[Overdosing of pipamperone from a squeeze bottle]. / Overdosering van pipamperon uit een knijpflacon.

BACKGROUND: Medication is not always delivered in a safe dosing format. Up to 33% of medication errors can be attributed to confusing packaging or labelling. CASE DESCRIPTION: A 6-year-old boy with ADHD, for which he was being treated with methylphenidate and pipamperone drops, was brought to the A&E department with signs of severe encephalopathy. He had apparently been given pipamperone in streams rather than in drops in the previous months. The pipamperone level in his blood was raised to toxic levels. The pipamperone drops were delivered in a plastic squeeze bottle (LDPE bottle), which makes correct dosing almost impossible. The treating psychiatrist and the prescribing GP had not noticed this medication error. The incident was reported to the Netherlands Pharmacovigilance Centre Lareb, the Netherlands Medicines Evaluation Board and the Portal for Patient Safety. A warning was also added to the Netherlands paediatric medication prescription website about pipamperone in a squeeze bottle. CONCLUSION: Drug packaging can be a cause of intoxication. The treatment provider should be aware of this in cases of drug intoxication.

Ten-year neonatal hepatitis B vaccination program, The Netherlands, 1982-1992: protective efficacy and long-term immunogenicity.

From 1982 to 1989, 705 infants born to HBsAg-positive mothers entered the Dutch neonatal hepatitis B vaccination program and received passive-active hepatitis B immunization in three randomized controlled trials testing variations in time of starting active vaccination, dose and type of vaccine, and number of hepatitis B immunoglobulin (HBIg) injections. A meta-analysis of individual patient data of the three randomized trials was performed to determine which independent host and vaccination related factors influence protective efficacy and long-term immunogenicity, and to assess whether hepatitis B vaccination concomitant with standard DKTP vaccination provides optimal protection. Statistical methodology included multivariate logistic regression analysis. Eight infants (1.1%), all born to HBeAg-positive mothers, became HBsAg carriers within the first year of life. The protective efficacy rate (PER) of passive-active immunization at 12 months follow-up was 92% for the total group of children from 114 HBeAg-positive mothers with no significant differences between children starting active immunization at birth or at 3 months of age, between infants starting at 3 months of age receiving one or two doses of HBIg or between those receiving plasma derived or recombinant vaccine. The only factor that affected the PER significantly was the level of maternal HBV DNA; PER was 100% if maternal HBV DNA was < 150 pg ml-1 and 68% for HBV DNA levels > 150 pg ml-1. After 5 years of follow-up, the group that started active immunization at birth had significantly more infants with loss of seroprotection (anti-HBs levels < 10 IU l-1, 15%) than the corresponding group starting at 3 months of age (anti-HBs < 10 IU l-2, 2%). One of 35 children with loss of seroprotection at 2 years became a HBsAg carrier in the fifth year of follow-up. This meta-analysis shows that the protective efficacy of passive-active hepatitis B vaccination is mainly influenced by material HBV DNA levels, and independent of the time of starting active vaccination at birth or at 3 months of age; long-term immunity was enhanced by starting active vaccination concomitant with DKTP vaccination. These findings allow incorporation of hepatitis B vaccine into the standard infant immunization programs for countries with a passive-active immunization strategy for the control of hepatitis B. Additional measures are needed to protect neonates of highly viremic women.

Immunogenicity of two different dosages (10 and 5 micrograms) of recombinant DNA hepatitis B vaccine in healthy neonates.

The immunogenicity of a half (5 micrograms) and a full (10 micrograms) dosage of recombinant DNA yeast-derived hepatitis B vaccine (HB-Vax-DNA) in healthy neonates was assessed in order to compare two candidate dosages of vaccine. After randomization 174 newborns of HBsAg-negative mothers entered the study. Neonates received four doses of either 10 or 5 micrograms hepatitis B vaccine, according to the DTP-polio immunization schedule at months 3, 4, 5 and 11. No serious adverse reactions were observed; 15.5% of vaccinated newborns suffered mild transient local symptoms. The vaccine was highly immunogenic irrespective of dosage of vaccine; all infants developed anti-HBs levels > or = 10 IU l-1, 99% > or = 100 IU l-1. A dosage of 10 micrograms hepatitis B vaccine produced higher antibody levels than 5 micrograms hepatitis B vaccine after primary vaccination (first three doses) but not after booster vaccination (fourth dose) (p = 0.06 and 0.75, respectively). Either vaccine dosage can be recommended for incorporation in the Expanded Programme on Immunization in the Netherlands.

Anti-HBs levels in infants of hepatitis B carrier mothers after delayed active immunization with recombinant vaccine concomitant with DTP-polio vaccine: is there need for a second dose of HBIg? Dutch Study Group on Prevention of Neonatal Hepatitis B.

