addressing the burden of neonatal hyperbilirubinaemia in countries with significant...

REVIEW ARTICLE

Addressing the burden of neonatal hyperbilirubinaemia in countries withsignificant glucose-6-phosphate dehydrogenase deficiencyBolajoko O. Olusanya ([email protected])1, Abieyuwa A. Emokpae2, Tara G. Zamora3, Tina M. Slusher4,5

1.Centre for Healthy Start Initiative, Ikoyi, Lagos, Nigeria2.Massey Street Children’s Hospital, Lagos, Nigeria3.Department of Paediatrics, University of Minnesota, Minneapolis, MN, USA4.Department of Paediatrics, University of Minnesota & Hennepin County Medical Center, Minneapolis, MN, USA

KeywordsAcute bilirubin encephalopathy, Child disability,Developing countries, Kernicterus, Phototherapy

CorrespondenceBolajoko O. Olusanya, FRCPCH, PhD, Director,Centre for Healthy Start Initiative, 286A CorporationDrive, Dolphin Estate, Ikoyi, P.O.Box 75130 VI,Lagos, Nigeria.Tel: +234 803 33 44 300 |Fax: +234 1 774 6999 |Emails: [email protected],[email protected]

Received3 January 2014; revised 3 March 2014;accepted 1 July 2014.

DOI:10.1111/apa.12735

ABSTRACTGlucose-6-phosphate dehydrogenase (G6PD) deficiency is an established worldwide risk

factor for severe hyperbilirubinaemia. This literature review examined the pattern and

management of severe hyperbilirubinaemia in low- and middle-income countries (LMICs)

where G6PD deficiency was 10% or more and found that it was frequently associated with

neonatal mortality and, or, neurodevelopmental disorders.

Conclusion: Low- and middle-income countries need to pay urgent attention to G6PD

deficiency to curtail the preventable burden of jaundice-related morbidity, mortality and

disability.

INTRODUCTIONSevere neonatal jaundice or hyperbilirubinaemia resultingfrom high levels of unconjugated bilirubin is the mostcommon cause of worldwide hospital admissions or rehos-pitalisation in the first week of life (1,2). The risk andburden of severe hyperbilirubinaemia are greatest in ethniccommunities with widespread and significant glucose-6-phosphate dehydrogenase (G6PD) deficiency (3–6). Since1989, when the World Health Organization (WHO) drewglobal attention to the epidemic of G6PD deficiency, nosystematic data on the burden of severe neonatal hyperbi-lirubinaemia in poorly resourced populations with signifi-cant G6PD deficiency has been reported (5,7). Suchevidence is needed to guide the development of a relevantroadmap for curtailing the burden of severe neonataljaundice in the affected communities (8,9). This review setout to summarise the available reports on the pattern andmanagement practices for severe hyperbilirubinaemia inthese countries since 1989 for this purpose.

SEVERE HYPERBILIRUBINAEMIA FROM G6PD DEFICIENCYG6PD deficiency is an X-linked hereditary genetic defectand the most common enzyme disorder in humans affecting

more than 400 million people globally (4). It is morecommon in men than women. The highest rates of up to34% are found in sub-Saharan Africa where it has also beenassociated with a protective effect against plasmodiumfalciparum malaria (3–5). People with black skin have oneof the highest incidences of G6PD deficiency (10). Inaddition, studies suggest that hyperbilirubinaemia may beexacerbated in ethnic African populations where (TA)npromoter polymorphism of the urine-diphosphate-glucu-ronosyltransferase 1A1 gene (UGT1A1) associated withGilbert’s syndrome is prevalent (11). Even though thepenetrance of the (TA)7 homozygous genotype is probablyincomplete as only 12.4% of European men developGilbert’s syndrome, the (TA)7 allele distribution is knownto be higher in African populations than in those of

Abbreviations

ABE, Acute bilirubin encephalopathy; CI, Confidence interval;G6PD, Glucose-6-phosphate dehydrogenase; LMICs, Low andmiddle-income countries; WHO, World Health Organization.

Key notes� Glucose-6-phosphate dehydrogenase (G6PD) defi-

ciency is an established worldwide risk factor for severehyperbilirubinaemia.

� This literature review examined severe hyperbilirubina-emia in low- and middle-income countries (LMICs)where G6PD deficiency was 10% or more and foundthat it was frequently associated with neonatal mortalityand, or, neurodevelopmental disorders.

