Nigerian Journal of Paediatrics

Glucose 6 phosphate dehydrogenase deficiency the single most important cause of neonatal hyperbilirubinaemia in Kano Nigeria

Niger J Paediatr 2017; 44 (2): 44 – 49

ORIGINAL

Farouk ZL

Glucose-6-phosphate dehydro-

Ibrahim M

Ogala WN

genase deficiency; the single most

important cause of neonatal

hyperbilirubinaemia in Kano,

Nigeria

DOI:http://dx.doi.org/10.4314/njp.v44i2.1

Accepted: 10th March 2017

Abstract : Introduction: Glucose-

proportion (60.6%) of the inborn

6-phosphate dehydrogenase defi-

neonates had G-6-PD deficiency

Farouk ZL (

)

ciency is the most common enzy-

(x ² = 5.5, p = 0.06). Jaundice was

Ibrahim M

matic disorder of the red cell and

noticed significantly earlier in the

Department of Paediatrics

an important risk factor for neona-

G-6-PD deficient neonates (mean

Bayero University Kano/Aminu

tal jaundice.

= 2.0, SD = 1 days) compared to

Kano Teaching Hospital, Kano

Methodology: The aim of the

(mean = 2.7, SD = 1.6 days) in the

Nigeria

study was to determine the inci-

sufficient neonates (t = 2.3, p =

Email: faroukzubaida@yahoo.com

dence of G-6-PD deficiency

0.02). Sixteen (16%) neonates de-

among jaundiced neonates, and

veloped kernicterus, of these 10

Ogala WN

describe the associated morbidity

(63%) were G-6-PD deficient. The

Department of Paediatrics Ahmadu

and mortality pattern in them.

mortality rate among G-6-PD defi-

Bello University Teaching Hospital,

A prospective cross sectional

cient neonates was 15% (7 of 46)

Zaria, Nigeria.

study was conducted and we stud-

twice as much as in the sufficient

ied one hundred consecutive jaun-

neonates 7% (4 of 54). Only six

diced neonates (55 males, 45 fe-

neonates 0.6% ware exposed to

males) presenting at Aminu Kano

naphthalene of whom three were G

Teaching Hospital from between

-6PD deficient. Five babies were

2004 and August 2005. G-6-PD

given traditional medicine two of

activity was assayed by Quantita-

which were G6-PD deficient.

tive spectrophotometric method of

Conclusion: G-6-PD deficiency is

Kornberg; serum bilirubin and

an important risk factor for neona-

haemoglobin levels were esti-

tal jaundice. Jaundice appeared

mated by standard techniques.

early in the deficient neonates.

Exposure to possible Icterogenic

There is high incidence of kernic-

agents, clinical features of kernic-

terus and mortality among them.

terus and the outcome were noted.

Low admission weight

signifi-

Results: The incidence of G-6-PD

cantly contributed to the mortality.

deficiency was found to be 46%

with male to female ratio of 3:1

Key Words: G-6-PD deficiency;

( Χ = 15, p = 0.001). A higher

Neonatal Jaundice; Kernicterus

Introduction

In Southern Nigeria reported incidence was 25 to 34.4%

among neonates with jaundice. About 60% of all full

7,8

The enzyme Glucose-6-Phosphate Dehydrogenase is

term babies and 80% of preterm babies will develop

jaundice. Significant hyperbilirubinaemia is seen in

present in all cells of the body. G-6-PD deficiency is a

genetic disorder in which the enzyme is inadequate in

10.5% of full term neonates and 25.3% near term in-

fants G-6-PD deficiency predisposes to development

quantities or lacking in the red blood cells. It is inherited

as an X-linked recessive disorder It plays a key role in

of significant hyperbilirubinaemia in the neonates, with

a reported relative risk of 3.27.

