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Citation: Kowalski, A.J.; Mayen, V.A.;
de Ponce, S.; Lambden, K.B.; Tilton,
N.; Villanueva, L.M.; Palacios, A.M.;
Reinhart, G.A.; Hurley, K.M.; Black,
M.M. The Effects of Multiple
Micronutrient Fortified Beverage and
Responsive Caregiving Interventions
on Early Childhood Development,
Hemoglobin, and Ferritin among
Infants in Rural Guatemala. Nutrients
2023,15, 2062. https://doi.org/
10.3390/nu15092062
Academic Editor: John Worobey
Received: 20 March 2023
Revised: 16 April 2023
Accepted: 22 April 2023
Published: 25 April 2023
Copyright: © 2023 by the authors.
Licensee MDPI, Basel, Switzerland.
This article is an open access article
distributed under the terms and
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Attribution (CC BY) license (https://
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4.0/).
nutrients
Article
The Effects of Multiple Micronutrient Fortified Beverage and
Responsive Caregiving Interventions on Early Childhood
Development, Hemoglobin, and Ferritin among Infants in
Rural Guatemala
Alysse J. Kowalski 1, Victor Alfonso Mayen 2, Silvia de Ponce 2, Kaley B. Lambden 3, Nick Tilton 4,
Lisa M. Villanueva 5, Ana M. Palacios 5,6 , Gregory A. Reinhart 5, Kristen M. Hurley 3,†
and Maureen M. Black 1, 7, *,†
1Department of Pediatrics, University of Maryland School of Medicine, Baltimore, MD 21201, USA;
akowalski@som.umaryland.edu
2Asociación para la Prevención y Estudio del VIH/Sida, Retalhuleu 11001, Guatemala;
valfonso@apevihs.org (V.A.M.); shdepster@gmail.com (S.d.P.)
3Department of International Health, Johns Hopkins Bloomberg School of Public Health,
Baltimore, MD 21205, USA; kaley.lambden@gmail.com (K.B.L.)
4Department of Epidemiology and Public Health, University of Maryland School of Medicine,
Baltimore, MD 21202, USA; natilton@gmail.com
5The Mathile Institute for the Advancement of Human Nutrition, Dayton, OH 45414, USA;
lisa@chispuditos.com (L.M.V.); apalacios@georgiasouthern.edu (A.M.P.); reinhart.greg@gmail.com (G.A.R.)
6Jiann Ping Hsu College of Public Health, Georgia Southern University, Statesboro, GA 30458, USA
7RTI International, Research Triangle Park, NC 27709, USA
*Correspondence: mblack@som.umaryland.edu
† These authors contributed equally to this work.
Abstract:
Undernutrition and a lack of learning opportunities can jeopardize long-term growth
and development among infants in low- and middle-income countries. We conducted a 6-month
2
×
2 cluster-randomized trial to assess the effects of multiple micronutrient-fortified beverages
and responsive caregiving interventions among infants 6–18 months in 72 community sectors in
southwest Guatemala. We administered baseline and endline assessments of childhood development
(Bayley Scales of Infant and Toddler Development) and socioemotional development (Brief Infant
Toddler Socio-Emotional Assessment) and measured ferritin and hemoglobin on a subsample. The
trial was analyzed using linear mixed models. At the baseline, the mean age (SD) was 13.0 (4.6)
months, including 49% males, 32% who were stunted, 55% who were anemic, and 58% who were iron
deficient. At the endline (n= 328/386, 85% retention), there was no synergistic effect on the fortified
beverage and responsive caregiving intervention. Compared to the non-fortified beverage group,
socioemotional development improved in the fortified beverage group. There were no intervention
effects on other measures of child development, hemoglobin, or ferritin. In a setting with high
rates of anemia and iron deficiency, a multiple micronutrient-fortified beverage improved infants’
socioemotional development.
Keywords:
multiple micronutrient supplementation; responsive caregiving; socioemotional develop-
ment; early child development; ferritin; hemoglobin; infant; Guatemala
1. Introduction
Early childhood development lays the foundation for subsequent learning throughout
the life course and is associated with health, schooling attainment, and earning potential,
and with individual, family, and societal implications [
1
,
2
]. Estimates of over
250 million
young children in low- and middle-income countries (LMICs) are not reaching their devel-
opmental potential, largely due to undernutrition and a lack of early learning opportunities,
Nutrients 2023,15, 2062. https://doi.org/10.3390/nu15092062 https://www.mdpi.com/journal/nutrients
Nutrients 2023,15, 2062 2 of 16
jeopardizing their long-term growth and development [
3
,
4
]. To support early development,
children need nurturing care, including health, nutrition, safety and security, and opportu-
nities for early learning in the context of responsive caregivers and a stable home [1,5].
Healthy brain development includes dendritic branching, synapse maturation and
function, and myelination is dependent on adequate nutrition, including multiple micronu-
trients [
6
]. Globally, over half of young children are deficient in at least one micronutrient,
with the prevalence of maternal and child micronutrient deficiencies ranging from an
estimated 9% for zinc deficiency to 20% for iron deficiency [
7
,
8
]. Dietary intake in LMICs is
often inadequate to meet micronutrient requirements. Multiple micronutrient supplemen-
tation is effective in improving serum micronutrient concentrations and in reducing rates
of anemia [9,10], but its effects on children’s development are understudied.
