Table 1 Characteristics of study participants
Characteristic
|
Maternal IPTp arm
|
Monthly SP (N=327)
|
Monthly DP (N=329)
|
Maternal characteristics at enrolment
|
Age in years, mean (SD)
|
24.0 (5.9)
|
24.0 (5.7)
|
Gravidity, n (%)
|
|
|
Primigravida/secundigravida
|
152 (46.5%)
|
156 (47.4%)
|
Multigravida
|
175 (53.5%)
|
173 (52.6)
|
House-hold type, n (%)
|
|
|
Modern House
|
77 (23.6%)
|
71 (21.6%)
|
Traditional House
|
250 (76.5%)
|
258 (78.4%)
|
Parasite prevalence by microscopy or qPCR, n (%)
|
|
|
No parasites
|
53 (16.2%)
|
63 (19.2%)
|
Sub-microscopic parasitemia
|
111 (33.9%)
|
88 (26.8%)
|
Microscopic parasitemia
|
163 (49.9%)
|
178 (54.1%)
|
Maternal characteristics during pregnancy
|
Parasite prevalence by microscopy, n/N (%)a
|
797/2212 (36.0%)
|
355/2260 (15.7%)
|
Incidence of malaria (episodes/ppy)
|
0.59
|
0.09
|
Placental malaria status
|
Placental malaria status, n (%)
|
|
|
No PM
|
119 (36.4%)
|
232 (70.5%)
|
Active PM
|
71 (21.7%)
|
7 (2.1%)
|
Past PM (Mild-moderate pigment)
|
97 (29.7%)
|
84 (25.5%)
|
Past PM (Severe pigment)
|
40 (12.2%)
|
6 (1.8%)
|
Characteristics of infants at birth
|
Preterm birth, n (%)
|
25 (7.7%)
|
17 (5.2%)
|
Gestation age in weeks, mean (SD)
|
39.4 (1.9)
|
39.6 (1.6)
|
Low birth weight, n (%)
|
33 (10.1%)
|
25 (7.6%)
|
Birth weight in grams, mean (SD)
|
3055 (505)
|
3024 (409)
|
Female sex, n (%)
|
161 (49.2%)
|
175 (53.2%)
|
Abbreviations: SP, sulfadoxine-pyrimethamine; DP, dihydroartemisinin-piperaquine; SD, standard deviation; ppy, per person year; qPCR, quantitative polymerase chain reaction
aDefined as number of routine positive blood smears divided by total number of routine blood smears
No PM=no parasites or pigment detected; active PM=parasites detected with or without pigment
Past PM (Mild-moderate)= >0-20% of high-power fields with pigment but no parasites; Past PM (severe)= >20%-60% of high-power fields with pigment but no parasites
Table 2. Association between different measures of placental malaria and incidence of malaria during infancy
|
Placental malaria categories (N)
|
Malaria episodes
|
Person years of follow-up
|
Malaria incidencea
|
Unadjusted
|
Adjustedb
|
Infant category
|
IRR (95% CI)
|
p-value
|
IRR (95% CI)
|
p-value
|
All
|
No PM (351)
|
574
|
327.4
|
1.75
|
reference group
|
reference group
|
Active PM (78)
|
152
|
68.9
|
2.21
|
1.27 (0.99-1.62)
|
0.06
|
1.30 (1.00-1.71)
|
0.05
|
Past PM (mild-mod) (181)
|
271
|
157.8
|
1.72
|
0.97 (0.79-1.18)
|
0.74
|
0.94 (0.76-1.16)
|
0.55
|
Past PM (severe) (46)
|
91
|
42.5
|
2.14
|
1.22 (0.91-1.63)
|
0.19
|
1.28 (0.89-1.83)
|
0.18
|
Male
|
No PM (168)
|
255
|
154.5
|
1.65
|
reference group
|
reference group
|
Active PM (45)
|
86
|
39.9
|
2.16
|
1.31 (0.93-1.87)
|
0.13
|
1.27 (0.87-1.84)
|
0.22
|
Past PM (mild-mod) (70)
|
129
|
77.7
|
1.66
|
0.98 (0.72-1.35)
|
0.92
|
1.02 (0.76-1.36)
|
0.90
|
Past PM (severe) (17)
|
49
|
15.3
|
3.20
|
1.87 (1.29-2.71)
|
0.001
|
2.17 (1.45-3.25)
|
<0.001
|
Female
|
No PM (183)
|
319
|
172.9
|
1.84
|
reference group
|
reference group
|
Active PM (33)
|
66
|
29.0
|
2.28
|
1.24 (0.89-1.73)
|
0.21
|
1.29 (0.87-1.91)
|
0.21
|
Past PM (mild-mod) (91)
|
142
|
80.1
|
1.77
|
0.96 (0.73-1.24)
|
0.74
|
0.81 (0.61-1.08)
|
0.15
|
Past PM (severe) (29)
|
42
|
27.1
|
1.55
|
0.85 (0.58-1.24)
|
