Birgitte Rode Diness

Randomized Trial of BCG Vaccination at Birth to Low-Birth-Weight Children: Beneficial Nonspecific Effects in the Neonatal Period?

BACKGROUND Observational studies have suggested that BCG may have nonspecific beneficial effects on survival. Low-birth-weight (LBW) children are not given BCG at birth in Guinea-Bissau; we conducted a randomized trial of BCG at birth (early BCG) vs delayed BCG. METHODS In the period 2004-2008 we recruited 2320 LBW children in Bissau. The children were visited at home at 2, 6, and 12 months of age. With a pretrial infant mortality of 250 per 1000, we hypothesized a 25% reduction in infant mortality for LBW children. RESULTS Infant mortality was only 101 per 1000 during the trial. In the primary analysis, infant mortality was reduced insignificantly by 17% (mortality rate ratio [MRR] = .83 [.63-1.08]). In secondary analyses, early BCG vaccine was safe with an MRR of .49 (.21-1.15) after 3 days and .55 (.34-.89) after 4 weeks. The reduction in neonatal mortality was mainly due to fewer cases of neonatal sepsis, respiratory infection, and fever. The impact of early BCG on infant mortality was marked for children weighing <1.5 kg (MRR = .43 [.21-.85]) who had lower coverage for diphtheria-tetanus-pertussis vaccinations. CONCLUSIONS Though early BCG did not reduce infant mortality significantly, it may have a beneficial effect in the neonatal period. This could be important for public health because BCG is often delayed in low-income countries.

Effect of 50 000 IU vitamin A given with BCG vaccine on mortality in infants in Guinea-Bissau: randomised placebo controlled trial

Objective To investigate the effect of high dose vitamin A supplementation given with BCG vaccine at birth in an African setting with high infant mortality. Design Randomised placebo controlled trial. Setting Bandim Health Project’s demographic surveillance system in Guinea-Bissau, covering approximately 90 000 inhabitants. Participants 4345 infants due to receive BCG. Intervention Infants were randomised to 50 000 IU vitamin A or placebo and followed until age 12 months. Main outcome measure Mortality rate ratios. Results 174 children died during follow-up (mortality=47/1000 person-years). Vitamin A supplementation was not significantly associated with mortality; the mortality rate ratio was 1.07 (95% confidence interval 0.79 to 1.44). The effect was 1.00 (0.65 to 1.56) during the first four months and 1.13 (0.75 to 1.68) from 4 to 12 months of age. The mortality rate ratio in boys was 0.84 (0.55 to 1.27) compared with 1.39 (0.90 to 2.14) in girls (P for interaction=0.10). An explorative analysis revealed a strong interaction between vitamin A and season of administration. Conclusions Vitamin A supplementation given with BCG vaccine at birth had no significant benefit in this African setting. Although little doubt exists that vitamin A supplementation reduces mortality in older children, a global recommendation of supplementation for all newborn infants may not contribute to better survival. Trial registration Clinical trials NCT00168597.

Vitamin A supplementation and BCG vaccination at birth in low birthweight neonates: two by two factorial randomised controlled trial.

