The American Journal of Clinical Nutrition 118 (2023) 433–442journal homepage: https://ajcn.nutrition.org/Original Research ArticlePrenatal and postnatal small-quantity lipid-based nutrient supplements and
children’s social–emotional difficulties at ages 9–11 y in Ghana: follow-up of
a randomized controlled trial
Elizabeth L. Prado 1,*, Seth Adu-Afarwuah 2, Charles D. Arnold 1, Ebenezer Adjetey 2,
Benjamin Amponsah 3, Helena Bentil 1, Kathryn G. Dewey 1, Amanda E. Guyer 4,5, Adom Manu 6,
Mavis Mensah 2, Brietta M. Oaks 7, Maku Ocansey 8, Xiuping Tan 1, Paul D. Hastings 4,9
1 Institute for Global Nutrition, Department of Nutrition, University of California–Davis, Davis, CA, USA; 2 Department of Nutrition and Food Science,
University of Ghana, Accra, Ghana; 3 Psychology Department, University of Ghana, Accra, Ghana; 4 Center for Mind and Brain, University of
California–Davis, Davis, CA, USA; 5 Department of Human Ecology, University of California–Davis, Davis, CA, USA; 6 Public Health, University of
Ghana, Accra, Ghana; 7 Department of Nutrition and Food Sciences, University of Rhode Island, Kingston, RI, USA; 8 McKing Consulting
Corporation; 9 Department of Psychology, University of California–Davis, Davis, CA, USAA B S T R A C T
Background: Provision of small-quantity lipid-based nutrient supplements (SQ-LNSs) during early life improves growth and development. In the In-
ternational Lipid-Based Nutrient Supplements DYAD–Ghana trial, prenatal and postnatal SQ-LNS reduced social–emotional difficulties at age 5 y, with
greater effects among children in less-enriched home environments.
Objectives: We aimed to investigate the effect of prenatal and postnatal SQ-LNS on children's social–emotional problems at age 9–11 y.
Methods: In 2009–2011, 1320 pregnant women 
20 wk gestation were randomly assigned to receive the following daily until 6 mo postpartum: 1) iron
and folic acid until delivery, then placebo, 2) multiple micronutrients (MMNs), or 3) SQ-LNS (20 g/d). Children in group 3 received SQ-LNS from 6 to 18
mo. In 2021, we evaluated children's social–emotional outcomes with 6 assessment tools that used caregiver, teacher, and/or self-report to measure
socioemotional difficulties, conduct problems, temperament, mood, anxiety, and emotion management.
Results: We assessed outcomes in 966 children, comprising 79.4% of 1217 participants eligible for re-enrolment. No significant differences were found
between the SQ-LNS and control (non-LNS groups combined) groups. Few children (<2%) experienced high parent-reported social–emotional diffi-
culties at 9–11 y, in contrast to the high prevalence at age 5 in this cohort (25%). Among children in less-enriched early childhood home environments, the
SQ-LNS group had 0.37 SD (0.04 to 0.82) lower self-reported conduct problems than the control group (P-interaction ¼ 0.047).
Conclusions: Overall positive effects of SQ-LNS on social–emotional development previously found at age 5 y are not sustained to age 9–11 y; however,
there is some evidence of positive effects among children in less-enriched environments. The lack of effects may be owing to low prevalence of
social–emotional problems at preadolescence, resulting in little potential to benefit from early nutritional intervention at this age in this outcome domain.
Follow-up during adolescence, when social-emotional problems more typically onset, may yield further insights.
This trial was registered at clinicaltrials.gov as NCT00970866. https://clinicaltrials.gov/ct2/show/record/NCT00970866
Keywords: social–emotional development, lipid-based nutrient supplements, SQ-LNS, child development, GhanaAbbreviations used: BPM-P, Brief Problem Monitor–Parent; CEMS, Children’s Emotion Management Scales; EATQ-P, Early Adolescent Temperament Questionnaire–Parent;
EC-HOME, Early Childhood Home Observation for the Measurement of the Environment; IFA, iron and folic acid; iLiNS, International Lipid-Based Nutrient Supplements; LNS,
lipid-based nutrient supplement; MC-HOME, Middle Childhood Home Observation for the Measurement of the Environment; MFQ, Mood and Feelings Questionnaire; MMN,
multiple micronutrient; SCARED, Screen for Child Anxiety-Related Emotional Disorders; SDQ, strengths and difficulties questionnaire; SQ-LNS, small-quantity lipid-based nutrient
supplement.
* Corresponding author.
E-mail address: elprado@ucdavis.edu (E.L. Prado).
https://doi.org/10.1016/j.ajcnut.2023.05.025
Received 21 November 2022; Received in revised form 16 May 2023; Accepted 23 May 2023; Available online 29 May 2023
0002-9165/© 2023 The Author(s). Published by Elsevier Inc. on behalf of American Society for Nutrition. This is an open access article under the CC BY license (http://
creativecommons.org/licenses/by/4.0/).
E.L. Prado et al. The American Journal of Clinical Nutrition 118 (2023) 433–442
TABLE 1
Nutrient and energy contents of the dietary supplements.