0.40
|
0.74 (0.46-1.20)
|
0.22
|
Abbreviations: CI, confidence interval; IRR, incidence rate ratio; mild-mod, mild-moderate; PM, placental malaria
a Episodes of malaria per person year of follow-up
bAdjusted for gravidity, maternal IPTp, maternal prasitemia at enrolment, and household type
No PM=no parasites or pigment detected; active PM=parasites detected with or without pigment past PM (mild-mod)= >0-20% of high-power fields with pigment but no parasites; past PM(severe)= >20%-60% of high-power fields with pigment but no parasites
Table 3. Association between placental malaria and other malaria outcomes during infancy
Outcome measure
|
Infant category
|
Placental malaria categories
|
Number of cases (incidence PPY)
|
unadjusted
|
Adjusteda
|
IRR (95% CI)
|
p-value
|
IRR (95% CI)
|
p-value
|
Incidence of complicated malaria
|
All
|
No PM (351)
|
30 (0.092)
|
reference group
|
reference group
|
Active PM (78)
|
12 (0.17)
|
1.89 (0.93-3.87)
|
0.08
|
1.72 (0.81-3.66)
|
0.16
|
Past PM (mild-mod) (181)
|
14 (0.09)
|
0.97 (0.52-1.81)
|
0.91
|
0.99 (0.52-1.92)
|
0.98
|
Past PM (severe) (46)
|
9 (0.21)
|
2.30 (0.97-5.43)
|
0.06
|
2.44 (0.93-6.37)
|
0.07
|
Male
|
No PM (168)
|
13 (0.08)
|
reference group
|
reference group
|
Active PM (45)
|
6 (0.04)
|
1.78 (0.63-5.02)
|
0.27
|
1.18 (0.39-3.62)
|
0.77
|
Past PM (mild-mod) (90)
|
11 (0.14)
|
1.68 (0.76-3.68)
|
0.20
|
1.54 (0.44-3.45)
|
0.30
|
Past PM (severe) (17)
|
6 (0.39)
|
4.61 (1.50-14.22)
|
0.008
|
3.88 (1.14-13.03)
|
0.03
|
Female
|
No PM (183)
|
17 (0.10)
|
reference group
|
reference group
|
Active PM (33)
|
6 (0.21)
|
2.09 (0.78-5.64)
|
0.15
|
2.60 (0.91-7.44)
|
0.14
|
Past PM (mild-mod) (91)
|
3 (0.04)
|
0.38 (0.11-1.29)
|
0.12
|
0.44 (0.13-1.54)
|
0.20
|
Past PM (severe) (29)
|
3 (0.11)
|
1.12 (0.34-3.66)
|
0.85
|
1.63 (0.46-5.81)
|
0.45
|
Prevalence measures
|
Infant category
|
Placental malaria categories
|
Prevalence n/N (%)
|
Risk ratio (95% CI)
|
p-value
|
Risk ratio (95% CI)
|
p-value
|
Prevalence of prasitemia
|
All
|
No PM (351)
|
377/4170 (9.0%)
|
reference group
|
reference group
|
Active PM (78)
|
82/858 (9.6%)
|
1.07 (0.76-1.52)
|
0.70
|
1.19 (0.82-1.73)
|
0.36
|
Past PM (mild-mod) (181)
|
154/1993 (7.7%)
|
0.85 (0.65-1.12)
|
0.26
|
0.86 (0.65-1.14)
|
0.28
|
Past PM (severe) (46)
|
61/542 (11.3%)
|
1.22 (0.84-1.77)
|
0.30
|
1.38 (0.90-2.10)
|
0.14
|
Male
|
No PM (168)
|
170/1964 (8.7%)
|
reference group
|
reference group
|
Active PM (45)
|
50/498 (10.0%)
|
1.17 (0.73-1.86)
|
0.52
|
1.19 (0.71-2.00)
|
0.51
|
Past PM (mild-mod) (90)
|
70/976 (7.2%)
|
0.81 (0.55-1.20)
|
0.29
|
0.87 (0.58-1.31)
|
0.50
|
Past PM (severe) (17)
|
31/191 (16.2%)
|
1.80 (1.08-2.99)
|
0.02
|
2.24 (1.34-3.74)
|
0.002
|
Female
|
No PM (183)
|
207/2206 (9.4%)
|
reference group
|
reference group
|
Active PM (33)
|
32/360 (8.9%)
|
0.97 (0.57-1.66)
|
0.91
|
1.05 (0.61-1.83)
|
0.85
|
Past PM (mild-mod) (91)
|
84/1017 (8.3%)
|
0.90 (0.61-1.31)
|
0.57
|
0.79 (0.53-1.17)
|
0.24
|
Past PM (severe) (29)
|
31/351 (8.6%)
|
0.90 (0.54-1.51)
|
0.70
|
0.86 (0.48-1.52)
|
0.60
|
Abbreviations: CI, confidence interval; IRR, incidence rate ratio; mild-mod, mild-moderate; PM, placental malaria; PPY, per person year
aAdjusted for gravidity, maternal IPTp, maternal prasitemia at enrolment, and household type
