Usha Et Al-2012-Paediatric and Perinatal Epidemiology

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]

bs_bs_banner

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.



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



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.




Tab

le1.

Des

crip

tion

ofin

terv

enti

onan

dob

serv

atio

nals

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ies

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rico

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tion

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and

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erna

land

child

heal

thou

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es

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tion

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rven

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mes

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rven

tion

tria

lsB

erry

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9920

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mun

ity-

base

din

terv

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on,2

4783

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hina

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enpr

epar

ing

for

mar

riag

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houn

der

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phys

ical

exam

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and

wer

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ter

regi

ster

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ith

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onit

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stem

that

reco

rds

pren

atal

care

and

del

iver

y

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lysu

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men

tco

ntai

ning

400

mgfo

licac

idN

TD

a

Cha

ouki

and

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milo

ud,1

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mun

ity-

base

din

terv

enti

on,1

536

Alg

eria

Wom

enw

how

ere

plan

ning

tobe

preg

nant

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liod

ised

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fore

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epti

onor

duri

ngth

efir

sttr

imes

ter

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birt

hs,B

Wa ,

PTD

Che

net

al.,

2008

31C

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unit

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rven

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043

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part

icip

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-up

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lem

ent,

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aini

ng23

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icro

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ents

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lud

ing

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acid

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TD

a

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etal

.,19

92,

1994

32,3

3R

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7540

Hun

gary

Wom

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35ye

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plan

ning

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(in

mos

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ses

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rfir

st)

who

qual

ified

for

the

Hun

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Plan

ning

Prog

ram

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lin

1984

Vita

min

supp

lem

ent

(con

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12vi

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give

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ned

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ild

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urre

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TD

a ,ea

rly

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nanc

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h

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al.,

1992

39D

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4Ir

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ant

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han

NT

Dan

dpl

anne

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her

child

Folic

acid

supp

lem

ent,

mul

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folic

acid

plus

mul

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tam

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for

�2

mon

thpr

ior

toco

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isse

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Rec

urre

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al.,

1981

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T,11

1W

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Non

-pre

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tw

omen

(<35

year

s)w

hoha

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da

prev

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preg

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Med

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itam

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144

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rand

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ind

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1817

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Folic

acid

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birt

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/da

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tle

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anon

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fore

conc

epti

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tilt

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thw

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ofpr

egna

ncy

Rec

urre

nce

ofN

TD

a

Ob

serv

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nal

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die

sB

itsk

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al.,

2007

23C

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cont

rol,

395

US

Cas

es:m

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fetu

ses

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rela

ted

maj

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clud

ing

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00mg

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acid

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wee

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ally

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nts

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ns

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-rep

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ifica

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-rep

ort

ofvi

tam

insu

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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

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licac

id(6

mon

ths

befo

repr

egna

ncy)

Bir

thd

efec

tsot

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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

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r)of

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once

ptio

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men

tati

onw

ith

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itho

utm

ulti

vita

min

s(�

1ye

aran

d<1

year

)

Pre-

ecla

mps

ia,S

GA

,PT

Da




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




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.




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




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




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




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




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

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lstu

die

sR

ecal

land

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ctio

nbi

asth

eN

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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.

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opr

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ctiv

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nere

tros

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iffe

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idw

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rm

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nutr

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72%

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Dam

ong

wom

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licac

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ning

supp

lem

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ncep

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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

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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

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dot

her

birt

hd

efec

tsas

wel

lB

irth

wei

ght

(g):

over

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alit

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=lo

w7

Two

inte

rven

tion

tria

lsB

lind

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uncl

ear

for

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yin

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allo

cati

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asbr

oken

earl

yin

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gari

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CT

No

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eria

(has

end

emic

goit

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Hun

gary

(low

risk

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ised

oil.

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ifica

ntly

high

erbi

rthw

eigh

tfo

rio

din

ebu

tno

dif

fere

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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

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min

supp

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ents

cont

aini

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dse

vera

loth

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ins.

Five

obse

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iona

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vari

edfr

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the

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and

s,U

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hina

,Ir

elan

dSt

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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•

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epr

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tros

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coho

rtL

BW

(<25

00g)

:ove

rall

qu

alit

yof

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ence

=lo

w6

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inte

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lloca

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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

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ethe

rlan

ds,

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naB

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itio

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tatu

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tus

ean

dpr

e-pr

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BM

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All

pros

pect

ive

stud

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sugg

est

bene

fitof

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conc

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epr

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rtE

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ronu

trie

ntst

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GA

:ove

rall

qu

alit

yof

evid

ence

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w8

Five

pros

pect

ive

coho

rt,

Rec

alla

ndse

lect

ion

bias

espe

cial

lyin

retr

ospe

ctiv

est

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s.N

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hina

,Vie

tnam

,US,

Net

herl

and

s,D

enm

ark

Stud

ies

exam

ined

bloo

dte

sts,

supp

lem

enta

tion

(fol

icac

id,m

ulti

ple

mic

ronu

trie

nt)

and

pre-

preg

nanc

yB

MI

Peri

conc

epti

onal

use

ofm

ulti

vita

min

supp

lem

ents

isas

soci

ated

wit

hre

duce

dri

skof

SGA

ind

evel

oped

coun

trie

s.Th

ree

retr

ospe

ctiv

eco

hort

Vary

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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.




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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