1. Epidemiology and Global Health

Vitamin A supplements, routine immunization, and the subsequent risk of Plasmodium infection among children under 5 years in sub-Saharan Africa

  1. Maria-Graciela Hollm-Delgado  Is a corresponding author
  2. Frédéric B Piel
  3. Daniel J Weiss
  4. Rosalind E Howes
  5. Elizabeth A Stuart
  6. Simon I Hay
  7. Robert E Black
  1. Johns Hopkins University, United States
  2. University of Oxford, United Kingdom
https://doi.org/10.7554/eLife.03925
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Cite this article
  1. Maria-Graciela Hollm-Delgado
  2. Frédéric B Piel
  3. Daniel J Weiss
  4. Rosalind E Howes
  5. Elizabeth A Stuart
  6. Simon I Hay
  7. Robert E Black
(2015)
Vitamin A supplements, routine immunization, and the subsequent risk of Plasmodium infection among children under 5 years in sub-Saharan Africa
eLife 4:e03925.
https://doi.org/10.7554/eLife.03925
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3 figures, 3 tables and 3 additional files

Figures

Figure 1
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Flow chart of subjects.
https://doi.org/10.7554/eLife.03925.003
Figure 2
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Adjusted relative risk of malaria infection according to different features of vitamin A supplementation and BCG vaccination

(Liu et al., 2012; World Health Organization, 2012). (A) Adjusted for the following factors: age, gender, wealth index score, mother's highest level of education, malaria treatment during previous week, ownership of bed net, proportion of household members under 5 years using bed net during previous night, indoor household insecticide spraying, mother's access to antenatal care during last pregnancy, mother's knowledge regarding vertical HIV transmission, malaria transmission season, and type of community setting (urban vs rural). (B) Covariates ‘Age at vaccination’ and ‘Time since vaccination’ treated as continuous terms when testing for effect modification in the model. (C) Seasonality only available for children vaccinated in 2010 or 2011 calendar year.

https://doi.org/10.7554/eLife.03925.006
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Proportion of children tested according to type of diagnostic used.

Tables

Table 1

Baseline characteristics of 8390 children tested for malaria using blood film, by survey location

https://doi.org/10.7554/eLife.03925.004
CharacteristicLocation of surveyOverall (n=8390)
Burkina Faso (n=2821)Mozambique (n=2266)Rwanda (n=2085)Senegal (n=1218)
Communities surveyed, n5376074903712005
(a) Children tested for malaria, n (%)
 Parasitemia2821 (99)2266 (100)2085 (99)1218 (99)8390 (99)
 Positive result among children tested for parasitemia 1696 (60) 578 (25) 16 (0.8) 22 (1.8) 2312 (28)
 Pƒ-HRP-22821 (100)na2060 (99)1217 (99)6098 (99)*
 Positive results among children tested for Pƒ-HRP-2 2051 (73)na 35 (1.7) 27 (2.2) 2113 (35)
(b) Type of immunization received, n (%)
 Bacille Calmette Guerin (BCG)2799 (99)2004 (96)2050 (100)1160 (98)8013 (98)
 Diphtheria–tetanus–pertussis (DTP)2721 (97)2107 (97)2055 (98)1161 (98)8044 (98)
 Measles2225 (80)1668 (78)1727 (86)830 (73)6450 (80)
 Poliomyelitis2810 (100)2156 (99)2061 (100)1204 (100)8231 (99)
 Vitamin A87 (9.3)1554 (87)351 (72)190 (59)2182 (62)
(c) Children's characteristics
 Age in months, median (IQR)22 (13–32)20 (13–31)24 (14–36)19 (12–29)22 (13–32)
 Girls, n (%)1347 (48)1151 (51)1020 (49)551 (45)4069 (48)
 Primigravidae, n (%)443 (16)477 (21)432 (21)251 (21)1603 (19)
 Low birth weight, n (%)867 (31)1003 (44)672 (32)536 (44)3078 (37)
(d) Malaria-based interventions, n (%)
 Child's family owns bed net2160 (77)1528 (67)1983 (95)1040 (85)6711 (80)
 Child received antimalarial during past week314 (11)117 (5.2)50 (2.4)24 (2.0)505 (6.0)
 Child's house had indoor insecticide spraying22 (0.8)541 (24)na148 (12)711 (8.5)†
 Mother took antimalarial during child's gestational period2616 (93)1109 (50)337 (16)1110 (91)5162 (62)
(e) Genetic mechanisms of malaria protection, median (IQR)
 Mean predicted HbS allele frequency0.06 (0.05–0.06)0.03 (0.01–0.03)0.03 (0.03–0.03)0.07 (0.06–0.07)0.04 (0.03–0.06)
 Median predicted G6PDd allele frequency0.06 (0.05–0.09)0.15 (0.15–0.17)0.04 (0.04–0.05)0.10 (0.09–0.13)0.08 (0.05–0.14)
(f) Climate of communities surveyed, median (IQR)
 Annual range of enhanced vegetation index (EVI)0.29 (0.24–0.32)0.33 (0.22–0.40)0.25 (0.20–0.29)0.28 (0.18–0.34)0.28 (0.22–0.33)
 Annual mean of EVI for the year0.22 (0.18–0.25)0.40 (0.32–0.47)0.39 (0.36–0.42)0.18 (0.16–0.20)0.29 (0.20–0.40)
 No. of days which EVI above annual mean136 (120–160)88 (56–128)320 (168–384)208 (184–264)152 (120–200)
 No. of days for rainy season (corresponding to first and last day EVI above annual mean)136 (120–152)128 (72–344)344 (296–352)216 (152–352)168 (120–344)
  1. *