3,11

the protection of cells against oxidative damage through

In 1994 neonatal jaun-

its role in glutathione metabolism.

dice was identified as one of the serious diseases affect-

It has been well-documented

2-5

that G-6-PD deficient

ing child health not covered by WHO programs in de-

neonates are more prone to neonatal jaundice than neo-

veloping countries.

nates with sufficient enzyme activity. An incidence of

G-6PD deficiency among jaundice neonates was found

The aim of the study was to determine the prevalence of

to be 12.8% among African Americans neonates, and as

G-6-PD deficiency, morbidity and mortality associated

high as 35% among Sephardic Jews, 61% in Ghana.

with G-6-PD deficiency among jaundiced neonates in

our area. There is paucity of data concerning the inci-

2000 version 1.1.2 statistical software. Statistical tests

dence of G-6-PD deficiency and its relationship with

Student’s t test for continuous variables; Fisher’s exact

hyperbilirubinaemia from Kano. This temporal gap

test, Analysis of Variance (ANOVA) and the chi-

along as well as the fact neonatal mortality and morbid-

squared test for discrete variables were employed where

ity has continued to be unacceptably high in Nigeria, the

appropriate. Probability (p) value less than 0.05 were

findings of this study will help in planning preventive

accepted as significant. Data on G-6-PD deficient neo-

measures, and consequently decreasing the burden of

nates were compared to sufficient neonates.

hyperbilirubinaemia. Neonates aged 0 to 28 days with

clinical jaundice

Results

There were 55 (55%) males and 45(45%) females’ neo-

Materials and methods

nates. Thirty-three (33%) of the babies were delivered at

AKTH and 67 (67%) were referred. Eighty (80%) neo-

The study was prospective descriptive in nature, it was

nates were born at term and twenty (20%) were born

carried at Aminu Kano Teaching Hospital, Kano Nigeria

preterm. Half of the preterm neonates were born at

from between November 2004 to and August 2005.

AKTH.

Clearance was obtained from the ethical committee of

Forty-six of 100 neonates studied had G-6-PD defi-

the hospital. Consent was obtained from the mothers of

ciency, giving an incidence of 46% with 95% confi-

the neonates. Consecutive neonates presenting with

dence interval of 36% to 56.3%. Of the 46 G-6-PD defi-

jaundice or who developed jaundice while on admission

cient neonates, 35 (76%) were males and 11 (24%) were

at the special care baby unit were enrolled. A total of

females. The male: female ratio was 3:1. The sex differ-

401 neonates were admitted into the unit during the

ence was statistically significant Table I ( Χ = 15, p =

study period, of these 115 (28.7%) had jaundice. Of

0.001).The mean G-6-PD activity in the whole study

these 100 met the inclusion criteria and were enrolled.

population of 100 neonates was 5.04 U/gHb. The mean

Neonates that had blood transfusion or whose parents

G-6-PD enzyme activity in the deficient neonates was

declined consent were excluded.

3.1, SD = 1.0 U/gHb Table I shows Jaundice was no-

For every neonate, prenatal history was obtained; history

ticed significantly earlier in the G-6-PD deficient neo-

suggestive of birth asphyxia, history of the time when

nates compared with the G-6-PD sufficient neonates

jaundice was noticed was also obtained. Exposure to

Inborn neonates were younger at presentation mean age

possible Icterogenic agents, such as naphthalene balls,

of 2.88 ± 2.3 days, range 1-9 days, compared with the

henna, dusting powder. The enrolled neonates were

mean age of 5.6 ± 4.8 days, range 2-21 days in neonates

closely monitored for morbidities like anaemia, haemo-

delivered at other hospitals and at home with the mean

globinuria, seizure, hypertonia, hypotonia, high pitched

age of 5.59 ± 2.9 days, range1-14 days. The difference

cry, windmill like movement of the limbs, retrocolis,

was statistically significant (F = 3.7 P = 0.013).

opistothonus feature s of Bilirubin Induced Neurological

Birth weight was recorded in only 39 neonates (all the

Dysfunction (BIND) Score were noted. The outcome

33 AKTH born babies and 6 babies born in other hospi-

discharge home, survival with Acute Bilirubin Encepha-

tals). This is because some jaundiced neonates were not

lopathy ABE were noted. Phototherapy or exchange

seen until they were several days old, and there was no

blood transfusion was carried out according to the proto-

record of their birth weight as they were delivered at

col of the unit.