IFA MMN Maternal Child
SQ-LNS SQ-LNS
Ration per day 1 capsule 1 capsule 20-g sachet 20-g sachet
Total energy (kcal) 0 0 118 118
Protein (g) 0 0 2.6 2.6
Fat (g) 0 0 10 9.6
Linoleic acid (g) 0 0 4.59 4.46
α-Linolenic acid (g) 0 0 0.59 0.58
Vitamin A (μg RE) 0 800 800 400
Vitamin C (mg) 0 100 100 30
Vitamin B-1 (mg) 0 2.8 2.8 0.3
Vitamin B-2 (mg) 0 2.8 2.8 0.4
Niacin (mg) 0 36 36 4
Folic acid (μg) 400 400 400 80
Pantothenic acid (mg) 0 7 7 1.8
Vitamin B-6 (mg) 0 3.8 3.8 0.3
Vitamin B-12 (μg) 0 5.2 5.2 0.5
Vitamin D (mg) 0 10 10 5
Vitamin E (mg) 0 20 20 6
Vitamin K (μg) 0 45 45 30
Iron (mg) 60 20 20 6
Zinc (mg) 0 30 30 8
Copper (mg) 0 4 4 0.34
Calcium (mg) 0 0 280 280
Phosphorus (mg) 0 0 190 190
Potassium (mg) 0 0 200 200
Magnesium (mg) 0 0 65 40
Selenium (μg) 0 130 130 20
Iodine (μg) 0 250 250 90
Manganese (mg) 0 2.6 2.6 1.2
IFA, iron and folic acid capsule; MMN, multiple micronutrient supplement
capsule; SQ-LNS, small-quantity lipid-based nutrient supplement. Informa-
tion from table previously published [15].Introduction
Millions of pregnant women and children globally consume inad-
equate diets, resulting in conditions among children such as stunting,
wasting, anemia, micronutrient deficiencies, and poor cognitive, motor,
and social-emotional development [1]. Adequate availability of nutri-
ents is necessary for the neurodevelopmental processes that occur
rapidly during pregnancy and infancy; therefore, improving maternal
and child diets is essential to supporting children to fulfill their
developmental potential [2]. Various strategies to improve maternal and
child diets have been evaluated, such as supplementation with a single
micronutrient (such as iron or vitamin A), supplementation with mul-
tiple micronutrients (MMNs) (such as a capsule or powder), and
nutrition education to caregivers. Although some positive effects of
such interventions have been shown [3], the strategy with the strongest
evidence for concurrent positive effects on children’s health, growth,
and development is provision of small-quantity lipid-based nutrient
supplements (SQ-LNSs) to young children. SQ-LNSs are typically
made from vegetable oil, peanut paste, milk powder, and sugar, with
added vitamins and minerals, thus providing many of the micro-
nutrients and fatty acids that are necessary for growth and brain
development [4].
Meta-analyses of data from a large number of randomized trials
and children (7 to 18 trials and 2700 to 41,000 children, depending
on the outcome) have shown that providing SQ-LNS to children
aged 6 to 24 mo resulted in better health, such as 27% reduction in
mortality [5], 16% reduction in anemia, and 64% reduction in
iron-deficiency anemia [6]; better growth, such as 12% reduction in
stunting, 14% reduction in wasting, and 13% reduction in under-
weight [7]; and better development, such as 16% to 19% reduction in
adverse language, motor, and social–emotional outcomes [8]. This is
the first intervention for young children to show beneficial effects
across these 4 crucial health outcome domains of growth, develop-
ment, anemia, and mortality. Given the substantial positive effects
evident at the end of the intervention period, the question remains
whether there are sustained positive effects on outcomes in later
childhood.
A follow-up study of the International Lipid-Based Nutrient
Supplements trial in Ghana at age 4–6 y showed reduced social-
–emotional difficulties (0.12 SD) in the group who was exposed to
SQ-LNS (indirectly in utero and through breast milk before 6 mo of
age, and directly at 6–18 mo of age), compared with control groups,
with greater effects among children in less-enriched home environ-
ments (0.22 SD) [9]. Of the nutrients provided by SQ-LNS, 2 po-
tential candidates regarding biological explanations for the lower
behavioral problem scores in the SQ-LNS group are the essential fatty
acids provided by SQ-LNS (prenatally and postnatally) and the iron
provided directly to children postnatally in the SQ-LNS group. De-
ficiencies in these nutrients have been associated with social–emo-
tional regulation and behavioral problems during childhood [10,11].
In this study, we investigated whether the positive effects on social-
–emotional development observed at 4–6 y were sustained to age
9–11 y.
Methods
Objectives and hypotheses
Our objective was to investigate the effect of prenatal and postnatal
SQ-LNS on social–emotional problems and self-regulation at age 9–11
y and in the context of children’s home environments. Our first434hypothesis was that, compared with children who were not exposed to
SQ-LNS in early life, those exposed to SQ-LNS would experience
fewer social–emotional problems and better self-regulation. Our sec-
ond hypothesis was that children in less-enriched home environments
during early childhood would experience more social–emotional
problems and worse self-regulation. Our third hypothesis was that
greater effects of SQ-LNS would be found among children from less-
enriched home environments.
Participants and procedure
The methods of the International Lipid-Based Nutrient Supple-
ments-DYAD–Ghana randomized controlled trial (RCT), performed in
2009–2014 [12,13], and the 5-y follow-up study performed in 2016 [9,
14], have been described in detail. In brief, 1320 pregnant women in
the Somanya-Odumase-Kpong area of Ghana, a semiurban area in the
Yilo Krobo and Lower Manya Krobo districts, were randomly assigned
to one of the 3 groups. The iron and folic acid (IFA) group was assigned
to receive 1 capsule per day containing 60 mg iron and 400 μg folic
acid from enrolment to delivery and a placebo capsule containing 200
mg calcium from delivery to 6 mo postpartum. The MMN group was
assigned to receive 1 capsule per day from enrolment to 6 mo post-
partum containing 20 mg iron and 400 μg folic acid plus 16 additional
micronutrients (Table 1) [15]. The SQ-LNS group was assigned to
receive daily sachets of SQ-LNS produced by Nutriset SAS (Malaunay,
France) from enrolment to 6 mo postpartum. The daily dose (20 g)
contained the same micronutrients as the MMN capsules, 4 additional
minerals (Ca, K, Mg, and P), protein, fat, and 118 kcal (Table 1). From
E.L. Prado et al. The American Journal of Clinical Nutrition 118 (2023) 433–442the 6 to 18 mo of age, children in the SQ-LNS group received 20 g per
day of SQ-LNS with micronutrient composition designed for children
(Table 1). Participants were aware whether they received SQ-LNS or a
capsule but were blinded to whether they received IFA or MMN. Field
workers who assessed outcomes and collected other data were blinded
to all intervention groups. Ethical approval for the study procedures
was obtained from the Ethics Committees at the University of Cali-
fornia Davis and the Ghana Health Service. The protocol was regis-
tered at clinicaltrials.gov as NCT00970866.
