- Email: [email protected]
Neonatal vitamin A: time to move on?
Correspondence
The continuing Ebola outbreak is unprecedented in its magnitude.1 The fragile health infrastructure of the three countries in which transmission spiralled out of control (Guinea, Sierra Leone, and Liberia) made them particularly susceptible to the outbreak.2 Present international discourse is focused on making health systems more resilient to Ebola and other epidemics. To accomplish this, any initiative must address poverty, strengthen the health workforce with technical and financial support, and develop basic facility and communication infrastructure. Before the Ebola outbreak, financing of health care was largely supported by donors.3 In the absence of a strong economy, no financial reserves are available for health care in normal circumstances, or during emergencies, as shown by the shortage of protective equipment for health-care workers during the Ebola outbreak. One underlying obstacle to economic progress is the absence of basic infrastructure. Inadequate transportation systems cut rural Liberia off from the capital, Monrovia, and other urban areas, preventing the distribution of crops and thus discouraging investment in agriculture. In April, 2014, and again in July, 2014, when the Ebola crisis was escalating in Liberia, health workers went on strike for increased pay. Additionally, many workers received no relevant training or equipment, which led to many Ebola deaths among them. The supply of health workers in these countries is at risk—eg, the University of Liberia Medical School is closed because of insufficient funding. Many facilities do not have basic medical and communication equipment, which severely affects patient care. Basic infection control www.thelancet.com Vol 386 July 11, 2015
is difficult without rubber gloves or running water and makes facilities vectors of disease rather than places of healing. During the initial phase of the Ebola outbreak, public health workers did not have the simple and inexpensive instruments needed to communicate vital information quickly. Present proposals for epidemic control, such as a new worldwide response team, or an emergency fund, are unlikely to help if these weaknesses are not addressed. Protection from worldwide pandemics starts locally, with investments in poverty reduction, health workforce development, and basic health and communication infrastructure. The Ministries of Health, Education, Public Works, Finance and Planning, and Agriculture, and the corporations responsible for utilities, such as electricity and internet, must all cooperate. We are calling for some of the post-Ebola funding to be used for long-term investment in the economy, in infrastructure, and in people, without which west Africa and the rest of the world will remain susceptible to Ebola and other epidemics. LAS and APG received support from the National Science Foundation Rapid Response Research Program. MF and Ed’H declare no competing interests.
*Mosoka Fallah, Laura A Skrip, Emmanuel d’Harcourt, Alison P Galvani [email protected] Ministry of Health and Social Welfare, 1000 Monrovia 10, Liberia (MF); University of Liberia, Monrovia, Liberia (MF, APG); Center for Infectious Disease Modeling and Analysis, Yale School of Public Health, New Haven, CT, USA (LAS, APG); and The International Rescue Committee, New York, NY, USA (Ed’H) 1 2
3
WHO. Ebola situation report—20 May 2015. Geneva: World Health Organization, 2015. WHO. Key Country Indicators. Country summaries for Liberia, Sierra Leone, and Guinea. 2014. http://apps.who.int/gho/data/ node.cco.keyind?lang=en#ndx-L (accessed May 23, 2015). Republic of Liberia. Ministry of Health and Social Welfare. National Health Policy: National Health Plan 2007–2011. Monrovia; 2007.
Neonatal vitamin A: time to move on? Results of the Neovita trial (April 4, p 1268)1 investigating vitamin A supplementation in newborn babies shortly after birth showed no effect in Africa but improved infant survival in south Asia. An accompanying Comment by Batool Haider and Zulfiqar Bhutta2 highlighted regional differences and context as accounting for these outcomes, especially prevalence and severity of pre-existing maternal vitamin A deficiency. Maternal vitamin A status in African settings was normal, and newborn dosing had no effect, but materal vitamin A was deficient in South Asia, where newborn dosing reduced infant mortality by 10–22% (excluding a study referenced from Nepal, where newborn babies were not dosed).3 Increased risk of having transient bulging fontanelle reported in infants given vitamin A was investigated in the first newborn vitamin A trial,4 in which it was not accompanied by any rise in intracranial pressure; nor were there differences in cognition at 3 years of age associated with a bulging fontanelle, irrespective of treatment group.5 Thus, a transient bulging fontanelle was deemed without clinical significance. In view of consistent findings across four south Asian trials, we do not understand why Haider and Bhutta2 do not recommend newborn vitamin A dosing for this region, where a 10% reduction in mortality could prevent 150 000 infant deaths each year. Since the last reported trial of vitamin A supplementation,6 about 1 million infants have probably died unnecessarily in this region. Few public health interventions are as cost effective. We agree with Haider and Bhutta that it is “time to move on”,2 but differ on direction. Guided by clear, observed regional differences, we suggest there be immediate efforts to scale up newborn vitamin A dosing across south Asia.
