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Neonatal Vitamin A Supplementation Associated With A Cluster Of Deaths And Poor Early Growth In A Randomised Trial Among Low-Birth-Weight Boys Of Vitamin A Versus Oral Polio Vaccine At Birth Najaaraq Lund1,2,3*, Sofie Biering-Sørensen1, Andreas Andersen1, Ivan Monteiro3, Luis Camala4, Mathias Jul Jørgensen3, Peter Aaby1,3 and Christine Stabell Benn1,5 Abstract Background: The effect of oral polio vaccine administered already at birth (OPV0) on child survival was not examined before being recommended in 1985. Observational data suggested that OPV0 was harmful for boys, and trials have shown that neonatal vitamin A supplementation (NVAS) at birth may be beneficial for boys. We set out to test this research question in a randomised trial. Methods: The trial was carried out at the Bandim Health Project, Guinea-Bissau. We planned to enrol 900 low-birth weight (LBW) boys in a randomised trial to investigate whether NVAS instead of OPV0 could lower infant mortality for LBW boys. At birth, the children were randomised to OPV (usual treatment) or VAS (intervention treatment) and followed for 6 months for growth and 12 months for survival. Hazard Ratios (HR) for mortality were calculated using Cox regression. We compared the individual anthropometry measurements to the 2006 WHO growth reference. We compared differences in z-scores by linear regression. Relative risks (RR) of being stunted or underweight were calculated in Poisson regression models with robust standard errors. Results: In the rainy season we detected a cluster of deaths in the VAS group and the trial was halted immediately with 232 boys enrolled. The VAS group had significantly higher mortality than the OPV0 group in the rainy season (HR: 9.91 (1.23 – 80)). All deaths had had contact with the neonatal nursery; of seven VAS boys enrolled during one week in September, six died within two months of age, whereas only one died among the six boys receiving OPV (p = 0.05). Growth (weight and armcircumference) in the VAS group was significantly worse until age 3 months. 1 Research Center for Vitamins and Vaccines (CVIVA), Bandim Health Project, Statens Serum Institut, Copenhagen, Denmark. 2 Department of Infectious Diseases, Aarhus University Hospital, Aarhus, Denmark. 3 Bandim Health Project, Indepth Network, Bissau, Guinea-Bissau. 4 Maternidade, Hospital Nacional Simão Mendes, Bissau, Guinea-Bissau. 5 OPEN, Institute of Clinical Research, University of Southern Denmark/Odense University Hospital, Odense, Denmark. This is an Open Access article distributed under the terms of the Creative Commons Attribution License. Conclusion: VAS at birth instead of OPV was not beneficial for the LBW boys in this study. With the premature closure of the trial it was not possible to answer the research question. However, the results of this study call for extra caution when testing the effect of NVAS in the future. Background In low income countries a policy of providing neonatal vitamin A supplementation (VAS) is currently under debate. Four randomised trials from Africa and one from Nepal have shown no overall effect on mortality of neonatal VAS [1-5]. Three trials from South East Asia have reported a beneficial effect [6-8]. Several of the trials suggested that while VAS conferred few benefits or even a negative effect for girls, it had a positive effect in boys [1,2,6,8]. From 1985 WHO recommended a dose of oral polio vaccine at birth (OPV0) in addition to the three doses at 6, 10 and 14 weeks of age (OPV1-3). This policy was introduced to improve coverage and immune responses [9-13]. The effect of OPV at birth on overall child mortality was never studied. The Bandim Health Project (BHP) has worked in Guinea Bissau since 1978 and has examined non-specific and sex-differential effects on mortality of childhood interventions. From 2002–2004 when BHP was conducting a trial of neonatal VAS to normal birth weight children, OPV was lacking for several periods [14] and some of the enrolled children did not get the recommended OPV0. Surprisingly, boys who did not receive OPV0 only had a third of the mortality of boys who got the vaccine. The tendency was slightly opposite in girls, resulting in a highly significant interaction between OPV at birth and sex (p = 0.006). We also studied the effect of OPV0 on the immune response to BCG vaccine; both sexes had a dampened immune response to BCG if they received OPV together with BCG [15]. Based on these results we hypothesised that newborn LBW boys might benefit from receiving VAS at birth instead of OPV0, and we conducted a randomised trial to test that hypothesis. As the previous studies suggested a harmful effect of VAS in girls [2], only boys were randomised to receive VAS or OPV0. Girls were enrolled in another trial. The trial proceeded as planned from February 2008 until November 2008 when the study supervisor noted a bulk of death reports. Seven boys born between 28 August and 16 September 2008 had died before the 2 months visit. Among the seven deaths six had received VAS. This looked like a cluster and the PI decided to halt the trial to examine possible causes and avoid continuing an intervention which potentially had negative effects. 44 neonatal INTENSIVE CARE Vol. 29 No. 4 • Fall 2016
