A Global Need for Affordable Neonatal Jaundice Technologies

A Global Need for Affordable Neonatal Jaundice Technologies Tina M. Slusher, MD,* Alvin Zipursky, MD,† and Vinod K. Bhutani, MD, FAAP‡ Globally, health care providers worldwide recognize that severe neonatal jaundice is a “silent” cause of significant neonatal morbidity and mortality. Untreated neonatal jaundice can lead to death in the neonatal period and to kernicterus, a major cause of neurologic disability (choreoathetoid cerebral palsy, deafness, language difficulty) in children who survive this largely preventable neonatal tragedy. Appropriate technologies are urgently needed. These include tools to promote and enhance visual assessment of the degree of jaundice, such as simpler transcutaneous bilirubin measurements and readily available serum bilirubin measurements that could be incorporated into routine treatment and follow-up. Widespread screening for glucose-6-phoshate dehydrogenase deficiency is needed because this is often a major cause of neonatal jaundice and kernicterus worldwide. Recognition and treatment of Rh hemolytic disease, another known preventable cause of kernicterus, is critical. In addition, effective phototherapy is crucial if we are to make kernicterus a “never-event.” Finally it is essential that we conduct appropriate population-based studies to accurately elucidate the magnitude of the problem. However, knowledge alone is not sufficient. If we are to implement these and other programs and technologies to relegate severe neonatal jaundice and its sequelae to the history books, screening and interventions must be low cost and technologically appropriate for low and middle income nations. Semin Perinatol 35:185-191 © 2011 Elsevier Inc. All rights reserved. KEYWORDS affordable technologies, developing nations, hyperbilirubinemia, newborn jaundice, phototherapy, severe neonatal hyperbilirubinemia

My baby was born healthy in February 2009. At home, his whole body turned yellow after 4 days. We took him to a hospital, where he was tested and treated for severe jaundice. Part of the treatment was blood transfusion twice within 2 weeks. We were discharged after 3 weeks. Till date, my baby cannot sit, cannot control his neck. He has impaired eye movement, abnormal teeth stain, and the front part of his head still pumps in and out. A doctor here told me he has kernicterus. Please, can this situation be treated or reversed? (JN-Nigerian father; edited e-mail, used with permission, August 2010)

*Center for Global Pediatrics, University of Minnesota, MN. †Programme for Global Paediatric Research, The Hospital for Sick Children, Toronto, ON, Canada. ‡Division of Neonatal-Developmental Medicine, Department of Pediatrics, Stanford University School of Medicine and Lucile Packard Children’s Hospital, Stanford, CA. Address reprint requests to Tina M. Slusher, MD, Associate Professor of Pediatrics Center for Global Pediatrics, University of Minnesota, Rm 362 Mail Cod 1932, 717 Delaware Street SE, Minneapolis, MN 55414. E-mail: [email protected]

0146-0005/11/$-see front matter © 2011 Elsevier Inc. All rights reserved. doi:10.1053/j.semperi.2011.02.014

T

his man’s story is pathetic; however, it reflects a global problem, namely the failure to recognize, prevent, and treat severe neonatal hyperbilirubinemia. Bilirubin-induced brain damage (kernicterus) is rare in developed countries but it is all too common in developing countries. This article clearly describes that what is required to prevent this disorder is application of known technology and implementation of a system of prevention and treatment. The Nigerian father’s story should be a sad note of the past; in the future kernicterus should no longer occur anywhere in the world.

Global Burden of Severe Hyperbilirubinemia and Kernicterus Newborn jaundice should usually be a benign condition for most infants.1 However, in some infants whose severe hyperbilirubinemia is unmonitored and/or untreated, it may result in death or acute bilirubin encephalopathy.2,3 Kernicterus or chronic bilirubin encephalopathy continues to be reported but not accurately recorded by current epidemiologic statis185

T.M. Slusher, A. Zipursky, and V.K. Bhutani

186

Table 1 A “Global” Snapshot of Frequency of Severe Neonatal Hyperbilirubinemia Encountered Among Clinical Practices With Diverse Public Health Infrastructures People’s Republic of China Source of admission (local database) TSB > 20 mg/dL, 342 ␮mol/L % TSB > 25 mg/dL, 427.5 ␮mol/L % severe ABE % exchange % not normal % MORTALITY % G6PD deficiency Time frame Data provided by