For the 10-y follow-up study, data collection was performed from
December 2020 to December 2021, when children were aged 9–11 y.
Field workers contacted caregivers of 1217 children eligible for re-
enrolment, excluding those known to have not survived. At a home
visit, field workers obtained informed consent, collected sociodemo-
graphic information, assessed the home environment, and scheduled
the caregiver to bring the children to the project office. At the project
office visit, field workers assessed children's health, anthropometric
status, and cognitive development and obtained parent and child re-
ports on child social–emotional and behavioral problems. Field
workers also visited each child’s school to administer teacher report
and school quality interviews.
On the basis of our successful follow-up of ~1000 children at age
4–6 y, we expected to reenroll ~900 at age 9–11 y. Because children in
the 2 control groups (IFA and MMN) did not receive any nutrition
supplements, the main goal of the follow-up assessments was to
compare the lipid-based nutrient supplement (LNS) with non-LNS
(IFA þ MMN groups combined) groups. A sample size of 900 (300
LNS, 600 non-LNS) provides 80% power to detect an effect size, that
is, a mean difference between 2 groups, of >0.20 SD for continuous
outcomes at a significance level of P < 0.05. For the analysis of
intervention effects among children exposed to less-enriched home
environments, we determined the HOME score cutoff for subgroup
analyses based on the regions of significance analysis, as described
below. For subgroup analyses, an analysis using half of the target
sample (150 LNS, 300 non-LNS) provided 80% power to detect an
effect size of >0.28 SD, and using a quarter of the target sample (75
LNS, 150 non-LNS) provided 80% power to detect an effect size of
>0.40 SD.
Assessment of background characteristics and home
environment
At enrolment into the parent trial, maternal and household infor-
mation, such as maternal age, parity, education, and household assets,
was collected by trained field workers using a questionnaire. Trained
laboratory personnel measured maternal blood hemoglobin concen-
tration at a clinic visit using a digital Hemocue (HemoCue model 301,
AG, Switzerland). Infant weight and length were measured within 48 h
of birth or between 3 and 14 d after birth for 87 children (9.4%) for
whom the former was not possible.
At the 5-y follow-up, we assessed the home environment using the
Early Childhood Home Observation for the Measurement of the
Environment (EC-HOME) inventory [16], which we adapted to the
local context in Ghana. The EC-HOME inventory is designed for
children aged 3–6 y. Our adapted version contained 46 items measuring
learning materials, language stimulation, physical environment, care-
givers’ responsivity, academic stimulation, desirable behavior
modeling, family lifestyle variety, and negative behavior acceptance.
The adapted EC-HOME showed reasonable test–retest reliability
(Pearson r) and internal reliability (Cronbach α) in the study setting
(>0.63) [9].435At the 10-y follow-up, we assessed the home environment using the
Middle Childhood version of the HOME inventory (MC-HOME),
which is designed for use in children aged between 6 and 10 y. Our
adapted version contained 58 items measuring parental responsivity,
physical environment, learning materials, active stimulation, encour-
aging maturity, emotional climate, parental involvement, and family
participation. We also assessed maternal depressive symptoms using
the Center for Epidemiological Studies–Depression test [17] and pu-
bertal development using the Petersen Pubertal Development Scale by
parent and child report [18]. Both the MC-HOME and Center for
Epidemiological Studies–Depression test showed high test–retest and
internal reliability (>0.75) (Supplemental Table 1), whereas reliability
was lower for reported pubertal development (0.51–0.70) (Supple-
mental Table 1).
Assessment of outcomes
We assessed children social–emotional problems through the
following tools: We administered the strengths and difficulties ques-
tionnaire (SDQ) by parent report, teacher report, and child self-report.
A set of 20 questions rate children’s behavior during the past 6 mo in 4
subscales: emotional symptoms, conduct problems, hyperactivity/
inattention, and peer relationship problems [19]. We administered the
Brief ProblemMonitor–Parent (BPM-P) by parent report, which is a set
of 19 questions that measure attention problems, internalizing prob-
lems, and externalizing problems [20]. We administered the Mood and
Feelings Questionnaire (MFQ) by child self-report, which is a set of 13
questions that rate mood and feelings during the past 2 wk [21]. We
administered the Screen for Child Anxiety-Related Emotional Disor-
ders (SCARED) by child self-report. The SCARED includes 41
questions designed to screen for signs of anxiety disorders in children,
such as panic disorder, generalized anxiety disorder, separation anxiety,
social anxiety disorder, and school avoidance; questions are combined
into a total score [22]. For all these assessments, a higher score in-
dicates higher problems.
We assessed child self-regulation through the following tools: We
administered the Revised Early Adolescent Temperament Question-
naire (EATQ-P) by parent report [23], measuring activation control (the
capacity to perform an action when there is a strong tendency to avoid
it), attention (the capacity to focus attention and to shift attention when
desired), and inhibitory control (the capacity to plan and to suppress
inappropriate responses). For this tool, a higher score indicates higher
self-regulation. We administered the Children’s Emotion Management
Scales (CEMS) by child self-report, in which 9 items measure
behaviorally oriented management of sadness, anger, and anxiety [24].
For this tool, a higher score indicates higher self-regulation problems.
Each item was translated into the local languages (Krobo, Ewe, and
Twi) and backtranslated to English. If any discrepancies were found be-
tween the original itemand the backtranslation, the translationwas revised
and backtranslation was repeated until the meanings matched. Adapted
assessments were evaluated for test–retest reliability in a series of 2 pilot
tests, each with a sample of 30 children aged 9–11 y in the study area.
Assessments that showed low reliability were revised and reevaluated.
Test–retest reliability (Pearson r) ranged from 0.45 to 0.83, with most
scores (9/12) >0.65 (Supplemental Table 1). Internal reliability (Cron-
bach α) in the full sample ranged from 0.54 to 0.88, with 6 of the 12 as-
sessments >0.7 and 2 assessments ~0.7 (α ¼ 0.67–0.68) (Supplemental
Table 1). The remaining 4 scales with an α of 0.54–0.62 consisted of only
3 to 6 items, thus it is not surprising that Cronbach α was slightly lower
given that it tends to be lower for scales with fewer items [25].