    Pƒ-HRP-2 testing not conducted as part of DHS survey protocol for Mozambique.

  2. †

    Information on insecticide spraying not collected as part of survey.

Table 2

Relative risk of malaria infection after standard vaccination and vitamin A supplementation among children 6–59 months of age

https://doi.org/10.7554/eLife.03925.005
Type of immunizationNo. of children vaccinated/total tested (%)No. of children with positive blood test (%)Unadjusted RRAdjusted RR (95% CI)‡,§
No vaccineVaccineUnweightedWeighted (IPW)
(a) Plasmodium species (parasitemia)*
 Bacille Calmette Guerin (BCG)8013/8140 (98)41 (32)2227 (28)0.811.25 (0.81–1.91)1.24 (0.76–2.05)
 Diphtheria–tetanus–pertussis (DTP)8044/8235 (98)83 (44)2202 (27)0.490.88 (0.64–1.20)0.06 (0.01–0.47)
 Measles6450/8069 (80)473 (29)1784 (28)0.931.11 (0.96–1.29)1.01 (0.20–5.19)
 Poliomyelitis8231/8272 (99)14 (34)2278 (28)0.740.80 (0.37–1.73)0.74 (0.27–2.01)
 Vitamin A supplement2182/3523 (62)596 (44)438 (20)0.310.46 (0.39–0.54)0.43 (0.36–0.52)
(b) Plasmodium falciparum (antigenemia)
 Bacille Calmette Guerin (BCG)6006/6047 (99)9 (22)2102 (35)1.914.06 (2.00–8.28)3.52 (1.66–7.48)
 Diphtheria–tetanus–pertussis (DTP)5933/6054 (98)59 (49)2049 (35)0.551.34 (0.88–2.02)0.06 (0.01–0.38)
 Measles4776/5937 (80)410 (35)1679 (35)0.991.15 (0.97–1.38)0.68 (0.15–3.12)
 Poliomyelitis6.072/6084 (99)5 (42)2111 (35)0.751.39 (0.55–3.49)0.93 (0.37–2.35)
 Vitamin A supplement629/1749 (36)621 (56)75 (12)0.100.23 (0.17–0.29)0.22 (0.16–0.29)

  1. HRP-2: histidine rich protein-2; RR: relative risk; CI: confidence interval; IPW: inverse probability weighted model.

  2. *

    Tested in four countries: Burkina Faso, Mozambique, Rwanda and Senegal.

  3. †

    Tested in three countries: Burkina Faso, Rwanda and Senegal.

