Bendabendae al. Mala J (2019)
18:143 h ps://doi.o g/10.1186/
s12936-019-2778-y
RESEARCH
Does an h opome ic s a us a 6mon hs
p edic heo e -dispe sion o mala ia in ec ions
inchild en aged 6–18mon hs? Ap ospec i e
coho s udy
Jaden Bendabenda1,2, Noel Pa son1,4, Lo a Hallamaa2, Ulla Asho n2, Ka h yn G. Dewey3, Pe Asho n2
and Kenne h Male a1*
Abs ac
Backg ound: In mala ia-endemic se ings, a small p opo ion o child en su e epea ed mala ia in ec ions, con ib-
u ing o mos o he mala ia cases, ye unde lying ac o s a e no ully unde s ood. This s udy was aimed o de e mine
whe he unde nu i ion p edic s his o e -dispe sion o mala ia in ec ions in child en aged 6–18 mon hs in se ings o
high mala ia and unde nu i ion p e alence.
Me hods: P ospec i e coho s udy, conduc ed in Mangochi, Malawi. Six-mon hs-old in an s we e en olled and had
leng h- o -age z-sco es (LAZ), weigh - o -age z-sco es (WAZ), and weigh - o -leng h z-sco es (WLZ) assessed. Da a
we e collec ed o ‘p esumed’, clinical, and apid diagnos ic es (RDT)-con i med mala ia un il 18 mon hs. Mala ia
mic oscopy was done a 6 and 18 mon hs. Nega i e binomial eg ession was used o mala ia incidence and modi ied
Poisson eg ession o mala ia p e alence.
Resul s: O he 2723 child en en olled, 2561 (94%) had an h opome y and mala ia da a. The mean (s anda d de ia-
ion [SD]) o LAZ, WAZ, and WLZ a 6 mon hs we e − 1.4 (1.1), − 0.7 (1.2), and 0.3 (1.1), espec i ely. The mean (SD)
incidences o ‘p esumed’, clinical, and RDT-con i med mala ia om 6 o 18 mon hs we e: 1.1 (1.6), 0.4 (0.8), and 1.3
(2.0) episodes/yea , espec i ely. P e alence o mala ia pa asi aemia was 4.8% a 6 mon hs and 9.6% a 18 mon hs.
Highe WLZ a 6 mon hs was associa ed wi h lowe p e alence o mala ia pa asi aemia a 18 mon hs (p e alence a io
[PR] = 0.80, 95% con idence in e al [CI] 0.67 o 0.94, p = 0.007), bu no wi h incidences o ‘p esumed’ mala ia (inci-
dence a e a io [IRR] = 0.97, 95% CI 0.92 o 1.02, p = 0.190), clinical mala ia (IRR = 1.03, 95% CI 0.94 o 1.12, p = 0.571),
RDT-con i med mala ia (IRR = 1.00, 95% CI 0.94 o 1.06, p = 0.950). LAZ and WAZ a 6 mon hs we e no associa ed
wi h mala ia ou comes. Household asse s, ma e nal educa ion, and ood insecu i y we e signi ican ly associa ed wi h
mala ia. The e we e signi ican a ia ions in hospi al-diagnosed mala ia by s udy si e.
Conclusion: In child en aged 6–18 mon hs li ing in mala ia-endemic se ings, LAZ, WAZ, and WLZ do no p edic
mala ia incidence. Howe e , WLZ may be associa ed wi h p e alence o mala ia. Socio-economic and mic o-geo-
g aphic ac o s may explain he a ia ions in mala ia, bu hese equi e u he s udy.
T ial egis a ion NCT00945698. Regis e ed July 24, 2009, h ps ://clini cal ials.go /c 2/show/NCT00 94569 8,
NCT01239693. Regis e ed No 11, 2010, h ps ://clini cal ials.go /c 2/show/NCT01 23969 3
Keywo ds: Child en, iLiNS s udies, In ec ions, Mala ia, O e -dispe sion, S un ing, Unde nu i ion, Was ing
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Open Access
Mala ia Jou nal
*Co espondence: [email p o ec ed]
1 Depa men o Public Heal h, School o Public Heal h, Uni e si y
o Malawi College o Medicine, Maha ma Gandhi Road, P i a e Bag 360,
Blan y e 3, Malawi
Full lis o au ho in o ma ion is a ailable a he end o he a icle
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Bendabendae al. Mala J (2019) 18:143
Backg ound
Mala ia is one o he mos se ious public heal h p oblems
in he wo ld, wi h an es ima ed 216 million cases and
445,000 dea hs epo ed in 2016, and app oxima ely 90%
o he cases and dea hs occu ing in he A ican Region
[1]. Malawi is one o he mala ia-hype endemic coun ies
in sub-Saha an A ica, wi h a ound 4 million mala ia cases
epo ed annually [2]. In mala ia-hype endemic coun ies,
i is assumed ha i ually all exposed indi iduals would
su e a mala ia episode by ea ly childhood [3]. Howe e ,
se e al s udies ha e shown ha in hese se ings, only
a small p opo ion o child en su e epea ed mala ia
in ec ions, and hese child en a e esponsible o mos o
he mala ia cases [4–6], an o e -dispe sion known as he
‘20/80’ ule [7].
The sugges ed unde lying ac o s o his o e -dis-
pe sion in mala ia in ec ions a e a ied, and include o
ins ance gene ic [5], beha iou al [8] and en i onmen-
al ac o s [6]. O he s udies sugges ha unde nu i-
ion plays an impo an ole in mala ia epidemiology
because o he syne gis ic in e ac ions be ween nu i-
ion and in ec ions [9–11]. Howe e , se e al e iews on
he ela ionship be ween unde nu i ion and mala ia
de e mined ha he cu en e idence is inconclusi e;
a ibu ed o he he e ogenei y in he s udy popula ions,
mala ia pa asi e species, and hos -pa asi e ela ionship
[12–14]. Hence he need o u he unde s anding o
he ole o unde nu i ion in mala ia epidemiology.
