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Impact of an integrated nutrition, health,
water sanitation and hygiene, psychosocial
care and support intervention package
delivered during the pre- and peri-
conception period and/or during
pregnancy and early childhood on linear
growth of infants in the first two years of
life, birth outcomes and nutritional status
of mothers: study protocol of a factorial,
individually randomized controlled trial in
India
Sunita Taneja
1
, Ranadip Chowdhury
1
, Neeta Dhabhai
1
, Sarmila Mazumder
1
, Ravi Prakash Upadhyay
1
,
Sitanshi Sharma
1
, Rupali Dewan
2
, Pratima Mittal
2
, Harish Chellani
2
, Rajiv Bahl
3
, Maharaj Kishan Bhan
4,5
,
Nita Bhandari
1*
and on behalf of the Women and Infants Integrated Growth Study (WINGS) Group
Abstract
Background: The period from conception to two years of life denotes a critical window of opportunity for promoting
optimal growth and development of children. Poor nutrition and health in women of reproductive age and during
pregnancy can negatively impact birth outcomes and subsequent infant survival, health and growth. Studies to improve
birth outcomes and to achieve optimal growth and development in young children have usually tested the effect of
standalone interventions in pregnancy and/or the postnatal period. It is not clearly known whether evidence-based
interventions in the different domains such as health, nutrition, water sanitation and hygiene (WASH) and psychosocial care,
when delivered together have a synergistic effect. Further, the effect of delivery of an intervention package in the pre and
peri-conception period is not fully understood. This study was conceived with an aim to understand the impact of an
integrated intervention package, delivered across the pre and peri-conception period, throughpregnancyandtill24months
of child age on birth outcomes, growth and development in children.
(Continued on next page)
© The Author(s). 2020 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0
International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and
reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to
the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver
(http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
* Correspondence: nita.bhandari@sas.org.in
1
Centre for Health Research and Development, Society for Applied Studies,
45, Kalu Sarai, New Delhi, India
Full list of author information is available at the end of the article
Taneja et al. Trials (2020) 21:127
https://doi.org/10.1186/s13063-020-4059-z
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(Continued from previous page)
Methods: An individually randomized controlled trial with factorial design is being conducted in urban and peri-urban low-
to mid-socioeconomic neighbourhoods in South Delhi, India. 13,500 married women aged 18 to 30 years will be enrolled
and randomized to receive either the pre and peri-conception intervention package or routine care (first randomization).
Interventions will be delivered until women are confirmed to be pregnant or complete 18 months of follow up. Once
pregnancy is confirmed, women are randomized again (second randomization) to receive either the intervention package
for pregnancy and postnatal period or to routine care. Newborns will be followed up till 24 months of age. The interventions
are delivered through different study teams. Outcome data are collected by an independent outcome ascertainment team.
Discussion: This study will demonstrate the improvement that can be achieved when key factors known to limit child
growth and development are addressed together, throughout the continuum from pre and peri-conception until early
childhood. The findings will increase our scientific understanding and provide guidance to nutrition programs in low-
and middle-income settings.
Trial registration: Clinical Trial Registry –India #CTRI/2017/06/008908; Registered 23 June 2017, http://ctri.nic.in/
Clinicaltrials/pmaindet2.php?trialid=19339&EncHid=&userName=society%20for%20applied%20studies
Keywords: Pre- and peri-conception, Pre-pregnancy, Stunting, Preterm, Small-for-gestation age, Low birth weight, Integrated
intervention, Pregnancy interventions, Nutrition interventions, Growth, Intergenerational effect
Background
The major focus of the Millennium Development Goals was
on reducing childhood mortality whereas the subsequent
Sustainable Development Goals (SDGs) lay emphasis not
only on improving survival but also on promotion of overall
health and wellbeing of children [1,2]. Adequate growth and
development of the child lays the foundation of adult health
and productivity and is an integral step towards achieving
the SDGs. Evidence indicates that the first 1000 days of life
i.e. from conception to two years of age are critical for opti-
mal growth and brain development [3,4]. Linear growth and
neurodevelopment are particularly interlinked in the first
two years of life as the etiology of poor growth (stunting)
and neurodevelopment, such as insufficient nutrition, re-
peated infections and sub-optimal care, are similar during
this period [5–7]. Birth weight, gestational age and size at
birth are key parameters influencing growth and develop-
ment in early life [8–10]. Low birth weight (LBW) resulting
from both preterm birth and intrauterine growth retardation
is a predictor of linear growth in early childhood and an
important risk factor for stunting and poor cognitive devel-
opment, in addition to its substantial contribution to mortal-
ity [11–13].
Most studies have tested the effect of standalone inter-
ventions within the first 1000 days window; primarily in
the domains of health, nutrition, WASH and psycho-
social health. These interventions were found to have
modest effects on linear growth. The largest impact of a
single intervention during pregnancy on birth weights
was ~ 50 g mean difference (0.1 standard deviation; SD)
and 15% reduction in those born LBW [14,15]. The im-
pact of a single intervention during pregnancy and/or
the postnatal period on attained length was ~ 0.4 cm
mean difference (0.1 SD) and ~ 15% reduction in stunt-
ing at 24 months of age was seen [16].
Valuable insights for the selection of study interventions
were provided by an extensive literature review on interven-
tions that influence birth, growth and development out-
comes in children. Firstly, the causes are multifactorial and
interventions are needed in the domains of health, nutri-
tion, WASH and psychosocial care and support. Secondly,
studies that tested the effect of standalone interventions
found modest effects. It is yet uncertain whether the effects
are synergistic, if interventions are delivered together as a
package. Thirdly, interventions need to be delivered across
the critical periods i.e. the 1000-days window from concep-
tion to birth and up to 24 months of child age. The review
also revealed that the impact of delivering an intervention
package covering the four different domains during the
pre- and peri-conception period is yet unexplored [17].
Although the 1000 days period is indeed a critical win-
dow for the infant, mother’s own health, both physical
and mental, as well as her nutrition at the time of con-
ception is important for her own wellbeing and healthy
birth outcomes and thriving of her child [18–20]. Poor
nutrition in women of reproductive age and during preg-
nancy can impair fetal growth, which is associated with
preterm birth and small-for-gestation (SGA) newborns
[21,22]. Undernutrition and deficiency of micronutri-
ents such as iron, iodine and folic acid in women can
have substantial effects on infant health and develop-
ment outcomes [21,23]. Hypothyroidism, hypertension
and diabetes, and reproductive tract infections (RTI) also
affect birth outcomes and subsequent infant survival,
health and growth [24–27].
Observational data reveal a relationship between substance
use in mothers, specifically of alcohol and tobacco, and
maternal depression, with child growth and development
[28–30]. The psychosocial health of women at the time of
pregnancy may also influence fetal and infant growth [31].
Taneja et al. Trials (2020) 21:127 Page 2 of 18
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Maternal height is an indicator of intergenerational
linkages between maternal and child nutrition and
health; short maternal height is associated with offspring
undernutrition [32].
We are conducting an individually-randomized con-
trolled trial in urban and peri-urban low- to mid-
socioeconomic neighborhoods in Delhi, India to ascer-
tain the impact that can be achieved on birth outcomes,
growth and development in children by intervening be-
fore women become pregnant, in addition to delivering
interventions during pregnancy and postnatal life. The
study aims to achieve optimal growth and development
in infants and children through concurrent delivery of
an integrated package of evidence-based interventions
covering the continuum from the pre- and peri-
conception period to early childhood. We used a factor-
ial design so that the impact of intervening during the
pre-pregnancy period alone could also be assessed.