  4. ‡

    Adjusted for the following factors: age, gender, wealth index score, mother's highest level of education, malaria treatment during previous week, ownership of bed net, proportion of household members under 5 years using bed net during previous night, indoor household insecticide spraying, mother's access to antenatal care during last pregnancy, mother's knowledge regarding vertical HIV transmission, malaria transmission season, and type of community setting (urban vs rural).

  5. §

    Inverse probability weighting (IPW) based on propensity score model with following factors: age, gender, low birth weight, presence of radio or television, urban versus rural setting, breastfeeding status, wealth index score, mother's age, mother's highest education level, antenatal care during last pregnancy, and mother's tetanus status during last pregnancy.

Table 3

Modifiers of the association between vitamin A supplementation and malaria infection among children 6–59 months of age

https://doi.org/10.7554/eLife.03925.007
Characteristics at blood testingLevel in the modelPlasmodium species (parasitemia)*Plasmodium falciparum (antigenemia)†
No. of children with positive blood film (%)Unadjusted RRAdjusted model3
No vitamin AVitamin ARR (95% CI)p Value (interaction term)Adjusted RR‡ (95%CI)p Value (interaction term)
(a) Individual level
Children's characteristics
 Age at malaria screening6–35 Months484 (43)344 (20)0.330.46 (0.38–0.55)<0.01#0.26 (0.20–0.34)<0.01#
36–59 Months112 (54)94 (21)0.230.34 (0.25–0.47)0.09 (0.05–0.14)
 GenderGirl274 (44)226 (21)0.340.54 (0.44–0.67)0.290.23 (0.16–0.32)0.99
Boy322 (45)212 (19)0.290.40 (0.32–0.49)0.23 (0.17–0.30)
 Pregnancy order of childPrimigravidae522 (47)366 (21)0.300.45 (0.38–0.53)0.270.20 (0.15–0.27)0.04
Multigravidae74 (31)72 (15)0.410.51 (0.39–0.66)0.33 (0.22–0.48)
 Birth weight2500 mg or greater332 (42)204 (15)0.240.39 (0.32–0.48)0.010.27 (0.20–0.36)0.02
Less than 2500 mg264 (48)234 (28)0.430.53 (0.43–0.66)0.13 (0.09–0.18)
 Treatment for intestinal worms during past 6 monthsNot received554 (46)212 (25)0.390.50 (0.40–0.61)0.080.38 (0.28–0.52)0.07
Received37 (30)221 (17)0.460.66 (0.52–0.86)0.15 (0.11–0.21)
Malaria-based interventions
 Malaria treatment during previous weekNot received550 (44)404 (19)0.310.44 (0.37–0.52)0.240.20 (0.16–0.27)0.02
Received46 (49)34 (33)0.510.88 (0.62–1.26)1.01 (0.60–1.68)
 Mother took antimalarial during child's gestational periodNo102 (28)226 (22)0.690.78 (0.59–1.03)<0.0010.38 (0.19–0.74)0.05
Yes491 (50)210 (19)0.230.36 (0.30–0.45)0.20 (0.16–0.27)
 Family owns bed netDoes not own bed net141 (47)123 (22)0.320.43 (0.34–0.56)0.420.20 (0.15–0.26)0.70
Owns bed net455 (44)315 (41)0.310.48 (0.40–0.58)0.24 (0.18–0.32)
(B) Community level (primary sampling unit)
 Type of settingRural518 (50)370 (25)0.350.46 (0.39–0.56)0.950.22 (0.17–0.30)0.91
Urban78 (26)68 (9.4)0.290.34 (0.22–0.51)0.22 (0.12–0.40)
Genetic mechanisms of malaria protection
 Mean predicted HbS allele frequency§Less than 2.5%14 (20)104 (14)0.780.78 (0.32–1.91)<0.01#-0.26#
2.5–4.9%181 (41)269 (25)1.490.95 (0.64–1.42)0.96 (0.24–3.91)
5% or greater401 (48)65 (18)0.210.31 (0.17–0.56)0.17 (0.08–0.39)
 Median predicted G6PDd allele frequency§Less than 7.5%336 (47)47 (11)0.045.42 (2.01–14.6)<0.001#1.43 (0.28–7.21)0.02#
7.5–14.9%194 (43)128 (18)0.800.89 (0.52–1.50)0.41 (0.12–1.34)
15% or greater66 (40)263 (25)0.650.74 (0.46–1.19)-
Climate of communities surveyed
 Season of malaria transmissionDry season198 (42)220 (19)0.320.40 (0.31–0.52)0.450.06 (0.03–0.13)<0.001
Wet season398 (46)218 (22)0.320.53 (0.42–0.66)0.39 (0.28–0.53)
 Length of rainy seasonLess than 120 days168 (49)151 (21)0.270.43 (0.31–0.61)<0.001#0.28 (0.15–0.50)0.03#
120–179 Days334 (56)105 (26)0.270.45 (0.33–0.62)0.22 (0.15–0.31)
180 Days or more94 (23)182 (17)0.700.77 (0.56–1.05)0.21 (0.10–0.43)
 Length of time enhanced vegetation index above annual meanLess than 120 days105 (42)220 (21)0.380.50 (0.37–0.69)0.18#0.37 (0.09–1.60)0.84#
120–179 Days486 (52)206 (27)0.340.52 (0.42–0.66)0.33 (0.24–0.45)
180 Days or more5 (3.3)12 (3.2)0.970.43 (0.12–1.62)0.66 (0.16–2.85)
 Range of enhanced vegetation index per yearLess than 0.2046 (25)41 (7.9)0.260.38 (0.22–0.63)0.18#0.24 (0.13–0.47)0.13#
0.20–0.29247 (44)105 (17)0.250.48 (0.36–0.64)0.36 (0.25–0.53)
0.30 or greater303 (51)292 (28)0.380.48 (0.39–0.61)0.19 (0.13–0.29)
 Annual mean for enhanced vegetation indexLess than 0.20150 (37)21 (7.2)0.130.17 (0.11–0.28)<0.01#0.16 (0.10–0.25)0.01#
0.20–0.29309 (59)89 (24)0.220.51 (0.37–0.70)0.34 (0.23–0.51)
0.30 or greater137 (33)328 (22)0.560.61 (0.46–0.81)0.56 (0.20–1.53)

