PEDIATRICS Vol. 106 No. 6 December 2000, pp. 1478-1479

COMMENTARY:
Glucose-6-Phosphate Dehydrogenase-Deficient Neonates: A Potential Cause for Concern in North America

In the last 2 decades there has been an accumulation of evidence of a possible resurgence of kernicterus in North America.^1,2 Many of the affected infants also had glucose-6-phosphate dehydrogenase (G-6-PD) deficiency, suggesting a relationship between the 2 conditions, as has been illustrated by several case reports.^3-7 In addition, this enzyme deficiency has recently been listed among the 10 most important factors contributory to nonhemolytic neonatal jaundice.⁸ Despite this, there are still many pediatricians and neonatologists practicing in the United States or Canada who regard G-6-PD deficiency as a condition confined to the Middle East or Orient and with little application to the patients under their care. Even as recently as 1998 and 1999, Maisels and Newman⁹ and Maisels⁸ were of the opinion that many American pediatricians did not think about G-6-PD deficiency as a likely cause for severe neonatal hyperbilirubinemia. Brown et al¹⁰ confirmed this impression with their finding that very few infants readmitted for hyperbilirubinemia in the greater New York area had had a test for G-6-PD deficiency performed.

Within certain population subgroups of the North American continent, especially blacks, and also among descendents of immigrants from Asia, Southeast Asia, Greece, and Italy (especially Sardinia), and Sephardic Jews, the incidence of G-6-PD deficiency may be sufficiently high to merit concern. By far, the largest such group is that of the blacks of whom 11% to 13% have been found to be G-6-PD-deficient.^11-14 Presuming the 1996 birth rate of 594 781 for this subgroup to be representative,¹⁵ and the male:female ratio to be 1:1, then between 32 000 and 39 000 black male G-6-PD-deficient hemizygote neonates will be born annually in the United States. These infants are potentially at high risk for severe neonatal hyperbilirubinemia. Unfortunately, the magnitude of the problem is unknown as there are, to date, no prospective population-based studies determining the incidence of severe hyperbilirubinemia in G-6-PD-deficient neonates in this population subgroup, nor, in fact, for any of the other subgroups with a high potential for G-6-PD deficiency in North America.

The original reports from Greece, and subsequently from other countries, in the early 1960s, of severe hyperbilirubinemia and kernicterus in association with G-6-PD deficiency were primarily of infants with the severe G-6-PD Mediterranean mutation. However, a high rate of G-6-PD deficiency-associated kernicterus and death in Nigeria and South Africa soon made it apparent that African infants with the less severe Gd A- mutation were also susceptible.^16-19 G-6-PD-deficient blacks born in North America, who can be expected to be genetically similar to their African counterparts, may also therefore be at high risk for bilirubin induced disease. The reason for the possible misconception that G-6-PD deficiency is not a significant problem in North America lies in some earlier reports showing that neither daily serum bilirubin levels, nor the incidence of hyperbilirubinemia, were significantly higher in G-6-PD-deficient neonates than in controls.^13,20,21 Reinforcing the concept that G-6-PD deficiency associated neonatal jaundice is not a cause for concern among black neonates may be the data that, as a group, black newborn infants in the United States have a lower incidence of hyperbilirubinemia (12.1%) than whites (20.0%) or Orientals (49.2%).²²

On the other hand, sufficient evidence has now accumulated showing that G-6-PD deficiency may well predispose to severe jaundice in neonates of these high-risk subgroups. For example, in New York City, Lopez and Cooperman²³ described 4 cases of hyperbilirubinemia in G-6-PD-deficient neonates, 3 of whom were in blacks. Brown et al^24,25 found that when jaundice and anemia developed in the first few days of life in black infants free of blood group incompatibilities, a high proportion of them were found to be G-6-PD-deficient. Karayalcin et al²⁶ reported 19 term black newborns with G-6-PD deficiency who developed hyperbilirubinemia, without any other demonstrable cause for the icterus. In Jamaica, where the G-6-PD mutation is also A-, G-6-PD deficiency was found in a high proportion of term infants with severe, unexplained jaundice, including some with kernicterus.²⁷ Eshaghpour et al¹⁴ studied male black premature infants in 2 Philadelphia, Pennsylvania, hospitals, and found that many of those who were G-6-PD-deficient developed serum bilirubin levels high enough to warrant exchange transfusion.

In an attempt to systematically collect data about infants who developed kernicterus, Johnson and Brown² have introduced an informal "Kernicterus Registry." Despite its limitations, including the fact that reports are made on a voluntary basis, and that there have been no set criteria for defining kernicterus, a preliminary report of these cases do give some idea as to the role of G-6-PD deficiency in the development of kernicterus: of 80 US infants recorded from 1984 to 1998, 18 (22.5%) were G-6-PD-deficient. Although we are aware that these 18 cases represent only a minute fraction of all the infants at high risk for G-6-PD deficiency who were born in the United States during that 14-year period, it must be taken into consideration that as the neurologic sequelae are permanent, and as kernicterus is entirely preventable, provided excessive hyperbilirubinemia and infections are identified and treated early, even these 18 tragic cases should ideally have been avoided.