Referrals

262

Iraq

Vietnam

Referrals

Referrals

Public

India Private

Infants referrals for jaundice vary by local practice 162 615 644

81

31

23

— 48 69 10.1 11.8

52 62 31 12 4

14 22 — 0.05 8.3 2 years Le et al*

1 year Lizhong et al*

Egypt

4 mo Hameed et al*

Inborn 7623 95

0/289

TSB: 19-38

0

44.4 41 26 12.6 G-6-PD? Similar causes Comparison (1 year) Iman Soud et al*

0 0 0 0

19 — 62 — 0 22 2 years Kumar et al*

ABE, acute bilirubin encephalopathy; G-6-PD, glucose-6-phoshate dehydrogenase; TSB, total serum bilirubin. *Personal communication from these physicians for the data provided.

tics.4 Despite limited published data, health care providers worldwide recognize that severe neonatal jaundice is a “silent” cause of significant neonatal morbidity and mortality. Table 1 lists the magnitude of the disease burden for nations with variable public health infrastructures. These data are based on personal communications provided by lead national investigators. In 2002, the National Quality Forum suggested that kernicterus should be classified as a “serious reportable event,” sometimes termed a “never or an avoidable event,” implying that with appropriate monitoring, surveillance, and intervention, this devastating condition can, or should, be eliminated.5,6 In certain circumstances (notably, glucose-6-phoshate dehydrogenase [G-6-PD] deficiency, sepsis, genetic predisposition, or other unknown stressors), acute, severe hyperbilirubinemia can occur and can produce brain damage despite appropriate monitoring and interventions. Several studies from Africa rank jaundice as the second or third cause of death in newborn.7-9 Ugwu et al10 found that severe jaundice caused a similar number of deaths as birth asphyxia and even more deaths than sepsis in infants ⬎24 hours old. In a recent ongoing study in Nigeria, among the first 320 infants enrolled 113 (37.9%) had exchange blood transfusions, and 45 (14%) had acute bilirubin encephalopathy (ABE; T.M.S., unpublished data). In Kenya, English et al8 reported that newborn jaundice was the third-leading cause of both newborn admissions and deaths. Studies from Kenya, Zimbabwe, Turkey, Egypt, and India list ABE and/or severe neonatal jaundice as a significant cause of morbidity in their nurseries.11-15 Numerous other nations in the developing world (North Vietnam, Oman, Turkey, India, China, Iraq) also report large numbers of infants with ABE,13,15-20 many of whom required exchange transfusions, which often were not available. Importantly, even phototherapy is not available to many infants with neonatal jaundice in these countries because of a lack of devices for delivery of effective phototherapy and/or of electricity to power the devices.21,22

Need for Technologies for Worldwide Application In a recent independent review of literature predominantly from developed nations with intact health care systems, the U.S. Preventive Task Force opined that a study that directly evaluates the effectiveness of different strategies to reduce the incidence of kernicterus is not feasible “given the rare occurrence of kernicterus.”23 The likelihood of an unmonitored or untreated newborn jaundice would occur in communities with a fragile, underdeveloped, or fractured public health system; recent reports from the worn-torn Baghdad estimated 1764 cases of ABE/100,000 live-births during a 4-month period in 2010.20 For practical consideration, studies on the effectiveness of different strategies to reduce the incidence of bilirubin encephalopathy can only rely on surrogate acute outcomes like serum bilirubin level, readmission for phototherapy, use of exchange transfusions or neonatal mortality associated with jaundice.24

Need for Visual Assessment of Jaundice All infants should be routinely monitored for the onset and progression of jaundice for further assessment (Fig. 1). Jaundice can be detected by blanching the skin with digital pressure on the forehead, midsternum or the knee/ankle to reveal the underlying color of the skin and subcutaneous tissue.25 Jaundice extent had poor overall accuracy for predicting risk of significant hyperbilirubinemia in term infants (c-statistic ⫽ 0.65). Clinicians should not solely rely on cephalo-caudal jaundice progression to estimate bilirubin levels or to predict subsequent severe neonatal hyperbilirubinemia.26 Progression of newborn jaundice to severe neonatal hyperbilirubinemia, estimated incidences based on reports from facilities that have tracked and

