No Adverse Events After Simultaneous Administration of 50 000 IU Vitamin a and Bacille Calmette-Guerin Vaccination to Normal-Birth-Weight Newborns in Guinea-Bissau

ORIGINAL ARTICLE No adverse events after simultaneous administration of 50 000 IU vitamin A and Bacille Calmette-Guerin vaccination to normal-birth-weight newborns in Guinea-Bissau

JE Nante1,3, BR Diness2,3, H Ravn2, A Roth1,2, P Aaby1,2 and CS Benn2

1Bandim Health Project, INDEPTH Network, Bissau, Guinea-Bissau and 2Bandim Health Project, Statens Serum Institut, Copenhagen, Denmark

Objective: To determine whether the combined intervention of 50 000 IU vitamin A administered together with Bacille Calmette-Guerin (BCG) vaccination at birth was associated with adverse events, in particular bulging fontanels and adverse reactions to BCG. Subjects/Methods: From an ongoing trial, 2145 infants randomized to 50 000 IU vitamin A or placebo with BCG vaccination were recruited. Adverse events were monitored in two different ways: (A) daily clinical examinations by a medical doctor during the first 3 days post supplementation; (B) weekly interviews by a trained assistant during the first month post supplementation. Results: In part A, 1271 infants were enrolled, in part B 2078. Vitamin A supplementation (VAS) was associated with a relative risk (RR) of bulging fontanels of 1.16 (95% confidence interval (CI) ¼ 0.82–1.65). The rate of health care contacts and various symptoms during the first month were comparable between the groups. VAS was associated with larger peak local reactions to BCG vaccination in boys, but not in girls (P-value for test of interaction between VAS and sex ¼ 0.02). Conclusion: 50 000 IU vitamin A with BCG was not associated with adverse events. The observed sex-differential effect of VAS on local reaction to BCG is in line with other observations of sex-differential effects of VAS. European Journal of Clinical Nutrition (2008) 62, 842–848; doi:10.1038/sj.ejcn.1602796; published online 30 May 2007

Keywords: adverse events; vitamin A; BCG vaccination; fontanel; randomized control trial; dosage and administration

Introduction that the effect of VAS may depend on amplification of non- specific effect of vaccines, being more beneficial when Two Asian studies reported vitamin A supplementation administered with live vaccines such as Bacille Calmette- (VAS) at birth to be associated with decreased mortality Guerin (BCG) or measles (Benn et al., 2003). World Health (Humphrey et al., 1996; Rahmathullah et al., 2003). Recently, Organization (WHO) recommends BCG vaccine at first a study in an African population reported no overall effect of health contact, preferably at birth. To explore the potential VAS at birth in infants of HIV-negative mothers (Malaba benefits of VAS given with BCG vaccination at birth in a et al., 2005) and a possible–negative effect in uninfected high-mortality African setting, we conducted a large rando- children of HIV-positive mothers (Humphrey et al., 2006). mized double-blind placebo-controlled trial in Guinea-Bissau None of the above studies reported whether VAS was given from 2002 to 2005. Normal birth-weight infants who were to with other interventions. We have previously hypothesized receive BCG vaccination were randomized to 50 000 IU vitamin A or placebo. In a subgroup of participants, we conducted a study of possible adverse events associated with Correspondence: Dr BR Diness, Bandim Health Project, Statens Serum Institut, this combined intervention. Artillerivej 5, Copenhagen S 2300, Denmark. High-dose vitamin A can transiently increase intracranial E-mail: [email protected] volume (ICV), leading to increased intracranial pressure 3Joint first authorship. Received 24 November 2006; revised 2 April 2007; accepted 12 April 2007; (ICP) (Olson, 1994). Several studies from Bangladesh, which published online 30 May 2007 administered VAS to 1–6-month-old infants with each of the Effects of vitamin A and BCG on newborns JE Nante et al 843 three DTP vaccinations (25 000 or 50 000 IU, reaching a total of the three assistants who were responsible for the of 75 000–150 000 IU), reported increased incidence of randomization procedures at the hospital and at the health transient fontanel bulging in the supplemented group (de centres had any idea about which bottles contained vitamin Francisco et al., 1993; Baqui et al., 1995; Rahman et al., 1995; A or placebo. The code was kept at the pharmacy until 12 Mahalanabis et al., 1997). In one of the studies, a positive months after the last child was enrolled. At enrolment, association between bulging and symptoms of raised ICP was information on baseline anthropometrics and socioeco- noted (Baqui et al., 1995); however, this was not the case in nomic characteristics was collected. other studies. The results have also been conflicting with We aimed to enrol 800 children from the randomized regard to VAS administered at birth. The first safety study of study into the study of adverse events, to reach a sample size 50 000 IU VAS at birth, performed in Indonesia, reported an comparable to the previous African study of adverse events increased incidence of fontanel bulging among VAS recipi- after 50 000 IU vitamin A at birth (Iliff et al., 1999). As the ents. The VAS and placebo groups did not differ with regard data collection proceeded well, we did not stop the inclusion to any other sign or symptom assessed (Agoestina et al., of children in the adverse event study until more children 1994). Increased bulging was not found in the two had been recruited. The adverse event study consisted of two other studies of neonatal supplementation from India parts: daily visits on days 1–3 by a medical doctor (Part A) (Rahmathullah et al., 2003) and Zimbabwe (Iliff et al., and weekly visits on the first 4 weeks by a trained field 1999), but the Indian study only registered adverse events assistant (Part B). The medical doctor and the field assistant after a first dose of 24 000 IU VAS. In the present study, we were unaware of treatment allocation. Eligibility criteria aimed to study the possible adverse events after 50 000 IU were enrolment in the randomized study and home address VAS administered with BCG vaccination in a high-mortality in one of the four districts closest to the office of the health African setting. We particularly aimed to assess the risk project. If the doctor was travelling or absent, no inclusions of bulging fontanels and adverse reactions to BCG vaccine. were made for Part A of the study, as described in Figure 1. For logistic reasons, a maximum of 35 children per week were enrolled into Part B. Methods