home or other hospitals. The mean birth weight of the

39 neonates was 2925.4, SD = 752.6 g, the range 900-

Laboratory investigations on all the jaundiced neonates

5100g. The mean admission weight of all the neonates

were as follows; Blood typing (ABO and Rhesus

was 2663.5, SD = 798.0g.

groups) for mothers and the babies, blood cultures when

A total of 94 of the 100 (94%) neonates were breast-

indicated. Total and direct reacting serum bilirubin (SB)

feeding.

using the modified method of Winsten and Cehelyk

Using an auto

analyzer

(Express Plus Chiron/

Table 1 : Comparison the mean age at presentation, mean age

Diagnostics Bio-Rad® California USA). Complete

at the onset of jaundice and mean total serum bilirubin of the

blood count with supra-vital staining for reticulocyte

neonates withG-6-PD deficiency compared with neonate with

count was done on each sample. Smears for malarial

sufficient enzyme activity

parasites were done when indicated.

Quantitative spectrophotometric method of Kornberg

G-6-PD ACTIVITY

Deficient(n = 46) Sufficient(n = 44)

was used to assay the G-6-PD activity, with G-6-PDH

Mean

Mean SD

kit procedure No. 345-UV Trinity biotech Wiclow, Ire-

land. Using Spectrulab spectrometer, Surgifield  Mid-

Peak TSB

227.4 97.6

225.5 108.6 - 0.02 0.92

dlesex London. The cut off point for enzyme deficiency

Age at presentation 4.6 4.1

4.8

3.9

0.29 0.29

is any value less than 4.6 U/gHb

(days)

Age Jaundice

2.0

1.0

2.7

1.6

2.3

0.02

Statistical analysis

Was noticed (days)

Statistical analysis was done with the aid of the EPI info

Table 2 : Comparison of the mean Total serum bilirubin, Hae-

sufficient neonates t ( t = 0.78, df 98, p = 0.44).

moglobin and Reticulocyte count of the jaundiced neonates. G-

The mean weight at presentation in the neonates that

6-PD deficient compared with G-6-PD sufficient neonates

died was significantly lower (both G-6-PDdeficient and

Mean ± SD

sufficient neonates) than the mean weight at presentation

G-6-PD Status

of neonates that survive as shown in Table 5 (Anova F=

G-6-PD deficient

G-6-PDsufficient

5.6, p = 0.001).

n= 46

n= 54

Parameter

Exposure to Icterogenic substances;

TSB µmol/l

227.5 ± 96.3

225.5 ± 106

0.90

For the majority of the neonates methylated spirit was

(81.6-517.0)

(87.4-609.9)

applied to the umbilical cord. Application of heat with a

Hb g/dl

13.25±2.9

12.91±3.03

0.57*

piece cloth or a piece of clay pot was also commonly

(4-18)

used in both groups of neonates. Mentholatum ointment

R etic count % 2.5 ± 2.6

2.6± 2.1

0.70*

was applied to the umbilicus in one G-6-PD deficient

(0.2-15.1)

(0.1-10.0)

baby . Five (5%) of the total 100 neonates in the study

There was no statistically significant difference in the mean

were exposed to naphthalene balls, of which 3 were G-6

TSB, haemoglobin levels, reticulocyte count Table 2

-PD deficient. None of the deficient neonates was ex-

posed to henna dye. Five (5%) of the neonates in the

Table 3: The mean total serum bilirubin and Haemoglobin

study were given traditional medicine. Of the drugs

levels by the age of baby when jaundice was noticed. G-6-PD

known to trigger haemolysis in G-6-PD deficient sub-

deficient compared with G-6-PD sufficient neonates

jects, Chloramphenicol eye ointment was used in one

G-6-PD Status

neonate with enzyme deficiency.

