Maternal Multiple Micronutrient Supplements and Child Cognition - Krissaesha

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DOI: 10.1542/peds.2012-0412; originally published online August 20, 2012;2012;130;e536PediatricsAnuraj H. Shankar

Elizabeth L. Prado, Katherine J. Alcock, Husni Muadz, Michael T. Ullman andRandomized Trial in Indonesia

Maternal Multiple Micronutrient Supplements and Child Cognition: A

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Maternal Multiple Micronutrient Supplements and ChildCognition: A Randomized Trial in Indonesia

WHAT

S KNOWN ON THIS SUBJECT:Micronutrients are essentialfor brain development during gestation and infancy. Fewrandomized trials of maternal multiple micronutrientsupplementation during pregnancy and postpartum haveexamined child outcomes beyond the neonatal period or testedwhich cognitive domains show long-term effects.

WHAT THIS STUDY ADDS:Children of undernourished mothersgiven multiple micronutrients performed as well as children of well-nourished mothers in motor and visual attention/spatialability at age 42 months; children of undernourished mothersgiven iron/folic acid showed 4- to 5-month delays in theseabilities.

abstractOBJECTIVES:We investigated the relative bene t of maternal multiplemicronutrient (MMN) supplementation during pregnancy and until 3months postpartum compared with iron/folic acid supplementationon child development at preschool age (42 months).

METHODS:We assessed 487 children of mothers who participated in the Supplementation with Multiple Micronutrients Intervention Trial, acluster-randomized trial in Indonesia, on tests adapted and validated in the local context measuring motor, language, visual attention/spatial,executive, and socioemotional abilities. Analysis was according tointention to treat.

RESULTS: In children of undernourished mothers (mid-upper armcircumference , 23.5 cm), a signi cant bene t of MMNs was observedon motor ability (B = 0.39 [95% con dence interval (CI): 0.08 0.70]; P =.015) and visual attention/spatial ability (B = 0.37 [95% CI: 0.11 0.62];P = .004). In children of anemic mothers (hemoglobin concentration, 110 g/L), a signicant bene t of MMNs on visual attention/spatialability (B = 0.24 [95% CI: 0.02 0.46]; P = .030) was also observed. Norobust effects of maternal MMN supplementation were found in anydevelopmental domain over all children.

CONCLUSIONS:When pregnant women are undernourished or anemic,provision of MMN supplements can improve the motor and cognitiveabilities of their children up to 3.5 years later, particularly for bothmotor function and visual attention/spatial ability. Maternal MMNbut not iron/folic acid supplementation protected children from thedetrimental effects of maternal undernutrition on child motor andcognitive development. Pediatrics 2012;130:e536 e546

AUTHORS:Elizabeth L. Prado, PhD,a ,b ,c Katherine J. Alcock,DPhil,b Husni Muadz, PhD,a ,d Michael T. Ullman, PhD,e andAnuraj H. Shankar, DSc, a ,f for the SUMMIT Study Groupa SUMMIT Institute of Development, Mataram, Indonesia; b Department of Psychology, Lancaster University, Lancaster,United Kingdom; c University of California at Davis Program in International and Community Nutrition, Davis, California; d Mataram University Center for Research on Language and Culture, Mataram, Indonesia; e Georgetown University Brain and Language Laboratory, Department of Neuroscience, Washington,DC; and f Department of Nutrition, Harvard University School of Public Health, Cambridge, Massachusetts

KEY WORDSchild development, cognitive development, international publichealth, maternal health, maternal nutrition, motor development,multiple micronutrient supplementation

ABBREVIATIONSHb hemoglobinIFA iron/folic acidMMN multiple micronutrientMUAC mid-upper arm circumferenceSUMMIT Supplementation with Multiple Micronutrients Inter-vention Trial

Dr Prado designed and supervised the developmental assessment,cleaned and analyzed the developmental data, and produced therst draft of the paper, as well as subsequent drafts andadditional analyses. Dr Prado and Dr Alcock were joint principalinvestigators of the preschool child development follow-up study.

Dr Alcock designed the developmental assessment battery withDr Prado and advised on the training of the assessors. These dataformed part of Dr Prado s doctoral thesis at Lancaster University.Dr Alcock supervised Dr Prado s doctoral studies, advised onanalysis and interpretation of the data, and contributed to themanuscript. Dr Shankar was the principal investigator of theSupplementation with Multiple Micronutrients Intervention Trial(SUMMIT) study. He designed the protocols and directed andcoordinated execution of the study. Dr Shankar helped with eldand data management of the preschool developmentalassessment and contributed to analysis and interpretation of thedata and preparation of the manuscript. Dr Muadz contributed to the design and adaptation of the developmental assessment to thelocal context and helped with the eld logistics and datamanagement of the developmental assessment. Dr Ullman advised

on the design of the developmental assessment, contributed toanalysis and interpretation of the data, and co-wrote sections of the paper with Dr Prado. All individual authors critiqued themanuscript and approved the nal report. The SUMMIT StudyGroup designed and executed the SUMMIT study.

