Hidden Risks: Early Discharge and Bilirubin Toxicity Due to Glucose 6-Phosphate Dehydrogenase Deficiency

(1)

Hidden

Risks:

Early

Discharge

and

Bilirubin

Toxicity

Due

to

Glucose

6-Phosphate

Dehydrogenase

Deficiency

Mhairi C. MacDonald, MBChB, FRCP (E), DCH

A little learning is a dangerois thing; Drink deep or taste not the Pierian spring: These shallow draughts intoxicate the brain, and

drinking largely sobers us again.

-Alexander Pope (1688-1744)

In the United States today it is common for a

mother and her term newborn to leave the hospital at

12 to 48 hours postnatally. Current opinion varies

widely regarding the desirability of this practice.

Proponents of early discharge claim that it is safe and

may be advantageous; opponents argue that

detec-tion of significant illness may be missed or delayed.

Economic considerations often limit the choice of

families and their physicians; as they fund

progres-sively shorter hospital stays, managed care and

health insurance companies constitute a major

driv-ing force toward earlier postpartum discharge.

The American Academy of Pediatrics (AAP)”2 and

the American College of Obstetricians and

Gynecol-ogists (ACOG) have published criteria to be met by

early discharge candidates.2 These basic criteria

in-dude attendance at prenatal classes, instruction

re-garding common neonatal problems, uncomplicated

term delivery, normal physical examination, thermal

homeostasis, a negative Coombs test, demonstration

of basic maternal skills, including successful infant

feeding, and “physician-directed” follow-up within

48 to 72 hours after discharge.

NEONATAL MORBIDITY AND MORTALITY:

RELATIONSHIP TO TIME OF DISCHARGE

Many neonatal problems do not become apparent

for several days. However, the risks of early

dis-charge remain poorly defined. Among published

se-ries of infants discharged early, mortality rates are

low and not significantly different from those of

control infants.6 Most studies have compared

mor-bidity (rates of hospital readmission) between infants

discharged early and late and have found similar

rates of readmission between groups.79 There are

few prospective, randomized studies; those that have

been published have significant methodological

flaws.3”#{176}’6 For example, length of hospital stay

var-ies, and length of stay and timing of follow-up

over-lap with control infants; study sample sizes are

From the Division of Neonatology, Children’s National Medical Center! George Washington University School of Medicine and Health Sciences, Washington, DC.

Received for publication Apr 25, 1995; accepted Jul 19, 1995.

Reprint requests to (M.G.M.) Neonatal Intensive Care Unit, Children’s National Medical Center, III Michigan Aye, NW, Washington, DC 20010. PEDIATRICS (ISSN 0031 4005). Copyright © 1995 by the American Acad-emy of Pediatrics.

small, usually less than 100 per study. Reported

re-admission diagnoses are similar, with

hyperbiliru-binemia accounting for approximately 75%#{149}17

MANAGEMENT OF HYPERBILIRUBINEMIA

In May 1992, an article entitled Evaluation and

Treatment of Jaundice in the Term Newborn: A Kinder, Gentler Approach was published in Pediatrics.18 The

authors, TB. Newman and M.J. Maisels,

recom-mended a reduction in “standard” diagnostic tests

for hyperbilirubinemia in the term newborn and

stressed the differentiation between those infants

who demonstrated evidence of hemolysis and those

who did not. The authors indicated that infants with

demonstrable hemolysis were at far greater risk for

central nervous system damage from

hyperbiliru-binemia (kernicterus) than were infants without

ev-idence of hemolysis. In the abstract of their article the

authors state: “such infants [those without evidence

of hemolysis] need not be closely followed for

jaun-dice.” There were several invited commentaries in

the same issue of Pediatrics.’927 Overall, these

com-mentaries provided a balanced review of the

recom-mendations made by Newman and Maisels.

The following four cases of severe neonatal

hyper-bilirubinemia with resulting kernicterus,

encoun-tered by the author since March 1993, illustrate the

difference between theory and practice in newborn

care and the hidden risks of early postpartum

dis-charge in the absence of early and adequate

fol-low-up care. A search of our computerized database

back to July 1985 revealed four previous cases of

confirmed glucose-6-phosphate dehydrogenase

(G6PD) deficiency, all of which presented with

sig-nificant jaundice in the second to third days of life,

before discharge from the birth hospital. In all three

infants, their serum bilirubin was monitored as

out-patients, and they had serum bilirubin levels of less

than 21 mg/dL (342 pmol/L) at the time of

admis-sion for treatment on the fourth to sixth days of life.

