Effect of Women’s Nutrition before and during Early Pregnancyon Maternal and Infant Outcomes: A Systematic Reviewppe_1281 285..301
Usha Ramakrishnan,a,b Frederick Grant,a,b Tamar Goldenberg,a Amanda Zongrone,c Reynaldo Martorella,b
aHubert Department of Global Health, Rollins School of Public Health, bDoctoral Program in Nutrition and Health Sciences, Graduate Division of
Biological and Biomedical Sciences, Emory University, Atlanta, GA, and cDivision of Nutritional Sciences, Cornell University, Ithaca, NY, USA
Abstract
Current understanding of biologic processes indicates that women’s nutritional status before and during earlypregnancy may play an important role in determining early developmental processes and ensuring successfulpregnancy outcomes. We conducted a systematic review of the evidence for the impact of maternal nutritionbefore and during early pregnancy (<12 weeks gestation) on maternal, neonatal and child health outcomes andincluded 45 articles (nine intervention trials and 32 observational studies) that were identified through PubMedand EMBASE database searches and examining review articles. Intervention trials and observational studies showthat periconceptional (<12 weeks gestation) folic acid supplementation significantly reduced the risk of neural tubedefects. Observational studies suggest that preconceptional and periconceptional intake of vitamin and mineralsupplements is associated with a reduced risk of delivering offspring who are low birthweight and/or small-for-gestational age (SGA) and preterm deliveries (PTD). Some studies report that indicators of maternal prepregnancysize, low stature, underweight and overweight are associated with increased risks of PTD and SGA. The availabledata indicate the importance of women’s nutrition prior to and during the first trimester of pregnancy, but there isa need for well-designed prospective studies and controlled trials in developing country settings that examinerelationships with low birthweight, SGA, PTD, stillbirth and maternal and neonatal mortality. The knowledge gapsthat need to be addressed include the evaluation of periconceptional interventions such as food supplements,multivitamin-mineral supplements and/or specific micronutrients (iron, zinc, iodine, vitamin B-6 and B-12) as wellas the relationship between measures of prepregnancy body size and composition and maternal, neonatal andchild health outcomes.
Keywords: early pregnancy, women’s nutrition, birth outcomes.
Women’s nutrition, before and during pregnancy, mayplay a key role in reproductive health and is recogn-ised as being important for optimising pregnancy out-comes.1,2 The availability and supply of nutrients tothe developing fetus depends on maternal nutritionalstatus which in turn depends on her nutrient stores,dietary intake and obligatory requirements. Mostof the studies that have examined the importanceof nutrition during pregnancy typically focus on thesecond and/or the third trimester by which time keyprocesses such as organogenesis have been com-pleted.3 Women’s nutritional status just before con-ception and/or during early pregnancy (<12 weeksgestation), when women are typically unaware of their
pregnancy status, may influence pregnancy outcomesby affecting critical developmental processes thatbegin early in pregnancy as well as the availabilityof nutrients. Animal studies suggest that peri-conceptional undernutrition may influence thehypothalamic-pituitary-adrenal axis which in turninfluences outcomes such as pre-eclampsia andpreterm delivery (PTD).4 Ensuring an adequatesupply of nutrients to the fetus throughout gestationalso depends on placental function which is deter-mined in early pregnancy and may be influenced bymaternal nutrition during early pregnancy.3,5 Maternalendocrine and metabolic responses that occur early inpregnancy in turn influence the supply and utilisationof available nutrients for the rapidly growing fetuslater in pregnancy.6,7
Various aspects of maternal nutrition that are par-ticularly relevant for the developing world and mayinfluence pregnancy outcomes are shown in Figure 1.
Correspondence: Usha Ramakrishnan, PhD, Hubert Departmentof Global Health, Rollins School of Public Health, EmoryUniversity, 1518 Clifton Road, N.E. Atlanta, GA 30032, USA.E-mail: [email protected]
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285doi: 10.1111/j.1365-3016.2012.01281.x
© 2012 Blackwell Publishing Ltd
Paediatric and Perinatal Epidemiology, 2012, 26 (Suppl. 1), 285–301
Women living in resource poor settings are often mal-nourished before pregnancy; they may be short as aresult of early childhood malnutrition, and under-weight and anaemic due to inadequate food intakesand infections. In some settings, overweight andobesity are also emerging concerns due to poor diet.8,9
Several observational studies have shown that mea-sures of body size such as height, weight and bodymass index (BMI) are associated with adverse birthoutcomes such as low birthweight (LBW) and small-for-gestational age (SGA), although the exact timing ofbody measurement is unclear.10–12 Age at the time ofconception and duration of inter-pregnancy intervalare also important as they may influence the availabil-ity of nutrients at the time of conception and duringearly pregnancy. Adolescent girls who have not com-pleted their own growth and development may beat increased risk of being shorter, lighter and/ordepleted stores of energy and micronutrients such asiron, iodine and vitamin A; women with short inter-pregnancy intervals may also be at increased riskof nutrient deficiencies in resource poor settings.13,14
Various nutrients may influence pregnancy outcomesby altering both maternal and fetal metabolism dueto their roles in modulating oxidative stress, enzymefunction, signal transduction and transcription path-ways that occur early in pregnancy,3,15 namely dur-ing the critical periods of preconception, conception,implantation, placentation and embryo- or organogen-
esis. Nutrients such as iron, zinc, iodine and longchain n-3 polyunsaturated fatty acids (LCPUFA) playcritical roles in development of the brain and nervoussystem, whereas vitamins A, B-6, B-12 and folic acidinfluence oxidative pathways and methylation.
Nutrition during early pregnancy may affectplacental function, which has been associated withadverse pregnancy outcomes such as pre-eclampsia,PTD and fetal growth restriction. Proposed mecha-nisms include lowered number and surface area ofarterioles in tertiary villi and reduction in spiral arteryformation as a result of impaired function of tropho-blasts due to oxidative stress and/or inflammation.5
LCPUFA and iron status during early pregnancy havebeen shown to be inversely associated with placentalweight and surface area of capillaries involved in gasexchange, respectively.16,17 Several micronutrients canalso influence inflammation and oxidative stress earlyin pregnancy; vitamins A and D, zinc and fatty acidsmay influence immune function whereas vitamins C,E, B-6, B-12 and folic acid may reduce oxidativedamage to the placenta. Nutrients such as vitamins A,B-6, B-12 and folic acid and zinc also affect embryo-genenesis that occurs early in pregnancy and may berelated to pregnancy loss and fetal malformations.These nutrients are involved are in several biochemi-cal pathways such as the homocysteine pathway andinfluence processes such as methylation which in turnaffects cell replication and differentiation.5 The most
Figure 1. Conceptual framework ofstages of pregnancy potentiallyimpacted by nutrition. BMI, body massindex; LBW, low birthweight.
MaternalMortality
Premature Delivery
LBW Poor Child Growth& Development
Maternal NutritionStatus
Food Micronutrient Supplementation
Nutrition Education
Nutritional Status BMI/FatStores
Height Micronutrient Status Age at FirstPregnancy
Mat
erna
l U
nder
lyin
g F
acto
rs
Inte
rven
tion
s E
ntry
Poi
nts
Out
com
es
286 U. Ramakrishnan et al.
© 2012 Blackwell Publishing Ltd
Paediatric and Perinatal Epidemiology, 2012, 26 (Suppl. 1), 285–301
well-studied effect of periconceptional nutrition isthe protective effect of folic acid in the first 28 days ofpregnancy in reducing the risk of delivering infantswith neural tube defect (NTD), which contribute tosignificant mortality and morbidity.18–20 Much less isknown about other nutrients.
The objective of this paper, which is part of a serieson the role of maternal nutrition for improving mater-nal, neonatal and child health outcomes (MNCH) thatare significant public health problems in many devel-oping countries, is to conduct a systematic reviewof the evidence on the role of nutrition before andduring early pregnancy on maternal morbidity andmortality, pregnancy loss including stillbirths, birthdefects, LBW, PTD and infant mortality.
Methods
Search strategy
We identified published studies using PubMed andEMBASE search engines. The search was carried outby combining the results of three separate strategiesusing the following key concepts and related keywords: (1) preconception and periconception terms(‘preconception’ or ‘periconception’ or ‘prepregnancy’or ‘pre-pregnancy’ or ‘before pregnancy’), (2) nutri-tional terms (‘intervention’ or ‘nutrition’ or ‘micro-nutrient supplementation’ or ‘food fortification’ or‘body mass index’ or ‘weight’ or ‘multivitamin’or ‘multivitamin-mineral’ or ‘vitamin’ or ‘iodine’ or‘zinc’ or ‘folic acid’ or ‘iron’), and (3) maternal, neona-tal and child health outcomes of interest (‘low birthweight’ or ‘birth size’ or ‘birth weight’ or ‘intrauterinegrowth restriction’ or ‘preterm birth’ or ‘pretermdelivery’ or ‘gestational age’ or ‘morbidity’ or ‘mortal-ity’ or ‘growth’ or ‘nutritional status’ or ‘stillbirth’or ‘pregnancy loss’ or ‘birth defects’ and ‘neonatal’or ‘infant’ or ‘child’ or ‘children’ or ‘maternal’). Weincluded all studies from 1950 to July 2011 with nolanguage restriction but limited to ‘humans’. Addi-tional studies were identified through hand search ofreferences from previous review articles. The inclu-sion and exclusion criteria were as follows:
Inclusion criteria: (1) intervention and observationalstudies, (2) nutrition exposure (intervention or indica-tors of nutritional status) was measured right before(within 1 year of conception) and/or during earlypregnancy (<12 weeks gestation), (3) studies thatincluded MNCH outcomes (namely, maternal morbid-
ity and mortality, pregnancy loss, stillbirths, birthdefects, birth size, PTD, neonatal and infant morta-lity), and (4) appropriate comparison group.