Affordable neonatal jaundice technologies

187 severe hyperbilirubinemia and validated by several other prospective studies. Bilirubin screening has a good ability to detect subsequent hyperbilirubinemia (Table 3): reported area-under the-curve (c-statistic) values range between 0.84 and 0.96, and reported sensitivities and specificities suggested similar diagnostic ability.29 TcB testing is a potentially accurate and noninvasive alternative to TSB measurement under specific conditions. However, TcB levels can be unreliable during phototherapy or with exposure to sunlight because of the bleaching effect of light on the skin, confounding effects of skin melanin content among different races and manufacturing inconsistencies among devices.28

Figure 1 A community-based tool to track progression of jaundice (may be complemented with a selective use of a transcutaneous or objective measure of skin color).

monitored these infants, and suggested clinical interventions are listed in Table 2.

Need for Bilirubin Testing On the basis of retrospective analyses among infants who had both early and late total serum bilirubin (TSB) measurements available, the combination of risk factors and early TSB measurement has better diagnostic ability to predict clinically significant hyperbilirubinemia compared with risk factors alone.27 Current convincing consensus and reported evidence has led an Expert American Association of Pediatrics Panel to recommend universal predischarge bilirubin screening via the use TSB, at the time of routine metabolic screening, or transcutaneous bilirubin (TcB) measurements, which help to assess the risk of subsequent severe hyperbilirubinemia.28 The panel also provides a more structured approach to management and follow-up according to the predischarge TSB/TcB, gestational age, and other clinical risk factors for hyperbilirubinemia. TSB/TcB measurement plotted on an hourspecific nomogram are the only currently available clinical tests that can be used to predict the risk of subsequent

Need for G-6-PD Screening An estimated 200-400 million people worldwide are G-6-PD deficient, and 7.5% of the global population carry 1 or 2 genes for the condition.30 Because it is an X-linked condition, the frequency of functional G-6-PD deficiency is expressed as the proportion of males in any given population found to be hemizygous for the condition. A further 10% of the enzyme-deficient population comprises female homozygotes, and an additional 10% may comprise heterozygotes who, because of non-random X-chromosome inactivation, may be phenotypically G-6-PD deficient.30 It is a major contributing cause to neonatal hyperbilirubinemia, both historically and in recent times.31-35 Recent reports of G-6-PD deficiency as a major etiologic factor for kernicterus emanate from countries, such as Greece, Hong Kong, Turkey, Nigeria, Oman, and India emphasizing it is indeed a global phenomenon.15,16,36-41 However, similar cases have been reported in developed nations, including the United States, in which the overall incidence of G-6-PD deficiency is low (Table 4), and in which G-6-PD deficiency is not ordinarily recognized as being a health hazard.42 The Pilot Kernicterus Registry reported 26 of the 125 (20.8%) newborns with kernicterus because of G-6-PD deficiency2 an association that is many-fold the estimated general frequency of the condition in the US (0.52.9%).42 In Canada, where even fewer individuals in the en-

Table 2 Progression of Newborn Jaundice to Severe Hyperbilirubinemia and Suggested Clinical Action Clinical Event

Incidence* (Range)

Action

Analogy

Newborn jaundice Bilirubin >75th percentile for age (hours) Bilirubin >15 mg/dL

60%-85% 25%-30% 8%-12%

Bilirubin screening Evaluate and treat Consider use of phototherapy For bilirubin rate of rise >5 mg/dL/24 h Emergency procedure for any neurologic signs Intensive monitoring for lifesaving interventions

“Use of a seat belt” “Safety precaution” “Effective Prevention”

Use of intensive phototherapy

4%-8%

Use of exchange transfusion

Rare event

Bilirubin level >30 mg/dL†

Avoidable event

“Crash-cart approach” “Crash Landing” “Sentinel Event”

*Estimated range, based on cumulative review of literature. †At facilities with limited access to intensive newborn care, this threshold for referrals may be lowered to 20-25 mg/100 mL, on the basis of local experiences.

