Balanced Protein-Energy Supplement in Pregnancy and Early Lactation on Birth Outcomes and Growth in Southern Nepal
Balanced Protein-Energy Supplement in Pregnancy and Early Lactation on Birth Outcomes and Growth in Southern Nepal
This project will test the efficacy of a balanced protein energy supplement for daily use
 during pregnancy and the first 6 months after delivery on the outcomes of pregnancy and
 growth of infants during the first 6 months of life. Approximately 1800 pregnant women from a
 district in southern Nepal will be recruited and randomly assigned to one of 4 groups,
 control in pregnancy & post-partum, supplementation in pregnancy & control post-partum,
 control in pregnancy & supplementation post-partum, or supplementation in pregnancy &
 post-partum. Pregnancies will be followed until delivery and the infants through 6 months of
 age. Outcomes of interest include birth size (weight and length), gestational age at
 delivery, maternal weight gain in pregnancy, maternal weight at 6 months post-partum, infant
 growth, and breast milk composition.
Background Undernourished women in many low and middle income countries (LMICs) enter
 pregnancy with low nutritional reserves, and low maternal body mass index (BMI) and short
 stature are associated with increased risks of a variety of adverse reproductive outcomes
 (Kozuki et al., 2015; Rahman et al., 2015). Balanced protein-energy (BE-P) supplementation
 during pregnancy shows moderate evidence than such dietary supplementation can decrease the
 risk of stillbirth and small-for-gestational-age (SGA) births (Ota et al., 2015; Stevens et
 al., 2015). The WHO antenatal care guidelines recommend providing pregnant women in
 undernourished populations with balanced protein energy dietary supplementation (WHO, 2016).
 The current evidence base for BP-E supplementation draws from a number of studies where BP-E
 supplements varied widely in composition and form (Imad & Bhutta, 2002). Recent studies using
 fortified blended foods found that although approximately 800 kcal/d was provided, the net
 energy intake increased by a much smaller amount (200-300 kcal) (Janmohamed et al., 2016;
 Saville et al., unpublished trial in Nepal).

 Evidence regarding dietary practices and preferences among pregnant women in Nepal is
 generally limited, however, some studies have shown that intra-household food allocation and
 specific food beliefs/behaviors do not favor adequate energy or micronutrient intake among
 adolescent girls and adult women (Gittelsohn, 1991; Gittelsohn et al., 1997). Christian et al
 showed that staple food intake can be reduced during pregnancy; which could be attributed to
 an aversion to food, lack of appetite, feeling unwell, or concern regarding having a "large"
 baby and difficulties with labor and delivery (Christian et al., 2006). Low nutrition
 knowledge may also play a role in suboptimal intake among women (Jones et al., 2005). Dynamic
 changes in access and use of services offer the opportunity to nest additional nutritional
 support services within the antenatal care system, including BP-E supplementation. However,
 information is limited regarding the impact such supplementation will have on the key birth
 outcomes that affect child health and development. It is this lack of evidence that this
 project will address.

 Methods This project will be done in three phases. Phase one will identify preferable
 supplement types for use in pregnancy in the South Asian context. Phase two will use the
 results of phase one to conduct a medium-term feeding trial to assess acceptability and
 consumption. Phase three will be a large, community-based randomized trial using at least one
 of these supplement options for use in pregnancy and through the first 6 months post-partum
 on birth outcomes and early infant growth.

 Specific Aim, Phase 1: Identify preferred product types for the provision of fortified BEP
 supplements among pregnant women in Southern Nepal.

 Specific Aim, Phase 2: Assess the 8-week acceptability and consumption of 2 selected
 supplements with nutrient content consistent with Bill and Melinda Gates Foundation (BMGF)
 guidance among pregnant women in Southern Nepal.