Exclusion criteria: (1) animal studies, (2) nutritionexposure was assessed or began at later stages ofpregnancy (beyond first trimester), (3) non-nutritionalstudies, (4) review articles, and (5) poorly definedcomparison group (for, e.g. in programme evaluations,intervention of interest continued during pregnancy).
Data abstraction
The abstracts of all potential publications werereviewed independently by two co-authors (T. G. andA. Z.) initially to identify eligible publications fordata abstraction. The senior author (U. R.) reviewedpublications that were identified for inclusion byonly one co-author to determine eligibility. Relevantstudy attributes (qualitative and quantitative) wereabstracted from the selected publications using stan-dardised forms developed for the overall project byone co-author (T. G.) and reviewed for accuracy byanother co-author (F. G.) and the senior author (U. R.).We assessed the overall quality of evidence forthe outcomes by the Grading of Recommendations,Assessment, Development and Evaluation criteria.21,22
Results
A total of 441 titles were identified on PubMed andEMBASE searches, of which we carefully reviewed 62articles that included five that appeared in the reviewarticles but not in the PubMed search (Figure 2).Careful examination of these studies resulted in theinclusion of 45 articles20,23–66 most of which were basedon observational studies (Table 1). The main reasonsfor excluding articles after completing abstractionwere: (i) the intervention and/or exposure occurredafter 12 weeks gestation,67–74 (ii) missing our outcomesof interest,75–83 and (iii) did not measure periconcep-tional exposures.84,85
We identified six intervention trials20,30,33,38,39,42,44,62,76
and seven observational studies26,29,34,36,43,48,51,52 thatexamined the relationship between preconceptionand/or periconception maternal nutritional status andmaternal morbidity and pregnancy loss includingstillbirth. In the case of child outcomes, we includednine intervention trials20,30–33,38,39,42,44,62 and 28 observa-tional studies23–28,34,35,37,40,41,43,45–50,53–61,63–66 that examinedthe effects on birth defects, birth size and PTD. We
Periconceptual nutrition and maternal and infant outcomes 287
© 2012 Blackwell Publishing Ltd
Paediatric and Perinatal Epidemiology, 2012, 26 (Suppl. 1), 285–301
did not find any studies that examined maternalor neonatal mortality. The key findings are describedby outcome in the following sections and additionaldetails are available on request.
Maternal health
Four observational studies26,29,43,48 examined the effectsof prepregnancy and/or periconceptional nutrition onthe risk of developing pre-eclampsia later in preg-nancy. Phithakwatchara and Titapant48 reported thatthe risk of pre-eclampsia was significantly increased[odds ratio (OR): 3.87 [95% confidence interval (CI)
2.09, 7.25]] in overweight Thai women (pre-pregnancyBMI � 27 kg/m2) compared with normal weightwomen (BMI of 20–25 kg/m2), after adjusting for theconfounding factors. This study used data from a ret-rospective review of medical records of the pregnantwomen who were at risk of gestational diabetes.Similar findings were reported in a large study ofsingleton nulliparous pregnancies delivered in threehospitals in Shenyang, China using data obtainedfrom medical records.43 Compared with normalweight women (18.5 � BMI < 24 kg/m2), overweight(24 � BMI < 28 kg/m2) and obese women (BMI �
28 kg/m2) had significantly increased risks [adjusted
Figure 2. Studies excluded and included in the review of the preconception nutrition and pregnancy outcomes. *Some studies hadmore than one publication. MNCH, maternal, neonatal and child health outcomes.
288 U. Ramakrishnan et al.
© 2012 Blackwell Publishing Ltd
Paediatric and Perinatal Epidemiology, 2012, 26 (Suppl. 1), 285–301
Tab
le1.
Des
crip
tion
ofin
terv
enti
onan
dob
serv
atio
nals
tud
ies
ofpe
rico
ncep
tion
alnu
trit
ion
and
mat
erna
land
child
heal
thou
tcom
es
Ref
eren
ceD
esig
n,n
Loc
atio
nPo
pula
tion
Inte
rven
tion
/ex
posu
reO
utco
mes
Inte
rven
tion
tria
lsB
erry
etal
.,19
9920
Com
mun
ity-
base
din
terv
enti
on,2
4783
1C
hina
Wom
enpr
epar
ing
for
mar
riag
ew
houn
der
wen
ta
phys
ical
exam
inat
ion
and
wer
ela
ter
regi
ster
edw
ith
am
onit
orin
gsy
stem
that
reco
rds
pren
atal
care
and
del
iver
y
Dai
lysu
pple
men
tco
ntai
ning
400
mgfo
licac
idN
TD
a
Cha
ouki
and
Ben
milo
ud,1
99430
Com
mun
ity-
base
din
terv
enti
on,1
536
Alg
eria
Wom
enw
how
ere
plan
ning
tobe
preg
nant
Ora
liod
ised
oil1
–3m
onth
sbe
fore
conc
epti
onor
duri
ngth
efir
sttr
imes
ter
Still
birt
hs,B
Wa ,
PTD
Che
net
al.,
2008
31C
omm
unit
y-ba
sed
inte
rven
tion
,52
043
Chi
naR
esid
ent
wom
enpl
anni
nga
preg
nanc
yw
hovo
lunt
eere
dto
part
icip
ate
info
llow
-up
Dai
lym
ulti
vita
min
supp
lem
ent,
cont
aini
ng23
vita
min
san
dm
icro
elem
ents
(inc
lud
ing
folic
acid
)N
TD
a
Cze
izel
etal
.,19
92,
1994
32,3
3R
CT,
7540
Hun
gary
Wom
en(<
35ye
ars)
plan
ning
apr
egna
ncy
(in
mos
tca
ses
thei
rfir
st)
who
qual
ified
for
the
Hun
gari
anFa
mily
Plan
ning
Prog
ram
tria
lin
1984
Vita
min
supp
lem
ent
(con
tain
ing
12vi
tam
ins
incl
udin
g0.
