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Confidential: For Review O

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The burden of severe neonatal jaundice: a systematic

review and meta-analysis

Journal: BMJ Paediatrics Open

Manuscript ID bmjpo-2017-000105

Article Type: Review

Date Submitted by the Author: 26-May-2017

Complete List of Authors: Slusher, Tina; University of Minnesota Academic Health Center, Pediatrics Zamora, Tara; University of Minnesota Academic Health Center, Pediatrics Appiah, Duke; Texas Tech University Stanke, Judith; University of Minnesota Academic Health Center, Biomedical Library Strand, Mark; North Dakota State University, Pharmacy

Lee, Burton; University of Pittsburgh Department of Medicine, Medicine Richardson, Shane; University of Arizona Arizona Health Sciences Center, Family Medicine; Valley-Wide Health Systems Inc Keating, Elizabeth; Baylor College of Medicine, Pediatrics Olusanya, Bolajoko; College of Medicine, University of Lagos, MCH Unit, Dept of Community Health

Keywords: Neonatology, Jaundice

https://mc.manuscriptcentral.com/bmjpo

BMJ Paediatrics Open


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Title: The burden of severe neonatal jaundice: a systematic review and meta-analysis

Short Title: Burden of severe neonatal jaundice

Slusher TM§1,2, Zamora TG

1, Appiah D

3, Stanke JU

4, Strand MA

5, Lee BW

6, Richardson

SB7, Keating EM

8, Olusanya BO

9,

§Tina M. Slusher, MD 1Professor of Pediatrics, University of Minnesota, Minneapolis, MN 55414 2Hennepin County Medical Center, Minneapolis, MN 55415, USA. Email: [email protected] Tara G. Zamora, MD 1Assistant Professor of Pediatrics, University of Minnesota, Minneapolis, MN 55414

Duke Appiah, PhD 3Assistant Professor, Texas Tech University Health Science Center, Abilene, TX, 79601 Judith U. Stanke, MA 4Reference Librarian, Biomedical Library, University of Minnesota, Minneapolis, MN 55455 Mark A. Strand, PhD 5Professor of Pharmacy, North Dakota State University, Fargo ND 58108 Burton W. Lee, MD 6Professor of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213 Shane B. Richardson, MD 7Resident, Department of Family Medicine, University of Arizona, Tucson, AZ 85721 Elizabeth M. Keating, MD 8Resident, Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030 Bolajoko O. Olusanya, MBBS, PhD 9Director, Center for Healthy Start Initiative, Ikoyi, Lagos, Nigeria

§Corresponding Author Address correspondence and requests for reprints to: Tina M. Slusher, University of Minnesota-Division of Global Pediatrics, 701 Park Avenue, MC G7, Minneapolis, MN 55415. [email protected], Phone: (612) 840-8883; Fax: (612) 904-4295 Dr. Tina Slusher wrote the first version of the manuscript. Dr. Slusher received no honorarium, grant, or other form of payment.

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Funding Source: Support for the quantitative analysis was provided in part by The Programme for Global Paediatric Research, Centre for Global Child Health, The Hospital for Sick Children, Toronto, Canada. The sponsor had no role in study design, data collection, data analysis, data interpretation, or writing of the report. Key Words: Kernicterus; Exchange transfusion; acute bilirubin encephalopathy; population-based study Financial Disclosure: The authors have no financial relationships relevant to this article to disclose. Competing Interests: The authors have no competing interests relevant to this article to disclose. All authors have completed the Unified Competing Interest Form and they corresponding author has these forms.

Abbreviations:

ABE acute bilirubin encephalopathy ET exchange transfusion LMICs low middle-income countries SNJ severe neonatal jaundice AME Region of the Americas

AFR African Region EMR Eastern Mediterranean Region EUR European Region SEA South-East Asian Region WPR Western Pacific Region

Contributor’s Statement:

Drs. Slusher and Olusanya conceptualized and designed the study, acquired data, analyzed and interpreted data, supervised the study, drafted the manuscript, and conducted a critical revision of the manuscript for intellectual content and approved the manuscript as submitted. Dr. Zamora conceptualized and designed the study, and assisted with acquiring data and approved the manuscript as submitted. Dr. Keating and Ms. Stanke were responsible for acquisition of data as well as providing administrative, technical and material support and approved the manuscript as submitted. Dr. Richardson was responsible for acquisition of data, analyzing and interpreting data, and provided administrative, technical and material support and approved the manuscript as submitted. Drs. Appiah, Strand, and Lee, analyzed and interpreted the data, conducted the statistical analysis, and conducted a critical revision of the manuscript for important intellectual content and approved the manuscript as submitted. All authors had full access to all data, take responsibility for the accuracy and integrity of the data, and approved the manuscript as submitted. Transparency Declaration: As the lead author, Dr. Slusher affirms that the manuscript is an honest, accurate, and transparent account of the study being reported, no important aspects of the study have been omitted, and any discrepancies from the study as planned have been explained.

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What this paper adds

What is already known on this subject: • Acute bilirubin encephalopathy, exchange transfusions, and death are frequent and costly

outcomes of severe neonatal jaundice especially in low resource setting • Long term disabilities including cerebral palsy and deafness can occur following acute

bilirubin encephalopathy • The actual burden of severe neonatal jaundice is not well documented

What this study adds: • A population based review of literature to assess the global impact of severe neonatal

jaundice highlighting the importance of this disease as defined by its clinical presentations

• Objective evidence that the burden of severe neonatal jaundice is not evenly distributed and that a heavier burden of disease is born by low resource settings

• The limited amount of population based data currently available and the need to capture this information globally

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Abstract

CONTEXT: To assess global burden of late and/or poor management of severe neonatal jaundice

(SNJ), a common problem worldwide, which may result in death or irreversible brain damage with

disabilities in survivors. Population-based data establishing the global burden of SNJ has not been

reported.

OBJECTIVE: Determine SNJ burden in all World Health Organization (WHO) regions, as

defined by clinical outcomes alone including acute bilirubin encephalopathy (ABE)/kernicterus

and/or exchange transfusion (ET) and/or jaundice-related death.

DATA SOURCES: PubMed, Scopus, and other health databases were searched, without language

restrictions, from 1990-2014 for studies reporting the incidence of SNJ.

STUDY SELECTION/DATA EXTRACTION: Stratification was performed for WHO regions

and results were pooled using random effects model and meta-regression.

RESULTS: Overall, 604 articles were reviewed with 324 including at least one marker of SNJ.

Only 18 English articles representing all WHO regions had population-based estimates and 13/18

(72%) were from high-income countries. The African Region (AFR) has the highest incidence of

SNJ per 10,000 livebirths at 667.8, followed by South-East Asian (SEA), Eastern Mediterranean

(EMR), Western Pacific (WPR), American (AME), and European regions (EUR) at 251.3; 165.7;

91.9; 3.7 and 6.2 respectively. The incidence of ET per 10,000 livebirths was significantly higher

for AFR and SEA regions at 186.5 and 107.1and lower in EMR (17.8), AME (0.41), and EUR

regions (0.35). Only 3 studies provided estimates of jaundice-related deaths [UK (2.8%), India

(30.8%) and Pakistan (50.0%)].

CONCLUSIONS: Compelling but limited evidence demonstrates that SNJ is associated with a

significant health burden especially in low-middle-income countries.

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Introduction: Newborn jaundice occurs in up to 85% of all livebirths.1-3 In the absence of

hemolysis, sepsis, birth trauma, or prematurity, it usually resolves within 3-5 days without

significant complications.1 However, epidemiological evidence suggests that severe neonatal

jaundice (SNJ) results in significant morbidity and mortality.4 Severe neonatal jaundice has been

recognized as a significant cause of long-term neurocognitive and other sequelae, namely cerebral

palsy, non-syndromic auditory neuropathy, deafness, and learning difficulties with acute

manifestation termed acute bilirubin encephalopathy (ABE).5,6 The burden is unacceptably high in

low and middle-income countries (LMICs) and has prompted calls for intense scrutiny and

attention.4 Under the erstwhile era of millennium development goals, the potential impact of

adverse perinatal conditions such as preterm birth complications and birth asphyxia on thriving

and well-being beyond survival rarely received any attention.7 With the current focus on

inclusiveness for persons with disability under the sustainable development goals (SDGs), it is

essential that we tackle SNJ as one key component of optimizing neurodevelopment, besides

reducing neonatal mortality.7,8

A recent report by Bhutani et al4, noted that at least 481,000 term and near-term infants are

affected by severe neonatal hyperbilirubinemia (jaundice) each year, with 114,000 dying and an

additional 63,000 surviving with kernicterus. However, these alarming estimates were based on

limited data determined by mathematical modeling as true population based data is limited and

difficult to find. Therefore, the incidence of SNJ and thus its contribution to global neonatal

morbidity and mortality presently remain unclear and possibly significantly under-estimated.

Phototherapy and exchange transfusion (ET) are the most widely used therapeutic modalities for

jaundice.2 However, due to constrained resources, devices for measuring bilirubin9,10 and effective

phototherapy are often lacking in LMICs.11 This, together with higher prevalence of glucose-6-

phosphate dehydrogenase (G6PD) deficiency, blood group incompatibilities, late referrals and

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delayed recognition of excessive bilirubin levels in resource-limited settings has necessitated

excessive use of ETs.12 13

We systematically reviewed the available evidence pertaining to the global burden of SNJ to

inform child health policy regarding its prevention and management especially in LMICs.

Methods

Search Criteria

We systematically reviewed published papers following PRISMA guidelines.13 We searched Ovid

Medline, PubMed, CINAHL, Global Health, Scopus, Popline, Africa Journal Online (AJOL),

Bioline, Cochrane and Ovid Medline In-Process and Non-Indexed Citation databases for

published articles on severe jaundice. We used both controlled subject headings and free-text

terms for neonatal jaundice, jaundice, bilirubin/blood levels, hemolytic anemia, G6PD deficiency

in various forms and in combination with terms for ET, ABE, kernicterus, death, mortality, and

phototherapy. The search results were limited to publication dates of 1990-2014 and to infants

≤24 months old. See Appendix 1 online for complete Ovid Medline search strategy.

We also reviewed references of selected retrieved articles and review papers, and contacted

authors of relevant articles for missing dates. No language restrictions were used. To be included,

a study must have reported estimates of incidence from a retrospective or prospective population-

based study, making it more likely that estimates obtained could be generalized to the geographic

location where the study was conducted. Other inclusion criteria were the report of

jaundice/jaundice in the first month of life; availability of data on incidence of ABE/ kernicterus;

provision of information on the incidence of ETs for SNJ; or recorded deaths related at least in

part to jaundice/jaundice (Appendix 2 online).

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For this review, ABE and kernicterus are used interchangeably in line with the practice in earlier

literature, although terms were subsequently clarified.14 Most SNJ occurs at TSB levels >20 mg/dl

(343 µmol/L). However, there is no standard or widely accepted definition of SNJ, or clinically

significant TSB necessitating medical intervention especially when confounded by risk factors

pertinent in LMICs. Therefore, in this review, jaundice associated with ET, ABE, or jaundice-

related/associated death (i.e.deaths at least partially related to jaundice/jaundice or ET) was

considered severe.

Data extraction

Two authors (TMS, TGZ) examined studies using a predetermined checklist (Appendix 2 online)

devised by three authors (TMS, TGZ, BOO) for selecting articles that met inclusion criteria after

one author (TMS) screened titles and abstracts. Both TMS and TGZ independently confirmed

eligibility of all full text articles. Discrepancies were resolved by discussion and when needed by a

third author (BOO). From each retrieved article, the following data was extracted: publication

year, study design, country, WHO region, sample size, definition of SNJ, and outcomes (ET,

ABE, mortality). Articles were excluded if they enrolled all infants before January 1990 or were

published after December 2014, had a sample size <10, reported use of ET for conditions

unrelated to jaundice, or failed to define neonates as having ABE, ET or jaundice-related death

(e.g., hearing loss or changes in auditory brainstem response alone without frank ABE).

Additionally, dissertations or unpublished manuscripts were excluded. In 42 reports, the study met

entry criteria but lacked study dates. Two authors (EMK, TMS) contacted study authors and

attempted to retrieve this data. Nine of 42 authors responded, five of whom provided additional

data and were included.

Quality assessment

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The methodological quality of included articles was reviewed and cross-checked by two authors

(TMS, SBR). Due to lack of a relevant standardized quality scoring system for relevant

observational studies, we chose to examine four important components of quality/risk of bias

assessment: selection of subjects (representativeness), case definition for SNJ (exposure

ascertainment), diagnostic criteria for jaundice and outcome measurement (see Appendix 3

online). Study quality was judged based on the number of criteria that were met: all 4 (high), 2-3

(medium), or 1 (low). Two authors (DA, TMS) determined which studies were population based.

Disagreements between authors were resolved through consensus after joint reassessment.