The In e na ional Lipid-based Nu ien Supplemen s
(iLiNS) P ojec DOSE and DYAD s udies we e and-
omized con olled ials conduc ed in Malawi o s udy
he impac o lipid-based nu ien supplemen s (LNS)
on g ow h o child en [15, 16]. Analysis o longi udi-
nal mala ia da a in he wo s udies showed ha 39%
o he in an s and young child en aged 6 o 18mon hs
did no epo any mala ia episode in he one-yea
s udy pe iod; only 30.7% epo ed mo e han one epi-
sode o ‘p esumed’ mala ia bu hese we e esponsible
o 73.7% o he ‘p esumed’ mala ia episodes [17]. The
aim o he cu en analysis was o u he in es iga e
he dis ibu ion o mala ia in child en in hese coho s
and de e mine whe he his dis ibu ion is p edic ed by
an h opome ic s a us a 6mon hs. The hypo hesis was
ha lowe leng h o age z-sco es (LAZ), weigh - o -age
z-sco es (WAZ), and lowe weigh o leng h z-sco es
(WLZ) a 6mon hs will be associa ed wi h a highe
incidence o mala ia om 6 o 18mon hs, and highe
p e alence o mala ia a 18mon hs.
Me hods
S udy se ing
The iLiNS-DOSE and iLiNS-DYAD-M s udies we e
conduc ed in ou acili ies: one public dis ic hospi al
(Mangochi), one mission hospi al (Malindi), and wo
u al public heal h cen es (Lungwena and Namwe a) in
Mangochi Dis ic , Sou he n Malawi. The o al ca ch-
men popula ion o 180,000 la gely subsis ed on a m-
ing and ishing. Mangochi si e is low-lying a an al i ude
o ~ 485 m abo e sea le el, bu a e sed by he Shi e
Ri e ( he la ges i e in Malawi). Two o he s udy si es
(Lungwena and Malindi) a e also low-lying wi h he
simila al i ude along he eas e n sho e o Lake Malawi.
In con as , Namwe a lies a he op o Namwe a Hills,
bo de ing Mozambique, a an al i ude o ~ 900m abo e
sea le el and is a om he la ge wa e bodies. Namwe a
expe ienced highe ain all and coole empe a u es han
he o he h ee s udy si es [18, 19].
In Malawian child en aged < 5yea s, he p e alence o
mala ia (by mic oscopy), dia hoea and acu e espi a o y
in ec ions we e 24.3%, 22% and 5%, espec i ely, wi h
seasonal luc ua ions [2, 20]. The sub- opical clima e
comp ising a wa m, we season om No embe o Ap il,
a cool, d y win e season om May o Augus , and a ho ,
d y season om Sep embe o Oc obe [21] is a ou -
able o he Anopheles mosqui oes which ansmi Plas-
modium pa asi es. Plasmodium alcipa um is he mos
dominan and causes abou 98% o all mala ia in ec ions
in Malawi. Mala ia ansmission occu s h oughou he
yea wi h highes ansmission a es occu ing be ween
Oc obe and Ap il ( ainy season), mainly in low-lying
and high empe a u e a eas.
S udy design, da a collec ion ande hics s a emen
The da a o his analysis we e aken om he iLiNS-
DOSE and iLiNS-DYAD-M s udies— wo la ge commu-
ni y-based andomized con olled ials conduc ed in
u al Malawi.
In he iLiNS-DOSE s udy, 6-mon hs old child en we e
andomly alloca ed o one o i e in e en ion g oups
p o ided wi h di e en doses o o mula ions o LNS
o o a con ol g oup ha did no ecei e LNS du ing
he 12-mon h s udy pe iod, be ween No embe 2009
and May 2012. In he iLiNS-DYAD-M s udy, p egnan
women < 20weeks’ ges a ion we e andomly alloca ed o
one o h ee g oups o ecei e i on and olic acid (IFA),
mul iple mic onu ien s (MMN) o a small-quan i y
(20g) o LNS daily. A e deli e y, women in he IFA
g oup ecei ed placebo able s, while MMN and LNS
supplemen a ion was con inued up o 6mon hs pos pa -
um. Child en o mo he s in he LNS g oup also ecei ed
LNS 10g wice daily om 6 o 18mon hs. This s udy was
conduc ed om Feb ua y 2011 o Ap il 2015. De ails o
design, andomiza ion and en olmen o he wo s udies
can be ound in he main ou come pape s [15, 16].
In bo h s udies, esea ch assis an s isi ed he child en’s
homes e e y week om age 6 o 18mon hs o in e iew
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Bendabendae al. Mala J (2019) 18:143
he gua dians abou he child’s heal h in he p e ious
7days using a s uc u ed ques ionnai e. The in o ma ion
was complemen ed by a pic u e calenda illed ou by he
gua dians daily o aid memo y o hei child en’s mo -
bidi y s a us. These we e done o minimise p oblems o
ecall associa ed wi h communi y mo bidi y assessmen s
[22, 23]. The use o ma e nal in e iews o collec da a
on child mo bidi y has been alida ed in p e ious s ud-
ies [24, 25]. The esea ch assis an s e e ed all cases o
e e o he nea by heal h acili y o a mala ia apid diag-
nos ic es (RDT) and ea men wi h a eme he /lume-
an ine, he na ionally ecommended an i-mala ial d ug.
The child en we e ollowed h oughou he yea , co e ing
pe iods o bo h high and low mala ia ansmission.
