Universal Hepatitis B Immunization

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Universal

Hepatitis

B Immunization

PEDIATRICS Vol. 89 No. 4 April 1992 795

Committee on Infectious Diseases

HEPATITIS B DISEASE AND EPIDEMIOLOGY

In the United States 200 000 to 300 000 acute

in-fections with hepatitis B virus (HBV) occur each

year.1’2 More than one million persons in the United

States have chronic HBV infection, and approximately

4000 to 5000 persons die each year from

HBV-in-duced chronic liver disease and hepatocellular

carci-noma. Although HBV infections occur during

child-hood and adolescence, the full impact of these

infec-tions is not recognized until many years later when

chronic liver disease and hepatocellular carcinoma

may develop. The incidence of HBV infection

in-creases rapidly during adolescence, with higher rates

among blacks than among whites (Fig 1). Although

rates vary by region, sex, and race, between 3.3% and

25% of all persons have had HBV infection by 25 to

34 years of age. The likelihood of becoming

chrom-cally infected with HBV varies inversely with the age

at which infection occurs. HBV transmitted from

hep-atitis B surface antigen (HBsAg)-positive mothers to

their newborns results in HBV carriage for up to 90%

of infants. Between 25% and 50% of children infected

before 5 years of age become carriers, whereas only

6% to 10% of acutely infected adults become carriers.

It is estimated that more than 25% of carrier infants

will die from primary hepatocellular carcinoma or

cirrhosis of the liver, with most of these deaths

oc-curing during adult life.

HBV infection occurs more commonly in certain

populations, including Pacific Islanders, Alaskan

Na-tives, immigrants from countries in which infection is

highly endemic, persons who require multiple

trans-fusions of blood or blood products, and persons with

high-risk lifestyles, including intravenous drug abuse

and contact with multiple sexual partners. However,

approximately 30% to 40% of acute HBV infections

in the United States occur in persons with no

identi-fiable risk factors.

HBV is transmitted through exposure to blood and

blood products, through sexual contact, and from

mothers to infants primarily at the time of birth. It

also can be acquired by close contact within families,

from person to person through contact between open

skin lesions, and possibly by exposure of mucous

membranes to other infected body fluids, such as

saliva.

The Recommendations in this publication do not indicate an exdusive course of treatment or serve as a standard of medical care.. Variations, taking into account individual circumstances, may be appropriate.

PEDIATRICS (ISSN 0031 4005). Copyright c 1992 by the American Acad-emy of Pediatrics.

VACCINES AND PREVIOUS

RECOMMENDATIONS

The first HBV vaccine in the United States was

licensed in 1982. Although both plasma-derived and

recombinant vaccines are licensed in the United

States, only recombinant vaccines are produced

cur-rently. Both plasma-derived and recombinant

vac-cines induce more than 90% protection against HBV

infection and are highly immunogenic in infants

when given in a variety of immunization

sched-ubes.48 More than 95% of infants have developed a

satisfactory serologic response (antibody to HBsAg

(anti-HB5)) concentration of 10 mIU/mL) after

ad-ministration of three doses of vaccine. Intervals of 4

or more months between the second and third doses

resulted in higher geometric mean titers than intervals

of 1 or 2 months. These vaccines have been shown

to be highly effective in preventing HBV infection in

infants whose mothers are chronic HBV carriers.8’9

The recommended doses and volumes of HBV

vac-cines differ by manufacturer, age of the individual to

be immunized, maternal HBsAg serologic status, and

presence of underlying disease (Table 1). The two

vaccines currently being marketed appear equally

immunogenic and may be used interchangeably in

their respective, recommended doses. Adverse effects

are minimal, consisting primarily of soreness at the

injection site. Hypersensitivity to yeast or preservative

in the recombinant vaccines has been reported rarely,

and no serious adverse effects in children have been

linked definitely to HBV vaccines.10

Previously, both the American Academy of

Pedi-atrics (AAP) and the US Public Health Service

Im-munization Practices Advisory Committee (ACIP)

recommended a two-part strategy for control of HBV

infection, which consisted of selective vaccination of

high-risk populations and serologic screening of all

pregnant women for HBsAg.’#{176}’1’Unfortunately,

Se-lective vaccination strategies have had little impact

on the control of HBV infections or their sequelae

(Fig 2).12 Individuals in high-risk groups are not

identified readily, and they often underuse preventive

health care seMces’2’3 Universal screening of

preg-nant women for HBsAg with active and passive

im-murnzation of their infants will prevent only about

6000 of the more than 200 000 HBV infections that

occur in the United States each year. A change in

strategy for vaccine use in this country is required to

control HBV infections.

