Neonatal jaundice and severity of glucose-6-phosphate dehydrogenase deficiency in Sardinian babies

We have investigated the association of neonatal jaundice (NNJ) and G6PD deficiency in consecutive births in a Northern Sardinian hospital. After excluding known causes for NNJ, and after correcting for the incidence of NNJ from unknown causes, we estimated that 20% of G6PD deficient male newborns develop NNJ resulting from their enzyme deficiency. By analyzing in detail 100 G6PD deficient babies we found no differences in birth weight or haemoglobin level between those without and those with NNJ, four of whom required exchange transfusion. We further showed by an accurate quantitative method that the residual G6PD enzyme activity was not significantly lower in G6PD deficient babies with NNJ compared to G6PD deficient babies without NNJ.     

Relationship between Exposure to Icterogenic Agents, Glucose-6-Phosphate Dehydrogenase Deficiency and Neonatal Jaundice in Nigeria

ABSTRACT. In a study of the relationship between exposure to icterogenic agents, G-6-PD deficiency and severe neonatal jaundice (NNJ) (serum bilirubin 3±205 umol/I) in 234 Nigerian term male neonates, 106 infants with severe NNJ and 128 controls, it was found that 62.3 % of the jaundiced infants and 13.3 % of the infants without NNJ were G6PD deficient (p<0.01). The proportion of infants exposed to icterogenic agents in the two groups was very similar (p<0.5). There was a strong association between exposure to icterogenic agents and NNJ in 83 G6PD deficient infants (p<0.01), but there was no association between exposure to icterogenic agents and NNJ in the whole group of 234 infants or in 151 infants with normal G6PD status. It is concluded that there is an association between genetically determined G-6-PD deficiency and exogenous agents in causing severe NNJ in Nigerian infants.     

Relationship between exposure to icterogenic agents, glucose-6-phosphate dehydrogenase deficiency and neonatal jaundice in Nigeria

In a study of the relationship between exposure to icterogenic agents, G-6-PD deficiency and severe neonatal jaundice (NNJ) (serum bilirubin greater than or equal to 205 mumol/l) in 234 Nigerian term male neonates, 106 infants with severe NNJ and 128 controls, it was found that 62.3% of the jaundiced infants and 13.3% of the infants without NNJ were G6PD deficient (p less than 0.01). The proportion of infants exposed to icterogenic agents in the two groups was very similar (p greater than or equal to 0.5). There was a strong association between exposure to icterogenic agents and NNJ in 83 G6PD deficient infants (p less than 0.01), but there was no association between exposure to icterogenic agents and NNJ in the whole group of 234 infants or in 151 infants with normal G6PD status. It is concluded that there is an association between genetically determined G-6-PD deficiency and exogenous agents in causing severe NNJ in Nigerian infants.     

Neonatal jaundice. A second 4-year experience in Toa Payoh Hospital (1986-1989).

A 4-year experience of neonatal jaundice, from 1982-1985, in Toa Payoh Hospital, Singapore was reported previously. The second 4-year experience (1986-1989) of neonatal jaundice is reported. The Department had a more liberal policy in the management of milder cases of neonatal jaundice since 1986, after acquisition of more phototherapy units. It is the purpose of this paper to examine the change in pattern of neonatal jaundice in the same department over these 2 study periods and a comparison is made. The reported frequency of neonatal jaundice in these 2 study periods rose from 7.9% to 10% of all babies in this hospital. Babies who have some form of treatment such as phototherapy are considered as cases of neonatal jaundice. However, the incidence of hyperbilirubinaemia (defined as serum bilirubin level of 255 umol/L or 15 mg/dl or greater) fell from 3.23% to 2.11% of all livebirths in these 2 study periods. ABO Incompatibility, glucose-6-phosphate dehydrogenase (G6PD) deficiency and low birth weights (LBW) remain as the common aetiological factors of neonatal jaundice. The indications of exchange blood transfusions have changed considerably. There were less exchange blood transfusions for severe neonatal jaundice due to G6PD deficiency. However, more LBW babies underwent exchange blood transfusion. No case of kernicterus was reported for more than 10 years.     