T.M. Slusher, A. Zipursky, and V.K. Bhutani

188

Table 3 Summary of Studies that Used Predischarge Risk Assessment to Predict High Late Bilirubin Measurements

Author, Year

Study Design

Number Enrolled

Keren et al, 200926

PC

522

Sarici et al, 200452

PC

366

Keren et al, 200553

993

Newman, 200554

Retrospective SC Retrospective MC Nested case control (MC) Nested case control (MC) Retrospective SC Retrospective

Keren et al, 200827

PC

823

Keren et al, 200827

PC

823

Keren et al, 200827

PC

823

Newman, 200554 Newman, 200554

Newman et al, 200055

Keren et al, 200553

High Bilirubin Predicted

Predischarge Risk Assessment

Visual assessment of jaundice >95th percentile Early TSB, plotted (by age <7 days) on nomogram >95th percentile Clinical risk (by age <7 days) factors >20 mg/dL (by 48 hours) Clinical risk factors >25 mg/dL (by 30 days) Clinical risk factors

0.71 [0.66-0.76]

496

>25 mg/dL (by 48 hour)

Clinical risk factors

0.84 [0.79-0.89]

996

>95th percentile (by age <7 days) >20 mg/dL

Early TSB, plotted on nomogram Early TSB, plotted on nomogram Early TcB, plotted on nomogram Clinical risk factors Combined clinical ⴙ bilirubin risk

0.83 [0.80-0.86]

5706 275

5706

>95th percentile (by age <7 days)

AUC [95% Confidence Interval]

>95th percentile (by age <7 days) >95th percentile (by age <7 days) >95th percentile (by age <7 days)

0.65 [0.50-0.80]

—

0.69 — 0.83 [0.77-0.89]

0.83 [0.80-0.85] 0.92 [0.89-0.95] 0.91 [0.86-0.96] 0.96 [0.93-0.98]

AUC, area under the curve; MC, multicenter; PC, prospective cohort; RC, retrospective cohort; SC, single center; TSB, total serum bilirubin; TcB, transcutaneous bilirubin.

tire population are expected to be affected (⬍0.5%), of 12 newborns with kernicterus encountered in Toronto between 1990 and 2000, 7 (58%) were G-6-PD deficient.43 More recently (2002-2004), of the 258 cases of severe neonatal hyperbilirubinemia (TSB ⬎25 mg/dL or having had an exchange transfusion), in 93 newborns a cause could be found for their severe hyperbilirubinemia and 20 (21.5%) were G-6-PD deficient.44 In the United Kingdome and Ireland, of 108 newborns with extreme neonatal hyperbilirubinemia (30 mg/dL) G-6-PD deficiency independently increased the risk of encephalopathy many fold (odds ratio 28.2, 95% confidence interval 2.6-307.7).45

Need for Recognition and Prevention of Kernicterus Attributable to Rh Hemolytic Disease It has not been recognized that Rh disease is a significant cause of kernicterus in developing countries. However, it is estimated that annually, in low income countries, 100,000 cases of Rh hemolytic disease of the newborn occur, resulting in death or bilirubin induced brain damage.46 The disease is preventable through screening and prevention of Rh isoim-

Table 4 Frequency of G-6-PD Deficiency Among US Military Recruits (Adapted from Kaplan et al32) Gender Differences of G-6-PD Deficiency

Ethnicity of Recruits Tested for G-6-PD Deficiency

Total Recruits Tested

Male Recruits Tested

Percent Male With G-6-PD Deficiency

Percent Female With G-6-PD Deficiency

African American Asian Hispanic Caucasian American Indian/Alaskan Other Total

11,276 2123 5304 42,126 604 1869 63,302

8513 1658 4462 38,108 492 1643 54,876

12.2 4.3 2.0 0.3 0.8 3.0 3.43%

4.1 0.9 1.2 0.0 0.9 1.8 1.48

G-6-PD, glucose-6-phoshate dehydrogenase; US, United States.