UNIVERSAL IMMUNIZATION

The Academy’s Committee on Infectious Diseases

considered several possible strategies to improve the

at Viet Nam:AAP Sponsored on September 1, 2020 www.aappublications.org/news

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Black

#{189}.

3#{149}6- 9- 12-15-

18-2 5 8 1114 17 24

White

Age in years

hepatitis B vaccine

70

§

§50

40

020

10

0

control of HBV infections including immunizing in

infancy, at adolescence, or a combination approach.

Infant immunization offers the most feasible

ap-proach to protecting all persons and eventual

elimi-nation of disease, but the complete effect of this

strategy will not be noted for 25 or more years.

Universal immunization of adolescents alone has the

advantage of a more immediate effect, but this

strat-egy is problematic. Adolescents at the highest risk

would most likely be the least compliant, and asking

adolescents to participate in a three-dose

immuniza-tion series over a 6-month period is likely to result in

high drop out rates.

Therefore, the Academy recommends a

combina-tion strategy, including universal immunization of all

infants. Immunization of all infants has been shown

to be cost-saving in controlling HBV infections

(Cen-ters for Disease Control, 1991).12 A major factor in

the cost-effectiveness is the bower dose of vaccine

given infants (Table 1). In Alaska the universal HBV

78715081 5088889 90

Year of Report

Fig 2. Estimated incidence of acute hepatitis B,United States, 1978 through 1990. Source: Centers for Disease Control, 1991.

Positive (S)

40

796 HEPATITIS B IMMUNIZATION

30

20

10

0

Fig 1. Age-specific prevalence of hepatitis B virus markers for white and black subjects. Data are from the National Center for Health Statistics.3

TABLE 1. Recommended Doses of Licensed He patitis B Vaccines

Vaccinet

Recombivax HB Engerix-B

(MSD) (SKI)

iig (mL) g (mL)

Infants of hepatitis B surface antigen (HBsAg)- 2.5 (0.25) 10 (0.5)

negative mothers and children <1 1 y

Infants of HBsAg-positive mothers (HBIG (0.5 5 (0.5) 10 (0.5) mL) should also be given)

Children and adolescents 11 to 19 y 5 (0.5) 20 (1.0)

Adults20y 10 (1.0) 20 (1.0)

Dialysis patients and other immunosuppressed 40 (1.0)11 40 (2.0) persons

SHeptavax B (MSD), a plasma-derived vaccine, is also licensed, but no longer produced in the US. tVaccines should be stored at 2#{176}Cto 8#{176}C.Freezing destroys effectiveness.

Merck, Sharp & Dohme.

§

The Food and Drug Administration has approved this vaccine for use in an optional schedule: four doses at 0, 1, 2, and 12 months (see 1991 Report of the Committee on Infectious Diseases’#{176}P244).

I Smith Kline Biologicals.

ISpecial formulation for dialysis patients.

5* Four-dose schedule recommended at 0, 1, 2, and 12 months.

Adapted from the 1991 Report of the Committee on Infectious Diseases.10244

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ACADEMY OF PEDIATRICS

immunization program has resulted in interruption of

HBV transmission among Native American

chil-dren.’4 Universal infant immunization has been

im-pbemented in several of the Pacific Islands under the

jurisdiction of the United States, and Hawaii recently

has initiated universal immunization of infants for

HBV. At least 20 other countries now recommend

HBV vaccine for all infants.15

Routine serologic screening of all pregnant women

for HBsAg continues to be recommended. Screening

should be performed during a prenatal visit for each

pregnancy. The dose and schedule of the vaccine to

be given to the infant, as well as the use of hepatitis

B immune globulin (HBIG), are based on the HBsAg

status of the mother (Table 1).