Statistical analysis

For the meta-analysis, when multiple reports were obtained from the same study population with

overlapping study years, the one providing sufficient data (i.e., numerator and denominator data)

to derive estimates of disease burden was selected. To facilitate meta-analytical techniques,

estimates of incidence were logit transformed to enable them to correspond to probabilities under

the standard normal and permit use of the normal distribution for significance testing. Pooled

estimates were calculated using DerSimonian and Laird’s random effects method, weighting

individual study estimates by the inverse of the variance of their transformed proportion as study

weight, with their 95% (CI) determined using Clopper-Pearson exact binomial method15. For

presentation, pooled transformed estimates were back transformed. Statistical heterogeneity

among studies was investigated using Cochran’s Q test and I2 with a conservative P value less than

0.1 chosen as the level of significance. Forest plots then were used to examine the overall effects

while funnel plots were produced to assess the presence of publication bias. Exploration of

potential sources of heterogeneity was undertaken using meta-regression. All analyses were

conducted using R Statistical Software.16

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Results

Search of electronic databases identified 6673 articles (Figure 1). Six-hundred and four papers

were reviewed. After excluding studies not meeting inclusion criteria for SNJ and/or dates, 324

studies were selected for further review. Multiple languages (Chinese, English, Farsi, French,

German, Hebrew, Italian, Norwegian, Polish, Portuguese, Serbian, Spanish) were represented

although all but 19/324 were English language articles. Of these, 324 papers included at least one

marker of SNJ but only 18 provided population-based data on 4,975,406 neonates and all were in

English. Thirteen (72%) were from high-income countries and 11 (61%) used a prospective cohort

design. See summary (Appendix 4 online).

The incidence of SNJ per 10,000 livebirths was highest in the African (AFR) region at 667.8,

followed by South-East Asian (SEA) at 251.3, Eastern Mediterranean (EMR) with 165.7 and

Western Pacific (WPR) region with 91.9. The American (AME) and European (EUR) regions

each had a substantially lower incidence of 3.7 and 6.2 respectively (Table 1).

The incidence of ET per 10,000 livebirths was significantly higher for the AFR (186.5) and SEA

(107.1) regions and lower in the EMR, AME and EUR regions reporting estimates of 17.8, 0.41,

and 0.35 respectively (Table 2).

Overall, incidence estimates of SNJ from high-income countries tended to be lower compared to

LMICs (Figure 2). High-quality studies tended to report lower incidence compared to low-

moderate-quality studies (Appendix 5 online). With regards to the sample included in the studies,

those which enrolled all neonates regardless of GA had a higher incidence of SNJ compared to

studies enrolling only term/near-term. (Appendix 6 online).

Visual inspection of funnel plot in which the incidences of SNJ were plotted against their standard

errors showed asymmetry. This was confirmed by formal tests of publication bias (Begg-

Mazumdar test: P = 0.063, Egger: bias, P = 0.001). The observed heterogeneity between studies

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may explain the asymmetric funnel plots. In random effects meta-regression analyses, we

observed that study design and duration, income classification of country, and GA of neonates

included in the study jointly explain 82.4% of the observed between-study heterogeneity.

Only three studies provided information on jaundice-related deaths with estimates of 2.8, 30.8 and

50.0 for UK (EUR), India (SEA) and Pakistan (EMR), respectively (Appendix 7 online). PRISMA

checklist is included in Appendix 8 online.

Discussion

Although the data is limited despite our extensive literature review, this systematic review and

meta-analysis suggests that the incidence of SNJ is high among neonates, with regions that include

predominantly LMIC’s bearing the greatest burden of disease. In the systematic review mentioned

earlier by Bhutani et al4 18% of 134 million livebirths had severe neonatal hyperbilirubinemia

with the greatest burden of disease in LMICs, and therefore also supports this hypothesis. But as

previously pointed out, these estimates were generated by mathematical modeling due to lack of

accurate incidence data available. Both Bhutani’s data as well as this review, highlight the glaring

paucity of studies particularly in LMICs. Although all WHO regions are represented in this review

only 4 of 136 (2.9%) LMICs countries were represented with most having only 1 study [India

(SEA) n=217,18, Nigeria (AFR) n=119, Pakistan(EMR) n=120, and Vietnam (WPR) n=121). In

contrast representation among high-income countries while low was better with 7/79 (8.9%) high-

income countries having population based data [Canada (AME) n=222,23, Denmark (EUR) n=324-

26, Norway (EUR) n=127, Netherlands (EUR) n=128, Switzerland (EUR) n=129, USA(AME) n=430-

33, UK(EUR) n=134]. No high middle income countries were represented in this review. This

general lack of population-based studies worldwide emphasizes the need for more accurate data to

determine the actual burden of disease.

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In some instances, an argument could be made for generalizing the data for the region. For

example, Nigeria is the most populous country in sub-Saharan Africa and one in 5 black Africans

is Nigerian. Therefore, data from Nigeria might provide a representative evidence for the AFR

region. Europe representation is better. So again, loose generalization of their data is likely

appropriate. However, Vietnam would likely not represent the WPR which also includes China.

Similarly, North America is quite different in compared to South America which has no

representation in this review. Although not readily generalizable, all regions do have numerous

hospital-based studies among the 324 articles with at least one clinical indicator of SNJ,

highlighting the prevalence of SNJ among neonatal admissions. For some countries, such as the

USA and many European nations where hospital birth is the norm, this data would more

accurately reflect true population-based data. However, in LMICS where Save the Children35

reports that “60 million women give birth outside a facility, usually at home” (2012), hospital data

cannot be assumed to reflect true population data. The higher incidence of home births correlates

well with the much higher incidence of SNJ noted in the studies from the AFR, SEA and EMR

regions noted in this review as compared to substantially lower incidence noted in the region of

AME and the EUR.

Although only one study from AME and one from EMR met the definition of population-based,

these 2 studies underscore the burden of ETs in LMIC’s with 186.5 and 107.1 ET’s per 10,000

livebirths in stark contrast to the region of the AME and the EUR with only 0.41 and 0.35 per

10,000 livebirths respectively. An even more recent study population based study from California

demonstrated a further decrease to only 0.19 per 10,000 livebirths. Serbia an upper middle

income country reported an incidence of 4.8 per 10,000 livebirths,36 but no more recent

population based studies for low-middle or high-middle income countries was noted in PubMed

since the end of this review in 2014.

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While many pediatricians and even neonatologists in high-income countries never perform an ET,

physicians in low resource settings continue to perform this on a regular basis. While population-

based data was available in only a few studies from under-resourced countries, other hospital

based studies support their findings. Of note again is the high prevalence of ET, reported in

studies from many LMIC (22-86%), particularly Nigeria,19,37,38 India,39,40 and Bolivia.41. In

addition, Turkey,42 an upper middle-income country, also had a high percentage of ETs (16%).

Access to ET, which also serves as a proxy indicator of the magnitude of SNJ often is limited in

resource poor countries.43,44 Multiple studies have suggested that early intervention including

phototherapy and appropriate ET can prevent sequelae of bilirubin toxicity. 43,45,46 However, some

studies reported complications and adverse events, including death, due to this treatment.42,47,48

Although ET can contribute to significant improvement in morbidity, current evidence suggests

the risk of long-term sequelae increases in infants who have received ET, possibly resulting from

delayed intervention. 49,50

SNJ is significant due to the mortality associated with it, but some would argue even more so

because of the long-term morbidity associated with it especially in low-resource settings ill-

equipped to handle these disabilities. Saluda et al reported auditory neuropathy spectrum disorder

in almost half of patients undergoing ET.51 Olusanya and Somefun,52 reported ET as a risk factor

for sensorineural hearing loss in their community-based study in Nigeria, as did da Silva et al in

Brazil.53 By definition, the presence of neurologic sequelae indicates ABE was present, even if it

was not clinically recognized, at the time of intervention. Thus, ABE is likely under-recognized

and under-reported, especially when follow-up evaluation is not ensured.

Jaundice was the primary diagnosis in 17% of neonates ≤ 1 week in a hospital-based study in

Kenya,54 and several other African-based studies demonstrate that jaundice is one of the most

common reasons for hospital admission in neonates. 55-57 This pattern is also observed in Asia,

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including the Middle East.54,58-62 Current evidence indicates that jaundice continues to contribute

significantly to the burden of cerebral palsy, deafness and other auditory processing disorders4. In

India, Mukhopadhyay et al, 63 found an abnormal MRI or brainstem audio evoked response in

61% and 76%, respectively, of children who underwent ET. At one year of age, 60% had

abnormal development.63 Wolfe et al,64 in Zimbabwe showed a 26% incidence of abnormal scores

on the Bayley Scale of Infant Development and a 12% incidence of choreo-athetoid cerebral palsy

in infants having a TSB >23.4 mg/dl. In Nigeria, Belonwu et al,65 reported that 12.5% of the

cerebral palsy resulted from jaundice, second only to birth asphyxia, while Ogunlesi et al, 66 also

from Nigeria, reported cerebral palsy, seizure disorders and deafness as the leading sequelae of

ABE, occurring in 86.4%, 40.9%, and 36.4% respectively in survivors. Oztürk et al,67 observed a

history of prolonged jaundice to be common in children affected with cerebral palsy. Summing up

the available estimates, a recent Lancet article by Lawn et al indicts68 pathologic

hyperbilirubinemia/jaundice in more than 114,000 deaths and states that there are over 63,000

damaged survivors.

While only three studies in this review,17,20,34 provided information on jaundice-related deaths,

other studies have shown striking numbers of death attributed at least in part to SNJ. Jaundice-

related deaths accounted for 34% of neonatal deaths in Port Harcourt Nigeria 38, 21% in Oshogbo,

Nigeria37, 14% in Kilifi District Kenya69, 6.7% in Cairo Egypt,70 and 5.5% in Lagos Nigeria. 71

The increased global awareness of SNJ has led to improvement in some countries and regions.

One notable example of this is in Myanmar where a package of services including a

photoradiometer, education and intensive phototherapy decreased ET by 69% in one hospital.72

Another example would be the development and ongoing testing and refinement of filtered

sunlight phototherapy to meet the needs of infants in areas without access to continuous electricity

or intensive phototherapy.73

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Some limitations of this comprehensive review should be noted, besides those inherent in meta-

analysis.74 Only 11 of the 195 sovereign nations75 are represented in the quantitative data. While

highlighting one of the greatest problems in determining the actual burden of disease from SNJ,

absence of data from other countries despite searches of multiple databases limits generalizability

of our findings. Another significant limitation is the marked variability in the actual focus of the

articles. The populations studied, availability of a TSB, recommendations and methods of

screening, definitions of actual bilirubin levels and many other variables of included articles span

an extremely wide range. For instance the article by Bang in India 17 is in a rural village, the only

study from Nigeria19 is in the huge metropolis of Lagos and the lone study from Vietnam21 is in a

mid-sized city. None of these studies included actual bilirubin levels. Because of the limited

number of available TSBs and our attempt to quantify the burden of clinical disease we did not use

TSB criteria to determine the burden of SNJ. However, it is still noteworthy that had we tried to

use TSB as part of the definition of SNJ this would have proved difficult because the definition of

SNJ using TSB alone were looking at TSB exceeding ET levels such as those by Flaherman31 and

Zoubir29 while others were focused on the number the actual TSB.24-26,30,32 As noted earlier,

studies used varying definitions of worrisome TSB levels i.e. Christensen30 and Eggert33 call

severe ≥20 mg/dL, Manning34 uses 30 mg/dL while the database from India18 included infants

with TSB>15mg/dL. Many other variables make the studies hard to compare. Tikmani in

Pakistan20 was focusing on reliability of the Kramer scale, Wainer in Canada23 were using

transcutaneous bilirubin data. Meberg in Norway27 states routine blood groups on mothers and

babies cannot be recommended while Sgro22 in Canada states the opposite. In addition, division

by risk categories did not seem to predict the need for intervention with most infants who

developed SNJ falling into the low risk category.31,32

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Despite the noted limitations, this review still fills critical holes in our knowledge about the true

burden of disease from this devastating but preventable tragedy. To our knowledge, this is the first

report to attempt to report the global burden of SNJ derived from population-based studies. While

providing strong evidence for the burden of disease, it highlights the notable lack of population-

based data from most countries in the world, especially lower resource countries where the disease

is more prevalent and arguably devastating. As noted in this review, SNJ is a significant cause of

morbidity and mortality worldwide, especially in Africa. The burden of this disease and its acute

and chronic ramifications establishes a strong case for appropriate health education, routine

screening, early diagnosis and effective treatment to prevent SNJ. The spectrum of disease crosses

ethnic and socioeconomic boundaries, impacting children everywhere, and is a commonly

encountered hospital diagnosis worldwide. It arguably represents the most common unrecognized

and/or under-reported cause of preventable brain damage. More research with capacity building

especially in LMICs and other areas where data is limited are needed to truly quantify the impact

of this disease and to better understand how to integrate screening and therapy to eliminate this

disease in the future.