This trial has been registered with the ISRCTN Register ( http://isrctn.org ) (identi er ISRCTN34151616).

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doi:10.1542/peds.2012-0412

Accepted for publication May 14, 2012

(Continued on last page)

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Micronutrients are necessary for braindevelopment during gestation and in-fancy. These are important periods for the formation of the brain, laying thefoundation for the development of cog-nitive, motor, and socioemotional skills

throughout childhood and adulthood.Children with restricted development of these skills during early life are at risk for later neuropsychological problems,poor school achievement, low-skilledemployment, and poor care of theirown children, thus contributing to theintergenerational transmission of po-verty. 1,2 More than 200 million childrenaged , 5 years in low- and middle-income countries, at a conservative

estimate, are not reaching their devel-opmental potential in these areas. 3

Suf cient micronutrient intake is es-pecially important when mothers arepregnant and breastfeeding, which areperiods of increased micronutrientneeds and crucial periods for the braindevelopment of the infant. 4 The neural tube begins to form 16 days after con-ception and within 7 months takes ona form that resembles the adult brain. 5

Micronutrients are necessary for manyof the biological processes that drive this transformation, including neuronproliferation, axon and dendrite growth,synaptogenesis, and myelination. Forexample, in animal models, maternalvitamin B6 de ciency results in de-creased synaptic density in the neo-cortex, 6 whereas maternal de ciencyin either vitamin B 6 or zinc leads to re-duced dendritic branching. 7,8 Maternal

deciency in iron and vitamin B 6, aswellas gestational hypothyroidism, whichcan be caused by de ciencies in iodineand selenium, result in reduced myeli-nation in the offspring. 8,9 Few studieshave examined the effects of maternalmicronutrient de ciencies on brain de-velopment in humans.

Although the World Health Organizationrecommends distribution of iron/folicacid (IFA) supplements to pregnant

women, provision of multiple micro-nutrients (MMNs), including those im-portant for brain development such asvitamin B6 , zinc, and iodine, may bemore bene cial for mothers and theirchildren. Three randomized trials have

examined the effect of maternal MMNsupplementation on motor and cogni- tivedevelopmentin infancy. Two of thesehave reported bene ts on Bayley Scalesof Infant Development motor scores inchildren (age 7 months) of undernour-ished mothers in Bangladesh 29 andchildren (age 6 18 months) of HIV-1

infected mothers in Tanzania. 30 A third trial in China found a bene t of mater-nal MMN supplementation compared

with IFA on Bayley Scales of Infant De-velopment mental but not motor scoresat 12 months of age. 10 These somewhatmixed results suggest that maternalMMN supplementation may improvemotor development, although perhapsonly in children of mothers who are atparticular risk (ie, with HIV-1 infectionor low BMI), and may also bene t othercognitive abilities.

Only 1 study has examined the effect of

maternalMMNsupplementationin olderchildren: a randomized trial in Nepal,which assessed a cohort of 7- to 9-year-old children. 11 Children whose mothershad received 15 micronutrients duringpregnancy scored higher on a test of executive function than those whosemothers had received vitamin A alone.However, this bene t was found for only1 of 6 tests of motor and cognitivefunction. Children of mothers in this

same study whoreceived iron, folic acid,and vitamin A scored higher on 5 of 6cognitive and motor tests than thosewhose mothers received vitamin Aalone. In this study, children whosemothers received iron, folic acid, andvitamin A were not directly comparedwith those who received 15 micro-nutrients. In addition, this study usedan MMN formulation that did notcontain iodine, which is important for

child motor and cognitive development,nor did it assess the speci c impact onchildren of undernourished or anemicmothers. Additional data are needed toinvestigate whether long-term bene tsof maternal MMN supplementation, over

IFA alone, may be observed for childrenin other contexts or for the develop-ment of other cognitive and socioemotional skills. Analyses directly comparing the cur rent UNICEF/World HealthOrganization/United Nations UniversityMMN formulation with IFA, as reportedhere, are also important to inform maternal health policy.

We examined the effect of maternalsupplementation with MMNs, compared

with IFA, on motor and socioemotionalskills, as well as several speci c aspectsof cognitive ability: language, attention(the ability to focus and sustain attention), visuospatial ability (the ability toperceive and mentally represent spatial relationships among objects), andexecutive function (cognitive self-regulation, such as planning, effort-ful control of attention, and inhibitionof automatic responses). In addition, in

prespeci

ed analyses, we examined in- teractions between maternal supple-ment type and 2 indicators of maternalnutritional status likely to be related topoor child development: undernourish-ment at enrollment (mid-upper armcircumference [MUAC] , 23.5 cm) andanemia at enrollment (hemoglobin [Hb]concentration , 110 g/L).