Objective To investigate the effect of vitamin A supplementation and BCG vaccination at birth in low birthweight neonates. Design Randomised, placebo controlled, two by two factorial trial. Setting Bissau, Guinea-Bissau. Participants 1717 low birthweight neonates born at the national hospital. Intervention Neonates who weighed less than 2.5 kg were randomly assigned to 25 000 IU vitamin A or placebo, as well as to early BCG vaccine or the usual late BCG vaccine, and were followed until age 12 months. Main outcome measure Mortality, calculated as mortality rate ratios (MRRs), after follow-up to 12 months of age for infants who received vitamin A supplementation compared with those who received placebo. Results No interaction was observed between vitamin A supplementation and BCG vaccine allocation (P=0.73). Vitamin A supplementation at birth was not significantly associated with mortality: the MRR of vitamin A supplementation compared with placebo, controlled for randomisation to “early BCG” versus “no early BCG” was 1.08 (95% CI 0.79 to 1.47). Stratification by sex revealed a significant interaction between vitamin A supplementation and sex (P=0.046), the MRR of vitamin A supplementation being 0.74 (95% CI 0.45 to 1.22) in boys and 1.42 (95% CI 0.94 to 2.15) in girls. When these data were combined with data from a complementary trial among normal birthweight neonates in Guinea-Bissau, the combined estimate of the effect of neonatal vitamin A supplementation on mortality was 1.08 (95% CI 0.87 to 1.33); 0.80 (95% CI 0.58 to 1.10) in boys and 1.41 (95% CI 1.04 to 1.90) in girls (P=0.01 for interaction between neonatal vitamin A and sex). Conclusions The combined results of this trial and the complementary trial among normal birthweight neonates have now shown that, overall, it would not be beneficial to implement a neonatal vitamin A supplementation policy in Guinea-Bissau. Worryingly, the trials show that vitamin A supplementation at birth can be harmful in girls. Previous studies and future trials should investigate the possibility that vitamin A supplementation has sex differential effects. Trial registration ClinicalTrials.gov NCT00168610.

Penetrance of hypertrophic cardiomyopathy in children and adolescents: a 12-year follow-up study of clinical screening and predictive genetic testing.

Background— The penetrance of hypertrophic cardiomyopathy (HCM) during childhood and adolescence has been only sparsely described. We studied the penetrance of HCM and the short- and long-term outcomes of clinical screening and predictive genetic testing of child relatives of patients with HCM. Methods and Results— Ninety probands and 361 relatives were included in a family screening program for HCM (1994–2001). Eleven sarcomere genes, CRYAB, &agr;-GAL, and titin were screened. Sixty-six relatives and 4 probands were <18 years of age at inclusion. Twelve child relatives were mutation carriers (age, 12 ± 5 years), and 26 had unknown genetic status, ie, relatives from families without identified mutations (n = 21) or not tested (n = 5) (age, 11 ± 5 years). Twenty-eight noncarriers (42%; age, 10 ± 4 years) served as control subjects. Two of 38 child relatives (5%) at risk of developing HCM fulfilled diagnostic criteria for HCM at inclusion. After 12 ± 1 years of follow-up, 2 of the 36 (6%; 95% confidence interval, 2–18) at-risk child relatives who were phenotype negative at inclusion had developed the HCM phenotype at 26 and 28 years of age. During follow-up, none of the child relatives experienced serious cardiac events. Participation in the screening program had no long-term negative psychological impact. Conclusions— The penetrance of HCM in phenotype-negative child relatives at risk of developing HCM was 6% after 12 years of follow-up. The finding of phenotype conversion in the mid-20s warrants continued screening into adulthood. Forty-two percent of the child relatives were noncarriers, and repeat clinical follow-up could be safely limited to the remaining children.Background— The penetrance of hypertrophic cardiomyopathy (HCM) during childhood and adolescence has been only sparsely described. We studied the penetrance of HCM and the short- and long-term outcomes of clinical screening and predictive genetic testing of child relatives of patients with HCM. Methods and Results— Ninety probands and 361 relatives were included in a family screening program for HCM (1994–2001). Eleven sarcomere genes, CRYAB, α-GAL, and titin were screened. Sixty-six relatives and 4 probands were <18 years of age at inclusion. Twelve child relatives were mutation carriers (age, 12 ± 5 years), and 26 had unknown genetic status, ie, relatives from families without identified mutations (n = 21) or not tested (n = 5) (age, 11 ± 5 years). Twenty-eight noncarriers (42%; age, 10 ± 4 years) served as control subjects. Two of 38 child relatives (5%) at risk of developing HCM fulfilled diagnostic criteria for HCM at inclusion. After 12 ± 1 years of follow-up, 2 of the 36 (6%; 95% confidence interval, 2–18) at-risk child relatives who were phenotype negative at inclusion had developed the HCM phenotype at 26 and 28 years of age. During follow-up, none of the child relatives experienced serious cardiac events. Participation in the screening program had no long-term negative psychological impact. Conclusions— The penetrance of HCM in phenotype-negative child relatives at risk of developing HCM was 6% after 12 years of follow-up. The finding of phenotype conversion in the mid-20s warrants continued screening into adulthood. Forty-two percent of the child relatives were noncarriers, and repeat clinical follow-up could be safely limited to the remaining children. # Clinical Perspective {#article-title-34}