Godong/BSIP/Science Photo Library
Strategies to prevent future Ebola epidemics
Submissions should be made via our electronic submission system at http://ees.elsevier.com/ thelancet/
131
Correspondence
We declare no competing interests.
*Keith P West, Alfred Sommer [email protected] Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 20215, USA 1
2
3
4
5
6
Edmond KM, Newton S, Shannon C, et al. Effect of early neonatal vitamin A supplementation on mortality during infancy in Ghana (Neovita): a randomised, double-blind, placebo-controlled trial. Lancet 2015; 385: 1315–23. Haider BA, Bhutta ZA. Neonatal vitamin A supplementation: time to move on. Lancet 2015; 385: 1268–71. West KP Jr, Katz J, Shrestha SR, et al. Mortality of infants <6 mo of age supplemented with vitamin A: a randomized, double masked trial in Nepal. Am J Clin Nutr 1995; 62: 143–48. Agoestina T, Humphrey JH, Taylor GA, et al. Safety of one 52-mumol (50,000 IU) oral dose of vitamin A administered to neonates. Bull World Health Organ 1994; 72: 85–68. Humphrey JH, Agoestina T, Juliana A, et al. Neonatal vitamin A supplementation: effect on development and growth at 3 y of age. Am J Clin Nutr 1998; 68: 109–17. Klemm RD, Labrique AB, Christian P, et al. Newborn vitamin A supplementation reduced infant mortality in rural Bangladesh. Pediatrics 2008; 122: e242–50.
When well intended trials of neonatal vitamin A supplementation (NVAS) fail to reduce mortality it is time to move on.1 But the direction depends on what we learned. According to current interpretation, NVAS works by preventing vitamin A deficiency, and many will reason that the trial populations were not sufficiently deficient, and NVAS might still have a role in deficient subgroups.1 However, there are alternative interpretations.
We have emphasised that NVAS has negative effects for girls at longer follow-up, possibly due to interaction with diphtheria-tetanuspertussis (DTP) vaccine administered after 6 weeks of age.2 Because of these concerns, the protocols for the Neovita trials were modified to include mortality by 12 months as secondary outcome, and to collect vaccination data to analyse potential interaction with DTP vaccine.3 The Ghanaian and Indian trials report adverse effects of NVAS with DTP vaccination up to 6 months of age (table).4,5 In Ghana, NVAS recipients had 36% (95% CI –4 to 92) higher mortality after receiving DTP. Conversely, India reports that NVAS recipients had 29% (2 to 49) lower mortality after DTP (p value for homogeneity=0·007). Unfortunately, the Indian data are flawed. The children were only visited at age 1 month, 3 months, and 6 months but virtually all deaths between 1 and 6 months were included in the analysis. Thus, children without information about DTP at 3 and 6 months were classified as DTP-unvaccinated. This number would include children who were vaccinated and died between visits. For survivors, vaccine status was updated retrospectively at next visit. This methodology introduces gross survival bias.6 Consequently, reported mortality in India among DTP-unvaccinated patients was high,
Vitamin A
Placebo
Deaths
Deaths Person- Mortality years per 1000 infants
Person- Mortality years per 1000 infants
324% (95% CI 255–407) higher than for the DTP-vaccinated patients (table). In Ghana, where vaccination data were collected monthly and survival bias would be less, unvaccinated children had 81% higher mortality than did vaccinated children. These results are incompatible (p value for homogeneity <0·001) and since there is a survival bias for the Indian data, only the Ghanaian suggestion that NVAS recipients tended to have increased mortality after DTP is valid. Meta-analysis of the existing and new NVAS trials only included follow-up to 6 months, 1 but the data from 6 to 12 months support a negative interaction between NVAS and subsequent DTP vaccine. On the basis of all studies with follow-up to 12 months and data presented by sex, female infants who received NVAS have 20% (95% CI 2–42) higher mortality than placebo recipients from 6 to 12 months (figure) and NVAS and sex interact significantly (p value for homogeneity=0·009). This tendency was also seen in the study in India.5 DTP has been linked to excess female mortality in numerous studies7 and is the most common vaccination by 6 months of age; hence, an unfortunate interaction between NVAS and DTP in girls is possible. A meta-analysis that includes follow-up to only 6 months and concludes that there is no sex interaction and that