Facili y heal h wo ke s we e ained o collec da a
on clinical diagnosis, RDT, and/o mala ia mic oscopy
esul s whene e he child was ea ed a he heal h
acili y. In addi ion, all child en had mala ia mic oscopy
es s done du ing he scheduled s udy clinic isi s a age
6mon hs and 18mon hs. Blood smea s we e ob ained
om all child en a he ime o he blood sampling o
biochemical assessmen s, s ained wi h 2% Giemsa o
30min. All hick slides we e e iewed by wo mic osco-
pis s using a high-powe mic oscope o de e mine he
p esence o mala ia pa asi es. Disc epan eadings we e
esol ed by a hi d e iewe . Mala ia RDT was also done
a 6mon hs scheduled clinic isi using apid es ki
(Clea iew Mala ial Combo, Ale e, Sou h A ica).
An h opome ic assessmen s we e done a 6mon hs and
18mon hs. S udy an h opome is s measu ed he in an ’s
leng h wi h a high-quali y leng h boa d (Ha penden In an-
ome e ; Hol ain Limi ed) and eco ded i o he nea es
1 mm. They weighed unclo hed in an s wi h elec onic
in an weighing scale (SECA 735; Seca GmbH & Co),
eco ding o he nea es 10g. The an h opome is s we e
ained and hei measu emen eliabili y was e i ied
a he s a o he s udy and a 6-mon hs in e als he e-
a e wi h me hods adap ed om he p ocedu es used in
he WHO Mul icen e G ow h Re e ence S udy [26]. The
an h opome is s calib a ed all equipmen wi h s anda d
weigh s and leng h ods daily.
S udy nu ses collec ed 5–7mL o blood by enepunc-
u e using a 23-gauge needle in o 7.5mL e acua ed, ace
elemen - ee polye hylene ubes con aining li hium hep-
a in (Sa s ed Mono e e, NH4‐hepa in, Sa s ed Inc.,
New on, NC, USA). The blood ube was immedia ely
in e ed 10 imes o mix he hepa in an icoagulan wi h
he blood o p e en clo ing. A small aliquo o he whole
blood was pipe ed ou and used o analyse haemoglobin
(Hb) on he Hemocue 201+ sys em (Hemocue, B ea, CA,
USA). The ube con aining he emaining whole blood
was hen placed in an insula ed coole wi h ice packs and
p ocessed wi hin 2h o collec ion. T ained labo a o y
s a hen aliquo ed whole blood in o mic ocu e es and
measu ed zinc p o opo phy in (ZPP) concen a ion om
unwashed enous blood sample using a haema o luo om-
e e (206D, AVIV Biomedical Inc., Lakewood, NJ, USA).
A en olmen , esea ch assis an s in e iewed he
mo he s o ob ain household le el in o ma ion includ-
ing asse s, numbe o child en, ma e nal educa ion (yea s
spen in school) and ma e nal age. Household ood
secu i y was assessed using Household Food Insecu i y
Access Scale (HFIAS) [27]. Use o insec icide ea ed
bed ne s (ITNs) was assessed by asking he gua dians he
numbe o days ha he child slep unde a bed ne du -
ing he week p eceding he in e iew a 6mon hs. Si e
was de ined based on he clinics whe e he wo s udies
we e conduc ed (i.e. Namwe a, Mangochi, Malindi, and
Lungwena).
De ini ion o  hep edic o s and heou comes
Ou come a iables
The p ima y ou come o his analysis was he incidence
o ‘p esumed’ mala ia, de i ed om he weekly mo bidi y
da a. ‘P esumed’ mala ia diagnosis was de ined as his o y
o e e ei he epo ed by he gua dians o ympanic
empe a u e ≥ 38°C measu ed by he esea ch assis an s
du ing he home isi . An episode o ‘p esumed’ mala ia
was de ined as he pe iod s a ing om he day he child
had mala ia symp oms, p eceded by a leas 2days o no
symp oms o no da a. The episode ended on he las day
he child had mala ia symp oms, i ollowed by a leas
2 symp om- ee days. Fe e episodes accompanied by
espi a o y signs o dia hoea we e excluded om he
mala ia diagnosis.
Seconda y ou comes included (1) incidence o clinical
mala ia, aken om he mala ia diagnosis made by he
heal h wo ke in he absence o a diagnos ic es when-
e e he child isi ed a heal h acili y, (2) incidence o
con i med mala ia, aken om he mala ia diagnosis
made by he heal h wo ke con i med by a posi i e RDT,
and (3) p e alence o mala ia pa asi aemia de i ed om
he mala ia mic oscopy esul s a age 18mon hs. Mala ia
incidence was calcula ed as o al episodes o mala ia/
o al child yea s a isk; mala ia pa asi aemia p e alence
was calcula ed as he p opo ion wi h a posi i e mala ia
pa asi e slide.
P edic o a iables
Leng h o age z-sco es (LAZ), weigh - o -age z-sco es
(WAZ), and weigh o leng h z-sco es (WLZ) we e
calcula ed om he an h opome y da a using WHO
g ow h s anda ds [26]. I on de iciency a age 6mon hs
was de ined as whole blood ZPP > 70 µmol/mol haem
[28]. HFIAS z-sco es we e gene a ed by summing he
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Bendabendae al. Mala J (2019) 18:143
alue o esponses o nine ques ions ega ding ood inse-
cu i y: he highe he sco e, he highe deg ee o ood
insecu i y in he las 4weeks [27]. Household asse sco es
we e de ined as he p incipal componen s sco e based on
baseline owne ship o a se o asse s and household qual-
i y: he highe he sco e, he be e he li ing condi ions.
Numbe o child en aged < 5yea s was de ined as num-
be o child en below he age o i e who we e pa o he
pa icipan ’s household a 6mon hs.