 Specific Aims Phase 3: Community-Based Randomized Field Trial

 There is one primary aim and a number of secondary aims for each marginal treatment arm of
 this trial. Primary aims:

 1. To compare the incidence of small-for-gestational-age (SGA) newborn infants born to
 mothers randomized to receive either a daily balanced protein-energy nutritional
 supplement with multiple micronutrients or control during pregnancy. SGA will be defined
 as <10th centile of birthweight for gestational age standard using InterGrowth 21st
 criteria (Villar et al., 2014).

 2. To compare the growth of live-born infants among mothers randomized to the two groups
 during the first 6 months post-partum. The primary infant growth outcome is
 Length-for-Age Z (LAZ) score using the WHO Child Growth Study criteria (WHO, 2006).

 Secondary aims:

 Pregnancy Supplementation

 1. To compare the incidence of short-for-gestational-age (ShGA) newborn infants born to
 mothers randomized to the two groups during pregnancy. ShGA defined as <10th centile of
 birth length for gestational age standard using InterGrowth 21st criteria.

 2. To compare the incidence of small-for-gestational-age (SGA) newborn infants born to
 mothers randomized to the two groups during pregnancy. SGA defined as <3rd centile of
 birthweight for gestational age standard using InterGrowth 21st criteria.

 3. To compare the incidence of short-for-gestational-age (ShGA) newborn infants born to
 mothers randomized to the two groups during pregnancy. ShGA defined as <3rd centile of
 birth length for gestational age standard using InterGrowth 21st criteria.

 4. To compare the means and distribution of birth weight, birth length and gestational age
 (and percent <2500 gm, <37 weeks gestation) in infants born to women randomized to the
 two groups during pregnancy.

 5. To compare the growth through 6 and 12 months of age (LAZ, weight-for-age Z (WAZ),
 weight-for-length Z (WLZ) scores) of infants born to women randomized to the two groups
 during pregnancy. 12 months follow-up will be available on approximately 2/3rd of
 infants.

 6. To compare the composition of breastmilk and the volume of a 24 hour feeding among women
 randomized to the two groups during pregnancy.

 7. To compare maternal weight gain during pregnancy among women randomized to the two
 groups during pregnancy.

 8. To compare the diversity of the gut microbiome in pregnancy among women randomized to
 receive either a daily balanced protein-energy nutritional supplement with multiple
 micronutrients or control during pregnancy.

 Post-Partum Supplementation

 1. To compare WAZ and WLZ scores through 6 and 12 months of age of infants born to women
 randomized to receive either a daily balanced protein-energy nutritional supplement or
 control during the first 6 months post-partum. 12 months follow-up will be available on
 approximately 2/3rd of infants and women.

 2. To compare the composition of breastmilk and the volume of a 24 hour feeding among women
 randomized to the two groups during the first 6 months post-partum.

 3. To compare the weight and BMI of mothers at 6 and 12 months post-partum among women
 randomized to the two groups during the first 6 months post-partum. 12 months follow-up
 will be available on approximately 2/3rd of mothers.

 4. To compare the diversity of the gut microbiome post-partum among women randomized to
 receive either a daily balanced protein-energy nutritional supplement with multiple
 micronutrients or control during post-partum.

 5. To compare the diversity of the gut microbiome among infants <6 months of age whose
 mothers were randomized to receive either a daily balanced protein-energy nutritional
 supplement or control during the post-partum period.

 Combination of Pregnancy and Post-Partum Supplementation

 1. To compare the impact of combined pregnancy and post-partum nutritional supplementation
 with women who received only pregnancy or post-partum supplementation alone on LAZ, WAZ,
 and WLZ scores at 6 and 12 months of age among infants born to these mothers. 12 months
 follow-up will be available on approximately 2/3rd of infants.

 Study Design for Phases 1 & 2: A two-phase, mixed methods approach combining qualitative
 and quantitative methods for data collection will be used.

 Phase 1: 11 product types will be introduced to participants in a single-meal test for
 their feedback on acceptability. Phase 1 will collect data to describe general
 preferences across product types and variations.