Conclusion:

Compelling but limited evidence from the literature demonstrates that SNJ is associated with a

significant health burden, especially in low-middle-income economies. There is an urgent need to

address this preventable disease in these regions, consistent with the inclusiveness advocated for

erstwhile disadvantaged populations under the current SDG dispensation.

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Acknowledgments: We would like to thank Dr. Vinod Bhutani, Ms Judith Hall RNC-NIC, and

Dr. Mark Ralston for their edits to an earlier version of the manuscript. We would like to thank Dr.

Philip Fischer, MD, Dr. Reza Khodaverdian Dr. Janielle Nordell, Ms. Ann Olthoff RN, Dr.

Clydette Powell, Dr. Hoda Pourhassan, ,Ms. Olja Šušilović, Dr. Deborah Walker, Ms. Allia Vaez,

and Ms. Agnieszka Villanti, RN for their help in the translation of foreign language literature used

in this review. We would like to thank Ms. Ayo Bode-Thomas, Dr. Katie Durrwachter Erno, Mr.

Jeffrey Flores, Ms. Judith Hall RNC-NIC, Mr. Jonathan Koffel, Dr. Mark Ralston, Mr. Paul Reid,

Ms. Katherine Warner, Dr. Olga Steffens for their help in editing the article/tables including

retrieving articles, verifying numbers, managing Endnote®.

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75. Independent States of the World. Available from: http://www.nationsonline.org/.

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Table 1 Incidence of severe neonatal jaundice (SNJ), per 10,000 live births, among all neonates aged 24 months or less

Region N Incidence* 95% CI

Overall† 18 13.7 5.2 - 36.4

African 1 667.8 603.4 - 738.5

Americas 6 6.2 2.0 - 19.1

Eastern Mediterranean 1 165.7 114.6 - 238.9

European 7 3.7 1.7 - 8.0

South-East Asian 2 251.3 132.0 - 473.2

Western Pacific 1 91.9 47.9 - 175.7

* Test for subgroup differences (Cochran Q= 315.9, p< 0.001)

† I2 = 99%, Cochran Q= 21382.3, p< 0.001

N: Number of studies, CI: Confidence Interval

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Table 2 Incidence of exchange transfusions, per 10,000 live births, among all neonates aged 24

months or less

Region

N

Incidence*

95% CI

Overall† 13 1.10 0.29 - 42.50

African 1 186.5 153.2 - 2267.7

Americas 4 0.41 0.17 - 9.90

Eastern Mediterranean 1 17.8 5.7 - 548.9

European 6 0.35 0.20 - 6.00

South-East Asian 1 107.1 102.0 - 1125.4

Western Pacific - - -

* Test for subgroup differences (Cochran Q= 626.4, p< 0.001)

† I2 = 99%, Cochran Q= 5212.0, p< 0.001


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APPENDICES

Appendix 1 Ovid Medline Strategy:

Database: Ovid MEDLINE(R) Search Strategy:

-----------------------------------------------------------------------------

1 exp hyperbilirubinemia/ or hyperbilirubinemia$.mp. or hyperbilirubinaemia$.mp. (23 145)

2 exp bilirubin/bl (12 488)

3 exp Rh-Hr Blood-Group System/ or exp Rh Isoimmunization/ (10 490)

4 exp Glucosephosphate Dehydrogenase/ (12 395)

5 exp Glucosephosphate Dehydrogenase Deficiency/ (4303)

6 (hemolytic or haemolytic or hemolysis or haemolysis).mp. or exp anemia, hemolytic/ (111 986)

7 1 or 2 or 3 or 4 or 5 or 6 (160 475)

8 exp ET, whole blood/ or ET$.mp. (5639)

9 kernicterus.mp. or exp kernicterus/ (1376)

10 acute bilirubin encephalopath$.mp. (47)

11 exp death/ or death$.mp. or mortalit$.mp. Or exp infant mortality/ (867 197)

12 exp patient admission/ or exp hospitalization/ or exp patient readmission/ (142 535)

13 (hospital admission$ or hospital readmission$ or hospitalization$ or hospitalisation$).mp. (137

413)

14 phototherap$.mp. or exp phototherapy/ (26 950)

15 8 or 9 or 10 or 11 or 12 or 13 or 14 (1 052 557)

16 7 and 15 (13 587)

17 exp infant mortality/ (23 631)

18 ep.fs. (1 067 849)

19 jaundice.mp. (31 484)

20 17 and 18 and 19 (68)

21 exp Jaundice, Neonatal/ep [Epidemiology] (377)

22 16 or 20 or 21 (13 823)

23 limit 22 to yr="1990 - 2011" (8344)

24 limit 23 to "all infant (birth to 23 months)" (2873)

25 23 and infant$.mp. (2984)

26 24 or 25 (2984)

27 limit 26 to case reports (370)

28 26 not 27 (2614)

29 limit 28 to humans (2595)

30 28 not 29 (19)

31 exp animal/ (16 281 169)

32 30 and 31 (15)

33 30 not 32 (4)

34 29 or 33 (2599)

Submitted by Judith Stanke, Librarian, Bio-Medical Library, University of Minnesota

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http://kernicterus.mp/

http://jaundice.mp/


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Appendix 2 Checklist for examining studies for possible inclusion

Inclusion criteria

Reported jaundice in the first month of life?

Reported objective data on the incidence of jaundice as defined by either bilirubin levels or

need for treatment of jaundice

Reported objective data on the incidence of ET for severe neonatal jaundice?

Reported data on jaundice related hospital admissions, encephalopathy or mortality?

Reported death and neonatal jaundice?

Exclusion criteria

Data collection prior to and not crossing 1990?

Sample size of <10?

Lack of inclusion dates of data collection?

Metabolic diseases?

Review articles?

Questionnaires/surveys?

ET for conditions unrelated to neonatal jaundice

Failure to define infant as having ABE (e.g. hearing loss or changes in ABR along without

frank ABE)

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Appendix 3. Scoring Sheet for assessing quality of studies

Quality Assessment checklist for observation studies on SNH incidence/prevalence

1. Was the sampling method representative of the target population?

A. No (0)

B. Yes (1)

2. Was the diagnosis of hyperbilirubinemia objective?

A. No (0)

B. By history, parental report or visual evaluation solely (0)

C. By bilirubin assay (1)

3. Was clinically significant hyperbilirubinemia clearly defined? (Either by level or need for

treatment)

A. No (0)

B. Yes (1)

4. Were the outcomes (ABE, kernicterus, ET, mortality and/or sequelae) clearly defined?

A. No (0)

B Yes (1)

Score

4=High

3=Medium

2=Low

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Confidential: For Review Only4

Appendix 4 Description of studies included in the Meta analysis

Study, reference Region Country Duration

(years)

Live births Study design Sample description Income Class Quality

score

Bang, 2001 17 South East Asia India 1 763 Prospective All Neonates Low-Middle 3

Bjerre, 2008 24 Europe Denmark 3 249308 Retrospective Term and Near Term High 4

Christensen, 2013 30 Americas USA 10 302399 Retrospective All Neonates High 4

Ebbesen, 2005 26 Europe Denmark 2 128344 Prospective Term and Near Term High 4

Ebbesen, 2012 25 Europe Denmark 8 502766 Prospective Term and Near Term High 4

Eggert, 2006 33 Americas USA 3.8 101272 Retrospective Term and Near Term High 4

Flaherman, 2012 31 Americas USA 3 18089 Retrospective Term and Near Term High 4

Gotink, 2013 28 Europe Netherlands 5 683048 Prospective Term and Near Term High 4

Kuzniewicz, 2014 32 Americas USA 17 525409 Retrospective Term and Near Term High 4

Le, 2014 21 South East Asia Vietnam 2 979 Retrospective All Neonates Low-Middle 3

Manning, 2007 34 Europe UK 3 1500052 Prospective All Neonates High 4

Meberg, 1998 27 Europe Norway 1 2424 Prospective All Neonates High 4

NNDP Databse, 2005 18 South East Asia India 2 145623 Prospective All Neonates Low-Middle 2

Olusanya, 2009 52 Africa Nigeria 2 5256 Retrospective All Neonates Low-Middle 3

Sgro, 2006 22 Americas Canada 2 639840 Prospective Term and Near Term High 4

Tikmani, 2010 3 Eastern

Mediterranean

Pakistan 2 1690 Prospective All Neonates Low-Middle 4

Wainer, 2012 23 Americas Canada 2 21856 Prospective Term and Near Term High 4

Zoubir, 2011 29 Europe Switzerland 2 146288 Prospective All Neonates High 4

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Appendix 5 Pooled incidence (per 10,000) of severe neonatal hyperbilirubinemia among all

neonates aged 24 months or less according to study quality

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Appendix 6. Incidence (per 10,000 live births) of SNH among all neonates aged 24 months or less

by gestation and study design

Characteristics N Incidence 95%CI

Gestation*

All 9 44.0 8.8 - 216.3

Term and near term 9 4.4 2.0 - 10.0

Design†

Prospective 11 14.5 2.4 - 85.5

Retrospective 7 13.1 1.3 - 129.8

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Confidential: For Review Only7

Appendix 7 Pooled proportion (%) of jaundice-related neonatal deaths among neonates aged 24 months or less

with severe neonatal hyperbilirubinemia

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8

Appendix 8. Checklist of items to include when reporting a systematic review or meta-analysis

Section/topic

Item

No Checklist item

Reported on

page No

Title Title 1 Identify the report as a systematic review, meta-analysis, or

both

1

Abstract Structured

summary

2 Provide a structured summary including, as applicable,

background, objectives, data sources, study eligibility criteria,

participants, interventions, study appraisal and synthesis

methods, results, limitations, conclusions and implications of

key findings, systematic review registration number

2

Introduction Rationale 3 Describe the rationale for the review in the context of what is

already known

3

Objectives 4 Provide an explicit statement of questions being addressed

with reference to participants, interventions, comparisons,

outcomes, and study design (PICOS)

4

Methods Protocol and

registration

5 Indicate if a review protocol exists, if and where it can be

accessed (such as web address), and, if available, provide

registration information including registration number

4

Eligibility criteria 6 Specify study characteristics (such as PICOS, length of

follow-up) and report characteristics (such as years

considered, language, publication status) used as criteria for

eligibility, giving rationale

4

Information

sources

7 Describe all information sources (such as databases with

dates of coverage, contact with study authors to identify

additional studies) in the search and date last searched

4-5

Search 8 Present full electronic search strategy for at least one

database, including any limits used, such that it could be

repeated

19

Study selection 9 State the process for selecting studies (that is, screening,

eligibility, included in systematic review, and, if applicable,

included in the meta-analysis)

4-6

Data collection

process

10 Describe method of data extraction from reports (such as

piloted forms, independently, in duplicate) and any processes

for obtaining and confirming data from investigators

5-6

Data items 11 List and define all variables for which data were sought (such

as PICOS, funding sources) and any assumptions and

simplifications made

5

Risk of bias in

individual studies

12 Describe methods used for assessing risk of bias of individual

studies (including specification of whether this was done at

the study or outcome level), and how this information is to be

used in any data synthesis

6

Summary

measures

13 State the principal summary measures (such as risk ratio,

difference in means).

6

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Section/topic

Item

No Checklist item

Reported on

page No

Synthesis of

results

14 Describe the methods of handling data and combining results

of studies, if done, including measures of consistency (such

as I2 statistic) for each meta-analysis

6

Risk of bias across

studies

15 Specify any assessment of risk of bias that may affect the

cumulative evidence (such as publication bias, selective

reporting within studies)

6, 7

Additional

analyses

16 Describe methods of additional analyses (such as sensitivity

or subgroup analyses, meta-regression), if done, indicating

which were pre-specified

7

Results Study selection 17 Give numbers of studies screened, assessed for eligibility, and

included in the review, with reasons for exclusions at each

stage, ideally with a flow diagram

7

Figure 1

Study

characteristics

18 For each study, present characteristics for which data were

extracted (such as study size, PICOS, follow-up period) and

provide the citations

7

Appendix 3

Risk of bias

within studies

19 Present data on risk of bias of each study and, if available,

any outcome-level assessment (see item 12).

