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. 2023 Jul 19;9(7):e18437. doi: 10.1016/j.heliyon.2023.e18437

Glucose-6-phosphate dehydrogenase deficiency among neonates with jaundice in Africa; systematic review and meta-analysis

Woldeteklehaymanot Kassahun a,∗, Abayneh Tunta b, Atitegeb Abera c, Mulu Shiferaw b
PMCID: PMC10393755  PMID: 37539282

Abstract

Background

Glucose-6-phosphate dehydrogenase (G6PD) deficiency is a genetic disorder caused by a structural abnormality in the enzyme. G6PD deficiency is most prevalent among African, Asian, and Mediterranean people. This study aimed to investigate how prevalent G6PD deficiency is in African neonates with jaundice.

Methods

The public sources, such as PubMed, Science Direct, Google Scholar, and Africa Journal Online were searched for articles that reported the prevalence of G6PD deficiency published before March 21st, 2022. The Joanna Briggs Institute’s (JBI) critical assessment checklist was used to evaluate the quality of individual studies. STATA-17 was used to do the statistical analysis. The pooled prevalence of G6PD deficiency in neonates with jaundice in Africa was calculated using a forest plot and a random effects model. I2 statistics and Galbraith plots were used to assess heterogeneity. Publication bias was assessed using a funnel plot and Egger’s statistical test.

Results

Ten studies involving 1555 neonates with jaundice were involved in the study. G6PD deficiency was prevalent in 24.60% of African neonates with jaundice (95% CI:12.47–36.74) with considerable heterogeneity (I2 = 100%). Nigerian neonates with jaundice had the highest G6PD deficiency (49.67%), whereas South Africans had the lowest (3.14%).

Conclusion

G6PD deficiency has been implicated in a significant portion of African neonates with jaundice, notwithstanding the need for greater research on predisposing variables from other countries. Therefore, it should be thought of performing screening and diagnostic laboratory tests for G6PD deficiency.

Keywords: Africa, Glucose-6-phosphate dehydrogenase deficiency, Hyperbilirubinemia, Meta-analysis, Neonates, Jaundice, Systematic review

1. Introduction

Around 80% of neonates worldwide have some degree of hyperbilirubinemia and jaundice. Severe cases of hyperbilirubinemia eventually result in kernicterus, leading to permanent developmental disorders. Several risk factors contribute to hyperbilirubinemia and kernicterus, including Glucose-6-phosphate dehydrogenase (G6PD) deficiency [1]. G6PD deficiency is the most prevalent enzyme deficiency in humans, affecting about 400 million people globally, with a high occurrence in African, Asian, and Mediterranean descent populations [2].

G6PD insufficiency is a genetic disorder caused by a structural flaw in G6PD, a “housekeeping” enzyme that is critical for red blood cell survival and the ability to respond to oxidative stress [3]. Single nucleotide polymorphisms (SNPs) in the protein G6PD cause single amino acid alterations, resulting in the enzyme deficiency. G6PD insufficiency has been linked to over 400 SNPs, resulting in 160 distinct amino acid alterations [4].

G6PD catalyzes the oxidation of glucose-6-phosphate to 6-phosphogluconate while reducing NADP+ to NADPH, making it the rate-limiting enzyme in the pentose phosphate pathway. The regeneration of reduced glutathione (GSH) is then fueled by NADPH, which neutralizes reactive oxygen species (ROS) [4,5]. G6PD is the principal generator of NADPH in erythrocytes, which lack mitochondria, and hence plays a critical role in ROS defense [6,7].

The deficiency of G6PD will induce an accelerated rate of hemolysis that causes serum bilirubin to be generated faster than it can be conjugated or diffuse into the skin and other bodily tissues; during this spike, bilirubin crosses the blood-brain barrier and enters brain cells [8]. Because bilirubin is lipophilic and concentrated in membrane compartments, damage occurs at the cell membranes. This causes lipid peroxidation and hinders membrane-bound proteins like ATPases from performing their tasks. Similarly, bilirubin attacks mitochondrial membranes, disrupting the electron transport chain and membrane-bound proteins, causing mitochondrial enlargement, membrane permeability, depolarization, cytochrome c release, and cell death by apoptosis and necrosis [[8], [9], [10], [11]]. High bilirubin causes behavioral and neurological damage (Neurotoxicity or Kernicterus) even in term neonates [[12], [13], [14]].

Every year, about 1.1 million babies worldwide acquire severe hyperbilirubinemia with or without bilirubin encephalopathy, with Sub-Saharan Africa and South Asia accounting for the majority [15]. According to the global burden of neonatal jaundice study, the African region has the greatest rate of severe neonatal jaundice per 1000 live births (667.8–738.5), followed by Southeast Asia (251.3–473.2) and the Americas and European regions (4.4 and 3.7, respectively) [16].