groups VAS at birth OPV at birth (N = 116) (N = 116) Table 1 Baseline characteristics of the two randomisation Enrolledgroups in rainy season, n (%) Enrolled at NH, n (%) 70 (60) VAS 102 at (88) birth 71 (61) OPV99 at(85) birth (N = 116) (N = 116) Living inside study area, n (%) 34 (29) 36 (31) Enrolled in rainy season, n (%) 70 (60) 71 (61) Twin, n Enrolled (%) at NH, n (%) 26102 (22) (88) 99 24 (85) (21) Admission Living to inside neonatal studynursery, area, n (%) n (%) 2934 (25) (29) 36 30 (31) (26) Age at inclusion, Twin, n (%) days (10–90 centiles) 2.5 26 (1–10) (22) 24 (1–10) (21) Birth weight, Admission kg (10–90 to neonatal centiles) nursery, n (%) 2.21 (1.66-2.45) 29 (25) 2.22 30 (1.66-2.46) (26) Age at inclusion, days (10–90 centiles) Ballard score* (10–90 centiles) 2.5 (1–10) 36 (27–43) 2 (1–10) 36 (27–43) Birth weight, kg (10–90 centiles) 2.21 (1.66-2.45) 2.22 (1.66-2.46) Median maternal age, years 23 (16–29) 22 (17–32) Ballard score* (10–90 centiles) 36 (27–43) 36 (27–43) (10–90 centiles) Median maternal age, years 23 (16–29) 22 (17–32) Maternal (10–90 schooling, centiles) n (%) NoneMaternal schooling, n (%) 3 23 (20) 24 (21) 23 (20) 24 (21) Unknown 1 (1) 1 (1) Unknown Maternal MUAC, mm (10–90 centiles) 1 (1) 232 (208–276) 1 (1) 238 (208–284) Maternal Abbreviations: MUAC, mm NH(10–90 National centiles) hospital; MUAC232 Mid (208–276) upper arm circumference. 238 (208–284) *Only available for children enrolled at the national hospital. Abbreviations: NH National hospital; MUAC Mid upper arm circumference. *Only available for children enrolled at the national hospital. Methods and supplemented. All mothers were encouraged to take setting their child to a health centre at 6 weeks of age to get and supplemented. The BHP runs a Health and Demographic Surveillance System BCG, OPV, andAll DTP. mothers At everywere home encouraged visit the assistants to take (HDSS) in six districts of Bissau, the capital of Guinea-Bissau. their child checked to the a health children’s centre vaccination at 6 weeks cardsof andage pointed to get Since 2002 the BHP has followed a cohort of LBW children from BCG, the out OPV, whole missing and capital. DTP. vaccines All At newborn for every thechildren mothers home weighing visit to ensure theless assistants that than all 2.5 checked kg children at the discharge children’s got OPV. from the Enrolment vaccination maternity staff ward cards did of the notand national take pointed part hospital out missing (NH) the follow-up are vaccines invited of to the participate. for children. the mothers At time toof ensure the trial, that 13% of all the children born at the NH were LBW. The children and their children got OPV. Enrolment staff did not take part in mothers Interventions are driven home from the hospital. A map is drawn the follow-up describing Vitamin Aof the was the localisation given children. as aof 0.5 their ml houses, oral supplement GPS coordinates which are was recorded, slowly released and a photo intoof the mouth house and of the mother child with is taken a Interventions to sterile ensure syringe that the by team a will nurse. be able Theto supplement localise the child came at in subsequent visits. When a child moves, a relative a neighbour Vitamin dark A glass was given bottlesas thata 0.5 were mlprepared oral supplement at Skanderborg which takes the team to the new address. In this way very few children was slowly Pharmacy, are lost released Denmark, to follow up. intoand LBW thecontained children mouth 20 living ofdoses inside the child of 25000 the BHP with IU study a vitamin A as retinyl palmitate and 10 IU vitamin E per sterilearea syringe who are by born aat nurse. home are The recruited supplement when they come camefor in their 0.5 ml first oil. vaccinations The bottles at one were of the kept three at health 2-8°C. centres Trivalent dark glass in the OPV study was bottles area. supplied that In Guinea-Bissau through were prepared the LBW national at children immunisation Skanderborg do not receive Pharmacy, BCG programme Denmark, at birth, but and and are administered contained told to come back orally. 