Deficient

Sufficient

Age

TSB µ/

Hb g/

TSB µ/

Hb g/

Table 4 : Causes of jaundice among the 100 babies in the study

mol

onset

Aetiology

n=46

n=54

[%]

G-6-PD deficiency alone

0-1

7[15]

218.6+_1

14.7±2

5[9.3]

237.3±17

Sepsis alone

±2.5

ABO incompatibility alone

(81-547)

(9-17)

(130-

(9-15)

Weight < 2500g

547)

G-6-PD deficiency+ weight < 2500g + ABO incompatibility 4

2-3

12[6]

166+_54

14.2±2

208.5 ±

14.4±

G-6-PD deficiency weight < 2500g + sepsis

(89.6-

[38]

77 (87.4

2.0

G-6-PD deficiency + Sepsis

265.2)

(9-17)

-359.)

(9-18)

G-6-PD deficiency + ABO incompatibility,

4-7

260.7+_9

12.4 ±

243.7

12.6

ABO incompatibility + weight < 2500g

[46]

3.3

[33]

±121

±2

G-6-PD deficiency + weight < 2500g

(110-609)

(4-18)

(110-

(8-18)

Unknown

611)

Total

100 100

6[13]

250.3+_1

12.7±3

230 ±103

10.9

[19]

(121-

±3.9

n denote number of neonates

(100.1-

(8-16)

436)

(4-

394)

15)

2.9

1.6

0.3

3.7

Table 5 : The weight by the outcome among the jaundiced

0.04

0.20

0.77

0.17

neonates. G-6-PD deficient compared with the G-6-PD

sufficient neonate

Data in parenthesis denote percentage [ ] or range ( ) of values

Outcome

G-6-PD status

recorded where appropriate. n is the total number of neonates

Deficient

Sufficient

Weight (g)

in the group. F = test value for ANOVA

n=46

Mean

n=54 Mean

EBT

No ABE

2768.7 711.0 44

2788.1

689.0 5.6 0.001

Survived

ABE

2788.1 689.0

3280.0

554.0

Exchange blood transfusion was done in 26% (26 of

ABE/Died 7

2192.0 749.0

1560.0

563.9

100) neonates. Proportionally there was higher fre-

quency of EBT 60% (15 of 26) among the G-6-PD defi-

F = test values for Anova, n = number of patients. ABE =

cient compared to G-6PD sufficient neonates this was

Acute Bilirubin Encephalopathy

not statistically significant. ( c = 1.9, p = 0.16).

Other causes of jaundice singly or in combinations are

A higher proportion of the G-6-PD deficient neonates

shown in table V. Two neonates had cephalohaematoma

21% (10 of 46) had clinical features of ABE In contrast,

in association with G-6-PD deficiency. And 20 neonates

11.1% (4 of 54) of G-6-PD sufficient neonates devel-

were preterm; of these 7 have G-6-PD deficiency. Clini-

oped ABE (c = 2.1, p = 0.15) as shown in figure1.

cal diagnosis of sepsis was made in 25 neonates, of

A total of 11 neonates died giving an overall mortality

these 12 had G-6-PD deficiency. Only two (8%) had

rate of 11%. Five (45.5%) of these were preterm with

bacteriologically proven sepsis. In one G-6-PD deficient

low weigh. The mortality rate among the G-6-PD defi-

baby Staphylococcus aureus was grown, and Proteus

cient neonates was proportionately higher 15.2% (7 of

was grown in another baby with no G-6-PD deficiency.

46 neonates) than the mortality of 7.4% (4 of 54) in the

The mean duration of hospital stay was 6.38, SD 5.5

G-6-PD sufficient neonates. All the G-6-PD sufficient

days. There was no statistically significant difference the

neonates that died were preterm low birth weight.

length of hospitalization between G-6-PD deficient and

Fig 1: Morbidity and mortality pattern among the jaundiced

those of G-6-PD deficient neonates. Other workers have

neonates:G-6-PD deficient compared with G-6-PD sufficient

reported similar findings.

On the other hand, Slusher

neonates

and co- worker’s reported significantly lower values of

haematocrit in jaundiced G-6-PD deficient babies com-

pared with G-6-PD sufficient neonates. They concluded

that haemolysis was the cause of hyperbilirubinaemia in

the G-6-PD deficient neonate.