S a is ical analysis
All child en who had mala ia da a a any poin om age
6 o 18mon hs we e included in he analysis. Nega i e
binomial eg ession was used o assess he associa ion
o LAZ, WAZ, and WLZ (independen a iables) wi h
he incidence o mala ia (dependen a iable), and Pois-
son eg ession (wi h a obus a iance es ima o ) [29]
o assess he associa ion o LAZ, WAZ, and WLZ wi h
p e alence o mala ia pa asi aemia.
To s udy he independen e ec o a ious p edic o s,
mul i a ia e eg ession models we e cons uc ed ha
included po en ial p edic o s collec ed a 6mon hs. The
ollowing we e po en ial p edic o s: household asse
sco es, ma e nal age (cen ed a ound he mean), and edu-
ca ion, numbe o child en aged < 5yea s, HFIA sco e,
whe he he child ecei ed he s udy in e en ion (LNS)
o no , adjus ed o he addi ional con ol g oup [MMN]
in iLiNS-DYAD, sex o he child, Hb concen a ion, i on
s a us, mon h o bi h, daily use o ITNs, dis ance o
heal h acili y and s udy si e. Collinea i y among he p e-
dic o s was es ed using he collin s a a command. I he
p edic o s we e highly collinea (> 0.5), he one ha was
less s ongly associa ed wi h he ou comes was d opped.
The esul s a e epo ed as incidence a e a ios [IRR]
o p e alence a io [PR] and hei 95% con idence in e -
als (95% CI) a p = 0.05. Robus s anda d e o s we e
compu ed o adjus o co ela ion o ecu en mala ia
episodes in a single child.
O he po en ial p edic o s we e conside ed including
immuniza ion s a us, ma ke s o in lamma ion (C- eac i e
p o ein and alpha1-acid glycop o ein concen a ions) a
6mon hs, ma e nal and child mala ia immuni y, and ma e -
nal HIV s a us. Howe e , hese a iables we e a ailable only
om a subsample o he wo s udies, hence we e e en u-
ally d opped om he inal models o maximize he sample
size. Fu he mo e, hese a iables showed li le e ec on he
model du ing sensi i i y analysis. S a a e sion 14 (S a a-
Co p, Texas, USA) was used o he main analyses.
Resul s
S udy popula ion
O he 2723 child en en olled in he wo s udy coho s,
2561 (94%) had da a o he p ima y ou come (1928
child en om he iLiNS DOSE s udy and 633 child en
om he iLiNS DYAD-M s udy). These we e included in
he inal analysis (Fig.1). A age 6mon hs, he mean (SD)
leng h- o -age z-sco es (LAZ), weigh - o -age z-sco es
(WAZ), and weigh - o -leng h z-sco es (WLZ) we e
− 1.4 (1.1), − 0.7 (1.2), and 0.3 (1.1) espec i ely. The p o-
po ions o child en who we e s un ed, unde weigh and
was ed we e 28.3%, 12.9%, and 2.0%, espec i ely. Fu he
cha ac e is ics o hese child en a age 6mon hs a e sum-
ma ized in Table1.
Incidence andp e alence o mala ia
The child en con ibu ed 2405.6 child yea s o ollow
up, i.e. he mean (SD) du a ion o ollow up was 344
(73) days/child. Du ing he home isi s, 27,340 mo -
bidi y episodes we e epo ed, 9.3% (2549/27,340)
o which we e episodes o ‘p esumed’ mala ia. The
es we e due o: ARI, 53.8% (14,708/27,340); dia -
hoea, 23% (6282/27,340) and mino condi ions, 13.9%
(3801/27,340).
O he o al mo bidi y episodes iden i ied a he home
isi s, 44% (12,048/27,340) we e epo ed and ea ed a a
heal h acili y, 32.5% (3917/12,048) o which we e ea ed
o mala ia, 76.8% (3007/3917) o hem con i med by
RDT.
F om he home isi s da a, he mean (SD) incidence o
all illnesses combined was 16.2 (13.1) episodes pe child
yea . The mean (SD) incidence o ‘p esumed’ mala ia
was 1.1 (1.6) episodes pe child yea . The mean (SD)
incidence o acu e espi a o y in ec ions was 7.8 (8.0)
episodes pe child yea and he mean (SD) incidence
o dia hoea was 2.7 (2.7) episodes pe child yea . Con-
e sely, he na ional da a show ha dia hoea incidence
is highe han ARI incidence in child en unde - i e,
p obably because he age anges a e sligh ly di e en .
The na ional da a do no p o ide speci ic incidences o
child en unde 18mon hs.
F om he hospi al isi s da a, he mean (SD) incidences
o clinical mala ia and con i med mala ia we e, espec-
i ely, 0.4 (0.8) and 1.3 (2.0) episodes pe child yea (i.e.
he mean (SD) incidence o all mala ia a hospi al isi s
was 1.7 (2.4) episodes pe child yea ).
The p e alence o mala ia pa asi aemia (by mic os-
copy) inc eased om 4.8% a age 6mon hs o 9.6%
a age 18 mon hs. Du ing he 12-mon h ollow up
pe iod, 45.1% (1156/2561) o he child en included
in his analysis did no epo any episode o mala ia,
28.4% (728/2561) epo ed one episode and 26.4%
(677/2561) epo ed > 1 mala ia episodes. The child en
who epo ed > 1 mala ia episodes we e esponsible o
71.4% (1821/2549) o all mala ia episodes epo ed in
he wo s udies. These indings we e simila ac oss he
di e en de ini ions o mala ia.