� LMICs need to pay urgent attention to G6PD deficiencyto curtail the preventable burden of jaundice-relatedmorbidity, mortality and disability.

1102 ©2014 Foundation Acta Pædiatrica. Published by John Wiley & Sons Ltd 2014 103, pp. 1102–1109

Acta Pædiatrica ISSN 0803-5253

European decent (0.426 versus 0.387), which could placethem at higher risk for hyperbilirubinemia, especially withconcurrent G6PD deficiency (12). Furthermore, unconju-gated bilirubin levels in infants with G6PD deficiency, incombination with (TA)n promoter polymorphism, often riseexponentially from haemolysis triggered by exposure tooxidant stressors, such as sepsis and menthol-based prod-ucts (5,6,11). The precise causal mechanism between G6PDdeficiency and hyperbilirubinaemia is not yet fully under-stood. However, early detection of high-risk infants accom-panied by timely phototherapy is essential in preventingcomplications such as acute bilirubin encephalopathy(ABE) or kernicterus (8,9). Exchange transfusion may bea necessary emergency treatment to forestall ABE. This isparticularly so where phototherapy is inadequate in arrest-ing excessive bilirubin levels, when a baby presents withextreme hyperbilirubinemia or if early signs/symptomssuggestive of ABE are observed (8,9).

Timely and effective phototherapy has made exchangetransfusion a rare intervention in the developed world(13,14). This is not the case in poorly resourced G6PDdeficient populations as high rates of exchange transfusionstill prevail (15). Whereas severe hyperbilirubinaemia israrely associated with mortality in developed countries, thecondition is still a significant cause of neonatal mortality inpopulations with high G6PD deficiency (15–17). Survivorswho experienced delays in receiving phototherapy and, or,exchange transfusion are commonly associated with diverselong-term neurodevelopmental impairments (18). Thesedisorders undermine optimal growth and development inthe early years of life and compromise educational andvocational attainment throughout the life course. For mostof the affected families, the psychosocial and economicburden over the life course of 45 years or more is prohib-itive and unbearable. Poor or a lack of service infrastructurefor rehabilitating and mainstreaming children with disabil-ities in these countries further makes primary prevention,early detection and effective treatment of all high-riskinfants imperative (19).

COUNTRIES WITH SIGNIFICANT G6PD DEFICIENCYFor the purposes of this review, a country was regarded assignificantly G6PD deficient if it has a national G6PDallele frequency of at least 10% based on more recentglobal prevalence map by Howes et al. (3). This spatiallycontinuous data of population estimates with uncertaintymetrics were used as it appears to provide a markedimprovement over two prior reports on the global prev-alence of G6PD deficiency (4,5). For example, twodecades of additional surveys since the most widelyreported 1989 WHO map were used in the Howes’ data(5). Additionally, despite the stricter inclusion criteriaadopted in the Howes’ report, it has more than six timesthe number of surveys (1734 versus 280) used by a similarreport by Nkhoma et al. (4).

A total of 36 low- and middle-income countries (LMICs)met the 10% threshold (Table 1). The majority (n = 25, i.e.

70%) are in sub-Saharan Africa, while only one country isfrom the Americas. All the countries are within the tropicsor subtropics and virtually all except Egypt, Jordan andJamaica are malaria-endemic countries (Fig. 1). Benin, withan annual birth rate of 356 000, has the highest prevalenceof G6PD deficiency, at 23%, while Nigeria, with the largestannual birth rate of 6.5 million, has a G6PD deficiencyprevalence of 16.9%.