Routine Immunization of Infants Born to

HBsAg-Negative Mothers

The Academy recommends administering the first

dose of HBV vaccine to newborns before hospital

discharge, the second dose at 1 to 2 months of age,

and the third dose at 6 to 18 months of age (Table 2).

The dose recommended for newborns of

HBsAg-negative mothers is different for the two vaccines

(Table 1). An alternative schedule of the three doses

administered at 2, 4, and 6 to 18 months during

regularly scheduled visits and concurrently with other

routine vaccines, may be used for HBsAg-negative

infants not vaccinated at birth.

These recommendations are based on the need for

flexible scheduling of HBV vaccination in the first 18

months of life to integrate this vaccine into routine

preventive health care. Since HBV vaccine is highly

immunogenic in a variety of schedules, extra visits

should not be required to incorporate it into a child’s

routine health care. A schedule of immunization at

birth, 1 month, and 6 to 18 months may avoid the

need to administer three injections of different

vac-cines at the same visit. Administration of the first

dose in the hospital also reduces the need for extra

office visits and helps to emphasize to parents and

hospital-based personnel the importance of

immuni-zations and preventive services. For premature and

other infants with illnesses in the first few days of

life, HBV vaccine may be delayed until hospital

dis-charge, provided the mother is not HBsAg-positive.

Immunization of Infants Born to HBsAg-Positive Mothers

Infants born to HBsAg-positive women should

re-ceive HBIG at or shortly after birth and should be

TABLE 2. Recommended Routine Hepatitis B Immunization Schedules

Maternal Hepatitis

B Surface Antigen

Dose Age Status Negative 1 2 3 0-2 d 1-2mo 6-l8mo Positive it 2 3 0 d imo #{243}mo

SAlternative schedule: dose one at 1 to 2 months of age, dose two at 4 months, and dose three at 6 to 18 months.

tHepatitis B immune globulin should also be administered.

immunized at birth (within 7 days, preferably with

12 hours). The second and third doses of vaccine

should be administered at 1 and 6 months of age,

according to current recommendations (Table 2). The

dose of Recombivax HB vaccine (Merck, Sharp &

Dohme) for infants of carrier mothers is twice (0.5

mL) that given to infants of HBsAg-negative mothers.

The dose of Engerix B vaccine (Smith Kline

Biobog-icals) is the same (0.5 mL) for infants of both

HBsAg-positive and HBsAg-negative mothers (Table 1).

For infants born to HBsAg-positive women,

im-munization starting at birth is highly effective in

preventin& HBV transmission from mother to

in-fant.9’16”7 In infants who have received three doses

of HBV vaccine with administration of the first dose

by 7 days of age, the risk of chronic HBsAg carriage

was reduced by 65% to 90%. The additional

admin-istration of HBIG at or shortly after birth has further

reduced the risk by 5% to 20%, according to some

studies.’6”7

Infants of HBsAg-positive mothers should be tested

for HBsAg and anti-HBs at 9 months of age or later

(at beast 1 month after the third dose of vaccine). A

fourth dose of HBV vaccine should be administered

to infants who are HBsAg-negative and have titers of

anti-HBs < 10 mIU/mL. These children should be

retested 1 month later for anti-HBs (see

The

Report of

the Committee

on Infectious

Diseases10’P251).

Additional

doses (up to two more) may be considered for those

who fail to respond.

Immunization of Infants Whose Mothers Have

Unknown HBsAg Status

An infant whose mother’s HBsAg status is

un-known and cannot be determined before delivery

should be immunized at birth with the dose of vaccine

recommended for infants of HBsAg-positive mothers

(Table 1). The additional administration of HBIG

should depend on the results of the serologic

screen-ing of the mother. The mother should be screened for

HBsAg as soon as possible, since the efficacy of HBIG

has been proven only when given within 12 hours of

birth. If the mother is HBsAg-positive, HBIG should

be administered immediately to the infant, provided

that the infant is bess than 1 week old. Efficacy of

HBIG given 12 to 48 hours after birth and 7 days of

age is not known. The HBsAg status of the mother

also determines the subsequent vaccine dose and

schedule, as previously described.