The need for an additional dose of hepatitis B immune globulin (HBIg) was studied by comparing infants receiving 1 ml HBIg at birth followed by hepatitis B immunization, concomitant with DTP-polio vaccine, at 3, 4, 5 and 11 months (schedule E), with infants receiving the same schedule with additional HBIg at 3 months (schedule F). The immune response to recombinant hepatitis B vaccine (20 micrograms) was evaluated in 195 infants born to HBsAg-positive mothers allocated to groups E and F and compared with historic controls who received plasma vaccine (10 micrograms) according to schedule F. Blood samples were drawn at 0, 3, 4, 6, 11, 12 and 24 months of age. No difference in efficacy between the two schedules was observed; 8 and 6% of infants born to HBeAg-positive HBsAg carrier mothers in groups E and F, respectively, became HBsAg carriers. Passively acquired antibodies at birth remained present for about 5 months in most infants. The seroprotection rates (anti-HBs > or = 10 IU l-1) were over 90% at all time points and similar for groups E and F. The titres of anti-HBs attained during the first 6 months were statistically lower (p < or = 0.02) for group E than for group F but similar thereafter. Anti-HBs titres in infants receiving the recombinant vaccine were significantly lower than in infants receiving the plasma vaccine (p << 0.001). Supplemental doses of HBIg in infants receiving a high dose of HBIg ( > 200 IU) at birth and the first dose of vaccine at the age of 3 months are not advised.

Failure of neonatal hepatitis B vaccination: the role of HBV-DNA levels in hepatitis B carrier mothers and HLA antigens in neonates.

In a hepatitis B vaccination program (1982-1992), 705 infants born to HBsAg-positive mothers received HBIg within 2 h of birth and were vaccinated according to a three- or four-dose vaccination schedule, starting either at 3 months or directly after birth. Eight children HBsAg-positive during the first year of life (group 1: infected nonresponders). To determine whether failure of the hepatitis B vaccination was due to perinatal high-level maternal viraemia or genetically determined infant nonresponsiveness to the vaccine, we measured HBsAg and anti-HBs levels in infants and HBeAg and hepatitis B virus-DNA levels in maternal serum, and determined the HLA type of the infants. Controls included 14 infants with a normal anti-HBs response 1 year after vaccination (group 2: noninfected responders) and all eight infants without HBsAg and anti-HBs 1 year after vaccination (group 3: noninfected low responders). HBsAg, HBeAg and anti-HBs were measured by radioimmunoassay (Abbott Laboratories), hepatitis B virus-DNA was measured quantitatively by solution hybridization for groups 1, 2, and 3 (Abbott hepatitis B virus-DNA assay, Abbott Laboratories), and HLA was characterized by microcytotoxicity test for groups 1 and 3. All infants in groups 1 and 2 were born to HBeAg carrier mothers, and those in group 3 to HBeAg-negative mothers. Hepatitis B virus-DNA levels in maternal serum in group 1 were significantly higher than in group 2 (Wilcoxon rank-sum test: p < 0.01). Hepatitis B virus-DNA was not observed in group 3 maternal serum samples.(ABSTRACT TRUNCATED AT 250 WORDS)

[The course of hepatitis B in 9 children who became positive for viral surface antigen HBsAg in spite of vaccination]. / Het beloop van hepatitis B bij 9 kinderen die ondanks vaccinatie positief werden voor het virale oppervlakteantigeen HBsAg.

OBJECTIVE: To describe the viral, clinical and biochemical course of infants, who, in spite of passive-active hepatitis B immunisation, became infected with hepatitis B. DESIGN: Prospective cohort study. SETTING: The Netherlands. MATERIAL AND METHOD: As part of the research programme of the Dutch study group 'Prevention neonatal hepatitis B', 705 newborns of HBsAg-positive mothers received passive and active immunisation. Despite passive-active immunisation, 9 children became positive for HBsAg. These children were analysed clinically and their HBsAg, anti-HBs, HBeAg, anti-HBc and anti HD were measured. RESULTS: Median follow up was 5 years (range 3-8 years). Of the 9 HBsAg-positive infants 8 also tested positive for HBeAg. At the end of the follow-up 1 child had lost HBsAg and 2 children had lost HBeAg. Only 1 child experienced a symptomatic hepatitis B infection with raised aminotransferase levels. The other 8 infants with chronic hepatitis B had no clinical symptoms. Aminotransferase levels were normal throughout in 7 infants. CONCLUSION: Most of the infants who, in spite of passive-active hepatitis B immunisation, became HBsAg positive developed a chronic hepatitis B infection without clinical or biochemical dysfunctions. On the basis of these findings and considering possible therapy, guidelines are given for the follow up of children with chronic hepatitis B.