PATTERN AND MANAGEMENT OF SEVERE HYPERBILIRUBINAEMIAWe set out to review published reports in the eligiblecountries to identify gaps in the management of near-termand full-term (≥35 weeks of gestation) newborns withsevere hyperbilirubinaemia. We focused on five majorthemes covering the incidence/prevalence of jaundice: thepattern of onset and early recognition, maternal health-seeking behaviour, treatment availability and effectiveness,adverse outcomes and follow-up evaluation. Details of thesearch strategy and the databases covered are as follows.We conducted searches of the following electronic data-bases to identify relevant articles published in, or on, the 36eligible countries between 1989 and September 2013, aperiod of approximately 25 years: PubMed, Scopus, OvidEMBASE, Cumulative Index to Nursing and Allied HealthLiterature (CINAHL), WHO Library Database (WHOLIS),African Index Medicus (AIM) and African Journals Online(AJOL). The search terms were ‘neonatal jaundice’ or‘hyperbilirubinaemia’ and ‘country name’ for PubMed andScopus. The search term for the other databases wasrestricted to ‘jaundice’ for the individual countries for animproved hit of relevant articles. Only studies that providedinformation relevant to any of the specified five themeswere selected. For example, papers exclusively exploring therisk factors for severe hyperbilirubinaemia were not con-sidered relevant. Papers that focused on special subpopu-lations of mothers, such as those with multiple pregnancies,HIV, diabetes or adolescents were also excluded. Publica-tions restricted to preterm newborns or children older than1 month were excluded. The reference lists of the selectedarticles were perused for additional articles or reports onneonatal jaundice in the eligible countries. Relevant articleswere retrieved from each database, based on the title andabstract and taking account of duplicates across thedatabases. The full texts of all articles with information onour specific themes were carefully reviewed. Where thesame findings were reported by several papers, the mostrepresentative or informative was selected. Relevant pub-lished data were found for 23 of the 36 countries (seeTable 1). The key findings, supported by additional infor-mation (Data S1), are summarised as follows.

INCIDENCE OF SEVERE NEONATAL JAUNDICEPopulation-based studies using serum bilirubin estimationwere rare. Two pseudo-community-based studies werereported in Nigeria and Pakistan (20,21). In the first studyfrom Nigeria, parental history of jaundice was reported for

©2014 Foundation Acta Pædiatrica. Published by John Wiley & Sons Ltd 2014 103, pp. 1102–1109 1103

Olusanya et al. Neonatal jaundice in high-risk populations

351 (6.7%) of the 5262 enrolled infants, of which 291(82.9%) received phototherapy and 98 (27.9%) also hadexchange transfusion (20). In effect, exchange transfusionwas administered in about one-third of those who receivedphototherapy. The incidence of jaundice necessitatingphototherapy and exchange transfusion was 5.5% (95%CI: 4.9–6.2) and 1.9% (95% CI: 1.5–2.3), respectively.Although there is no uniform guideline for the manage-ment of severe hyperbilirubinaemia, the serum bilirubinthreshold for administering phototherapy was rarely below

12 mg/dL, while exchange transfusion was usually initi-ated at 20 mg/dL for full-term or near-term infants (15).However, it was not uncommon for exchange transfusionto be performed at bilirubin levels below recommendedinternational thresholds (8,9), due to early signs of ABE/kernicterus, sometimes after prolonged treatment withsuboptimal phototherapy. In the second study from Paki-stan, the incidence of jaundice, as assessed by trainedcommunity health workers, was 275 cases per 1000 livebirths (95% CI: 250.4–292.8) compared with 116 per 1000

Table 1 Profile of countries with estimated G6PD-deficiency prevalence of 10% or greater

No Country [Income class]a World region Population (‘000)G6PD deficiency allelefrequency (IQR)b