Objectives
The primary objective is to determine the effect of inte-
grated and concurrent delivery of interventions to im-
prove health, nutrition, WASH and psychosocial status
during the pre- and peri-conception period alone (pre-
and peri-conception intervention package); during preg-
nancy and early childhood (enhanced antenatal, postnatal
and early childhood care) and; throughout the pre- and
peri-conception period, pregnancy and early childhood
(pre- and peri-conception intervention package and en-
hanced antenatal, postnatal and early childhood care), on
preterm birth, LBW and SGA, and stunting at 24 months
of age compared to routine care and additionally, to assess
whether the effect of these interventions differs by mater-
nal stature (< 150 cm or ≥150 cm).
The secondary objectives are to determine the effect of the
same package on nutritional status, morbidity and neurode-
velopment in children, and on women’snutritionalstatus
and morbidity in the pre- and peri-conception, pregnancy
and postpartum periods.
Methods
Study design, setting and participants
The study is an individually randomized trial with a fac-
torial design and is being conducted in urban and peri-
urban low-to mid-socioeconomic neighborhoods of South
Delhi, India [33]. In this setting, the proportion of infants
born LBW (~ 25%), the stunting rates among under twos
(~ 40%) and maternal undernutrition (body mass index
[BMI] < 18.5 kg/m
2
) ~ 22%, are similar to the national
average [34].
Eligible women are identified through a door-to-door
survey. Those who consent for participation are enrolled
(first randomization) and followed up until they are con-
firmed to be pregnant, or have completed 18 months of
follow up post-enrolment. Once pregnancy is confirmed,
consent is taken (second randomization) from the
women for her and her infant’s participation in the trial
(Fig. 1).
Inclusion criteria
Women aged 18–30 years, married and living with their
husband, with no or one child and wish to have a child,
and consent for participation in the study.
Exclusion criteria
Families who plan to move out of the study area or live
in temporary housing (households without concrete
roof, toilet, water connection and legal electricity) are
excluded as they are likely to be relocated by the govern-
ment in the near future.
Sample size
Sample sizes were calculated for 90% power and 95% con-
fidence level except for the preterm birth outcome for
which the power is 80% for comparison between effect of
pre- and peri-conception intervention package and en-
hanced antenatal, postnatal and early childhood care.
Larger effect sizes than those shown for single interven-
tions were assumed for the combined effect of pre- and
peri-conception intervention package, enhanced antenatal,
postnatal and early childhood care group [14–16]. A 1.5
times higher effect size for the impact of either pre- and
peri-conception intervention package or enhanced ante-
natal, postnatal and early childhood care compared with
control, and at least 2 times higher for combined effect of
pre- and peri-conception intervention package and en-
hanced antenatal, postnatal and early childhood care com-
pared to control was assumed (Tables 1and 2).
We propose to enrol a total of 13,500 eligible women
(6750 in pre- and peri-conception intervention package
group and 6750 in control group) based on the following
assumptions: 45% of reproductive-age women random-
ized get pregnant in the 18 months of the pre- and peri-
conception intervention period, 30% loss (abortions, still
births, maternal deaths, moving away, refusals) between
pregnancy and live birth and 20% loss (loss-to-follow-up
and child deaths) between birth and 24 months of age.
We will get ~ 1100 live births per group. This will en-
able us to detect a 25% difference in preterm births, pro-
portion LBW and SGA between pre- and peri-
conception package alone and control group (A + B vs
C + D) and enhanced antenatal, postnatal and early
childhood care alone and control group (A + C vs B + D)
and a mean difference of 0.15 SD in LAZ score at 24
months for the above comparisons.
We will get at least 600 children in each of the four
groups (A, B, C, D) at 24 months. We will be able to de-
tect 0.2 SD difference in mean LAZ score at 24 months
Taneja et al. Trials (2020) 21:127 Page 3 of 18
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and 0.2 SD difference in birth weight and birth length
between pre- and peri-conception intervention package
and enhanced antenatal, postnatal and early childhood
care and control group.
The sample size of ~ 2400 (at least 600 children in
each of the 4 groups) at 24 months of age will also allow
us to detect an interaction odds ratio (lOR) of ≥1.70 to
1.85 in the proportion of stunted children among short
mothers (< 150 cm) and among tall mothers (≥150 cm)
between the control (routine care) and the intervention
group who received the intervention package through-
out, with 80% power and 95% confidence level.
Study interventions
The interventions are in four domains i.e. health, nu-
trition, psychosocial care and support, and WASH
during pre- and peri-conception period, pregnancy
and the postnatal (0 to 24 months) periods. These
were selected based on evidence of their impact on
preterm birth, SGA, birth weight and length and lin-
ear growth at 24 months, and finalized in consultation
with the Technical Advisory Group (TAG) constituted
for the study (Additional file 1). A summary of the
intervention packages is shown in Table 3; details are
given in Additional file 2.
Fig. 1 Study design
Table 1 Sample size estimates for effect of pre- and peri-conception intervention package alone A + B vs C + D) or Enhanced
antenatal, postnatal and early childhood care alone (A + C vs B + D)
Main effect size Sample size per two groups
Linear growth at 24 months
- Mean length-for-age z-score (LAZ) 0.15 SD (absolute value 0.65 cm at 24 mo) 935
- Proportion stunted (30%) 25% relative reduction 772
Birth weight/birth length 0.15 SD (absolute value 75 g birth weight and 0.35 cm birth length) 935
Proportion LBW (25%) 25% relative reduction 918
Preterm birth (12%) [35] 25% relative reduction 2193
SGA at birth (36%) [10] 25% relative reduction 558
90% power and 95% confidence level for all outcomes
Taneja et al. Trials (2020) 21:127 Page 4 of 18
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The principles underlying the selection of interven-
tions for the pre- and peri-conception period are that
women are infection-free, nutritionally-replete and in a
positive state of mental health when they conceive.
Women are screened and treated for health conditions
known to affect fetal and infant growth [17,36,37].
Around 50% women of reproductive age in the study set-
ting are micronutrient deficient [38]. In consultation with
the TAG, it was decided to give half to three-quarters of
the recommended daily allowance (RDA) of the micronu-
trients daily which are known to contribute to optimal
birth outcomes. Around 20% women of reproductive age
group in this setting are undernourished [34]. These
women are given food supplements in the form of a
choice of snacks prepared locally: 500 Kcal and 6–10 g
protein for women with BMI between 16 kg/m
2
and 18.5
kg/m
2
and double the amount for women with BMI < 16
kg/m
2.
to be consumed daily. One egg or milk (180 ml)
both containing 70 Kcal and 6 g protein is given to all
women with BMI < 21 kg/m
2
6 days a week, as a source of
high-quality protein.