ADMINISTRATION OF HEPATITIS B VACCINE

Concurrent Administration With Other Vaccines

Hepatitis B virus vaccine can be given

simultane-ously with diphtheria-tetanus toxoids-pertussis

(DTP),

Haemophilus

influenzae

type b, polio, and/or

measles-mumps-rubella vaccines without

interfer-ence.6”8 Hepatitis Bvirus vaccine should not be mixed

in the same syringe with any other vaccine or

medi-cation because compatibility between products has

not been demonstrated. Combined products are likely

to become available in the future (see ‘Future

Devel-opments’).

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Site of Administration

Hepatitis B virus vaccine can be given

intramuscu-larly safely and effectively in the anterolateral thigh

or in the upper arm at all ages, including at birth

(Coberly

J,

Halsey N. Personal communication, 1991).

HBV vaccine and other vaccines should not be

ad-ministered in the buttocks, because this practice has

resulted in inadequate serologic response rates in

adults and could cause damage to the sciatic nerve.’9

Intradermal immunization is not recommended for

infants or children since intradermal injections are

difficult in infants and have no advantage over

intra-muscular administration (Coberby

J,

Halsey N.

Per-sonal communication, 1991). When simultaneous

ad-ministration of HBV vaccine and other vaccines, such

as DTP and H influenzae type b vaccines, is indicated,

two injections, one or more inches apart, may be

administered in the same anterolateral thigh or

del-toid.

DURATION OF IMMUNITY

The full duration of protection induced by three

doses of HBV vaccine administered in infancy has not

been determined. However, adult recipients of

plasma-derived HBV vaccine have been protected

from acute and chronic illness for as long as 9 years.5

Although 20% to 60% of vaccinated adults had

anti-HBs titers decline to less than 10 mIU/mL 5 to 9 years

after immunization, immunologic memory was

re-tamed, and anamnestic antibody responses occurred

after exposure to HBV. Studies of infants whose

mothers are chronic HBsAg carriers have shown that

the vaccine has provided the infants with continued

high levels of protection from chronic HBV infection

for at least 5 years. Routine administration of booster

doses for infants born to HBsAg-negative mothers

and routine testing for antibodies to HBsAg, therefore,

are not indicated at this time.

IMMUNIZATION OF ADOLESCENTS AND OLDER

CHILDREN

Older children and adolescents at increased risk of

exposure to HBV infection (see Table 3) should be

immunized. Major risk factors for acquisition of HBV

infection in adolescents include multiple sexual

part-ners (defined as more than one in 6 months) and

intravenous drug abuse. In addition, immunization

should be emphasized for adolescents living in areas

where increased rates of parenterab drug abuse,

teen-age pregnancy, and/or sexually transmitted diseases

occur.

The AAP recommends that universal immunization

of all adolescents should be implemented when

re-sources permit. The current policy of selective

im-munization of teenagers at high risk for acquisition of

HBV infection requires prospective assessment of

be-havioral risk factors, which is often difficult and

inadequate. Although the costs would be higher than

for infant immunization due to the larger dose of

vaccine administered, the additional strategy of

uni-versal adolescent immunization will result in a more

rapid reduction of HBV transmission and infection,

TABLE 3. High-Risk Groups Who Should Receive Hepatitis B Immunization Regardless of Age*

. Hemophiliac patients and other recipients of certain blood products

. Intravenous drug abusers

. Heterosexual persons who have had more than one sex partner in the previous 6 months and/or those with a recent episode of a sexually transmitted disease

. Sexually active homosexual and bisexual males

. Household and sexual contacts of hepatitis B virus (HBV) car-tiers

. Members of households with adoptees from HBV-endemic, high-risk countries who are hepatitis B surface antigen-positive . Children and other household contacts in populations of high

HBV endemnicity

. Staff and residents of institutions for the developmentally dis-abled

. Staff of nonresidential day care and school programs for devel-opmentally disabled if attended by known HBV carrier; other attendees in certain circumstances

. Hemodialysis patients

. Health care workers and others with occupational risk

. International travelers who will live for more than 6 months in areas of high HBV endemnicity and who otherwise will be at risk

. Inmates of long-term correctional facilities

*Adapted from the 1991 Report of the Committee on Infectious

Disease’#{176}(see pp 246-249 for further details and explanation).

particularly among adolescents, the age group of

chil-dren currently most at risk for acquiring HBV

infec-tion. Universal infant immunization will have an

immediate impact on reducing vertical transmission

of HBV infection from mothers to infants and will

diminish or eliminate horizontal transmission

be-tween preschool-age children within 5 years.