The frequency of G-6-PD deficiency was proportion-

ately higher among the jaundiced neonates inborn com-

pared with the out born babies. This finding is similar to

what was reported by other workers from Zaria Expo-

sureto yet to be identified substances e.g cleaning

chemicals in all babies born at AKTH might have con-

tributed to the jaundice in the G-6-PD deficient neo-

nates. The AKTH babies constitute a ‘homogeneous’

group or cohort. The out born neonates constituted a

wider group with a less well-defined denominator. The

babies would have been taken to any other health facility

or may have indeed been left at home. These factors

would conceivably reduce the number of out-born ba-

Discussion

bies presenting to AKTH.

Nevertheless, significant hyperbilirubinaemia in the pre-

The incidence of G-6-PD deficiency in the present study

sent study was observed among relatively higher num-

was found to be high in the order of 46% is in keeping

ber of the out born neonates compared with the inborn

with previous reports from Nigeria 34%, 25%, 62.1%

neonates, in agreement with previous reports from

7,8,11

Zaria Late detection of jaundice and delay at presenta-

The male to female ratio of 3:1 in the present study

is similar to what was previously reported from USA,

tion to hospital observed in the out-born babies might

3,4,5

Israel and Middle East

It is in keeping with what

have contributed to the greater severity of jaundice in

would be expected from the gene distribution, and the X

these neonates.

linked mode of inheritance of the enzyme deficiency.

The mean TSB in the G-6-PD deficient babies was simi-

The jaundiced inborn neonates were significantly

lar to the mean TSB in the G-6-PD sufficient neonates.

younger at presentation, compared with the out born

This finding is similar to the findings of Kaplan and co-

neonates (P = 0.013). This could be ascribed to a higher

workers, who demonstrated poor correlation between

level of vigilance for jaundice by trained hospital care-

quantitative values of enzyme activity and peak TSB

givers at AKTH, compared with staff of basic or secon-

values. Jaundice in the G-6-PD deficient neonates in the

dary health care facilities and mothers at home.

present study was noticed earlier than in those neonates

There was a high frequency of Acute Bilirubin Encepha-

with sufficient enzyme activity (p = 0.02). This finding

lopathy in the present study, 16% (16 of 100). Glucose-6

is in keeping what has been reported previously. There

-phosphate dehydrogenase deficiency was found in 63%

is some evidence that jaundice in the G-6-PD deficient

of the kernicteric babies (10 of 16). . This is similar to

neonates may have its origin in-utero. However, the age

what was reported by other workers in developing coun-

tries.

4,6,7,8

of presentation was similar between G-6-PD deficient

Even in developed countries a resurgence of

and sufficient neonates. This may suggest a significant

kernicterus is being observed in places where ABE was

previously less frequently observed.

19-21

delay (average of 2 days) from the time jaundice was

noticed and the time of presentation in these babies. This

could be the reason why greater proportion (32%) of the

A combination of late presentation and genetic predispo-

G-6-PD deficient babies in the study had EBT, also

sition (G-6PD deficiency)appear to play a great role in

21.1% developed kernicterus compared with 20% and

the high incidence of ABE observed. The present prac-

11% of the sufficient respectively.

tice of early discharge of sufficient neonates from our

hospital after delivery (within 24 hour of birth) might

The mean Hb level in the G-6-PD deficient neonate in

have contributed to late identification of jaundice in

the study was slightly low but comparable to what was

some of the neonates with consequent hyperbilirubinae-

found in the sufficient neonates. Similarly the mean re-

mia and kernicterus. The late recognition of jaundice by

ticulocyte count in the G-6-PD deficient was similar to

mother’s and/ or health care providers and delay in re-

that of the sufficient neonates. These findings may im-

ferral of jaundiced neonates to tertiary health centers

ply that G-6-PD deficiency does not show association

might have contributed to the higher frequency of ker-

with decrease in Hb or reticulocyte count This could be

nicterus in the present study.