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Bendabendae al. Mala J (2019) 18:143
Associa ion o LAZ a 6mon hs wi hmala ia om6
o18mon hs
In bi a ia e analysis, a highe LAZ a 6mon hs was
associa ed wi h a lowe incidence o clinical mala ia
and lowe incidence o con i med mala ia om 6 o
18 mon hs (Table 2, unadjus ed), and lowe p e a-
lence o mala ia pa asi aemia a 18mon hs (Table3,
unadjus ed), bu no incidence o ‘p esumed’ mala ia
(Table2, unadjus ed). When adjus ed o o he p e-
dic o s, hese associa ions we e no longe e iden
(Tables2, 3, adjus ed, and 4).
Associa ion o WLZ a 6mon hs wi hmala ia om6
o18mon hs
The e was no associa ion be ween WLZ a 6mon hs and
he incidence o ‘p esumed’ mala ia, clinical mala ia o
con i med mala ia om 6 o 18mon hs, in ei he bi a i-
a e o mul i a ia e analyses (Table 2). In mul i a ia e
analysis, highe WLZ a 6mon hs was associa ed wi h
lowe p e alence o mala ia pa asi aemia a 18mon hs,
adjus ed o o he p edic o s (i.e. 1 SD highe WLZ a
6mon hs was associa ed wi h 20% dec ease in p e alence
o mala ia pa asi aemia a 18mon hs) (Tables3, 4).
Associa ion o WAZ a 6mon hs wi hmala ia om6
o18mon hs
In bi a ia e analysis, a highe WAZ a 6mon hs was asso-
cia ed wi h lowe incidence o con i med mala ia om 6
o 18mon hs (Table2, unadjus ed), and lowe p e alence
o mala ia pa asi aemia a 18mon hs (Tables3, unad-
jus ed, 4), bu no incidence o ‘p esumed’ mala ia no
incidence o clinical mala ia (Table2, unadjus ed). When
adjus ed o o he p edic o s, hese associa ions we e no
longe e iden (Tables2, 3, adjus ed and 4).
Independen p edic o s o mala ia
Independen p edic o s ha we e signi ican ly associ-
a ed wi h mala ia ou comes a e p esen ed in Tables3,
4. Incidence o ‘p esumed’ mala ia om 6 o 18mon hs
was independen ly associa ed wi h ma e nal age and
asse sco e a 6mon hs (i.e. each yea highe in ma e -
nal age was associa ed wi h 1% inc ease in incidence
o ‘p esumed’ mala ia; and 1 SD highe asse sco e was
associa ed wi h 14% dec ease in incidence o ‘p esumed’
mala ia).
Incidence o clinical mala ia om 6 o 18mon hs was
independen ly associa ed wi h Hb concen a ion and
HFIAS a 6mon hs (i.e. each g/L highe Hb a 6mon hs
Fig. 1 Flow cha o he child en en olled and included in he inal analysis. The igu e shows he numbe o child en en olled, child en los o
ollow up, and child en who we e e en ually included in he analysis om he iLiNS DOSE and iLiNS DYAD-M coho s

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Bendabendae al. Mala J (2019) 18:143
was associa ed wi h 1% dec ease in incidence o clinical
mala ia; and 1-uni highe HFIAS was associa ed wi h
2% inc ease in incidence o clinical mala ia). Highe
HFIAS ep esen s highe deg ee o ood insecu i y.
The e was also a signi ican a ia ion in he incidence
o clinical mala ia be ween he heal h acili ies (s udy
si es), wi h Namwe a si e epo ing highe incidence o
clinical mala ia compa ed o Mangochi, while he o he
wo si es (Malindi and Lungwena) had lowe incidence
o clinical mala ia compa ed o Mangochi.
Incidence o con i med mala ia om 6 o 18mon hs
was independen ly associa ed wi h i on de iciency,
ma e nal educa ion and asse sco e a 6mon hs (i.e.
i on de iciency a 6mon hs was associa ed wi h 20%
highe incidence o con i med mala ia; each yea highe
in ma e nal schooling was associa ed wi h 3% dec ease
in incidence o con i med mala ia; 1 SD highe asse
sco e was associa ed wi h 27% dec ease in incidence o
con i med mala ia). The e was also a signi ican a ia-
ion in he incidence o con i med mala ia be ween he
s udy si es wi h Namwe a si e epo ing highe inci-
dence o con i med mala ia compa ed o Mangochi,
while he o he wo si es (Malindi and Lungwena)
epo ed lowe incidence o con i med mala ia com-
pa ed o Mangochi.