Study design Registration of symptoms The Bandim Health Project runs a demographic surveillance Part A. On the medical doctor’s daily visits, information system in six suburban districts of Bissau, Guinea-Bissau. The about morbidity was collected and the infant was examined. present study was done in a subcohort of children included To judge irritability of the infant, the mother was asked how in a randomized study of vitamin A vs placebo. The much the child cried compared with other newborns: ‘less enrolment in the randomized study has been described in than normal’, ‘normally’ or ‘more than normal’. The detail elsewhere (Benn et al., 2007). In brief, all infants from temperature was measured in the axilla using an electronic the study area born at the main hospital in Bissau or thermometer recording one decimal. Fever was defined as reporting for BCG vaccination at two out of three health axillary temperature equal to or above 37.51C. Respiratory centres in the study area were screened for enrolment. frequency was counted over 1 min while the child relaxed. Mothers were invited to participate if the infant weighed The fontanels were examined when the child was calm and X2500 g and had no overt illness. All children were in an upright position, and characterized as ‘very depressed’, vaccinated intradermally in the upper left deltoid region ‘slightly depressed’, ‘normal’, ‘slightly bulging’ or ‘very with 0.05 ml BCG (Statens Serum Institut, Copenhagen, bulging’. A study from Indonesia found good inter-observer Denmark). If she accepted to participate in the study, the correlation of judgement of bulging fontanel and a weak mother had to draw a lot from an envelope determining association between this outcome and the resistive index in whether the child should receive VAS or placebo. The envelopes were prepared by the study supervisor. Each contained 100 lots, 50 marked ‘1’ and 50 marked ‘2’, indicating from which of the two numbered bottles, ‘1’ or ‘2’, the child should receive its supplement. A total of 4345 infants were randomized to receive oral vitamin A (50 000 IU retinol palmitate in vegetable oil, with 20 IU vitamin E as antioxidant) or placebo (the same amount of vegetable oil and vitamin E). Vitamin A and placebo were prepared at Skanderborg Pharmacy, Skanderborg, Denmark. Apart from the randomization number, the bottles looked alike. A total of 112 mothers were asked whether they believed their child had received vitamin A or placebo. There were no differences in answers from mothers of VAS or placebo recipients. None Figure 1 Time line of adverse event study.