Passive-active immunization in infants of hepatitis Be antigen-positive mothers. Comparison of the efficacy of early and delayed active immunization.

OBJECTIVE: To assess the efficacy of late active immunization against hepatitis B concomitant with diphtheria, pertussis, tetanus, and polio vaccine in high-risk infants receiving hepatitis B immune globulin at birth. DESIGN: Randomized study of infants born to mothers positive for hepatitis B surface antigen (HBsAg) and hepatitis Be antigen (HBeAg). SETTING: Three large city hospitals and one rural area providing prenatal care and obstetric services. SUBJECTS: Eighty neonates of HBsAg- and HBeAg-positive carrier mothers received 0.5 mL/kg of body weight hepatitis B immune globulin within 2 hours of birth and hepatitis B vaccine (10 micrograms) at 0, 1, 2, and 11 months of age (group A) or at 3, 4, 5, and 11 months of age concomitant with diphtheria, pertussis, tetanus, and polio immunization (group B). A second dose of hepatitis B immune globulin was given to infants on schedule B at 3 months. MAIN OUTCOME MEASURES: Blood samples were collected at 0, 3, 6, 11, and 12 months of age and tested for antibodies against hepatitis B core antigen and HBsAg. Follow-up visits were scheduled annually up to 5 years of age. RESULTS: Eight infants were excluded from analysis. During the study period, six children became HBsAg carriers, three in each group, which corresponds to a 5-year incidence of infection of 9% and 8% for groups A (three of 35) and B (three of 37), respectively. Subclinical infections (persistent anti-HBc positivity beyond month 12 or appearance of anti-HBc) were encountered in another eight infants (four in each group). CONCLUSION: Late active immunization starting at 3 months of age appears to provide similar protective efficacy as active immunization starting at birth when combined with hepatitis B immune globulin at 0 and 3 months of age.

Immunogenicity of 20 micrograms of recombinant DNA hepatitis B vaccine in healthy neonates: a comparison of three different vaccination schemes.

The immunogenicity of a full dose (20 micrograms) of recombinant DNA yeast-derived hepatitis B vaccine (Engerix-B) was assessed in healthy neonates in order to compare three candidate vaccination schemes. After randomization 162 newborns of hepatitis B surface antigen (HBsAg) negative mothers entered the study. Neonates received hepatitis B vaccine according to a four-dose vaccination scheme starting either at month 3 (scheme I: months 3, 4, 5, and 11) or at birth (scheme III: months 0, 1, 2, and 11). Another group of neonates received hepatitis B vaccine according to a three-dose scheme starting at birth (scheme II: months 0, 1, and 6). Serious adverse reactions were not observed; 2.5% of the vaccinated newborns suffered mild transient local symptoms. The vaccine was highly immunogenic irrespective of vaccination scheme; all infants developed anti-HBs levels > or = 10 IU/L, 97% > or = 100 IU/L. The immunogenicity of hepatitis B vaccine after primary and booster vaccinations, administered in the four-dose scheme started at birth, was significantly higher (P < 0.05) than in the three-dose scheme started at birth. Hepatitis B vaccination according to the four-dose scheme started at month 3 produced significantly higher (P < 0.05) antibody levels in comparison to the four-dose scheme started directly after birth. This study showed that a four-dose hepatitis B vaccination scheme starting at month 3 resulted in the highest antibody levels of the three schemes investigated and can be recommended for incorporation in the Expanded Programme on Immunization in The Netherlands.

[Premature infants and hepatitis B vaccination. Study Group Prevention Neonatal Hepatitis B]. / Prematuren en hepatitis B-vaccinatie. Werkgroep Preventie Neonatale Hepatitis B.

Since 1986 health authorities in the Netherlands advise to vaccinate preterm infants at similar age as term infants, without correction for their shortened gestational age. This advice was based on a study, which showed comparable immune responses after DTP vaccination in preterm and term infants. To assess the immunogenicity of hepatitis B vaccination not corrected for gestational age in preterm infants, we compared the antiHBs titer after hepatitis B vaccination in 44 preterm infants with the antiHBs titer in 829 term infants. More than 95% of the preterm infants developed an adequate immune response (> 10 IU/l antiHBs), irrespective the vaccination scheme which varied in vaccine dose, the number of vaccinations and the onset of the first vaccination. The percentage preterm infants with an antiHBs titer > 10 IU/l (98%) was not different of the corresponding percentage of term infants (98%). Similarly, no difference between preterm and term infants was observed when an antiHBs value of 100 IU/l was considered a positive response, neither when active immunisation started at month 0 or month 3. The geometric mean titre at 12 months of age was considered.