Independen p edic o s o mala ia pa asi aemia p e -
alence we e WLZ, ma e nal age, ma e nal educa ion,
Hb concen a ion, and i on de iciency (i.e. 1 SD highe
WLZ was associa ed wi h 20% dec ease in p e alence o
mala ia pa asi aemia (see Tables3, 4); each yea highe in
ma e nal age was associa ed wi h 3% dec ease in p e a-
lence o mala ia pa asi aemia; each addi ional yea in
ma e nal schooling was associa ed wi h 10% dec ease in
p e alence o mala ia pa asi aemia; each g/L highe Hb
a 6mon hs was associa ed wi h 2% dec ease in p e a-
lence o mala ia pa asi aemia; and i on de iciency a
Table 1 Pa icipan cha ac e is ics a age 6mon hs
ITN, insec icide- ea ed bed ne s; LNS, lipid-based nu ien supplemen ; RDT, mala ia an igen apid diagnos ic es ; ZPP, zinc p o opo phy in
a Measu ed om unwashed enous blood
b A week p io o he day o assessmen
Mean (SD) o n (%) N
Child ac o s
Mean (SD) weigh - o -leng h z-sco e 0.3 (1.1) 2561
Mean (SD) weigh - o -age z-sco e − 0.7 (1.2) 2561
Mean (SD) leng h- o -age z-sco e − 1.4 (1.1) 2561
Mean (SD) haemoglobin, g/L 104 (16) 2523
P opo ion o boys 1265 (49.4%) 2561
P opo ion was ed 50 (2.0%) 2561
P opo ion unde weigh 330 (12.9%) 2561
P opo ion s un ed 725 (28.3%) 2561
P opo ion wi h haemoglobin < 105 g/L 1334 (51.5%) 2523
P opo ion wi h ZPP > 70 µmol/mole haema1567 (66.1%) 2371
P opo ion wi h mala ia posi i e by RDT 349 (14.6%) 2389
Ma e nal ac o s
Mean (SD) ma e nal age (yea s) 25.8 (6.2) 2265
Mean (SD) ma e nal educa ion, comple ed yea s 4.4 (3.6) 2425
Socio-economic and household ac o s
Mean (SD) Household Food Insecu i y Access Sco e 6.1 (5.6) 2128
Mean (SD) asse sco e − 0.02 (0.99) 2179
Mean (SD) numbe o child en aged < 5 yea s in he household 1.6 (0.7) 2149
P opo ion who slep unde ITN dailyb2065 (81.1%) 2546
En i onmen al ac o s
P opo ion who ecei ed LNS in e en ion 1804 (70.6%) 2556
S udy si e
Mangochi 1667 (65.2%) 2561
Namwe a 445 (17.4%) 2561
Malindi 120 (4.7%) 2561
Lungwena 324 (12.7%) 2561
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Bendabendae al. Mala J (2019) 18:143
Table 2 Associa ion o leng h- o -age, weigh - o -leng h, andweigh - o -age z-sco es a age 6mon hs wi hmala ia incidence omage 6mon hs o18mon hs
CI: con idence in e al; IRR: incidence a e a io; LAZ: leng h- o -age z-sco e; WAZ: weigh - o -age z-sco e; WLZ: weigh - o -leng h z-sco e
a Adjus ed o he ollowing ac o s a age 6mon hs: sex o he child, haemoglobin concen a ion, i on s a us, mon h o bi h, daily use o insec icide- ea ed bed ne s, dis ance o heal h acili y, s udy si e, asse sco es,
ma e nal age, ma e nal educa ion, child en < 5yea s, HFIA sco e, and whe he he child ecei ed he s udy in e en ion (LNS) o no
b Incidence a e a io, ob ained using nega i e binomial eg ession. The IRR ep esen s he a e o change in incidence o mala ia o each 1-SD highe LAZ, WAZ, o WLZ
Incidence o ‘p esumed’ mala ia (N = 2561) Incidence o clinical mala ia (N = 2497) Incidence o con i med mala ia (N = 2497)
Unadjus ed Adjus edaUnadjus ed Adjus edaUnadjus ed Adjus eda
IRRb (95% CI) p- alue IRRb (95% CI) p- alue IRRb (95% CI) p- alue IRRb (95% CI) p- alue IRRb (95% CI) p- alue IRRb (95% CI) p- alue
P edic o a age 6 mon hs
LAZ 0.98 (0.94 o 1.02) 0.370 1.03 (0.98 o 1.09) 0.394 0.91 (0.85 o 0.98) 0.011 0.98 (0.89 o 1.07) 0.703 0.92 (0.87 o 0.97) 0.003 1.00 (0.94 o 1.07) 0.882
WLZ 0.96 (0.92 o 1.01) 0.098 0.97 (0.92 o 1.02) 0.190 0.99 (0.95 o 1.04) 0.762 1.03 (0.94 o 1.12) 0.571 0.99 (0.94 o 1.04) 0.623 1.00 (0.94 o 1.06) 0.950
WAZ 0.97 (0.93 o 1.01) 0.094 1.10 (0.50 o 2.42) 0.810 0.95 (0.88 o 1.01) 0.093 1.07 (0.29 o 3.91) 0.916 0.95 (0.90 o 0.99) 0.030 1.46 (0.48 o 4.40) 0.506
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Bendabendae al. Mala J (2019) 18:143
6mon hs was associa ed wi h 111% highe p e alence o
mala ia pa asi aemia).
Discussion
The s udy hypo hesis was ha lowe leng h o age
z-sco es (LAZ) and lowe weigh o leng h z-sco es
(WLZ) a 6 mon hs will be associa ed wi h a highe
incidence o mala ia om 6 o 18mon hs and highe
p e alence o mala ia pa asi aemia a 18mon hs. In a
sample o 2561 Malawian child en, LAZ a 6 mon hs
was no associa ed wi h incidence o mala ia om 6 o
18 mon hs, no p e alence o mala ia pa asi aemia a
18mon hs. Highe WLZ a 6mon hs was associa ed wi h
lowe p e alence o mala ia pa asi aemia a 18mon hs
(20% dec ease in p e alence o mala ia pa asi aemia a
18mon hs o e e y 1 SD highe WLZ a 6mon hs), bu
no wi h incidence o mala ia om 6 o 18mon hs.