METHODS

This study was conducted as part of theSupplementation with Multiple Micro-nutrients Intervention Trial (SUMMIT). Adetailed description of the design andprocedures of SUMMIT has been pub-lished previously. 12 SUMMITwasa double-blind, cluster-randomized trial conductedon the Indonesian island of Lombok from2001 through 2004. Pregnant women throughout Lombok were enrolled inSUMMIT at prenatal care clinics held

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by local midwives. Written informedconsent was obtained from all partic-ipants. Consenting women received adaily supplement throughout the dura- tion of pregnancy and until 3 monthspostpartum. Midwives were randomly

assigned to distribute either IFA orMMNs. The contents of the 2 supple-ments are presented in Table 1. Allwomen who received prenatal carefrom the same midwife received thesame supplement. All SUMMITscientistsand personnel, government staff, andparticipants were unaware of the allo-cation of MMNs and IFA. The study pro- tocol was approved by the NationalInstitutes of Health Research and De-

velopment of the Ministry of Health of Indonesia, the Provincial Planning De-partment of Nusa Tenggara BaratProvince, and the Johns Hopkins JointCommittee on Clinical Investigation(Baltimore, Maryland). Analysis wasaccording to intention to treat.

SUMMIT staffvisitedparticipantswithin72 hours of enrollment to record base-line information, including MUAC andHb concentration, which were used to

classify mothers as undernourished oranemic, respectively, in strati ed anal-yses. Because midwives had been pre-viously randomized to distribute IFA orMMNs, this classi cation was indepen-dent of randomization. Additional datawere also collected (see Supplemental

Information ). The follow-up sample wasdrawn from a random sample of 2369women who provided blood samplesboth before and after supplementation.

Follow-up Sample

Figure 1 shows the trial pro le. A totalof 28 426 children were born live, with26 228 being alive at 12 weeks post-partum after mortality and loss tofollow-up. To power the study to detecta difference of 0.3 SD and adding 15%for potential attrition, we targeted 549mothers, comprising all mothers whogave birth between September 24,2003, and March 31, 2004, and who had their blood drawn both before and af-

ter supplementation. We were able to test children of 484 of these mothers,including 3 sets of twins, for a total of 487 children. Of the targeted partic-ipants, the proportion who were not tested did not differ between IFA (32 of 272) and MMN (33 of 277) (P = .957).Fourteen motor scores (5 IFA, 9 MMN),8 visual attention/spatial scores (2 IFA,6 MMN), and11 executivefunction scores(4 IFA, 7 MMN) were missing because thechild refused to attempt the tests.

All testing was conducted from April toSeptember 2007 at the homes of theparticipants within 3 weeks of the day the child turned 42 months. Written in-formed consent was obtained from aparent. Ethicalapproval for theinformed

consent and research procedures for the follow-up study was obtained from the Lancaster University Ethics Com-mittee and the Mataram University Eth-ical Research Committee.

Developmental Tests

Developmental tests wereselected thatassess speci c abilities which developduring early childhood and are likely tobe sensitive to nutritional in uences.Research in maternal and child un-dernutrition in humans and animalssuggests possible effects on motor de-velopment, 13 language development, 14,15

and nonverbal cognitive development,including visual attention, visuospatial

ability, and executive function,16

as wellas socioemotional development. 17,18

Tests that assess each of these domainswere adapted to the local language,culture, and setting in Lombok, andwere evaluated for reliability and val-idity. A full description of the test se-lection criteria, adaptations, and thereliability and validity results is reported in Prado et al. 19 The tests are de-scribed in Table 2.

Additional Measures

The following data were also collectedat the time of child testing: an adaptedversion of theHome Observation for theMeasurement of the Environment in-ventory, 20 the child s Hb concentration,and maternal depression. For details,see Supplemental Information .

Statistical Analyses

Group Characteristic Comparisons First, we examined whether childrenwhose mothers received MMNs and IFAwere matched on the characteristicslisted in Table 3. For the continuousvariables, the difference was estimatedin mixed effects models. A randomeffectof midwife code on intercept was in-cluded in all analyses because the ran-domization was allocated by midwiferather than by individual participant;

TABLE 1 Contents of the 2 Maternal Supplements

IFA MMNs

Iron (ferrous fumarate) 30 mg Iron (ferrous fumarate) 30 mg

Folic acid 400 mg Folic acid 400 mgRetinol (retinyl acetate) 800 mgVitamin D (ergocalciferol) 200 IUVitamin E (a -tocopherol acetate) 10 mgAscorbic acid 70 mgVitamin B1 (thiamine mononitrate) 1.4 mgVitamin B2 (ribo avin) 1.4 mgNiacin (niacinanide) 18 mgVitamin B6 (pyridoxine) 1.9 mgVitamin B12 (cyanocobalamin) 2.6 mgZinc (zinc gluconate) 15 mgCopper 2 mgSelenium 65 mgIodine 150 mg

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speci cation of this random effectaccounts for variation between midwifeclusters. 21 For the categorical variables, the difference between groups was estimated by using generalized linearmodels, with midwife code as a repeatedmeasure. For details, see SupplementalInformation .