Affordable neonatal jaundice technologies

189

Need for Evaluation for Cause of Infant Mortality

Figure 2 Irradiance distribution of audited Nigerian phototherapy devices (n ⫽ 77). From Cline BK, Vreman HJ, Faber KL, et al: Phototherapy device effectiveness in Nigeria: current irradaince levels and simple strategies for improvement: Accepted for poster presentation at the Pediatric Academic Societies Annual Meeting at Denver, CO, April 30 to May 3, 2011. E-PAS2011:754-766. Audit of PT devices in Nigeria (n ⫽ 77), unpublished (with permission). AAP recommendation for effective phototherapy is an irradiance level ⬎30 ␮W/cm2/nm.

munization of Rh negative women. Affected infants can be diagnosed and treated with existing technology.

Need for Effective Phototherapy Use of effective phototherapy (PT) has dramatically reduced the need for exchange blood transfusions in the developed world.47,48 However, exchange transfusions are indicated for infants admitted for acute bilirubin encephalopathy. Often, these life-saving procedures are performed under suboptimal conditions in an environment where infectious complications are real and intensive monitoring is impaired. Unnecessary procedures are often conducted because of delayed intervention or use of ineffective PT. Limited data from the developing world suggest that PT is often suboptimal.49,50 In one study in Nigeria, none of the PT units in 12 referral nurseries provided intensive PT, and only 6% of the 63 devices provided irradiances of ⬎10 ␮W/cm/nm (Fig. 2). With effective PT bilirubin levels usually fall significantly in the first 24 hours of therapy, thus eliminating the need for most exchange transfusions. Simple and inexpensive measures can be taken to improve the quality of phototherapy provided. Two of these measures to improve the irradiance are to lower the phototherapy units to 10-15 cm above the infant when possible and expose maximal body surface exposure. Other practical measures for improving the quality of phototherapy include using special blue bulbs, changing of phototherapy bulbs at the recommended 2000 hours, or use of white slings around phototherapy devices. In addition, there is a need to develop low-cost devices that do not require continuous electricity, including sunlight filters, solar-powered devices, and battery-operated devices. Recognition of the need to prescribe effective phototherapy is key to preventing severe hyperbilirubinemia, acute bilirubin encephalopathy and kernicterus.

Efforts to reduce or eliminate the sequelae of severe neonatal hyperbilirubinemia are hampered by an inability to quantify the magnitude of the problem. Studies by the global health agencies have been limited by lack of an appropriate survey instrument to accurately determine the percentage of infants with ABE in the community. Recently, the World Health Organization published Standard Verbal Autopsy Method for Investigating Causes of Death in Infants and children to provide a tool for health care workers to arrive at a reasonable cause of death in countries where systems for recording deaths are not well developed, or where most deaths occur outside of medical facilities.51 This verbal autopsy tool uses a structured interview with the next of kin (or significant others) for these mortality investigations. Specific questions suggestive of severe hyperbilirubinemia, ABE and kernicterus, for example, questions about shrill or high-pitched cry, paralysis of upward gaze, and tone change different from those in tetanus are absent in this questionnaire.

Need for Affordable Technologies and to Provide for a “Safer First Week After Birth” Earlier experiences and knowledge of the “know-do” gaps that span private versus public healthcare systems among emerging nations have led us to conclude that building an interdisciplinary leadership approach to provide innovative strategies and affordable technologies will bridge the existing social and access barriers in micro- and macro-health environments. At the newborn jaundice workshops held at The Programme for Global Pediatric research during the Pediatric Societies meeting in 2009 and 2010, a consensus for research and/or health-system evaluation questions to promote implementation a “Safer First Week” after birth was promoted to reduce Neonatal Mortality and Morbidities (including severe neonatal hyperbilirubinemia [Appendix 1]). To meet these global objectives, we propose 2 strategic goals: (i) to develop an interdisciplinary mentoring program to train future local leaders engaged in the health care delivery and services of maternal child health and (ii) to convene an interdisciplinary study group (network) composed of worldwide experts to conduct, guide, and implement multifaceted strategies for both clinical practice and testing of newborn jaundice technologies. Safe and effective care of both healthy and sick infants requires seamless transition from a birthing facility to home following discharge and potential need for expert management. Providing for a warm, safe, and nurturing environment that allows for secure monitoring and prevention of neonatal illnesses is integral to “good clinical practice.” Of these, the unacceptable occurrence of severe hyperbilirubinemia and kernicterus are emblematic of a fractured or a fragile maternal child health care system, with inadequate monitoring during the first week after birth. The Baghdad experiences indicate the dramatic consequences of a fractured maternal child