 Phase 2: 2 product types identified in Phase 1 will be tested in an 8-week feeding
 trial. Each participating woman will experience one selected product type for a total of
 8 weeks. Hedonic properties will be assessed at 2 and 8 weeks.

 Complementary qualitative data will also be collected using in-depth interviews and
 focus group discussions during both phases 1 and 2.

 Setting for all Phases This project will be conducted in a chronically food insecure
 study site in southern Nepal (Sarlahi District). This site is representative of a region
 (South Asia) and meets the criteria of having adequate local security conditions and
 presence of a strong field research site.

 Study population and sample size estimates Phases 1 & 2:

 Pregnant Women (PW): In Phase 1, a convenience sample of 40 PW will be selected to
 evaluate 11 product types. In Phase 2, women participating in the home feeding trial (n
 = 40 for each of two product types, total n=80) will additionally participate in
 in-depth interviews.

 Data Collection: Phases 1 & 2:

 Phase 1. Identify preferred product types Direct observation of single meal with hedonic
 testing: During the single meal observation, each participant will receive 1 serving of
 each product. Acceptability will be assessed based on Likert-like scoring using hedonic
 scales of overall liking, appearance, smell, taste and consistency.

 Focus group discussion: Focus groups (maximum of 40 women) will be conducted following
 the single meal direct observation.

 Phase 2. Home-feeding trial to assess acceptability and at-home consumption Two product
 types selected in Phase 1 will be assessed for medium-term acceptability and utilization
 through an 8-week feeding trial. Two measures of adherence will be assessed at each
 weekly home distribution; adherence in the last 24 hours using direct questioning and
 adherence using direct sachet/packet count.

 Hedonic testing: Hedonic testing will be done at 8 weeks (de Graaf et al., 2005).

 In-depth interviews: For both products, interviews will be conducted with PW and other
 household members, and health staff.

 Focus group discussions: Focus groups among PW receiving both products will be conducted
 at the end of Phase 2.

 Data analysis, Phases 1 & 2:

 Adherence data: Adherence by self-report will be calculated as the percentage of days
 the supplement was reported to be consumed and mean portion when consumed, and adherence
 by sachet count will be calculated as total empty packages returned divided by total
 packages expected to be consumed.

 Hedonic test data: Product liking, and left over quantities over time will be summarized
 by product type using means for continuous variables.

 Qualitative data: Analysis will be ongoing throughout data collection, and conducted by
 the research team using an exploratory, inductive approach that will draw from Grounded
 Theory and allow for the analysis of emergent themes (Charmaz, 2014; Ridder et al.,
 2014; Charmaz, 2006). Data will be systematically coded using Dedoose computer software
 (Consultants, 2016) (Glesne & Peshkin, 1992).

 Phase 3: Randomized Trial Design The design of this study is a community-based,
 household level-randomized 2x2 factorial trial among women who become pregnant in the
 study area over a 9 month period.

 Study Population The study population for this trial will include all women who become
 pregnant during a 9-month period in a set of Nagarpalikas or Gaunpalikas in Sarlahi
 District, Nepal. Newly pregnant women will be identified through a pregnancy
 surveillance system.

 Intervention

 Two interventions strategies will be tested in a factorial design in this trial;
 nutritional supplementation during pregnancy and nutritional supplementation during the
 first 6 months post-partum. The exact forms of this supplement will be selected in
 Phases one and two but its composition will be in conformance with the recommendations
 from the expert panel convened by the BMGF on nutritional supplementation in pregnancy
 (Expert Consultation, 2016). Women in households allocated to the control groups will
 receive a standard package of antenatal services and nutritional counseling by study
 staff. In all four groups, the following antenatal and post-natal interventions will be
 offered:

 -  Women will be encouraged to enroll in routine antenatal care at their local health
 post/center.

 -  A clean birthing kit will be provided consisting of a clean blade, string, and
 plastic disc for cutting the cord, a plastic sheet, a bar of soap, and a tube of
 chlorhexidine ointment for application to the umbilical stump.