8m
gof
folic
acid
,fou
rm
iner
als
and
thre
etr
ace
elem
ents
)or
atr
ace
elem
ent
supp
lem
ent
(con
tain
ing
copp
er,m
anga
nese
,zin
can
da
very
low
dos
eof
vita
min
C)
daily
for
�1
mon
thbe
fore
conc
epti
onan
dun
til
the
date
ofth
ese
cond
mis
sed
men
stru
alpe
riod
orla
ter
NT
Da ,
BW
,GA
,L
BW
,PT
D,e
arly
preg
nanc
ylo
ss,
still
birt
h
Ind
ian
Cou
ncil
ofM
edic
alR
esea
rch
Col
labo
rati
ngC
entr
esan
dC
entr
alTe
chni
cal
Co-
ord
inat
ing
Uni
t,20
0038
Dou
ble-
blin
d,R
CT,
l466
Ind
iaN
on-p
regn
ant
wom
enw
hoha
dpr
evio
usly
give
nbi
rth
toa
child
wit
hop
enN
TD
and
plan
ned
toha
vean
othe
rch
ild
Mul
tivi
tam
insu
pple
men
t(f
erro
ussu
lpha
te,c
alci
umph
osph
ate,
vita
min
sA
,D,B
-1,B
-2,B
-6an
dC
,nic
otin
amid
e,zi
ncan
dfo
licac
id)
orpl
aceb
o(f
erro
ussu
lpha
tean
dca
lciu
msu
lpha
te)
for
�1
mon
thpr
ior
toco
ncep
tion
upto
3m
onth
afte
rco
ncep
tion
Rec
urre
nce
ofN
TD
a ,ea
rly
preg
nanc
ylo
ss,
still
birt
h
Kir
keet
al.,
1992
39D
oubl
e-bl
ind,
RC
T,35
4Ir
elan
dN
on-p
regn
ant
wom
enw
hoha
dpr
evio
usly
give
nbi
rth
toa
child
wit
han
NT
Dan
dpl
anne
dto
have
anot
her
child
Folic
acid
supp
lem
ent,
mul
tivi
tam
ins
wit
hout
folic
acid
,or
folic
acid
plus
mul
tivi
tam
ins
for
�2
mon
thpr
ior
toco
ncep
tion
unti
lthe
thir
dm
isse
dm
enst
rual
peri
od
Rec
urre
nce
ofN
TD
a
Lau
renc
eet
al.,
1981
42D
oubl
e-bl
ind,
RC
T,11
1W
ales
Non
-pre
gnan
tw
omen
(<35
year
s)w
hoha
dha
da
prev
ious
preg
nanc
yco
mpl
icat
edby
afe
talN
TD
4m
gfo
licac
id/
day
orpl
aceb
ofr
omth
eti
me
cont
race
ptiv
eus
ew
asst
oppe
dun
til6
wee
ksaf
ter
am
isse
dm
enst
rual
peri
odR
ecur
renc
eof
NT
Da
Med
ical
Res
earc
hC
ounc
ilV
itam
inSt
udy
Res
earc
hG
roup
,199
144
Mul
tice
nter
rand
omis
edd
oubl
e-bl
ind
prev
enti
ontr
ial,
1817
UK
Wom
enat
high
risk
ofha
ving
apr
egna
ncy
wit
han
NT
D,b
ecau
seof
apr
evio
usaf
fect
edpr
egna
ncy
Folic
acid
,oth
ervi
tam
ins,
both
orne
ithe
rN
TD
a
Ver
gele
tal.,
1990
62C
omm
unit
y-ba
sed
inte
rven
tion
,81
Cub
aN
on-p
regn
ant
wom
enw
ith
ahi
stor
yof
apr
evio
usN
TD
birt
h5
mg
folic
acid
/da
yfo
rno
tle
ssth
anon
em
enst
rual
peri
odbe
fore
conc
epti
onun
tilt
he10
thw
eek
ofpr
egna
ncy
Rec
urre
nce
ofN
TD
a
Ob
serv
atio
nal
stu
die
sB
itsk
oet
al.,
2007
23C
ase–
cont
rol,
395
US
Cas
es:m
othe
rsof
infa
nts/
fetu
ses
wit
h�
2un
rela
ted
maj
orbi
rth
def
ects
affe
ctin
g�
2d
iffe
rent
orga
nsy
stem
s;C
ontr
ols:
rand
omsa
mpl
eof
liveb
orn,
non-
mal
form
edin
fant
sbo
rnin
the
sam
eti
me
peri
odto
resi
den
tsof
the
sam
ege
ogra
phic
alar
ea
Self
-rep
ort
ofvi
tam
insu
pple
men
tati
onin
clud
ing
�40
00mg
folic
acid
�3
tim
es/
wee
kpe
rico
ncep
tion
ally
(3m
onth
sbe
fore
and
afte
rco
ncep
tion
)or
duri
ngth
efir
sttr
imes
ter
Mul
tipl
eco
ngen
ital
anom
alie
s
Bow
eran
dSt
anle
y,19
9225
Cas
e–co
ntro
l,15
4A
ustr
alia
Cas
es:w
omen
who
had
infa
nts/
fetu
ses
wit
han
NT
D;C
ontr
ols:
Wom
enw
hoha
din
fant
s/fe
tuse
sw
ith
mal
form
atio
nsot
her
than
NT
Ds
orm
othe
rsof
liveb
orn
infa
nts
wit
hout
mal
form
atio
ns
Self
-rep
ort
ofvi
tam
insu
pple
men
tus
ein
the
3m
onth
sbe
fore
conc
epti
onan
dth
efir
st6
wee
ksof
preg
nanc
yN
TD
Bow
eret
al.,
2006
24C
ase–
cont
rol,
1053
Aus
tral
iaC
ases
:wom
enw
hoha
din
fant
s/fe
tuse
sw
ith
anO
FC,
CH
D,u
rina
rytr
act
def
ect,
limb
redu
ctio
nd
efec
t,or
othe
rm
ajor
birt
hd
efec
t;C
ontr
ols
wer
ea
rand
omsa
mpl
ese
lect
edfr
omth
eM
idw
ives
’Not
ifica
tion
Syst
em
Self
-rep
ort
ofvi
tam
insu
pple
men
tati
onpe
rico
ncep
tion
ally
,co
nsum
ptio
nof
174
food
san
dbe
vera
ges
(6m
onth
sbe
fore
preg
nanc
y),a
ndco
nsum
ptio
nof
any
ofa
list
ofsp
ecifi
cfo
ods
fort
ified
wit
hfo
licac
id(6
mon
ths
befo
repr
egna
ncy)
Bir
thd
efec
tsot
her
than
NT
D
Buk
owsk
ieta
l.,20
0926
Pros
pect
ive
coho
rt,
3448
0U
SW
omen
who
had
sing
leto
nbi
rths
at20
–42
wee
ksge
stat
ion
Self
-rep
ort
(dur
ing
the
first
trim
este
r)of
prec
once
ptio
nalf
olat
esu
pple
men
tati
onw
ith
orw
itho
utm
ulti
vita
min
s(�
1ye
aran
d<1
year
)
Pre-
ecla
mps
ia,S
GA
,PT
Da
Periconceptual nutrition and maternal and infant outcomes 289
© 2012 Blackwell Publishing Ltd
Paediatric and Perinatal Epidemiology, 2012, 26 (Suppl. 1), 285–301
Tab
le1.
Con
tinu
ed
Ref
eren
ceD
esig
n,n
Loc
atio
nPo
pula
tion
Inte
rven
tion
/ex
posu
reO
utco
mes
Bur
ris
etal
.,20
1027
Ret
rosp
ecti
veco
hort
,24
64U
SN
on-H
ispa
nic
whi
tean
dbl
ack
mot
hers
ofno
n-m
alfo
rmed
infa
nts
who
part
icip
ated
inth
eSl
one
Epi
dem
iolo
gyC
ente
rB
irth
Def
ects
Stud
y
Peri
conc
epti
onal
mul
tivi
tam
inus
e�
4ti
mes
per
wee
k,co
ntai
ning
at�
2w
ater
-sol
uble
and
two
fat-
solu
ble
vita
min
sco
nsum
eddu
ring
the
peri
odin
clud
ing
the
28da
ysbe
fore
and
28da
ysaf
ter
the
last
men
stru
alpe
riod
BW
a ,w
eigh
tfo
rG
A,G
A
Cat
ovet
al.,
2009
29Pr
ospe
ctiv
eco
hort
,28
601
Den
mar
kPr
egna
ntw
omen
earl
yin
gest
atio
nM
ulti
vita
min
orfo
late
-onl
ysu
pple
men
tus
edu
ring
a12
-wee
kpe
rico
ncep
tion
alpe
riod
(4w
eeks
prio
r8
wee
ksaf
ter
the
last
men
stru
alpe
riod
)
Pre-
ecla
mps
iaa
Cat
ovet
al.,
2011
28Pr
ospe
ctiv
eco
hort
,35
897
Den
mar
kPr
egna
ntw
omen
earl
yin
gest
atio
nM
ulti
vita
min
orfo
late
-onl
ysu
pple
men
tus
edu
ring
a12
-wee
kpe
rico
ncep
tion
alpe
riod
(4w
eeks
prio
r8
wee
ksaf
ter
the
last
men
stru
alpe
riod
)
SGA
a ,PT
Da
De
Wee
rdet
al.,
2003
34Pr
ospe
ctiv
eco
hort
,240
the
Net
herl
and
sN
on-p
regn
ant
wom
enw
hobe
cam
epr
egna
ntdu
ring
the
obse
rvat
ion
peri
odB
ody
wei
ght
was
mea
sure
dan
dve
nous
bloo
dsa
mpl
esw
ere
assa
yed
for
seve
ralm
icro
nutr
ient
s(v
itam
ins
A,E
,B-1
,B-2
,B-6
,B-1
2,fo
late
and
iron
)
Preg
nanc
ylo
ss,B
Wa
Dei
erle
inet
al.,
2011
35Pr
ospe
ctiv
eco
hort
,363
US
Mot
hers
ofin
fant
sw
how
ere
not
pret
erm
and
wer
eno
td
iagn
osed
wit
hill
ness
esre
late
dto
infa
ntgr
owth
Self
-rep
ort
ofm
ater
nalp
re-p
regn
ancy
BM
I(u
nder
wei
ght,
norm
al,
over
wei
ght,
obes
e)W
AZ
,LA
Z,L
WZ
Ehr
enth
alet
al.,
2011
36R
etro
spec
tive
coho
rt,
1658
2U
SW
omen
who
del
iver
edsi
ngle
ton
preg
nanc
ies
that
wer
eno
t<2
0w
eeks
gest
atio
nSe
lf-r
epor
tof
mat
erna
lpre
-pre
gnan
cyB
MI
(und
erw
eigh
t,no
rmal
,ov
erw
eigh
t,ob
ese)
PIH
a
Han
etal
.,20
1137
Ret
rosp
ecti
veco
hort
,83
0So
uth
Kor
eaPr
egna
ntw
omen
inth
eir
seco
ndan
dth
ird
trim
este
rsSe
lf-r
epor
tof
mat
erna
lpre
-pre
gnan
cyB
MI
(und
erw
eigh
t,no
rmal
,ov
erw
eigh