20 doses when There of 25000 they have wasgained noIU Figure 1 Trial profile. vitamin weight, blinding. A as and retinyl they typically palmitate get BCG and together 10 IUwith vitamin the DTP E and per 0.5 ml OPV oil. scheduled The bottles at 6 weeks were of age. kept at 2-8°C. Trivalent OPV was supplied through the national immunisation The neonatal nursery offers a very basic care level with programme possibility and of phototherapy administered and intravenous orally. There infusion. was Intubation no Figure 1 Trial profile. blinding. and oxygen therapy was not possible at the time the trial was Figure 1 Trial profile. Primary outcome: infant mortality The LBW children were visited within the first 3 days after enrolment, and children living inside the study area Outcomes conducted. Admitted children did often share the available Primary incubators. outcome: The infant service mortality of the neonatal nursery is free, and Thechildren LBW children of all gestational were visited ages are within admitted. the first There 3 days is no after possibility enrolment, of and transmission children to living a higher inside specialised the study unit. area were visited on day 1–3 after enrolment to check for adverse events. All children who had not died, moved or enrolment The study was initiated 20 February 2008. LBW children wereidentified travelling at were the hospital visitedwere at 2, examined 6, and 12 by a months doctor or ofa age trained (Figure nurse 1). The who children also assessed living maturity inside the using BHPBallard study score area[16]. were Anthropometric furthermore measurements followed by the were HDSS. obtained If and the the child child moved was examined. outside Bissau Eligible or were was boys absent with ata the weight visit, below relatives 2.5 kg. orExclusion neighbours criteria were were asked major if the malformations, child was still female alivesex, and and howeight soonat they enrolment would of be≥ told 2500 ifg. the Children child died. who had Children already travelling received at BCG 12and months children were with visited clinical again signs at of vitamin 15–18 A deficiency months of were age. also When excluded, a deathas was were registered, children that thewere assistant too sick asked to be for discharged the child’s by health local standards. card. A verbal These autopsy was conducted around three months after the children were referred for treatment. There was no age criterion, as all children weighing less than 2500 g and coming for their first death by a trained assistant. A local doctor read the autopsyold, and and proposed the age distribution a diagnosis. is described The causein of Table death 1. The in mothers vaccines were eligible. The oldest child enrolled was 64 days broad were categories informed was of the determined study the later local after language, reading Creole, the and verbal got autopsy a written and explanation taking into of the account study the in the local official doctor’s diagnosis and possible hospital records. language, diagnosis Portuguese. and possible Oral and hospital written records. consent was obtained. The mother We signed collected the enrolment information on if she temperature, could write, respiratory if not she put frequency, a fingerprint, weight and gain an and independent a few other observer variables signed inthe the form. firstProvided three days consent, after enrolment the mother todrew be able a lot to from detect a bag. possibledecided adversewhich effects treatment, of the intervention VAS or OPV, her (which son would we did receive at The lot not enrolment. find); however, Randomisation we did not was collect done in information blocks of 24. on The bags were prepared by the study supervisor; each bag contained 24 stapled lots in separate opaque envelopes. Twins were allocated the same treatment to prevent potential confusion regarding were visited on day 1–3 after enrolment to check for adverse events. All children who had not died, moved or were travelling were visited at 2, 6, and 12 months of age (Figure 1). The children living inside the BHP study area were furthermore followed by the HDSS. If the child moved outside Bissau or was absent at the visit, relatives or neighbours were asked if the child was still alive and how soon they would be told if the child died. Children travelling at 12 months were visited again at 15–18 months of age. When a death was registered, the assistant asked for the child’s health card. A verbal autopsy was conducted around three months after the death by a trained assistant. A local doctor read the autopsy and proposed a diagnosis. The cause of death in broad categories was determined later after reading the verbal autopsy and taking into account the local doctor’s We collected information on temperature, respiratory frequency, weight gain and a few other variables in the first three days after enrolment to be able to detect possible adverse effects of the intervention (which we did not find); however, we did not collect information on neonatal 2 INTENSIVE CARE Vol. 29 No. 4 Fall 2016 neonatal INTENSIVE CARE Vol. XX No. X Xxxx XXXX 45 • •
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