Calculation of Test Scores

Foreach test score (described in Table1),z scores were computed on the basisof the distribution of our sample. Thecomputation of z scores harmonizedevery test score to the same scale.This allowed us to compute compositedomain scores as the average of eachchild s test z scores from that domain,in the following domains: language

development, Picture Vocabulary andSentence Complexity z scores; socio-emotional development, socioemotionalcompetence and problem z scores; ex-ecutive function, Snack Delay and Win-dows z scores; and visual attention/spatial ability, Visual Search and Block Design z scores. For details, see Sup-

plemental Information . For the motorscale, 9.4% of item scores were missing.These missing items were imputed byusing the sequential regression imputation method described in Raghunathanet al.22 For details, see Supplemental In-formation . We additionally performed the analyses on motor scores bycounting refused (missing) items as afailure, rather than using imputation,and found a similar pattern of results.

Effect of Maternal MMN Versus IFA

The effect of MMN versus IFA supple-mentation on each domain score wasestimated in mixed effects models witha xed effect of supplement type anda random effect of midwife code. This

model was estimated rst with a xedeffect of supplement type as the onlyindependent variable, and second, withxed effects of supplement type and anyvariables from Table 3 that indepen-dently predicted each domain score. Fora detailed description of covariate se-lection, see Supplemental Information .Because gestational age at birth (preterm, full-term, or post-term) did not sig-nicantly predict any domain score, this

variable was not included as a covariate.To examine the effect on each domainscore in children of mothers who wereundernourished (MUAC , 23.5 cm) atenrollment and mothers who wereanemic (Hb , 110 g/L) at enrollment, the interaction between each of these 2variables and supplement type was(separately) added to the model. If thisinteraction was signi cant at the P , .1level, the effect of MMNs was estimated

for each subgroup.

RESULTS

The effect of MMN supplementation on the composite score for each develop-mental domain is reported in Table 4.The estimate (B) represents the un-standardized estimate of the differencein developmental scores between chil-dren of mothers who received MMNsand IFA, expressed as a fraction of the

variation (SD) of the developmentalscore. For example, children of motherswho received MMNs scored 0.12 SDhigher in motor development comparedwith those who received IFA ( P = .253).Although this effect on motor develop-ment was signi cant when adjusting for the covariates ( P = .036), it was not sig-nicant in the unadjusted analysis. Nosigni cant effects of MMNs were foundin any other developmental domain,

FIGURE 1Trial pro le.

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suggesting that there were no robusteffects of maternal MMN supplementation in the full group of children.

Children of UndernourishedMothers

The interaction between maternal sup-plementtype andmaternalundernutrition(MUAC, 23.5 cm) was signi cant formotor development (B = 0.412;SE= 0.199;

t(399) = 2.07; P = .039) and visualattention/spatial ability (B = 0.454, SE =0.168, t (420) = 2.71, P = .007) but not forlanguage, executive function, or socio-emotional development.

In motor development, children of un-dernourished mothers who receivedMMNs scored0.35 SD higher than thosewho received IFA (P = .044) (Table 5).In a group of children aged 30 to 55

months in Lombok tested to establish the developmental sensitivity of the tests, 19 the estimate of the effect of age(in months) on the motor developmentz score was 0.08, indicating that motordevelopment increased 0.08 SD witheach additional month of age. Thus, thiseffect of maternal MMN supplementation on motor development (0.35 SD)represents an advantage equivalent to

TABLE 2 Motor, Cognitive, and Socioemotional Tests

Domain/Test Method and Scores

Motor DevelopmentFine and Gross Motor

Development ScalesThe ne and gross motor scales were developed by selecting age-appropriate items (10 ne motor items

and 10 gross motor items) from both the Bayley Scale of Motor Development 42 and the Ages and StagesQuestionnaire 43 ; for example, Jumps over a rope 20 cm high and Threads three beads on a string.

The motor score was calculated as the total number of items, out of 20, that a child performed successfully.

Cognitive DevelopmentLanguage Ability

Picture Vocabulary Test Based on the British Picture Vocabulary Scale, 44 the child was presented 50 items, each consisting of 4 pictures(1 target and 3 distracters) and a word spoken by the tester. The child was asked to point to the picturecorresponding to the word. Item scores were summed for a total score.

Sentence Complexity Scale Based on the MacArthur-Bates Communicative Development Inventory Level III,45 the child s parent or anothercaregiver was asked 16 questions concerning the child s expressive language ability. For example, the parentwas asked, given an appropriate context, Which one more closely resembles your child s speech: Tas te kadu

(Im using my bag) or Tas te kadu jauq robot (Im using my bag to carry a robot)? A score of 0 was given for theless complex structure and a score of 1 for the more complex structure. These items were adapted to the Sasak language based on transcripts of child speech. 19 For each test, item scores were summed for a total score.