Of course, other factors such as breast milk, or poor nursing technique, and perinatal factors such as maternal diabetes or use of oxytocin to induce or augment labor, on the backdrop of G-6-PD deficiency, may also exacerbate hyperbilirubinemia. Clearly, the fact that a G-6-PD-deficient infant also develops kernicterus does not mean that G-6-PD deficiency was the primary cause of the severe hyperbilirubinemia. However, there is little doubt that, under certain circumstances, G-6-PD A- may be a predisposing cause of hyperbilirubinemia in North America. Unfortunately, few authors of textbook chapters have attempted to warn readers that term G-6-PD-deficient black neonates may indeed develop severe hyperbilirubinemia.²⁸ Readers of some texts published as recently as 1999²⁹ would certainly receive the impression that, in black infants with G-6-PD deficiency, only prematures are at increased risk for spontaneous hemolysis or neonatal hyperbilirubinemia while term G-6-PD-deficient neonates of this population subgroup go unscathed. Thus, when a black, term infant develops significant jaundice, the possibility of G-6-PD deficiency may not be considered.

Public awareness that certain agents including Chinese remedies, naphthalene, henna, and fava can produce hemolysis and hyperbilirubinemia in G-6-PD-deficient newborns could prevent severe jaundice in some infants. However, this is unlikely to be helpful in the majority of cases as, in most cases, no trigger can be identified, nor is there any convenient in vitro test that will identify the hemolytic potential of new drugs or household chemicals and sprays. Although drugs or chemical agents have been regarded as the primary inducers of hemolysis, Beutler³⁰ has emphasized that infection may be an even more common trigger of clinically evident hemolysis. This concept may be supported by recently reported cases of documented infections in G-6-PD-deficient neonates with kernicterus.^3,5 Clearly, transiently diminished physiologic bilirubin conjugation in the face of even moderately increased hemolysis may increase the susceptibility to hyperbilirubinemia. Although carboxyhemoglobin studies have shown a clear role for excessive hemolysis in the pathogenesis of kernicterus in some population groups, in others increased hemolysis clearly cannot completely explain the jaundice and may not be the primary icterogenic factor.³¹ Certainly, ABO incompatibility, superimposed on G-6-PD deficiency, did not result in either increased hemolysis or a significantly increased incidence of hyperbilirubinemia than any one of these conditions individually.³² Rather, a crucial factor in pathogenesis of the condition has recently been identified as a deficiency in bilirubin conjugation (Gilbert's syndrome).³³

A large, prospectively designed study of G-6-PD deficiency associated neonatal hyperbilirubinemia in American blacks and other high-risk minority population subgroups would be necessary to elucidate the true dimensions of the problem. Meanwhile, in the era of early discharge, there is no easy answer to the problem of identifying G-6-PD-deficient neonates at especially high risk of developing significant jaundice. A high degree of physician awareness is essential. The importance of eliciting an adequate ethnic background history from both parents cannot be underestimated. Successful establishment of breastfeeding is mandatory. It must be pointed out that routine screening of all high risk newborns will not identify every affected G-6-PD-deficient neonate: the male G-6-PD-deficient infants will be detected, but many female heterozygyotes will be missed.³⁴ This may be of concern as heterozygotes with G-6-PD Mediterranean have recently been shown to have an incidence of hyperbilirubinemia close to that of deficient homozygote females or hemizygote males.³⁴

An alternative way to determine the risk of subsequent hyperbilirubinemia, and facilitate follow up of a target group, would be to routinely perform a single serum bilirubin measurement at the time of routine metabolic screening, and to plot this value on a nomogram timed according to age in hours at the time of sampling, as described by Bhutani et al.³⁵ Both in low-risk neonates³⁵ and now in high-risk G-6-PD-deficient newborns as well,³⁶ it has been shown that those infants with a timed serum bilirubin value below the 50th percentile had a very low risk of developing hyperbilirubinemia. It would appear that these G-6-PD-deficient infants with predischarge hour-specific bilirubin values below the 50th percentile can be safely discharged along with their G-6-PD normal counterparts. On the other hand, those G-6-PD-deficient infants who had timed serum bilirubin values above the 50th percentile but below the 75th percentile were at moderate risk for hyperbilirubinemia (23%), while of those above the 75th percentile, 82% developed a serum total bilirubin value 15.0 mg/dL, compared with 25% of controls (P < .0001). This is the subgroup of newborns that has to be meticulously observed for the development of jaundice. Universal predischarge bilirubin screening would undoubtedly complement visual recognition of significant jaundice that might be hampered by skin pigmentation. Certainly those infants discharged within 48 hours of birth should, according to guidelines of the American Academy of Pediatrics, be examined by an experienced health care provider within 48 hours of discharge.³⁷ After discharge, attention must be paid to instruction in breastfeeding technique and in support for the breastfeeding mother. Careful observation for the development of jaundice with timely institution of therapy, coupled with awareness that G-6-PD deficiency does exist as a risk factor in black and other population subgroups in North America, should decrease the likelihood of kernicterus, a rare but devastating condition.

Michael Kaplan, MB, ChB
Cathy Hammerman, MD
Department of Neonatology
Shaare Zedek Medical Center
Faculty of Medicine of the Hebrew University
Jerusalem 91031, Israel

FOOTNOTES

Received for publication Jun 14, 1999; accepted Feb 16, 2000.

Address correspondence to Michael Kaplan, MB ChB, Department of Neonatology, Shaare Zedek Medical Center, Box 3235, Jerusalem 91031, Israel. E-mail: kaplan{at}cc.huji.ac.il

ABBREVIATIONS

G-6-PD, glucose-6-phosphate dehydrogenase.

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