From a recent study, the pooled magnitude of neonatal hyperbilirubinemia in sub-Saharan Africa was reported about 28.08% [17]. Neonatal jaundice is frequently associated with sepsis in Africa, which is a leading cause of neonatal death. In developing Sub-Saharan African nations, newborn morbidity and mortality are still common, and neonatal hyperbilirubinemia is one of the main causes of morbidity and mortality, with G6PD deficiency being one of the linked factors [17,18]. Therefore, the aim of this systematic review and meta-analysis was to estimate the pooled prevalence of G6PD deficiency among African neonates with jaundice.

2. Methods

2.1. Search strategy

The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA-2020) guideline was followed for this systematic review and meta-analysis [19]. Published and unpublished studies reporting the prevalence of G6PD deficiency among neonates with jaundice were found in online public sources such as PubMed, Science Direct, African Journals Online, and Google Scholar up until March 21, 2022.

The search terms were used in agreement with the Medical Subject Heading (MeSH) using the arrangement of key words which were used to select related research articles. The search approach used to retrieve related articles was as follows: (Prevalence AND Glucose-6-phosphate dehydrogenase OR G6PD AND “newborn with jaundice” OR “icterus newborn” AND Africa). EndNote 20 citation and referencing manager was used to arrange references and remove duplicates.

2.2. Eligibility criteria

All original research articles published in English and containing basic information concerning sample size and prevalence of G6PD deficiency among jaundiced neonates ((0–28 days old) (age indicated at time of diagnosis)) in different parts of Africa were included. Duplicated articles, articles unable to access the full text, and abstracts were removed from the review. Moreover, studies conducted among all non-jaundiced neonates, children, unknown sample size, and lack clear figure about cases were excluded from this review.

2.3. Selection process and quality assessment

Two authors (MS and WK) individually conducted a search in PubMed, Science Direct, African Journals Online, and Google Scholar using keywords. The searched articles were screened by title and abstract to transfer the articles in the full-text review. Two authors (AA and AT) independently assessed the quality of the journals included in this review using JBI-critical appraisal checklist. The differences in the inclusion and quality of individual articles between the two authors were resolved by discussion with the third author (MS).

2.4. Outcome variable

The outcome of interest for this systematic review was G6PD deficiency prevalence among African neonates with jaundice.

2.5. Data extraction

Data extraction protocol consisting of names of the first author, year of publication, study area (country), design, sample size, and prevalence of G6PD deficiency was developed by two authors (MS and WK) and evaluated by AT and AA. The extracted data were entered in to Excel.

2.6. Data analysis

Eligible primary studies were extracted, entered into Microsoft Excel, and then exported to STATA version 17. Descriptive characteristics of the studies included were presented in tables. Forest plots were used to estimate the pooled effect size and effect of each study with their confidence interval (CI) and to provide a visual image of the data. The degree of heterogeneity between the included studies was evaluated by the inverse of variance (I2) and Galbraith plot. Publication bias across studies were evaluated by the funnel plot and Egger’s regression test objectively.

3. Result

3.1. Identification of included studies

We found 267 papers by searching Google Scholar, African Journals Online, PubMed/MEDLINE, and Science Direct, with 210, 3, 50, and 4 articles from each database, respectively. After removing the duplications, there were 260 articles left. After reading the titles, 80 articles were retained, eliminating 180. After removing 56 articles based on abstract reading, 24 remained for full article review. Finally, the pooled prevalence of G6PD deficiency among neonates with jaundice was determined using 10 papers that met the inclusion criteria (Fig. 1).

Fig. 1.

Fig. 1

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PRISMA flow diagram showing search results for the inclusion of studies focusing on G6PD deficiency among neonates with jaundice in Africa published to March 21, 2022.

3.2. Characteristics of studies included

Nine of the studies included were cross-sectional, while one was a case series. The sample sizes in the included studies ranged from 21 to 400. A total of 1555 neonates with jaundice were included in this meta-analysis. The studies were reported from five African countries, with Egypt and Nigeria contributing the most (Table 1).

Table 1.

Characteristics of studies reporting G6PD deficiency among neonates with jaundice in Africa published up to March 21, 2022.