Case 1

CASE REPORTS

An African-American male infant with a birth weight of 3.47 kg

was born by normal spontaneous vertex delivery to a gravida 4,

para 2 African-American mother at 39 weeks’ gestation after a

normal pregnancy. His mother received good prenatal care. He

was discharged home at 24 hours of age, breast-feeding every 2 to

3 hours. No arrangements were made for early follow-up. The

infant seemed well until 5 days of age, when he was noted by his

mother to be jaundiced and less active. At the private

pediatri-cian’s office the infant was found to be extremely jaundiced and

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sleepy. Total serum bilirubin was 42.5 mg/dL (726.75 pmol/L).

He had a mild anemia with a normal peripheral blood smear.

Physical examination on admission to the neonatal intensive

care unit (NICU) showed marked jaundice and lethargy. Total

serum bilirubin was 37 mg/dL (633.7 pmol/L). His peripheral

blood smear was normal, and his reticulocyte count was 3.6%.

Coombs test was negative.

A work-up was done for infection; antibiotics were started; and

a double-volume exchange transfusion was performed. Episodes

of apnea and cyanosis developed during the exchange transfusion

and were thought to be seizures. He became hypotonic and

opis-thotonic, consistent with kernicterus. An electroencephalogram

showed a “burst-suppression” pattern. Blood, urine, and cerebral

spinal fluid cultures remained sterile. The posturing and

hypo-tonia resolved, and he began to feed. He was discharged home

after 1 1 days in the hospital. Brain stem auditory-evoked response

testing revealed profound hearing loss bilaterally. He was found

to be G6PD deficient, as was his mother, who had never been

symptomatic. No precipitating factors (eg, oxidant drugs or infec-tion) could be determined. At 13 months of age he had persistence of a severe hearing deficit and generalized hypotonia.

Case 2

A male infant, with parents of mixed Peruvian and Chinese

descent was born by normal spontaneous vertex delivery with a

birth weight of 2.84 kg at 37 weeks’ gestation to a 16-year-old

gravida 1, para 0 mother after an uneventful pregnancy. The

mother had minimal prenatal care, and a detailed family history

was not obtained. The infant was discharged at less than 48 hours

of age, slightly jaundiced (no serum bilirubin was measured) and

was breast-feeding every 2 to 3 hours. No arrangements were

made for early follow-up. His parents recalled that he seemed well

until, at 5 days of age, he was noted to have decreased interest in feeding, lethargy, and staring spells. In the emergency department

at the birth hospital he began to make continuous lip smacking

motions and was found to be extremely jaundiced and

dehy-drated. His serum total bilirubin was 49.2 mg/dL (806.32 pmol/

L). Rehydration was initiated; a work-up was performed for

in-fection; and antibiotic therapy was started.

On admission to the NICU, vital signs included mild pyrexia

and weight of 2.5 kg (decreased 340 g from birth weight). His cry

was occasional and weak, with repetitive lip smacking and

opis-thotonus. He had a normal hemoglobin level and a decreased

white blood count (5000/mm3 with 27% bands). His peripheral

blood smear was normal, the platelet count was decreased to

92 00()/mm1, the reticulocyte count was 3.6%, and total serum

bilirubin was 39.5 mg/dL (654.45 pmol/L). Coombs test was

negative. He began receiving phenobarbital for seizures. A

dou-ble-volume exchange transfusion was performed, during which

his seizure activity and posturing worsened. All cultures

re-mained sterile. His electroencephalogram was consistent with

en-cephalopathy, and his neurologic and general clinical status

con-tinued to deteriorate. His parents agreed to placing him in “no

code” status. He died on the third hospital day. Autopsy was

refused. He was found to be G6PD deficient. Both parents were

found to carry a partial gene deletion for G6PD; both had been

asymptomatic. No precipitating factor for the hyperbilirubinemia was apparent.

Case 3

was born at 40 weeks’ gestation, to a G2P1 mother, at home after

an uneventful pregnancy. He was transferred to a hospital for

neonatal care and was discharged at less than 48 hours of life,

breast-feeding, with a bilirubin level of 9.9 mg/dL (146.19 pmol/

L). No arrangements were made for early follow-up. His parents

did not notice any abnormality until, on day 7 of life, he was noted by his mother to be jaundiced and not feeding well. At his private

pediatrician’s office the serum total bilirubin was 26.3 mg/dL

(450.73 pmol/L). Family history was significant for a healthy

17-month-old sibling with a history of neonatal

hyperbiliru-binemia.