Visuospatial AbilityBlock Design Test Based on aspects of both the Brit ish Abili ty Scale 46 and the Wechsler Preschool and Primary Scale of Intelligence Third

Edition,47 the child was presented 7 shapes made with wooden blocks and was asked to build a copy of each.Thirty seconds were allowed per attempt. Children who failed on the rst attempt were given a second attempt,only for the rst 4 items. Children were scored on the average amount of time per correct item completed,which was then reciprocal transformed, reversing the score to match the direction of theother scores (higher is better).

Visual AttentionVisual Search Test This test was based on the NEPSY Developmental Neuropsychological Assessment visual search subtest. 48

In each of 2 items, the child was shown an array of pictures and asked to point to every instance of a targetpicture in the array, while the tester circled each picture the child indicated. The score was calculated as thenumber of hits (number of targets correctly indicated) minus the number of false alarms(number of distracter pictures incorrectly indicated).

Executive FunctionSnack Delay Test In the Snack Delay Test, 49 ,50 the tester placed a snack in the child s hand and told the child to wait until given permission

to eat the snack. Four trials were administered, with delays of 5, 15, 30, and 45 seconds. If the child ate the snack before the allotted time, the amount of time the child waited before eating the snack was recorded. The averageamount of time the child waited before eating the snack across the four trials was calculated.

Windows Test In the Windows Test,51

the tester placed a treat inside 1 of 2 boxes, each of which had a clear window through which the child could see the treat. The child was initially instructed to point to the box with the treat to obtain the treat.After 2 trials, the rule was reversed and the child was instructed to point to the box without the treat to obtain it.The score was calculated as the number of correct trials after the rule was reversed, out of 6 trials.

Socioemotional DevelopmentSocioemotional Development Scale A Socioemotional Development Scale was developed based on the Brief Infant-Toddler Social and Emotional

Assessment. 52 In an interview format, the child s parent or caregiver rated 29 items probing speci c aspects of thechild s behavior on a scale from 0 to 2 (0 = not true/rarely, 1 = somewhat true/sometimes, 2 = very true/often).Both competence items (eg, Plays well with other children ) and problem items (eg, Does not make eye contact )were presented. A competence score was calculated as the sum of the competence item ratings and a problemscore was calculated as the sum of the problem item ratings. The problem score was reversed, to match thedirection of the other scores (higher scores representing better functioning), by subtracting the raw scorefrom the maximum possible score. 42

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4.5 months of age. No difference inmotor scores was found in children of mothers who were not undernourishedduring pregnancy. This nding suggests that the effect of MMNs on motor de-velopment observed over all children in

the adjusted analysis ( Table 4) was due to this effect in children of under-nourished, rather than well-nourished,mothers.

In visual attention/spatial ability, chil-dren of undernourished mothers who

received MMNs scored 0.35 SD higher than those who received IFA ( P = .011)(Table 5). Children of mothers whowere not undernourished during preg-nancy did not show this advantage. Theeffect of age in months on this score, in

TABLE 3 Group Characteristic Comparisons of the Preschool Follow-up Sample Who Received IFA and MMNs

Characteristic IFA MMN IFA Versus MMN

n Mean 6 SD or % n Mean 6 SD or % T or z a P

Baseline maternal age, y 234 25.7 6 6.0 241 25.5 6 5.5 0.28 .777Baseline maternal height, cm 216 149.6 6 4.9 217 149.6 6 4.9 0.11 .915Mean compliance (percentage of supplements consumed) 209 79.6 6 21.3 201 75.5 6 21.3 1.15 .254Maternal cognitive z score 82 2 004 6 0.56 93 010 6 066 1.52 .133Maternal mood score at cognitive testing 41 41.4 6 7.7 50 39.8 6 6.9 1.08 .280Maternal mood score at child testing 160 42.0 6 5.5 160 42.1 6 5.7 0.16 .877Childs birth weight, g 197 3199.5 6 519.2 195 3265.4 6 497.9 1.32 .188Childs Hb concentration, g/L 218 109 6 13 208 110 6 13 0.44 .661HOME inventory score 241 39.3 6 5.3 246 38.8 6 5.7 1.05 .296Childs hours of sleep in the 24 hours before testing 241 11.3 6 1.3 246 11.3 6 1.4 0.25 .804Baseline maternal Hb concentration 0.24 .622

, 110 g/L 109/240 45 117/243 48$ 110 g/L 131/240 55 126/243 52

Baseline maternal MUAC 0.19 .665, 23.5 cm 68/212 32 75/220 34$ 23.5 cm 144/212 68 145/220 66

Baseline maternal education (completed years of formaleducation)

0.10 .917

0 18/236 8 22/243 91 6 121/236 51 121/243 507 9 66/236 28 59/243 24. 9 31/236 13 41/243 17

Baseline paternal education (completed years of formaleducation)

0.42 .675

0 16/225 7 21/231 91 6 94/225 42 96/231 427 9 47/225 21 50/231 22. 9 68/225 30 64/231 28

Baseline socioeconomic index b 0.71 .4790 85/237 36 98/243 401 69/237 29 66/243 272 48/237 20 43/243 18. 2 35/237 15 36/243 15