First Author name, Publication year Country Study design Studied population (N) G6PD deficiency Prevalence (%) Age range in days Mean age in days G6PD deficiency screening/diagnosis method Reference
Mostefa M. et al., 2014 Egypt CS* 300 6.0 2–10 4.18 Quantitative Enzyme assay (Not specified) [20]
Mohammed AF. et al., 2010 Egypt Case series 69 14.4 <28 5.87 Qualitative screening (Methemoglobin reduction test) [21]
Zehra M. et al., 2013 Egypt CS 21 42.0 <28 4.66 Qualitative screening (Methemoglobin reduction test) [22]
Waffa MM et al., 2016 Egypt CS 202 8.9 1–13 3.75 Quantitative Spectrophotometric assay (Cutt-off<4.6 U/g Hb¥) [23]
Bienzle U et al., 1976 Nigeria CS 70 51.0 <28 NS** Qualitative screening (Methemoglobin reduction test) [24]
Farouk ZLet al. 2017 Nigeria CS 100 46.0 1–21 4.6 Quantitative Spectrophotometric assay (Cutt-off<4.6 U/g Hb¥) [25]
George IO et al., 2011 Nigeria CS 400 52.0 <28 NS** Qualitative screening test (Methaemoglobin reduction test) [26]
Levin Se et al., 1964 South Africa CS 159 3.14 <14 6.6 Qualitative screening test (Motulsky-Campbell technique) [27]
Ahmed et al., 2015 Sudan CS 80 3.75 <28 NS** [28]
Rym D et al., 2020 Tunisia CS 154 18.83 <28 4.5 Quantitative colorimetric assay (cut-off <7.0 IU/g Hb¥) [29]
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*Cross-sectional study.

** Not specified.

¥ Unit of G6PD activity per gram of hemoglobin (G6PD/hemoglobin).

3.3. Pooled estimates of G6PD deficiency among neonates with jaundice in Africa

The pooled prevalence of G6PD deficiency among jaundiced neonates in Africa was 24.60% (95% CI: 12.47, 36.74%) with considerable heterogeneity between studies (I2 = 100%%) (Fig. 2) however they fall in 95% confidence interval on the Galbraith plot for qualitative heterogeneity of studies (Fig. 3).

Fig. 2.

Fig. 2

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Forest plot showing the prevalence of G6PD deficiency among neonates with jaundice in Africa from studies published up to March 21, 2022.

Fig. 3.

Fig. 3

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Assessment of the qualitative variability of studies reporting a G6PD deficiency among neonates with jaundice in Africa in Africa published up to March 21, 2022, using the Galbraith plot.

3.4. Sub group analysis by country and design

The test of no difference between the groups (countries) is rejected, with chi-square test statistics of 397.04 and a p-value of less than 0.01. Subgroup analysis by county showed that the lowest G6PD deficiency was found among South African neonates with jaundice (3.14%) followed by Sudan neonates with jaundice (3.75%) while the highest was recorded in Nigeria (49.67% (Fig. 4).

Fig. 4.

Fig. 4

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Subgroup analysis of the proportion of G6PD deficiency among neonates with jaundice in Africa from studies published up to March 21, 2022.

3.5. Publication bias assessment

Funnel plot shows some studies are missing both in the right and left portion of the funnel plot, which makes it look asymmetrical. Heterogeneity may be the reason for the asymmetry of the plot. To test the asymmetry statistically, a small study effect in the meta-analysis was tested using Egger test under the random effects model and found that there was small study effect (z = 2.88, p = 0.004) (Fig. 5).

Fig. 5.

Fig. 5

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Funnel plot showing publication bias among studies reporting the prevalence of G6PD deficiency among neonates with jaundice in Africa from studies published up to March 21, 2022.

4. Discussion

Glucose-6-phosphate dehydrogenase (G6PD) enzyme is involved in the hexose monophosphate pathway, producing NADPH, which maintains reduced glutathione that maintains the oxidative state of red blood cells [30]. G6PD deficiency makes red blood cells (RBCs) vulnerable to oxidative stress, resulting in hemolysis. Clinical, biochemical, and molecular variability, as well as a wide range of prevalence, describe G6PD deficiency [[31], [32], [33], [34]]. G6PD deficiency is the most prevalent cause of neonatal jaundice, according to reports from throughout the world [17,[35], [36], [37]]. Neonatal jaundice, if left untreated, can cause neurological issues such as poor neurocognitive development, cerebral palsy, neuropathy, deafness, and death [38].

The pooled prevalence of G6PD deficiency among neonates with jaundice in Africa was 24.60% (95% CI: 12.47–36.74%) in the current study. This incidence is consistent with research conducted in Egypt (14.4%), Iraq (16%), and Tunisia (18.83%) [21,29,39], while it was higher than a global estimation for Africa (7.5%) [2] and studies done in Dubai (10.5%), Southern Brazil (4.6%), India (1.8%), Tehran (2.1%), China (8.36) and Iran (7%) [30,[40], [41], [42], [43], [44]]. However, the pooled prevalence of this study was lower than the prevalence of G6PD deficiency among Nigeria (51.0%) and Egypt (42.2%) [22,24]. These differences can be explained by the fact that different ethnic groups have different versions of the G6PD enzyme, resulting in variable degrees of severity among those who are affected. G6PD deficiency is more common in places where people have been exposed to endemic malaria in the past, such as Africa, Mediterranean Europe, Southeast Asia, and Latin America. Enzyme deficiency primarily affects African and Mediterranean-descent groups in the United States [45].