European Journal of Clinical Nutrition Effects of vitamin A and BCG on newborns JE Nante et al 844 the anterior cerebral artery as evaluated by duplex Doppler Ethical considerations (Agoestina et al., 1994). The protocol was presented to The Ministry of Health in Guinea-Bissau and to the Danish Central Ethical Committee for approval (2004-7041-19). The study was registered under Part B. The visits were conducted on approximately days 7, clinicaltrials.gov, number NCT00168598. The sponsors had 14, 21 and 28 after inclusion. The trained field worker no role in the study design, data collection, data analysis, systematically interviewed the mother/caretaker of the child data interpretation or the writing of the report. about symptoms and health care contacts since the last visit. The injection site of the BCG vaccine was examined. Any local reaction was measured horizontally and vertically to Results nearest millimetre with a transparent ruler. The mean of the horizontal and vertical diameter was used in the analysis of In part A, 1271 children were enrolled, in part B 2078. size of reaction. For each child, the largest size of reaction Because 1204 children participated in both parts, this led to a observed at any of the home visits was considered the peak total of 2145 individual children being enrolled. The local reaction to the vaccine. children enrolled represented 49% of the children included Deaths were registered in visits from part A or B deaths and in the main study (Figure 2), and 95% of eligible children. detected by the routine surveillance system. Cause of death The remaining eligible children (n ¼ 109) were not included was investigated by verbal autopsy. for logistic reasons and/or because they did not have a valid address at the time. There was no difference between the vitamin A and placebo groups in terms of baseline characteristics (Table 1). Statistical analysis Risks of adverse effects were compared for the vitamin A and the placebo groups during the first 3 days and the first 4 Risk of adverse events during the first 3 days post supplementation weeks post supplementation. A symptom was defined as Of 1271 infants enrolled in part A (624 from the VAS group, present if noted at any one visit, irrespective of whether all 647 from the placebo group), 1150 (90%) were met at least visits were conducted. A symptom was defined as absent if once. Mean number of successful visits was 2.8 in both the symptom was not recorded at any visit. We calculated relative risks (RRs) separately for each sex as the previous two studies conducted in India and Indonesian indicated that there might be differential effects of VAS in boys and girls (Benn et al., 2006). We have presented separate results where relevant, otherwise the results were adjusted for sex by Mantel–Haenszel stratification. Continuous vari- ables were compared using Student’s t-test. For explorative analyses of interactions, linear regression analysis was performed. In order not to overlook any adverse events in potentially vulnerable subgroups, we examined three groups: (I) highest quartile of weight-at-inclusion, presumably having had the highest retinol level before supplementation, (II) lowest quartile of weight-at-inclusion, representing the group receiving the highest per kg dose of vitamin A, and (III) children included during the rainy season, because our mortality data demonstrated a less favourable effect of supplementation in this group. Again, analyses were performed both for each sex separately and together. To gain power, one or more of the following symptoms was categorized as ‘serious event’: (1) very bulging fontanel, (2) bulging fontanel with simultaneous irritability or vomiting, (3) local reactions to BCG vaccine 410 mm in diameter or requiring incision or antibiotics, (4) illness leading to medical contact, (5) hospitalization, and (6) death. Significance was defined as P-valueo0.05. Statistical analysis was conducted with the use of Stata 9.2 (StataCorp, Figure 2 Flow of participants in randomized trial and adverse event TX, USA). study.