Annualbirth (‘000)c

Hospitaldelivery (%)c

1 Benin [1] West Africa 9212 23.0% (17.0–30.1) 356 87

2 Congo [2] Central Africa 3759 22.5% (17.3–29.6) 145 92

3 Solomon Islandsf [2] Pacific 536 22.3% (15.7–30.9) 17 85

4 Togoe[1] West Africa 6780 21.2% (16.7–26.6) 195 67

5 Mozambique [1] Southern Africa 23 406 21.1% (14.7–29.8) 889 58

6 Zambia [2] Southern Africa 13 257 21.0% (14.6–29.4) 622 48

7 Malawi [1] Southern Africa 15 692 20.8% (10.2–36.4) 686 73

8 Ghana [2] West Africa 24 333 19.6% (14.2–27.0) 776 67

9 Madagascarf[1] Southern Africa 21 146 19.4% (11.5–30.3) 747 35

10 Dem Rep of Congo (DRC)f [1] Central Africa 67 827 19.2% (14.7–25.1) 465 75

11 Nigeria [2] West Africa 170 123 16.9% (14.1–20.2) 6458 35

12 Tanzania [1] East Africa 45 040 16.4% (11.9–22.3) 1913 50

13 Lao People’s Dem Repf [2] Southeast Asia 6436 15.6% (11.6–20.5) 140 17

14 Sudan [2] East Africa 31 894 15.3% (12.7–18.2) n/a 21

15 Angolaf [3] Southern Africa 18 993 15.3% (10.4–22.2) 830 46

16 Senegal [2] West Africa 12 861 15.1% (11.3–20.3) 471 73

17 Pakistan [2] Central Asia 170 260 15.0% (10.8–20.4) 4764 41

18 Cote d’Ivoire [2] West Africa 21 571 15.0% (8.5–25.5) 679 57

19 Zimbabwe [1] Southern Africa 12 644 14.8% (11.2–19.4) 377 65

20 Uganda [1] East Africa 33 796 14.5% (12.8 -16.5) 1545 57

21 Cambodiaf [1] Southeast Asia 13 396 14.3% (11.8–17.2) 317 54

22 Comoros [1] East Africa 691 14.0% (5.5–30.4) 28 n/a

23 Thailand [3] Southeast Asia 63 525 13.6% (11.9–15.5) 824 99

24 Chadf [1] Central Africa 11 274 13.4% (8.5–20.2) 511 16

25 Cameroon [2] Central Africa 19 958 12.5% (9.9–15.5) 716 61

26 Gabonf [3] Central Africa 1501 12.3% (6.0–23.4) 42 85

27 Malif [1] West Africa 14 517 12.2% (8.6–17.3) 728 45

28 Iran [3] Central Asia 75 078 11.8% (9.9–14.1) 1225 96

29 Guineaf [1] West Africa 10 324 11.7% (7.4–18.8) 394 39

30 Gambiaf [1] West Africa 1751 11.5% (8.1–15.9) 67 56

31 Kenya [1] East Africa 40 863 11.3% (9.2–13.7) 1560 43

32 Iraq [3] Middle-East 31 467 10.6% (8.1–13.5) 1144 65

33 Azerbaijanf [3] Central Asia 8997 10.2% (8.9%–11.7) 184 78

34 Egyptd [2] Middle-East 82 537 10–15%e 1866 72

35 Jordand [3] Middle-East 6330 10–15%e 154 99

36 Jamaicad [3] Americas 2751 10–15%e 50 97

aWorld Bank’s GNI per capita classification: [1] Low income: $1025 or less; [2] Lower middle income: $1026 to $4035; [3] Upper middle income: $4036 to

$12 475.bHowes RE, et al. G6PD deficiency prevalence and estimates of affected populations in malaria-endemic countries: a geostatistical model-based map. PLoS Med.

2012;9(11):e1001339.cUnited Nations Children’s Fund (UNICEF). State of the world’s children 2013: Children with disabilities. New York, UNICEF, 2013.dNonmalaria-endemic country.eEstimated range provided by authors based on additional data from other sources.fRelevant published data not found.


Neonatal jaundice in high-risk populations Olusanya et al.

live births (95% CI: 101.3–131.9) based on physicianvisual assessment of the Cephalocaudal progression scale(21). Among the 125 (26.8%) newborns in whom plasmabilirubin could be determined from the 466 referred bycommunity health workers, 13.0 per 1000 live births (95%CI: 7.6–18.4) and 3.5 per 1000 live births (95% CI: 0.4–5.5) were estimated to have serum bilirubin levels of 15–20 mg/dL and >20 mg/dL, respectively. Barring minorvariations across research on the threshold for severehyperbilirubinaemia, the reported rates in these twocountries were well above the range of 7.1 and 45 per100 000 live births reported in developed countries (22).This is consistent with the expected impact of clinicallysignificant G6PD deficiency, the presence of urine-diphos-phate-glucuronosyltransferase 1A1 gene polymorphism(11) and widespread exposure of newborns to menthol-based products, such as creams and powder for dressingthe umbilical cord as well as naphthalene–camphor ballsto preserve infant clothing against moths (20). Other riskfactors such as Rhesus disease, ABO incompatibilities andsepsis could not be ruled out completely. Few researchstudies have suggested that the prophylactic use of poten-tially haemolytic vitamin K3 for bleeding in newborns mayhave contributed to this burden (23,24). Several hospital-based studies have also shown that severe hyperbilirubi-naemia remains a leading cause for hospital admissionsand readmissions of newborns in high- and low-incomecountries (2,25,26).

