet]. 2005;353(15):1574–84. Available from: https://www.ncbi.nlm.nih.gov/pubmed/16221780/