Glucose-6-phosphate dehydrogenase deficiency in neonates

Objective: Glucose-6-phosphate dehydrogenase (G6PD) deficiency is an inherited deficiency that may be the cause of neonatal hyperbilirubinemia, as has been found in several countries and among widely different ethnic groups, especially in Mediterranean region. Our aim was to study the prevalence of G6PD deficiency in relation to neonatal jaundice.Methods : From March 1998 to April 2001 we studied 705 clinically icteric neonates who were admitted to Al-Zahra and Beheshti hospitals, two teaching hospitals in Isfahan, Iran. Laboratory investigations included determination of direct and indirect serum bilirubin concentrations, blood group typing, direct coomb’s test, hemoglobin, blood smear, reticulocyte count and G6PD level.Results: In only 53(7.5%) of cases G6PD deficiency was diagnosed. In all G6PD deficient neonates no evidence of other factors known to cause hyperbilirubinemia were detected. The sex distribution was 13(24.5%)females and 40(75.5%)males in the G6PD deficient group. The mean bilirubin level in G6PD deficient and G6PD normal groups were 22.26 +/-8.36 and 18.14 +/-3.85 mg/dl, respectively (p=0.001). Phototherapy was required in G6PD deficient and other icteric neonates with duration of 3.76 +/-1.93 and 3.13 +/-2.14 days, respectively (p=0.045). Twenty-seven of the 53(50.9%) G6PD deficient infants required exchange transfusion. None of them developed kernicterus.Conclusions: Since the prevalence of severe hyperbilirubinemia among our neonates was relatively high and about half of them required exchange transfusion, early detection of this enzymopathy regardless of sex and close surveillance of the affected newborns may be important in reducing the risk of severe hyperbilirubinemia and exchange transfusion.     

Neonatal Hyperbilirubinemia in infants with G6PD c.563C > T Variant

ABSTRACT: BACKGROUND: There is a strong correlation between glucose-6-phosphate dehydrogenase (G6PD) deficiency and neonatal hyperbilirubinemia with a rare but potential threat of devastating acute bilirubin encephalopathy. G6PD deficiency was observed in 4-14% of hospitalized icteric neonates in Pakistan. G6PD c.563C > T is the most frequently reported variant in this population. The present study was aimed at evaluating the time to onset of hyperbilirubinemia and the postnatal bilirubin trajectory in infants having G6PD c.563C > T. METHODS: This was a case-control study conducted at The Aga Khan University, Pakistan during the year 2008. We studied 216 icteric male neonates who were re-admitted for phototherapy during the study period. No selection was exercised. Medical records showed that 32 were G6PD deficient while 184 were G6PD normal. Each infant was studied for birth weight, gestational age, age at the time of presentation, presence of cephalhematoma, sepsis and neurological signs, peak bilirubin level, age at peak bilirubin level, days of hospitalization, whether phototherapy or exchange blood transfusion was initiated, and the outcome. During hospital stay, each baby was tested for complete blood count, reticulocyte count, ABO and Rh blood type, direct antiglobulin test and quantitative G6PD estimation [by kinetic determination of G6PDH]. G6PDgenotype was analyzed in 32 deficient infants through PCRRFLP analysis and gene sequencing. RESULTS: G6PD variants c.563C > T and c.131 C > G were observed in 21 (65%) and three (9%) of the 32 G6PD deficient infants, respectively. DNA of eight (25%) newborns remained uncharacterized. In contrast to G6PD normal neonates, infants with c.563C > T variant had significantly lower enzyme activity (mean +/- 1SD; 0.3 +/- 0.2 U/gHb vs. 14.0 +/- 4.5 U/gHb, p < 0.001) experienced higher peak levels of total serum bilirubin (mean +/- 1SD; 16.8 +/- 5.4 mg/dl vs. 13.8 +/- 4.6 mg/dl, p = 0.008) which peaked earlier after birth (mean +/- 1SD 2.9 +/- 1.6 vs. 4.3 +/- 2.3 days, p = 0.007). No statistically significant difference was observed in mean weight, age at presentation, hemoglobin, reticulocyte count, TSH level, hospital stay or in the frequency of initiation of phototherapy or blood exchange between the two groups. CONCLUSIONS: We concluded that infants with G6PD c.563C > T variant developed jaundice earlier than infants with normal G6PD enzyme levels. Compared to G6PD normal infants, G6PD c.563C > T carrying infants had significantly low G6PD activity.     

