Impact of a Balanced Protein-Energy Supplement in Pregnancy and Early Lactation on Reproductive Outcomes and Growth in Southern Nepal View Homepage


Ontology type: schema:MedicalStudy     


Clinical Trial Info

YEARS

2018-2021

ABSTRACT

This project will test the acceptability and 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 1600 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. Detailed Description 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the net energy intake increased by a much smaller amount (200-300 kcal) (Janmohamed et al., 2016; Saville et al., unpublished trial in Nepal).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). Uptake of reproductive health services and antenatal care has increased dramatically over the past 15 years in Nepal (Ministry of Health, 2017). Approximately 80% of rural women report attending at least one antenatal care visit, but this varies by socioeconomic status (SES) with lower SES women significantly less likely to present for antenatal care (Ministry of Health, 2017; Furuta & Salway, 2006). Use of antenatal care (ANC) is also influenced by other household members, especially the mother-in-law (Simkhada et al., 2010). A randomized study has shown that participation in women's groups can improve antenatal care uptake in Nepal (Manandhar et al., 2004). This finding, together with the government's incentive scheme for improving rates of facility deliveries, have likely played a large role in the improving use of antenatal care services in Nepal. These 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 practices and preferences for delivery of such nutritional supplements and 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 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. 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. 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 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. Sample size for in-depth interviews and focus group discussions is a maximum of 40 women (Kodish et al., 2014; Sandelowski et al., 2000; Bernard, 2006). Community & household Influencers : In Phase 2, we will recruit key influencers who may help to add information on the potential determinants of acceptability and utilization by supplement type. Those individuals may include community leaders, health providers, husbands, in-laws and health staff. 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 repeated at 2 and 8 weeks (de Graaf et al., 2005). Direct observations of household meals: Direct observations will be used to understand supplement utilization, sharing and general household dietary behaviors (Bernard, 2006). Women will have two 12-hour home observations. In-depth interviews: For both products, interviews will be conducted with PW and other household members, community leaders, 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: All qualitative data will be transcribed and translated into English. 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: Cluster Randomized Trial Design The design of this study is a community-based, cluster-randomized 2x2 factorial trial among women who become pregnant in the study area over a 9 month period. Follow-up will be through 6 months post-partum for women and their infants. Study Population The study population for this trial will include all women who become pregnant during a 9-month period in a set of Palikas in Sarlahi District, Nepal. Newly pregnant women will be identified through a pregnancy surveillance system. Cluster Formation Palikas in Nepal are divided into multiple wards. We will limit participation to high-yield wards (clusters) that will provide an average of 22.3 (SD = 16.0) eligible live births per ward who can be measured within 72 hours of delivery over the 9 month enrollment period. 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 intervention product will be a daily fortified balanced protein-energy nutritional supplement. The exact form 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 clusters 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 in a transparent manner with involvement of senior study staff and local officials. Geographic clusters (wards) will be assigned a specific number 1 through 72. Identically sized paper slips with numbers 1 through 72 will be prepared and placed in an opaque container. Senior study staff and local officials will draw individual slips from the container in a masked fashion until 18 have been selected. These 18 clusters will constitute treatment group 1. The other 54 clusters will be assigned to treatment groups 2 through 4 using the same process. Next, 4 identically sized paper slips will be prepared, one indicating the active supplementation group in pregnancy only, one the active supplementation group post-partum only, one the active supplementation group in both periods, and one the control group in both periods. These slips will be placed in the opaque container and the District Public Health Officer will draw one slip at a time in a masked fashion to assign treatment groups 1 to 4. T Biospecimen Sub-study A random sample of participating women will be selected from each of the 4 groups for inclusion in this sub-study. Blood will be collected 3 times (baseline, ~34 weeks gestation, and 3-4 months post-partum). Breastmilk will be collected twice during lactation, once between months 1 & 2 and again between months 3 & 4. Infant stool will be collected twice during early infancy at the same time a breastmilk collection. Maternal blood will be assessed for hemoglobin and a variety of nutrients. The nutrients to be assessed in breastmilk include vitamins