E.L. Prado et al. The American Journal of Clinical Nutrition 118 (2023) 433–442Statistical analyses
A statistical analysis plan was posted to Open Science Framework
before performing analyses (https://osf.io/bmv9d/). Analyses were
conducted in R v4.1.1.
Group characteristic comparisons
We examined whether children in the SQ-LNS and control groups
were similar in key baseline characteristics by presenting descriptive
statistics for each intervention group. To evaluate potential bias in the
sample, we compared baseline characteristics between the sample
included in the analysis and the sample enrolled in the parent trial but
lost to follow-up, using t tests for continuous variables and χ2 tests for
categorical variables.
Effect of SQ-LNS
We conducted a complete case intention-to-treat analysis. To test
hypothesis 1, for each of the 8 outcomes described earlier (SDQ-Child,
SDQ-Parent, SDQ-Teacher, BPM-P, MFQ, SCARED, EATQ-P, and
CEMS), we examined the difference between the intervention (SQ-
LNS) and control (non-LNS) groups using multivariate analysis of
covariance (MANCOVA) models for outcomes with multiple subscales
and ANCOVA models for single scale outcomes. Our primary com-
parison of interest was the SQ-LNS group with the control group (IFA
and MMN groups combined). However, we also compared the IFA and
MMN groups to confirm that it was appropriate to combine them, as
demonstrated by no significant difference at P > 0.10 in outcomes
between those 2 groups. If the IFA and MMN groups were found to be
different from one another, we conducted a 3-group comparison
analysis and post hoc Tukey-Kramer pairwise comparisons. For out-
comes with multiple subscale scores (SDQ: 4 subscales, EATQ: 3
subscales, CEMS: 3 subscales), we used the MANCOVA global effect
test to determine the overall effect on the outcome and examined post
hoc tests on each subscale score using the Holm–Bonferroni method to
adjust for multiple testing within each model.
Three versions of each model were assessed. The first model was
adjusted for child age at follow-up only. The second model was
additionally adjusted for child sex, developmental assessment data
collector, and any of the following baseline variables that were
significantly associated (P < 0.10) with the outcome in the correlation
analysis: maternal age, maternal education, maternal prepregnancy
BMI, maternal hemoglobin concentration, household asset index, and
parity. The third model was additionally adjusted for any factors
collected after enrolment (birth weight) or at follow-up (school grade
and quality, EC-HOME score, MC-HOME score, maternal depressive
symptoms, and child pubertal development score) that were signifi-
cantly associated (P < 0.10) with the outcome in the correlation
analysis. For any covariates that were collected after baseline, we first
determined whether they were different between the intervention
groups at P< 0.10. If so, we did not include them in the model because
they are potential mediators. Birth weight was excluded based on this
criterion. If inclusion of covariates resulted in reduction in sample size
of >10% owing to missing covariates, which was the case for the
school quality indicators, we used simple imputation to fill in missing
covariate values in model 3.
To test hypotheses 2 and 3, we added to models 1 and 3 the EC-
HOME score at 5 y, then the interaction between the intervention
group and EC-HOME scores. As reported previously, EC-HOME
scores did not differ between the intervention groups [9]. Significant
interactions (P < 0.10) were further examined with regions of signif-
icance analyses overall and for each subscale score [26]. For outcomes436with multiple subscale scores, we used the MANCOVA global inter-
action test and examined post hoc tests for the interaction term within
each subscale using the Holm–Bonferroni method to adjust for multiple
testing within each model.
Effect modifiers
In exploratory analyses, we evaluated potential effect modification
by 5 additional variables: baseline household asset index, maternal
education, prepregnancy BMI, primiparity, and child sex. We tested the
interaction between each potential effect modifier and intervention
groups. Significant interactions (P < 0.10) were further examined with
regions of significance analyses [7].
Results
We successfully reenrolled 979 children at the home visit and
collected data from 966 children at the project office visit, representing
107% of our target sample size (900), 73.2% of the 1320 pregnant
women enrolled in the parent trial, and 79.4% of the 1217 children
eligible for re-enrolment (excluding those known not to have survived).
We successfully completed teacher interviews at school visits for 906
children. The proportion lost to follow-up was balanced between the
intervention groups (P ¼ 0.23) (Figure 1).
The 966 included in the analysis were similar to the 354 enrolled in
the parent trial but lost to follow-up regarding most background
characteristics, such as baseline maternal age, education, and BMI
(Supplemental Table 2). However, those lost to follow up recorded
lower gestational age at delivery (mean 38.9 vs. 39.3 wk) and a greater
proportion of their mothers were nulliparous at enrolment (40% vs.
32%).
Among those included in the analysis, background characteristics
were similar in the SQ-LNS and control groups (Table 2) [27]. In both
groups, children were, on average, aged 9.9 y at follow-up assessment.
Effects of SQ-LNS on child social–emotional problems
and self-regulation (hypothesis 1)
Children in the SQ-LNS group did not significantly differ from
those in the combined control group in any outcome score, with mean
differences ranging from 0.3 to 0.5 points and P values ranging from
0.14 to 0.99 (Table 3 and Supplemental Table 3). Children in the IFA
and MMN groups did not significantly differ in any outcome, except
that the IFA group showed lower internalizing problems (mean 2.21)
than the MMN group (mean 2.52) on the BPM-P (Supplemental
Table 4). However, the BPM-P scores were not significantly different in
the 3-group comparison (P ¼ 0.18) (Supplemental Table 5). At age
9–11 y, a small percentage (1.6%) of children had social–emotional
difficulties scores in the high/very high range on the parent-reported
SDQ (17), although the prevalence was higher for teacher-reported
(11.6% with scores 16) and children self-reported (6.3% with
scores 18) SDQ [28].