At admission, laboratory values included a normal hemoglobin

level, normal peripheral blood smear, and a reticulocyte count of

0.49 .The serum total bilirubin was 26.3 mg/dL (450.73 pmol/L).

Phototherapy was initiated, and breast-feeding was stopped. His

biliruhin decreased within 48 hours to 13.8 mg/dL (235.98 pmol/

L). Breast-feeding was restarted, and within 48 hours he was again

significantly jaundiced, with decreased appetite and lethargy. His

serum bilirubin rose to a level of 36 mg/dL (625.6 pmol/L), and

seizures developed. His hematocrit decreased to 33% from 46.9%

the day previously, with a reticulocyte count of 1.4%. His

periph-eral blood smear began to suggest hemolysis. A double-volume

exchange transfusion was performed. Staphylococcus epidermidis

was isolated in significant numbers from his urine. The infant, his

mother, and his sibling are G6PD deficient. His mother had never

had symptoms related to her deficiency.

Case 4

was born by normal spontaneous vertex delivery to a gravida 1,

para 0 mother after a normal pregnancy. He was discharged at less

than 48 hours of life, breast-feeding. Arrangements were made for

him to be seen by a visiting nurse approximately 48 hours after

discharge. Jaundice was noted by the visiting nurse, who did not

recommend any action. The infant seemed well until on the sixth

day of life, when he was noted by his mother to be lethargic and

not feeding well. On admission to the NICU his serum bilirubin

was 41 mg/dL (711.1 pmol/L). Before a double-volume exchange

transfusion, the infant was noted to have apnea, which evolved

into frank seizures. He was treated with phenobarbital. A

peniph-eral blood count showed severe anemia; the reticulocyte count

was 8.1%. The peripheral blood smear was normal. He had a full

sepsis work-up for infection; all cultures grew Escherichia coli. He

and his mother were found to be G6PD deficient. His mother had

never had symptoms related to her deficiency. At the time of

discharge he was showing evidence of neurologic damage,

includ-ing generalized hypotonia, absence of visual tracking, and

inter-mittent sunsetting of his eyes.

DISCUSSION

Reports of the impact of early postnatal discharge

are beginning to appear in the lay press [Squires S.

Making house calls. Washington Post (Health

Sec-tion). January 10, 1995: 11-12; Boodman 5G.

Dis-charged too soon? Washington Post (Health Section).

June 27, 1995: 10-12]. Most of the data available are

anecdotal and lack reliable denominator

informa-tion. However, these data are sufficiently disturbing

that awaiting results of a controlled study involving

the very large numbers of infants required for

scien-tific verification could be questioned both from a

pragmatic and ethical viewpoint. I selected

hyperbi-lirubinemia due to G6PD deficiency with severe

cen-tral nervous system sequelae (kernicterus) to

illus-trate the hidden risks of early postnatal discharge,

because G6PD deficiency is a condition that is

fre-quently encountered in practice but is easy to

over-look in the absence of a high suspicion index, and

because the incidence of kernicterus in well,

full-term infants should currently approach zero in the

United States. Its rarity is emphasized by the

publi-cation of a single case report (interestingly in a

G6PD-deficient newborn infant with sepsis) in

Pediatrics in 1994.28 Thus, for one physician to have

encountered four cases of neonatal kernicterus in

full-term infants in less than 18 months (having

pre-viously not encountered a case in more than 20 years

of practice, 15 of them at the current institution)

indicates a problem worthy of note.

Financial savings and better use of health care

resources are often cited as advantages of early

hos-pital discharge; yet published studies vary in their

conclusions with respect to these issues.3’6”#{176}”3.2934

Most recently published studies describe outcomes

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char-acteristics.337 As a result, it is often difficult to

com-pare data from different reports or to generalize

re-sults from one program to other settings.

Based on the AAP and ACOG criteria,2 all four of

the infants described would have been considered

clinically suitable for early discharge. Only in case 4

were the educational and follow-up criteria at least

partially fulfilled.

G6PD deficiency affects millions of people

world-wide.38 Mutant isoenzymes of G6PD are under the

control of genes on the X chromosome.