t,ob
ese)
LB
Wa ,
PTD
a
Kra
pels
etal
.,20
0440
,41
Cas
e–co
ntro
l,40
9N
ethe
rlan
ds
Cas
es:m
othe
rsof
ach
ildw
ith
non-
synd
rom
icO
FC;
Con
trol
s:w
omen
wit
hno
n-af
fect
edch
ildof
the
sam
eag
e
Die
tary
inta
keac
cord
ing
toFF
Q14
mon
ths
afte
rin
dex
birt
hto
esti
mat
epr
econ
cept
ion
die
t;Pe
rico
ncep
tion
alvi
tam
infr
om4
wee
ksbe
fore
and
8w
eeks
afte
rco
ncep
tion
OFC
Liu
etal
.,20
1143
Ret
rosp
ecti
veC
ohor
t,50
47C
hina
Wom
enw
hoha
dsi
ngle
,nul
lipar
ous
preg
nanc
ies
and
del
iver
edin
one
ofth
ree
hosp
itals
inth
eSh
enya
ngar
ea
Pre-
preg
nanc
yB
MI
Pre-
ecla
mps
iaa ,
PTD
,SG
Aa ,
still
birt
hM
urri
net
al.,
2007
45Pr
ospe
ctiv
eco
hort
stud
y,10
48Ir
elan
dPr
egna
ntw
omen
,14–
16w
eeks
gest
atio
nat
tend
ing
thei
rfir
stan
tena
talv
isit
Self
-rep
ort
ofpr
e-pr
egna
ncy
BM
I(<
25,2
5–30
,>30
)B
W
Od
dyet
al.,
2009
46C
ase–
cont
rol,
710
Aus
tral
iaC
ases
:mot
hers
ofin
fant
s/fe
tuse
sbo
rnw
ith
aco
ngen
itala
nom
aly;
Con
trol
s:liv
ebor
nin
fant
sbo
rn>2
0w
eeks
gest
atio
n
Self
-rep
ort
ofm
ater
nalp
re-p
regn
ancy
BM
I(u
nder
wei
ght,
norm
al,
over
wei
ght,
obes
e)he
art
def
ects
,co
notr
unca
ld
efec
ts,N
TD
s,ur
inar
ytr
act
def
ects
,OFC
s,lim
bre
duct
ion
def
ects
Ota
etal
.,20
1147
Pros
pect
ive
coho
rt,3
022
Vie
tnam
Preg
nant
wom
enw
ith
sing
leto
npr
egna
ncie
sSe
lf-r
epor
tof
pre-
gest
atio
nalB
MI
(low
:<18
.5,n
orm
al:1
8.5–
24.9
,hig
h:�
25.0
)SG
Aa ,
larg
e-fo
r-ge
stat
iona
lag
ePh
itha
kwat
char
aan
dTi
tapa
nt,2
00748
Ret
rosp
ecti
veco
hort
,66
0Th
aila
ndPr
egna
ntw
omen
atri
skfo
rge
stat
iona
ldia
bete
sPr
e-pr
egna
ncy
BM
Iba
sed
onm
edic
alre
cord
s,w
omen
wit
hB
MI�
27w
ere
com
pare
dw
ith
wom
enw
ith
aB
MI
of20
–25
Pre-
ecla
mps
iaa ,
LB
W,P
TD
Ray
co-S
olon
etal
.,20
0549
Ret
rosp
ecti
veco
hort
,29
77G
ambi
aW
omen
who
had
spon
tane
ous
vagi
nalb
irth
sat
hom
eor
atth
epr
imar
yca
recl
inic
wit
hth
eas
sist
ance
ofa
mid
wif
e
Mon
thof
birt
h(d
eter
min
esch
ange
sin
mat
erna
lwei
ght
beca
use
offl
uctu
atio
nin
rain
s)G
Aa
Ron
nenb
erg
etal
.,20
0251
Cas
e–co
ntro
l,45
8C
hina
Fem
ale
text
ilew
orke
rsw
hoex
peri
ence
dat
leas
ton
ecl
inic
ally
reco
gnis
edpr
egna
ncy
duri
ngfo
llow
up;
Cas
es:e
nded
infe
tald
eath
<100
day
gest
atio
nor
liveb
irth
;Con
trol
s:en
ded
ina
liveb
irth
Hom
ocys
tein
e,fo
late
,and
vita
min
sB
-6an
dB
-12
conc
entr
atio
nsw
ere
mea
sure
din
plas
ma
obta
ined
befo
reco
ncep
tion
Preg
nanc
ylo
ssa
290 U. Ramakrishnan et al.
© 2012 Blackwell Publishing Ltd
Paediatric and Perinatal Epidemiology, 2012, 26 (Suppl. 1), 285–301
Tab
le1.
Con
tinu
ed
Ref
eren
ceD
esig
n,n
Loc
atio
nPo
pula
tion
Inte
rven
tion
/ex
posu
reO
utco
mes
Ron
nenb
erg
etal
.,20
02,
2004
50,5
4Pr
ospe
ctiv
eco
hort
,405
Chi
naN
on-p
regn
ant
wom
ente
xtile
wor
kers
,new
lym
arri
ed,a
ged
21–3
4H
omoc
yste
ine,
fola
te,a
ndvi
tam
ins
B-6
and
B-1
2co
ncen
trat
ions
wer
em
easu
red
inpl
asm
aob
tain
edbe
fore
conc
epti
onL
BW
,SG
Aa ,
BW
,IU
GR
,GA
,PT
D,
infa
ntle
ngth
,he
adci
rcum
fere
nce
Ron
nenb
erg
etal
.,20
0353
Pros
pect
ive
coho
rt,5
75C
hina
Non
-pre
gnan
tw
omen
text
ilew
orke
rs,n
ewly
mar
ried
,age
d21
–34
Exa
min
edm
ater
nalB
MI
prio
rto
prec
once
ptio
n(m
oder
atel
yun
der
wei
ght
orse
vere
lyun
der
wei
ght
vs.n
orm
alB
MI)
BW
a ,L
BW
a ,B
Wra
tio,
IUG
R,G
A,
PTD
,inf
ant
head
circ
umfe
renc
ean
dle
ngth
,pon
der
alin
dex
Ron
nenb
erg
etal
.,20
0752
Pros
pect
ive
coho
rt,3
64C
hina
Non
-pre
gnan
tw
omen
text
ilew
orke
rs,n
ewly
mar
ried
,age
d21
–34
Hom
ocys
tein
e,fo
late
,and
vita
min
sB
-6an
dB
-12
conc
entr
atio
nsw
ere
mea
sure
din
plas
ma
obta
ined
befo
reco
ncep
tion
Preg
nanc
ylo
ssa
Shaw
etal
.,19
9556
Cas
e–co
ntro
l,10
89U
SC
ases
:mot
hers
ofin
fant
s/fe
tuse
sw
ith
anN
TD
;C
ontr
ols:
mot
hers
ofsi
ngle
ton
infa
nts
wit
hout
NT
Ds
Self
-rep
ort
ofvi
tam
insu
pple
men
tus
eco
ntai
ning
folic
acid
3m
onth
sbe
fore
/af
ter
conc
epti
onN
TD
a
Shaw
etal
.,19
9957
Cas
e–co
ntro
l,82
9U
SC
ases
:mot
hers
ofin
fant
s/fe
tuse
sw
ith
anN
TD
;C
ontr
ols:
mot
hers
ofsi
ngle
ton
infa
nts
wit
hout
NT
Ds
Nut
rien
tin
take
acco
rdin
gto
FFQ
,sel
f-re
port
ofsu
pple
men
talv
itam
inco
ntai
ning
folic
acid
begi
nnin
g3
mon
ths
befo
reco
ncep
tion
NT
Da ,
spin
abi
fida,
isol
ated
CPa
Shaw
etal
.,20
0255
Cas
e–co
ntro
l,18
60U
SC
ases
:mot
hers
ofin
fant
s/fe
tuse
sw
ith
aco
ngen
ital
anom
aly;
Con
trol
s:m
othe
rsof
liveb
orn
infa
nts
wit
hno
maj
orco
ngen
itala
nom
alie
s
Wom
en’s
repo
rtof
use
ofa
vita
min
supp
lem
ent
that
cont
aine
dfo
licac
idin
the
peri
od1
mon
thbe
fore
conc
epti
onth
roug
h3
mon
ths
afte
rco
ncep
tion
Con
otru
ncal
def
ects
,is
olat
edC
L,C
LP,
orC
P,N
TD
,lim
bd
efici
ency
def
ects
a
Tim
mer
man
set
al.,
2009
58Pr
ospe
ctiv
eco
hort
,635
3th
eN
ethe
rlan
ds
Preg
nant
wom
enSe
lf-r
epor
ted
folic
acid
supp
lem
ent
use
(0.4
–0.5
mg/
day)
duri
ngfir
st8
wee
ksof
preg
nanc
yL
BW
a ,SG
Aa ,
GA
,PT
D,
van
Bey
num
etal
.,20
1059
Cas
e–co
ntro
l,30
12th
eN
ethe
rlan
ds
Cas
es:m
othe
rsof
infa
nts
wit
his
olat
edor
com
plex
hear
td
efec
ts,w
itho
utan
yre
late
dsy
ndro
me
orge
neti
cab
norm
alit
y;C
ontr
ols:
mot
hers
ofin
fant
sw
ith
akn
own
chro
mos
omal
orge
neti
cd
efec
tor
wit
hot
her
non-
fola
tere
late
dco
ngen
ital
mal
form
atio
ns
Self
-rep
ort
offo
licac
idsu
pple
men
tati
on(�
400
mg/
day)
star
ting
atle
ast
4w
eeks
prio
rto
conc
epti
onan
dco
ntin
uing
upto
8w
eeks
ther
eaft
er
CH
Ds
van
Dri
elet
al.,
2008
60C
ase–
cont
rol,
281
the
Net
herl
and
sC
ases
:fam
ilies
wit
hch
ildre
nw
ith
aC
HD
;Con
trol
s:fa
mili
esw
ith
child
ren
wit
hout
aco
ngen
ital
mal
form
atio
nor
chro
mos
omal
abno
rmal
ity
Self
-rep
ort
ofpe
rico
ncep
tion
alus
eof
folic
acid
supp
lem
ents
and
com
plet
ion
ofa
valid
ated
FFQ
ond
ieta
ryfo
licac
idan
dvi
tam
inB
-2in
take
17m
onth
saf
ter
ind
expr
egna
ncy
CH
D
Vel
ieet
al.,
1999
61C
ase–
cont
rol,
859
US
Cas
es:m
othe
rsw
ith
NT
D-a
ffec
ted
infa
nts/
fetu
ses;
Con
trol
s:ra
ndom
lyse
lect
edno
n-m
alfo
rmed
infa
nts
Self
-rep
ort
ofpr
econ
cept
iona
luse
ofvi
tam
in,m
iner
al,a
ndfo
odsu
pple
men
tsan
dco
mpl
etio
nof
aFF
QN
TD
Vuj
kovi
cet
al.,
2007
63C
ase–
cont
rol,
381
the
Net
herl
and
sC
ases
:mot
hers
ofa
child
wit
hC
Lor
CL
P;C
ontr
ols:
mot
hers
ofno
n-m
alfo
rmed
child
ren
Mat
erna
lnut
riti
onal
inta
kes
asse
ssed
14m
onth
saf
ter
ind
exbi
rth
toes
tim
ate
prec