Risk ratio for neonatal vitamin A vs placebo (95% CI)
Ghana
p value for Combined risk ratio homogeneity DTP-unvaccinated/ DTP-vaccinated (95% CI)
0·089
Before receiving DTP-HEPB-HIB
29
973
30
36
980
37
0·81 (0·50–1·32)
··
After receiving DTP-HEPB-HIB
76
3579
21
56
3591
16
1·36 (0·96–1·92)
··
India
0·167
1·81 (1·34–2·43) ·· ·· 4·24 (3·55–5·07)
Before receiving DTP
293
4368
67
325
4436
73
0·92 (0·78–1·07)
··
··
After receiving DTP
63
4586
14
87
4501
19
0·71 (0·51–0·98)
··
··
Children followed up from 1 to 5 months of age. DTP=diphtheria-tetanus-pertussis vaccine. HEPB=hepatitis B vaccine. HIB=Haemophilus influenzae b vaccine.
Table: Effect of neonatal vitamin A supplementation in relation to first dose of DTP-containing vaccine
132
www.thelancet.com Vol 386 July 11, 2015
The continuing Ebola outbreak is unprecedented in its magnitude.1 The fragile health infrastructure of the three countries in which transmission spiralled out of control (Guinea, Sierra Leone, and Liberia) made them particularly susceptible to the outbreak.2 Present international discourse is focused on making health systems more resilient to Ebola and other epidemics. To accomplish this, any initiative must address poverty, strengthen the health workforce with technical and financial support, and develop basic facility and communication infrastructure. Before the Ebola outbreak, financing of health care was largely supported by donors.3 In the absence of a strong economy, no financial reserves are available for health care in normal circumstances, or during emergencies, as shown by the shortage of protective equipment for health-care workers during the Ebola outbreak. One underlying obstacle to economic progress is the absence of basic infrastructure. Inadequate transportation systems cut rural Liberia off from the capital, Monrovia, and other urban areas, preventing the distribution of crops and thus discouraging investment in agriculture. In April, 2014, and again in July, 2014, when the Ebola crisis was escalating in Liberia, health workers went on strike for increased pay. Additionally, many workers received no relevant training or equipment, which led to many Ebola deaths among them. The supply of health workers in these countries is at risk—eg, the University of Liberia Medical School is closed because of insufficient funding. Many facilities do not have basic medical and communication equipment, which severely affects patient care. Basic infection control www.thelancet.com Vol 386 July 11, 2015
is difficult without rubber gloves or running water and makes facilities vectors of disease rather than places of healing. During the initial phase of the Ebola outbreak, public health workers did not have the simple and inexpensive instruments needed to communicate vital information quickly. Present proposals for epidemic control, such as a new worldwide response team, or an emergency fund, are unlikely to help if these weaknesses are not addressed. Protection from worldwide pandemics starts locally, with investments in poverty reduction, health workforce development, and basic health and communication infrastructure. The Ministries of Health, Education, Public Works, Finance and Planning, and Agriculture, and the corporations responsible for utilities, such as electricity and internet, must all cooperate. We are calling for some of the post-Ebola funding to be used for long-term investment in the economy, in infrastructure, and in people, without which west Africa and the rest of the world will remain susceptible to Ebola and other epidemics. LAS and APG received support from the National Science Foundation Rapid Response Research Program. MF and Ed’H declare no competing interests.