Responsive caregiving refers to caregivers’ prompt, age-appropriate, and sensitive
response to children’s behavior [
11
,
12
]. Positive experiences for caregivers and children
are mutually reinforcing and promote continued interactions, supporting attachment and
self-regulation [
13
]. Applied to feeding, responsive caregiving is a culturally adaptable
strategy that encourages children to eat autonomously and in response to physiological and
developmental needs, thereby building self-regulation [
14
]. Applied to play, responsive
caregiving interventions include early learning in a responsive and nurturant context which
build parents’ knowledge, attitudes, and practices related to responsive care, with positive
effects on children’s cognitive, language, psychosocial, and motor development [15,16].
Integrating nutrition and responsive caregiving interventions may be an efficient use of
resources to promote early childhood development. Meta-analyses and systematic reviews
of combined interventions have shown specificity, with beneficial effects on nutrition
attributable to nutrition components and beneficial effects on development attributable to
psychosocial components, with few investigations of synergistic effects [17–19].
Guatemala provides a unique opportunity to investigate the impact of combined
nutrition and responsive caregiving interventions. Guatemala has one of the highest
rates of undernutrition seen globally, and the highest in Latin America. Over 45% of
children < 5 years
are stunted (height-for-age z-scores <
−
2), with higher rates among rural
and indigenous communities, reflecting inequity and poverty [
20
]. Stunting, an indicator
of linear growth failure, is a marker of general environmental deprivation characterized
by inadequate sanitation, food insecurity, and other aspects of poverty [
21
]. In such
environments, micronutrient deficiencies are common and opportunities for early learning
may be limited.
The objective of this study was to evaluate the independent and synergistic effects
of multiple micronutrient supplementation and responsive caregiving interventions on
young children’s development and nutritional status in rural Guatemala. The study was
designed to test three hypotheses: (1) multiple micronutrient-fortified beverage groups will
have better development and nutritional status compared to placebo groups,
(2) responsive
caregiving groups will have better development than groups without responsive care-
giving, and (3) the combined multiple micronutrient-fortified beverage and responsive
caregiving group will have better development than the other three groups, attributed to
synergistic effects.
2. Materials and Methods
In collaboration with the non-governmental organization APEVIHS (Association
for the Prevention and Study of HIV and AIDS, Spanish acronym) located in western
Guatemala, we conducted a study, titled Mejorando la Inteligencia en la Niñez del Takalik
Abaj (Improving Childhood Intelligence of the Takalik Abaj), a reference to a Mayan
archeological site of cultural significance to the communities. We evaluated two home-
based interventions: multiple micronutrient-fortified beverages and responsive caregiving
coaching, singly and in combination, with regard to development and nutrition biomarkers
of infants 6–18 months (the focus of this study) and preschoolers 36–52 months (the focus
of a separate study).
Nutrients 2023,15, 2062 3 of 16
2.1. Site and Study Design
We conducted a cluster-randomized controlled trial in the Department of Retalhuleu
from 2015 to 2017. The department is located in southwestern Guatemala and extends
from the mountains to the Pacific Ocean. The area was selected due to the high prevalence
of stunting (39% in children 6–72 months), suggesting nutritional inadequacies and food
insecurity [
22
]. A rural municipality with proximity to an urban center was selected as the
study site. In 2018, the municipality had a population of 41,000 [
23
]. The municipality was
organized into smaller units of communities and locally recognized sectors. We approached
and shared information with 32 communities (representing 77 sectors), and all expressed
interest in participating in the study. Four communities were subsequently excluded due
to community violence or agriculturally driven seasonal fluctuations in population size.
A 2
×
2 factorial design was used to efficiently test the multiple micronutrient-fortified
beverage and responsive caregiving interventions and their interaction [
24
]. Treatments
were allocated at the sector level to reduce contamination and a stratification procedure
was used to reduce the risk of imbalance. Using Guatemalan census data, we characterized
sectors with respect to size, distance from a highway, and access to a health center. We orga-
nized non-contiguous sectors sharing common characteristics into fourteen strata of at least
four sectors per group. Sectors were allocated to treatments in two randomization steps
within each stratum: multiple micronutrient supplementation or placebo and responsive
caregiving or no caregiving intervention, yielding four treatment groups:
(1) fortified
bever-
age only, (2) responsive caregiving + placebo, (3) fortified beverage + responsive caregiving,
and (4) placebo + no responsive caregiving (control). The researchers and evaluation team
were unaware of treatment assignments and supplement classification (fortified bever-
age/placebo). Home visitors and participants were unaware of beverage classification.
2.2. Sample Size
We a priori determined the sample size needed to evaluate the primary outcome,
childhood development. Presuming 32 communities with an average size of 15 infants and
assuming a moderate effect size on childhood development (0.5 SD) using 2-sided tests
(
α
= 0.05, 80% power) with 85% retention, an intraclass correlation of 0.03, and repeated
measures correlation of 0.4, the study required a sample size of 480 infants.
2.3. Ethical Approval
We obtained ethical approval from the Universidad Francisco Marroquín and the
Institution Review Board of the University of Maryland School of Medicine. The trial was
registered at ClinicalTrials.gov (NCT02302729, registered on 27 November 2014).
2.4. Recruitment
After obtaining approval from municipality leaders, surveillance was conducted
in the targeted communities to identify potential participants. Home visitors recruited
parents of infants 6–18 months (97% mothers, 3% maternal grandmothers). To focus on
children at nutritional risk, we prioritized children with length-for-age z-score (LAZ) <
−
1.