For the care component, the intent is to identify the
presence of stressors and manage them to the extent pos-
sible, so that women enter the pregnancy in a positive
state of mental health. Further, with improved psycho-
logical wellness, women are more likely to adopt behav-
iours that are beneficial for them. The study intervention
focuses on counselling women to “think healthy”. A coun-
selling module has been developed through adaptation of
the WHO Thinking Healthy Module [39]. The adapted
version of the module emphasizes the basic five principles
- empathetic listening, guided discovery using pictures,
family engagement, problem solving and behavioural acti-
vation and is aligned to the local context which makes it
easy to comprehend by the participant. All women in the
intervention group are counselled to promote generic
problem-solving skills, inculcate positive thinking and
Table 2 Sample size estimates for the combined effect of pre-
and peri-conception intervention package and enhanced
antenatal, postnatal and early childhood care (A vs D)
Main effect size Sample size
per group
Linear growth at 24 months
- Mean LAZ 0.20 SD
(absolute value 0.80 cm at 24 mo)
527
- Proportion
stunted (30%)
30% relative reduction 491
Birth weight/birth
length
0.20 SD (absolute value 100 g birth
weight and 0.45 cm birth length)
527
Proportion LBW (25%) 30% relative reduction 624
Preterm birth
(12%) [35]
30% relative reduction 1100
SGA at birth
(36%) [10]
30% relative reduction 381
90% power for all outcomes except 80% for preterm births. 95% confidence
level for all outcomes
Table 3 Intervention packages in the pre- and peri-conception period, pregnancy and postnatal period
a
Period Intervention group Control group
Health Nutrition Psychosocial
care
WASH
Pre- and
peri-conception
Screen and treat
medical conditions
Screen and treat malnutrition and
anemia;
Promote
positive
thinking and
problem-
solving skills
Promote
personal,
menstrual and
hand hygiene
Only weekly IFA
supplementation as part
of National Program
(National Iron Plus
Initiative)
Provide iron-folic acid, multiple micro
nutrients, locally-prepared snacks, egg
or milk
Pregnancy > 8 antenatal contacts,
screen and treat medical
conditions, calcium and
vitamin D supplementation
Provide iron-folic acid, multiple micro
nutrients, locally-prepared snacks and
milk, monitor weight
Promote
positive
thinking and
problem-
solving skills
Provide water
filters, soap,
hand washing
station,
disinfectant
Routine antenatal care
Postnatal Empower family to identify
danger signs and seek care
early
0–6 mo: lactation support for early
and exclusive breastfeeding
Promote early
child play
and
responsive
care
Provide play
mat and potty
Routine Postnatal care
Childhood 6–24 mo: promote timely
complementary feeding and
continued breastfeeding, provide
quality food, monitor inadequate
weight gain
Mothers
(0 to 6 mo)
Facilitate postnatal visit at 6
weeks
Iron-folic acid, multiple micronutrients,
calcium and Vitamin D, locally-
prepared snacks and milk
supplementation
Promote
positive
thinking and
problem-
solving skills
Provide water
filters, soap, hand
washing station,
disinfectant
a
Electronic monitoring to track women and children with problems to improve intervention delivery across all periods
Taneja et al. Trials (2020) 21:127 Page 5 of 18
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empower them in a way that they learn to devise strat-
egies, within their prevailing circumstances, to overcome
day-to-day stressors. Women are also screened for depres-
sive symptoms, use of tobacco, exposure to second-hand
smoke and alcohol use by the spouse and are managed
and counselled accordingly. The WASH interventions
during this period are limited to prevention of RTI
through promotion of menstrual and personal, and hand
hygiene.
During pregnancy, the intent is to screen and treat
medical conditions known to affect fetal and infant
growth [40–44]. As micronutrient deficiency is high in
this setting; pregnant women are advised ~ 1 RDA of
daily micronutrient supplementation daily throughout
pregnancy [45–47]. To meet the additional energy and
protein requirements, food supplements are given to all
women with BMI < 25 kg/m
2
[43]. The consensus by the
TAG was to estimate additional requirements assuming
a 12 kg weight gain during pregnancy [48] . The supple-
ments are provided through a choice of locally-prepared
snacks (containing cereal, pulses, soya, oil, sugar, salt,
milk powder) - 210 kcal, 2 g protein in second trimester;
400 kcal, 21 g protein in third trimester [49,50]. All
women are also given milk (180 ml, 70 Kcal, 6 g protein)
6 days a week throughout pregnancy. Additionally,
women with BMI < 18.5 kg/m
2
are given 500 Kcal, 20 g
protein in the form of a hot-cooked meal as the first
meal in the morning. Weight gain is monitored monthly;
those with inadequate weight gain defined based on In-
stitute of Medicine Guidelines get a hot cooked meal
(500 Kcal, 20 g protein), 6 days a week [48,51,52].
Evidence suggests that maternal psychosocial health
during pregnancy is related to pregnancy complications,
fetal growth and birth outcomes. Further, depression
and mood disorders can impair an individual’s ability to
make rational decisions and access health services. An
adaptation of the WHO Thinking Healthy Module is
used for counselling during pregnancy [39]. The content
covers three broad domains: personal health of the
mother, her relationship with other family members and
her relationship with the child. The components of care
intervention essentially remain the same as for the precon-
ception period; however, the frequency of visits is aligned
to the antenatal care visits. The WASH interventions dur-
ing pregnancy (and continued during postnatal period) in-
clude improvement of drinking water quality through
provision of water filters and storage bottles; reducing
fecal load in the environment by providing detergents for
cleaning toilets (if not available at home), and promotion
of handwashing to reduce fecal transmission by placing a
handwashing station in households where these are not
available, counselling on correct handwashing technique
and timing and provision of soap for handwashing. We
did not attempt to make infrastructural changes for
sanitation as these are not feasible in an individually ran-
domized trial. We also did not intervene to increase the
quantity of water due to ethical and social reasons.
During the postnatal period (first 6 months), mothers
are encouraged to visit the delivery facility according to
the follow up schedule advised by them. Micronutrient
supplementation is continued. Women are provided
locally-prepared snacks (500 kcal, 15 g protein) and milk
(180 ml, 70 Kcal, 6 g protein) 6 days a week to meet the
additional requirements during lactation [49]. For the
care component, the intent is to decrease the risk of
postpartum depression which has been shown to nega-
tively affect breastfeeding performance and long-term
child growth and development. Counselling is done
using a module developed through adaptation of the
WHO Thinking Healthy Module [39].
From birth to 6 months of age, mothers are counselled
on early initiation of breastfeeding and exclusive breast-
feeding. Monthly growth monitoring is done for early
identification of growth faltering. Those with inadequate
weight gain (<15th centile as per WHO weight velocity/
month) are referred to the outreach clinic for a physician
examination for morbidity and for lactation counseling.
Micronutrient supplementation (calcium, iron, phos-
phorus, vitamin D) for LBW and very LBW infants is
done according to WHO guidelines [53].
Caregivers of children aged 6 to 24 months are coun-
selled on timely introduction of complementary foods at
6 months, on the frequency of feeding and types of food
to be fed and their amounts, recipes of energy and
nutrient-dense meals made from locally-available,
culturally-acceptable foods are shared. Additionally a daily
cereal mix packet (6 to 12 months; 125 Kcal per day, 2.5 g
protein 12 to 24 months; 250 Kcal per day, 5g protein that
includes 80% to 100% RDA of micronutrients) is provided.
This covers 40% to 60% of the energy requirement be-
tween 6 to 24 months of age assuming the child is breast-
fed [54]. Monthly weighing is continued to detect growth
faltering. Those with inadequate weight gain (<25th
centile according to WHO weight velocity/month) are re-
ferred to the physicians in the outreach clinic for assess-
ment of morbidity. Additional food supplements in the
form of snacks providing (~ 125 Kcal per day, ~ 2.5 g pro-
tein during 6 to 12 months; ~ 250 Kcal per day, ~ 5 g pro-
tein during 12 to 24 months) are offered.
Age-specific child play and stimulation activities, soon
after birth, along with early identification of develop-
mental deviations and their prompt management are the
core components of the child-care package as brain
growth is highly dynamic in the first two years of life
and structured stimulation provided soon after birth by
the mother and family members would accelerate devel-
opment. The interventions for early child development
have been adapted using Care for Child Development
Taneja et al. Trials (2020) 21:127 Page 6 of 18
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manual developed by WHO and UNICEF [55]. The
pregnancy WASH interventions are continued in the
postnatal period. Additional interventions are promotion
of safe disposal of child feces and providing a potty at ~
1 year of age. To promote a clean area for children, a
play mat is provided ~ 6 months of age.