*Mosoka Fallah, Laura A Skrip, Emmanuel d’Harcourt, Alison P Galvani [email protected] Ministry of Health and Social Welfare, 1000 Monrovia 10, Liberia (MF); University of Liberia, Monrovia, Liberia (MF, APG); Center for Infectious Disease Modeling and Analysis, Yale School of Public Health, New Haven, CT, USA (LAS, APG); and The International Rescue Committee, New York, NY, USA (Ed’H) 1 2
3
WHO. Ebola situation report—20 May 2015. Geneva: World Health Organization, 2015. WHO. Key Country Indicators. Country summaries for Liberia, Sierra Leone, and Guinea. 2014. http://apps.who.int/gho/data/ node.cco.keyind?lang=en#ndx-L (accessed May 23, 2015). Republic of Liberia. Ministry of Health and Social Welfare. National Health Policy: National Health Plan 2007–2011. Monrovia; 2007.
Neonatal vitamin A: time to move on? Results of the Neovita trial (April 4, p 1268)1 investigating vitamin A supplementation in newborn babies shortly after birth showed no effect in Africa but improved infant survival in south Asia. An accompanying Comment by Batool Haider and Zulfiqar Bhutta2 highlighted regional differences and context as accounting for these outcomes, especially prevalence and severity of pre-existing maternal vitamin A deficiency. Maternal vitamin A status in African settings was normal, and newborn dosing had no effect, but materal vitamin A was deficient in South Asia, where newborn dosing reduced infant mortality by 10–22% (excluding a study referenced from Nepal, where newborn babies were not dosed).3 Increased risk of having transient bulging fontanelle reported in infants given vitamin A was investigated in the first newborn vitamin A trial,4 in which it was not accompanied by any rise in intracranial pressure; nor were there differences in cognition at 3 years of age associated with a bulging fontanelle, irrespective of treatment group.5 Thus, a transient bulging fontanelle was deemed without clinical significance. In view of consistent findings across four south Asian trials, we do not understand why Haider and Bhutta2 do not recommend newborn vitamin A dosing for this region, where a 10% reduction in mortality could prevent 150 000 infant deaths each year. Since the last reported trial of vitamin A supplementation,6 about 1 million infants have probably died unnecessarily in this region. Few public health interventions are as cost effective. We agree with Haider and Bhutta that it is “time to move on”,2 but differ on direction. Guided by clear, observed regional differences, we suggest there be immediate efforts to scale up newborn vitamin A dosing across south Asia.
Godong/BSIP/Science Photo Library
Strategies to prevent future Ebola epidemics
Submissions should be made via our electronic submission system at http://ees.elsevier.com/ thelancet/
131
Correspondence
We declare no competing interests.
*Keith P West, Alfred Sommer [email protected] Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 20215, USA 1
2
3
4
5
6
Edmond KM, Newton S, Shannon C, et al. Effect of early neonatal vitamin A supplementation on mortality during infancy in Ghana (Neovita): a randomised, double-blind, placebo-controlled trial. Lancet 2015; 385: 1315–23. Haider BA, Bhutta ZA. Neonatal vitamin A supplementation: time to move on. Lancet 2015; 385: 1268–71. West KP Jr, Katz J, Shrestha SR, et al. Mortality of infants <6 mo of age supplemented with vitamin A: a randomized, double masked trial in Nepal. Am J Clin Nutr 1995; 62: 143–48. Agoestina T, Humphrey JH, Taylor GA, et al. Safety of one 52-mumol (50,000 IU) oral dose of vitamin A administered to neonates. Bull World Health Organ 1994; 72: 85–68. Humphrey JH, Agoestina T, Juliana A, et al. Neonatal vitamin A supplementation: effect on development and growth at 3 y of age. Am J Clin Nutr 1998; 68: 109–17. Klemm RD, Labrique AB, Christian P, et al. Newborn vitamin A supplementation reduced infant mortality in rural Bangladesh. Pediatrics 2008; 122: e242–50.