Heterozy-gous females may present with a degree of enzyme

deficiency, which varies from near normal levels to

almost a total lack of enzyme activity, depending on

which X chromosome is “Lyonized.”39 Most

isozymes are unique to certain individuals or

fami-lies or are limited to small ethnic groups.38 Certain

abnormal enzyme mutants are frequent in some

pop-ulations. (an enzyme with nearly absent

activity) is commonly observed among populations

in the southern Mediterranean area (eg, 0.7% to 3%

of Greeks and 53% of Kurds). This enzyme is also

found among Indians and Asians (5.5% of Chinese).

Two different mutant enzymes are observed in

West-em and Central Africa; Gda- is associated with

de-creased activity (5% to 15% of normal) in the red

cells; Gda+ has more than 80% activity. Affected

African-Americans (10% to 14%) tend to manifest the

less-severe deficiency.

G6PD plays a key role in the red cell’s defense

against the oxidation of hemoglobin. In

G6PD-defi-cient cells this protection is inadequate, leading to

precipitation of oxidized hemoglobin and hemolysis.

The equilibrium between hemolysis and the ability

of the liver to convert heme byproducts into bilirubin

is precarious in the newborn. Any factor that either

increases hemolysis or decreases bilirubin

conjuga-tion may result in hyperbilirubinemia. Because

nor-mal newborn red cells have a diminished capacity to

deal with oxidative stress as the result of lower levels

of glutathione peroxidase and catalase and a relative

deficiency of vitamin E, infants with G6PD

defi-ciency are at greater risk of developing hemolysis

than are adults with the deficiency.

Testing newborns for G6PD is not routine in the

United States. A screening test may give a

false-negative result if older, more severely deficient red

blood cells are destroyed, leaving younger cells with

near normal enzyme activity in the circulation.

Eth-nic background can be very difficult to determine

visually, and, as in case 2, the detailed ethnic origins

of the parents can be easily overlooked if a detailed

family history is not obtained. Even when a family

history is obtained, the significance of the

informa-tion obtained may be overlooked, and the data may

be incomplete, as in case 3, in which the sibling’s

serum bilirubin levels had exceeded 20 mg/dL (342

pmol/L), but this fact was not ascertained. It is

im-portant to note that in none of the cases described

did the affected parents demonstrate any

recogniz-able signs of their enzyme deficiency. In the case

described by Penn et al,28 maternal anaemia was

ascribed to iron deficiency.

Most physicians recognize that there is marked

variation in the severity of G6PD deficiency between

major ethnic groups. Often not understood is the fact

that small communities and families within a given

population may demonstrate a unique degree of

en-zyme deficiency and marked variation in the

mci-dence of severe neonatal hyperbilirubmnemia.4#{176}’41

Lack of understanding of the variability and the

se-verity of enzyme deficiency in population subgroups

and the impact of increasing ethnic diversity and

intermarriage has tended to maintain a low

suspi-cion index for G6PD deficiency as a cause for severe

neonatal jaundice. In addition, early reports from the

United States indicated that G6PD-deficient

African-Americans did not demonstrate an increased

mci-dence of neonatal jaundice. Subsequent observations

in the United States, Jamaica, and Africa indicate that

this is not the case.38

A review of several current textbooks conveys the

impression that evidence of hemolysis and a history

of exposure to oxidant drugs are frequently present

in the neonate with hyperbilirubinemia due to G6PD

deficiency. In fact, concurrent infection seems to be

the most frequently encountered precipitator of

hy-perbilirubinemia in G6PD-deficient newborns.

However, as in the four cases described, a

precipi-tating factor is usually not identified. It is commonly

difficult to demonstrate evidence of hemolysis in

affected neonates.38 Reticulocytosis either may not

occur at all or may not become apparent until the

serum bilirubin has risen significantly. A fall in the

hemoglobin, if it occurs, is usually delayed; only

patient 4 demonstrated a clearly elevated

reticulo-cyte count and anemia. Beutler, in his excellent

re-view of G6PD deficiency,38 points out that G6PD

deficiency is not limited to the red blood cells in an

affected individual. Deficiency also has been

docu-mented in the leukocytes, platelets, fibroblasts,

adre-nals, kidneys, eye lenses, breast milk, and liver. Thus,

the rise in bilirubin may not primarily be due to

increased red blood cell destruction but to impaired

liver function.

It is interesting that all of the infants described

were breast-fed, as were three of the four previous

infants identified from our data bank, and the infant

described by Penn et al.28 The oft-repeated “fact” that

jaundice associated with breast feeding does not

cause brain damage may tend to decrease

inappro-priately the diagnostic suspicion index and the sense

of urgency to test and treat the jaundiced breast-fed

infant. What part, if any, breast-feeding played as a

cause of the severe hyperbilirubinemia in the four

described cases could not be defined, despite a

care-ful review of maternal diet and drug use.