An electronic monitoring system has been developed
to track women and children with problems and those
who require additional support to achieve high compli-
ance to interventions delivered during all the periods.
All participants (women and children) in both the
groups are free to access the usual care pathways includ-
ing free services from the government health system.
Outcome measures
The primary outcomes include proportion preterm birth
(ultrasound-confirmed gestational age at birth < 37 com-
pleted weeks); proportion SGA (birth weight centile <10th
as per INTERGROWTH-21 standard) on day 7 of birth;
proportion LBW (birth weight < 2500 g); mean birth
weight and length; attained length (LAZ) at 24 months of
age and proportion stunted (LAZ < -2 SD).
The list of secondary outcomes along with the timing of
measurements during the pre- and peri-conception, preg-
nancy and postnatal periods are provided in Additional file 3.
The key secondary outcomes for children are propor-
tion stunted at 6 and 12 months, wasted and under-
weight at 6, 12 and 24 months, weight and length
trajectories from birth to 24 months, body composition
(in a subsample) at 1 month of age and neurodevelop-
ment at 6, 12, 18 and 24 months (in a subsample),
micronutrients and anemia status at 24 months, morbid-
ity and hospitalization from birth to 24 months (Add-
itional file 3).
The key secondary outcomes for women are micronu-
trients and anemia status, depressive symptoms and in-
fection at the end of pre- and peri-conception, during
pregnancy and postpartum period (Additional file 3).
Study procedures
Screening and enrollment
The screening and enrolment team (SET) identify eli-
gible women through a door-to-door survey in the study
areas of Dakshinpuri, Govindpuri, Madangir and Tigri,
Khanpur, Sangam Vihar, Jaitpur and Meethapur and
Madanpur Khadar areas of South Delhi. Information
about the study is shared with families and written
informed consent is taken from those who meet the
inclusion criteria and are willing to participate in the
study. Height (Seca-213 stadiometer) and weight
(Salter 9509 weighing scale) measurements are taken
and the participant is allocated to the intervention
(pre- and peri-conception) or control (routine care)
group [56,57]. The intervention delivery team is
informed if the woman is randomized to the interven-
tion group.
Post-enrolment, information is documented on
sociodemographic characteristics and the enrolled
woman is requested to inform the study team by call-
ing designated phone numbers if she gets pregnant.
Workers from the SET make calls to all women every
month (or home visits if the call is unsuccessful) to
enquire about missed periods. If women report two
missed periods or inform that they are pregnant (self-
testing using a pregnancy kit), a trans-abdominal
ultrasound is scheduled.
Randomization, allocation and masking
The randomization list was prepared by an independent
statistician at World Health Organization (WHO) using
random permuted blocks, stratified by maternal height
[< 150 cm (< −2 SD) and ≥150 cm (≥−2 SD)] of the
WHO standards [58].
The first randomization is done at enrollment when
married women aged 18 to 30 years fulfil the eligibility
criteria and consent to participate in the study. The sec-
ond randomization is done when women become preg-
nant during the 18 months follow up period, and are
eligible (not moving away from the study area) at rescre-
ening and consent to their own and their baby’s partici-
pation in the study. The group allocation is done
through a web-based system. There are no additional
criteria for discontinuation or modification of allocated
interventions.
Masking participants and study teams is not possible
because of the nature of interventions in this trial. How-
ever, attempts are made to keep the independent out-
come ascertainment team unaware of the group
allocation, to the extent possible.
Intervention delivery
Pre- and peri-conception period
The intervention delivery team conducts the first visit
post enrolment and three-monthly follow up visits there-
after for a period of 18 m or till the women gets preg-
nant. At the first visit, symptoms of RTI and
tuberculosis (TB) are ascertained and a history of epi-
lepsy is taken. Blood pressure is measured (Omron 1300
digital blood pressure device) [59]. A blood specimen
taken to check for anemia (hemoglobin - Hb), diabetes
(Glycated hemoglobin - HbA1c), thyroid disorder (Thy-
roid-stimulating hormones - TSH) and syphilis (Rapid
plasma regain; RPR).
Women with severe anemia (Hb < 8 g/dl), prediabetes
(HbA1c 5.7% to 6.4%), diabetes (HbA1c ≥6.5%), high
blood pressure (≥140/90 mmHg; at least two measure-
ments 48 h apart), hypo- (TSH > 5.5 IU/mL) or hyper-
thyroidism (TSH < 0.4 IU/mL), presence of symptoms of
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suspected TB, RPR positivity, reporting of symptoms of
RTI or sexually transmitted diseases (STI), epilepsy and
severe undernutrition (BMI < 16 kg/m
2
) are referred to
the collaborating tertiary care hospital (Safdarjung
Hospital). An outreach clinic manned by study physi-
cians, nutritionists, psychologists and laboratory staff has
been set up in the study area. Women with mild to
moderate anemia (Hb 8 to < 12 g/dL) are treated with
iron-folic acid for three months or till they are non-
anemic. Women with RTI or STI are managed in the
outreach clinic or hospital using algorithms of the syn-
dromic approach [60]. Family planning advice is offered
to recently (< 1 year) married women, those with a
young (< 1 year) child and if women have moderate to
severe anemia, symptoms and signs of RTI/STI, under-
nutrition, hypo- or hyper-thyroidism and diabetes re-
quiring treatment.
Women are screened for depressive symptoms using
the Patients Health questionnaire (PHQ-9) and are man-
aged according to the severity of depressive symptoms
and whether they have suicidal ideation [61]. All women
are counselled on positive thinking and problem-solving
skills [39]. Women are also counselled against tobacco
use (smoke and smokeless form) and on ways to reduce
exposure to second-hand smoke. All women in the
intervention group are counselled at home, using the
module described earlier [39]. Those with moderate de-
pressive symptoms (PHQ-9 score 10–14) are counselled
in the outreach clinic by a trained psychologist. For
women with a score of 15 or more or those reporting
suicidal thoughts, urgent referral to a psychiatrist is
facilitated.
Family members who smoke inside the house are
counselled with the intention of motivating them to ei-
ther decrease or quit smoking and if that is not possible,
then avoid smoking inside the house or in the vicinity of
the women. If a woman permits a male counsellor to
meet the spouse for his drinking habits, a study team
member approaches the spouse at a convenient time
and administers the AUDIT tool to assess severity of al-
cohol use [62]. Referral is facilitated to a tertiary care
hospital for those with a score of ≥20; in those with a
score of < 20, counselling is done at home on ways to
quit or reduce alcohol use.
Women are counselled on personal, menstrual and
hand hygiene.
This team contacts each woman three-monthly for the
following:
–Follow up investigations for illnesses diagnosed at
the previous visit
–Ascertainment of symptoms of RTI
–Administration PHQ 9 to screen for depressive
symptoms and counselling if needed
–Assessment of use of tobacco by woman exposure to
second hand smoke and alcohol use in spouse and
counselling, if needed
–Counselling on personal, menstrual and hand
hygiene.
After 12 months of enrolment, a blood specimen is ob-
tained from all women in the study except those who
have become pregnant and the investigations done at
baseline are repeated.