The longi udinal s udy design helped o de e mine he
empo ali y o he associa ions because (1) mala ia ou -
comes we e ob ained om 6 o 18mon hs a e iden i-
ying he p edic o s a 6mon hs, and (2) mala ia is less
Table 3 Associa ion o  leng h- o -age, weigh - o -leng h,
and weigh - o -age z-sco es a  age 6 mon hs wi h
p e alence o mala ia pa asi aemia a age 18mon hs
CI: con idence in e al; LAZ: leng h- o -age z-sco e; PR: p e alence a io; WAZ:
weigh - o -age z-sco e; WLZ: weigh - o -leng h z-sco e
a Posi i e esul om mala ia mic oscopy eadings
b Adjus ed o he ollowing ac o s a age 6mon hs: sex o he child,
haemoglobin concen a ion, i on s a us, mon h o bi h, daily use o insec icide-
ea ed bed ne s, dis ance o heal h acili y, s udy si e, asse sco es, ma e nal
age, ma e nal educa ion, child en < 5yea s, HFIA sco e, and whe he he child
ecei ed he s udy in e en ion (LNS) o no
c P e alence a io, ob ained using a modi ied Poisson eg ession (wi h a obus
a iance es ima o ) [29]. The PR ep esen s he a e o change in p e alence o
mala ia pa asi aemia o each 1-SD highe LAZ, WAZ, o WLZ
P e alence o mala ia pa asi aemia a age 18mon hs
(N = 1662)a
Unadjus ed Adjus edb
PRc (95% CI) p- alue PRc (95% CI) p- alue
P edic o a age 6 mon hs
LAZ 0.82 (0.72 o 0.93) 0.003 1.11 (0.93 o 1.33) 0.259
WLZ 1.01 (0.88 o 1.16) 0.877 0.80 (0.67 o 0.94) 0.007
WAZ 0.85 (0.75 o 0.96) 0.007 0.88 (0.75 o 1.03) 0.115
Table 4 Independen p edic o s o incidence andp e alence o mala ia inmul i a ia e analysis
O he ac o s included in he models bu no signi ican we e: sex o he child, bi h mon h, numbe o child en in household, and daily use o insec icide- ea ed bed
ne s
CI: con idence in e al; IRR: incidence a e a io; LNS: lipid-based nu ien supplemen s; PR: p e alence a io; ZPP: zinc p o opo phy in
a Incidence a e a io, ob ained using nega i e binomial eg ession. The IRR ep esen s he a e o change in incidence o mala ia ( o each 1-uni highe in he
con inuous p edic o s o o each g oup compa ed o he e e ence g oup in he ca ego ical p edic o s), adjus ed o o he a iables
b P e alence a io, ob ained using a modi ied Poisson eg ession (wi h a obus a iance es ima o ) [29]. The PR ep esen s he a e o change in p e alence o mala ia
pa asi aemia ( o each 1-uni highe in he con inuous p edic o s o o each g oup compa ed o he e e ence g oup in he ca ego ical p edic o s), adjus ed o o he
a iables
c ZPP > 70µmol/mol heme [28]
Incidence o ‘p esumed’
mala ia (N = 2561) Incidence o clinical
mala ia (N = 2497) Incidence o con i med
mala ia (N = 2497) P e alence o mala ia
pa asi aemia a age
18mon hs (N = 1662)
IRRa (95% CI) p- alue IRRa (95% CI) p- alue IRRa (95% CI) p- alue PRb (95% CI) p- alue
Child ac o s a age 6 mon hs
Haemoglobin (g/L) 1.00 (0.99 o 1.01) 0.529 0.99 (0.98 o 1.00) 0.016 1.00 (0.99 o 1.01) 0.845 0.98 (0.97 o 0.99) 0.001
I on de iciencyc1.04 (0.91 o 1.18) 0.587 1.03 (0.83 o 1.28) 0.773 1.20 (1.04 o 1.39) 0.012 2.11 (1.24 o 3.57) 0.006
Ma e nal ac o s a en ollmen
Ma e nal age 1.01 (1.00 o 1.02) 0.011 0.99 (0.97 o 1.01) 0.149 1.00 (0.98 o 1.01) 0.200 0.97 (0.94 o 0.99) 0.033
Ma e nal educa ion 0.99 (0.97 o 1.01) 0.427 1.00 (0.98 o 1.03) 0.783 0.97 (0.95 o 0.99) 0.024 0.90 (0.85 o 0.96) 0.001
Household ac o s a en ollmen
Household Food Insecu i y
Access Sco e 1.00 (0.99 o 1.01) 0.809 1.02 (1.01 o 1.04) 0.022 1.01 (0.99 o 1.02) 0.065 1.02 (0.99 o 1.05) 0.184
Asse sco es 0.86 (0.80 o 0.93) < 0.001 0.94 (0.83 o 1.07) 0.343 0.73 (0.64 o 0.83) < 0.001 0.92 (0.63 o 1.34) 0.666
En i onmen al ac o s
LNS in e en ion ( s con ol) 1.00 (0.88 o 1.14) 0.983 1.11 (0.89 o 1.37) 0.343 1.02 (0.86 o 1.22) 0.783 1.07 (0.70 o 1.62) 0.765
S udy si e
Mangochi Re e ence Re e ence Re e ence Re e ence
Namwe a 0.94 (0.81 o 1.09) 0.457 1.49 (1.20 o 1.85) < 0.001 1.73 (1.50 o 1.99) < 0.001 1.49 (0.99 o 2.24) 0.054
Malindi 1.12 (0.88 o 1.42) 0.337 0.45 (0.27 o 0.73) 0.001 0.58 (0.43 o 0.78) < 0.001 0.74 (0.29 o 1.88) 0.531
Lungwena 0.91 (0.75 o 1.09) 0.303 0.24 (0.14 o 0.41) < 0.001 0.33 (0.25 o 0.44) < 0.001 0.65 (0.36 o 1.19) 0.163
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Bendabendae al. Mala J (2019) 18:143
common in child en < 6 mon hs due o he p o ec i e
e ec o e al haemoglobin and ma e nal an ibodies
[30–32]. Ano he s eng h o he s udy was he enhance-
men o mo bidi y ecall using a daily pic o ial calenda
which minimized ecall bias associa ed wi h home mo -
bidi y assessmen s [22, 23]. The s udy had a long ollow
up which allowed assessmen o he associa ions in all
seasons, and by pooling da a om wo la ge coho s we
ended up wi h a la ge sample size wi h adequa e powe o
de ec associa ions.