ONSET AND RECOGNITION OF NEONATAL JAUNDICEThe proportion of babies delivered in a health facilityranged from as low as 16% in Chad to 99% in Thailand andJordan (Table 1). The 36 countries we studied recordapproximately 32 million live births a year, and about40% of these are delivered outside hospitals. In the majorityof the healthy infants delivered in hospitals, onset ofjaundice occurred after discharge. Regardless of the placeof birth, onset of jaundice in the vast majority occurred inthe infants’ homes. Therefore, mothers and carers wereoften the first to detect the onset of jaundice in the majorityof the affected infants. Bilirubin estimation for the earlydetection of high-risk newborns for subsequent monitoring,as recommended in developed countries, was rare and infact impracticable among infants delivered outside hospitals(8,9). Routine community-based screening for G6PD defi-ciency to identify high-risk newborns, as recommended bythe WHO, was also uncommon (5). Surveys suggested thatmost mothers had some knowledge of jaundice, but this wasoften poorer among first-time mothers (26–29). Studies inNigeria, for example, showed that more than three-quartersof mothers who claimed to be aware of jaundice were ableto accurately recognise one or more of its clinical featurestypically through the yellow(ish) colour of the baby’s skin,sclera and mucous membranes (28,29). Health workerswere often cited as the main source of information onjaundice, and this was primarily obtained during antenatalclinics.

Figure 1 Countries with estimated G6PD deficiency allele frequency of 10% or greater.



MATERNAL HEALTH-SEEKING BEHAVIOUR AND PRESENTATION INHOSPITALWith the exception of community health workers andphysicians, there was no evidence that mothers weretrained to assess the severity of jaundice based on Kramer’sscale of Cephalocaudal progression (30). The same obser-vation has been reported in other settings (31). Even whenthe onset of jaundice was accurately recognised, thedecision to seek treatment for the child was mainlyprompted by advanced signs of severe hyperbilirubinaemia,such as cessation of feeding, abnormal movements/cryingor possible seizures (27,28). Glaring failure of prior self-medication with antibiotics or traditional therapies was alsoa common reason for going to the hospital. Clearly,maternal awareness and knowledge of jaundice are notalways accompanied by appropriate health-seeking prac-tices (28,29). Mothers are generally not able to determinevisually the level or severity of jaundice in their babies.Many are also unaware of the possible harmful effects ofmany haemolytic agents used traditionally in newborn care(32). Prior success of treating physiological jaundice in theaffected infants with traditional therapies such as herbalconcoctions (33), water extract of unripe paw-paw (27) orexposure to direct sunlight (29) fosters widespread miscon-ceptions on the efficacy of these therapies for treatingpathologic jaundice. Many infants with severe hyperbiliru-binaemia, therefore, presented late in hospitals as emergen-cies (15,27,28).

Two studies from Nigeria and Iran perhaps best exem-plify the maternal health-seeking patterns in our focalcountries (27,28). In the Nigerian study, late presentationwas defined as an interval ≥48 h between observation anddocumentation of jaundice at presentation to the hospital,and it reported that 62 (34.1%) mothers of the 182 babiesenrolled delayed seeking appropriate care for jaundice(28). In this group, the period of delay was 48–96 h among48 (77.4%) babies, 120–168 h for seven (11.3%) babiesand more than 168 h for seven (11.3%) babies. Themajority (112 or 61.5%) of the mothers administeredvarious forms of self-medication at home before going tohospital. Moreover, infants who experienced delayed care≥48 h were at significantly higher risk of ABE/kernicterus(RR: 2.4; 95% CI: 1.76–3.35) and exchange transfusion(RR: 1.7; 95% CI: 1.33–2.29). Similarly, in the Iranianstudy, 40% of mothers of 1666 infants hospitalised becauseof jaundice initially attempted various traditional therapiesbefore seeking medical consultation (27). Possible reasonsfor sequential care-seeking practices included poor per-ception of the seriousness of this illness and previousnegative experiences with health service facilities, as wellas financial and accessibility constraints (34). The need totrain community health workers as facilitators of appro-priate health-seeking practices by mothers was also dem-onstrated in one study that found that some of theseworkers delayed referral for appropriate hospital care forthe affected infants regardless of their knowledge of thecondition (35).