 -  Women will be encouraged to deliver at a certified birthing facility and
 participate in the government's incentive scheme.

 -  Additional nutritional, hygiene, and infant care counseling will be provided by
 study staff.

 -  If a woman reports not attending ANC and/or not receiving tetanus toxoid or
 iron-folic acid supplements, our study staff will provide them.

 Masking While it will not be possible to mask the participants or the Ward Data
 Collectors to the treatment assignment, we will attempt to mask the birth and growth
 assessment teams to the treatment assignments.

 Randomization Randomization will be done at the household level for this study. This
 means that once the first pregnant woman from a given household is identified and
 consents to be in the trial, that household will be allocated to either the supplement
 or non-supplement group (for pregnancy). Any other woman or women from this household
 who subsequently become pregnant within the 9-month enrollment period, would also be
 assigned to that group.

 We will pre-generate a randomization sequence denoting the two pregnancy allocation
 possibilities (supplement, no-supplement) using the R software environment for
 statistical programming (www.r-project.org) using randomly permuted blocks of size 4, 8,
 and 12, to ensure sequential balance across the groups throughout the enrollment period.

 For randomization to the post-delivery exposure (i.e. supplement, no-supplement), a
 slightly modified procedure will be followed. Here, we will construct two pre-generated
 allocation sequences, again constructed with randomly permuted blocks of size 4, 8, and
 12. These two sequences will be stored in our database, and annotated/labelled to allow
 for allocating post-delivery exposures stratified by pregnancy exposure.

 Substudies A group of substudies will be conducted among a systematic sample of 120
 pregnant women per treatment group (total of 240). These substudies include assessments
 of maternal nutritional status using serum assays for micronutrients and inflammatory
 markers, the gut microbiome using multiplex PCR and metabolomic assays in stool,
 breastmilk composition, and dietary intake.

 Maternal Blood and Microbiome SubStudy The objective is to examine whether a BP-E
 nutritional supplement during pregnancy and breastfeeding will improve the nutrient
 concentrations in serum of mothers, decrease the level of systemic inflammation in
 mothers, and promote a more diverse and normal gut microbiome in pregnant and
 breastfeeding women.

 Methods:

 Blood and stool will be collected among all 120 women per group at the following times:

 -  Blood and stool in women at the time of baseline enrollment in early pregnancy.

 -  Stool in women at mid-2nd trimester.

 -  Blood and stool at the late pregnancy visit (~34 weeks gestation).

 -  Blood and stool at 1-2 and 3-4 months post-partum.

 -  Infant stool at 1-2 and 3-4 months of age. Blood analytes will include Hb and a
 full battery of nutrients and inflammatory markers (to be decided).

 Breastmilk Composition:

 The objective is to examine whether a BP-E post-partum nutritional supplement will
 improve the nutritional composition of breastmilk among breastfeeding women.

 Methods: Breastmilk will be collected twice during lactation, once between months 1 & 2
 and again between months 3 & 4. The nutrients to be assessed will include the following
 which have demonstrated response to supplementation in previous studies and/or are
 associated with growth of infants:

 -  Vitamin A

 -  Vitamin E

 -  Thiamin

 -  Riboflavin

 -  Niacin

 -  Vitamin B6

 -  Vitamin B12

 -  Choline

 -  Biotin

 -  Iron

 -  Copper

 -  Zinc

 -  Selenium

 -  Fat

 -  Lactose

 -  Total protein.

 Dietary Intake Sub-Study The purpose of this sub-study is to assess whether there is
 significant dietary diversion occurring in the supplementation groups compared with
 controls. We will use daily energy and protein intake as the primary indicators of
 diversion. A quantitative 24-hour recall instrument will be used once in pregnancy (in
 duplicate) and once in the post-partum period (in duplicate). We will adapt dietary
 instruments that have been used previously in this population for this sub-study (Sudo
 et al, 2006; Parajuli et al, 2012; Campbell et al, 2014; Henjum et al, 2015).