The main weakness o he s udy is he change in he
exposu e (an h opome ic s a us) du ing he ollow up.
The e was signi ican dec ease in mean LAZ, WAZ, and
WLZ om 6mon hs o 18mon hs. Compa ed o base-
line, mo e child en had de eloped s un ing, unde weigh ,
and was ing by 18 mon hs (41.5% s 28.3%, 16.5% s
12.9%, and 5% s 2% espec i ely), indica ing ha some
child en became nu i ionally wo se o du ing ollow up
which may ha e led o misclassi ica ion bias.
The e is possibili y o esidual con ounding due o
unmeasu ed ac o s associa ed wi h mala ia including
HIV in ec ion [33], polypa asi ism [34], i amin A and
zinc de iciency [35–38], and gene ic a ia ions including
haemoglobinopa hies [39–41].
P esump i e diagnosis o mala ia may also ha e led o
o e es ima ing he ou come whe eas he use o RDT-
con i med mala ia may ha e led o unde -es ima ing he
ou come because (1) 23% o he child en we e ea ed
o mala ia a he hospi al wi hou RDT con i ma ion,
and (2) child en who had mala ia episodes bu ecei ed
home ea men o no ea men and did no p esen o
he hospi als we e missed (only 44% o he mo bidi y epi-
sodes we e ea ed a he hospi al). Howe e , he consis -
ency o he esul s ac oss he di e en mala ia de ini ions
sugges s ha his weakness did no bias he esul s, and
conside ing he s eng hs o his s udy, he conclusions
a e easonably alid.
The inding o no associa ion be ween s un edness
a 6mon hs and mala ia in he subsequen 12-mon h
pe iod is simila o esul s o p e ious s udies [42–45],
which sugges s ha s un ing may be o li le signi icance
in mala ia epidemiology. These esul s a e howe e di -
e en om hose o o he s udies ha epo ed an
inc eased isk o mala ia associa ed wi h s un ing. In he
Gambia, a p ospec i e s udy o child en aged < 5yea s
epo ed an inc eased isk o mala ia associa ed wi h
s un ing (c ude RR = 1.35; 95% CI 1.08–1.69) [9]. The
ollow up was e y sho (du ing he mala ia season
ha las ed only 20weeks), and al hough he ou comes
we e adjus ed o age, sex, and e hnici y, c ude RR we e
epo ed. The au ho s also did no adjus o socio-eco-
nomic and household ac o s he e o e could no ule
ou he in luence o hese con ounde s in hei esul s. In
Kenya, s un ing in child en aged 0–36mon hs was asso-
cia ed wi h an inc eased odds o mala ia pa asi aemia
(odds a io = 1.98, p < 0.0001) [10]. The c oss-sec ional
design o his s udy sugges s he obse ed associa ion
may ha e been due o e e se causa ion, i.e. he cumu-
la i e dele e ious e ec s o mala ia on linea g ow h. In
Uganda, mild s un ing (IRR = 1.24, 95% CI 1.06–1.46)
and mode a e-se e e s un ing (IRR = 1.24, 95% CI 1.03–
1.48) in child en aged < 2.5 yea s we e associa ed wi h
inc eased incidence o mala ia pa asi aemia [11]. How-
e e , al hough his was a coho s udy, i was no clea
whe he exposu e assessmen p eceded he ou comes,
he e o e, he empo al ela ionship be ween s un ing
and isk o mala ia was di icul o asce ain.
Howe e , a s udy in Papua New Guinea epo ed
ha lowe LAZ was associa ed wi h lowe incidence o
mala ia in he subsequen one-yea pe iod, a ibu ed
o inc eased in e e on γ (IFN-γ) esponse o speci ic
mala ial an igens obse ed in s un ed child en, al hough
he mechanisms we e no ully explained [46]. Mala ia
a ies wi h age (incidence o mala ia dec eases whe eas
p e alence o mala ia pa asi aemia inc eases wi h age)
[13, 47, 48], he e o e, he wide age ange o he s udy
pa icipan s ( om 10mon hs o 10yea s) makes o di i-
cul compa isons be ween he s udies. In he Papua New
Guinea s udy, he au ho s no ed ha in e e on-γ elease
inc eased wi h age, he p e alence a es o splenomegaly
and pa asi aemia inc eased wi h age, whe eas he inci-
dence o mala ia dec eased wi h age, u he muddling
he in e p e a ion o he indings.
In his popula ion, supplemen a ion wi h LNS did
no al e mala ia an ibody acquisi ion [49], which was
a ibu ed o he inding ha he nu i ional supple-
men s also did no p omo e in an g ow h [16]. Fu he
analysis showed no di e ence in mala ia an ibody acqui-
si ion be ween he s un ed and non-s un ed child en a
6mon hs (da a no shown), suppo ing he null indings.
In his s udy, highe WLZ a 6 mon hs was associ-
a ed wi h lowe p e alence o mala ia pa asi aemia a
18mon hs, when adjus ed o o he p edic o s. Was ing
is associa ed wi h low le els o lep in h ough deple ion
o a mass [50]. Low le els o lep in can lead o educed
immune esponse [51], esul ing in inc eased isk o
mala ia associa ed wi h was ing. So a , he e idence
o associa ion (inc eased o dec eased isk) o mala ia
wi h WLZ has mainly come om c oss-sec ional s ud-
ies [10, 52, 53]. A ecen sys ema ic e iew de e mined
ha he ela ionship be ween was ing and isk o mala ia
is hi he o inconclusi e wi h mos longi udinal s ud-
ies epo ing no associa ion [54]. This associa ion was
no conclusi e and may be due o chance (e.g., because
o mul iple es ing [55]), conside ing ha WLZ was