Inclusionary criteria were Spanish-speaking and an intention to remain in the area for the
coming year. Exclusionary criteria were severe undernutrition (length- or weight-for-age
z<−3)
or chronic illness or disabling conditions that could interfere with growth and/or
development. Children with severe undernutrition were referred for medical treatment.
Parents provided informed consent for themselves and their infants.
2.5. Multiple Micronutrient-Fortified Beverage/Placebo Interventions
Atoles are traditional beverages, typically prepared from masa corn flour, that are
widely consumed throughout Central America. Chispuditos
®
was a corn-soy blend for-
tified with 21 micronutrients (i.e., iron, zinc, and B vitamins) that was consumed as a
beverage (see Table 1). Chispuditos
®
was developed by a team of nutrition scientists at
the Mathile Institute for the Advancement of Human Nutrition and manufactured locally.
Nutrients 2023,15, 2062 4 of 16
Pre-post-acceptability studies with young children suggest high acceptance and daily
adherence [22,25–27].
Table 1. Formulation of fortified beverages, Chispuditos®and the placebo.
Quantity per Serving a
Chispuditos®Placebo
Calories (Energy) 73 kcal 73 kcal
Protein 4 g 4 g
Fat 1 g 1 g
Dietary Fiber 2 g 2 g
Carbohydrates 12 g 12 g
Sugars 0 g 0 g
Micronutrients
Iron 12 mg -
Folic Acid 150 mcg -
Zinc 9 mg
Iodine 90 mcg -
Vit A 250 mcg -
Vit C 40 mg -
Vit B12 0.9 mcg -
Thiamine 0.5 mg -
Niacin 6 mg -
Riboflavin 0.5 mg 0.5 mg
Vit B6 0.5 mg -
Copper 300 mcg -
Vitamin D3 5 mcg -
Vitamin E 5 mg -
Calcium 200 mg -
Phosphorus 150 mg -
Magnesium 40 mg -
Selenium 17 mcg -
Manganese 0.17 mg -
Biotin 8 mcg -
Vitamin B5 1.8 mg -
aOne serving = 18.75 g of dry product/day.
The placebo for the study consisted of the same corn-soy blend fortified only with
vitamin B2 (which has no known effect on the outcomes) that was otherwise identical to
Chispuditos
®
. The two products were supplied in identical packets with manufacturer-
assigned codes to differentiate the multiple micronutrient supplements from the placebo.
Codes were stored in a sealed envelope at the Mathile Institute. Products were not com-
mercially available and were provided to participating families free of charge.
Home visitors were scheduled to visit households at 3-week intervals for 6 months,
where they delivered 1 lb bags of Chispuditos
®
/placebo (24 servings) in quantities suf-
ficient for other children in the household and provided nutrition counseling. Mothers
were instructed to serve Chispuditos
®
/placebo to the target infant daily in addition to
typical meals.
2.6. Responsive Caregiving Intervention
The responsive caregiving intervention utilized parent coaching adapted from the
WHO/UNICEF Care for Child Development package that uses play and communication to
promote responsive caregiving activities [
28
]. Home visitors incorporated age-appropriate
behavior messages into the coaching intervention using hand-held flipcharts with local
examples on one side and notes for the home visitor on the other (see Table 2). The
6-session infant curriculum emphasized responsive caregiving applied to both feeding
and play and learning. Responsive feeding included responding to children’s cues of
Nutrients 2023,15, 2062 5 of 16
hunger and satiety in a prompt, emotionally supportive, contingent, and developmentally
appropriate manner, ensuring that the feeding context is pleasant, with verbal and non-
verbal encouragement and modeling during feeding [
11
]. Responsive caregiving during
play and learning included providing opportunities to play and explore while following the
child’s lead through imitation and responding. Home visitors reinforced the key messages
using questioning to check for understanding, demonstration, and practice activities with
mothers and children, and motivational strategies such as goal-setting activities, praise
and positive feedback, and problem-solving [
29
]. Coaching sessions lasted approximately
20 min
, with each session reviewing the previous lesson’s material before introducing
new concepts.
Table 2.
Responsive feeding and caregiving key messages in English and Spanish for infants by age
group (6–12 months, 12–18 months).
Age Group Lesson
Number Message Category aPicture b
6–12 months
1Smile and look at the child during feeding.
Sonría y mire a su hijo(a) mientras lo(a) alimenta. RF, RC
Mother and child
looking, smiling,
feeding
2
Give your child opportunities to explore objects and people.
Tummy time.
Dele a su hijo(a) la oportunidad de explorar nuevos objetos,
personas y alimentos. Es tiempo de estar boca abajo!
RC Child on tummy
playing
Give your child family food of soft and thick consistency
Alimente a su hijo(a)con comida de consistencia suave y espesa.
RF Soft, thick food
3
Eat and play with your child.
Coma y juegue con su hijo(a). RF, RC
Mother and child
facing playing
peek-a-boo, playing
with household
items
Respond to your child’s cues of hunger and satiety.
Reconozca las señales de hambre y saciedad de su niño. RF Mother feeding
eager child
4
Talk and sing to your child during daily activities.
Háblele y cántele a su hijo(a) durante las actividades diarias. RC
Mother singing and
looking at child
Have patience, love, and good humor when feeding your child.