  1. HRP-2: histidine rich protein 2; RR: relative risk; CI: confidence interval; na: not applicable: ref: reference category; HbS: hemoglobin S; G6PD: glucose 6-phosphate dehydrogenase deficiency.

  2. *

    Tested in four countries: Burkina Faso, Mozambique, Rwanda and Senegal.

  3. †

    Tested in three countries: Burkina Faso, Rwanda and Senegal.

  4. ‡

    Adjusted for the following factors: age, gender, wealth index score, mother's highest level of education, malaria treatment during previous week, ownership of bed net, proportion of household members under 5 years using bed net during previous night, indoor household insecticide spraying, mother's access to antenatal care during last pregnancy, mother's knowledge regarding vertical HIV transmission, malaria transmission season, and type of community setting (urban vs rural).

  5. §

    Geographical waypoints were not recorded for 40 communities. Subjects from these PSUs were excluded from analysis.

  6. #

    Covariate treated as continuous term when testing for effect modification in the model.

Additional files

Supplementary file 1

Comparison of subject groups with complete and missing information on confounders.

https://doi.org/10.7554/eLife.03925.008
Supplementary file 2

Comparison of standardized bias for factors associated with vaccine/vitamin A supplement uptake, before and after inverse probability weighting (IPW).

https://doi.org/10.7554/eLife.03925.009
Supplementary file 3

Overview of immunization schedules for each country.

https://doi.org/10.7554/eLife.03925.010

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  1. Maria-Graciela Hollm-Delgado
  2. Frédéric B Piel
  3. Daniel J Weiss
  4. Rosalind E Howes
  5. Elizabeth A Stuart
  6. Simon I Hay
  7. Robert E Black
(2015)
Vitamin A supplements, routine immunization, and the subsequent risk of Plasmodium infection among children under 5 years in sub-Saharan Africa
eLife 4:e03925.
https://doi.org/10.7554/eLife.03925