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ADC Online First, published on September 8, 2014 as 10.1136/archdischild-2014-306691 Archimedes

Should newborns of mothers with isolated antibodies to hepatitis B core antigen be immunised?

prevent perinatal infection with HBV (outcome)? If yes, what type and timing of immunisation?

SCENARIO

SEARCH STRATEGY AND OUTCOME

The midwife calls you to assess a newborn in the delivery room. The pregnancy was uneventful, but the mother’s serology results show the following: hepatitis B surface antigen (HBsAg) negative, antibodies against hepatitis B surface antigen (anti-HBs) negative, but antibodies against hepatitis B core antigen (anti-HBc) positive. You wonder if the baby is at risk for perinatal transmission of hepatitis B virus (HBV) requiring preventive measures at this time.

STRUCTURED CLINICAL QUESTION Does a newborn of a mother with isolated antibodies against hepatitis B core antigen need immunisation (intervention) to

We searched MEDLINE via PubMed (January 1950 to November 2013) for the following terms: “anti-HBc AND vertical transmission”, “anti-HBc AND vaccination AND newborn”, “vaccination AND newborn AND perinatal transmission AND hepatitis B”, “isolated antibody AND hepatitis B AND pregnancy/pregnant”. Two hundred and forty-three abstracts were screened, 11 were considered for full text review. Of those, four were eligible and seven were excluded: four did not address the main question, two provided no follow-up data of the infants and one was not available as full text in English. We identified one additional eligible article by screening references of articles from full text review. Finally, five eligible articles were included (table 1).

Table 1 Number of infants of anti-HBc only positive mothers

Citation Descos et al

6

Study type (Level of evidence)

52

Prospective cohort study (2b)

5

Prospective cohort study (2b)

Bart et al3

101

Walz et al7

105

Prospective cohort study (2b) Prospective cohort study (2b)

Roingeard et al4

Khamduang et al5

47*

Prospective cohort study (2b)

Laboratory testing for hepatitis B infection (age at follow-up) HBsAg, anti-HBs, anti-HBc, anti-HBc IgM, HBeAg, anti-HBe, HBV DNA, ALT (2 months, 3 months, 6 months and 12 months) HBsAg, HBeAg, anti-HBc, anti-HBs, anti-HBe (birth and 6–7 months)

HBsAg, HBV DNA in cord blood (no follow-up) HBsAg, anti-HBs, HBeAg, anti-HBe, anti-HBc, HBV DNA (3–4 months and 5–15 months) HBV DNA (4 months)

Key results

Comments

2 infants HBsAg positive within 6 months, Newborns not immunised 1 infant transiently anti-HBc positive (2–6 months), 1 infant transiently positive for HBV DNA at 3 months, HBsAg negative, anti-HBc positive until 6 months of age Newborns not immunised 1 infant HBsAg positive at birth and follow-up, 1 infant anti-HBc positive at birth and follow-up, 1 infant anti-HBc positive at birth and additionally anti-HBs and anti-HBe positive at follow-up, 1 infant negative at birth, anti-HBc positive at follow-up 1 cord blood sample positive for HBsAg Postnatal vaccination and HBV DNA strategy not reported 2 infants HBsAg positive, 5 infants HBV All infants received active immunisation DNA positive at 3–4 months; 5 infants from 2–3 months on (3 doses) followed at 5–15 months, all negative for HBV DNA and HBsAg.

All infants negative for HBV DNA

All mothers HIV-1 positive. 81% of the infants had a documented active immunisation within the first 2 days of life. The national Expanded Program of Immunisation includes a second and third active immunisation at 1–2 months and 6 months of age. No information available about immunoglobulin application†

*All mothers also HBV DNA positive. †Personal communication with corresponding author, Wasna Sirirungsi, 27 March 2014. ALT, alanine aminotransferase; HBV, hepatitis B virus; anti-HBc, antibodies against hepatitis B core antigen; HBeAg, hepatitis B e antigen; HBsAg, hepatitis B surface antigen.