Hyperbilirubinemia in healthy neonates with glucose-6-phosphate dehydrogenase deficiency

A cohort study was carried out to assess the association between glucose-6-phosphate dehydrogenase (G6PD) deficiency, diagnosed by quantitative enzyme assay, and neonatal hyperbilirubinemia, defined as serum total bilirubin >/=15 mg/dl, in the well-baby nursery of Chang Gung Children's Hospital. Among 42,110 inborn infants, 757 male (3.54%) and 326 female (1.57%) newborns were G6PD-deficient. Compared to the occurrence of hyperbilirubinemia in G6PD-normal newborns (1.41% in male, 1.44% in female) in the well-baby nursery, a significantly higher incidence was observed in both G6PD-deficient male (11.36%) and female (7.06%) newborns. Further analyses demonstrated that the enzyme activity of G6PD in G6PD-deficient male newborns with hyperbilirubinemia (1.56+/-1.37 U/g Hb) were significantly lower than the subjects without hyperbilirubinemia (2.01+/-1.7 U/g Hb). No significant difference was observed in G6PD-deficient female newborns with hyperbilirubinemia (6.91+/-2.76 U/g Hb) compared to those without hyperbilirubinemia (7.81+/-2.84 U/g Hb). These data suggest that the G6PD-deficient neonates are at increased risk for hyperbilirubinemia even in the nursery free from agents that can potentially cause hemolysis to G6PD-deficient red cells. The lower G6PD enzyme activity was associated with the neonatal hyperbilirubinemia in G6PD-deficient male neonates.     

Why we are still doing so many exchange blood transfusion for neonatal jaundice in Nigeria

Background  Since exchange blood transfusion (EBT) is associated with serious complications, phototherapy has been made more powerful to reduce the need for EBT in the developed world. This study was undertaken to determine the indications for EBT in neonatal jaundice (NNJ) at our unit and what proportion of EBTs was possibly avoidable. Methods  All the babies who had EBT for hyperbilirubinemia over a three-year period were included. Age, sex, weight, place of delivery, blood group of baby and mother, other investigations, management, and the outcome of the babies were recorded. Results  Of the 1686 babies admitted to the neonatal unit, 90 (5.3%) had EBT. Fourteen (15.6%) were inborn while 76 (84.4%) were out-born babies. Fifty-six (62.2%) babies were admitted primarily for NNJ while 34 (37.8%) developed NNJ during admission. Thirty-six (40.0%) of the babies had phototherapy for more than 24 hours prior to EBT either because they were of very low birthweight or NNJ was detected very early and therapy was so commenced. Sixty-eight (75.6%) babies had single EBT while the remaining 22 (24.4%) had two sessions of EBT. Factors associated with severe NNJ in babies requiring EBT included low birthweight (<2500 g, 44.4%), ABO incompatibility (30.0%), glucose-6-phosphate dehydrogenase deficiency (34.4%) and septicemia (26.1%). Twenty-seven (30.0%) of the neonates developed features of kernicterus: 26 before admission while 1 during admission; all except one were delivered outside the hospital. Conclusions  The EBT rate in our center was high. With more effective phototherapy, EBT could be avoided in most of the babies who initially had phototherapy for more than 24 hours before EBT and repeated EBT sessions. Health education of the population at risk, especially pregnant women, and early referral at the primary health care level will reduce the burden of severe NNJ.     

G6PD deficiency in neonates: A prospective study

One thousand consecutively born babies were screened for G6PD deficiency and observed for seven days for development of jaundice. Frequency of the deficiency was 3.9%, being 5% in males and 2.8% in females. Religion did not have any bearing on the frequency. Parental screening in cases of babies deficient in G6PD enzyme revealed deficiency of the enzyme in majority of the mothers. Hyperbilirubinemia developed in 48.7% of babies having G6PD deficiency : It is recommended that any neonate presenting with jaundice must be screened for G6PD deficiency not only to define the etiology of hyperbilirubinemia but also to prevent future hemolytic episodes.     

Increased incidence of hyperbilirubinaemia in 'unchallenged' glucose-6-phosphate dehydrogenase deficiency in term Saudi newborns.