A, E, B6, B12, Riboflavin, Thiamin, Niacin, Choline, Biotin and minerals Iron, Zinc, Copper and Selenium. Macronutrients will include fat, lactose and total protein. The infant intestinal microbiome will be assessed for diversity and specific pathogens. Dietary Intake Sub-Study A random sample of 60 women in each group during pregnancy and again in the post-partum groups will be selected to participate in this dietary intake sub-study. The purpose 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 (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. Clearly, outcomes of pregnancy cannot be affected by nutritional supplementation given only after birth, but infant growth may be affected by supplementation during both time periods. Primary Outcomes: Small-for-gestational-age (SGA) is the primary outcome that we have used to drive the sample size calculations. Over a period of 9 months, we expect that clusters will provide an average of 22.3 (SD = 16.2) pregnancy outcome measures. We used Intergrowth21 standards to estimate the overall proportion of SGA (10th percentile) among 14,468 infants in similar clusters in a previous study; 41.3% were SGA ((k=0.107). In the table below, we show the number of clusters needed (in each group) to detect a 22.5% reduction in SGA with 80% and 90% power using the approach described by Hayes/Moulton, 2009. We have chosen a 22.5% reduction as the minimally important reduction for detection with high power as we believe this level of reduction would be compelling from the perspective of policy makers in countries with similar characteristics to southern Nepal. Sample Size Requirements for Primary Outcome Outcome (Number of Clusters in Each Group) 80% Power 90% Power Primary SGA (10th centile) 27 36 We will include 36 clusters per marginal group in order to achieve 90% power to detect a 22.5% reduction in SGA when comparing the treatment groups that receive supplementation during pregnancy versus those that do not. This number of clusters translates to approximately 803 live births per group (# clusters x mean number of births per cluster). Given 36 clusters per group, we have also estimated the detectable difference (reduction) in the pregnancy supplementation group versus those not supplemented during pregnancy for a number of the secondary outcomes with 80% and 90% power in the table below. Detectable Difference in Secondary Outcomes (Marginal Comparisons) Outcome Detectable Difference Between Groups 80% Power 90% Power Secondary ShGA (10th centile)a 24.3% 27.9% SGA (3rd centile)b 29.2% 33.4% ShGA (3rd centile)c 35.9% 40.9% Mean Birth Weight d 75.3 g 87.1 g Mean Birth Length e 3.7 mm 4.3 mm LAZ at 6 months1 0.25 Z scores 0.20 Z Scores WAZ at 6 months2 0.26 Z scores 0.29 Z scores WLZ at 6 months3 0.20 Z scores 0.24 Z scores Maternal Weight Gain in Pregnancy4 418 g 494 g Maternal Weight at 6 months Post-Partum5 1.16 kg 1.35 kg a ShGA (10th centile expected rate is 30.1% (k=0.135). b SGA (3rd centile) expected rate is 22.1% (k=0.156). c ShGA (3rd centile) expected rate is 14.4% (k=0.138). d Expected mean birth weight is 2708 g (SD=429), (k=0.018). e Expected mean birth length is 47.6 cm (SD=2.2) (k=0.005). 1. Expected mean LAZ at 6 months is -1.04 (k=0.251). 2. Expected mean WAZ at 6 months is -1.63 (k=0.186). 3. Expected mean WLZ at 6 months is -1.23 (k=0.118). 4. Expected mean weight gain in pregnancy is 7.55 kg (SD=3.23 kg), (k=0.027). 5. Expected mean maternal weight at 6 m PP is 44.07 kg (SD=6.21 kg), (k=0.02). While detectable relative differences in ShGA (10th centile) and SGA and ShGA at the 3rd centile will be larger than 20%, at 80% power they remain within a range of plausible outcomes. Increases in continuous measures of birth weight, birth length, Z scores at 6 months, maternal weight gain in pregnancy, and maternal weight at 6 months post-partum are detectable with high power at even moderate mean changes/differences. Note that the primary outcome for assessing the effect of the post-partum supplementation is LAZ score at 6 months. Since we are assuming no interaction between the marginal effects, the detectable difference is 0.20 Z scores with 90% power. Note that the detectable growth secondary outcomes are slightly larger at 0.29 Z scores for WAZ and 0.24 Z scores for WLZ. Biospecimen Composition Sub-study: We used the breastmilk aim to drive this sample size estimate. 90 persons per group will be required 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. 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). We used the average of their estimated intake of energy (kcal) and protein (g) and the associate average standard errors for our calculation. As this sub-study is designed to assess dietary diversion due to the supplement, we used a minimally detectable difference of -15% for energy and protein as an indicator that dietary diversion was occurring. Given these parameters and a 20% increase in sample size to account for the clustered design, 60 persons per group will provide over 90% power for energy intake and approximately 85% power for protein intake. Data Analysis, Phase 3 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) to account for the clustered study design. 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. P-values will not be used. 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. These assays will be conducted by colleagues at the USDA Center at the University of California-Davis. A similar analysis for that proposed for continuous anthropometric outcomes will be used. Volume of breastmilk consumed over a 24 hour period will be calculated by the difference in weights of the infant 24 hours apart divided by the specific gravity of breastmilk. 