DIAGNOSIS OF SEVERE HYPERBILIRUBINAEMIAClearly defined clinical pathways or uniform guidelines forthe management of severe hyperbilirubinaemia were rarelyreported (36). In some settings, management of jaundicewas based on adaptations of the WHO guidelines (37) orthe American Academy of Paediatrics guidelines (9,38). Thenormograms recommended by the American Academy ofPaediatrics were frequently used, with or without modifi-cation, to predict the risk and severity of hyperbilirubina-emia. However, objective and reliable evaluation of theseverity of hyperbilirubinaemia based on plasma bilirubinestimation was frequently hampered by the lack of bilirubinmeasuring/monitoring devices and in-house laboratoryfacilities (39,40). Clinical investigations for blood groupincompatibilities and G6PD deficiency to determine therisk profile of infants were not routinely undertaken, evenin some tertiary hospitals. In some hospitals, laboratorieswere not in close proximity to the neonatal ward, therebyforestalling real-time bilirubin monitoring. So, treatmentdecisions were frequently restricted to visual assessment ofCephalocaudal progression and, or, early signs of ABE/kernicterus. Good correlation between the noninvasivetranscutaneous bilirubin measurement and the more inva-sive but diagnostic total serum bilirubin assessment hasbeen demonstrated in few countries (41). This has encour-aged the wider use of transcutaneous bilirubin with, orwithout, total serum bilirubin measurement in many hos-pitals. However, the cost of a typical relatively inexpensivetranscutaneous bilirubin device of about US$5000 or more(compared with total serum bilirubin devices) still prohib-ited their use outside tertiary hospitals.

TREATMENT AVAILABILITY AND EFFECTIVENESSThe therapeutic effects of conventional blue-light emittingphototherapy and exchange transfusion were widely dem-onstrated across different hospital-based studies. However,these facilities were not routinely available in most hospi-tals, thereby compounding delays in presentation at appro-priately equipped hospitals, usually in major tertiaryinstitutions (28). Effective phototherapy entails specificblue-light wavelengths (peak emission: 450 � 20 nm), pref-erably in a narrow bandwidth that is delivered at anirradiance of ≥30 lW/cm2/nm to about 80% of an infant’sbody surface area (42). In some settings where photother-apy was routinely offered, treatment effectiveness wasusually compromised by erratic power supplies, suboptimalirradiance levels, frequent breakdowns and poor devicemaintenance (43). Jaundiced infants across cultures werealso exposed to direct sunlight with, or without, supportfrom health workers (44–46). Safety concerns had led tomany guidelines in developed (8,9), and some developingcountries (47) to expressly discourage the use of sunlightphototherapy. However, the prospects of carefully con-trolled and safe utilisation of sunlight phototherapy throughspecially filtered canopies have been demonstrated in anumber of research in this region (48,49). The canopies



allow mothers to sit comfortably while holding or feedingtheir babies during treatment. This simple, low-cost deviceholds promise for some of the 36 countries in this reviewparticularly those located within the tropics where effectiveconventional phototherapy is not readily available.

Lack of effective or intensive phototherapy increased thefrequency of ABE/kernicterus and exchange transfusions inmany countries (15). In fact, exchange transfusion was morefrequently offered without objective assessment of thebilirubin levels as practiced in high-income countries pre-emptively to avoid imminent fatal outcome resulting fromkernicterus or bilirubin-induced neurological damage.Whileexchange transfusions were often linked with reversibleadverse events, such as thrombocytopenia, hypocalcaemia,aponea and infection, they were also more commonlyassociated with mortality, particularly in sub-Saharan Africa(15–17,50). Lack of routine screening for G6PD-deficiency-exposed infants to the risk of receiving exchange transfusionwith G6PD-deficient donor blood which prolonged theduration of phototherapy and fostered avoidable repeatexchange transfusions (51).

ADVERSE OUTCOMES AND FOLLOW-UP EVALUATIONBesides its contribution to hospitalisation in the first weekof life, severe hyperbilirubinaemia was associated withsignificant morbidity (2,25,26) and mortality (15–17). Inaddition, the effects of bilirubin-induced neurological dam-age, such as cerebral palsy, hearing impairments, epilepsy,gross motor deficits, behavioural problems and intellectualdifficulties, have been reported in some countries(18,52,53). However, studies correlating long-term devel-opmental sequelae with serum bilirubin levels were sparse.Follow-up evaluation of survivors of severe hyperbilirubi-naemia for potential neurodevelopmental sequelae wasuncommon in these countries. For example, auditorybrainstem response audiometry for hearing impairment orfollow-up for cerebral palsy was rarely done, possiblybecause survival was often regarded as the sole end-pointor outcome of interest. Availability of facilities for develop-mental screening and evaluation, as well as rehabilitativesupport services for survivors of severe hyperbilirubinaemiawith developmental impairments, were major challenges inthese countries with possible risk of infanticide and mercykillings (54).