Cuando alimente a su niño tenga paciencia, amor y buen humor.
RF, RC Mother feeding
with a smile
5
Imitate your child’s actions and gestures.
Imite las acciones y gestos de su hijo(a). RC Mother imitating
child
Offer finger foods.
Ofrezca alimentos que se puedan comer con la mano. RF Child picking up
food with fingers
6
Help your child learn signals, such as bye-bye.
Ayude a su niño a reconocer señales, por ejemplo adiós. RC Child waving
Feed your child an adequate amount and variety of food.
Dele a su hijo(a) una alimentación apropiada, variada,
especialmente de frutas y verduras.
RF Mother feeding
child; family meal
Nutrients 2023,15, 2062 6 of 16
Table 2. Cont.
Age Group Lesson
Number Message Category aPicture b
12–18
months
1
Offer finger foods.
Déle a su niño alimentos que se puedan comer con la mano. RF Child picking up
food with fingers
Imitate your child’s actions.
Imite las acciones de su hijo(a). RC Mother doing what
child is doing
2
Play with your child.
Juegue con su hijo. RC
Mother and child
facing playing
peek-a-boo, with
a ball
Respond to your child’s cues of hunger and satiety.
Responda las señales de hambre y saciedad de su hijo(a). RF
Child turning away
from food, mother
not forcing
3
Establish a routine where you look at a book with your child.
Establezca una rutina para observar un libro de cuentos con
su hijo(a).
RC Child in bed,
mother with a book
Eat in a calm, relaxed environment without distractions, such as
TV or radio.
Coma en un lugar tranquiloy sin distracciones.
RF Family eating food
together
4
Talk and sing to your child throughout the day.
Háblele y cántele a su hijo(a) a lo largo del día. RC Mother talking
to child
Take away uneaten food without comments.
Retire los alimentos que el niño(a) no se comiósin decir nada. RF
Mother picking up
plate from child
with food on it
Talk to your child about daily household objects and activities.
Hable con su hijo(a) acerca de objetos domésticos cotidianos y
sobre actividades diarias.
RC Child playing with
household items
5
Play matching games with your child.
Juegue con su hijo(a) a buscar parejas (juegos de asociación). RP
Mother and child
looking at pictures
in a book
Make positive comments about the food (yummy).
Haga comentarios positivos acerca de la comida. RF
Mother smiling and
eating with child
6
Give adequate amounts of food at every meal.
Dele a su hijo(a) cantidades adecuadas de alimentos en
cada comida.
RF Mother serving
child
Praise your child for good efforts even if he does not succeed.
Felicite a su niño por los buenos esfuerzos a pesar de que no
haya tenido éxito.
RC Mother smiling at
child
Be sure that your child is hungry at meals and has not filled up
on sweetened drinks or snacks.
Asegúrese de que su niño tiene hambre en las comidas, y que no
se haya llenado de bebidas dulces o golosinas no nutritivas.
RF
Child looking ready
to eat
a
RC = responsive caregiving applied to play and learning, RF = responsive feeding.
b
Describes the picture that
appears on the flip chart with each lesson.
2.7. Training and Intervention Delivery
Enrollment and intervention delivery were conducted by home visitors who lived in
the study communities. Home visitors participated in a 7-day training led by the research
team on nutrition counseling, parental coaching, informed consent, and data entry using
a combination of didactic instruction and role-playing. Due to safety concerns, all home
visitors were male and reached the communities via motorbike. A supervisor with extensive
field experience and a background in nutrition supervised the intervention delivery.
Nutrients 2023,15, 2062 7 of 16
Home visitors were scheduled to visit households at 3-week intervals for 6 months,
where they delivered the interventions. Due to election-related violence in the communities,
the study visits were curtailed at times and extended over 8 months, with a doubling of
visits when necessary.
2.8. Evaluation
Evaluations were conducted at the baseline prior to randomization and the endline (six
months post-baseline). The outcome measures included standardized measures of child
development, socioemotional development, and nutrition biomarkers. Questionnaires
addressed family demographics and social and environmental factors and were either
validated in Spanish-speaking populations or adapted, translated, and/or developed
for Guatemala.
Participants were transported to a centralized site for evaluations, ensuring that eval-
uators were unaware of community-level assignments. The evaluation team received
specialized training to conduct direct assessments of children’s development and anthro-
pometry. Most evaluators had a background in teaching; all had experience working with
children. The evaluation team was overseen by a licensed psychologist from Guatemala.
Data were collected on tablets using the mobile data collection software Magpi
®
by Data-
Dyne LLC (Washington, DC, USA) and uploaded from the field office daily.
2.9. Outcome Measures
2.9.1. Child Development
Infant development was measured at the baseline and the endline using the Bayley
Scales of Infant and Toddler Development-III Spanish, yielding scores on cognitive, lan-
guage, and motor development [
30
]. Infant social and emotional behaviors were assessed
using the BITSEA (Brief Infant Toddler Social-Emotional Assessment), yielding scores on
socioemotional competence and problems [31].
2.9.2. Nutrition Biomarkers
A contracted phlebotomist collected blood from a subsample of infants at the baseline
and the endline, which was chosen using a randomization procedure to assess changes
in hemoglobin and ferritin concentrations. Ferritin concentration reflects iron stores and
hemoglobin concentration measures the red blood cell supply and is affected by multiple
determinants. Acute phase proteins C-reactive protein and alpha-1 acid glycoprotein
were assayed and used to correct ferritin for the effects of inflammation [
32
]. Ferritin was
right-skewed, and log transformed prior to analysis.