No PM=no parasites or pigment detected; active PM=parasites detected with or without pigment; past PM (mild-mod)= >0-20% of high-power fields with pigment but no parasites; past PM(severe)= >20%-60% of high-power fields with pigment but no parasites
Table 4. Association between placental malaria and non-malaria outcomes in infants during the first year of life
Outcome measure
|
Placental malaria category (N)
|
Number of cases (incidence PPY)
|
unadjusted
|
Adjusteda
|
IRR (95% CI)
|
p-value
|
IRR (95% CI)
|
p-value
|
Incidence of all-cause hospitalizations
|
No PM (351)
|
9 (0.027)
|
reference group
|
reference group
|
Active PM (78)
|
3 (0.044)
|
1.66 (0.40-7.00)
|
0.49
|
1.14 (0.22-5.98)
|
0.87
|
Past PM (mild-mod) (181)
|
7 (0.044)
|
1.72 (0.58-5.12)
|
0.33
|
1.26 (0.44-3.64)
|
0.66
|
Past PM (severe (46)
|
6 (0.141)
|
4.85 (1.38-17.00)
|
0.01
|
2.90 (0.59-14.44)
|
0.19
|
Incidence of non-malarial febrile illnesses
|
No PM (351)
|
1128 (3.45)
|
reference group
|
reference group
|
Active PM (78)
|
203 (2.95)
|
0.86 (0.72-1.03)
|
0.10
|
0.84 (0.64-1.10)
|
0.20
|
Past PM (mild-mod) (181)
|
536 (3.40)
|
0.98 (0.86-1.13)
|
0.82
|
1.03 (0.84-1.25)
|
0.79
|
Past PM (severe (46)
|
152 (3.58)
|
1.04 (0.85-1.26)
|
0.72
|
1.06 (0.72-1.57)
|
0.76
|
Prevalence measures
|
Categories
|
Prevalence n/N (%)
|
Risk ratio (95% CI)
|
p-value
|
Risk ratio (95% CI)
|
p-value
|
Anemiac
|
No PM (351)
|
227/934 (24.3%)
|
reference group
|
reference group
|
Active PM (78)
|
48/190 (25.3%)
|
1.07 (0.76-1.50)
|
0.69
|
1.00 (0.69-1.47)
|
0.98
|
Past PM (mild-mod) (181)
|
106/441 (24.0%)
|
1.01 (0.80-1.29)
|
0.92
|
0.94 (0.73-1.22)
|
0.64
|
Past PM (severe (46)
|
37/118 (31.4%)
|
1.29 (0.94-1.77)
|
0.12
|
1.16 (0.79-1.70)
|
0.44
|
Abbreviations: CI, confidence interval; IRR, incidence rate ratio; mild-mod, mild-moderate; PM, placental malaria
aAdjusted for gravidity, maternal IPTp, maternal parasitemia at enrolment, and household type
b Defined as hemoglobin < 10 g/dL measured routinely at 12, 28, and 52 weeks of age
No PM=no parasites or pigment detected; active PM=parasites detected with or without pigment; past PM (mild-mod)= >0-20% of high-power fields with pigment but no parasites; past PM (severe)= >20%-60% of high-power fields with pigment but no parasites
Table 5. Effect of IPTp on malaria incidence in infants that is mediated by preventing placental malaria
|
Total Effect
|
|
Direct effect
|
|
Mediated effect
|
% of mediated effect*
|
|
IRR (95% CI)
|
p-value
|
|
IRR (95% CI)
|
p-value
|
|
IRR (95% CI)
|
p-value
|
All sexes
|
0.89 (0.75-1.04)
|
0.16
|
|
0.94 (0.73-1.17)
|
0.58
|
|
0.95 (0.77-1.16)
|
0.61
|
43.5%
|
Males
|
0.77 (0.61-0.99)
|
0.05
|
|
0.97 (0.67-1.36)
|
0.89
|
|
0.79 (0.56-1.09)
|
0.17
|
89.7%
|
Females
|
1.01 (0.81-1.26)
|
0.96
|
|
0.92 (0.71-1.22)
|
0.56
|
|
1.09 (0.87-1.38)
|
0.45
|
--
|
Abbreviations: CI, confidence intervals and IRR, incidence rate ratio
Note: IRRs represent the effect of IPTp DP versus SP on the incidence of malaria in infants. Confidence intervals reported here were obtained by bootstrapping and may differ from those reported in the primary analysis which used the delta method specifying robust standard errors.
* Proportion of mediated effect was calculated using [ln(IRRmediated effect)/ln(IRRtotal effect)]*100.