Follow up visits in the pre- and peri-conception period for
the intervention group
Study community workers –the Sangini (“friend”) simi-
lar in background to government community workers -
Accredited Social Health Activists (ASHA; http://www.
nhm.gov.in/communitisation/asha/about-asha.html) visit
enrolled women at least once a week throughout the fol-
low up period of 18 months or till women become preg-
nant. They counsel on study interventions, observe
intake of supplements when possible, replenish supplies
and organize referrals to hospital and the outreach
clinic, when necessary. “High risk”women i.e. those with
moderate to severe anemia, hypo- and hyper-thyroidism,
symptoms and signs of RTI/STI and undernutrition, are
visited more often. These visits also provide women an
opportunity to discuss their personal problems with the
Sangini. Eggs or milk are delivered 6 days a week
through neighborhood depots managed by women resid-
ing in the study communities. These women visit en-
rolled participants and attempt to observe the intake of
egg or milk. If the woman is not available, repeat visits
are made. The intake by each woman is documented
every day.
Pregnancy, postnatal and early childhood period after the
second randomization
When a pregnancy is reported, trans-abdominal ultra-
sound (GE ultrasound Voluson S8, PI Healthcare Inc.,
23865 Via Del Rio, Yorba Linda CA 92887, USA) is done
between 9 and 13 weeks of gestation. If women are eli-
gible at rescreening (not moving away from the study
area) and consent is given for further participation in
the study, they are randomized to either receive En-
hanced Antenatal, Postnatal and Early Childhood Care
(national and/or WHO-recommended interventions de-
livered well - intervention group) or routine care (con-
trol group). Each woman is allocated to a worker in the
intervention delivery team for pregnancy. This worker
visits the women monthly and ensures registration in
Safdarjung Hospital (if the woman does not want to go
to Safdarjung Hospital, she is encouraged to register in a
hospital of her choice) for delivery, counsels on the im-
portance of regular antenatal care, danger signs during
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pregnancy, on the benefits of an adequate diet during
pregnancy and preparation for breastfeeding and infant
care and promotes institutional delivery [43]. The
workers encourage the woman for timely antenatal care
(1 visit in the first trimester, 2 in the second and 5 in the
third trimester). They also ensure uninterrupted supplies
of iron folic acid, calcium, vitamin D and multiple
micronutrient supplements to the woman throughout
pregnancy [43].
Milk is delivered to pregnant women through neigh-
bourhood depots; an attempt is made to observe the in-
take and compliance is documented at each visit.
Women are encouraged to consume snacks given to
them (details given earlier). Monthly weight measure-
ments are taken at home or at the outreach clinic.
The collaborating hospital follows the WHO recom-
mendations on antenatal care [43]. The first visit for
registration and the visits in the last trimester are done
in Safdarjung Hospital. Women with complications
(hypertension, gestational diabetes, severe anemia, previ-
ous bad obstetric history etc) are encouraged to visit the
hospital for all antenatal visits; those without complica-
tions may use the outreach clinic.
Sanginis counsel pregnant women on positive thinking
and problem solving skills using the module described
earlier [39]. The use of tobacco by woman, exposure to
second-hand smoke and alcohol use in the spouse is
ascertained. The ensuing counselling is similar to that in
the pre-conception period. Women are screened for de-
pressive symptoms using the PHQ-9 questionnaire four
times during the pregnancy (once in the first trimester,
twice in the second and once in the third trimester) [61].
The management strategy is similar to the preconcep-
tion phase.
The team also counsels on the WASH interventions
i.e. on personal and hand hygiene and use of safe drink-
ing water from water filters.
Post-birth, the Prerna (“inspiration”) workers conduct
follow up visits to the intervention group households.
The first visit is made within 24 h of hospital discharge
or birth in case of home delivery. Mothers are encour-
aged to comply with postnatal visits advised by the
hospital for themselves, encouraged to consume milk,
iron-folic acid, calcium, vitamin D and multiple micro-
nutrients for the first 6 months post-delivery.
Home visits for all births are made by Prerna on days
3, 7, 10, 14, 28, and monthly from 2 to 24 months [63,
64]. Additional visits are made for those born preterm,
LBW and for mothers with breastfeeding problems. Ex-
clusive breastfeeding is promoted for the first 6 months.
If the mothers report breastfeeding problems, visits by
the study lactation counsellors are arranged. The Pre-
rna’scounsel mothers on positive thinking and problem
solving skills using the module described earlier. During
these visits, the team also assesses the use of tobacco by
woman, exposure to second-hand smoke and alcohol
use in spouse. A brief questionnaire (Patient Health
Questionnaire-2) is administered to women within a
week of delivery to assess her mood and screen for de-
pression [65].
The Prerna demonstrates to the families ways to inter-
act and communicate with their babies. They also assess
key developmental milestones at specified ages. Infants
who do not attain age-specific milestones are referred to
the paediatricians and psychologists.
Mothers are counselled to initiate complementary feeding
at 6 months while continuing to breastfeed till 24 months of
age. Recipes are shared on foods that can be prepared at
home, along with ways to encourage the infant to eat.
Packets of milk-cereal mix are provided to all children. Intake
of daily iron supplementation is encouraged.
Monthly weight and length measurements are taken by
the Prerna. Infants (0 to 6 months) with inadequate weight
gain (<15th centile according to WHO weight velocity/
month) are visited by a lactation counsellor and referred to
the physician at the outreach clinic if morbidity is present.
Children between 6 to 24 months of age with inadequate
weight gain (<25th centile according to WHO weight vel-
ocity/month) are referred to outreach clinic for examination
by physicians. Additional locally-procured snacks or extra
packets of foods are provided. Children with severe acute
malnutrition (weight-for-length Z-score, WLZ < -3 SD) are
managed at facilities.
Six-monthly deworming is given to all children from
12 months of age. Families are counselled about timely
immunization, taught to recognize danger signs and to
seek care promptly when the infant is ill.
The Prerna’scounsel on WASH interventions as dur-
ing pregnancy. Additionally, counselling is done on hand
hygiene for child feeding, safe disposal of feces, use of
diapers and their disposal, and use of clean play area.
Process evaluation
Observed and independent observations are done for
each worker at least once a month. Different activities
(delivery of interventions and counselling for consump-
tion of nutrient supplements, coping strategies, personal
hygiene, hand washing practices, timely antenatal visits,
optimal breast feeding practices and immunization in
childhood, etc) conducted by the workers are observed
by accompanying them. During these visits, the follow-
ing aspects are evaluated; the quality of interaction be-
tween the workers and the family, whether the questions
in the forms are asked correctly, quality of counselling
and whether all procedures are performed as planned.
During independent visits, the participants are asked
whether the worker visited, the activities performed at
the visit and the counselling provided.
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The study also has a “Program Learning Team”which
comprises of two social scientists who conduct inter-
views and observations around the key study activities.
They assess compliance to interventions through inter-
views and observations. Additionally, in-depth interviews
are done with non-responders to anemia and those with
inadequate weight gain to ascertain possible reasons.
The findings are communicated to the relevant study
teams and are used to strengthen intervention delivery
through retraining of workers and improvement in pro-
cesses, whatever is applicable.
Outcome ascertainment
Participants in both groups are visited by the independent
outcome ascertainment team at the end of pre- and peri-
conception period. The symptoms of RTI, depressive
symptoms, compliance to interventions, micronutrient,
anemia, thyroid and diabetes status are ascertained. Dur-
ing pregnancy, weight gain, compliance to interventions
and micronutrient status is assessed. Weight, length, head-
and mid-upper arm circumference, child care practices,
prevalence of illness and care seeking and hospitalization
are assessed during early childhood (Additional file 3).
Weights and lengths are taken by pair of workers using
digital weighing scale (model 354; Seca, California, USA)
and infantometer (model 417; Seca, California, USA) to
the nearest 10 g and 0.1 cm, respectively. Head and mid-
upper arm circumference is taken using a measuring tape
(model 212; Seca, California, USA) [66–68].