Association of home environment with children
social–emotional problems and self-regulation
(hypothesis 2)
Children with higher EC-HOME scores, indicating higher respon-
sive care and learning opportunities in the home environment during
early childhood, showed lower SDQ conduct problems (by parent and
teacher reports) and lower SDQ hyperactivity/inattention (by parent
report). They also demonstrated lower BPM-P externalizing and
E.L. Prado et al. The American Journal of Clinical Nutrition 118 (2023) 433–442
1320 pregnant 
women enrolled
441 received IFA at 439 received MMN 440 received SQ-LNS 
enrollment at enrollment at enrollment
1 misdiagnosed 4 misdiagnosed 
pregnancy pregnancy
25 miscarriage 12 miscarriage
22 s llbirth 7 s llbirth
18 child died 14 child died
814 Eligible for re-enrollment at 403 Eligible for re-
age 9-11 y enrollment at 
age 9-11 y
140 not traced 64 not traced
15 refused 6 refused
2 child died a er 0 child died a er 
5-y follow-up 5-y follow-up
9 moved 2 moved
648 Re-enrolled at age 9-11 years 331 Re-enrolled at 
age 9-11 years
13 48 0 unable 25
unable to unable to to unable to 
complete complete complete complete 
project school project school 
office visit office visit
visit visit
635 600 school 331 306 school 
assessed at visit assessed at visit 
age 9-11 completed age 9-11 completed
FIGURE 1. Trial profile. IFA, iron and folic acid; MMN, multiple micronutrient; SQ-LNS, small-quantity lipid-based nutrient supplement.attention problems and higher EATQ-P self-regulation in attention and
inhibitory control. EC-HOME scores were not significantly associated
with self-report SDQ or MFQ scores or parent-report SCARED or
CEMS scores (Table 4).
MC-HOME scores were included as a covariate in model 3 if they
were independently associated with the outcome at P < 0.10. When
included, coefficients for MC-HOME scores were generally similar to
or larger than coefficients for EC-HOME scores in model 3 (Table 4).
Children with higher MC-HOME scores showed lower SDQ conduct
problems (by self-report and parent report), lower SDQ hyperactivity/
inattention (by self-report and parent report), and lower SDQ peer
relationship problems (by the parent report). They also exhibited lower
BPM-P externalizing and attention problems and higher EATQ-P self-
regulation in activation control, attention, and inhibitory control. MC-437HOME scores were not associated with teacher-report SDQ, self-report
MFQ, or parent-report CEMS scores. The only result that was in the
opposite direction, as expected, was that higher MC-HOME scores
were associated with higher SCARED scores (anxiety). All but one of
the prospective associations between EC-HOME scores and children's
adjustment that were significant in model 1 remained significant in
model 3, after including MC-HOME scores that were concurrent with
children's adjustment measures.
Interaction of SQ-LNS with home environment
(hypothesis 3) and other potential effect modifiers
The interaction between the intervention group and EC-HOME
score was significant for self-report SDQ conduct problems (P-inter-
action¼ 0.05) and hyperactivity/inattention (P-interaction¼ 0.08). For
E.L. Prado et al. The American Journal of Clinical Nutrition 118 (2023) 433–442
TABLE 2
Group characteristic comparisons.
Variable SQ-LNS, n ¼ 331* Control, n ¼ 635*
Baseline maternal age (y) 27.0 (5.5) 26.8 (5.4)
Prepregnancy BMI1 (kg/m2) 24.9 (4.5) 24.3 (4.4)
Gestational age at enrolment (wk) 16.0 (3.3) 16.2 (3.2)
Baseline maternal education (y) 7.6 (3.8) 7.7 (3.4)
Baseline maternal hemoglobin (g/L) 111 (11) 111 (13)
Baseline household asset index2 0.07 (0.97) 0.08 (0.98)
Nulliparous (%) 30.8 [102/331] 31.8 [202/635]
Gestational age at delivery (wk) 39.3 (1.8) 39.3 (1.8)
Child male (%) 48.3 [160/331] 48.3 [307/635]
Child age at follow-up (y) 9.9 (0.5) 9.9 (0.5)
Mean maternal adherence from pregnancy through 6 mo postpartum (% of supplements consumed) 71.5 (19.4) 73.9 (22.0)
EC-HOME score at 5-y follow-up 28.0 (4.5) 28.0 (4.8)
MC-HOME score at 10-y follow-up 35.0 (5.5) 35.1 (6.1)
EC-HOME, Early Childhood Home Observation for the Measurement of the Environment Inventory; MC-HOME, Middle Childhood Home Observation for the
Measurement of the Environment Inventory; SQ-LNS small-quantity lipid-based nutrient supplement.
* Values are given as mean (SD) or % [n/total]. Control refers to iron and folic acid þ multiple micronutrient groups.
1 Estimated prepregnancy BMI was calculated from estimated prepregnancy weight (based on polynomial regression with gestational age, gestational age
squared, and gestational age cubed as predictors) [27] and height at enrolment.
2 Proxy indicator for household socioeconomic status constructed for each household based on ownership of a set of assets (e.g., radio and television), lighting
source, drinking water supply, sanitation facilities, and flooring materials. Household ownership of this set of assets is combined into an index (with a mean of zero
and standard deviation of one) using the principal components analysis. A higher value represents a higher socioeconomic status.
TABLE 3
Effect of SQ-LNS on each outcome score.