because the G-6-PD sufficient neonates might be experi-

Exchange blood transfusion was done proportionately

encing haemolysis from other causes like blood group

more often in the G-6-PD deficient neonates than in

incompatibility, sepsis and so on. Therefore, their hae-

sufficient neonates. The mean TSB in the neonates that

moglobin and reticulocyte responses would be similar to

had EBT was higher than the mean TSB in the neonates

with no EBT (Anova F= 32 p = 0.001) and in line with

may be a reflection of low standard of living and poor

what was previously reported. In keeping with the fact

antenatal care in the environment. The setting for ABO

that severe hyperbilirubinaemia was the main indication

incompatibility was present in about a quarter of the

for EBT in the neonates.

neonates.

Sepsis did not seem to contribute significantly to hyper-

bilirubinaemia in the study

The high mortality rate of 15% (7 of 46) among G-6-PD

Only 2 neonates had bacte-

deficient jaundiced newborns in the present study is

riologically proven sepsis. This could be because a high

similar to previous reports

6, 8

Late identification of jaun-

proportion of the neonates were delivered at AKTH

dice and delay in presentation to the hospital observed in

where standard antiseptic procedures are available,

the present study could account for this pattern of mor-

which significantly reduced the likelihood of sepsis

tality. Preterm neonates contributed significantly to the

among them. And the out born neonates might have had

mortality. Low weight on admission significantly con-

antibiotics before presentation, which might affect bac-

tributed to the mortality in both the G-6-PD deficient

terial culture. This finding agrees with findings of other

and sufficient neonates. This is because of the relatively

researchers that infection does not play a significant role

high number of premature neonate in the mortality.

in the hyperbilirubinaemia associated with G-6-PD defi-

ciency.

23, 24

Exposure to naphthalene balls and Menthol containing

balm and powder among the G-6-PD deficient neonates

in the present study was not common and was seen only

The most common factor associated with jaundice in the

8.7% (4 of 46). In contrast, reports from southern

present study was G-6-PD deficiency, which was associ-

part of Nigeria found exposure rate to Icterogenic agents

ated with early onset of jaundice, and relative delay of

to be as high as 73.5%, and thus clearly demonstrated

presentation to the hospital. There was a higher fre-

the association between exposure to Icterogenic agents

quency of kernicterus among the G-6-PD deficient neo-

and jaundice in the G-6-PD deficient neonate.

The

nates, and the neonates with G-6-PD deficiency had a

observed variation in the exposure rate could be ascribed

higher mortality rate.

to cultural differences in the care of the newborn be-

The findings of the present study are indications that G-

tween Kano in the north and the southern parts of the

6-PD deficiency was an important factor in jaundice

country. It is probable that naphthalene-containing sub-

related morbidity, and it contributes significantly to the

stances were not commonly used in households in Kano.

cost of management of jaundice in the study.

Only two neonates were exposed to Mentholatum in the

present study, (one dusting powder, one mentholated

balm), both had G-6-PD deficiency.

Conclusion

Henna dye was applied to one baby only, who had suffi-

cient enzyme activity. Even though women in the north-

There is a high incidence of Glucose – 6-phosphate dehy-

ern part of Nigeria use henna for skin decoration, it ap-

drogenase deficiency among jaundiced neonates in

pears that its use in the newborn is not common.

Kano, and it was the single most important aetiological

It was difficult to evaluate the role of breast-feeding in

factor with respect to neonatal jaundice.

the etiology of jaundice in the present study, as 94% of

It is recommended that neonatal screening for G-6-PD

all the babies were breast-feeding at the time of presen-

deficiency should be done with the use of hour specific

tation. If breast-feeding contributed to neonatal jaundice

normogram to monitor the rate of rise of TSB in the

it is possible that it did so in association with other fac-

deficient babies There is a need for public heath cam-

tors in these neonates.

paign on neonatal jaundice and G-6-PD deficiency.

Other common causes of jaundice in the study included,

low admission weight being the second most frequent

cause of jaundice, similar to a previous report. And

Conflict of interest: None

twenty percent of the babies were born preterm. This

Funding: None

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