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Archimedes COMMENTARY Neonatal immunisation after birth is well established for newborns of HBsAg positive mothers. However, it is unclear if neonates whose mothers are positive for anti-HBc antibodies only should be immunised. There are several case reports in the literature showing that HBV transmission can occur from anti-HBc only positive blood donors or organ donors to their recipients.1 2 For vertical transmissions the risk in this setting is believed to be low, and anti-HBc screening is not part of the standard serological workup during pregnancy. Consequently, there is little guidance for newborns of mothers who are ‘accidentally’ found to be anti-HBc only positive. Our literature search revealed only cohort studies with relatively small numbers of ‘anti-HBc only’ mother-child pairs. Bart et al3 studied 101 cord blood samples, of which one was found to be positive for HBsAg and HBV DNA. Unfortunately no follow-up was done in this study and therefore the rate of transmission is unknown. Roingeard et al4 studied infants in Senegal and reported that one of five infants was HBV infected, and additional three infants showed changing patterns of antibodies, but none developed HBsAg positivity. None of the children in this study had received HBV vaccine or passive immunisation. Khamduang et al5 recently examined infants of 47 HIV-1 positive mothers with anti-HBc only antibodies. At 4 months of age HBV DNA was not detected in the blood of any of the infants. The authors were contacted for further details on the vaccination strategy and stated that the first HBV vaccine was documented for 81% of all infants in the study within the first 2 days of life, 10% had no documented immunisation and 9% were not immunised (W Sirirungsi, personal communication, 2014). Information regarding administration of immunoglobulin and further doses of HBV vaccine was unavailable (W Sirirungsi, personal communication, 2014). Descos et al6 followed up 52 infants and found 2 infants (4%) HBsAg positive at 6 months and a 3rd infant transiently positive for HBV DNA. None of these infants had received HBV vaccine or passive immunisation. The longest follow-up was done in a study by Walz et al,7 in which seven infants (7%) of 105 mothers were positive for either HBsAg or HBV DNA at 3–4 months of age and subsequently all five infants with a second follow-up at 5–15 months of age became negative for HBV DNA and HBsAg. All infants in this study received HBV vaccine at 2 months, 3 months and 4 months of age as part of the regular immunisation schedule. In summary, although there is limited data available, the risk of HBV transmission from anti-HBc only positive mothers to their newborns appears to be low. In infants who received HBV vaccine starting at 2 months of age, transmission of HBV has not been described to date. This suggests that in the absence of better evidence, active HBV immunisation initiated within the first 2 months of age should be recommended. Immunisation of these newborns in the first months of life may particularly be important in countries which do not universally recommend HBV

2

immunisation in all infants. As screening of anti-HBc-antibodies is not routinely done, most newborns exposed to an anti-HBc only positive mother are not detected. In countries where HBV is endemic universal HBV immunisation in the first year of life is therefore most important as transmission can be reduced independent of the screening practice and serology results.

Clinical bottom line ▸ Hepatitis B virus (HBV) transmission from anti-HBc only positive mothers to their newborns has been described (Grade C). ▸ Initiation of active HBV immunisation within the first 2 months of age may prevent infection (Grade C). ▸ Initiation of active HBV immunisation or anti-hepatitis B immunoglobulin in the delivery room appears unnecessary (Grade D).

Isabelle Pramana,1 Ulrich Heininger,2 Nicole Ritz2 1

Department of Neonatology, University Children’s Hospital Basel, Basel, Switzerland Paediatric Infectious Diseases and Vaccinology Unit, University Children’s Hospital Basel, Basel, Switzerland

2

Correspondence to Dr Isabelle Pramana, Department of Neonatology, University Children’s Hospital Basel 4058, Switzerland; [email protected] Contributors IP conducted the systematic review and wrote the manuscript. NR designed the study, supervised the systematic review and critically revised the manuscript. UH critically revised the manuscript. Competing interests None. Provenance and peer review Not commissioned; externally peer reviewed. Accepted 17 August 2014 Arch Dis Child 2014;0:1–2. doi:10.1136/archdischild-2014-306691

REFERENCES 1 2 3

4 5

6 7

Patil RS, Wadgaonkar P, Joshi SH, et al. Viral infections in newborns through exchange transfusion. Indian J Pediatr 1998;65:723–8. Wachs ME, Amend WJ, Ascher NL, et al. The risk of transmission of hepatitis B from HBsAg(-), HBcAb(+), HBIgM(-) organ donors. Transplantation 1995;59:230–4. Bart PA, Jacquier P, Zuber PL, et al. Seroprevalence of HBV (anti-HBc, HBsAg and anti-HBs) and HDV infections among 9006 women at delivery. Liver 1996;16:110–16. Roingeard P, Diouf A, Sankale JL, et al. Perinatal transmission of hepatitis B virus in Senegal, west Africa. Viral Immunol 1993;6:65–73. Khamduang W, Ngo-Giang-Huong N, Gaudy-Graffin C, et al. Prevalence, risk factors, and impact of isolated antibody to hepatitis B core antigen and occult hepatitis B virus infection in HIV-1-infected pregnant women. Clin Infect Dis 2013;56:1704–12. Descos B, Scotto J, Fayol V, et al. Anti-HBc screening for the prevention of perinatal transmission of hepatitis B virus in France. Infection 1987;15:434–9. Walz A, Wirth S, Hucke J, et al. Vertical transmission of hepatitis B virus (HBV) from mothers negative for HBV surface antigen and positive for antibody to HBV core antigen. J Infect Dis 2009;200:1227–31.

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Should newborns of mothers with isolated antibodies to hepatitis B core antigen be immunised? Isabelle Pramana, Ulrich Heininger and Nicole Ritz Arch Dis Child published online September 8, 2014

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References

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Articles on similar topics can be found in the following collections ADC Archimedes (203) Immunology (including allergy) (1747) Vaccination / immunisation (295) Child health (3340) Infant health (731) Screening (epidemiology) (471) Screening (public health) (471) Drugs: infectious diseases (820) Hepatitis and other GI infections (65) Liver disease (157) Pregnancy (464) Reproductive medicine (843) Artificial and donated transplantation (125) Epidemiologic studies (1550) HIV/AIDS (129) Sexual health (302)

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