2.10. Control Measures
Data on household, maternal, and child characteristics were assessed at the baseline
to examine their potential influence on the outcome measures. Data were gathered on
social factors and environmental conditions, including family ethnicity and household
food security using the Household Food Insecurity Access Scale [
33
]. Socioeconomic status
was assessed by household asset ownership. Data were gathered on maternal age, marital
status, and schooling attainment. Child weight and length were measured using Seca
scales and Schorr length boards following a standardized protocol. Measurements were
collected in triplicate and averaged. Weight-for-age, length-for-age, weight-for-length, and
BMI-for-age were converted to z-scores using WHO standards [34].
2.11. Statistical Analysis
For all outcomes, we conducted an intent-to-treat analysis using linear mixed-effects
regression models with random intercepts for community and subject to account for the
clustered design and baseline scores, respectively. To assess the synergistic effects of
receiving both the fortified beverage and responsive caregiving interventions on measures
of early childhood development, we included a 3-way interaction term between each
Nutrients 2023,15, 2062 8 of 16
intervention and time. A significant 3-way interaction would indicate a multiplicative
effect between the two interventions and the interaction term would be retained. If the
3-way interaction was nonsignificant, the interaction term would be dropped, and the
effects of each intervention would be reported independently. Analyses were conducted
using R v4.2.0 [35], with significance at p< 0.05.
3. Results
3.1. Baseline Characteristics
The infant sample included 386 infants from 72 sectors (Figure 1). There were no
significant baseline differences in household, maternal, child characteristics, or child devel-
opment measures. The mean (SD) age of mothers was 27.5 (8.1), and 85% were married or
in a relationship (Table 3). Most mothers (81%) had completed primary school or beyond.
Over half (59%) of families were food-insecure at the baseline and 16% identified as an
indigenous. Children were an average of 13.0 (4.6) months at enrollment, and 49% were
boys. Stunting prevalence was 32%, 3% were wasted, and 19% were overweight or obese.
At the endline, 329/386 children (85%) were retained. Retained children had significantly
higher motor development scores and lower LAZ at the baseline. Children lost to follow-up
were more likely to come from indigenous families.
Blood specimens were collected from a subsample of 209 infants (54%). Compared to
infants without a blood sample, infants with a blood sample had significantly higher scores
(range: 3–4 points) on the child development assessments at the baseline. Maternal and
household characteristics did not differ between infants with and without blood samples.
Hemoglobin did not differ between treatment groups at the baseline. Median (IQR) ferritin
was significantly lower among the responsive caregiving + fortified beverage group at the
baseline. The prevalence of anemia and iron deficiency was 55% and 58%, respectively.
3.2. Intervention Effects
The inclusion of a 3-way interaction term between the fortified beverage intervention,
responsive caregiving intervention, and time did not significantly improve model fit,
indicating that there was not a multiplicative effect of receiving both interventions on
measures of early childhood development (see Table 4footnote). The 3-way interaction
term was, therefore, removed, and intervention effects were examined between intervention
and no intervention groups.
Table 4displays the observed mean (SD) baseline and endline values for measures of
early child development and nutrition biomarkers in the fortified beverage, non-fortified
beverage, responsive caregiving, and no responsive caregiving groups, as well as the
difference in the change from the baseline to the endline for each outcome, comparing the
fortified beverage to the non-fortified beverage group and the responsive caregiving to the
no responsive caregiving group.
Nutrients 2023,15, 2062 9 of 16
Nutrients 2023, 15, x FOR PEER REVIEW 9 of 16
Figure 1. A cluster-randomized control trial CONSORT diagram.
Figure 1. A cluster-randomized control trial CONSORT diagram.
Nutrients 2023,15, 2062 10 of 16
Table 3.
Baseline household, mother, and child characteristics by intervention group among infants
in 72 community sectors (n= 386) a.