Although not the primary thrust of the article by

Newman and Maisels, reduction in health care costs

for jaundiced, term neonates without evidence of

hemolysis was clearly implied by such statements as:

“In this low-risk group, the risks and costs of

iden-tifying high bilirubin levels may exceed the

bene-fits.”8 The fact that infants with G6PD deficiency

may not present evidence of hemolysis and that

ker-nicterus occurs in a significant number of

G6PD-deficient infants with serum bilirubin levels greater

than 20 mg/dL (342 pmol/L) was addressed by

(4)

these authors. However, their conclusion that, “in

areas where genetic or environmental risk factors are

prevalent, screening for G6PD deficiency, with more

aggressive treatment of deficient jaundiced infants

may be worthwhile,” presupposes a more

sophisti-cated database than most clinicians possess and

un-deremphasizes the impact of increased population

mobility and intermarriage.

LESSONS TO BE LEARNED

The cases presented emphasize the need to use

caution when making cost-cutting proposals for

health care. Unrecognized or unpredictable factors

may combine to produce a devastating outcome for

individual patients and their families. The total

num-ber of affected cases may be small, rendering them

virtually invisible to those viewing the big picture.

The AAP and ACOG criteria for early postpartum

discharge seem to be based on a middle-class

popu-lation with adequate medical insurance.”2

Unfortu-nately, many families for whom early discharge is

either financially attractive or mandated by

third-party payers also may be at risk for inadequate

fol-low-up or recognition of medical problems. Even

after signing a contract to return for follow-up within

24 to 36 hours after discharge, in a study of

low-income mothers discharged with their infants 24 to

36 hours postpartum, 10% failed to return for a

fol-low-up visit within 48 hours.15 In this study, despite

the fact that the mothers and infants were screened

for medical risk factors, infants discharged early had

a 2.3% rate of hospital readmission compared with

0.89% for infants hospitalized more than 48 hours.

Low-income mothers and their infants who are less

carefully screened might be at even greater risk for

unidentified problems. Limitations of local public

health support or resources will enhance this risk

further.

Even in the absence of a reliable screening test for

G6PD deficiency, and taking into account the

rela-tively later onset of significant jaundice due to G6PD

deficiency compared with other causes of hemolysis

in the newborn (third to fifth day of life compared

with the second to third day of life), it is probable

that early postpartum discharge can be rendered safe

for the majority of newborns, including those with

G6PD deficiency, as long as a detailed family history

is obtained and adequate and timely follow-up care

is arranged. The timing of the admission and

dis-charge examinations needs to be carefully reviewed.

The current AAP and ACOG guidelines42

recom-mend examination of the apparently healthy

new-born by a physician within 12 to 18 hours of birth

and within 24 hours before discharge from the

hos-pital. These guidelines are not suitable for infants

discharged within 48 hours of birth. In cases 1, 2, and

3 the admission and discharge examinations were

separated by less than 12 hours, and the discharge

examinations in cases 2 and 3 took place more than

12 hours before discharge. A single examination,

with careful review of pertinent history,

per-formed shortly before discharge probably would

allow more reliable detection of potential

prob-lems. Steps also should be taken to ensure that the

parent follows through with follow-up

arrange-ments. There must be a shared responsibility

be-tween the third-party payers, perinatal health

pro-fessionals, and those responsible for follow-up of

the mother and infant to develop a safe

postpar-tum program tailored to individual factors such as

the number of previous children (parental

experi-ence), socioeconomic status, and ease of access to

medical systems. The provision of such a system

will require a significant amount of educational

effort at all levels, including the lay public,

regard-ing optimal postpartum care, how to recognize

common problems such as jaundice, and when to

seek attention for them. As illustrated in the cases

in this article, once symptoms are clearly

recogniz-able to the parent, it may be too late to prevent

morbidity. The provision of home care services is a

potential means to achieve early follow-up, as in

case 4. However, the individuals providing these

services must possess the specialized training and

skills in perinatal health care required to recognize

problems early and to ensure that they are

managed appropriately.

ACKNOWLEDGMENTS

I thank Karen Narkewicz, MD, for her assistance in abstracting the case histories and Carol Keyhoe for typing the manuscript.

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1995;96;734

Pediatrics

Mhairi G. MacDonald

Dehydrogenase Deficiency