European Journal of Clinical Nutrition Effects of vitamin A and BCG on newborns JE Nante et al 845 groups. We registered a lower risk of having passed more to be slightly bulging in 115 (10%) of the children (60 than five stools during the last 24 h in the vitamin A group vitamin A, 55 placebo) and very bulging in 1 (0.1%) of the (Table 2). There were no other significant differences children (a boy from the placebo group). This child had not between the two groups (Table 2). The fontanels were found vomited, suggesting that he did not have increased intracranial pressure. The group of children with slightly bulging fontanel did not display increased frequency of symptoms Table 1 Baseline characteristics of participants in the study of the that could indicate raised intracranial pressure (irritability or adverse effects of vitamin A with BCG vaccination, Guinea-Bissau vomiting) as compared with children without bulging, nor Variable Vitamin A, Placebo, did mothers of children with bulging fontanel consider their N ¼ 1086 N ¼ 1059 child to be more ill (data supplied at request). The RR for N (%) N (%) having slightly or very bulging fontanels between the VAS and placebo groups was 1.16 (0.82–1.65). There was no Enrolment difference in effect of vitamin A with regard to any of the Enrolled health centre 604 (55.6) 587 (55.4) Enrolled hospital 482 (44.4) 472 (44.6) outcomes between boys and girls. Enrolled dry season 690 (63.5) 657 (62.0) Enrolled rainy season 396 (36.5) 402 (38.0) Enrolled and BCG vaccinated within 1062 (97.8) 1025 (96.8) 24 h Risk of adverse events during the first month post supplementation a Enrolled after BCG vaccination 24 (2.2) 34 (3.2) Of 2078 infants enrolled (1068 VAS group, 1010 placebo group), 1955 were visited at least once. The mean number of Child characteristics Male 541 (49.8) 552 (52.1) visits in both groups was 3.7. The results are presented in Female 545 (50.2) 507 (47.9) Table 3. We observed no differences in any of the measured Median age in days at inclusion (25–75 1 (1–10) 1 (1–10) outcomes. percentiles) Weight at inclusion (kg)7s.d. 3.3670.74 3.3570.70 Missing 9 (0.8) 10 (0.9) Reaction to BCG vaccination Maternal characteristics Ethnicity Overall 50.5% of the children developed a measurable Pepel 357 (32.9) 337 (31.8) reaction to BCG vaccination during the 4 weeks after its Fula 171 (15.8) 156 (14.7) administration. There was no difference in the percentage of Others 519 (47.8) 539 (50.8) children having a local reaction to the vaccine in the two Missing 39 (3.6) 28 (2.6) groups. One child, a boy in the vitamin A group, had a very Years in school large local reaction (63*50 mm). The child was not described 0–4 440 (40.5) 437 (41.3) as sick or febrile by the mother. He died shortly before 2 5–12 475 (43.7) 476 (45.0) months of age, presumably from an acute pneumonia (data Missing 171 (15.7) 147 (13.8) Mean arm circumference in mm (s.d.) 255730 256730 from verbal autopsy). We have no information about his HIV Missing 111 (10.2) 106 (10.0) status. This reaction was considered outside the normal range and was excluded from all analyses of local reactions. Abbreviation: BCG, Bacille Calmette-Guerin. Results are presented in Table 4. Boys in the vitamin A group aA few children received vitamin A more than 24 h after BCG vaccination, the majority because they were delivered by caesarean section. Enrolment, but had significantly larger peak local reactions to BCG vaccina- not BCG vaccination, in these cases awaited maternal consent. tion than their peers receiving placebo (P ¼ 0.01), and the

Table 2 Symptoms at daily visit by physician 1–3 days after vitamin A supplementation with BCG vaccination in Guinea-Bissau

Vitamin A, N ¼ 551 Placebo, N ¼ 599 Relative risk Relative risk for boys Relative risk for girls N (%) N (%) (95% CI)a (95% CI) (95% CI)

Mother thinks the child is not well 38 (6.9) 48 (8.0) 0.86 (0.57–1.30) 0.86 (0.48–1.53) 0.87 (0.49–1.54) Hospitalized 3 (0.5) 2 (0.3) 1.63 (0.27–9.72) —b —b Bulging fontanel 60 (10.9) 56 (9.4) 1.16 (0.82–1.65) 1.11 (0.70–1.76) 1.23 (0.73–2.08) Irritability 205 (37.2) 237 (39.6) 0.94 (0.81–1.09) 0.90 (0.73–1.09) 0.99 (0.80–1.23) TemperatureX37.51 12 (2.2) 9 (1.5) 1.46 (0.62–3.41) 2.16 (0.20–23.7) 1.37 (0.55–3.41) Frequent stools (5 þ ) 103 (18.7) 146 (24.4) 0.77 (0.61–0.96) 0.76 (0.57–1.03) 0.77 (0.55–1.08) Vomiting 104 (18.9) 123 (20.5) 0.92 (0.73–1.16) 0.93 (0.68–1.28) 0.91 (0.64–1.28)

Abbreviations: BCG, Bacille Calmette-Guerin; CI, confidence interval. aAdjusted for sex. bNo male hospitalizations in the vitamin A group and no female hospitalizations in the placebo group hindered calculation of relative risks.

European Journal of Clinical Nutrition Effects of vitamin A and BCG on newborns JE Nante et al 846 Table 3 Symptoms at weekly visits during the first 4 weeks following vitamin A supplementation with BCG vaccination, Guinea-Bissau

Vitamin A, N ¼ 991 Placebo, N ¼ 964 Relative risk Boys relative risk Girls relative risk N (%) N (%) (95% CI)a (95% CI) (95% CI)

No health problemb 609 (61.5) 563 (58.4) 1.05 (0.98–1.13) 1.07 (0.96–1.18) 1.04 (0.93–1.15) At least one health problem reported 382 (38.6) 401 (41.6) 0.93 (0.83–1.03) 0.91 (0.78–1.06) 0.95 (0.81–1.11)

Maternal report of specific events and symptoms Sought medical help 98 (9.9) 110 (11.4) 0.87 (0.67–1.12) 0.71 (0.50–1.02) 1.08 (0.74–1.57) Hospitalized 6 (0.6) 8 (0.8) 0.75(0.26–2.15) 0.69 (0.20–2.42) 0.91 (0.13–6.46)