Table 2

Table 3

Appendix 4

Results of

individual studies

20 For all outcomes considered (benefits or harms), present for

each study (a) simple summary data for each intervention

group and (b) effect estimates and confidence intervals,

ideally with a forest plot

Table 2

Table 3

Figures 2, 3

Appendices 4, 6

Synthesis of

results

21 Present results of each meta-analysis done, including

confidence intervals and measures of consistency

Table 2

Table 3

Figures 2, 3

Appendices 4, 5

Risk of bias across

studies

22 Present results of any assessment of risk of bias across studies

(see item 15)

8

Additional

analysis

23 Give results of additional analyses, if done (such as

sensitivity or subgroup analyses, meta-regression) (see item

16)

8

Discussion Summary of

evidence

24 Summarise the main findings including the strength of

evidence for each main outcome; consider their relevance to

key groups (such as health care providers, users, and policy

makers)

7-8

Limitations 25 Discuss limitations at study and outcome level (such as risk

of bias), and at review level (such as incomplete retrieval of

identified research, reporting bias)

12-13

Conclusions 26 Provide a general interpretation of the results in the context of

other evidence, and implications for future research

8-14

Funding Funding 27 Describe sources of funding for the systematic review and

other support (such as supply of data) and role of funders for

the systematic review

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181x219mm (200 x 200 DPI)

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Manuscript ID bmjpo-2017-000105.R1


Date Submitted by the Author: 06-Sep-2017


Lee, Burton; University of Pittsburgh Department of Medicine, Medicine Richardson, Shane; University of Arizona Arizona Health Sciences Center, Family Medicine; Valley-Wide Health Systems Inc Keating, Elizabeth; Baylor College of Medicine, Pediatrics Siddappa, Ashajoythi ; University of Minnesota Academic Health Center, Pediatrics Olusanya, Bolajoko; College of Medicine, University of Lagos, MCH Unit, Dept of Community Health





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1, Appiah D

3, Stanke JU

4, Strand MA

5, Lee BW

6, Richardson SB

7,

Keating EM8, Siddappa AM

1,2, Olusanya BO

9,


Duke Appiah, PhD 3Assistant Professor, Texas Tech University Health Science Center, Abilene, TX, 79601 Judith U. Stanke, MA 4Reference Librarian, Biomedical Library, University of Minnesota, Minneapolis, MN 55455 Mark A. Strand, PhD 5Professor of Pharmacy, North Dakota State University, Fargo ND 58108 Burton W. Lee, MD 6Professor of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213 Shane B. Richardson, MD 7Resident, Department of Family Medicine, University of Arizona, Tucson, AZ 85721 Elizabeth M. Keating, MD 8Resident, Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030 Ashajoythi M. Siddappa, MD 1Assistant Professor of Pediatrics University of Minnesota, Minneapolis, MN 55414 2Hennepin County Medical Center, Minneapolis, MN 55415 Bolajoko O. Olusanya, MBBS, PhD 9Director, Center for Healthy Start Initiative, Ikoyi, Lagos, Nigeria


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Funding Source: Support for the quantitative analysis was provided in part by The Programme for Global Paediatric ReSouth-East Asianrch, Centre for Global Child Health, The Hospital for Sick Children, Toronto, Canada. The sponsor had no role in study design, data collection, data analysis, data interpretation, or writing of the report. Key Words: Kernicterus; Exchange transfusion; acute bilirubin encephalopathy; population-based study Financial Disclosure: The authors have no financial relationships relevant to this article to disclose. Competing Interests: The authors have no competing interests relevant to this article to disclose. All authors have completed the Unified Competing Interest Form and they corresponding author has these forms.

List of Abbreviations:

ABE: Acute Bilirubin Encephalopathy ET: Exchange Transfusion LMICs: Low Middle-Income Countries SDG: Sustainable Development Goals SNJ: Severe Neonatal Jaundice TSB: Total Serum Bilirubin

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Drs. Slusher and Olusanya conceptualized and designed the study, acquired data, analyzed and interpreted data, supervised the study, drafted the manuscript, and conducted a critical revision of the manuscript for intellectual content and approved the manuscript as submitted. Dr. Zamora conceptualized and designed the study, and assisted with acquiring data and approved the manuscript as submitted. Dr. Siddappa assisted in acquiring data and approved the manuscript as submitted. Dr. Keating and Ms. Stanke were responsible for acquisition of data as well as providing administrative, technical and material support and approved the manuscript as submitted. Dr. Richardson was responsible for acquisition of data, analyzing and interpreting data, and provided administrative, technical and material support and approved the manuscript as submitted. Drs. Appiah, Strand, and Lee, analyzed and interpreted the data, conducted the statistical analysis, and conducted a critical revision of the manuscript for important intellectual content and approved the manuscript as submitted. All authors had full access to all data, take responsibility for the accuracy and integrity of the data, and approved the manuscript as submitted. Transparency Declaration: As the lead author, Dr. Slusher affirms that the manuscript is an honest, accurate, and transparent account of the study being reported, no important aspects of the study have been omitted, and any discrepancies from the study as planned have been explained.



outcomes of severe neonatal jaundice especially in low-middle income countries (LMICs) • Long term disabilities including cerebral palsy and deafness can occur following acute


What this study adds: • A population based review of literature to assess the global impact of severe neonatal


• Objective evidence that the burden of severe neonatal jaundice is not evenly distributed and that a heavier burden of disease is born by LMICs


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Abstract

CONTEXT: To assess the global burden of late and/or poor management of severe neonatal jaundice (SNJ), a

common problem worldwide, which may result in death or irreversible brain damage with disabilities in

survivors. Population-based data establishing the global burden of SNJ has not been previously reported.

OBJECTIVE: Determine SNJ burden in all World Health Organization (WHO) regions, as defined by clinical

jaundice associated with clinical outcomes including acute bilirubin encephalopathy (ABE)/kernicterus and/or

exchange transfusion (ET) and/or jaundice-related death.

DATA SOURCES: PubMed, Scopus, and other health databases were searched, without language restrictions,

from 1990-2017 for studies reporting the incidence of SNJ.

STUDY SELECTION/DATA EXTRACTION: Stratification was performed for WHO regions and results

were pooled using random effects model and meta-regression.

RESULTS: Overall, 820 articles were reviewed with 416 including at least one marker of SNJ. Only 21 English

articles representing all WHO regions had population-based estimates and 16/21 (76%) were from high-income

countries. The African Region has the highest incidence of SNJ per 10,000 livebirths at 667.8 (95% Confidence

interval: 603.4 - 738.5), followed by South-East Asian, Eastern Mediterranean, Western Pacific, Americas’, and

European regions at 251.3 (132.0 - 473.2); 165.7 (114.6 - 238.9); 9.4 (0.1 - 755.9); 4.4 (1.8 - 10.5) and 3.7 (1.7 -

8.0) respectively. The incidence of ET per 10,000 livebirths was significantly higher for Africa and South-East

Asian regions at 186.5 (153.2 - 226.8) and 107.1 (102.0 - 112.5) and lower in Eastern Mediterranean (17.8 (5.7 -

54.9)), Americas’ (0.38 (0.21 - 0.67)), European (0.35 (0.20 - 0.60)) and Western Pacific regions (0.19 (0.12 -

0.31). Only 3 studies provided estimates of jaundice-related deaths [UK (2.8%), India (30.8%) and Pakistan

(50.0%)].

CONCLUSIONS: Limited but compelling evidence demonstrates that SNJ is associated with a significant

health burden especially in low-middle-income countries.

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Introduction: Newborn jaundice occurs in up to 85% of all livebirths.1-3 In the absence of hemolysis, sepsis,

birth trauma, or prematurity, it usually resolves within 3-5 days without significant complications.1 However,

epidemiological evidence suggests that severe neonatal jaundice (SNJ) results in substantial morbidity and

mortality.4 SNJ has been recognized as a significant cause of long-term neurocognitive and other sequelae,

cerebral palsy, non-syndromic auditory neuropathy, deafness, and learning difficulties.5,6 The burden is

unacceptably high in low and middle-income countries (LMICs) and has prompted calls for intense scrutiny and

attention.4 Under the millennium development goals, the potential impact of adverse perinatal conditions such

as preterm birth complications and birth asphyxia on thriving and well-being beyond survival rarely received

attention.7 With the current focus on inclusiveness for persons with disability under the sustainable development

goals (SDGs), it is essential that we tackle SNJ as one key component of optimizing neurodevelopmental

outcome.7,8

A recent report by Bhutani et al4, noted that at least 481,000 term/near-term neonates are affected by

SNJ/hyperbilirubinemia each year, with 114,000 dying and an additional 63,000 surviving with kernicterus.

However, these alarming estimates were based on limited data determined by mathematical modeling as true

population based data is limited and difficult to find. Therefore, the incidence of SNJ and thus its contribution

to global neonatal morbidity and mortality presently remain unclear and possibly significantly under-estimated.

Jaundice is usually recognized around a total serum bilirubin (TSB) of 5 mg/dL in neonates.3 SNJ is unlikely to

happen before a TSB of at least 20-25mg/dL in term neonates presenting early.4 TSB is unfortunately often

either not available or delayed in many LMICs.9 Therefore for the purposes of this article severe SNJ is defined

as jaundice associated with acute bilirubin encephalopathy (ABE)/kernicterus and/or exchange transfusions (ET)

and/or jaundice-related death.

Phototherapy and ET are widely used therapeutic modalities for jaundice.2 However, due to constrained

resources, devices for measuring bilirubin10,11 and effective phototherapy are often lacking in LMICs.12 This,

together with higher prevalence of glucose-6-phosphate dehydrogenase (G6PD) deficiency, blood group

incompatibilities, late referrals and delayed recognition of excessive bilirubin levels in LMICs has necessitated

excessive use of ETs.13

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We systematically reviewed the available evidence pertaining to the global burden of SNJ to inform child health

policy regarding its prevention and management especially in LMICs.

Methods

Search Criteria

Although most SNJ occurs at TSB at 20mg/dL (343 µmol/L) there is no standard worldwide definition of SNJ

or clinically significant TSB necessitating medical intervention. There is a wide range of definitions of

significant jaundice. In studies reviewed in this article with TSB levels confounded by risk factors especially

pertinent in LMICs ranging from 15-30mg/dL.14-27 Even though beginning in 2004, the American Academy of

Pediatrics (AAP) recommended ABE be used for acute manifestations of SNJ in the first weeks of life and

kernicterus for chronic manifestations of SNJ/ABE,28 many still use the terms interchangeably. Because of

limited availability of TSBs and our attempt to quantify the burden of clinical disease, we defined SNJ clinically

using ABE, ET, and jaundice-related death.

We systematically reviewed published papers following PRISMA guidelines (Appendix 1 online).13 Databases

searched included Ovid Medline, PubMed, CINAHL, Global Health, Scopus, Popline, Africa Journal Online

(AJOL), and Bioline databases for published articles on SNJ. We used both controlled subject headings and

free-text terms for neonatal jaundice, jaundice, bilirubin/blood levels, hemolytic anemia, G6PD deficiency in

various forms and in combination with terms for ET, ABE, kernicterus, death, mortality, and

phototherapy. Other inclusion criteria were jaundice in first month of life; availability of data on incidence of

ABE/ kernicterus; provision of information on incidence of ETs for SNJ; or jaundice-related death which we

defined as SNJ. We also reviewed references of selected retrieved articles and review papers, and contacted

authors of relevant articles for missing dates. No language restrictions were used. To be included in the meta-

analysis, a study must have reported estimates of incidence from a retrospective or prospective population-based

study, increasing likelihood that estimates could be generalized to the geographic location where the study was

conducted. The search results were limited to publication dates of 1990-June 2017. See Appendix 2 online for

complete Ovid Medline search strategy.

Data extraction

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Two authors (TMS, TGZ or AMS) examined studies using a predetermined checklist (Appendix 3 online)

devised by three authors (TMS, TGZ, BOO) for selecting articles that met inclusion criteria after one author

(TMS) screened titles and abstracts. Both TMS and TGZ or AMS independently confirmed eligibility of all full

text articles. Discrepancies were resolved by discussion and when needed by a fourth author (BOO). The

following data was extracted from each article: publication year, study design, country, WHO region, sample

size, SNJ definition, and outcomes (ET, ABE, mortality). Articles were excluded if neonates were enrolled

before 1990; study published after June 2017; sample size <10; ET unrelated to SNJ, results limited to only

metabolic or primary liver diseases, studies with defined enrollment period, failure to define neonates as having

ABE, ET or jaundice-related death and for the meta-analysis if they included only premature neonates.

Quality assessment

We explored several quality assessment tools reported in the literature for observational studies including the

Newcastle-Ottawa Scale,29 and found none directly applicable for evaluating diagnostic studies on neonatal

jaundice/hyperbilirubinemia. We therefore chose to adopt the tool validated by Wong et al30 with all the critical

components for assessing the risk of bias across studies. Two authors (TMS, SBR) examined four important

components of quality/risk of bias assessment: selection of subjects (representativeness), case definition for SNJ

(exposure ascertainment), diagnostic criteria for jaundice, and outcome measurement. Study quality was judged

based on number of criteria that were met: all 4 (high), 2-3 (medium), or 1 (low). Two authors (DA, TMS)

determined which studies were population-based. We defined population-based studies as studies that addressed

the incidence of SNJ for a defined population with every individual in the population having the same

probability of being in the study and the results of the study having the ability to be generalizable to the whole

population from which study participants were sampled and not necessarily the individuals included in the

study. 31 Disagreements were resolved through consensus after joint reassessment.