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 to account for the clustered study design. 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. P-values will not be used. 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. P-values will not be used. 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 are allowed 3 orthogonal contrasts and 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. GEE will be used to adjust for the clustered design. 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 have defered to the IRB of record at George Washington University. This trial will be conducted according to Good Clinical Practice (GCP) guidelines (WHO, 2005). An independent in-country Safety Officer will be appointed from among the faculty at the Institute of Medicine of Tribhuvan 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 (Dr. Subarna K. Khatry) 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. More... »

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    "description": "This project will test the acceptability and 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 1600 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.\n\nDetailed Description\nBackground 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). Uptake of reproductive health services and antenatal care has increased dramatically over the past 15 years in Nepal (Ministry of Health, 2017). Approximately 80% of rural women report attending at least one antenatal care visit, but this varies by socioeconomic status (SES) with lower SES women significantly less likely to present for antenatal care (Ministry of Health, 2017; Furuta & Salway, 2006). Use of antenatal care (ANC) is also influenced by other household members, especially the mother-in-law (Simkhada et al., 2010). A randomized study has shown that participation in women's groups can improve antenatal care uptake in Nepal (Manandhar et al., 2004). This finding, together with the government's incentive scheme for improving rates of facility deliveries, have likely played a large role in the improving use of antenatal care services in Nepal. These 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 practices and preferences for delivery of such nutritional supplements and 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 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. 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. 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 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. Sample size for in-depth interviews and focus group discussions is a maximum of 40 women (Kodish et al., 2014; Sandelowski et al., 2000; Bernard, 2006). Community & household Influencers : In Phase 2, we will recruit key influencers who may help to add information on the potential determinants of acceptability and utilization by supplement type. Those individuals may include community leaders, health providers, husbands, in-laws and health staff. 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 repeated at 2 and 8 weeks (de Graaf et al., 2005). Direct observations of household meals: Direct observations will be used to understand supplement utilization, sharing and general household dietary behaviors (Bernard, 2006). Women will have two 12-hour home observations. In-depth interviews: For both products, interviews will be conducted with PW and other household members, community leaders, 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: All qualitative data will be transcribed and translated into English. 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: Cluster Randomized Trial Design The design of this study is a community-based, cluster-randomized 2x2 factorial trial among women who become pregnant in the study area over a 9 month period. Follow-up will be through 6 months post-partum for women and their infants. Study Population The study population for this trial will include all women who become pregnant during a 9-month period in a set of Palikas in Sarlahi District, Nepal. Newly pregnant women will be identified through a pregnancy surveillance system. Cluster Formation Palikas in Nepal are divided into multiple wards. We will limit participation to high-yield wards (clusters) that will provide an average of 22.3 (SD = 16.0) eligible live births per ward who can be measured within 72 hours of delivery over the 9 month enrollment period. 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 intervention product will be a daily fortified balanced protein-energy nutritional supplement. The exact form 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 clusters 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 in a transparent manner with involvement of senior study staff and local officials. Geographic clusters (wards) will be assigned a specific number 1 through 72. Identically sized paper slips with numbers 1 through 72 will be prepared and placed in an opaque container. Senior study staff and local officials will draw individual slips from the container in a masked fashion until 18 have been selected. These 18 clusters will constitute treatment group 1. The other 54 clusters will be assigned to treatment groups 2 through 4 using the same process. Next, 4 identically sized paper slips will be prepared, one indicating the active supplementation group in pregnancy only, one the active supplementation group post-partum only, one the active supplementation group in both periods, and one the control group in both periods. These slips will be placed in the opaque container and the District Public Health Officer will draw one slip at a time in a masked fashion to assign treatment groups 1 to 4. T Biospecimen Sub-study