Selected symptoms Diarrhoea 11 (1.1) 10 (1.0) 1.07 (0.46–2.51) 0.69 (0.20–2.42) 1.60 (0.47–5.42) Vomiting 15 (1.5) 12 (1.2) 1.22 (0.57–2.61) 0.77 (0.27–2.22) 2.05 (0.64–6.63) Runny nose 334 (33.7) 353 (36.6) 0.92 (0.82–1.04) 0.90 (0.76–1.07) 0.94 (0.79–1.12) Cough 211 (21.3) 208 (21.6) 0.99 (0.83–1.17) 0.90 (0.71–1.14) 1.09 (0.85–1.39)

Abbreviations: BCG, Bacille Calmette-Guerin; CI, confidence interval. aAdjusted for sex. bBesides the outcomes presented in this table, mothers were asked about fever, skin conditions and ‘other problems’. Only children with no report of any sign or symptom are included in this category.

Table 4 Local reaction to BCG during the first 4 weeks following vitamin A supplementation with BCG vaccination, Guinea-Bissau

Boys Girls All

Vitamin A, Placebo, RR (95% CI) Difference Vitamin A, Placebo, RR (95%CI) Difference RRa (95%CI) Differencea N ¼ 496 N ¼ 512 (P-value) N ¼ 495 N ¼ 452 (P-value) (P-value)

% responding 49.8 50.2 0.99 (0.88– — 50.9 51.3 0.99 (0.88– — 0.99 (0.91– — within 4 weeks 1.12) 1.12) 1.0) Peak size of local 3.93 3.70 — þ 0.23b 3.68 3.75 — À0.07b — þ 0.08 (0.24) reaction among (0.01) (0.43) reactors (mm)

Abbreviations: BCG, Bacille Calmette-Guerin; CI, confidence interval; RR, relative risk. aAdjusted for sex. bTest by linear regression of interaction between sex and intervention group with regard to peak size of reaction: P ¼ 0.02.

interaction between sex and randomization group was (0.62–2.07). Asphyxia/sepsis was the most frequent cause, significant (P ¼ 0.02). accounting for 25 fatalities (15 VAS, 10 placebo). Six deaths were due to haemorrhage (two VAS, four placebo); other causes were respiratory infection (three from the placebo Potentially vulnerable subgroups group) and bowel obstruction (one from the placebo group). In the potentially vulnerable subgroups, VAS was not In seven deaths (five VAS, two placebo), the cause was not associated with increased risk of serious events, the overall established. Effect of VAS did not vary significantly by sex; frequency of events defined as serious was 14.8%, with an RR the causes of death were similar in boys and girls. between the VAS and the placebo group of 1.01 (0.82–1.25). The figures were comparable within each of the three vulnerable subgroups and between the two sexes (data not shown). Discussion

No serious adverse events or side effects were detected to be Mortality more common in the vitamin A group in the present study. Seventeen children (nine VAS, eight placebo) of the 4345 Only one case of very bulging fontanel was observed, and it participants in the randomized study died within the first 3 was in the placebo group. Potentially VAS affects the local days after supplementation, (RR ¼ 1.16 (0.45–2.98)). A reaction to BCG vaccination in boys but the significance of further 25 infants (13 VAS, 12 placebo) died within the first this finding is uncertain. 28 days after supplementation, leading to an RR of death The children enrolled in the adverse event study constitute within the first 28 days following supplementation of 1.14 49% of the children included in the main randomized study.