Laboratory investigations
At enrolment, ~ 10 ml blood sample is obtained from
women in the intervention group to screen for anemia,
thyroid disorders, diabetes, RPR and micronutrient assays.
Around 10 ml blood is taken from women in both inter-
vention and control groups when they report pregnancy
or do not get pregnant during 18months of the pre- and
peri-conception period, in the third trimester of preg-
nancy and at 6 months postpartum from women in the
intervention and control groups for anemia assessment,
micronutrient status and inflammatory markers. 5 ml
blood will be collected from children at 24 months of age
in both groups for micronutrient assays.
The samples are centrifuged and serum is stored in a
−80 °C deep freezer in the “Clinical and Research La-
boratory”set up in the field office, which is accessible
only to the laboratory managers. Laboratory investiga-
tions are done in an accredited commercial laboratory
(Strand-Quest Diagnostics Laboratory) and at referral
hospitals (Safdarjung Hospital). The body composition
analysis will be done by isotope dilution technique using
deuterium oxide (2H2O) at 1 month of age in a sub-
sample [69]. The infant saliva samples will be analyzed
for enrichment of deuterium by Fourier transform infra-
red (FTIR) spectrophotometry [69].
Ultrasounds for assessment of pre term birth and fetal
growth restriction
Ultrasounds in enrolled women during pregnancy (interven-
tion and control groups) are done at the designated ultra-
sound centers. A trans-abdominal ultrasound is scheduled
between 9 and 13 weeks of gestation to estimate gestational
age calculated by fetal crown-rump length (CRL). If CRL is >
95 mm, femur length and head circumference will be used to
assess gestational age [70]. Repeat ultrasounds are done at
26–28 weeks and 35–36 weeks of gestation and biparietal
diameter (BPD), occipito-frontal diameter (OFD), head cir-
cumference (HC, using ellipse facility), abdominal circumfer-
ence (AC using ellipse facility) and femur length (FL) are
measured. All measurements are taken by trained radiologists
according to the INTERGROWTH-21 standards [71].
Three measurements are taken for each fetal biometric
variable: CRL, BPD, OFD, FL, HC and AC, with the
woman in the lateral recumbent position [71]. The radi-
ologists performing the scan are blinded to the group al-
location of the pregnant women. All digital images are
stored in a secured server. Images from 10% of all study
participants are randomly selected and sent for external
review for quality assurance.
Training and standardization
Prior to study initiation, all staff were trained in the
study objectives, study strategy and in good clinical prac-
tices [72]. Additionally, each team underwent intensive
training in their area of work (door-to-door survey, con-
senting, anthropometry measurements, assessment of
morbidity, nutritional and psychosocial counselling, etc).
Inter- and intra-observer standardization exercises for
weight, length, height, mid upper arm circumference
and head circumference were conducted before study
initiation for the SET, the independent outcome ascer-
tainment team and for all other workers who take
weight and length measurements; these are repeated 6
monthly. Weighing scales and infantometers are cali-
brated daily using standard weights and length measure-
ment rods.
Study oversight and monitoring
Coordinators designated for each activity oversee the
work of their teams. Weekly status reports are shared
with the investigators. Periodic reviews meetings are or-
ganized between the study teams, coordinators and the
investigators.
The WHO, Geneva and Biotechnology Industry Re-
search Assistance Council (BIRAC), Department of Bio-
technology, Government of India are responsible for
oversight of the study. Technical staff from WHO and
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Bill & Melinda Gates Foundation interact with the in-
vestigators through conference calls once in two
months and twice-yearly site visits to review study
progress.
Data management
Data are captured electronically on tablets and mobile
phones. Range and logical checks are built in to ensure
data quality. The data management centre is set up in
the field office. Real time data are transferred to the
server. Logical errors and checks across different
forms are run twice weekly; queries generated are
given to study team for resolution and corrections
incorporated.
Data and safety monitoring committee
A Data Safety Monitoring Committee (DSMC) has been
constituted by the WHO and BIRAC to review the data,
monitor the progress of the trial and assess safety of the
interventions. The committee reviews data twice a year.
The members include - an epidemiologist, a statistician
and a clinician and a social scientist. An interim analysis
will be conducted in a blinded manner when 50% of the
babies in the study are born, a second review will be done
when 50% of the babies in the study reach 2 years of age.
The committee will advise the team on study continu-
ation, modification or termination based on pre-decided
stopping rules. This is a low-risk trial and serious adverse
events are not anticipated. However, all deaths in enrolled
participants are being reported to the local ethics commit-
tee and the World Health Organization for further com-
munication to the DSMC. Additionally, adverse events
reported with any supplement are being documented and
all severe adverse events will be reported to the ethics
committees and the DSMC.
Statistical analyses
Primary comparisons
The primary analysis will be factorial, for comparison of
the pre- and peri-conception intervention package (pre-
and peri-conception intervention package alone or with
enhanced antenatal, postnatal and early childhood care
package i.e. Group A + B) with no pre- and peri-
conception intervention package (enhanced antenatal,
postnatal and early childhood care package alone or rou-
tine care i.e. Group C + D), and the enhanced antenatal,
postnatal and early childhood care (with pre- and peri-
conception intervention package or enhanced antenatal,
postnatal and early childhood care alone i.e. Group A +
C) with no enhanced antenatal, postnatal and early
childhood care (pre- and peri-conception intervention
package alone or routine care i.e. Group B + D) on birth
outcomes (mean birth weight and length, proportion
stunted at birth, proportion of babies born preterm and
spontaneous preterm births, SGA and LBW) and mean
length for age z-score and proportion stunted at 24
months.
In addition to the factorial analysis, we will also
examine the impact of the combined pre- and peri-
conception intervention package and enhanced ante-
natal, postnatal and early childhood care (Group A) on
birth outcomes and attained length at 24 months of age,
compared to routine care (Group D).
We will examine if there is an interaction between the
intervention package delivered during peri-preconception
period and that delivered during antenatal and early child-
hood period on primary outcomes.
Definitions of primary outcomes
Birth weight will be defined as weight taken by the study
team at day 7 after birth and birth length as length taken
by the study team any time within the first 7 days after
birth to ensure comparability across the groups. Weight
taken on day 0 is available for large proportion of in-
fants. However, this proportion is likely to be unequal
between the intervention groups (A + C) compared to
control groups (B + D) because of greater ability to
contact the intervention group mothers immediately
after birth. We will therefore use weight on day7 taken
consistently on the same day for both the groups as a
measure of birth weight.
LBW will be defined as weight < 2500 g on day 7
after birth; proportion stunted as length-for-age z-
score < −2SD according to WHO standards [58]. Ges-
tation at birth will be estimated by subtracting date
of birth from date of dating ultrasound and adding it
to gestational age as assessed by dating ultrasound ac-
cording to INTERGROWTH-21 [70]. Preterm births
will be defined as births occurring at < 37 completed
weeks of gestation. Spontaneous preterm births will
be defined as births occurring at < 37 weeks of gesta-
tion and preterm pre-labor rupture of membranes or
spontaneous onset of labor.
Birth weight centiles will be calculated using the
INTERGROWTH-21 standard based on day-7 weight and
gestational age at birth [70]. SGA will be defined as birth
weight centile <10th and < 3rd as per INTERGROWTH-
21 standard [70]. Length-for-age z-score will be calculated
based on length measured at 24 months (±28 days) and
proportion stunted will be defined as those with length-
for-age z-score < −2 SD by WHO standards [58].