Early diphtheria-tetanus-pertussis vaccination associated with higher female mortality and no difference in male mortality in a cohort of low birthweight children: an observational study within a randomised trial

Background Studies from low-income countries have suggested that diphtheria-tetanus-pertussis (DTP) vaccine provided after Bacille Calmette-Guerin (BCG) vaccination may have a negative effect on female survival. The authors examined the effect of DTP in a cohort of low birthweight (LBW) infants. Methods 2320 LBW newborns were visited at 2, 6 and 12 months of age to assess nutritional and vaccination status. The authors examined survival until the 6-month visit for children who were DTP vaccinated and DTP unvaccinated at the 2-month visit. Results Two-thirds of the children had received DTP at 2 months and 50 deaths occurred between the 2-month and 6-month visits. DTP vaccinated children had a better anthropometric status for all indices than DTP unvaccinated children. Small mid-upper arm circumference (MUAC) was the strongest predictor of mortality. The death rate ratio (DRR) for DTP vaccinated versus DTP unvaccinated children differed significantly for girls (DRR 2.45; 95% CI 0.93 to 6.45) and boys (DRR 0.53; 95% CI 0.23 to 1.20) (p=0.018, homogeneity test). Adjusting for MUAC, the overall effect for DTP vaccinated children was 2.62 (95% CI 1.34 to 5.09); DRR was 5.68 (95% CI 1.83 to 17.7) for girls and 1.29 (95% CI 0.56 to 2.97) for boys (p=0.023, homogeneity test). While anthropometric indices were a strong predictor of mortality among boys, there was little or no association for girls. Conclusion Surprisingly, even though the children with the best nutritional status were vaccinated early, early DTP vaccination was associated with increased mortality for girls.

Neonatal Vitamin A Supplementation: Sex-Differential Effects on Mortality?

Humphrey et al. and Malaba et al. recently presented the results of a large vitamin A supplementation (VAS) study in Zimbabwe. In this study neonates and their mothers were randomized to receive either vitamin A (50000 I for infants and 400000 I for mothers) or placebo in a 2-by-2 factorial design. In contrast to the findings of 2 previously published studies of neonatal VAS conducted in Indonesia and India the Zimbabwe study found no beneficial effect of neonatal VAS on mortality among infants of HIV-negative mothers and among infants of HIV-positive mothers neonatal VAS was associated with increased mortality in infants who remained negative by polymerase chain reaction at 6 weeks of age. The results of the Zimbabwe study were not reported by sex. (excerpt)

Two Different Doses of Supplemental Vitamin A Did Not Affect Mortality of Normal-Birth-Weight Neonates in Guinea-Bissau in a Randomized Controlled Trial

Whether neonatal vitamin A supplementation (NVAS) should be policy in areas with vitamin A deficiency is debated. We observed that a smaller dose of vitamin A may decrease mortality more than a larger dose and conducted a randomized, double-blind, placebo-controlled trial in Guinea-Bissau with the primary aim of comparing the effect of 50,000 with 25,000 IU neonatal vitamin A on infant mortality. The secondary aim was to study the effect of NVAS vs. placebo, including a combined analysis of NVAS trials. Between 2004 and 2007, normal-birth-weight neonates were randomly assigned in a 1:1:1 ratio to be administered 2 different doses of vitamin A (50,000 or 25,000 IU) or placebo. Infant mortality rates (MRs) were compared in Cox models providing MR ratios (MRRs). Among 6048 children enrolled, there were 160 deaths in 4125 person-years (MR = 39/1000). There was no difference in mortality between the 2 dosage groups: the MRR for 25,000 vs. 50,000 IU was 0.96 (95% CI: 0.67, 1.38). Neither dose of NVAS was associated with lower mortality than placebo (MRR = 1.28; 95% CI: 0.91, 1.81). In a combined analysis of the present trial and 2 previous NVAS trials in Guinea-Bissau, the effect of receiving NVAS (any dose) vs. placebo was 1.13 (95% CI: 0.94, 1.36) and differed significantly (P = 0.01) between boys (0.80; 95% CI: 0.58, 1.09) and girls (1.35; 95% CI: 1.04, 1.75). We could not confirm that a smaller dose of neonatal vitamin A reduces mortality more than a larger dose. We confirmed 2 other trials in Guinea-Bissau that showed no beneficial effect of NVAS. This trial was registered at clinicaltrials.gov as NCT00168610.