For the meta-analysis, when multiple reports were obtained from the same population with overlapping study

years, the one providing sufficient data (i.e., numerator and denominator data) to derive estimates of disease

burden was selected. To facilitate meta-analytical techniques, estimates of incidence were logit transformed to

enable them to correspond to probabilities under the standard normal and permit use of the normal distribution

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for significance testing. Pooled estimates were calculated using DerSimonian and Laird’s random effects

method, weighting individual study estimates by the inverse of the variance of their transformed proportion as

study weight, with their 95% (CI) determined using Clopper-Pearson exact binomial method32. For presentation,

pooled transformed estimates were back transformed. Statistical heterogeneity among studies was investigated

using Cochran’s Q test and I2 with a conservative P value less than 0.1 chosen as the level of significance.

Forest plots were then used to examine the overall effects. Exploration of potential sources of heterogeneity was

undertaken using meta-regression. Whether it is an interventional or an observational study, small studies are

more likely to show more extreme values given wider confidence intervals compared to larger studies. Since

more extreme findings may be more newsworthy and hence more likely to be published, potential for

publication bias was assessed by visual inspection of the funnel plot as well as by formal means using Begg’s

adjusted rank correlation and Egger’s regression asymmetry tests33. All analyses were conducted using R

Statistical Software.34

Results

Search of electronic databases identified 6844 articles (Figure 1). Eight hundred twenty papers were reviewed.

After excluding studies not meeting inclusion criteria, 416 studies were selected for further review. Multiple

languages (Chinese, English, Farsi, French, German, Hebrew, Italian, Norwegian, Polish, Portuguese, Serbian,

and Spanish) were represented, with translation of relevant sections, but only 26/416 were non-English, none of

which were population based. Of these, 416 papers included at least one marker of SNJ but only 21 provided

population-based data on 4,975,406 neonates. (Table 1)

Sixteen (76%) were from high-income countries and 13 (62%) used a prospective study design. High-quality

studies tended to report lower incidence compared to low-moderate-quality studies. (Figure 2) High quality

studies tended to come from high income countries with less disease while low quality studies tend to come

from LMICs. Overall, incidence estimates of SNJ from high-income countries tended to be lower compared to

LMICs (Figure 3). Studies which enrolled all neonates regardless of gestational age had a higher incidence of

SNJ compared to studies enrolling only term/near-term. (Table 2).

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The incidence of SNJ per 10,000 livebirths was highest in the African region at 667.8, followed by South-East

Asian at 251.3, Eastern Mediterranean with 165.7 and Western Pacific region with 9.4. The Americas’ and

European regions each had substantially lower incidence of 4.4 and 3.2 respectively (Table 3).

The incidence of ET per 10,000 livebirths was significantly higher for the African (186.5) and South-East Asian

(107.1) regions and lower in Eastern Mediterranean, Americas’, European and Western Pacific regions reporting

estimates of 17.8, 0.38, 0.35 and 0.19 respectively (Table 4).

Visual inspection of funnel plot in which incidences of SNJ were plotted against their standard errors showed

asymmetry. This was confirmed by formal tests of publication bias (Begg-Mazumdar test: P = 0.016, Egger:

bias, P = 0.002). The observed heterogeneity between studies may explain the asymmetric funnel plots. In

random effects meta-regression analyses, we observed that study design and duration, income classification of

country, and gestational age included jointly explain 66.2% of the observed between-study heterogeneity.

Only three studies provided information on jaundice-related deaths with estimates of 2.8, 30.8 and 50.0 for UK

(European)22, India (South-Eastern)35 and Pakistan3 (Eastern Mediterranean), respectively (Figure 4).

Discussion

Although data is limited despite our extensive literature review, this systematic review and meta-analysis

suggests that the incidence of SNJ is high, with regions that include predominantly LMIC’s bearing the greatest

burden of disease. In the systematic review mentioned earlier by Bhutani et al4 18% of 134 million livebirths

had SNJ with the greatest burden of disease in LMICs, and therefore supporting this hypothesis. But as

previously pointed out, these estimates were generated by mathematical modeling due to lack of accurate

incidence data available. Both Bhutani’s data as well as this review, highlight the glaring paucity of studies

particularly in LMICs. Although all WHO regions are represented, only 4/136 (2.9%) LMICs countries were

represented with most having only 1 study [India (South-East) n=225,35, Nigeria (African) n=136, and

Pakistan(Eastern Mediterranean) n=13, Vietnam (Western Pacific) n=137]. In contrast representation among

high-income countries while low was better with 8/79 (10.1%) high-income countries having population based

data [Australia (Western Pacific) n=123, Canada (Americas’) n=326,38, Denmark (European) n=315,17,39, Norway

(European) n=124, Netherlands (European) n=120, Switzerland (European) n=127, USA(Americas’) n=5 16,18,19,40,

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UK and Ireland(European) n=122]. This general lack of population-based studies worldwide emphasizes the need

for more accurate data to determine the actual burden of disease.

Jaundice was the primary diagnosis in 17% of neonates ≤ 1 week in a hospital-based study in Kenya,41 and

several other African-based studies demonstrate that SNJ commonly leads to hospital admissions. 42-44 This

pattern is also observed in Asia, including the Middle East.41,45-49

Although not readily generalizable, all regions do have numerous hospital-based studies among the 416 articles

with at least one clinical indicator of SNJ, highlighting the prevalence of SNJ among admissions. For some

countries, such as the USA and many European nations where hospital birth is the norm, this data would more

accurately reflect true population-based data. However, in LMICs where “60 million women give birth outside

a facility” (2012)50 and recorded data population data spares, hospital data cannot be assumed to reflect true

population data. The higher incidence of home births correlates well with the much higher incidence of SNJ

noted in the studies from the African, South-East Asian and Eastern Mediterranean regions compared to

substantially lower incidence noted in the region of Americas’ and the Europe.

Although only one study each from Africa and Eastern Mediterranean met the definition of population-based,

these 2 studies underscore the burden of ETs in LMIC’s with 186.5 and 107.1 ET’s per 10,000 livebirths in stark

contrast to the Americas’ and European regions with only 0.38 and 0.35 per 10,000 livebirths respectively.

Exchange Transfusions for SNJ

While many pediatricians and even neonatologists in high-income countries never perform an ET, physicians in

LMICs continue to perform ETs on a regular basis.13 Although population-based data was available in only a

few LMICs studies, other hospital based studies support their findings. Of note again is the high prevalence of

ETs, reported in studies from many LMIC (22-86%), particularly Nigeria,36,51,52 India,53,54 and Bolivia.55

Access to ET, a proxy indicator of the magnitude of SNJ, is often limited in resource poor countries.13,56,57

Multiple studies have demonstrated early intervention including phototherapy and appropriate ET can prevent

kernicterus. 56,58,59 Despite benefits of ET, there are associated complications 13 making it important to provide

effective phototherapy before ET is needed.60

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SNJ is significant due to the associated mortality, but some would argue even more so because of associated

long-term morbidity especially in LMICs ill-equipped to handle these disabilities. Farouk et al reported

abnormal neurological findings in almost 90% of infants returning for follow-up after ABE in their nursery.61

Olusanya and Somefun,62 reported ET as a risk factor for sensorineural hearing loss in their community-based

study in Nigeria, as did da Silva et al in Brazil.63

Contribution of SNJ to neonatal mortality

While only three studies in this review,22,35,64 provided information on jaundice-related deaths, other studies have

shown striking numbers of jaundice-related deaths where it reportedly accounted for 34% of neonatal deaths in

Port Harcourt Nigeria 52, 21% in Oshogbo, Nigeria51, 14% in Kilifi District Kenya65, 6.7% in Cairo Egypt,66 and

5.5% in Lagos Nigeria.67

Multiple factors contributing to kernicterus in LMICs and the need for solutions addressing these factors has

been spelled out in articles by Olusanya et al68 and Slusher et al2 including the need for national guidelines,60,68

effective phototherapy, rapid reliable diagnostic tools, maternal and healthcare provider education. 69

Contribution of SNJ to long term disability

Current evidence indicates SNJ continues to contribute significantly to the burden of cerebral palsy, deafness

and other auditory processing disorders.4 In India, Mukhopadhyay et al, 70 found an abnormal MRI or brainstem

audio evoked response in 61% and 76%, respectively, of children who underwent ET. In Nigeria, Ayanniyi et

al,71 reported NNJ as the leading cause of cerebral palsy (39.9%) trumping birth asphyxia (26.8%), while

Ogunlesi et al, 72 also from Nigeria, reported cerebral palsy, seizure disorders and deafness as leading sequelae

of ABE, occurring in 86.4%, 40.9%, and 36.4% respectively. Oztürk et al from Turkey,73 observed a history of

prolonged jaundice commonly in children affected with cerebral palsy. Summing up available estimates, a

recent Lancet article by Lawn et al 74 indicts pathologic hyperbilirubinemia/jaundice in >114,000 deaths and

states that there are >63,000 damaged survivors.

The increased global awareness of SNJ has led to improvement in some locations. One notable example of this

is Myanmar where a package of services including a photoradiometer, education and intensive phototherapy

decreased ET by 69%.75 Another example is the development, ongoing testing and refinement of filtered

sunlight phototherapy in areas without access to continuous electricity or intensive phototherapy.76 Several

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studies have shown that maternal and health worker education, screening programs14,18,28,38 and national

guidelines77 can and do improve outcomes and decrease the observed clinical sequelae of severe neonatal

jaundice. 14,38,77 Many programs supported by groups such as the World Health Organization78 and Essential

Care for Every Baby79 now strongly support screening for jaundice and highlight it as a danger sign needing

urgent care. This increased focus and awareness on SNJ is beginning to lead to decreases of this problem even in

LMICs where recent studies though not always population based are beginning to show decreases in severe

sequela.75

Some limitations of this comprehensive review should be noted, besides those inherent in meta-analysis.80 Only

12/195 sovereign nations81 are represented in the quantitative data. While highlighting one of the greatest

problems in determining the actual burden of disease from SNJ, absence of data from other countries despite

searching multiple databases limits generalizability of our findings. Another significant limitation is the marked

variability in the actual focus of the articles. The populations studied, availability of a TSB, recommendations

and methods of screening, differences in TSBs, and many other variables of included articles span an extremely

wide range. Finally, the initial search excluding articles by title was done by only 1 author (TMS) and audio-

evoked brainstem changes alone where not included in the criteria for SNJ.

Despite these limitations, this review still fills critical holes in our knowledge about the true burden of disease

from this devastating but preventable tragedy. To our knowledge, this is the first attempt to report the global

burden of SNJ derived from population-based studies. While providing strong evidence for the burden of

disease, it highlights the notable lack of population-based data from most countries, especially LMICs where the

disease is more prevalent and most devastating. The burden of SNJ and its acute and chronic ramifications

establish a strong case for appropriate health education, routine screening, early diagnosis and effective

treatment. The spectrum of disease crosses ethnic and socioeconomic boundaries, impacting children

everywhere, and is a commonly encountered hospital diagnosis worldwide. SNJ may represent the most

common unrecognized and/or under-reported neonatal cause of preventable brain damage.82 More research with

capacity building especially in LMICs and other areas where data is limited are needed to truly quantify the

impact of this disease and to better understand how to integrate screening and therapy to eliminate this disease in

the future.

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Conclusion:

Compelling but limited evidence from the literature demonstrates that SNJ is associated with a significant acute

and chronic health burden, especially in LMICs. There is an urgent need to address this preventable disease in

these regions, consistent with the inclusiveness advocated for erstwhile disadvantaged populations under the

current SDGs dispensation.

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Acknowledgments: We would like to thank Dr. Vinod Bhutani, Ms. Judith Hall RNC-NIC, and Dr. Mark Ralston for their edits to an earlier version of the manuscript. We would like to thank Dr. Philip Fischer, MD, Dr. Reza Khodaverdian Dr. Janielle Nordell, Ms. Ann Olthoff RN, Dr. Clydette Powell, Dr. Hoda Pourhassan, Dr. Maryam Sharifi-Sanjani, Ms. Olja Šušilović, Dr. Deborah Walker, Ms. Allia Vaez, and Ms. Agnieszka Villanti, RN for their help in the translation of foreign language literature used in this review. We would like to thank Ms. Ayo Bode-Thomas, Dr. Katie Durrwachter Erno, Mr. Jeffrey Flores, Ms. Judith Hall RNC-NIC, Mr. Jonathan Koffel, Ms. Toni Okuyemi, Dr. Mark Ralston, Mr. Del Reed, Mr. Paul Reid, Dr. Yvonne Vaucher, Ms. Mabel Wafula, Ms. Katherine Warner, Dr. Olga Steffens for their help in editing the article/tables including retrieving articles, verifying numbers, managing Endnote®.