A random sample of participating women will be selected from each of the 4 groups for inclusion in this sub-study. Blood will be collected 3 times (baseline, ~34 weeks gestation, and 3-4 months post-partum). Breastmilk will be collected twice during lactation, once between months 1 & 2 and again between months 3 & 4. Infant stool will be collected twice during early infancy at the same time a breastmilk collection. Maternal blood will be assessed for hemoglobin and a variety of nutrients. The nutrients to be assessed in breastmilk include vitamins A, E, B6, B12, Riboflavin, Thiamin, Niacin, Choline, Biotin and minerals Iron, Zinc, Copper and Selenium. Macronutrients will include fat, lactose and total protein. The infant intestinal microbiome will be assessed for diversity and specific pathogens. Dietary Intake Sub-Study A random sample of 60 women in each group during pregnancy and again in the post-partum groups will be selected to participate in this dietary intake sub-study. The purpose 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 (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. Clearly, outcomes of pregnancy cannot be affected by nutritional supplementation given only after birth, but infant growth may be affected by supplementation during both time periods. Primary Outcomes: Small-for-gestational-age (SGA) is the primary outcome that we have used to drive the sample size calculations. Over a period of 9 months, we expect that clusters will provide an average of 22.3 (SD = 16.2) pregnancy outcome measures. We used Intergrowth21 standards to estimate the overall proportion of SGA (10th percentile) among 14,468 infants in similar clusters in a previous study; 41.3% were SGA ((k=0.107). In the table below, we show the number of clusters needed (in each group) to detect a 22.5% reduction in SGA with 80% and 90% power using the approach described by Hayes/Moulton, 2009. We have chosen a 22.5% reduction as the minimally important reduction for detection with high power as we believe this level of reduction would be compelling from the perspective of policy makers in countries with similar characteristics to southern Nepal. Sample Size Requirements for Primary Outcome Outcome (Number of Clusters in Each Group) 80% Power 90% Power Primary SGA (10th centile) 27 36 We will include 36 clusters per marginal group in order to achieve 90% power to detect a 22.5% reduction in SGA when comparing the treatment groups that receive supplementation during pregnancy versus those that do not. This number of clusters translates to approximately 803 live births per group (# clusters x mean number of births per cluster). Given 36 clusters per group, we have also estimated the detectable difference (reduction) in the pregnancy supplementation group versus those not supplemented during pregnancy for a number of the secondary outcomes with 80% and 90% power in the table below. Detectable Difference in Secondary Outcomes (Marginal Comparisons) Outcome Detectable Difference Between Groups 80% Power 90% Power Secondary ShGA (10th centile)a 24.3% 27.9% SGA (3rd centile)b 29.2% 33.4% ShGA (3rd centile)c 35.9% 40.9% Mean Birth Weight d 75.3 g 87.1 g Mean Birth Length e 3.7 mm 4.3 mm LAZ at 6 months1 0.25 Z scores 0.20 Z Scores WAZ at 6 months2 0.26 Z scores 0.29 Z scores WLZ at 6 months3 0.20 Z scores 0.24 Z scores Maternal Weight Gain in Pregnancy4 418 g 494 g Maternal Weight at 6 months Post-Partum5 1.16 kg 1.35 kg a ShGA (10th centile expected rate is 30.1% (k=0.135). b SGA (3rd centile) expected rate is 22.1% (k=0.156). c ShGA (3rd centile) expected rate is 14.4% (k=0.138). d Expected mean birth weight is 2708 g (SD=429), (k=0.018). e Expected mean birth length is 47.6 cm (SD=2.2) (k=0.005). 1. Expected mean LAZ at 6 months is -1.04 (k=0.251). 2. Expected mean WAZ at 6 months is -1.63 (k=0.186). 3. Expected mean WLZ at 6 months is -1.23 (k=0.118). 4. Expected mean weight gain in pregnancy is 7.55 kg (SD=3.23 kg), (k=0.027). 5. Expected mean maternal weight at 6 m PP is 44.07 kg (SD=6.21 kg), (k=0.02). While detectable relative differences in ShGA (10th centile) and SGA and ShGA at the 3rd centile will be larger than 20%, at 80% power they remain within a range of plausible outcomes. Increases in continuous measures of birth weight, birth length, Z scores at 6 months, maternal weight gain in pregnancy, and maternal weight at 6 months post-partum are detectable with high power at even moderate mean changes/differences. Note that the primary outcome for assessing the effect of the post-partum supplementation is LAZ score at 6 months. Since we are assuming no interaction between the marginal effects, the detectable difference is 0.20 Z scores with 90% power. Note that the detectable growth secondary outcomes are slightly larger at 0.29 Z scores for WAZ and 0.24 Z scores for WLZ. Biospecimen Composition Sub-study: We used the breastmilk aim to drive this sample size estimate. 90 persons per group will be required 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. 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). We used the average of their estimated intake of energy (kcal) and protein (g) and the associate average standard errors for our calculation. As this sub-study is designed to assess dietary diversion due to the supplement, we used a minimally detectable difference of -15% for energy and protein as an indicator that dietary diversion was occurring. Given these parameters and a 20% increase in sample size to account for the clustered design, 60 persons per group will provide over 90% power for energy intake and approximately 85% power for protein intake. Data Analysis, Phase 3 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) to account for the clustered study design. 