The impact of different doses of vitamin A supplementation on male and female mortality. A randomised trial from Guinea-Bissau

BackgroundVitamin A supplementation (VAS) given to children between 6 months and 5 years of age is known to reduce mortality in low-income countries. We have previously observed that girls benefit more from a lower dose of VAS than the one recommended by WHO, the effect being strongest if diphtheria-tetanus-pertussis vaccine (DTP) was the most recent vaccination. We aimed to test these observations.MethodsDuring national immunisations days in Guinea-Bissau, West Africa, combining oral polio vaccination and VAS, we randomised 8626 children between 6 months and 5 years of age to receive the dose of VAS recommended by WHO or half this dose. Mortality rate ratios (MRRs) were assessed after 6 and 12 month.ResultsThe overall mortality rate among participants was lower than expected. There was no significant difference in mortality at 6 months and 12 months of follow up between the low dose VAS group and the recommended dose VAS group. The MRRs were 1.23 (0.60-2.54) after 6 months and 1.17 (0.73-1.87) after 12 months. This tendency was similar in boys and girls. The low dose was not associated with lower mortality in girls if the most recent vaccine was DTP (MRR = 0.60 (0.14-2.50) after 6 months).ConclusionOur sample size does not permit firm conclusions since mortality was lower than expected. We could not confirm a beneficial effect of a lower dose of VAS on mortality in girls.Trial registrationThe study was registered under clinicaltrials.gov, number NCT00168636

The effect of high-dose vitamin A supplementation given with bacille Calmette-Guérin vaccine at birth on infant rotavirus infection and diarrhea: a randomized prospective study from Guinea-Bissau.

BACKGROUND Prophylactic vitamin A supplementation (VAS) reduces mortality and may reduce morbidity associated with diarrhea in children >6 months of age. Rotavirus is the most common cause of acute dehydrating diarrhea among children worldwide. METHODS In a randomized placebo-controlled study of 50,000 IU of vitamin A versus placebo given with bacille Calmette-Guérin vaccine at birth, 287 infants were followed up with weekly interviews and stool sample obtainment to test the hypothesis that VAS reduced the risk of rotavirus infection. RESULTS VAS was associated with increased risk of rotavirus infection and diarrhea (incidence rate ratio [IRR] of infection, 1.72 [95% confidence interval (CI), 1.04-2.85]; IRR of diarrhea, 3.74 [95% CI, 1.40-9.98]) among children <6 months of age. There was no effect in older children. VAS had a beneficial effect on nonrotavirus diarrhea in boys <6 months of age (IRR, 0.51; 95% CI, 0.27-0.95) and a detrimental effect in girls >6 months of age (IRR, 1.84; 95% CI, 0.96-3.55). CONCLUSION VAS at birth did not reduce rotavirus morbidity. The effect of VAS on nonrotavirus diarrhea may differ by sex, being more beneficial in boys. Clinical trials registration. NCT00168597 .

Interaction between neonatal vitamin A supplementation and timing of measles vaccination: A retrospective analysis of three randomized trials from Guinea-Bissau ☆

Highlights • Early measles vaccine and neonatal vitamin A supplementation may become policy in low-income countries.• Vaccines and vitamin A may interact.• In children who received early measles vaccine, neonatal vitamin A was associated with 5-fold higher overall mortality.• Implementation of both policies at the same time may lead to increased child mortality.• Co-packaging of child health interventions should be investigated for the effect on overall mortality.