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Confidential: For Review Only

20

Table 1. Studies that met the inclusion criteria to be included in the Meta-Analysis

Study Region Country Duration

(years)

Live

births

Study design P= Prospective

R= Retrospective

Sample

description

Income

Class

Quality

score

Definition of Jaundice and

Clinical indicators

Bang, 2001 South-East Asia

India 1 763 P All Neonates

Low-Middle

2 Deaths from NNJ

Bhutani, 2016

Americas USA 5 2935674 R Term and Near Term

High 3 Both ET and TSB>25mg/dL TSB>30mg/dL

Bjerre, 2008 Europe Denmark 3 249308 R Term and Near Term

High 3 TSB≥510µmole /L (30mg/dL), ABE, ET

Christensen, 2013

Americas USA 10 302399 R All Neonates

High 4 TSB>25mg/dL, TSB >30mg/dL, ABE, ET

Ebbesen, 2005

Europe Denmark 2 128344 P Term and Near Term

High 3 TSB>ET indicated, ABE

Ebbesen, 2012

Europe Denmark 8 502766 P Term and Near Term

High 3 TSB≥450µmole/L (26mg/dL), ABE

Eggert, 2006 Americas USA 3.8 101272 R Term and Near Term

High 3 TSB>20mg/dL, TSB≥25mg/dL ABE, ET

Flaherman, 2012


High 3 TSB>ET indicated

Gotink, 2013 Europe Netherlands 5 683048 P Term and Near Term

High 4 TSB>500µmole/L (29mg/dL) or received ET + TSB > 340µmole/L (20 mg/dL), ET + TSB >430 µmole/L (25mg/dL), ABE

Kuzniewicz, 2014


High 3 TSB≥ 25mg/dL, ET

Le, 2014 Western Pacific

Vietnam 2 979 R All Neonates

Low-Middle

2 Need for PT, ET, kernicterus, death

Manning, 2007

Europe UK 3 1500052 P All Neonates

High 4 TSB≥510µmole/L (30mg/dL), ABE, death

McGillivray Western Australia 3 P Term and High 3 TSB≥450µmole/L (26mg/dL),

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2016 Pacific Near Term ABE signs, ET

Meberg, 1998

Europe Norway 1 2424 P All Neonates

High 4 TSB>350µmole/L (20mg/dL), ET, ABE

NNDP Databse, 2005

South-East Asia


Low-Middle

4 TSB>15mg/dL, ET

Olusanya, 2009

Africa Nigeria 2 5256 R All Neonates

Low-Middle

2 PT, ET

Sgro, 2006 Americas Canada 2 639840 P Term High 3 TSB >425µmole/L (25mg/dL), ET

Sgro, 2016 Americas Canada 2 760000 P Term High 3 TSB>425µmole/L, or ET, ABE symptoms

Tikmani, 2010

Eastern Mediterranean

Pakistan 2 1690 P All Neonates

Low-Middle

4 Referred for jaundice, >15mg/dL, ET

Wainer, 2012

Americas Canada 2 21856 P Term and Near Term

High 3 TSB≥342 µmole/L (20mg/dL) 427µmole/L (25mg/dL), ≥513 µmole/L (30mg/dL), ET

Zoubir, 2011 Europe Switzerland 2 146288 P All Neonates

High 3 TSB>ET, ET

ABE: Acute Bilirubin Encephalopathy; ET: Exchange Transfusion; NNJ: Neonatal Jaundice; TSB: Total Serum Bilirubin

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Table 2: Incidence (per 10,000 live births) of severe neonatal jaundice among all neonates aged 24 months or less by gestation and study design

* Test for subgroup differences (Cochran Q= 7.42, p=0.025)

† Test for subgroup differences (Cochran Q= 0.002, p= 0.963)


Characteristics N Live births Incidence 95%CI

Gestation*

All 9 2642234 37.8 6.9 - 205.4

Term and near term 10 5522699 4.0 1.9 - 8.8

Term only 2 1399840 2.2 0.7 - 7.2

Design†

Prospective 13 5426387 9.7 1.7 - 53.8

Retrospective 8 4138386 10.3 1.3 - 80.4

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Table 3: Incidence of severe neonatal jaundice per 10,000 live births, among all neonates aged 24 months or less

Region N Live births Incidence* 95% CI

Overall† 21 9564773 9.9 2.8 - 35.6

African 1 5256 667.8 603.4 - 738.5

Americas 8 5304539 4.4 1.8 - 10.5

Eastern Mediterranean 1 1690 165.7 114.6 - 238.9

European 7 3212230 3.7 1.7 - 8.0

South-East Asian 2 146386 251.3 132.0 - 473.2

Western Pacific 2 894672 9.4 0.1 - 755.9

* Test for subgroup differences (Cochran Q= 346.9, p< 0.001) † I2 = 99%, Cochran Q= 34721, p< 0.001 N: Number of studies, CI: Confidence Interval

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Table 4: Incidence of exchange transfusions, per 10,000 live births, among all neonates aged 24 months or less

Region N Live births Incidence* 95% CI

Overall† 16 9437479 8.4 2.7 - 25.7

African 1 5256 186.5 153.2 - 226.8

Americas 6 5181411 0.38 0.21 - 0.67


European 6 3209806 0.35 0.20 - 0.60

South-East Asian 1 145623 107.1 102.0 - 112.5

Western Pacific 1 893693 0.19 0.12 - 0.31

* Test for subgroup differences (Cochran Q= 1501.2, p< 0.001) † I2 = 99%, Cochran Q= 8730.7, p< 0.001 N: Number of studies, CI: Confidence Interval

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Figure 1 Flowchart of study selection for the meta‐analysis

Records identified through database searches (n=14,228)

Records after duplicates removed (n=8375)

Records screened (n=6844)

Excluded after review of title

(n= 1531)

Additional records identified through other sources

(n=6)

Full-text papers retrieved for detailed evaluation

(n= 820)

Studies included in qualitative synthesis

(n= 416)

Studies included in quantitative synthesis

(Meta-analysis) (n=21)

Excluded records unrelated to topic or no abstract and/or full text

available (n=6024)

Excluded from meta-analysis owing to

inadequate information (n=395)

Studies excluded for not meeting eligibility criteria

(n=404)

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Figure 2 Pooled incidence (per 10,000) of severe neonatal jaundice among all neonates aged 24 months or less according to income

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Figure 3 Pooled incidence (per 10,000) of severe neonatal jaundice among all neonates aged 24 months or less according to study quality

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Figure 4: Pooled proportion (%) of jaundice-related neonatal deaths among neonates aged 24 months or less with severe neonatal hyperbilirubinemia

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116x150mm (96 x 96 DPI)

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168x119mm (288 x 288 DPI)

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165x115mm (288 x 288 DPI)

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171x72mm (288 x 288 DPI)

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Manuscript ID bmjpo-2017-000105.R2


Date Submitted by the Author: 25-Sep-2017


Lee, Burton; University of Pittsburgh Department of Medicine, Medicine Richardson, Shane; University of Arizona Arizona Health Sciences Center, Family Medicine; Valley-Wide Health Systems Inc Keating, Elizabeth; Baylor College of Medicine, Pediatrics Siddappa, Ashajoythi ; University of Minnesota Academic Health Center, Pediatrics Olusanya, Bolajoko; College of Medicine, University of Lagos, MCH Unit, Dept of Community Health





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1, Appiah D

3, Stanke JU

4, Strand MA

5, Lee BW

6, Richardson SB

7,

Keating EM8, Siddappa AM

1,2, Olusanya BO

9,


Duke Appiah, PhD 3Assistant Professor, Texas Tech University Health Science Center, Abilene, TX, 79601 Judith U. Stanke, MA 4Reference Librarian, Biomedical Library, University of Minnesota, Minneapolis, MN 55455 Mark A. Strand, PhD 5Professor of Pharmacy, North Dakota State University, Fargo ND 58108 Burton W. Lee, MD 6Professor of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213 Shane B. Richardson, MD 7Resident, Department of Family Medicine, University of Arizona, Tucson, AZ 85721 Elizabeth M. Keating, MD 8Resident, Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030 Ashajoythi M. Siddappa, MD 1Assistant Professor of Pediatrics University of Minnesota, Minneapolis, MN 55414 2Hennepin County Medical Center, Minneapolis, MN 55415 Bolajoko O. Olusanya, MBBS, PhD 9Director, Center for Healthy Start Initiative, Ikoyi, Lagos, Nigeria


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Funding Source: Support for the quantitative analysis was provided in part by The Programme for Global Paediatric ReSouth-East Asianrch, Centre for Global Child Health, The Hospital for Sick Children, Toronto, Canada. The sponsor had no role in study design, data collection, data analysis, data interpretation, or writing of the report. Key Words: Kernicterus; Exchange transfusion; acute bilirubin encephalopathy; population-based study Financial Disclosure: The authors have no financial relationships relevant to this article to disclose. Competing Interests: The authors have no competing interests relevant to this article to disclose. All authors have completed the Unified Competing Interest Form and they corresponding author has these forms.

List of Abbreviations:

ABE: Acute Bilirubin Encephalopathy ET: Exchange Transfusion LMICs: Low Middle-Income Countries SDG: Sustainable Development Goals SNJ: Severe Neonatal Jaundice TSB: Total Serum Bilirubin

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Drs. Slusher and Olusanya conceptualized and designed the study, acquired data, analyzed and interpreted data, supervised the study, drafted the manuscript, and conducted a critical revision of the manuscript for intellectual content and approved the manuscript as submitted. Dr. Zamora conceptualized and designed the study, and assisted with acquiring data and approved the manuscript as submitted. Dr. Siddappa assisted in acquiring data and approved the manuscript as submitted. Dr. Keating and Ms. Stanke were responsible for acquisition of data as well as providing administrative, technical and material support and approved the manuscript as submitted. Dr. Richardson was responsible for acquisition of data, analyzing and interpreting data, and provided administrative, technical and material support and approved the manuscript as submitted. Drs. Appiah, Strand, and Lee, analyzed and interpreted the data, conducted the statistical analysis, and conducted a critical revision of the manuscript for important intellectual content and approved the manuscript as submitted. All authors had full access to all data, take responsibility for the accuracy and integrity of the data, and approved the manuscript as submitted. Transparency Declaration: As the lead author, Dr. Slusher affirms that the manuscript is an honest, accurate, and transparent account of the study being reported, no important aspects of the study have been omitted, and any discrepancies from the study as planned have been explained.



outcomes of severe neonatal jaundice especially in low-middle income countries (LMICs) • Long term disabilities including cerebral palsy and deafness can occur following acute


What this study adds: • A review of population-based literature to assess the global impact of severe neonatal


• Objective evidence that the burden of severe neonatal jaundice is not evenly distributed and that a heavier burden of disease is born by LMICs


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Abstract

CONTEXT: To assess the global burden of late and/or poor management of severe neonatal jaundice, a

common problem worldwide, which may result in death or irreversible brain damage with disabilities in

survivors. Population-based data establishing the global burden of severe neonatal jaundice has not been

previously reported.

OBJECTIVE: Determine the burden of severe neonatal jaundice in all World Health Organization (WHO)

regions, as defined by clinical jaundice associated with clinical outcomes including acute bilirubin

encephalopathy (ABE)/kernicterus and/or exchange transfusion (ET) and/or jaundice-related death.

DATA SOURCES: PubMed, Scopus, and other health databases were searched, without language restrictions,

from 1990-2017 for studies reporting the incidence of severe neonatal jaundice.

STUDY SELECTION/DATA EXTRACTION: Stratification was performed for WHO regions and results

were pooled using random effects model and meta-regression.

RESULTS: Of 416 articles including at least one marker of severe neonatal jaundice, only 21 reported

estimates from population-based studies, with 76% (16/21) of them conducted in high-income countries.

The African Region has the highest incidence of severe neonatal jaundice per 10,000 livebirths at 667.8 (95%

Confidence interval: 603.4 - 738.5), followed by South-East Asian, Eastern Mediterranean, Western Pacific,

Americas’, and European regions at 251.3 (132.0 - 473.2); 165.7 (114.6 - 238.9); 9.4 (0.1 - 755.9); 4.4 (1.8 -

10.5) and 3.7 (1.7 - 8.0) respectively. The incidence of ET per 10,000 livebirths was significantly higher for

Africa and South-East Asian regions at 186.5 (153.2 - 226.8) and 107.1 (102.0 - 112.5) and lower in Eastern

Mediterranean (17.8 (5.7 - 54.9)), Americas’ (0.38 (0.21 - 0.67)), European (0.35 (0.20 - 0.60)) and Western

Pacific regions (0.19 (0.12 - 0.31). Only 3 studies provided estimates of jaundice-related deaths [UK (2.8%),

India (30.8%), Pakistan (50.0%)].