Flow of participants
The flow and number of participants through assess-
ment of eligibility, randomization, follow-up, and ana-
lysis will be presented (Fig. 2) along with reasons for
exclusions and withdrawals for all time points.
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Comparability between the two groups
Summary values (means, proportions) for sociodemo-
graphic characteristics among the groups will be pre-
sented in the baseline table. We will not perform
any test of significance. Our large sample size is
likely to yield a balance between the groups. How-
ever, we will carefully examine the size of any base-
line differences. Imbalanced characteristics that may
Fig. 2 Trial profile
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influence the primary outcomes will be adjusted
appropriately.
Main effects
Analysis will be done by intention-to-treat. Mean (SD)
birth weight, birth length, LAZ score at 24 months, pro-
portion of preterm birth and spontaneous preterm birth,
SGA, LBW, stunting at birth and 24 months will be pre-
sented for the different groups.
For binary outcomes, generalized linear models (GLMs)
of the binomial family with a log-link function will be used
to calculate the effect size [relative risk and 95% confi-
dence interval (CI)]. For continuous outcomes, GLMs of
the Gaussian family with an identity-link function will be
used to calculate the effect size (difference in means and
95% CIs). The effect of interventions on secondary out-
comes will be assessed using the same models as for pri-
mary outcomes.
Weight and length growth trajectories between birth and
24 months
A multivariable linear mixed-effect regression model
with an unstructured covariance matrix will be used to
examine the effect of the interventions on weight and
length trajectories from birth to 24 months [73]. In this
model, in order to account for the interdependence of
multiple observation periods in the same child, time (age
in months) of assessment will be taken to be the level-1
source of variation, with individual children at level 2.
All potential covariates will be included as fixed effect
variables in this model. The interaction between mater-
nal stature and time (age in months) of assessment on
different anthropometric outcomes i.e. LAZ, WAZ
(weight-for-age z-score) and WLZ scores will be exam-
ined. If significant, the interaction term will be included
in the model to obtain the independent effect of mater-
nal stature at different ages.
Pre-specified subgroup analysis
We will conduct subgroup analysis for women according
to their height (< 150 cm and ≥150 cm), underweight,
BMI status at enrolment and at the time of pregnancy
confirmation, years of education and high risk preg-
nancy. We will also conduct subgroup analysis by wealth
quintile of the household. The relative measures of effect
within each of these subgroups will be estimated.
The effect of interventions on secondary outcomes will
be assessed using the same models as for primary
outcomes.
Discussion
This study is conceived with the underlying belief that
investing efforts in promoting growth and development
in children could potentially drive the transformation
aimed to be achieved by 2030 under the SDG3 i.e. good
health and wellbeing for all [1]. Existing evidence sup-
ports that the first 1000 days of life i.e. from conception
to two years are critical for optimal growth and brain de-
velopment but may not be sufficient [3,4]. Studies have
examined the effects of individual interventions on birth
outcomes and early childhood growth and development,
targeting the pregnancy period and/or the postnatal
period and have observed low to modest effects sizes.
Observational studies indicate that health prior to con-
ception (pre- and peri-conception period) is linked to
birth outcomes and could influence health across gener-
ations [17,74]. However, intervention trials are yet to
substantiate the initial observations and reliable evidence
is required.
The study has been designed to examine the effect of
an integrated package of evidence based interventions in
four key domains namely health, nutrition, WASH and
psychosocial care on birth outcomes, growth and devel-
opment in early childhood. The health of the mother
and her baby are strongly interlinked and therefore the
interventions have been selected so that they focus on
promotion of maternal health during the pre- and peri-
conception period, pregnancy and postnatal period as
well as the health of the offspring during the first two
years of life. These interventions emerge from the
national and WHO recommendations that take into
account available evidence. In the health and nutrition
interventions, attention has been given to the notable
risk factors for poor birth and childhood outcomes,
such as maternal anemia, undernutrition, maternal
depression, hypothyroidism, diabetes, RTI and sub-
optimal infant feeding and responsive child care
practices.
This study aims to demonstrate that healthy growth
and development can only be achieved when the envir-
onment is enabling and free from constraints. The find-
ings will help understand the extent to which linear
growth can be accelerated when all the nutritional and
health care needs of the mother and the child are ad-
dressed. The study will also show the importance of pro-
viding interventions during the pre- and peri-conception
period for improving linear growth. The design also en-
ables us to examine the effect of maternal height reflect-
ing intergenerational adversities, on the efficacy of
interventions to improve birth and child outcomes. If
successful, the study will reveal what is potentially
achievable in terms of improvement in linear growth.
The findings from this study will advance our scientific
understanding and will be helpful in designing relevant
programs in India and other similar low-middle-income
settings.
There are strengths and unique features of this study.
First, this study involves a factorial design with a large
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sample size which will help us clearly understand the
importance of pre-and peri-conception interventions on
key birth and growth outcomes with adequate power.
Second, the women will be followed up from pre-
conception, through pregnancy till childhood. This
spectrum of follow up will help provide insights into the
transition and inter connectivity of epidemiological, clin-
ical, biochemical and biological data and their effect on
important birth and child health related outcomes.
Third, we would be able to understand the role of inter-
generational effects in altering the effects of the inter-
ventions on growth and development of children.
Fourth, majority of the interventions are delivered at
home through trained study workers and the compliance
to these interventions is observed when possible. Any
queries are promptly addressed and problems resolved.
The intention is to deliver the interventions with high
quality so as to maximize the internal validity and
generalizability of the study findings.
The study has some limitations. First, it is an individu-
ally randomized trial. A cluster randomized design may
have been better suited considering that the majority of
the interventions aim to influence the behavior and
practices of the individuals. The design therefore, limits
conduct of community mobilization activities which
have been shown to be effective [75]. However, the indi-
vidually randomized nature allows for factorial design
which, in turn, provides an opportunity to examine the
effect of pre- and peri-conception interventions on birth
and growth outcomes. Second, it is difficult to imple-
ment the whole set of WASH interventions at the indi-
vidual household level. Certain aspects such as
improving sanitation facilities were not possible in an in-
dividually randomized design. Third, in spite of the body
of evidence of the role of domestic violence among
women, child neglect and child abuse in influencing
birth and child growth and developmental outcomes, the
interventions directly targeting these issues were not in-
cluded in the package. The study investigators felt that
intervening on such sensitive issues could have created
resistance or other problems among the families and in
the study communities.
Conclusion
The findings emerging from the study will provide useful
insights on the maximum achievable reductions in ad-
verse birth outcomes and improvements in growth and
development of young children from lower middle socio
economic settings, when the majority of the known ad-
versities are adequately addressed. The insights from the
pregnancy and postnatal phase of the trial will help in
the strengthening of the already existing maternal and
child health programs in India and other low-middle-
income settings whereas those emerging from the pre-
and peri-conception period will provide reasonable
grounds for policy discussions pertaining to
Fig. 3 Schedule of Study Activities: SPIRIT Figure
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development of pre- and peri-conception programs,
which currently are largely non-existing.
Trial status
The recruitment of participants commenced in July 2017
and enrollment will be completed by November 2019.
Follow up visits will continue till enrolled women report
pregnancy or complete 18 months in the pre- and peri-
conception period. Pregnant women who provide
consent are randomized again and followed up till their
children are aged 2 years (Protocol version: 6.0 dated
July 19, 2019; Fig. 3and Additional file 4).
As the study duration is long, it is planned that learn-
ings from the intervention group e.g. prevalence of non-
communicable diseases, nutritional problems, infectious
disease, different practices and behaviours in the study
communities will be published to enable ongoing learn-
ing to be shared with policy makers.