 Sample Size / Power Calculations These calculations assume the nutritional
 supplementation in pregnancy and post-partum periods have independent effects on the
 outcomes of interest. We are not powered to detect specific interaction effects on
 either primary or secondary outcomes.

 Primary Outcomes: Small-for-gestational-age (SGA) is the primary outcome that we have
 used to drive the sample size calculations. While not a truly individually randomized
 trial (households will be randomized), the very small likelihood of identifying more
 than one eligible pregnant women in a household over a 9 month period is quite low
 (<3.5% of "clusters" will have more than 1 individual outcome). We've estimated the
 effect of this level of clustering on sample size and found it to be extremely small
 versus individual randomization. Therefore, all our sample size/power estimates are
 based on individual randomization.

 Over a period of 9 months, we expect that eligible households in our study area will
 yield approximately 1600 pregnant women whose infants will be seen within 72 hours of
 birth for measurement of the primary birth outcome.

 Table: Effect Size Detectable for Primary Birth Outcome Given 774 Infants per Group
 Measured within 72 Hours of Birth Outcome Relative Risk Detectable
 (Supplemented/Unsupplemented) 80% Power 90% Power Primary SGA (10th centile) 0.825 0.798

 We will be able to detect a 17.5% reduction in SGA with 80% power and a 20.2% reduction
 with 90% power assuming a type 1 error of 5% (two-sided).

 The table below presents the detectable relative risks or mean differences for a variety
 of secondary outcomes with 80% and 90% power.

 Table: Detectable Difference in Secondary Outcomes (Marginal Comparisons) Outcome
 Detectable Relative Risk or Difference Between Groups 80% Power 90% Power Secondary ShGA
 (10th centile)a 0.778 0.745 SGA (3rd centile)b 0.726 0.686 ShGA (3rd centile)c 0.653
 0.604 Mean Birth Weight d 60.7 g 70.2 g Mean Birth Length e 3.0 mm 3.5 mm LAZ at 6
 months1 0.16 Z scores 0.18 Z Scores WAZ at 6 months2 0.17 Z scores 0.20 Z scores WLZ at
 6 months3 0.18 Z scores 0.21 Z scores Maternal Weight Gain in Pregnancy4 463 g 536 g
 Maternal Weight at 6 months Post-Partum5 0.89 kg 1.03 kg

 a ShGA (10th centile expected rate is 30.1%. b SGA (3rd centile) expected rate is 22.1%.
 c ShGA (3rd centile) expected rate is 14.4%. d Expected mean birth weight is 2708 g
 (SD=429). e Expected mean birth length is 47.6 cm (SD=2.2). 1 Expected mean LAZ at 6
 months is -1.04. 2 Expected mean WAZ at 6 months is -1.63. 3 Expected mean WLZ at 6
 months is -1.23. 4 Expected mean weight gain in pregnancy is 7.55 kg (SD=3.23 kg). 5
 Expected mean maternal weight at 6 m PP is 44.07 kg (SD=6.21 kg).

 Breastmilk Composition Sub-study: We will be able to detect a 0.5 SD increase in
 breastmilk concentrations with 80% power for those nutrients identified previously based
 on marginal comparisons. Concentrations for some of these nutrients prior to
 supplementation were estimated from lactating women in Bangladesh (Hampel et al., 2017).
 Reported medians and IQRs were converted to means and SDs (Wan et al. 2014) and PASS
 version 14 (NCSS LLC, Kaysville, UT) was used for sample size calculations. Note that we
 will not be powered to detect an interaction between the pregnancy and lactation
 supplementation.

 Blood and Stool Sub-Study: All substudy women in both groups will have stool collections
 at each indicated point in time. There are very few guidelines for sample size in
 microbiome studies. We consider these analyses to be exploratory and may provide
 important information regarding the mechanisms of how nutritional supplementation can
 improve birth outcomes and early infant growth.