CONCLUSIONS: Limited but compelling evidence demonstrates that severe neonatal jaundice is associated

with a significant health burden especially in low-middle-income countries.

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Introduction: Newborn jaundice occurs in up to 85% of all livebirths.1-3 In the absence of hemolysis, sepsis,

birth trauma, or prematurity, it usually resolves within 3-5 days without significant complications.1 However,

epidemiological evidence suggests that severe neonatal jaundice (SNJ) results in substantial morbidity and

mortality.4 SNJ has been recognized as a significant cause of long-term neurocognitive and other sequelae,

cerebral palsy, non-syndromic auditory neuropathy, deafness, and learning difficulties.5,6 The burden is

unacceptably high in low and middle-income countries (LMICs) and has prompted calls for intense scrutiny and

attention.4 Under the millennium development goals, the potential impact of adverse perinatal conditions such

as preterm birth complications and birth asphyxia on thriving and well-being beyond survival rarely received

attention.7 With the current focus on inclusiveness for persons with disability under the sustainable development

goals (SDGs), it is essential that we tackle SNJ as one key component of optimizing neurodevelopmental

outcome.7,8

A recent report by Bhutani et al4, noted that at least 481,000 term/near-term neonates are affected by

SNJ/hyperbilirubinemia each year, with 114,000 dying and an additional 63,000 surviving with kernicterus.

However, these alarming estimates were based on limited data determined by mathematical modeling as true

population based data is limited and difficult to find. Therefore, the incidence of SNJ and thus its contribution

to global neonatal morbidity and mortality presently remain unclear and possibly significantly under-estimated.

Jaundice is usually recognized around a total serum bilirubin (TSB) of 5 mg/dL in neonates.3 SNJ is unlikely to

happen before a TSB of at least 20-25mg/dL in term neonates presenting early.4 TSB is unfortunately often

either not available or delayed in many LMICs.9 Therefore for the purposes of this article severe SNJ is defined

as jaundice associated with acute bilirubin encephalopathy (ABE)/kernicterus and/or exchange transfusions (ET)

and/or jaundice-related death.

Phototherapy and ET are widely used therapeutic modalities for jaundice.2 However, due to constrained

resources, devices for measuring bilirubin10,11 and effective phototherapy are often lacking in LMICs.12 This,

together with higher prevalence of glucose-6-phosphate dehydrogenase (G6PD) deficiency, blood group

incompatibilities, late referrals and delayed recognition of excessive bilirubin levels in LMICs has necessitated

excessive use of ETs.13

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We systematically reviewed the available evidence pertaining to the global burden of SNJ to inform child health

policy regarding its prevention and management especially in LMICs.

Methods

Search Criteria

Although most SNJ occurs at TSB at 20mg/dL (343 µmol/L) there is no standard worldwide definition of SNJ

or clinically significant TSB necessitating medical intervention. There is a wide range of definitions of

significant jaundice. In studies reviewed in this article with TSB levels confounded by risk factors especially

pertinent in LMICs ranging from 15-30mg/dL.14-27 Even though beginning in 2004, the American Academy of

Pediatrics (AAP) recommended ABE be used for acute manifestations of SNJ in the first weeks of life and

kernicterus for chronic manifestations of SNJ/ABE,28 many still use the terms interchangeably. Because of

limited availability of TSBs and our attempt to quantify the burden of clinical disease, we defined SNJ clinically

using ABE, ET, and jaundice-related death.

We systematically reviewed published papers following PRISMA guidelines (Appendix 1).13 Databases

searched included Ovid Medline, PubMed, CINAHL, Global Health, Scopus, Popline, Africa Journal Online

(AJOL), and Bioline databases for published articles on SNJ. We used both controlled subject headings and

free-text terms for neonatal jaundice, jaundice, bilirubin/blood levels, hemolytic anemia, G6PD deficiency in

various forms and in combination with terms for ET, ABE, kernicterus, death, mortality, and

phototherapy. Other inclusion criteria were jaundice in first month of life; availability of data on incidence of

ABE/ kernicterus; provision of information on incidence of ETs for SNJ; or jaundice-related death which we

defined as SNJ. We also reviewed references of selected retrieved articles and review papers, and contacted

authors of relevant articles for missing dates. No language restrictions were used. To be included in the meta-

analysis, a study must have reported estimates of incidence from a retrospective or prospective population-based

study, increasing likelihood that estimates could be generalized to the geographic location where the study was

conducted. The search results were limited to publication dates of 1990-June 2017. See Appendix 2 online for

complete Ovid Medline search strategy.

Data extraction

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Two authors examined studies using a predetermined checklist (Appendix 3 online) devised by three authors for

selecting articles that met inclusion criteria after one author screened titles and abstracts. Two authors

independently confirmed eligibility of all full text articles. Discrepancies were resolved by discussion and when

needed by a third author. The following data was extracted from each article: publication year, study design,

country, WHO region, sample size, SNJ definition, and outcomes (ET, ABE, mortality). Articles were excluded

if neonates were enrolled before 1990; study published after June 2017; sample size <10; ET unrelated to SNJ,

results limited to only metabolic or primary liver diseases, studies with defined enrollment period, failure to

define neonates as having ABE, ET or jaundice-related death and for the meta-analysis if they included only

premature neonates.

Quality assessment

We explored several quality assessment tools reported in the literature for observational studies including the

Newcastle-Ottawa Scale,29 and found none directly applicable for evaluating diagnostic studies on neonatal

jaundice/hyperbilirubinemia. We therefore chose to adopt the tool validated by Wong et al30 with all the critical

components for assessing the risk of bias across studies. Two authors examined four important components of

quality/risk of bias assessment: selection of subjects (representativeness), case definition for SNJ (exposure

ascertainment), diagnostic criteria for jaundice, and outcome measurement. Study quality was judged based on

number of criteria that were met: all 4 (high), 2-3 (medium), or 1 (low). Finally, two authors determined which

studies were population-based. We defined population-based studies as studies that addressed the incidence of

SNJ for a defined population with every individual in the population having the same probability of being in the

study and the results of the study having the ability to be generalizable to the whole population from which

study participants were sampled and not necessarily the individuals included in the study. 31 Disagreements were

resolved through consensus after joint reassessment.


For the meta-analysis, when multiple reports were obtained from the same population with overlapping study

years, the one providing sufficient data (i.e., numerator and denominator data) to derive estimates of disease

burden was selected. To facilitate meta-analytical techniques, estimates of incidence were logit transformed to

enable them to correspond to probabilities under the standard normal and permit use of the normal distribution

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for significance testing. Pooled estimates were calculated using DerSimonian and Laird’s random effects

method, weighting individual study estimates by the inverse of the variance of their transformed proportion as

study weight, with their 95% (CI) determined using Clopper-Pearson exact binomial method32. For presentation,

pooled transformed estimates were back transformed. Statistical heterogeneity among studies was investigated

using Cochran’s Q test and I2 with a conservative P value less than 0.1 chosen as the level of significance.

Forest plots were then used to examine the overall effects. Exploration of potential sources of heterogeneity was

undertaken using meta-regression. Whether it is an interventional or an observational study, small studies are

more likely to show more extreme values given wider confidence intervals compared to larger studies. Since

more extreme findings may be more newsworthy and hence more likely to be published, potential for

publication bias was assessed by visual inspection of the funnel plot as well as by formal means using Begg’s

adjusted rank correlation and Egger’s regression asymmetry tests33. All analyses were conducted using R

Statistical Software.34

Results

Search of electronic databases identified 6844 articles (Figure 1). Eight hundred twenty papers were reviewed.

After excluding studies not meeting inclusion criteria, 416 studies were selected for further review. Multiple

languages (Chinese, English, Farsi, French, German, Hebrew, Italian, Norwegian, Polish, Portuguese, Serbian,

and Spanish) were represented, with translation of relevant sections, but only 26/416 were non-English, none of

which were population based. Of these, 416 papers included at least one marker of SNJ but only 21 provided

population-based data on 4,975,406 neonates. (Table 1)

Sixteen (76%) were from high-income countries and 13 (62%) used a prospective study design. High-quality

studies tended to report lower incidence compared to low-moderate-quality studies. (Figure 2) High quality

studies tended to come from high income countries with less disease while low quality studies tend to come

from LMICs. Overall, incidence estimates of SNJ from high-income countries tended to be lower compared to

LMICs (Figure 3). Studies which enrolled all neonates regardless of gestational age had a higher incidence of

SNJ compared to studies enrolling only term/near-term. (Table 2).

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The incidence of SNJ per 10,000 livebirths was highest in the African region at 667.8, followed by South-East

Asian at 251.3, Eastern Mediterranean with 165.7 and Western Pacific region with 9.4. The Americas’ and

European regions each had substantially lower incidence of 4.4 and 3.2 respectively (Table 3).

The incidence of ET per 10,000 livebirths was significantly higher for the African (186.5) and South-East Asian

(107.1) regions and lower in Eastern Mediterranean, Americas’, European and Western Pacific regions reporting

estimates of 17.8, 0.38, 0.35 and 0.19 respectively (Table 4).

Visual inspection of funnel plot in which incidences of SNJ were plotted against their standard errors showed

asymmetry. This was confirmed by formal tests of publication bias (Begg-Mazumdar test: P = 0.016, Egger:

bias, P = 0.002). The observed heterogeneity between studies may explain the asymmetric funnel plots. In

random effects meta-regression analyses, the overall observed between-study heterogeneity explained by

covariates which were selected a priori (study design and duration, income classification of country, and

gestational age) was 66.23%; p < 0.001. However, only income classification of country was statistically

significant determinant of the incidence of SNJ (Table 5). Only three studies provided information on jaundice-

related deaths with estimates of 2.8, 30.8 and 50.0 for UK (European)22, India (South-Eastern)35 and Pakistan3

(Eastern Mediterranean), respectively (Figure 4).

Discussion

Although data is limited despite our extensive literature review, this systematic review and meta-analysis

suggests that the incidence of SNJ is high, with regions that include predominantly LMIC’s bearing the greatest

burden of disease. In the systematic review mentioned earlier by Bhutani et al4 18% of 134 million livebirths

had SNJ with the greatest burden of disease in LMICs, and therefore supporting this hypothesis. But as

previously pointed out, these estimates were generated by mathematical modeling due to lack of accurate

incidence data available. Both Bhutani’s data as well as this review, highlight the glaring paucity of studies

particularly in LMICs. Although all WHO regions are represented, only 4/136 (2.9%) LMICs countries were

represented with most having only 1 study [India (South-East) n=225,35, Nigeria (African) n=136, and

Pakistan(Eastern Mediterranean) n=13, Vietnam (Western Pacific) n=137]. In contrast representation among

high-income countries while low was better with 8/79 (10.1%) high-income countries having population based

data [Australia (Western Pacific) n=123, Canada (Americas’) n=326,38, Denmark (European) n=315,17,39, Norway

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(European) n=124, Netherlands (European) n=120, Switzerland (European) n=127, USA(Americas’) n=5 16,18,19,40,

UK and Ireland(European) n=122]. This general lack of population-based studies worldwide emphasizes the need

for more accurate data to determine the actual burden of disease.

Jaundice was the primary diagnosis in 17% of neonates ≤ 1 week in a hospital-based study in Kenya,41 and

several other African-based studies demonstrate that SNJ commonly leads to hospital admissions. 42-44 This

pattern is also observed in Asia, including the Middle East.41,45-49

Although not readily generalizable, all regions do have numerous hospital-based studies among the 416 articles

with at least one clinical indicator of SNJ, highlighting the prevalence of SNJ among admissions. For some

countries, such as the USA and many European nations where hospital birth is the norm, this data would more

accurately reflect true population-based data. However, in LMICs where “60 million women give birth outside

a facility” (2012)50 and recorded data population data spares, hospital data cannot be assumed to reflect true

population data. The higher incidence of home births correlates well with the much higher incidence of SNJ

noted in the studies from the African, South-East Asian and Eastern Mediterranean regions compared to

substantially lower incidence noted in the region of Americas’ and the Europe.

Although only one study each from Africa and Eastern Mediterranean met the definition of population-based,

these 2 studies underscore the burden of ETs in LMIC’s with 186.5 and 107.1 ET’s per 10,000 livebirths in stark

contrast to the Americas’ and European regions with only 0.38 and 0.35 per 10,000 livebirths respectively.