Characteristic
Responsive
Caregiving
(n= 87)
Fortified Beverage
(n= 98)
Responsive
Caregiving +
Fortified Beverage
(n= 105)
Control
(n= 96) pb
Household
Family ethnicity, n(%) indigenous 14 (19%) 14 (17%) 10 (11%) 12 (15%) 0.59
Food insecurity, n(%) 52 (61%) 55 (59%) 55 (56%) 55 (60%) 0.90
Household assets, n6.45 (2.66) 6.9 (2.93) 6.94 (3.14) 7.06 (3.02) 0.53
Household CHAOS score 14.12 (4.7) 15.3 (5.79) 13.49 (5.05) 14.33 (5.41) 0.12
Mother
Age, y 27.62 (7.85) 28.76 (8.87) 26 (6.6) 27.84 (8.75) 0.10
Married/in a relationship, n(%) 75 (86%) 82 (84%) 93 (89%) 80 (83%) 0.69
<Primary schooling 17 (20%) 16 (17%) 20 (19%) 20 (21%) 1.0
Completed primary schooling 46 (53%) 50 (53%) 55 (52%) 49 (51%)
≥Secondary schooling 24 (28%) 29 (31%) 30 (29%) 27 (28%)
Child
Age, months 12.87 (4.37) 12.78 (4.73) 13.19 (4.81) 13.02 (4.26) 0.93
Male sex, n(%) 43 (49%) 52 (53%) 49 (47%) 47 (49%) 0.84
LAZ −1.6 (0.91) −1.53 (1.05) −1.37 (1.06) −1.71 (1.01) 0.14
WAZ −0.74 (0.93) −0.79 (0.95) −0.68 (0.92) −0.96 (0.92) 0.20
WHZ 0.02 (0.93) −0.02 (1.1) 0.01 (0.93) −0.13 (0.95) 0.73
BMIZ 0.23 (0.94) 0.17 (1.15) 0.2 (0.96) 0.09 (0.94) 0.82
Child development
Cognitive score 91.73 (11.21) 94.11 (11.55) 93.18 (12.19) 94.78 (12.22) 0.35
Language score 84.04 (15.31) 86.13 (14.73) 84.07 (15.6) 86.13 (14.21) 0.62
Motor score 85.86 (10.78) 87.46 (11.89) 86.17 (12.33) 88.34 (13.78) 0.49
Socioemotional competence 10.4 (5.67) 11.6 (5.64) 11.15 (5.97) 11.47 (6.05) 0.62
Socioemotional problems 17.1 (9.34) 19.7 (10.57) 16.87 (8.58) 17.86 (9.5) 0.21
Nutrition biomarkers
Hemoglobin 10.98 (1.32) 10.86 (1.12) 10.61 (1.49) 10.76 (1.29) 0.58
Ferritin c10.4 (25.28) 12.48 (18.99) 8.05 (6.06) 11.29 (15.10) 0.05 *
a
Values are means (SDs) unless otherwise indicated.
b
p-value for baseline differences between groups from
ANOVA. * p< 0.05. cValues are medians (IQRs). p-Value for baseline differences between groups from Kruskal–
Wallis non-parametric ANOVA.
3.2.1. Fortified Beverage Intervention Effects
Baseline to endline changes in socioemotional competence significantly differed be-
tween the fortified and non-fortified groups (p= <0.01), such that socioemotional compe-
tence increased in the fortified beverage group and declined in the non-fortified bever-
age group over time (fortified beverage vs. no fortified beverage = 2.34 [95% CI: 0.98,
3.7], Figure 2). Changes in cognitive, language, motor, and socioemotional problem
scores and hemoglobin and ferritin did not differ between the fortified and non-fortified
beverage groups.
3.2.2. Responsive Caregiving Intervention Effects
Changes in the measures of early childhood development, hemoglobin, and ferritin
from the baseline to the endline did not differ between the responsive caregiving and no
responsive caregiving groups.
Nutrients 2023,15, 2062 11 of 16
Table 4. Measures of child development and nutrition biomarkers by intervention group from the baseline to the endline a,b.
Wave
Fortified
Beverage
(n= 203)
No Fortified
Beverage
(n= 183)
Responsive
Caregiving
(n= 192)
No Responsive
Caregiving
(n= 194)
Fortified Beverage vs. No
Fortified Beverage
(95% CI) c
Responsive Caregiving vs.
No Responsive Caregiving
(95% CI) c
Child development
Cognitive score dBL 93.63 (11.86) 93.32 (11.82) 92.51 (11.74) 94.44 (11.86) −1.23 (−3.52, 1.06) −0.59 (−2.88, 1.7)
EL 88.76 (9.8) 89.97 (9.32) 88.79 (9.7) 89.85 (9.46)
Language score dBL 85.08 (15.17) 85.13 (14.74) 84.05 (15.42) 86.13 (14.43) 0.13 (−2.71, 2.97) 0.06 (−2.78, 2.91)
EL 82.98 (11.35) 82.78 (11.52) 82.66 (11.7) 83.09 (11.18)
Motor score dBL 86.8 (12.1) 87.15 (12.47) 86.03 (11.62) 87.89 (12.82) −0.14 (−2.65, 2.38) −0.36 (−2.87, 2.16)
EL 87.89 (11.3) 88.27 (12.13) 87.57 (11.59) 88.55 (11.8)
Socioemotional competence eBL 11.35 (5.81) 10.98 (5.88) 10.83 (5.84) 11.53 (5.84) 2.34 (0.98, 3.7) ** 0.17 (−1.19, 1.53)
EL 11.97 (6.7) 9.61 (6.44) 10.96 (6.59) 10.7 (6.76)
Socioemotional problems eBL 18.15 (9.61) 17.49 (9.4) 16.97 (8.91) 18.75 (10.05) 1.26 (−0.5, 3.02) −0.83 (−2.59, 0.93)
EL 11.05 (6.62) 9.64 (5.83) 9.86 (5.36) 10.84 (7)
Nutrition biomarkers
Hemoglobin, g/dL BL 10.75 (1.3) 10.87 (1.3) 10.79 (1.42) 10.82 (1.19) 0.13 (−0.23, 0.49) −0.15 (−0.51, 0.22)
EL 11.07 (0.98) 10.98 (0.99) 10.95 (0.9) 11.09 (1.04)
Ferritin, µg/L fBL 9.79 (14.85) 10.82 (19.31) 8.74 (12.65) 11.75 (17.1) 0.1 (−0.24, 0.45) 0.14 (−0.21, 0.49)
EL 35.72 (87.3) 31.1 (76.73) 34.2 (76.13) 31.24 (90.5)
a
Observed BL and EL values are means (SDs). BL, baseline; EL, endline; CI, confidence interval.