ADDRESSING THE BURDEN OF SEVERE HYPERBILIRUBINAEMIAImproving maternal awareness to encourage appropriatecare-seeking behaviour and discourage the use of haemo-lytic agents and potentially harmful traditional therapies isparamount in ensuring timely treatment of infants with, orat risk of, severe hyperbilirubinaemia. There is a need todevelop relevant clinical pathways for the management ofinfants with neonatal jaundice from the time of firstdetection to presentation at different levels of healthcaredelivery in primary care centres, secondary/district hospi-tals and tertiary/teaching hospitals.

The early identification of G6PD deficiency provides anaetiological diagnosis for severe hyperbilirubinaemia, aswell as the opportunity to offer the newborn’s familyvaluable information on the prevention of a potentialhaemolytic crisis. The recommendation of the WHOWorking Group is that population screening of all newbornbabies should be carried out in areas with a prevalence ofG6PD deficiency of 3–5% or more in men (5). Therefore,screening for G6PD deficiency in all the countries in thisreview therefore needs to be promoted, wherever possible,to facilitate early detection of high-risk infants, as universalscreening of all newborns would seem impracticableimmediately in many settings due to resource constraints.However, such screening should be routine in all secondaryand tertiary points-of-care for neonatal jaundice. Cost-effective tools for accomplishing this intervention havebeen demonstrated in several resource-limited countries(55,56).

It is also important that infants presenting in healthfacilities receive effective treatment. Provision of photo-therapy units is necessary, but not sufficient, to achieve thisgoal. Health workers need to be trained on the proper useof conventional blue-light phototherapy, paying closeattention to periodic monitoring of the irradiance levelsand general equipment maintenance. Where sunlightphototherapy can be safely implemented with window-tinting films, this option should be explored especially insettings where effective conventional phototherapy isimpracticable. The intervention goal of reducing the fre-quency of exchange transfusion to the barest minimummust be shared by all service providers, considering that thisprocedure is not entirely risk free. For infants whounavoidably have to be treated with phototherapy orexchange transfusion, every effort should be made to ensurethat they undergo development assessment including objec-tive hearing test in the first year of life.

CONCLUSIONThis review has shown that the burden of severe hyperbi-lirubinaemia is substantial in poorly resourced populationswith significant G6PD deficiency, although we did notexplore the various G6PD mutations and their severity. Thevast majority of these countries lack clearly defined practiceguidelines and face many daunting, but surmountablechallenges in the optimal care of newborns with neonataljaundice, many of whom develop ABE/kernicterus or die.The risk of mortality and the dire future awaiting survivorsshould stimulate the development of appropriate nationalroadmap that encompasses primary prevention, earlydetection and improved management of severe hyperbiliru-binaemia in these populations without further delay. Whiledata were not available from 13 of the eligible 36 countries,the key findings should be applicable to the other countrieswho share similar geographical, socio-economic and cul-tural practices. Additionally, it is unlikely that these findingswill not be relevant to other LMICs with less ‘significant’deficiency based on the 10% threshold. Finally, the



evidence from this review demonstrates clearly that theglobal response first proposed by the WHO in 1989 shouldbe revisited to reduce the burden of severe hyperbilirubi-naemia due to G6PD deficiency.

ACKNOWLEDGEMENTSThe authors gratefully acknowledge the contributions ofRosalind Howes and colleagues for the supplementary dataon the national G6PD deficiency frequency from nonma-laria-endemic countries used in this report. We thankVinod Bhutani, Professor, Department of Pediatrics Stan-ford University, Stanford, CA, USA for his invaluableperspectives on an earlier draft of this manuscript andMichael Kaplan, Professor, Department of Neonatology,Shaare Zedek Medical Center, Jerusalem Israel, for sharinghis expertise on Gilberts syndrome in the current editionand for his invaluable contributions to an earlier draft ofthis manuscript.

FUNDINGNone.

CONFLICT OF INTERESTSNone declared.

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SUPPORTING INFORMATIONAdditional Supporting Information may be found in theonline version of this article:

Data S1. Supplementary literature on the pattern andmanagement of severe hyperbilirubinaemia from eligblecountries.



addressing the burden of neonatal hyperbilirubinaemia in countries with significant...

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