Gestational age at enrollment 0.26 .795First trimester 93/241 39 96/246 39Second trimester 112/241 47 105/246 43Third trimester 36/241 15 45/246 18

Parity (birth order of the tested child) 0.67 .4111 81/237 34 78/243 322 3 109/237 46 123/243 514 5 40/237 17 32/243 13$ 6 7/237 3 10/243 4

Gestational age at birth 0.54 .587Preterm (28 36 wk) 49/241 20 59/246 24Full-term (37 42 wk) 157/241 65 157/246 64Post-term ( . 42 wk) 35/241 14 30/246 12

Childs gender (number of girls) 108/241 45 123/246 50 1.19 .236

All baseline measures were taken within 72 hours of enrollment. Maternal cognitive and mood scores were taken from Prado et al. 39a Comparisons using mixed effects models for continuous variables ( t is reported) and generalized linear models for categorical variables ( z is reported).b The socioeconomic index was derived from a survey administered at enrollment to determine whether participants owned 12 household items. Subsequently, we discarded 6 items withcorrelations with the total score of , 0.1. Removing these items improved the internal consistency of the index from Cronbach s a = 0.41 to 0.57. The 6 remaining items (owned a radio;a television; a refrigerator; a bike; a motorbike; and a small sales business, such as selling snacks, commonly operated out of the home) were summed for a total score.

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the aforementioned sample of childrenaged 30 to 55 months, was 0.07, in-dicating that this score increased by 0.07 SD with each month of age.Therefore, the effect of MMNs in chil-dren of undernourished mothers rep-resents an advantage equivalent to 5months of age. Both the effects on motorand visual attention/spatial ability inchildren of undernourished motherswere slightly stronger in the analyses

adjusting for the covariates (B = 0.39and B = 0.37, respectively).

The mean z score for each domain inchildren of mothers who received IFAand MMNs strati ed on the basis of themother s MUAC is presented in Fig 2.

Children of undernourished motherswhoreceived IFA scored substantially lowerin motor development (mean: 0.28) andvisual attention/spatial ability (mean:

0.35) than all other groups (mean:0.01 0.10). Children of undernourishedmotherswho received MMNs had scores(mean: 0.07 for motor ability and 0.01 forvisual attention/spatial ability) similar tochildren of mothers who were not un-dernourished in either supplement group

(mean: 0.01 0.10). This nding suggests that maternal MMN supplementationprotected children of undernourishedmothers from negative developmentaleffects of the mother s poor nutritionalstatus during pregnancy.

Children of Anemic Mothers

The interaction between maternalsupplement type and maternal anemia(Hb , 110 g/L) was signi cant at theP , .1 level for visual attention/spatialability (B = 0.292, SE = 0.157, t (469) =1.86, P = .063) but not for any otherdomain score.

Children of anemic mothers who re-ceived MMNs scored 0.23 SD higher invisual attention/spatial ability than those who received IFA, an effect whichapproached signi cance in the un-adjusted analysis ( P = .055) and wassigni cant in the adjusted analysis (B =0.24, P = .030) (Table 5). This effect sizerepresents an advantage equivalent to 3 months of age. Children of motherswho were not anemic during preg-nancy did not show a bene t of maternal MMN supplementation on visualattention/spatial ability.

DISCUSSION

In a randomized trial in Indonesia thatexamined the effects of maternal MMNsupplementation, compared with IFA,on the motor, cognitive, and socio-emotionalabilities of children at age 42months, the following results werefound.No signi cant effects were foundfor children overall, except in the adjusted analysis on motor development.Strati ed analysis showed that this

TABLE 4 Effect of MMNs on Motor, Cognitive, and Socioemotional Domain Scores

Domain

Adjusted for Cluster Randomization

Adjusted for Cluster Randomizationand Other Covariates That

Independently Predicted EachDomain Score

n Estimate (95% CI) P n Estimate (95% CI) P

Motor development 473 0.12 ( 0.08 to 0.32) .253 425 0.19 (0.02 to 0.37)a .036Language development 487 0.00 ( 0.20 to 0.19) .971 380 0.07 ( 0.11 to 0.25)b .463Visual attention/spatial ability 479 0.08 ( 0.09 to 0.24) .355 424 0.07 ( 0.08 to 0.22)c .342Executive function 476 2 0.06 ( 0.21 to 0.09) .427 385 2 0.04 ( 0.19 to 0.11)d .634Socioemotional development 487 2 0.02 ( 0.16 to 0.12) .777 410 0.00 ( 0.15 to 0.15)e .981

The estimate of the effect of MMNs represents the difference in scores between children of mothers who received MMNs andIFA, expressed as a fraction of the variation (SD) of the score. Positive estimates indicate that those who received MMNsscored higher than those who received IFA. CI, 95% con dence interval.a Adjusted for Home Observation for the Measurement of the Environment Inventory (HOME) inventory score and child s Hbconcentration.b Adjusted for HOME inventory score, child s Hb concentration, and mother s MUAC, 23.5 cm.c Adjusted for HOME inventory score and mother s MUAC, 23.5 cm.d Adjusted for HOME inventory score and birth weight.e Adjusted for HOME inventory score and compliance (mean percentage of supplements consumed).