Trans-mission among teenagers, however, would remain

unaffected for the next one to two decades.

Other groups who should receive HBV vaccine are

listed in Table 3. Children who are not in these groups

will be immunized at adolescence. Although it may

be ideal to immunize such children at this time, this

recommendation is not being made currently because

of limited resources.

The usual schedule of immunization for older

chil-dren, adolescents, and adults is 0, 1, and 6 months.

The dose, according to vaccine and age, is listed in

Table 1.

FUTURE DEVELOPMENTS

Manufacturers are developing products combining

HBV vaccine with DTP and/or

H influenzae

type b

vaccines. If and when these products become

avail-able, integration of HBV vaccine into the routine

immunization schedule for infants of HBsAg-negative

mothers at 2, 4, and 6 months of age will be

simpli-fled.

The need for booster doses of HBV vaccine in older

children and adolescents and for those immunized in

infancy will be assessed as individuals are followed

for 10 or more years after primary immunization.

Routine serologic testing for HBV immunity is not

indicated for these persons.

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OF PEDIATRICS

SUMMARY OF RECOMMENDATIONS

The highest priority should be for immunization of

high-risk children and all infants, followed by

im-munization of adolescents living in high-risk areas,

and then all adolescents. A summary of

recommen-dations is as follows:

1. Routine serologic screening of all pregnant women

for HB5Ag should continue.

2. All infants should be immunized with HBV

vac-cine. The appropriate doses and schedules are

detailed in Tables 1 and 2.

A. For infants born to HBsAg-negative mpthers:

. The recommended schedule is

adniinistra-tion of the first dose to newborns before discharge from the hospital; the second dose

should be administered at 1 to 2 months of

age, followed by the third dose at 6 to 18

months of age (Table 3).

. Infants who did not receive a dose of vaccine

at birth should receive three doses by 18

months of age. The minimal interval

be-tween the first two doses is 1 month and

between the second and third doses is 2

months, but 4 months or more may be

pref-erable.

. The alternative schedule of immunization at

2, 4, and 6 to 18 months of age, although

not preferred, is acceptable, provided the

infant’s mother is HBsAg-negative.

B. Infants born to HBsAg-positive women must

be immunized at or shortly after birth with the

appropriate dose of vaccine (Table 1) and

should receive one dose of HBIG as soon as

possible after birth. The second dose of vaccine

should be administered at 1 month and the

third dose at 6 months. These infants should

be followed up and their serologic status

checked at 9 months of age, as recommended

in the 1991 Report ofthe Committee on Infectious

Diseases.’#{176}’249

C. If the mother’s HBsAg status is unknown at

the time of delivery, the infant should be

im-munized at birth with the dose of vaccine

recommended for infants born to

HBsAg-pos-itive mothers. The mother should be screened

for HB5Ag as soon as possible to determine the

subsequent management of the infant,

includ-ing the need to administer HBIG.

3. Older children, adolescents, and adults at

in-creased risk of HBV infection (Table 3) should be

immunized with HBV vaccine (Table 1).

4. Routine immunization of all adolescents against

HBV should be encouraged and implemented

when feasible.

5. The dose of vaccine depends on the manufacturer,

the patient’s age, the maternal HBsAg status, and

the presence of underlying disease (Table 1).