SQ-LNS, Control, Model 1 Model 3
mean (SD) mean (SD) adjusted P1 adjusted P2
Strengths and Difficulties Questionnaire–Child (SDQ-C), overall MANCOVA P 0.895 0.954
SDQ-C emotional symptoms 3.58 (1.52) 3.58 (1.50) 0.999 0.999
SDQ-C conduct problems 1.90 (1.35) 1.94 (1.40) 0.999 0.999
SDQ-C hyperactivity/inattention 3.66 (1.52) 3.61 (1.71) 0.999 0.999
SDQ-C peer relationship problems 2.45 (1.25) 2.50 (1.31) 0.999 0.999
Strengths and Difficulties Questionnaire–Parent (SDQ-P), overall MANCOVA P 0.488 0.266
SDQ-P emotional symptoms 1.76 (1.40) 1.72 (1.43) 0.999 0.999
SDQ-P conduct problems 1.46 (1.29) 1.49 (1.38) 0.999 0.999
SDQ-P hyperactivity/inattention 2.77 (2.05) 2.74 (1.93) 0.999 0.999
SDQ-P peer relationship problems 1.28 (1.16) 1.41 (1.24) 0.399 0.102
Strengths and Difficulties Questionnaire–Teacher (SDQ-T), overall MANCOVA P 0.392 0.396
SDQ-T emotional symptoms 2.43 (2.10) 2.28 (2.12) 0.999 0.999
SDQ-T conduct problems 1.70 (1.84) 1.69 (1.89) 0.999 0.999
SDQ-T hyperactivity/inattention 3.18 (2.17) 3.37 (2.32) 0.999 0.384
SDQ-T peer relationship problems 1.76 (1.41) 1.82 (1.48) 0.999 0.999
Brief Problem Monitor–Parent (BPM-P), overall MANCOVA P 0.653 0.848
BPM-P internalizing problems total score 2.40 (1.69) 2.37 (1.68) 0.999 0.999
BPM-P externalizing problems 2.53 (2.16) 2.52 (2.23) 0.999 0.999
BPM-P attention problems 2.71 (2.12) 2.87 (2.18) 0.846 0.999
Mood and Feelings Questionnaire (MFQ) total score 2.05 (2.35) 2.00 (2.04) 0.766 0.799
Screen for Child Anxiety-Related Emotional Disorders (SCARED) total score 18.9 (5.8) 19.3 (6.0) 0.253 0.212
Revised Early Adolescent Temperament Questionnaire–Parent (EATQ-P), overall MANCOVA P 0.463 0.406
EATQ-P activation control subscale score 26.0 (5.4) 26.1 (5.5) 0.999 0.999
EATQ-P attention subscale score 22.2 (4.0) 22.0 (4.2) 0.999 0.999
EATQ-P inhibitory control subscale score 18.4 (3.9) 18.5 (4.0) 0.999 0.999
Children's Emotion Management Scales (CEMS), overall MANCOVA P 0.146 0.159
CEMS anger subscale score 1.46 (0.42) 1.51 (0.45) 0.202 0.211
CEMS sadness subscale score 1.47 (0.39) 1.52 (0.41) 0.202 0.211
CEMS worried subscale score 1.54 (0.47) 1.55 (0.48) 0.592 0.711
Control refers to iron and folic acid þ multiple micronutrient groups. Results based on MANCOVA. For all assessments, a higher score indicates higher
social–emotional problems, except the EATQ-P for which a higher score indicates a higher self-regulation.
SQ-LNS, small-quantity lipid-based nutrient supplement.
1 Model 1 was adjusted for child age at follow-up only. P values adjusted for multiple comparisons within scales based on the Holm–Bonferroni method. Model
2 results are reported in Supplemental Table 3.
2 Model 3 was additionally adjusted for child sex, developmental assessment data collector, and any of the following variables that were significantly associated
at the P < 0.1 level with the outcome in the correlation analysis: baselin—maternal age, maternal education, maternal prepregnancy BMI, maternal hemoglobin
concentration, household asset index, parity; and at the follow-up—school grade and quality, EC-HOME score, MC-HOME score, maternal depressive symp-
toms, and child pubertal development score. P values adjusted for multiple comparisons within scales based on the Holm–Bonferroni method.
438
E.L. Prado et al. The American Journal of Clinical Nutrition 118 (2023) 433–442
TABLE 4
Association of home environment scores with each outcome.1
Model 12 Model 33 Model 33
5-y EC-HOME 5-y EC-HOME 10-y MC-HOME
Estimate (SE) P Estimate (SE) P Estimate (SE) P
Strengths and Difficulties Questionnaire–Child (SDQ-C)
SDQ-C emotional symptoms 0.01 (0.01) 0.374 -0.01 (0.01) 0.300 0.01 (0.01) 0.218
SDQ-C conduct problems 0.01 (0.01) 0.334 0.00 (0.01) 0.992 0.02 (0.01) 0.019
SDQ-C hyperactivity/inattention 0.02 (0.01) 0.128 0.00 (0.01) 0.938 0.03 (0.01) 0.016
SDQ-C peer relationship problems 0.01 (0.01) 0.552 0.00 (0.01) 0.811 0.00 (0.01) 0.699
Strengths and Difficulties Questionnaire–Parent (SDQ-P)
SDQ-P emotional symptoms 0.00 (0.01) 0.735 0.01 (0.01) 0.510 0.00 (0.01) 0.819
SDQ-P conduct problems 0.04 (0.01) <0.001 0.03 (0.01) 0.008 0.03 (0.01) 0.001
SDQ-P hyperactivity/inattention 0.05 (0.01) <0.001 0.04 (0.02) 0.026 0.03 (0.01) 0.011
SDQ-P peer relationship problems 0.02 (0.01) 0.059 0.00 (0.01) 0.972 0.02 (0.01) 0.002
Strengths and Difficulties Questionnaire–Teacher (SDQ-T)
SDQ-T emotional symptoms 0.02 (0.02) 0.231 0.01 (0.02) 0.792 — —
SDQ-T conduct problems 0.03 (0.01) 0.032 0.03 (0.02) 0.038 — —
SDQ-T hyperactivity/inattention 0.03 (0.02) 0.059 0.02 (0.02) 0.280 — —
SDQ-T peer relationship problems 0.00 (0.01) 0.693 0.00 (0.01) 0.728 — —
Brief Problem Monitor–Parent (BPM-P)
BPM-P internalizing problems total score 0.01 (0.01) 0.455 0.01 (0.01) 0.718 0.01 (0.01) 0.491
BPM-P externalizing problems 0.08 (0.02) <0.001 0.05 (0.02) 0.005 0.05 (0.01) 0.001
BPM-P attention problems 0.07 (0.02) <0.001 0.04 (0.02) 0.017 0.05 (0.01) 0.001
Mood and Feelings Questionnaire (MFQ) total score 0.02 (0.02) 0.321 0.02 (0.02) 0.183 — —
Screen for Child Anxiety-Related Emotional Disorders (SCARED) total score 0.02 (0.04) 0.712 0.05 (0.05) 0.256 0.10 (0.04) 0.005
Revised Early Adolescent Temperament Questionnaire–Parent (EATQ-P)
EATQ-P activation control subscale score 0.14 (0.04) 0.001 0.06 (0.04) 0.178 0.10 (0.03) 0.003
EATQ-P attention subscale score 0.17 (0.03) <0.001 0.10 (0.03) 0.002 0.09 (0.03) 0.001
EATQ-P inhibitory control subscale score 0.09 (0.03) 0.002 0.06 (0.03) 0.056 0.05 (0.03) 0.041
Children’s Emotion Management Scales (CEMS)
CEMS anger subscale score 0.00 (0.00) 0.828 0.00 (0.00) 0.808 — —
CEMS sadness subscale score 0.00 (0.00) 0.370 0.00 (0.00) 0.594 — —
CEMS worried subscale score 0.00 (0.00) 0.946 0.00 (0.00) 0.681 — —
EC-HOME, Early Childhood Home Observation for the Measurement of the Environment; MC-HOME, Middle Childhood Home Observation for the Mea-
surement of the Environment.