TABLE 5 Effect of MMNs on Motor Development and Visual Attention/Spatial Ability in Strati ed Analyses

DomainAdjusted for Cluster Randomization

Adjusted for Cluster Randomization and Other Covariates ThatIndependently Predicted Each Domain Score

n Estimate (95% CI) P Interaction Term P n Estimate (95% CI) P Interaction Term P

Motor developmentMother s MUAC, 23.5 cm 139 0.35 (0.01 to 0.69) .044 .039 128 0.39 (0.08 to 0.70)a .015 .073Mother s MUAC$ 23.5 cm 280 2 0.06 ( 0.31 to 0.19) .633 251 0.04 ( 0.18 to 0.27)a .703

Visual attention/spatial abilityMother s MUAC, 23.5 cm 140 0.35 (0.08 to 0.63) .011 .007 140 0.37 (0.11 to 0.62)b .004 .005Mother s MUAC$ 23.5 cm 284 2 0.10 ( 0.29 to 0.09) .312 284 2 0.08 ( 0.26 to 0.10)b .399Mother s Hb , 110 g/L 222 0.23 (0.00 to 0.46) .055 .063 188 0.24 (0.02 to 0.46)c .030 .038Mother s Hb $ 110 g/L 253 2 0.07 ( 0.28 to 0.15) .560 232 2 0.07 ( 0.27 to 0.13)c .488

The estimate of the effect of MMNs represents the difference in scores between children of mothers who received MMNs and IFA, expressed as a fraction of the variation (SD) of the score.Positive estimates indicate that those who received MMNs scored higher than those who received IFA. The interaction term P value represents the P value associated with the interactionbetween maternal supplement type and the strati cation variable (mother s MUAC or Hb). CI, 95% con dence interval.a Adjusted for Home Observation for the Measurement of the Environment Inventory (HOME) inventory score and child s Hb concentration.b Adjusted for HOME inventory score.c Adjusted for HOME inventory score and mother s MUAC, 23.5 cm.

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effecton motor development wasfoundonly in children of mothers who wereundernourished during pregnancy andwas equivalent to an advantage of 4.5months of age. Maternal MMN supple-mentation also yielded advantages invisual attention/spatial ability in 2 sub-groups of children: children of motherswho were undernourished during preg-nancy, equivalent to 5 months of age,and children of mothers who wereanemic during pregnancy, equivalent to 3 months of age. These ndingshave several implications.

First, these results demonstrate thatadequate maternal micronutrient intake is necessary for intact braindevelopment, a conclusion that in thepast has largely depended on animal

models. Although acute maternal de -ciencies in certain micronutrients areknown to result in severe neurologicimpairment (eg, maternal iodine de-ciency resulting in cretinism), 4 theeffect of mild to moderate micro-nutrient de ciencies during preg-nancy in humans has not yet beenclari ed. The nding that children of undernourished mothers who re-ceived IFA performed at substantially

lower motor and cognitive levelscompared with those who receivedMMNs and compared with children of well-nourished mothers ( Fig 2) sug-gests that supplementation with IFAalone is insuf cient to protect againstnegative long-term developmental ef-fects of maternal undernutrition. TheMMN supplement in the current studycontained iodine, zinc, and vitamin B 6,all of which are important for braindevelopment. Maternal iodine supple-mentation has been found to improvemotor and cognitive development inseveral studies. 14,23,24 Maternal zincsupplementation has been found toimprove muscle mass in 12-month-oldinfants, 25 which could lead to improvedmotor development, although improve-

ments in motor development have notbeen observed in 2 other studies of maternal zinc supplementation. 26,27 Thus,adequate intake of other micronutrientsin addition to iron/folic acid duringpregnancy and lactation seems to beimportant for healthy motor and cog-nitive development.

Second, the nding that MMN sup-plementation bene ted these child-ren s motor and cognitive abilities in

undernourished mothers is consistentwith previous evidence that maternalMMN supplementation can provide oth-er important advantages, such as re-ductions in low birth weight 28 and infantmortality 3 months postpartum, 12 andsuggests that these advantages extendbeyond gestational and early infanthealth outcomes. The nding is alsoconsistent with the positive ndings of the 3 previousstudies that examined theeffect of MMN supplementation on Bay-ley Scales of Infant Development mentaland motor scores 10,29,30 and providesimportant additional elements, such as the evaluation of multiple domains of early child development and the care-ful adaptation of the tests to the localsetting. 19 Perhaps most importantly,whereas those studies focused on in-

fants (up to age 18 months), the currentstudy examined children at 42 monthsof age. Infant development scores aregenerally poor predictors of later-cognitive abilities 31 ; in contrast, thosescores of children ages 3 to 7 yearspredict later outcomes such as schoolachievement, 32 34 which in turn leads tohigher skilled employment and higherwages in adulthood. The fact that wefound a bene t of MMN supplementation

FIGURE 2Mean z score in each developmental domain for children of mothers who received IFA and MMNs strati ed on the basis of the MUAC of the mother.Error bars show the SEM.