Even though there are numerical variations with in a wide range, when we compare the combined prevalence of G6PD deficiency among neonates with jaundice in Africa to the national or large population estimates of the participating countries, it was greater than Egypt (4.9%) and Sudan (5.5%) [46,47] but comparable Nigeria (24.6%) [48]. However, we couldn’t retrieve a representative estimate for Tunisia and South Africa.

More than 200 mutations have been documented for the highly polymorphic G6PD gene worldwide. However, only a small percentage of mutant G6PD variants lead to a functionally defective G6PD enzyme [49]. The geographical distribution of G6PD mutation variants in Africa is heterogenous across nations and even with in a population. The two most common G6PD variants of clinical significance on the African continent are the African-type G6PD A-variant, which is primarily found in sub-Saharan Africa, and the Mediterranean-type G6PD B- variant, which is primarily found in North Africa [50]. In addition, there are also ethnogeography specific variants reported from different parts of the continent. For example, G6PD Cairo, G6PD Aures and G6PD Chatham reported from Egypt and Tunisia [22,51]. This can result in significant differences in the prevalence of G6PD deficiency between different regions and populations as the degree of disease severity and triggering factors vary from place to place [52].

As individuals with silent manifestations will not complain and frequent investigations will not be undertaken, the incidence of G6PD deficiency may be comparatively higher in locations where variants can cause severe hemolytic anemia. Therefore, the prevalence by country level was subjected to subgroup analysis. The subgroup analysis showed that Nigerian neonates with jaundice (49.67%), Tunisians (18.83%), and Egyptians (17.82%) had higher rates of G6PD deficiency, while South African and Sudanese jaundiced neonates (3.14% and 3.75%, respectively) had lower rates of G6PD deficiency. The increased prevalence of G6PD deficiency among Nigerian neonates with jaundice could be attributed to malaria endemicity, ethnicity, and sample size differences, whereas Arab descent may contribute to the increase in Tunisia and Egypt [53,54].

In G6PD-deficient neonates, environmental variables such as maternal exposure to oxidant medications, herbal medicines, and clothes containing naphthalene may trigger or worsen neonatal jaundice [55]. Other stressors including infections, oxidative drugs, immaturity, hypoxia and fava beans can lead to acute hemolytic anemia and hyperbilirubinemia in G6PD deficient individuals include [17,56,57].

Several researchers recently concluded that hemolysis is not the cause of jaundice in G6PD-deficient neonates [58,59]. Indeed, the neonate liver’s lower ability to conjugate bilirubin appears to be the most important component, especially when G6PD deficiency is co-inherited with mutations in UDP-glucuronosyltransferase-1, which appear to be the other variable involved in newborn jaundice [60].

In addition to phototherapy and exchange transfusion for jaundiced neonates, long-lasting treatment approaches for G6PD deficient neonates are directed toward avoiding these and other stressors, which can cause acute hemolytic anemia and hyperbilirubinemia in G6PD deficient individualism [57,61].

From this analysis, we learned that the overall magnitude of G6PD deficiency is high and more frequently observed around the Northern part of the continent.

4.1. Limitations of the study

This analysis may have limitations due to the small number of publications from which full papers could be obtained and the significant heterogeneity of the studies included.

4.2. Conclusion and recommendations

This study has shown that nearly one out of four neonates with jaundice have a chance to be deficient for G6PD enzyme activity. As G6PD deficiency is a genetic mutation, the current clinical treatment approaches can only alleviate the suffering and complications. However, G6PD deficiency not only cause hemolytic anemia and hyperbilirubinemia but also sever neurological consequences like kernicterus, increased infection susceptibility and predispose to some forms of chronic disease like diabetes. Therefore, in order to provide evidence-based treatment, routine screening for G6PD activity in all neonates with jaundice could be necessary to reduce the complication of G6PD deficiency and better to incorporate it to the health care system of Africa, particularly Nigeria.

Author contribution statement

All authors listed have significantly contributed to the development and the writing of this article.

Data availability statement

Data included in article/supplementary material/referenced in article.

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper

Contributor Information

Woldeteklehaymanot Kassahun, Email: teklu1142@gmail.com, wolde.t@wldu.edu.et.

Abayneh Tunta, Email: abaynehtunta@gmail.com.

Atitegeb Abera, Email: kidiemihiret@gmail.com.

Mulu Shiferaw, Email: mulushi9804@gmail.com.

List of abbreviations and acronyms

ATP

Adenosine Triphosphate

G6PD

Glucose 6 phosphate Dehydrogenase

NADH

Reduced Nicotinamide Adenine Dinucleotide

NADPH

Reduced Nicotinamide Adenine Dinucleotide Phosphate

ROS

Reactive Oxygen Species

SNPs

Single Nucleotide Polymorphisms

UDP

Uridine Diphosphate

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