European Journal of Clinical Nutrition Effects of vitamin A and BCG on newborns JE Nante et al 847 For practical reasons, we did not enrol children living in the tion. We observed a significant increase in the peak size of district farthest away from the health project and we stopped the local reaction in the vitamin A group among boys, inclusion while enrolment for the main study was still resulting in a significant interaction between sex and effect ongoing. We do not believe that this selection has intro- of supplementation. This finding is in line with previous duced bias. However, the eligible children not enrolled findings from Guinea-Bissau. In a study of VAS with measles because of lack of known address at the time of enrolment vaccine, we found VAS to be significantly associated with are likely to represent a group with more migration than the higher levels of measles-specific antibodies in boys, but not enrolled children. Fortunately, most of these children were in girls (Benn et al., 1997). Also, we found a smaller dose of later identified, and mortality in the group was comparable VAS than the currently recommended to be beneficial in to mortality in the studied group. If tolerance of vitamin A girls, but not in boys (Benn et al., 2005). In the present study, was different among migrating children, we could have boys who received VAS tended to survive better than boys failed to detect it. However, that seems unlikely. who received placebo, whereas the opposite was seen in girls High-dose vitamin A is associated with increased intra- (Benn et al., 2007). Thus, the currently available data suggest cranial volume (Olson, 1994). In Indonesia, VAS at birth was that boys may benefit more from VAS than girls. To our associated with a significant increase in episodes of bulging knowledge, no study has linked size of the local post- fontanel within the first 24 h after birth; 50 000 IU VAS vaccination reaction with long-term efficacy of BCG vaccine, increased the percentage significantly by 1.9–4.6%. Some of but it seems possible that larger size could reflect a better the infants with bulging fontanel were subjected to duplex immune stimulation. Doppler cranial sonography; bulging fontanels were not Overall, the present study confirms the finding of previous associated with increased ICP, probably due to the accom- studies, demonstrating that a 50 000 IU oral dose of vitamin modation of the infant cranium (Agoestina et al., 1994). A A is well tolerated by young infants, also when given with follow-up study at 3 years of age found no long-term effect of BCG. Should simultaneous administration of BCG and bulging on growth and development (Humphrey et al., vitamin A become policy, the combination can be expected 1998). Thus, VAS may induce fontanel bulging, but this to be safe in terms of side effects, although the increased bulging appears to be without short- or long-term neurolo- local reaction to BCG in boys who received VAS merits gical consequences. further investigation. In our study, the prevalence of bulging fontanel was much higher (10.9 and 9.4% in the VAS and placebo groups, respectively) than in the Indonesian (4.6 and 2.7%) (Agoes- Acknowledgements tina et al., 1994) and the Zimbabwean study (1.5 and 1.0%) (Iliff et al., 1999). The Indian study reported no cases among PA, AR and CB designed the study and initiated enrolment. 11 619 infants 24 h after 24 000 IU (Rahmathullah et al., JEN collected data for part A. BRD and JEN wrote the first 2003). However, we only found one case of very bulging draft of the paper. HR assisted with the statistical analyses. fontanel in the placebo group, the rest being only slightly All authors contributed to the final version. The study was bulging. We did not find VAS to be associated with bulging supported by the EU (ICA4-CT-2002-10053), DANIDA and fontanels. In our study, as in most others, there was no the Danish Graduate School of Public Health Science. association between symptoms of raised ICP (irritability and vomiting) and bulging fontanel. Irrespectively, a bulging fontanel may be perceived by the mother as a negative References consequence of VAS and could lead to decreased participa- tion in VAS programmes. However, we found no indication Agoestina T, Humphrey JH, Taylor GA, Usman A, Subardja D, Hidayat S et al. (1994). Safety of one 52-mumol (50 000 IU) oral dose of that mothers of children with bulging fontanels perceived vitamin A administered to neonates. Bull World Health Organ 72, their children to be more irritable or less well. 859–868. We tested many different signs and symptoms and Baqui AH, de Francisco A, Arifeen SE, Siddique AK, Sack RB (1995). statistical significance in some of the comparisons was not Bulging fontanelle after supplementation with 25 000 IU of vitamin A in infancy using immunization contacts. Acta Paediatr unexpected, due to multiple testing. We found a significant 84, 863–866. difference between the vitamin A and placebo groups with Benn CS, Aaby P, Bale C, Olsen J, Michaelsen KF, George E et al. regard to occurrence of five or more bowel movements (1997). Randomised trial of effect of vitamin A supplementation during a 24 h period. This may be a chance finding; however, on antibody response to measles vaccine in Guinea-Bissau, West Lancet it should be noted that in the Indonesian adverse events Africa. 350, 101–105. Benn CS, Bale C, Sommerfelt H, Friis H, Aaby P (2003). Hypothesis: study only four infants experienced three or more loose vitamin A supplementation and childhood mortality: amplifica- stools between 12 and 24 h post dosing, and all four were in tion of the non-specific effects of vaccines? Int J Epidemiol 32, the control group (Agoestina et al., 1994). 822–828. Benn CS, Diness BR, Roth A, Nante E, Fisker AB, Lisse IM et al. (2007). We found no indication that vitamin A supplementation Randomised trial of the effect on mortality of 50 000 IU vitamin A affected the overall frequency of adverse reactions to BCG given with BCG vaccine to infants in Guinea-Bissau, West Africa. vaccination when given simultaneously with BCG vaccina- Submitted.

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