The incidence of severe hyperbilirubinaemia was significantly higher among the G6PD-deficient Saudi infants born at term than in non-deficient babies (34% vs 9%) (p less than 0.005). No apparent offending factors were detected in either the babies or their mothers. All babies who developed hyperbilirubinaemia did so during the 1st week of life. The highest mean bilirubin level for all jaundiced G6PD-deficient babies was recorded on the 4th postnatal day. Although the incidence of severe hyperbilirubinaemia among our neonates was relatively high, only two of them (7%), a boy and a girl, required exchange transfusions. Five of 29 jaundiced babies with G6PD deficiency were readmitted after discharge because of significant jaundice. One required exchange transfusion. Since G6PD deficiency seems to be a relatively common cause of neonatal jaundice in Saudi newborns, early detection of this enzymopathy by cord blood screening is justified to avoid morbidity and deaths.     

Red cell pyruvate kinase deficiency in neonatal jaundice cases in India

Objective Pyruvate Kinase (PK) deficiency is the most common enzymopathy of the glycolytic pathway in erythrocytes. It constitutes one of the common causes of hereditary non-spherocytic hemolytic anemia. The aim of this study was to screen newborns in India for pyruvate kinase (PK) deficiency in relation to unconjugated hyperbilirubinemia. Methods Laboratory investigations done included complete blood counts, reticulocyte counts, direct and indirect bilirubin, assay of G6PD and PK activity, ATP and 2,3 DPG levels. All variables were studied in 50-cord blood samples from normal deliveries and 218 neonates with hyperbilirubinemia. Results 7 of the 218 cases of neonatal jaundice were PK deficient with 30–40% reduction in PK activity. These cases also had a 3–4-fold increase in 2,3 DPG:ATP ratios, which is one of the additional indicators for PK deficiency. Six of the 7 infants had a severe clinical course. Conclusion This study shows that the prevalence of PK deficiency in Indian neonatal jaundice cases is 3.21%, which is relatively high. This emphasizes the need for screening neonatal hyperbilirubinemia cases in India for PK deficiency.     

Neonatal bilirubin production-conjugation imbalance: effect of glucose-6-phosphate dehydrogenase deficiency and borderline prematurity

OBJECTIVE: To evaluate relations between production and conjugation of bilirubin in the pathophysiology of jaundice in glucose-6-phosophate dehydrogenase (G6PD) deficient neonates. METHODS: Term and borderline premature (35-37 weeks gestational age), healthy, male, G6PD deficient neonates were studied close to the beginning of the 3rd day. Blood carboxyhaemogobin corrected for inspired CO (COHbc; an index of bilirubin production) and serum total conjugated bilirubin (TCB; a reflection of bilirubin conjugation) were measured in simultaneously drawn blood samples by gas chromatography and reverse phase high performance liquid chromatography respectively. A bilirubin production-conjugation index comprising COHbc/TCB was determined; a high index reflects imbalance between the bilirubin production and conjugation processes. COHbc and TCB individually and the production-conjugation index were studied in relation to serum total bilirubin (STB) concentration. RESULTS: Fifty one G6PD deficient neonates were sampled at 51 (8) hours. COHbc values did not correlate with STB (r=0.22, p=0.15). TCB did correlate inversely with STB (r=-0.42, p=0.004), and there was a positive correlation between the production-conjugation index and STB (r=0.45, p=0.002). The production-conjugation index (median (interquartile range)) was higher in the premature (n=8) than term neonates (2.31 (2.12-3.08) v 1.05 (0.53-1.81), p=0.003). This difference was the result of changes in TCB. CONCLUSIONS: The data show that jaundice in G6PD deficient neonates is the result of an imbalance between production and conjugation of bilirubin with a tendency for inefficient bilirubin conjugation over increased haemolysis in its pathogenesis. Borderline premature infants are at special risk of bilirubin production-conjugation imbalance.     