1 Estimates are unstandardized β coefficients.
2 Model 1 was adjusted for the child age at the follow-up and for the intervention group only.
3 Model 3 was additionally adjusted for child sex, developmental assessment data collector, and any of the following variables that were significantly associated
at the P < 0.1 level with the outcome in the correlation analysis: baseline—maternal age, maternal education, maternal prepregnancy BMI, maternal hemoglobin
concentration, household asset index, and parity; and at the follow-up—school grade and quality, MC-HOME score, maternal depressive symptoms, and child
pubertal development score.conduct problems, among children in less-enriched early childhood
HOME environments (EC-HOME score of <23 based on the regions
of significance analysis), the SQ-LNS group showed significantly
lower conduct problems (mean ¼ 1.67, SD ¼ 1.49, n ¼ 30) than the
control group (mean ¼ 2.26, SD ¼ 1.61, n ¼ 62), with a subgroup
estimated standardized mean difference of 0.37 SD (95% CI, 0.04 to
0.82). Among children with high EC-HOME scores, there were no
significant differences in self-report SDQ conduct problems between
the intervention groups (Figure 2). For hyperactivity/inattention, the
regions of significance analysis showed that there were no significant
differences between the SQ-LNS and control groups at any values of
EC-HOME scores.
Because the parent-report SDQ was the only measure administered
at both 4–6 y and 9–11 y, we examined the mean SDQ total difficulties
scores at both time points by the intervention group and high compared
with low EC-HOME scores (split at the median ¼ 28) (Figure 3). At
both time points, the rank order of the group means remained similar,
with the lowest difficulties in the SQ-LNS group with high EC-HOME
scores, followed by the control group with high EC-HOME scores,
then the SQ-LNS group with low EC-HOME scores, and, finally, the
control group with low EC-HOME scores. However, total mean439difficulties declined over time in all groups and converged such that
there were no significant intervention group differences in total diffi-
culties at age 9–11 y.
For the exploratory effect modifiers, of the 115 interaction tests (23
outcomes by 5 exploratory effect modifiers), 14 (12%) were significant
at P < 0.1, which is the number that would be expected by chance.
Although the number of significant interactions was at chance levels,
the pattern of findings for maternal education was consistent with the
hypothesis of greater positive effects of SQ-LNS on child self-
regulation in less-enriched home environments (i.e., those with lower
maternal education). Details are reported in Supplemental Results and
shown in Supplemental Figure 1.
Discussion
In this long-term follow-up study of an RCT that provided a
comprehensive daily nutritional supplement during most of the first
1000 d, from early pregnancy to 18 mo postpartum, we did not find
effects on social–emotional problems at age 9–11 y. Thus, the previous
finding showing reduced social–emotional difficulties in the SQ-LNS
group at age 4–6 y was not sustained to age 9–11 y. We did find that
E.L. Prado et al. The American Journal of Clinical Nutrition 118 (2023) 433–442
FIGURE 2. Association of SQ-LNS with self-reported SDQ conduct
problems by Early Childhood Home Observation for the Measurement of the
Environment (EC-HOME) scores. Among children with low EC-HOME
scores (<23), the SQ-LNS group showed significantly lower conduct prob-
lems than the control group, whereas there were no significant differences
between SQ-LNS and control groups amoung children with high EC-HOME
scores. SDQ, strengths and difficulties questionnaire; SQ-LNS, small-quan-
tity lipid-based nutrient supplement.children who experienced less-enriched early childhood home envi-
ronments tended to have higher social–emotional difficulties at age
9–11 y for 8 of the 23 social–emotional scores examined. These as-
sociations were attenuated, but 7 remained significant, when adjusting
for concurrent home environment, which was significantly associated
with 11 of the 23 social–emotional scores. Among children who
experienced less-enriched early childhood home environments, those
in the SQ-LNS group recorded 0.37 SD lower self-reported conduct
problems than those in the control group. This is consistent with the
previous finding at age 4–6 y in the same cohort that SQ-LNS buffered
children from social–emotional difficulties associated with less-
enriched home environments.14
12
10
8
6
Age 4-6 y Age 9-11 y
Low HOME LNS Low HOME Control
High HOME LNS High HOME Control
FIGURE 3. Total difficuties score on the parent-reported SDQ at age 4–6 y
and 9–11 y by the intervention group and high compared with low EC-
HOME scores. At the age 4–6 y, there were significantly greater effects of
SQ-LNS among children with low HOME scores (less than the median). At
the age 9–11 y, there were no signficiant differences between the groups.
HOME, Home Observation for the Measurement of the Environment; LNS,
lipid-based nutrient supplement; SDQ, strengths and difficulties
questionnaire.