once
ptio
nin
take
CL
,CL
Pa
Wer
ler
etal
.,19
9364
Cas
e–co
ntro
l,30
78U
San
dC
anad
aC
ases
:mot
hers
ofin
fant
s/fe
tuse
sw
ith
NT
D;
Con
trol
s:m
othe
rsof
infa
nts/
fetu
ses
wit
hot
her
maj
orm
alfo
rmat
ion,
excl
udin
gO
FCs
Self
repo
rtof
mul
tivi
tam
inus
eco
ntai
ning
�2
vita
min
s,on
ew
hich
was
wat
erso
lubl
eta
ken
28da
ysbe
fore
and
afte
rco
ncep
tion
NT
Da
Yazd
yet
al.,
2007
65Pr
e–po
st,4
2083
2U
SW
omen
givi
ngbi
rth
in54
stat
esin
the
US
(and
DC
)Im
pact
offo
licac
idfo
rtifi
cati
on(p
revs
.pos
t-fo
rtifi
cati
on)
OFC
a
Yeh
and
Shel
ton,
2007
66R
etro
spec
tive
coho
rt,
1342
US
Wom
enw
hod
eliv
ered
live-
born
twin
sin
Wes
tern
upst
ate
New
York
Mat
erna
lpre
-pre
gnan
cyB
MI
(und
erw
eigh
t,no
rmal
,ove
rwei
ght,
obes
e)ba
sed
onin
form
atio
nfr
ombi
rth
cert
ifica
tes
mea
ntw
inB
W,G
A
a Rep
orte
dsi
gnifi
cant
asso
ciat
ions
.B
MI,
body
mas
sin
dex
;B
W,
Bir
thw
eigh
t;C
HD
,co
ngen
ital
hear
td
efec
ts;
CL
,cl
eft
lip;
CL
P,cl
eft
lipw
ith
clef
tpa
late
;C
P,cl
eft
pala
te;
FFQ
,fo
odfr
eque
ncy
ques
tion
nair
e;G
A,
gest
atio
nal
age;
IUG
R,
intr
aute
rine
grow
thre
stri
ctio
n;L
AZ
,len
gth-
for-
age
z-sc
ore;
LB
W,l
owB
irth
wei
ght;
LWZ
,len
gth-
for-
wei
ghtz
-sco
re;N
TD
,neu
ralt
ube
def
ects
;OFC
,oro
-fac
ialc
left
;PIH
,pre
gnan
cyin
duce
dhy
pert
ensi
on;P
TD
,pre
term
del
iver
y;R
CT,
rand
omis
edco
ntro
lled
tria
l;SG
A,s
mal
l-fo
r-ge
stat
iona
lage
;WA
Z,w
eigh
t-fo
r-ag
ez-
scor
e.
Periconceptual nutrition and maternal and infant outcomes 291
© 2012 Blackwell Publishing Ltd
Paediatric and Perinatal Epidemiology, 2012, 26 (Suppl. 1), 285–301
risk ratio (RR): 5.7 [95% CI 4.0–8.1] and 3.0 [95% CI2.2–4.1]] of pre-eclampsia. Ehrenthal et al.36 also foundthat prepregnancy BMI (based on self-report) waspositively associated with the risk of pregnancy-induced hypertension.
In a secondary analysis of a large prospectivecohort study, Bukowski et al.26 found no significantassociation between duration of preconceptionalfolate supplementation and the risk of pre-eclampsia(OR: 1.05 [95% CI 0.85, 1.31]) or placental abruption(OR: 0.80 [95% CI 0.55, 1.14]). In contrast, regularconsumption of multivitamin supplements duringthe periconceptional period was associated with a22% reduced risk of pre-eclampsia [hazards ratio(HR): 0.78 [95% CI 0.60, 0.99]] in a study usingdata from the Danish National Birth Cohort (1997–2003).29
Pregnancy loss
De Weerd et al.34 evaluated the relation between mater-nal periconceptional biochemical and haematologicalparameters and early pregnancy loss in a prospectivestudy of 240 women in the Netherlands. Women wererecruited before pregnancy and body weight mea-surements and blood samples were taken precon-ceptionally and at 6 and 10 weeks amenorrhea.Prepregnancy weight was positively associated withthe risk of early pregnancy loss (P < 0.05) but relation-ships with concentrations of several biomarkersof vitamin status were non-significant in this well-nourished population. In contrast, findings from anobservational study of Chinese women textile workerssuggest that preconception micronutrient statusmay be negatively associated with pregnancy loss.51,52
Ronnenberg et al.51 found that suboptimal preconcep-tion folate and vitamin B-6 status, especially whenthey occurred together, was associated with anincreased risk of clinical spontaneous abortion (P fortrend = 0.06 and 0.07, respectively) in a case–controlanalysis in which cases (n = 49) were women with aclinically recognised pregnancy who experienced afetal death before 100 days’ gestation and controls(n = 409) were women who maintained a pregnancythat ended in a livebirth. Ronnenberg et al.52 alsofound that compared with women in the lowest quar-tile of vitamin B-6 levels, those in the third and fourthquartiles were more likely to conceive (adjusted HR:2.2 [95% CI 1.3, 3.4], HR: 1.6 [95% CI 1.1, 2.3], respec-tively), and the risk of early pregnancy loss in concep-
tive cycles was lower in the fourth quartile (OR: 0.5[95% CI 0.3, 1.0]). This analysis was done in the sub-sample of 364 women who conceived at least onceduring the period 1996–1998. Liu et al.43 did not findany significant differences in the risk of stillbirth bycategories of prepregnancy BMI.
Five intervention trials33,38,39,42,44 evaluated the effectof periconceptional folic acid on miscarriages and/orstillbirths and found no significant differences. Thesetrials were conducted primarily in developed coun-tries among women at risk of delivering a child withNTD and have been described below. One trial thatwas conducted in Algeria, evaluated the effect ofproviding iodised oil in women either before orduring the first trimester of pregnancy and reporteda non-significant reduction in the incidence of still-births when compared with women who received nointervention.30
Birth defects
We found eight intervention trials20,31–33,38,39,42,44,62 and 14observational23–25,40,41,46,55–57,59–61,63–65 studies that evaluatedthe relationship between maternal preconceptual andpericonceptional nutrition and risk of birth defects,especially NTD. Czeizel et al.32,33 compared the risk ofNTD births among women receiving vitamin supple-ment (containing 0.8 mg folic acid) and those receiv-ing trace-element supplements daily from at least1 month before conception and until the date ofthe second missed menstrual period or later in arandomised controlled trial (RCT) among 7540Hungarian women (<35 years) and showed signifi-cant reductions (P < 0.05) in congenital malformations(13.3/1000 and 22.9/1000 in the vitamin and trace-element group, respectively) and the first time occur-rence of NTD (6 vs. 0 NTD cases in the trace-elementand vitamin supplement group). The MRC VitaminStudy Group44 also evaluated the effects of supple-mentation with folic acid or a mixture of seven othervitamins (A, D, B-1, B-2, B-6, C and nicotinamide)around the time of conception in a large multicenterdouble blind RCT of 1817 women in the UK andother countries and reported a 72% reduction in theincidence of NTDs in the folic acid group (RR: 0.28[95% CI 0.12, 0.71]) but no significant protective effectfor the other vitamins group (RR: 0.80 [95% CI 0.32,1.72]) when compared with a placebo. Interventiontrials in China, India and Ireland have shown similarresults.20,31,38,39