Supplementary information
Supplementary information accompanies this paper at https://doi.org/10.
1186/s13063-020-4059-z.
Additional file 1. Technical Advisory Group.
Additional file 2. Details of interventions.
Additional file 3. Secondary outcomes in women and children and
timing of measurement.
Additional file 4. SPIRIT 2013 Checklist: Recommended items to address
in a clinical trial protocol and related documents.
Abbreviations
AC: Abdominal circumference; AGP: Alpha-acid glycoprotein;
ASHA: Accredited Social Health Activist; BIRAC: Biotechnology Industry
Research Assistance Council; BMI: Body mass index; BPD: Biparietal diameter;
CI: Confidence interval; CRL: Crown-rump length; DSMC: Data Safety
Monitoring Committee; FL: Femur length; FTIR: Fourier transform infrared;
GEE: Generalized Estimating Equation; GLM: Generalized linear model;
Hb: Hemoglobin; HbA1c: Glycated hemoglobin; HC: Head circumference;
IFA: Iron-folic acid; IUD: Intrauterine device; LAZ: Length-for-age z-score;
LBW: Low birth weight; lOR: Interaction odds ratio; MUAC: Mid-upper arm
circumference; OFD: Occipito-frontal diameter; PHQ-9: Patient Health
Questionnaire-9; RDA: Recommended daily allowance; RPR: Rapid Plasma
Reagin; RTI: Reproductive tract infections; SD: Standard deviation;
SDGs: Sustainable Development Goals; SET: Screening and enrolment team;
SGA: Small-for-gestation; STI: Sexually Transmitted Infections; TAG: Technical
Advisory Group; TB: Tuberculosis; UNICEF: United Nations Children’s Fund;
WASH: Water, Sanitation and Hygiene; WAZ: Weight-for-age z-score;
WHO: World Health Organization; WINGS: Women and Infants Integrated
Growth Study; WLZ: Weight-for-length z-score
Acknowledgements
We acknowledge the contribution and support of the enrolled women and
their families. We are thankful to the community leaders for their
cooperation and support.
We acknowledge the study Technical Advisory Group (Additional file 1).
We are thankful to Dr. Tarun Dua for helping in adaptation of the WHO
Thinking Healthy Module and training of the study team; Ms. Suman Bhatia
for training the intervention delivery team in counselling skills.
We are grateful to the Departments of Gynecology & Obstetrics and
Pediatrics, Vardhman Mahavir Medical College and Safdarjung Hospital, New
Delhi, India for medical management of the enrolled participants and the
Department of Radiology at Hamdard Institute of Medical Sciences and
Research, New Delhi, India for their support in conducting ultrasounds. We
are also thankful to BR Diagnostics and Millennium Diagnostics for
conducting ultrasounds. We acknowledge Strand-Quest Diagnostics Labora-
tory for analyses of biological samples and TATA Swach for provision of
water filters for the study.
We acknowledge the core support provided by the Department of Maternal,
Newborn, Child and Adolescent Health, World Health Organization, Geneva
(WHO Collaborating Centre IND-158). We also acknowledge the support ex-
tended by the Knowledge Integration and Technology Platform (KnIT), a
Grand Challenges Initiative of the Department of Biotechnology and Biotech-
nology Industry Research Assistance Council (BIRAC) of Government of India
and Bill & Melinda Gates Foundation (USA).
We are grateful for the excellent administrative support provided by Manju
Bagdwal, at the Centre for Health Research and Development, Society for
Applied Studies, New Delhi.
Women and Infants Integrated Growth Study (WINGS) Group
Farhana Rafiqui, Jasmine Kaur, Gunjan Aggarwal, Nikita Arya, Anita Kate,
Medha Shekhar ,Shruti Verma, Ratan Shekhawat, Neelam Kaur, Richa
Chauhan, Kaavya Singh, Geeta Mehto, Runa Ghosh, Neha Tyagi, Payal
Chakraborty, Ramanjit Kaur, Kunal Kishore, Navneet Mehra, Anuradha
Tamaria, Ritu Chaudhary, Aparna Singh, Priyanka Singh, Dolly Jain, Gulafshan
Ansari, Tivendra Kumar, Savita Sapra, Afifa Khatun, Kiran Bhatia, Manisha
Gupta, Girish Chand Pant, Tarun Shankar Choudhary, Ankita Dutta, Deepak
More, KC Aggarwal, Sujata Das, Pradeep Debata, Anita Yadav, Reeta Bansiwal,
Abhinav Jain, Nitika
Authors’contributions
ST was involved in proposal development, study design, is responsible for
study implementation and engaged in design and development of data
management system. RC was involved in proposal development, study
design and is responsible for study implementation. ND was involved in
study design and is responsible for medical management of enrolled
participants. SM was involved in development of the WASH interventions.
RPU was involved in development of CARE interventions. SS was involved in
development of infant and child interventions, RD and PM are involved in
management of women in Safdarjung hospital, HC is involved in
management of infant and children in Safdarjung Hospital. RB participated in
proposal development and study design, as well as providing technical
support and trial monitoring. MKB participated in proposal development and
study design, as well as providing technical support. NB was involved in
proposal development, study design and is responsible for overall study
implementation and provides technical support to the study teams. ST, RC,
ND, SM, RPU, SS, NB, RB and MKB participate in frequent reviews of study
implementation. All authors contributed to preparation and finalization of
the manuscript, and all authors read and approved the final manuscript.
Funding
The study is funded by Biotechnology Industry Research Assistance Council
(BIRAC) of the Department of Biotechnology, Government of India and by
the Bill & Melinda Gates Foundation, USA. The funding agency did not play
any role in the design of study and are neither involved in nor have any
influence over the collection, analyses or interpretation of data.
Availability of data and materials
We are collaborators in the Healthy Birth, Growth, and Development
Knowledge Integration (HBGDKi) initiative launched by the Bill & Melinda
Gates Foundation. The data generated from the study will be shared as part
of the HBGDKi repository (https://github.com/HBGDki) after study
completion. The results of the research will be published in peer-reviewed
biomedical journals. The findings will also be disseminated at conferences
and communicated to the local and national health authorities, as well as to
the World Health Organization.
Ethics approval and consent to participate
Clearances have been obtained from the Ethics Review Committee of the
Society for Applied Studies, Vardhman Medical College and Safdarjung
Hospital and the World Health Organization, Geneva.
A written individual informed consent in local language is obtained from
participants prior to enrolment. A second consent is taken when the woman
gets pregnant for her and her child’s participation in the study. For those
who are unable to read, the form is read aloud to them. In those who are
Taneja et al. Trials (2020) 21:127 Page 15 of 18
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
unable to sign, a thumb imprint is taken witnessed by an impartial literate
witness.
The protocol amendments are reported to the ethics committees and
funding agencies. These amendments are also updated in the Trial Registry
(CTRI/2017/06/008908). All protocol deviations will be documented and
reported to the ethics committees.
Consent for publication
Not applicable.
Competing interests
The authors declare that they have no competing interests.
Author details
1
Centre for Health Research and Development, Society for Applied Studies,
45, Kalu Sarai, New Delhi, India.
2
Vardhman Mahavir Medical College and
Safdarjung Hospital, New Delhi, India.
3
Department of Maternal, Newborn,
Child and Adolescent Health, World Health Organization, Geneva,
Switzerland.
4
Knowledge Integration and Translational Platform (KnIT),
Biotechnology Industry Research Assistance Council (BIRAC), Department of
Biotechnology, Government of India, New Delhi, India.
5
Indian Institute of
Technology, New Delhi, India.
Received: 29 October 2019 Accepted: 8 January 2020
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