Exchange Transfusions for SNJ

While many pediatricians and even neonatologists in high-income countries never perform an ET, physicians in

LMICs continue to perform ETs on a regular basis.13 Although population-based data was available in only a

few LMICs studies, other hospital based studies support their findings. Of note again is the high prevalence of

ETs, reported in studies from many LMIC (22-86%), particularly Nigeria,36,51,52 India,53,54 and Bolivia.55

Access to ET, a proxy indicator of the magnitude of SNJ, is often limited in resource poor countries.13,56,57

Multiple studies have demonstrated early intervention including phototherapy and appropriate ET can prevent

kernicterus. 56,58,59 Despite benefits of ET, there are associated complications 13 making it important to provide

effective phototherapy before ET is needed.60

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SNJ is significant due to the associated mortality, but some would argue even more so because of associated

long-term morbidity especially in LMICs ill-equipped to handle these disabilities. Farouk et al reported

abnormal neurological findings in almost 90% of infants returning for follow-up after ABE in their nursery.61

Olusanya and Somefun,62 reported ET as a risk factor for sensorineural hearing loss in their community-based

study in Nigeria, as did da Silva et al in Brazil.63

Contribution of SNJ to neonatal mortality

While only three studies in this review,22,35,64 provided information on jaundice-related deaths, other studies have

shown striking numbers of jaundice-related deaths where it reportedly accounted for 34% of neonatal deaths in

Port Harcourt Nigeria 52, 15% in Ile-Ife, Nigeria65, 14% in Kilifi District Kenya66, 6.7% in Cairo Egypt,67 and

5.5% in Lagos Nigeria.68

Multiple factors contributing to kernicterus in LMICs and the need for solutions addressing these factors has

been spelled out in articles by Olusanya et al69 and Slusher et al2 including the need for national guidelines,9,60

effective phototherapy, rapid reliable diagnostic tools, maternal and healthcare provider education. 70

Contribution of SNJ to long term disability

Current evidence indicates SNJ continues to contribute significantly to the burden of cerebral palsy, deafness

and other auditory processing disorders.4 In India, Mukhopadhyay et al, 71 found an abnormal MRI or brainstem

audio evoked response in 61% and 76%, respectively, of children who underwent ET. In Nigeria, Ayanniyi et

al,72 reported NNJ as the leading cause of cerebral palsy (39.9%) trumping birth asphyxia (26.8%), while

Ogunlesi et al,73 also from Nigeria, reported cerebral palsy, seizure disorders and deafness as leading sequelae of

ABE, occurring in 86.4%, 40.9%, and 36.4% respectively. Oztürk et al from Turkey,74 observed a history of

prolonged jaundice commonly in children affected with cerebral palsy. Summing up available estimates, a

recent Lancet article by Lawn et al 75 indicts pathologic hyperbilirubinemia/jaundice in >114,000 deaths and

states that there are >63,000 damaged survivors.

The increased global awareness of SNJ has led to improvement in some locations. One notable example of this

is Myanmar where a package of services including a photoradiometer, education and intensive phototherapy

decreased ET by 69%.76 Another example is the development, ongoing testing and refinement of filtered

sunlight phototherapy in areas without access to continuous electricity or intensive phototherapy.77 Several

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studies have shown that maternal and health worker education, screening programs14,18,28,38 and national

guidelines78 can and do improve outcomes and decrease the observed clinical sequelae of severe neonatal

jaundice. 14,38,78 Many programs supported by groups such as the World Health Organization79 and Essential

Care for Every Baby80 now strongly support screening for jaundice and highlight it as a danger sign needing

urgent care. This increased focus and awareness on SNJ is beginning to lead to decreases of this problem even in

LMICs where recent studies though not always population based are beginning to show decreases in severe

sequela.76

Some limitations of this comprehensive review should be noted, besides those inherent in meta-analysis.81 Only

12/195 sovereign nations82 are represented in the quantitative data. While highlighting one of the greatest

problems in determining the actual burden of disease from SNJ, absence of data from other countries despite

searching multiple databases limits generalizability of our findings. Another significant limitation is the marked

variability in the actual focus of the articles. The populations studied, availability of a TSB, recommendations

and methods of screening, differences in TSBs, and many other variables of included articles span an extremely

wide range. Finally, the initial search excluding articles by title was done by only 1 author and the audio-evoked

brainstem response, which is rarely available in LMICs, where not included in the criteria for SNJ.

Despite these limitations, this review still fills critical holes in our knowledge about the true burden of disease

from this devastating but preventable tragedy. To our knowledge, this is the first attempt to report the global

burden of SNJ derived from population-based studies. While providing strong evidence for the burden of

disease, it highlights the notable lack of population-based data from most countries, especially LMICs where the

disease is more prevalent and most devastating. The burden of SNJ and its acute and chronic ramifications

establish a strong case for appropriate health education, routine screening, early diagnosis and effective

treatment. The spectrum of disease crosses ethnic and socioeconomic boundaries, impacting children

everywhere, and is a commonly encountered hospital diagnosis worldwide. SNJ may represent the most

common unrecognized and/or under-reported neonatal cause of preventable brain damage.83 More research with

capacity building especially in LMICs and other areas where data is limited are needed to truly quantify the

impact of this disease and to better understand how to integrate screening and therapy to eliminate this disease in

the future.

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Conclusion:

Compelling but limited evidence from the literature demonstrates that SNJ is associated with a significant acute

and chronic health burden, especially in LMICs. There is an urgent need to address this preventable disease in

these regions, consistent with the inclusiveness advocated for erstwhile disadvantaged populations under the

current SDGs dispensation.

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Acknowledgments: We would like to thank Dr. Vinod Bhutani, Ms. Judith Hall RNC-NIC, and Dr. Mark Ralston for their edits to an earlier version of the manuscript. We would like to thank Dr. Philip Fischer, MD, Dr. Reza Khodaverdian Dr. Janielle Nordell, Ms. Ann Olthoff RN, Dr. Clydette Powell, Dr. Hoda Pourhassan, Dr. Maryam Sharifi-Sanjani, Ms. Olja Šušilović, Dr. Deborah Walker, Ms. Allia Vaez, and Ms. Agnieszka Villanti, RN for their help in the translation of foreign language literature used in this review. We would like to thank Ms. Ayo Bode-Thomas, Dr. Katie Durrwachter Erno, Mr. Jeffrey Flores, Ms. Judith Hall RNC-NIC, Mr. Jonathan Koffel, Ms. Toni Okuyemi, Dr. Mark Ralston, Mr. Del Reed, Mr. Paul Reid, Dr. Yvonne Vaucher, Ms. Mabel Wafula, Ms. Katherine Warner, Dr. Olga Steffens for their help in editing the article/tables including retrieving articles, verifying numbers, managing Endnote®.

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Table 1. Studies that met the inclusion criteria to be included in the Meta-Analysis

Study Continent WHO Region Country Duration

(years)

Live

births

Study

design

Sample

description

Income

Class

Quality

score

Definition of Jaundice and

Clinical indicators

Bang, 2001 Asia South-East Asia


Low-Middle

2 Deaths from NNJ

Bhutani, 2016

North America


High 3 Both ET and TSB>25mg/dL TSB>30mg/dL

Bjerre, 2008 Europe Europe Denmark 3 249308 R Term and Near Term

High 3 TSB≥510µmole /L (30mg/dL), ABE, ET

Christensen, 2013

North America

Americas USA 10 302399 R All Neonates

High 4 TSB>25mg/dL, TSB >30mg/dL, ABE, ET

Ebbesen, 2005

Europe Europe Denmark 2 128344 P Term and Near Term

High 3 TSB>ET indicated, ABE

Ebbesen, 2012

Europe Europe Denmark 8 502766 P Term and Near Term

High 3 TSB≥450µmole/L (26mg/dL), ABE

Eggert, 2006

North America

Americas USA 3.8 101272 R Term and Near Term

High 3 TSB>20mg/dL, TSB≥25mg/dL ABE, ET

Flaherman, 2012

North America


High 3 TSB>ET indicated

Gotink, 2013

Europe Europe Netherlands 5 683048 P Term and Near Term

High 4 TSB>500µmole/L (29mg/dL) or received ET + TSB > 340µmole/L (20 mg/dL), ET + TSB >430 µmole/L (25mg/dL), ABE

Kuzniewicz, 2014

North America


High 3 TSB≥ 25mg/dL, ET

Le, 2014 Asia Western Pacific

Vietnam 2 979 R All Neonates

Low-Middle

2 Need for PT, ET, kernicterus, death

Manning, 2007

Europe Europe UK 3 1500052 P All Neonates

High 4 TSB≥510µmole/L (30mg/dL), ABE, death

McGillivray Australia Western Australia 3 893693 P Term and High 3 TSB≥450µmole/L (26mg/dL), ABE signs, ET

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2016 Pacific Near Term

Meberg, 1998

Europe Europe Norway 1 2424 P All Neonates

High 4 TSB>350µmole/L (20mg/dL), ET, ABE

NNDP Databse, 2005

Asia South-East Asia


Low-Middle

4 TSB>15mg/dL, ET

Olusanya, 2009

Africa Africa Nigeria 2 5256 R All Neonates

Low-Middle

2 PT, ET

Sgro, 2006 North America

Americas Canada 2 639840 P Term High 3 TSB >425µmole/L (25mg/dL), ET

Sgro, 2016 North America

Americas Canada 2 760000 P Term High 3 TSB>425µmole/L, or ET, ABE symptoms

Tikmani, 2010

Asia Eastern Mediterranean

Pakistan 2 1690 P All Neonates

Low-Middle

4 Referred for jaundice, >15mg/dL, ET

Wainer, 2012

North America

Americas Canada 2 21856 P Term and Near Term

High 3 TSB≥342 µmole/L (20mg/dL) 427µmole/L (25mg/dL), ≥513 µmole/L (30mg/dL), ET

Zoubir, 2011

Europe Europe Switzerland 2 146288 P All Neonates

High 3 TSB>ET, ET

ABE: Acute Bilirubin Encephalopathy; ET: Exchange Transfusion; NNJ: Neonatal Jaundice; TSB: Total Serum Bilirubin

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Table 2: Incidence (per 10,000 live births) of severe neonatal jaundice among all neonates aged 24 months or less by gestation and study design

* Test for subgroup differences (Cochran Q= 7.42, p=0.025)

† Test for subgroup differences (Cochran Q= 0.002, p= 0.963)


Characteristics N Live births Incidence 95%CI

Gestation*

All 9 2642234 37.8 6.9 - 205.4

Term and near term 10 5522699 4.0 1.9 - 8.8

Term only 2 1399840 2.2 0.7 - 7.2

Design†

Prospective 13 5426387 9.7 1.7 - 53.8

Retrospective 8 4138386 10.3 1.3 - 80.4

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Table 3: Incidence of severe neonatal jaundice per 10,000 live births, among all neonates aged 24 months or less

WHO Region N Live births Incidence* 95% CI

Overall† 21 9564773 9.9 2.8 - 35.6

African 1 5256 667.8 603.4 - 738.5

Americas 8 5304539 4.4 1.8 - 10.5


European 7 3212230 3.7 1.7 - 8.0

South-East Asian 2 146386 251.3 132.0 - 473.2

Western Pacific 2 894672 9.4 0.1 - 755.9

* Test for subgroup differences (Cochran Q= 346.9, p< 0.001) † I2 = 99%, Cochran Q= 34721, p< 0.001 N: Number of studies, CI: Confidence Interval

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Table 4: Incidence of exchange transfusions, per 10,000 live births, among all neonates aged 24 months or less

WHO Region N Live births Incidence* 95% CI

Overall† 16 9437479 8.4 2.7 - 25.7

African 1 5256 186.5 153.2 - 226.8

Americas 6 5181411 0.38 0.21 - 0.67


European 6 3209806 0.35 0.20 - 0.60

South-East Asian 1 145623 107.1 102.0 - 112.5

Western Pacific 1 893693 0.19 0.12 - 0.31

* Test for subgroup differences (Cochran Q= 1501.2, p< 0.001) † I2 = 99%, Cochran Q= 8730.7, p< 0.001 N: Number of studies, CI: Confidence Interval

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Table 5 Meta-regression analysis potential factors* influencing the heterogeneity of incidence of severe neonatal jaundice

Variable Coefficient 95% Confidence Interval P value

Intercept -6.55 -8.76, -4.81 0.001

Study design -0.48 -1.75, 0.79 0.461

Study duration -0.15 -0.32, 0.03 0.100

Gestation -0.18 -1.64, 1.28 0.812

Income 3.59 1.79, 5.38 0.001

*Study design (prospective vs. retrospective); Study duration (years); Gestation (All vs. term and near term); Income (low vs. high) based on World Bank classifications (https://datahelpdesk.worldbank.org/knowledgebase/articles/906519)

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Figure Legend:

Figure 1: Flowchart of study selection for the meta‐analysis Figure 2: Pooled incidence (per 10,000) of severe neonatal jaundice among all neonates aged 24 months or less according to study quality Figure 3: Pooled incidence (per 10,000) of severe neonatal jaundice among all neonates aged 24 months or less according to income Figure 4: Pooled proportion (%) of jaundice-related neonatal deaths among neonates aged 24 months or less with severe neonatal hyperbilirubinemia

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