When well intended trials of neonatal vitamin A supplementation (NVAS) fail to reduce mortality it is time to move on.1 But the direction depends on what we learned. According to current interpretation, NVAS works by preventing vitamin A deficiency, and many will reason that the trial populations were not sufficiently deficient, and NVAS might still have a role in deficient subgroups.1 However, there are alternative interpretations.
We have emphasised that NVAS has negative effects for girls at longer follow-up, possibly due to interaction with diphtheria-tetanuspertussis (DTP) vaccine administered after 6 weeks of age.2 Because of these concerns, the protocols for the Neovita trials were modified to include mortality by 12 months as secondary outcome, and to collect vaccination data to analyse potential interaction with DTP vaccine.3 The Ghanaian and Indian trials report adverse effects of NVAS with DTP vaccination up to 6 months of age (table).4,5 In Ghana, NVAS recipients had 36% (95% CI –4 to 92) higher mortality after receiving DTP. Conversely, India reports that NVAS recipients had 29% (2 to 49) lower mortality after DTP (p value for homogeneity=0·007). Unfortunately, the Indian data are flawed. The children were only visited at age 1 month, 3 months, and 6 months but virtually all deaths between 1 and 6 months were included in the analysis. Thus, children without information about DTP at 3 and 6 months were classified as DTP-unvaccinated. This number would include children who were vaccinated and died between visits. For survivors, vaccine status was updated retrospectively at next visit. This methodology introduces gross survival bias.6 Consequently, reported mortality in India among DTP-unvaccinated patients was high,
Vitamin A
Placebo
Deaths
Deaths Person- Mortality years per 1000 infants
Person- Mortality years per 1000 infants
324% (95% CI 255–407) higher than for the DTP-vaccinated patients (table). In Ghana, where vaccination data were collected monthly and survival bias would be less, unvaccinated children had 81% higher mortality than did vaccinated children. These results are incompatible (p value for homogeneity <0·001) and since there is a survival bias for the Indian data, only the Ghanaian suggestion that NVAS recipients tended to have increased mortality after DTP is valid. Meta-analysis of the existing and new NVAS trials only included follow-up to 6 months, 1 but the data from 6 to 12 months support a negative interaction between NVAS and subsequent DTP vaccine. On the basis of all studies with follow-up to 12 months and data presented by sex, female infants who received NVAS have 20% (95% CI 2–42) higher mortality than placebo recipients from 6 to 12 months (figure) and NVAS and sex interact significantly (p value for homogeneity=0·009). This tendency was also seen in the study in India.5 DTP has been linked to excess female mortality in numerous studies7 and is the most common vaccination by 6 months of age; hence, an unfortunate interaction between NVAS and DTP in girls is possible. A meta-analysis that includes follow-up to only 6 months and concludes that there is no sex interaction and that
Risk ratio for neonatal vitamin A vs placebo (95% CI)
Ghana
p value for Combined risk ratio homogeneity DTP-unvaccinated/ DTP-vaccinated (95% CI)
0·089
Before receiving DTP-HEPB-HIB
29
973
30
36
980
37
0·81 (0·50–1·32)
··
After receiving DTP-HEPB-HIB
76
3579
21
56
3591
16
1·36 (0·96–1·92)
··
India
0·167
1·81 (1·34–2·43) ·· ·· 4·24 (3·55–5·07)
Before receiving DTP
293
4368
67
325
4436
73
0·92 (0·78–1·07)
··
··
After receiving DTP
63
4586
14
87
4501
19
0·71 (0·51–0·98)
··
··
Children followed up from 1 to 5 months of age. DTP=diphtheria-tetanus-pertussis vaccine. HEPB=hepatitis B vaccine. HIB=Haemophilus influenzae b vaccine.
Table: Effect of neonatal vitamin A supplementation in relation to first dose of DTP-containing vaccine
132
www.thelancet.com Vol 386 July 11, 2015