292 U. Ramakrishnan et al.
© 2012 Blackwell Publishing Ltd
Paediatric and Perinatal Epidemiology, 2012, 26 (Suppl. 1), 285–301
Observational studies have also shown the protec-tive effect of folic acid in reducing birth defects. Shawet al.56 found that women who consumed a folic acid-containing supplement in the 3 months before concep-tion had a lower risk of having an NTD-affectedpregnancy (OR: 0.65 [95% CI 0.45, 0.94]) when com-pared with non-users. Werler et al.64 also found thatdaily periconceptional intake of 0.4 mg of folic acidwas associated with a 60% reduction in the risk ofoccurrent NTDs in a case–control study where caseswere mothers of infants/fetuses with NTD whilecontrols consisted of mothers of infants/fetuses withother major malformation, excluding oro-facial clefts(OFC). The exposure was defined as consumption ofmultivitamin supplements containing �2 vitaminsincluding folic acid 28 days before and after concep-tion. In contrast, Bower and Stanley25 did not find anassociation between periconceptional vitamin supple-mentation and NTDs in a case–control study inAustralia. Recall bias and small sample size mayhave been limitations. We also found a case–controlstudy61 in which higher preconceptional zinc intakewas associated with a reduced risk for NTD(quintile 5 vs. quintile 1, OR: 0.65 [95% CI 0.43, 0.99])cases were 430 NTD-affected fetuses/infants, andcontrols were 429 randomly selected non-malformedinfants.
A few studies have examined the relationshipbetween preconceptional nutrition and other birthdefects such as cleft palate and congenital heart defects(CHD). Vujkovic et al.63 assessed maternal preconcep-tional nutritional intakes in a case–control study of 203mothers of a child with a cleft lip or cleft palate and178 mothers with non-malformed offspring and foundthat the Western dietary pattern, for example, high inmeat, pizza, legumes and potatoes, and low in fruits,was associated with a high risk of a cleft lip or cleftpalate (OR: 1.9 [95% CI 1.2, 3.1]). Bower et al.24 foundno association between folic acid supplement useduring the periconceptional period and risk of birthdefects other than NTD. Cases were women whoseinfants had OFC (n = 62), CHD (n = 151), urinarytract defects (n = 117), limb reduction defects (n = 26)or other major birth defects (n = 119). There were 578control women. Van Driel et al.60 in a case–controlstudy of Dutch women also found no significant dif-ferences in periconceptional use of folic acid supple-ments and dietary intakes of total energy, folate, andvitamin B-2 between case (infants with CHD) andcontrol-mothers, but reported a significant interaction
between genetics and folic acid supplement useduring the periconceptional period (P = 0.008); theOR [95% CI] of the mothers carrying the MTHFR ACand CC genotypes in the supplemented vs. the non-supplemented group was 1.8 [95% CI 1.01–3.1] vs. 0.6[95% CI 0.3–1.1], respectively. A case–control study inthe Netherlands40,41 also showed a trend towards riskreduction for OFC with increasing dietary intake ofthiamine (P = 0.04) and pyridoxine (P = 0.03) amongwomen who consumed folic acid supplements peri-conceptionally. Finally, Yazdy et al.65 reported a signifi-cant decline in OFC prevalence following folic acidfortification (prevalence risk: 0.94 [95% CI 0.92, 0.96])based on retrospective cohort analysis of US birthcertificate data from 45 states and the District ofColumbia in which births were compared during thepre-fortification period (January 1990–December 1996)and post-fortification period (October 1998–December2002).
Birth size
We identified two intervention trials30,33 and 14 obser-vational studies26,27,34,35,37,43,45,47,48,50,53,54,58,66 that examinedthe relationship between prepregnancy and/or peri-conceptual nutrition and birth size. Chaouki andBenmiloud30 evaluated the benefits of providing oraliodised oil to women just before conception or duringthe first trimester in a study conducted in a region ofendemic goiter in Algeria. The offspring of treatedwomen (n = 1536) had significantly higher birth-weight (+6.25%) when compared with non-treatedwomen. Czeizel et al.33 found no significant differ-ences in the risk of LBW when they compared womenwho received folic acid containing supplementsbefore 12 weeks gestation with those who received asupplement containing only trace elements (copper,manganese and zinc) and vitamin C. Mean birth-weight was much higher in both groups comparedwith the general population.
Several observational studies have examined theassociation with maternal nutritional status based onanthropometric measurements such as weight andheight and/or vitamin supplement use during thepericonceptional period and birth size. Liu et al.43
reported an increased risk of delivering a SGA infant(adjusted RR: 1.7 [95% CI 1.1, 2.6]) among under-weight women (BMI < 18.5 kg/m2) in a retrospectivestudy of Chinese women. Ronnenberg et al.53 reportedsimilar findings in a prospective cohort study that
Periconceptual nutrition and maternal and infant outcomes 293
© 2012 Blackwell Publishing Ltd
Paediatric and Perinatal Epidemiology, 2012, 26 (Suppl. 1), 285–301
examined the relationship between pre-pregnancyBMI and birth outcomes among 20- to 34-year-oldChinese women (n = 575); infants born to motherswho were underweight before pregnancy (BMI �
18.5 kg/m2) were at increased risk for fetal growthdeficits. Being underweight was also associated withsmaller infant head circumference and lower ponderalindex. Prepregnancy weight (P < 0.01; partial r2 = 0.24)was positively associated with infant birthweight in aprospective study of 240 women in whom measure-ments were obtained preconceptually in the Nether-lands.34 Most recently, a large prospective studyfrom Vietnam47 also reported a significantly higherrisk of delivering a SGA infant (adjusted OR: 1.95 [95%CI 1.52–2.50], P < 0.01) among women who wereunderweight before conception (BMI < 18.5 kg/m2)compared with those with BMI between 18.5 and23.0 kg/m2. There were no significant differences forthe group with higher BMI (>23 kg/m2). Similarly, nosignificant differences were reported in the risk ofLBW (OR: 0.57 [95% CI 0.29, 1.14]) by maternal over-weight (BMI � 27 kg/m2) in a retrospective study ofThai women.48
Ronnenberg et al.54 also assessed the associationbetween preconception anaemia and iron statusand infant growth and pregnancy outcomes andfound that preconception anaemia, particularlyiron-deficiency anaemia, was associated with reducedinfant growth (lower birthweight). The risks ofLBW and fetal growth restriction (defined as <85%of a birthweight ratio calculated as the observedbirthweight*100/mean birthweight of infants with thesame gestational age within the cohort) were signifi-cantly greater among women with moderate anaemiacompared with non-anaemic controls (OR: 6.5 [95%CI 1.6, 26.7], P = 0.009 and OR: 4.6 [95% CI 1.5, 13.5],P = 0.006, respectively). A few studies, primarily indeveloped countries have also examined the relation-ship between periconceptional multivitamin use andbirth size. In a retrospective cohort study of non-Hispanic white (n = 2331) and non-Hispanic black(n = 133) mother–infant pairs, Burris et al.27 assessedthe association of maternal periconceptional multivita-min use and infant birthweight disparities betweeninfants delivered by whites and those delivered bytheir African American women counterparts. Multivi-tamin use was associated with a 536 g increasedbirthweight (P = 0.001) among African Americans; noassociation between multivitamin use and birthweightor gestational age was found among white subjects.
This study used a more restrictive definition of peri-conceptional as the period between 28 days prior tothe date of the last menstrual period to 28 days afterlast menstrual period. In a population-based prospec-tive cohort study, Timmermans et al.58 evaluated theimpact of self-reported folic acid supplement (0.4–0.5 mg/day) and found that periconceptional folicacid supplementation (<8 weeks of gestation) wasassociated with higher placental (13 g [95% CI 1.1,25.5]) and birthweight (68 g [95% CI 37.2, 99.0]);reduced risks for LBW (OR: 0.43 [95% CI 0.28, 0.69])and SGA (OR: 0.40 [95% CI 0.22, 0.72]) were observedfor women who started supplementation preconcep-tionally, compared with those who did not usefolic acid. A significant interaction by parity was alsoobserved, with larger differences in birthweight bysupplement use among multiparous compared withnulliparous women. The adjusted risk for a SGA birthwas also significantly reduced among regular usersof multivitamins during the periconceptional period(<12 weeks gestation) regardless of their prepreg-nancy BMI (HR: 0.83 [95% CI 0.73, 0.95]) comparedwith non-users in the Danish National Birth CohortStudy (n = 35 897).28
Preterm delivery/gestational age
We found two intervention trials30,33 and 11 observa-tional studies26–28,37,43,48–50,53,54,58,66 that examined the rela-tionship between preconceptual or periconceptionalnutrition and gestational age and/or risk of PTD.There were no significant differences in the incidenceof PTD in the large intervention trial in Hungary thatexamined the benefits of providing folic acid contain-ing supplements before 12 weeks of gestation, butboth groups received other micronutrients like zinc.Chaouki and Benmiloud30 found no differences inPTD among women who received iodised oil duringthe first trimester of pregnancy.