 Dietary Intake Sub-Study: We used two studies conducted among adults in the terai that
 use quantitative methods to estimate actual intake (Parajuli et al, 2012; Sudo et al,
 2006). Both provided estimates of daily intake for a variety of nutrients for adult
 women and were very similar in their results. We used the average of their estimated
 intake of energy (kcal) and protein (g) and the associate average standard errors for
 our calculation. Mean energy intake was 1700 kcal/day (SD=350) and 42.3 g (SD=10.4) of
 protein. As this sub-study is designed to assess dietary diversion due to the
 supplement, we used a minimally detectable difference of -12% for energy and protein as
 an indicator that dietary diversion was occurring. Given these parameters, 120 persons
 per group will provide over 90% power for energy intake and approximately 85% power for
 protein intake.

 Data Analysis, Phase 3: More detail will be available in the Statistical Analysis Plan
 document that will be posted to this site.

 Data analysis will proceed in two phases, an exploratory data analysis phase followed by
 a confirmatory analysis phase and focuses on the specific aims of this project. The
 exploratory phase will involve final data cleaning and editing as well as examination of
 the distributions for all variables and the application of appropriate transformations.
 We will populate a CONSORT diagram. Next, comparisons will be made between the four
 treatment groups on a variety of variables at the household and individual levels to
 assess their comparability. All eligible birth outcomes will be limited to those
 measured within 72 hours of delivery.

 Pregnancy Intervention Primary Aim: Data analysis will be by intent to treat. The
 proportion of babies born SGA (10th centile) will be compared in the two treatment
 groups using generalized estimating equations (GEE). An effect size will be estimated as
 the proportionate change in the intervention group relative to the control group. A 95%
 confidence interval will be calculated around this effect size estimate that accounts
 for the correlation within households. A secondary, post-hoc stratification by level of
 compliance with supplement use will be done within the active treatment group and the
 proportion SGA will be compared across groups. A dose-response effect will be estimated
 by linear regression techniques.

 Secondary Aims 1, 2, and 3: A similar analysis to that of the primary aim will be done
 for the outcome ShGA (10th centile), SGA (3rd centile), and ShGA (3rd centile).

 Secondary Aim 4: Mean birthweight and the distribution of birthweights will be compared
 by treatment group (supplementation during pregnancy versus not). Means and proportions
 below 2500 grams will be compared using GEE. A comparison of the full distribution of
 birthweights between treatment groups will also be done as previous research in this
 study area has indicated that treatment effects may vary by location on the birthweight
 distribution. (Katz et al, 2006; Dominici et al, 2006). A similar analysis of birth
 length will be conducted. A similar analysis will be conducted for the mean and
 distribution of gestational age and the proportion preterm (<37 weeks gestation).

 Secondary Aim 5: Mean Length-for-Age, Weight-for-Age, Weight-for-Length, and proportions
 (<-2 Z scores) at 6 months of age will be compared by treatment group using GEE.

 Secondary Aim 6: The nutritional composition of breastmilk collected at 2 time points
 during the first 6 months following delivery will be compared by treatment group. A
 similar analysis for that proposed for continuous anthropometric outcomes will be used.

 Post-Partum Intervention Primary Aim: Data analysis will be by intent to treat. The mean
 LAZ score among infants at 6 months of age will be compared in the two treatment groups
 using GEE. An effect size will be estimated as the proportionate change in the
 intervention group relative to the control group. A 95% confidence interval will be
 calculated around this effect size estimate that accounts for the correlation within
 clusters. A secondary, post-hoc stratification by level of compliance with supplement
 use during lactation will be done within the active treatment group and the mean LAZ
 score will be compared across groups. A dose-response effect will be estimated by linear
 regression techniques.

 Secondary Aim 1: A similar analysis to that of the primary aim will be done for the
 outcome WAZ and WLZ scores.