COMMFI-rEE ON INFECTIOUS DISEASES,

1991 TO 1992

Caroline Breese Hall, MD, Chair James G. Easton, MD

Dan M. Granoff, MD

Donald S. Gromisch, MD

Neal A. Halsey, MD

Steve Kohl, MD

Edgar K. Marcuse, MD Melvin I. Marks, MD

George A. Nankervis, MD

Larry K. Pickerin& MD

Gwendolyn B. Scott, MD

Russell W. Steele, MD

Ex-Officio

Georges Peter, MD Liaison Representatives Kenneth J. Bart, MD, MPH,

National Vaccine Program Claire Broome, MD, Centers for

DIsease Control

M. Carolyn Hardegree, MD, Food

and Drug Administration

John R. La Montagne, PhD,

National Institute of Allergy and

Infectious Diseases

Noni E. MacDonald, MD, Canadian

Paediatric Society

Walter A. Orenstein, MD, Centers

for Disease Control

REFERENCES

1. Alter MJ, Hadler SC, Margolis HS, et al. The changing epidemiology of hepatitis B in the United States. Need for alternative vaccination

strat-egies. JAMA. 1990;263:1218-1222

2. Margolis HS, Alter MJ, Hadler SC. Hepatitis B: evolving epidemiology and implications for control. Semin Liver Dis. 1991;1 1:84-92

3. McQuillan GM, Townsend TR, Fields HA, et al. Seroepidemiology of hepatitis B in the United States: i976 to 1980. Am I Med. 1989;87: 5S-1OS

4. Szmuness W, Stevens CE, Harley EJ, et al. Hepatitis B vaccine: demon-stration of efficacy in a controlled clinical trial in a high-risk population in the United States. N Engi IMed. 1980;303:833-841

5. Hadler SC, Francis DP, Maynard JE, et al. Long-term immunogenicity and efficacy of hepatitis B vaccine in homosexual men. N Engi /Med.

1986;315:209-214

6. Smego R, Halsey N. The case for routine hepatitis B immunization in infancy for populations at increased risk. Pediatr Infect Dis I. 1987;6:

ii-i9

7. Stevens CE, Toy PT, Tong MJ, et a!. Pennatal hepatitis B virus transmis-sion in the United States. Prevention by passive-active immunization.

JAMA. 1985;253:1740-1745

8. Stevens CE, Toy PT, Tong MJ, et al. Yeast-recombinant hepatitis B

vaccine: efficacy with hepatitis Bimmune globulin in prevention of pennatal hepatitis B virus transmission. JAMA. 1987;257:2612-2616

9. Poovorawan Y, Sanpavat 5, Pongpunlert W, et a!. Protective efficacy of a recombinant DNA hepatitis B vaccine in neonates of HBs antigen-positive mother. JAM.4. 1989;261:3278-3281

10. Committee on Infectious Diseases, American Academy of Pediatrics. The Report ofthe Committee on Infectious Diseases. 22nd ed. Elk Grove Village, IL: American Academy of Pediatrics; 1991:238-255

I I. Centers for Disease Control. Protection against viral hepatitis: recom-mendations of the Immunization Practices Advisory Committee (ACIP).

MMWR. 1990;39:5-22

12. Jonas MM, Schiff EF, O’Sullivan MJ, et al. Failure of the Centers for

Disease Control criteria to identify hepatitis B infection in a large

municipal obstetrical population. Ann Intern Med. 1987;107:335-337 13. McQuillan GM, Townsend TR, Johannes CB, et al. Prevention of

peri-natal transmission of hepatitis B virus: the sensitivity specificity and predictive value of the recommended screening questions to detect high risk women in an obstetric population. Am I Epidemiol. 1987;126: 484-491

14. McMahon BJ, Rhoades ER, Heyward WL, et al. A comprehensive pro-gramme to reduce the incidence of hepatitis B virus infection and its sequelae in Alaskan natives. Lancet. 1987;2:1134-1136

15. MaynardJE, Kane MA, Hadler SC. Global control of hepatitis B through vaccination: role of hepatitis B vaccine in Expanded Programme on Immunization. Rev Infect Dis. 1989;il:574-578

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16. Ip HMH, Lelie PN, Wong VCW, et al. Prevention of hepatitis B virus carrier state in infants according to maternal serum levels of HBV DNA.

Lancet. 1989;1:406-409

17. Xu Z-Y, Liu C-B, Francis DP, et al. Prevention of perinatal acquisition

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randomized, double-blind placebo-controlled and comparative trial.

Pc-diatrics. 1985;76:713-718

18. Huang LM, Lee CY, Hsu CY, et al. Effect of monovalent measles and

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19. Shaw FE, Guess HA, Roets JM, et al. Effect of anatomic injection site,

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1992;89;795

Pediatrics