Rayco-Solon et al.49 evaluated the effect of pre-conceptional undernutrition among rural Gambianwomen who experience annual fluctuations in energybalance and found significantly shorter gestationalages for pregnancies conceived in September toNovember (when lower weights are recorded) thanthose from better-fed months (38.6 vs. 39.0 weeks;log-rank c2 = 17.4, P < 0.0001). Data were obtained pro-spectively in this study. Liu et al.43 obtained measuresof body size (weight and height) before 12 weeks ges-tation from health records and found that the adjusted
294 U. Ramakrishnan et al.
© 2012 Blackwell Publishing Ltd
Paediatric and Perinatal Epidemiology, 2012, 26 (Suppl. 1), 285–301
odds of early PTD (<34 weeks) was significantlyelevated (RR: 3.4 [95% CI 1.2, 9.4]) among obesewomen (BMI > 28 kg/m2) when compared withnormal weight women (18.5 < BMI < 24); there wereno differences in the risk of PTD (<37 weeks) bymaternal prepregnancy size in contrast to findingsfrom earlier observational studies.37,48,53,58,86–88 Hanet al.37 found that high pre-pregnancy maternal BMI(>25 kg/m2) increased the risk of PTD (OR: 2.85 [95%CI 1.20, 6.74]) in a study of Korean women.
Using a case–control design, Ronnenberg et al.50
found that elevated homocysteine (�12.4 mmol/L)during the preconceptional period was associatedwith a higher risk of PTD (OR: 3.6 [95% CI 1.3, 10.0],P < 0.05). The risk of PTD was also 60% lower amongwomen with serum vitamin B-12 �258 pmol/L thanamong vitamin B-12-deficient women (OR: 0.4 [95% CI0.2, 0.9], P < 0.05). Similar reductions were seen withamong vitamin B-6-deficient women (OR: 0.5 [95% CI0.2, 1.2]), but they were not statistically significant.Folate status was not associated with PTD. In contrast,Bukowski et al.26 reported that preconceptional folatesupplementation that was prospectively recorded inthe first trimester of pregnancy was associated withsignificant reductions in the incidence of early sponta-neous PTD (HR: 0.22 [95% CI 0.08, 0.61], P = 0.004).Regular periconceptional multivitamin use was associ-ated with reduced risk of PTD in non-overweightwomen (HR: 0.84 [95% CI 0.73, 0.95]) who participatedin the Danish Birth Cohort Study.28 We did not findany reports of controlled trials in developing countrypopulations where there is greater risk of inadequatenutrient intakes.
Comments
The majority of studies identified in our review wereobservational with few well-designed interventiontrials. The overall quality of evidence was low formost outcomes with the exception of the benefits ofmaternal preconception folic acid for reducing therisk of NTD, which was high (Table 2) and based onseveral well-designed intervention trials. The mostrecent meta-analysis by De-Regil et al.89 that includedfive intervention trials32,33,38,39,42,44 confirmed the find-ings of an earlier review18 that estimated a 72% reduc-tion in the risk of NTD (RR: 0.28 [95% CI 0.13, 0.58]).These findings have led to recommendations promot-ing the use of supplements and/or fortified foodscontaining folic acid by women of reproductive age
(WRA) in many countries. The universal fortificationof staple foods such as flour and ready-to-eat cerealsin countries such as the US, Canada, Chile and CostaRica has been linked to significant reductions in theincidence of NTD in these countries.90,91 Some ofthe studies we reviewed also suggest that increasedintakes of folic acid and other nutrients are asso-ciated with reduced risk of other congenital birthdefects.40,41,63,65 Unpublished findings based onfollow-up of offspring in the SINO-US NTD preven-tion project have shown that daily consumption of400 mg of folic acid during the periconceptional periodwas associated with reduced infant mortality amonginfants without major birth defects (RR = 0.78 [95% CI0.72, 0.85]) and improved linear growth.92,93 Therewere no differences in behaviour and cognitive devel-opment during early childhood in the same studypopulation94,95 in contrast to a recent study in whichmaternal consumption of supplements containingfolic acid during the periconceptional period (4 weeksbefore pregnancy to <8 weeks gestation) was associ-ated with a significant reduction (20%) in the risk ofmoderate language delay among the offspring (single-ton non-intrauterine growth restriction) at 3 years ofage in a Norwegian birth cohort.96 Finally, no benefitwas reported in a recent meta-analysis of four trialsthat examined the effects of were periconceptual folicacid supplementation on stillbirths (RR: 0.96 [95% CI0.51, 1.83]); all trials were conducted among womenwith a history of NTD in a previous pregnancy.89
Overall, we found few studies from develop-ing country settings where maternal malnutrition iscommon. Short interpregnancy interval, which has thepotential to result in maternal depletion of nutrientsincluding folate, iodine and iron, has been associatedwith increased risk of adverse outcomes such as fetalgrowth restriction and developmental abnormali-ties.13,14 For example, severe iodine deficiency duringpregnancy has been associated with adverse preg-nancy outcomes including cretinism97 and althoughwe found a few intervention studies30,69,74 that suggestthat providing iodine during early pregnancy towomen living in iodine deficient areas improve birthsize, we had to exclude some of them because theexact nature and timing of the intervention wasunclear. Universal salt iodisation has been a successfulstrategy towards the elimination of iodine deficiencydisorders but the importance of iodine in settingswhere mild-moderate iodine deficiency exists has notbeen studied adequately and appropriate intervention
Periconceptual nutrition and maternal and infant outcomes 295
© 2012 Blackwell Publishing Ltd
Paediatric and Perinatal Epidemiology, 2012, 26 (Suppl. 1), 285–301
Tab
le2.
Qua
lity
asse
ssm
ent
and
sum
mar
yof
find
ings
No.
ofst
udie
sSt
udy
des
ign
Qua
lity
asse
ssm
ent
Qua
litat
ive
sum
mar
yof
find
ings
Lim
itati
ons
Con
sist
ency
Gen
eral
isab
leto
reso
urce
-poo
rpo
pula
tion
sG
ener
alis
able
toin
terv
enti
onof
inte
rest
Pre
-ecl
amp
sia:
over
all
qu
alit
yof
evid
ence
=ve
rylo
w4
Thre
epr
ospe
ctiv
eco
hort
,on
ere
tros
pect
ive
coho
rtU
ncle
arif
mea
sure
sof
expo
sure
wer
ere
stri
cted
topr
econ
cept
ion
and
/or
the
first
trim
este
rof
preg
nanc
yon
ly;
noin
terv
enti
ontr
ials
No
US,
Den
mar
kan
dov
erw
eigh
tTh
aiw
omen
atri
skfo
rge
stat
iona
ldia
bete
s;C
hina
Two
stud
ies
exam
ined
peri
conc
epti
onal
mul
tivi
tam
inus
e.O
neof
two
larg
est
udie
ssh
owed
redu
ctio
nsin
pre-
ecla
mps
iain
mul
tivi
tam
inus
ers;
one
stud
yfr
omC
hina
show
edpo
siti
veas
soci
atio
nsw
ith
over
wei
ght
Two
stud
ies
exam
ined
prep
regn
ancy
BM
I.
Pre
gnan
cylo
ss:o
vera
llq
ual
ity
ofev
iden
ce=
low
10Si
xin
terv
enti
ontr
ials
Blin
din
gun
clea
rfo
rso
me
tria
ls;
stud
ies
amon
gw
omen
wit
hhi
stor
yof
NT
D
No
Alg
eria
(hig
hri
skof
end
emic
goit
er)
Iod
ised
oil.
No
sign
ifica
ntd
iffe
renc
esfo
rin
still
birt
h
Irel
and,
Hun
gary
,UK
,Ind
iaan
dC
hina
Five
ofsi
xst
udie
spr
ovid
edm
ulti
vita
min
sco
ntai
ning
folic
acid
.
Four
obse
rvat
iona
lstu
die
sR
ecal
land
sele
ctio
nbi
asth
eN
ethe
rlan
ds,
Chi
naB
iom
arke
rsof
nutr
itio
nals
tatu
s(w
ater
solu
ble
vita
min
san
dir
on)
insa
mpl
esco
llect
edju
stbe
fore
and
/or
inea
rly
preg
nanc
y.
One
pros
pect
ive
stud
yin
Chi
nafo
und
asso
ciat
ions
betw
een
vita
min
stat
usan
dpr
egna
ncy
loss
whe
reas
the
one
from
Net
herl
and
sfo
und
noas
soci
atio
ns.
•Tw
opr
ospe
ctiv
eco
hort
•O
nere
tros
pect
ive
coho
rt
•O
neca
se–c
ontr
olPr
epre
gnan
cyB
MI.