Glucose-6-phosphate dehydrogenase enzyme activity in normal, hemizygote and heterozygote Kelantanese Malays

This prospective study was performed to quantify glucose-6-phosphate dehydrogenase (G6PD) enzyme activity in deficient males and female heterozygotes. The methods used in the study were the fluorescent spot test, G6PD enzyme electrophoresis on cellulose acetate and quantitative assays. Forty-seven children who had been detected as spot screen deficient at birth were rescreened. Their first degree relatives were also included in the study. The mean enzyme activity of deficient males was 0.74 iu/g Hb (s.d. +/- 0.8), of female heterozygotes was 6.5 iu/g Hb (s.d. +/- 3.2) and of normal males was 12.1 iu/g Hb (s.d. +/- 3.5). The mean activity in deficient males was 6.1% of normal males. Most (35 of 47) of these fell into class 2 in Beutler's classification of G6PD variants. This indicates a population which may be susceptible to favism. Female heterozygotes had an intermediate enzyme activity with a wide scatter. Using a cut off point of enzyme activity of below 9.0 iu/g Hb gave sensitivity and specificity of 87% and 84% in detecting female heterozygotes. This group could be defined more accurately by combining quantitative assays with family studies.     

Neonatal jaundice and glucose-6-phosphate dehydrogenase deficiency in Basrah

In a study on a group of 186 newborn babies presenting with jaundice, erythrocyte glucose-6-phosphate dehydrogenase (G6PD) deficiency was detected in 95 (51%) of the patients. The incidence of severe hyperbilirubinaemia appeared to be much greater in G6PD-deficient infants (46%) than in infants who did not have the red cell defect (15%). No change was found in this association when ABO incompatibility was excluded. Phototherapy did not reduce the need for exchange transfusion, which was necessary in 27 babies. Eight babies developed kernicterus and one died. Early detection of G6PD deficiency and close surveillance of the affected newborns may be important in reducing the risk of severe neonatal jaundice and kernicterus associated with G6PD deficiency in Basrah.     

Glucose-6-phosphate dehydrogenase deficiency in neonatal indirect hyperbilirubinemia

The aim of this article is to investigate the prevalence of Glucose-6-phosphate dehydrogenase (G6PD) deficiency in neonatal hyperbilirubinemia and to compare the clinical presentation and course of G6PD-deficient and normal patients. This study included a total of 624 term neonates with indirect hyperbilirubinemia from March 2001 to September 2004. Birth weight, sex, weight at admission, serum bilirubin at admission, maximum bilirubin, phototherapy duration, duration of hospitalization and the need for exchange transfusion were recorded. Laboratory evaluations included blood group typing of mother and newborn, complete blood count, peripheral blood smear, serum total and direct bilirubin, direct coombs test, reticulocyte count, serum-free T4 and TSH, urine analysis, urinary reducing substance and erythrocyte G6PD level. The analysis of the results indicated that 24 neonates with indirect hyperbilirubinemia were G6PD-deficient. No statistically significant difference was detected between G6PD-deficient and normal groups in relation to the time of onset of jaundice, reticulocyte count, hematocrit level, phototherapy duration and duration of hospitalization. Serum bilirubin at admission, maximum serum bilirubin level and the need for exchange transfusion were higher in G6PD-deficient group. From this study our conclusion is that the G6PD deficiency is a common enzyme defect causing severe indirect hyperbilirubinemia which may result in kernicterus. Early neonatal screening programmes should be instituted in countries where the deficiency is prevalent.     

Efficacy of phototherapy in neonatal hyperbilirubinaemia associated with glucose-6-phosphate dehydrogenase deficient status

The efficacy of phototherapy in a group of 427 infants with hyperbilirubinaemia associated with glucose-6-phosphate dehydrogenase (G6PD) deficiency and a comparable group of 3924 G6PD normal infants with non-haemolhtic hyperbilirubinaemia was evaluated. Phototherapy was highly effective in reducing bilirubin levels in both groups of infants, being significantly more effective in the group with normal G6PD status. Failure rate was very low (2.03/1000) in the group with normal G6PD status and nil in the G6PD deficient group. Bilirubin rebound after phototherapy was unremarkable with very few infants requiring a second exposure —4.68/1000 in the G6PD deficient group and 6.37/1000 in the G6PD normal group. All the babies tolerated phototherapy well. Phototherapy would therefore seem to be a simple and effective method for the management of severe jaundice associated with G6PD deficiency.     