b
Multiplicative interactions between fortified beverage and responsive caregiving
interventions were nonsignificant. Specific p-values for each dependent variable are as follows: cognitive score, p= 0.70; language score, p= 0.83; motor, p= 0.19; socioemotional
competence, p= 0.44; socioemotional problems, p= 0.98.
c
Difference (95% CI) in change from the baseline to the endline in intervention vs. no intervention group. ** p< 0.01.
dCognitive
,
language, and motor scores were assessed using the Bayley Scales of Infant Development III. Cognitive scores are composite score equivalents. Language and motor scores are composite
scores. Scores ranged from 40 to 160 with a mean of 100 (SD 15).
e
Socioemotional competence and problem scores were assessed using the Brief Infant-Toddler Social and Emotional
Assessment. Competence scores ranged from 0 to 22. Problem scores ranged from 0 to 62.
f
BL and El values are median (IQR). Intervention vs. no intervention represents the geometric
mean ratio of the relative change from the baseline to the endline comparing intervention groups with non-intervention groups.
Nutrients 2023,15, 2062 12 of 16
Nutrients 2023, 15, x FOR PEER REVIEW 10 of 16
Blood specimens were collected from a subsample of 209 infants (54%). Compared to
infants without a blood sample, infants with a blood sample had significantly higher
scores (range: 3–4 points) on the child development assessments at the baseline. Maternal
and household characteristics did not differ between infants with and without blood sam-
ples. Hemoglobin did not differ between treatment groups at the baseline. Median (IQR)
ferritin was significantly lower among the responsive caregiving + fortified beverage
group at the baseline. The prevalence of anemia and iron deficiency was 55% and 58%,
respectively.
3.2. Intervention Effects
The inclusion of a 3-way interaction term between the fortified beverage intervention,
responsive caregiving intervention, and time did not significantly improve model fit, in-
dicating that there was not a multiplicative effect of receiving both interventions on
measures of early childhood development (see Table 4 footnote). The 3-way interaction
term was, therefore, removed, and intervention effects were examined between interven-
tion and no intervention groups.
Table 4 displays the observed mean (SD) baseline and endline values for measures of
early child development and nutrition biomarkers in the fortified beverage, non-fortified
beverage, responsive caregiving, and no responsive caregiving groups, as well as the dif-
ference in the change from the baseline to the endline for each outcome, comparing the
fortified beverage to the non-fortified beverage group and the responsive caregiving to
the no responsive caregiving group.
3.2.1. Fortified Beverage Intervention Effects
Baseline to endline changes in socioemotional competence significantly differed be-
tween the fortified and non-fortified groups (p = <0.01), such that socioemotional compe-
tence increased in the fortified beverage group and declined in the non-fortified beverage
group over time (fortified beverage vs. no fortified beverage = 2.34 [95% CI: 0.98, 3.7], Fig-
ure 2). Changes in cognitive, language, motor, and socioemotional problem scores and
hemoglobin and ferritin did not differ between the fortified and non-fortified beverage
groups.
Figure 2. Predicted changes in socioemotional competence score from the baseline to the endline by
intervention group.
Figure 2.
Predicted changes in socioemotional competence score from the baseline to the endline by
intervention group.
4. Discussion
In a cluster-randomized controlled trial of fortified beverages and responsive caregiv-
ing interventions among infants at risk of micronutrient deficiencies in western Guatemala,
there was no synergistic effect of the combined interventions on measures of child develop-
ment or nutrition biomarkers. A receipt of the multiple micronutrient-fortified beverage
improved infants’ socioemotional development. There was no effect of the responsive
caregiving intervention.
Our finding that the fortified beverage was beneficial to socioemotional development
is consistent with the findings from a systematic review and meta-analysis that showed that
multiple micronutrient supplementation was positively associated with socioemotional
scores in young children < 5 years [
19
]. More specifically, iron deficiency has been associated
with non-adaptive socioemotional behavior including shyness and decreasing soothability,
affect, and engagement [
36
]. These behaviors can interfere with the play and interactions
that promote infant development.
We found no difference between the placebo and fortified beverage groups with respect
to cognitive, language, and motor development, which was consistent with findings from
other studies. In a trial of 3300 infants (age 8 + 0.3 months) in Bangladesh, infants received
iron syrup, multiple micronutrient powders, or a placebo daily for 3 months [
37
]. Iron
status and anemia improved, with no effects on the Bayley Scales of Infant Development
scores following the intervention or at the 9-month follow-up and no impact on any other
developmental or growth outcomes. In a systematic review of iron supplementation from 6
to 24 months, there was no clear relation between iron status and developmental outcomes
up to age 4 [38].
Ferritin improved in each treatment group, while hemoglobin remained unchanged,
which was inconsistent with a systematic review that found that ferritin and hemoglobin
increased in response to multiple micronutrient supplementation [
10
]. The placebo group
reflects the secular trend in ferritin during the study period. Similar increases in ferritin in
the fortified beverage group might suggest that adherence to the fortified beverage/placebo
intervention was suboptimal. While the fortified beverage/placebo was provided in
quantities sufficient for each child in the family, atoles are common foods, and the study
beverage may have been consumed by other children or family members. Adherence may
Nutrients 2023,15, 2062 13 of 16
also have been negatively impacted by disruptions to the home visits related to election
violence, which has been widespread since the country’s transition to democracy in the mid-
1980s [
39
]. Alternatively, both the fortified beverage and placebo groups received nutrition
education counseling, which has been shown to improve minimum dietary diversity and
minimum acceptable diet in young children in Guatemala [40].