One
stud
ysh
owed
nod
iffe
renc
esin
still
birt
hby
mat
erna
lBM
I.B
irth
def
ects
:ove
rall
qu
alit
yof
evid
ence
=h
igh
22E
ight
inte
rven
tion
tria
lsYe
sIr
elan
d,H
unga
ry,U
K,I
ndia
,C
hina
Prec
once
ptio
nalu
seof
supp
lem
ents
cont
aini
ngfo
licac
idw
ith
othe
rm
icro
nutr
ient
s
72%
redu
ctio
nin
NT
Dam
ong
wom
enw
hoco
nsum
edfo
licac
idco
ntai
ning
supp
lem
ents
duri
ngth
epe
rico
ncep
tion
alpe
riod
14C
ase–
cont
rol
Rec
allb
ias
and
smal
lsam
ple
size
for
som
est
udie
sM
any
stud
ies
inN
orth
Am
eric
a,E
urop
e,A
ustr
alia
,and
Chi
naR
egul
arus
eof
mul
tivi
tam
insu
pple
men
ts,
die
tary
inta
kes,
folic
acid
fort
ifica
tion
Mix
edfin
din
gsw
ith
sugg
esti
onof
bene
fitof
NT
Dan
dot
her
birt
hd
efec
tsas
wel
lB
irth
wei
ght
(g):
over
all
qu
alit
yof
evid
ence
=lo
w7
Two
inte
rven
tion
tria
lsB
lind
ing
uncl
ear
for
stud
yin
Alg
eria
and
allo
cati
onw
asbr
oken
earl
yin
Hun
gari
anR
CT
No
Alg
eria
(has
end
emic
goit
er),
Hun
gary
(low
risk
ofd
efici
enci
es)
Iod
ised
oil.
Sign
ifica
ntly
high
erbi
rthw
eigh
tfo
rio
din
ebu
tno
dif
fere
nces
for
mul
tivi
tam
ingr
oup
but
cont
rolg
roup
also
rece
ived
sele
cted
nutr
ient
s(C
u,Z
n,Ir
onan
dM
g)M
ulti
vita
min
supp
lem
ents
cont
aini
ngfo
licac
idan
dse
vera
loth
ervi
tam
ins.
Five
obse
rvat
iona
lstu
die
sE
xpos
ures
vari
edfr
ompr
epre
gnan
cybo
dysi
zeto
mic
ronu
trie
ntst
atus
No
the
Net
herl
and
s,U
S,C
hina
,Ir
elan
dSt
udie
sex
amin
edbl
ood
test
s,su
pple
men
tati
on(f
olic
acid
,mul
tipl
em
icro
nutr
ient
)an
dpr
e-pr
egna
ncy
BM
I
Und
erw
eigh
tis
posi
tive
lyas
soci
ated
wit
hbi
rthw
eigh
t•
Thre
epr
ospe
ctiv
eco
hort
•Tw
ore
tros
pect
ive
coho
rtL
BW
(<25
00g)
:ove
rall
qu
alit
yof
evid
ence
=lo
w6
One
inte
rven
tion
tria
lA
lloca
tion
was
brok
enea
rly
inH
unga
rian
RC
TN
oH
unga
ry(l
owri
skof
defi
cien
cies
)M
ulti
vita
min
supp
lem
ents
cont
aini
ngfo
licac
idan
dse
vera
loth
ervi
tam
ins
No
sign
ifica
ntd
iffe
renc
es
Five
obse
rvat
iona
lstu
die
sR
ecal
land
sele
ctio
nbi
ases
peci
ally
inre
tros
pect
ive
stud
ies.
No
Kor
ea,T
haila
nd,N
ethe
rlan
ds,
Chi
naB
iom
arke
rsof
nutr
itio
nals
tatu
s,pr
econ
cept
iona
lmul
tivi
tam
insu
pple
men
tus
ean
dpr
e-pr
egna
ncy
BM
I
All
pros
pect
ive
stud
ies
sugg
est
bene
fitof
peri
conc
epti
onal
mic
ronu
trie
ntst
atus
orsu
pple
men
tus
e•
Thre
epr
ospe
ctiv
eco
hort
•Tw
ore
tros
pect
ive
coho
rtE
xpos
ures
vari
edfr
ompr
epre
gnan
cybo
dysi
zeto
mic
ronu
trie
ntst
atus
.S
GA
:ove
rall
qu
alit
yof
evid
ence
=lo
w8
Five
pros
pect
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for-
gest
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ge.
296 U. Ramakrishnan et al.
© 2012 Blackwell Publishing Ltd
Paediatric and Perinatal Epidemiology, 2012, 26 (Suppl. 1), 285–301
in WRA may have the potential to improve MNCHoutcomes. Several intervention trials have also shownthat the provision of weekly iron-folic acid supple-ments to WRA in developing country populations canimprove iron status and reduce the risk ofanaemia73,75,76,78–80,82 but few have evaluated the benefitsof these interventions for pregnancy outcomes. This isa major gap given the high prevalence of iron defi-ciency and anaemia in WRA (before and during preg-nancy) in many developing countries and ourunderstanding of the mechanisms that suggest thatiron status during the periconceptual period may beas important as iron status during the latter half ofpregnancy for improving MNCH outcomes.3 Wefound only one observational study that showed thatanaemia during the preconception period in WRA isassociated with increased risk of unfavourable preg-nancy outcomes and reduced infant growth.54 Themajor cause of anaemia is iron deficiency, however,deficiencies of other micronutrients such as folate,vitamins B-6 and B-12 can also cause anaemia, indicat-ing that the inclusion of these nutrient may be benefi-cial. Periconceptional anaemia may influence thesynthesis of hormones and thus adversely affectinfant growth.3,98 The current review, including mostlyobservational studies in developed countries, suggeststhat preconceptional and periconceptional intake ofvitamin and mineral supplements or dietary intake ofsuch nutrients may reduce the risk of adverse out-comes such as PTD and LBW.
We found few well-designed studies that carefullyexamined the relationship between maternal size andbody composition during the periconceptional periodwith adverse pregnancy outcomes such as stillbirth,PTD and LBW. Recent reviews and meta-analyseshave concluded that balanced protein-energy supple-mentation during pregnancy was associated withreduced stillbirth rates and LBW, but none of thestudies examined the effect of these interventionsbefore and during the first trimester of pregnancy.99
Several observational studies especially in developedcountries have examined the relationship betweenmaternal BMI and adverse pregnancy outcomes, butmost of them used data that were obtained after deliv-ery or based on medical records obtained duringpregnancy making it difficult to ascertain the qualityof the data and exact timing of measurement.12,86,88,100
Nevertheless, these studies do suggest that over-weight and/or obesity is associated with increasedrisk of pregnancy complications such as gestational
diabetes and hypertensive disorders which in turninfluence subsequent maternal and child health andwell-being.87 The Institute of Medicine, which recentlyrevised the US guidelines for gestational weight gain(GWG) based on the concerns about the obesity epi-demic, also concluded that the risk of SGA wasgreater among women who had low GWG and lowprepregnancy BMI and that there was strong evidenceof a U shaped relationship between low GWG andPTD in normal and underweight women.11 Thesefindings have important policy implications forindustrialised countries such as the US as well ascountries like Mexico that are facing the dual burdenof malnutrition, that is, undernutrition that manifestsas stunting during early childhood and contributesto short maternal stature combined with overweightas a result of the nutrition transition. Careful examina-tion of the relationship between prepregnancy bodysize and composition and MNCH outcomes in devel-oping country settings using well-designed prospec-tive cohort studies is needed to develop appropriateinterventions.
Overall, the paucity of intervention trials, especiallyin developing country settings is striking. The major-ity of the studies in our review were observational indesign, which make inferences of causality difficultespecially when the exposure was based on maternalrecall. Only a third of the studies measured the expo-sure, that is, nutritional status and/or intakes usinga prospective cohort study design. Key limitationsinclude the inability to determine if the outcomes arespecifically the result of preconceptional supplementa-tion because women who consumed nutrient supple-ments before and during early pregnancy continuedto take them through delivery, recall bias (in the caseof retrospective studies) and differences in the timingof exposure. There is no clear definition of the ‘peri-conceptional’ period; we used <12 weeks, that is, firsttrimester which has been used by others and typicallyin many settings especially developing countries,most women do not identify and/or seek antenatalcare before 12 weeks. Some studies clearly state thatthey measured nutrient intakes and/or status beforepregnancy (maternal recall or prospectively) but thepericonception period ranged from 1 month prior tothe last menstrual period to 4 to 12 weeks of gestation.We also excluded several studies because they eitherused a slightly different definition, namely <16 or 20weeks gestation, and/or the timing of the interventionwas not clear.
Periconceptual nutrition and maternal and infant outcomes 297
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In summary, there is evidence supporting theimportance of nutritional status before and duringearly pregnancy to reduce the risk of adverse preg-nancy outcomes especially birth defects and to a lesserextent, PTD and LBW. Little is known about outcomessuch as stillbirths and maternal and infant mortality.The limited available evidence suggests improvingprepregnancy maternal nutritional status will improveMNCH outcomes, although there are emerging con-cerns of overweight and obesity. There is a need forRCTs that evaluate the benefits of preconceptionalnutritional interventions to confirm the findings fromobservational studies. These studies will need largesample sizes and should evaluate interventions suchas providing supplements that contain nutrients suchas iron, zinc, iodine and/or a combination of severalmicronutrients in addition to providing folic acid,targeted use of fortified foods and or behaviourmodification to improve intakes. The dissemination ofmessages about the importance of a healthy diet andlifestyle before and during pregnancy along with mes-sages about family planning that address timing andspacing of pregnancies have the potential to optimiseMNCH outcomes in many settings. Evaluation ofinnovative approaches such as counselling newlywed mothers101 is also lacking and will help guideprogramme implementation.
Conflicts of interest
The authors declare no conflicts of interests.
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