A new glucose-6-phosphate dehydrogenase deficiency variant, G6PD Mizushima, showing increases in serum ferritin and cytosol leucine aminopeptidase levels

We made a diagnosis of glucose-6-phosphate dehydrogenase (G6PD) deficiency with a new mutation of 848A→G (exon 8) in a 16-year-old male patient presenting with severe hemolysis. He was administered a diclofenac sodium suppository (50 mg) at the time of first visit to our hospital because of pyrexia. In the acute phase, pyrexia, severe general fatigue, lumbar back pain, hemoglobinuria, and jaundice developed. Laboratory blood examinations showed hemolysis, and remarkable increases in serum ferritin and cytosol leucine aminopeptidase levels. Serum interleukin-6 and interferon-γ levels were also increased. No liver injury was found. He had neonatal jaundice persisting over 3 weeks. He did not have a history of chronic hemolysis or hyperbilirubinemia. Increases in serum ferritin or cytosol leucine aminopeptidase levels in G6PD-deficient patients were not reported earlier. In this case, it is presumed that infection and administration of anti-inflammatory agents induce the hemolytic episode and that hypercytokinemia deteriorates the disease condition.     

THE RISK OF JAUNDICE IN GLUCOSE-6-PHOSPHATE DEHYDROGENASE DEFICIENT BABIES EXPOSED TO MENTHOL

Abstract. Olowe, S. A. and Ransome-Kuti, O. (Department of Paediatrics, College of Medicine of the University of Lagos, Lagos, Nigeria). The risk of jaundice in glucose-6-phosphate dehydrogenase babies exposed to menthol. Acta Paediatr Scand, 69:341, 1980.—A major cause of neonatal morbidity and mortality in Lagos, Nigeria, is severe neonatal jaundice seen in G-6-PD deficient babies. The observation that the jaundice is more severe in outpatient than in inpatient babies suggests that its cause is exogenous. "Mentholated" powder which is commonly used in many clinics and at home to dress umbilical cords was suspected to be the offending agent. A controlled study of the effects of one of these powders was carried out on 60 consecutive G-6-PD deficient babies. In 30 of them the umbilical cords were dressed daily with the powder while the remaining half who were untreated served as controls. The treated babies developed statistically more significant jaundice than the controls. Inability of neonates to conjugate menthol in this power is probably responsible for the jaundice developed by these G-6-PD deficient babies. It is concluded that the use of menthol and/or camphor-containing commercial products on neonates be discontinued, especially in communities where the incidence of G-6-PD deficiency is high as the use of such products may be contributing to the severity of neonatal jaundice.     

重庆市新生儿高胆红素血症患儿G6PD基因突变类型及临床特点

目的研究重庆市新生儿黄疸儿G6PD三种常见基因突变与其临床表现特点之间的关系。初步估计其基因突变频率并探讨其临床意义和遗传学特征。方法应用突变特异性扩增系统(ARMS)法,检测54例重庆市新生儿黄疸儿的G6PD基因突变类型。结果检出G1388A突变39例(72%),G1376T突变8例(15%),未定型者7例(13%)。未检出G95A。结论本研究首次对重庆市新生儿黄疸儿进行G1388A、G1376T和A95G突变检测。提示G1388A和G1376T为重庆市新生儿黄疸儿G6PD缺乏症基因突变的主要类型。ARMS法是一种简便、快速、经济的检测G6PD已知基因突变的方法。本研究发现这两种突变类型仅见于中国人和华裔人群,具有遗传学及临床意义。     

A novel G6PD mutation leading to chronic hemolytic anemia

Glucose-6-phosphate dehydrogenase (G6PD) deficiency is an important cause of hemolytic anemia worldwide. Severely affected patients have chronic hemolysis with exacerbations following oxidative stress. Mutations causing severe chronic non-spherocytic hemolytic anemia (CNSHA) commonly cluster in Exon 10, a region important for protein dimerization. An African-American male presented at age 2 weeks with pallor and jaundice, and was found to have hemolytic anemia with G6PD deficiency. His severe clinical course was inconsistent with the expected G6PD A(-) variant. DNA sequencing revealed two common mutations (A(-)) and a third novel Exon 10 mutation. This inherited haplotype represents a novel triple G6PD coding mutation causing chronic hemolysis.