Parenting programs that encourage nurturing care have been shown to have positive
effects on children’s cognitive, language, and motor development in meta-analyses; effects
on socioemotional development are inconclusive [
15
,
16
]. Effects were greater in LMICs
and vulnerable groups, such as rural communities and caregivers with low education
levels [
15
,
16
]. Programs that focused on responsive caregiving had greater effects on
parenting knowledge, practices, and parent–child interactions with benefits to cognitive
development [
15
]. Despite empirical evidence for responsive caregiving interventions, our
study did not find an effect on children’s development.
There are several possible explanations for this lack of findings. First, periodic violence
required the study to be paused several times, which disrupted intervention fidelity and
may have increased stress for families. To compensate for missed visits, home visitors were
instructed to combine lessons which may have resulted in lessons being rushed or too many
messages at one time for caregivers to absorb and implement [
41
]. A second contributing
factor may have been that the home visitors were male, which given the widespread
cultural context of machismo that focuses on masculine pride with little attention to
caregiving [
42
], may have limited the effectiveness of the responsive caregiving intervention,
which relies on rapport building and coaching with primary caregivers, which in Guatemala
are primarily mothers.
Given the lack of effect of responsive caregiving intervention, it is perhaps unsurpris-
ing that we did not observe a synergistic effect of combining the fortified beverage and
responsive caregiving on children’s development, as hypothesized. Although combined
interventions have positively affected development, the effect sizes tend not to differ from
caregiving interventions alone [17,18]. While the theoretical basis for combining nutrition
and caregiving interventions is strong and pragmatic from a program delivery standpoint,
as both target young children during periods of rapid growth and development, bundling
interventions may diminish the quality of the individual components by increasing the
workload of the home visitor or overloading the recipient with information. Additional
research is needed to ensure that caregiving and nutrition interventions are integrated such
that home visitors can introduce them in a seamless manner that is respectful of caregivers’
time and cultural context.
Strengths of the study include high participant retention (85%). The intervention was
delivered through a successful partnership with a local non-governmental organization and
used a locally produced, culturally accepted beverage to deliver micronutrients. The study
measured multiple aspects of children’s development using direct observation and maternal
reports and objective measures of nutritional status. Limitations include disruptions to
the fieldwork, which prevented the intervention from being implemented as designed.
The lack of process monitoring data limits our ability to understand the uptake of the
fortified beverage/placebo and responsive caregiving interventions. Lastly, the study was
under-enrolled, as reflected by the width of the confidence intervals.
Following community enthusiasm for the product, the multiple micronutrient-fortified
beverage Chispuditos
®
continues to be produced in Guatemala and is distributed in
Guatemala, Nicaragua, and Honduras through a combination of grant-funded and direct-
to-consumer distribution channels.
5. Conclusions
Fortification is an important strategy to address micronutrient deficiencies. The find-
ing that a multiple micronutrient-fortified beverage improved socioemotional development
is consistent with other multiple micronutrient trials, warranting further investigation into
the mechanisms by which micronutrients influence socioemotional development. Future
Nutrients 2023,15, 2062 14 of 16
studies targeting micronutrient deficiencies should measure socioemotional development.
Although the theoretical underpinnings for combining multiple micronutrients and respon-
sive caregiving interventions to support children’s development are strong, more careful
integration and implementation strategies are needed.
Author Contributions:
Conceptualization, M.M.B., K.M.H., V.A.M. and A.J.K.; methodology, V.A.M.
and S.d.P.; software, K.B.L.; validation, K.M.H. and K.B.L.; formal analysis, A.J.K. and N.T.; resources,
V.A.M. and S.d.P.; data curation, K.B.L.; writing—original draft preparation, A.J.K. and M.M.B.;
writing—review and editing, K.M.H., V.A.M., S.d.P., K.B.L., L.M.V., A.M.P., N.T. and G.A.R.; super-
vision, S.d.P. and L.M.V.; project administration, V.A.M.; funding acquisition, G.A.R., M.M.B. and
K.M.H. All authors have read and agreed to the published version of the manuscript.
Funding:
This research was funded by the Mathile Institute for the Advancement of Human Nutrition
and The New York Academy of Sciences (no funding numbers). The analysis and preparation of
the manuscript and the APC were supported by the University of Maryland, Baltimore, Institute for
Clinical and Translational Research TL1 TR003100 given to A.J.K.
Institutional Review Board Statement:
The study was conducted in accordance with the Declaration
of Helsinki and was approved by the Institutional Review Board of the University of Maryland
Baltimore, protocol HP-00061322, 8 November 2014.
Informed Consent Statement: Informed consent was obtained from all subjects involved in the study.
Data Availability Statement:
The data presented in this study is available upon request from the
first or corresponding author. These data are not publicly available due to privacy issues.
Acknowledgments:
The authors acknowledge Raquel Arbaiza, who assisted in the curation of
the data, the staff of APEVIHS, who assisted in data collection, and the children and families in
Guatemala who participated in the research. We acknowledge the support of the University of
Maryland, Baltimore, Institute for Clinical and Translational Research (ICTR), and the National
Center for Advancing Translational Sciences (NCATS) Clinical Translational Science Award (CTSA),
grant number 1UL1TR003098.
Conflicts of Interest: The authors declare no conflict of interest.
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