 Secondary Aim 2: The nutritional composition of breastmilk collected at 2 time points
 during the first 6 months following delivery will be compared by treatment group. A
 similar analysis for that proposed for continuous anthropometric outcomes will be used.

 Secondary Aim 3: Weight (and BMI) of mothers at 6 months post-partum will be compared by
 treatment group using GEE. An effect size will be estimated as the proportionate change
 in the intervention group relative to the control group. A 95% confidence interval will
 be calculated around this effect size estimate that accounts for the correlation within
 clusters. A secondary, post-hoc stratification by level of compliance with supplement
 use during lactation will be done within the active treatment group and the mean weight
 and BMI will be compared across groups. A dose-response effect will be estimated by
 linear regression techniques.

 Combination of Pregnancy and Post-Partum Supplementation

 Secondary Aim 1: The combined effect of both pregnancy and post-partum supplementation
 on 6 and 12 month LAZ, WAZ, and WLZ scores will be estimated two ways. First a
 stratified analysis will be done comparing mean and 95% CI on Z scores among control in
 both periods with pregnancy alone, post-partum alone, and both pregnancy and post-partum
 supplementation. For significance testing we have chosen the following 3 comparisons to
 apply tests of significance:

 -  Control in both periods versus post-partum alone.

 -  Pregnancy alone versus post-partum alone.

 -  Post-partum alone versus both pregnancy and post-partum. The second approach will
 be to model the effects of the treatment groups using linear regression models that
 include an interaction term for the combined treatment arm. A test of interaction
 will be used but we will primarily rely on interpreting the size of the interaction
 effect relative to the changes in the period-specific supplementation effects.

 A variety of additional analyses will be conducted to explore the consistency of the
 main effects of these interventions.

 Ethical Considerations The project has been approved by Institutional Review Boards
 (IRBs) at the George Washington University, the Johns Hopkins Bloomberg School of Public
 Health, and the Nepal Health Research Council. The IRB at the Harvard T.H. Chan School
 of Public Health has defered to the IRB of record at George Washington University.

 Adverse Event Reporting Serious Adverse Events: Serious adverse events (SAE) under GCP
 guidelines include death, a life-threatening reaction to the supplement or other study
 procedure, hospitalization, significant or persistent disability or impairment, or a
 congenital anomaly/birth defect.

 Other Adverse Events: These include any untoward medical event that occurs in a
 participant, any unfavorable sign or symptom of disease temporally associated with the
 provision of the supplement, or any noxious and unintended response to the supplement.
 Anticipated adverse events include signs/symptoms of allergic reaction to the
 supplement, preeclampsia, infection during pregnancy, gestational diabetes.
 Unanticipated adverse events are either unexpected in terms of nature, severity and
 frequency. An example would include newborn macrosomia (BW>97th centile according to
 InterGrowth21 standards).

 All adverse events will be reported to the designated local investigator for review
 within 48 hours. If there is a possibility of the event being related to the study, a
 report will be made to the independent Safety Officer within 24 hours of receipt by the
 investigator. The Safety Officer will review the file and make a determination regarding
 attribution to study procedures or the intervention. If the adverse event is considered
 by the Safety Officer to be minor in severity, it will be logged and a summary of such
 events will be reported to the DSMB at their next meeting. If the severity of the
 adverse event is considered to be moderate or severe by the Safety Officer, he/she will
 indicate to the Principal Investigator that it should be reported to the DSMB and the
 cognizant IRBs immediately. The PI will then forward all materials together with the
 Safety Officer's summary to the DSMB and the IRBs.
Inclusion Criteria:

 -  all women who become pregnant during a 9-month period in a set of Nagarpalikas and
 Gaunpalikas in Sarlahi District, Nepal.

 Exclusion Criteria:

 -  Women who do not intend to deliver their child in the study area.

 -  Women who are allergic to milk, nuts or soy.

 -  Women who are unwilling to commit to daily consumption of the nutritional supplement
 if they are randomized to an active treatment arm.

 -  Women who refuse to provide consent.