440
Parent-Report SDQ 
Total Difficul esTo our knowledge, this is the first RCT in Africa to report a long-
term follow-up assessment after nutritional supplementation with
both macronutrients and micronutrients in both the prenatal and post-
natal periods, which is a foundational period for brain development. We
are aware of only 2 previous studies with a similar design, both of
which were conducted in Latin America in the 1970s. One of these
randomized only 4 villages to the intervention and control groups [29],
and the other had a high rate of attrition, reenrolling only 55% of the
original sample in the follow-up study [30,31]. Thus, our study, which
was an individually randomized trial with a large sample size and high
follow-up rate, makes an important contribution to the evidence for
long-term effects of early nutrition on behavioral development. Our
primary focus was on social–emotional outcomes due to the positive
effects previously found at age 5 y. Effects on cognitive and academic
skills, for which initial analyses were not significant [32], and other
outcomes will be reported in future publications.
The lack of overall effects of SQ-LNS on child social–emotional
problems may have been due to the low prevalence of social–emotional
problems at 9–11 y of age, such that there was little potential to benefit
fromearly nutritional intervention at this age in this outcomedomain. Few
children (<2%) experienced high social–emotional difficulties on the
parent-reported SDQ at 9–11 y, in contrast to the high prevalence on this
measure at age 5 y in the same cohort (25%). As shown in Figure 3, SDQ
total difficulties declined over time in all intervention and home envi-
ronment groups and converged such that there were no significant group
differences at age 9–11 y. However, group means remained in the same
order that was observed at age 4–6 y, with the highest difficulties in the
control groupwith lowEC-HOMEscores.Adolescence is a period ofhigh
susceptibility to the onset of mental health problems, such as depressive
and anxiety disorders and impulse control disorders [33]. At the next
follow-up assessment at 11–13 y, which is currently in progress, we may
observe an increase in social–emotional problems and divergence of
group means, such that intervention effects may be easier to detect.
The finding that a less-enriched home environment during
both early and middle childhood was associated with higher child
social–emotional problems is consistent with findings among children
in high-income countries [34,35]. A higher score on the HOME in-
ventory reflects multiple aspects of the home environment, such as
higher learning opportunities, parental responsivity and involvement,
family participation, and a positive emotional climate. Our findings
suggest that these aspects of the home environment are important for
social–emotional development in diverse contexts, given that the
setting and culture in Ghana is different from high-income countries
where most research on social–emotional development has been con-
ducted. These aspects of the home environment were associated with
lower child behavior problems, particularly externalizing problems,
such as conduct problems and hyperactivity/inattention, but not inter-
nalizing problems, such as mood symptoms and anxiety. The finding
that both early childhood and preadolescent home environment scores
were associated with behavior problems suggests that both early
childhood and preadolescence are important periods to promote posi-
tive home environments for children's social–emotional well-being.
Our hypothesis that greater effects of SQ-LNS would be found
among children from less-enriched home environments was partly
supported by the interaction found for self-report conduct problems.
Among children in less-enriched early childhood home environments,
those in the SQ-LNS group scored substantially lower than the control
group (0.37 SD) in this domain. This pattern is consistent with
developmental theories that posit that children who experience bio-
logical vulnerabilities may show similar outcomes compared with
E.L. Prado et al. The American Journal of Clinical Nutrition 118 (2023) 433–442children without biological vulnerabilities when raised in positive en-
vironments but may falter under conditions of environmental stress
[36]. This finding should be interpreted with caution because this
pattern was found for only one of the outcomes we examined. How-
ever, the robustness of the finding is supported by the consistency with
the pattern found for social–emotional difficulties at age 4–6 y and the
consistency of the pattern of the group means over time (Figure 2).
Follow-up at future time points will provide further evidence to
examine this hypothesis.
Strengths of the study were the individually randomized design,
large number of children assessed 10 y after the trial was completed,
balance of background characteristics between the intervention groups,
a comprehensive assessment of various types of social–emotional
problems using multiple tools and multiple respondents (self, parent,
and teacher), and demonstrated reliability of the translated tools in the
local context. One limitation was that those lost to follow-up differed
significantly from those included in the analysis in gestational age at
delivery and maternal parity. However, it is unlikely that this led to bias
in the results because the difference in gestational age was small (38.9
vs. 39.3 wk) and there was no interaction between the intervention
group and parity for most outcomes. Another limitation was that the
minimum effect size we were able to detect with our sample size was
0.2 SD, whereas previous studies have shown positive effects of
nutritional supplementation on developmental outcomes of ~0.1 SD
[37]. Thus, we may have missed significant effects owing to a lack of
power to detect smaller differences between the groups.
Our study adds to the evidence base for the effectiveness of nutri-
tional interventions such as SQ-LNS during the prenatal and post-
partum periods. Although we did not find long-term effects on
children's social–emotional problems, we found some evidence that
there may be a positive effect among children in less-enriched home
environments. Future work will examine other outcomes at this age,
such as direct assessments of child behavior and physiology, and will
follow up the cohort later in adolescence.
Acknowledgments
We thank the families, teachers, and schools who participated in and
supported this follow-up study and the Assistant Data Manager, Richard
Azumah, for his contribution to data collection and cleaning. The authors’
responsibilities were as follows—KGD, SAA, ELP, PDH, AEG, AM,
BMO: designed the research; SAA, EA, HB, MM, MO: conducted the
research; CDA, XT, ELP: analyzed the data; ELP: wrote the paper, with
critical input and comments from all other authors; ELP: had primary
responsibility for final content; and all authors: have read and approved
the final manuscript. The authors report no conflicts of interest.Funding
This publication is based on research funded by grants to the Uni-
versity of California, Davis, from the National Institutes of Health
(R01HD099811) and the Bill &Melinda Gates Foundation (OPP49817).
The funders did not play a role in the design or implementation of the
study or interpretation of the data. Thefindings and conclusions contained
within are those of the authors and do not necessarily reflect positions or
policies of the Bill & Melinda Gates Foundation.Data availability
Deidentified individual participant data (such as data dictionaries)
will be made available on request to researchers who provide a441methodologically sound proposal and statistical analysis plan contin-
gent on approval by the principal investigators. Proposals should be
submitted to the corresponding author.Appendix A. Supplementary data
Supplementary data to this article can be found online at https
://doi.org/10.1016/j.ajcnut.2023.05.025.
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