W.P.F. Fetter

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.

BEHAVIOUR PROBLEMS OF VERY LOWBIRTHWEIGHT CHILDREN

Parent and clinician reports of behaviour problems among very low‐birthweight (VLBW) children at 3½ years of age were studied in relation to indicators of neonatal cerebral damage, cognition and social factors. VLBW children had more depressed behaviour and more internalizing problems by parent report, and also scored significantly more often within the clinical range on total problem scores, than children in the comparison group. Neither neonatal cerebral ultrasound nor neurological examinations were directly associated with behavioural outcome. Cerebral damage was related to cognitive development. Cognition directly influenced behaviour problems according to clinician report, while the home environment did so according to parent report. The authors suggest that depressed behaviour of preschool VLBW children might be associated with parental reactions to the birth of a VLBW child, and that their attention problems might be linked indirectly to brain damage via cognitive impairments.

Visual field and grating acuity development in low-risk preterm infants during the first 2 1/2 years after term

The effect of early visual experience on visual field size and grating acuity development was studied longitudinally in 36 appropriate for gestational age (AGA) and 26 small for gestational age (SGA) low-risk preterm infants. These were selected out of 194 very low birth weight (VLBW) infants (birthweight less than 1500 g) born in 1985 and 1986. Criteria for inclusion as low-risk were the absence of neurological, respiratory, circulatory and alimentary problems in the neonatal period; no retinopathy of prematurity and no evidence of abnormality on the neonatal cranial ultrasound scans. Binocular field sizes were assessed using kinetic arc perimetry. Binocular grating acuity was tested by means of the prototype version of the acuity card procedure. Results were compared with norms obtained in control fullterms in earlier studies. Infants were tested at 6 weeks, 6, 6, 9 and 12 months of age from the expected term date. Twenty-two of these infants were retested at 2 1/2 years of corrected age. Visual field size and visual acuity estimates of (both AGA and SGA) low-risk, VLBW preterms and control fullterms overlapped at all test ages, except for a slight but significantly faster development of the upper and the lower visual field at 6 weeks corrected age in the preterm group. These results indicate that for clinical purposes visual experience before the expected term date has not only no measurable effect on the normal development of behavioural acuity, but also no accelerating effect on the development of peripheral vision.

Neonatal cerebral ultrasound, neonatal neurology and perinatal conditions as predictors of neurodevelopmental outcome in very low birthweight infants

To determine the assessments before discharge from the intensive care unit, that will predict outcome most accurately, a prospective longitudinal study in a cohort of 79 high risk VLBW children was conducted from birth to 3.6 years of age. Birthweight, gestational age, obstetrical and neonatal optimality, neonatal neurological examinations and neonatal cerebral ultrasound were studied in relation to outcome. The best predictor for outcome was a simple cerebral ultrasound classification according to the presence or absence of ventriculomegaly and intraparenchymal damage of any cause. Infants with normal neonatal cerebral scans or abnormal scans without ventriculomegaly almost invariably had a normal neurological outcome. In infants with cerebral lesions with ventriculomegaly the incidence of normal neurological outcome decreased to less than 50%. Intraparenchymal damage was associated with cerebral palsy as well as other (mental and sensori) handicaps in over 85% of the cases. Neonatal neurological examinations at preterm age had additional value in predicting neurological outcome especially in the group with ventriculomegaly. Neither birthweight, nor gestational age, obstetrical or neonatal optimality were independent variables in the prediction of outcome in high risk VLBW children at 3.6 years of age.

Effects of very low birth weight (VLBW) on visual development during the first year after term

Behavioural visual functions were assessed in 155 very low birth weight (VLBW) infants during the first 12 months after expected term. Visual development was examined (mainly cross-sectionally) at 6 weeks, 3, 6, 9, and 12 months of corrected age by assessment of visual acuity, visual fields, optokinetic nystagmus and visual threat response. Many VLBW infants showed visual impairments (54.2%). No single visual function appeared to be specifically susceptible to impairments, deficits were often apparent across a range of functions. Visual impairments were observed at all test ages, and could already be assessed at 6 weeks of corrected age. The highest incidence of visual impairments was scored at 6 months corrected age. Beyond 6 months, less deficits were observed, suggesting in many infants a delayed rather than a permanently impaired visual development. In some infants deficits became evident at a later stage, after an apparently normal initial development. The results suggest that VLBW infants are at risk for impaired visual development.

The influence of contamination of culture medium with hepatitis B virus on the outcome of in vitro fertilization pregnancies

Heat-inactivated human serum is added to the culture medium used for in vitro fertilization and other forms of assisted conception. Because one batch of pooled serum contained hepatitis B virus, an epidemic occurred among women participating in the treatment program. Seventy-nine women had serologic proof of hepatitis B infection. This incident gave the opportunity to study the effect of hepatitis B virus on pregnancy outcome and the newborn. The situation is unique because the preimplantation embryo was exposed to hepatitis B virus or the pregnancy was complicated by a (sub)clinical infection. Twenty-four women were or became pregnant while having an acute hepatitis B infection. Five pregnancies ended in abortion. The remaining 19 pregnancies ended in the birth of 24 children. No evidence for any harmful effect of exposure to hepatitis B virus in the embryonic or fetal period on the newborn could be found.

Immune response to hepatitis B vaccine in pregnant women receiving post-exposure prophylaxis

Hepatitis B immunoglobulin and vaccine were given as post-exposure prophylaxis to 73 women after an outbreak of hepatitis B due to in vitro fertilization treatment. The immunization schedule consisted of 5 ml of hepatitis B immunoglobulin (125 IU/ml) at months 0 and 1 and recombinant hepatitis B vaccine (10 micrograms of HBvaxDNA) at months 0, 1, 2 and 6. The safety and immunogenicity of hepatitis B vaccine were studied in 16 women who became pregnant after in vitro fertilization; 57 non-pregnant women receiving the same treatment served as controls. Blood samples were drawn at 0, 1, 2, 6 and 7 months. One patient had a clinical abortion 2 days after initial immunization; other side effects of vaccination were not found in vaccinees or in their offspring. All vaccinees exhibited antibodies against hepatitis B surface antigen after vaccination but relatively low peak geometric mean titers of 258 IU/l and 684 IU/l were attained in pregnant and non-pregnant women, respectively. There were no significant differences in seroconversion rates and geometric mean titers between the two groups although the immune response to hepatitis B vaccine was slower and lower in pregnant women at all times. Our results suggest that when post-exposure prophylaxis for hepatitis B infection is indicated, passive active immunization can be started safely during pregnancy. The relative weak response to the vaccine calls for monitoring of the anti-HBs 1 month after the initial series of vaccinations.

Effects of perinatal hypoxia on visual development during the first year of (corrected) age

Visual development was assessed in 124 infants (112 preterms and 12 fullterms) who had suffered from perinatal hypoxia and in 55 control preterm infants during the first year of corrected age. Using behavioural techniques, visual functions were tested during follow-up visits in the Sophia Childrens Hospital. Corrected ages at testing ranged from 3 months to 1 year. During this period, infants with perinatal hypoxia showed more abnormalities in visual functions than preterm control infants. Gestational age at birth did not influence the outcome of visual development after perinatal hypoxia. Most visual impairments were demonstrated at 3 and 6 months of age. All infants with severe neuro-developmental handicaps showed visual deficits, although neuro-developmental abnormalities and visual deficits could be present as isolated phenomena. Ultrasound abnormalities related well with visual dysfunctions. Prospective studies of infants with visual deficits and a history of perinatal hypoxia are indicated.