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in visual attention/spatial ability is in- triguing because focusing and sus- taining attention are important skills forschool success. 35 Moreover, attentionmeasured before and during elemen- tary school has been found to predict

school achievement up to 5 yearslater. 36 38 Thus, the results obtained heresuggest that maternal MMN supple-mentation might have much longer-termadvantages for children of under-nourished and anemic mothers.

Third, the nding that the motor andcognitive bene ts were observed pri-marily in the children of mothers whowereundernourishedoranemic duringpregnancy is consistent with previous

studies that have observed a particularbene t of MMN supplementation in these subgroups on infant survival, 12

maternal cognition, 39 and infant motordevelopment, 29 although not on birthweight. 28,40 Together, these ndings sug-gest that micronutrient de ciency maybe especially problematic among thesesubgroups, and that these mothersand their children particularly bene tfrom MMN supplementation during

pregnancy and postpartum in certainimportant outcomes. Given that somestudies have found no differences between maternal MMN and IFA supple-mentation on neonatal infant mortality 41

or on cognitive performance at age 7 to9 years, 11 this highlights the importance

of examining effects in subgroups of mothers who are particularly likely tobene t from MMN supplementation.

We found no effects on language, ex-ecutive, or socioemotional skills. Onelimitation of this study was that the

children were tested at an age in whicha wide variation in performance isnormal. For example, because a widevariation in language ability falls withina normal range at age 3 years, it may bedif cult to detect effects in languagedevelopment at this age. Another limitation was that the tests of executivefunction in the current study primarilyassessed inhibition ability (in both theSnack Delay and Windows tests) and,

to some extent, task switching (in theWindows test). In later childhood, it be-comes easier to assess other aspects of executive function, including planningand task monitoring, which might bemore sensitive to maternal MMN sup-plementation. A third limitation was thatour measure of socioemotional devel-opment relied on parent report rather than direct assessment of the child,which may also be more sensitive to ef-

fects of maternalMMNsupplementation.

CONCLUSIONS

Our ndings suggest that, in a popula- tion such as that examined here in In-donesia,maternalMMNsupplementation

compared with IFA supplementation canimprove the motor and cognitive abilities of children as late as 3.5 years, inparticular when women are under-nourishedor anemic during pregnancy,and especially for motor function and

visual attention/spatial ability. The lossof developmental potential in earlychildhood is a critical problem in low-and middle-income countries. The ndings suggest that providing MMNsupplements to mothers during preg-nancy and lactation, particularly to those who are undernourished oranemic, is an effective intervention to address this loss and to promotehealthy motor and cognitive devel-

opment in children.

ACKNOWLEDGMENTSThe SUMMIT Study Group designed andexecuted the SUMMIT study. We ac-knowledge the substantial contribu- tion of Dr Abas Jahari in the supportand completion of thestudy. Sri Hartini,Astri Hidayanti, Siti Nurul Hikmah, BaiqElfa Ismayani, Atik Rahmawati, andFitriati conducted pilot testing, test ad-

aptation, and data collection. Nurhafni,Indah Qoriana, Rosmawarty, andNuniksI.Gayatri provided administrative sup-port. Farhiyah, Nurmawati, and Maryati transcribed childspeech samples to val-idate the parent-reported languagemeasure.

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(Continued from rst page)

Address correspondence to Elizabeth L. Prado, PhD, SUMMIT Institute of Development, Kantor Bappeda Provinsi Nusa Tenggara Barat, Lantai 2, Jalan Flamboyan No 2,Mataram, NTB, Indonesia. E-mail: [email protected] and Katherine Alcock, DPhil, Department of Psychology, Lancaster University, Bailrigg, Lancaster, LA1 4YF,United Kingdom. E-mail: [email protected]

PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275).

Copyright 2012 by the American Academy of Pediatrics

FINANCIAL DISCLOSURE:The authors have indicated they have no nancial relationships relevant to this article to disclose.

FUNDING:Support for this project was provided by the Allen Foundation, a National Science Foundation Graduate Research Fellowship, the Turner Foundation,UNICEF, the Centre for Health and Human Development, and the United States Agency for International Development Indonesia (grant 497-G-00-01-00001-00). Thesponsors of the study had no role in the study design, data collection, data analysis, data interpretation, or writing of the report. The corresponding author had fullaccess to all the data in the study and had nal responsibility for the decision to submit for publication.

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DOI: 10.1542/peds.2012-0412; originally published online August 20, 2012;2012;130;e536PediatricsAnuraj H. Shankar

Elizabeth L. Prado, Katherine J. Alcock, Husni Muadz, Michael T. Ullman andRandomized Trial in Indonesia

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