T.M. Slusher, A. Zipursky, and V.K. Bhutani

190 health infrastructure.20 Thus, implementation of evidencebased strategies to “Screen and Prevent” severe neonatal hyperbilirubinemia serves as the ideal entry initiative to this arena. Our ability to design, test and implement jaundice related technologies will serve as a template for other and future affordable newborn health products.

21. 22. 23.

Conclusions This report has described the terrible global problem of neonatal hyperbilirubinemia and resultant brain damage. This is a preventable and/or treatable disorder that demands only application of existing technology and a system of care that can prevent and treat the problems. The global problem of kernicterus can be prevented.

24.

25. 26.

27.

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Appendix: 1 Research and/or Evaluation Questions to Promote Implementation of a “Safer First Week” after Birth to reduce Neonatal Mortality and Morbidities (including Severe Neonatal Hyperbilirubinemia) (A) CHWs as SFW caregivers 1. Effect of added responsibility? 2. Ability to understand the natural history of disease and integrate to a “safer first week?” 3. Barriers to sustain quality performance of clinical assessment and technologies? 4. Cost factors for training and mentoring CHWs with diverse skills and learning potential? 5. Identification of best practice performances by CHW? 6. Define ideal personnel assignment to optimal technology performance? 7. Define strategies to mentor and peer-review CHWs? 8. Identify barriers to recruitment and prevention of attrition? 9. Advocacy and assessment for optimal remuneration/incentives for effective and sustained performance? (B) Implementation issues for an SFW program 1. What is the cost and cost-effectiveness of integrated “safer first week program?” 2. Which are appropriate methods for cost recovery and financing? 3. How can effective coverage be achieved through a “safer first week program” (e.g., equity, community effectiveness, etc.)? 4. Identify role of community and private sector to deliver integrated “safer first week program?” 5. How acceptable are CHWs to the regional health system and how can requirements for technologies, supplies, supervision, etc. be met? 6. What are regional healthcare effects on referral, transport and case-load and case mix? 7. What is the effect of a “safer first week program” on the community? (C) Impact of a SFW program 1. What is the impact of integrated “safer first week program” on health and survival of neonates? 2. Does a “safer first week program” lead to increased penetration in reaching the poor? (effective coverage) (D) Management of Illnesses during the first week after birth 1. How can emerging affordable technologies (bilirubin screening devices, laboratory-on-a-chip, effective phototherapy) be combined into clinical algorithms of “screen and prevent?” 2. What is the “screen and prevent” algorithm performance in different epidemiologic settings? 3. What is the appropriate duration of phototherapy treatment of moderate hyperbilirubinemia? 4. Can CHWs treat severe neonatal hyperbilirubinemia in the community? 5. What is the impact of universal screening on clinical outcomes of neonates at risk for severe hyperbilirubinemia? 6. How can infants with severe hyperbilirubinemia at risk for exchange transfusion be transported safely to regional centers? 7. What is the most appropriate and effective phototherapy device that has least energy and maintenance burden? 8. What are the most appropriate strategies to evaluate and trouble shoot for optimal technology performance? E. Families and community caregivers 1. Do family members recognize the onset and progression of jaundice to seek prompt care? 2. What are the elements that facilitate family members to use CHW services? 3. Do family members understand and follow treatment recommendations? 4. How do multiple interventions for multiple clinical issues (eg, low-birth weight, sepsis, poor breastfeeding) impact on family capacity to provide care? F. Training of expert care givers 1. Ensure that pediatric residency training programs (wordwide) include standardized and evidence based approaches to global child health issue. 2. Ensure that global pediatric health training opportunities are strategically chosen, designed and harmonized. 3. Mentorship and leadership training are critical elements of pediatric training. CHW, community health workers; SFW, safe first week.