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. P-values will not be used. 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. These assays will be conducted by colleagues at the USDA Center at the University of California-Davis. A similar analysis for that proposed for continuous anthropometric outcomes will be used. Volume of breastmilk consumed over a 24 hour period will be calculated by the difference in weights of the infant 24 hours apart divided by the specific gravity of breastmilk. 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 to account for the clustered study design. 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. P-values will not be used. 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. P-values will not be used. 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 are allowed 3 orthogonal contrasts and 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. GEE will be used to adjust for the clustered design. 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 have defered to the IRB of record at George Washington University. This trial will be conducted according to Good Clinical Practice (GCP) guidelines (WHO, 2005). An independent in-country Safety Officer will be appointed from among the faculty at the Institute of Medicine of Tribhuvan 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 (Dr. Subarna K. Khatry) 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.", 
    "endDate": "2021-05-01T00:00:00Z", 
    "id": "sg:clinicaltrial.NCT03668977", 
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1 sg:clinicaltrial.NCT03668977 schema:about anzsrc-for:3177
2 schema:description This project will test the acceptability and 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 1600 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. Detailed Description 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). Uptake of reproductive health services and antenatal care has increased dramatically over the past 15 years in Nepal (Ministry of Health, 2017). Approximately 80% of rural women report attending at least one antenatal care visit, but this varies by socioeconomic status (SES) with lower SES women significantly less likely to present for antenatal care (Ministry of Health, 2017; Furuta & Salway, 2006). Use of antenatal care (ANC) is also influenced by other household members, especially the mother-in-law (Simkhada et al., 2010). A randomized study has shown that participation in women's groups can improve antenatal care uptake in Nepal (Manandhar et al., 2004). This finding, together with the government's incentive scheme for improving rates of facility deliveries, have likely played a large role in the improving use of antenatal care services in Nepal. These 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 practices and preferences for delivery of such nutritional supplements and 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 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. 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. 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 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. Sample size for in-depth interviews and focus group discussions is a maximum of 40 women (Kodish et al., 2014; Sandelowski et al., 2000; Bernard, 2006). Community & household Influencers : In Phase 2, we will recruit key influencers who may help to add information on the potential determinants of acceptability and utilization by supplement type. Those individuals may include community leaders, health providers, husbands, in-laws and health staff. 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 repeated at 2 and 8 weeks (de Graaf et al., 2005). Direct observations of household meals: Direct observations will be used to understand supplement utilization, sharing and general household dietary behaviors (Bernard, 2006). Women will have two 12-hour home observations. In-depth interviews: For both products, interviews will be conducted with PW and other household members, community leaders, 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: All qualitative data will be transcribed and translated into English. 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: Cluster Randomized Trial Design The design of this study is a community-based, cluster-randomized 2x2 factorial trial among women who become pregnant in the study area over a 9 month period. Follow-up will be through 6 months post-partum for women and their infants. Study Population The study population for this trial will include all women who become pregnant during a 9-month period in a set of Palikas in Sarlahi District, Nepal. Newly pregnant women will be identified through a pregnancy surveillance system. Cluster Formation Palikas in Nepal are divided into multiple wards. We will limit participation to high-yield wards (clusters) that will provide an average of 22.3 (SD = 16.0) eligible live births per ward who can be measured within 72 hours of delivery over the 9 month enrollment period. 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 intervention product will be a daily fortified balanced protein-energy nutritional supplement. The exact form 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 clusters 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 in a transparent manner with involvement of senior study staff and local officials. Geographic clusters (wards) will be assigned a specific number 1 through 72. Identically sized paper slips with numbers 1 through 72 will be prepared and placed in an opaque container. Senior study staff and local officials will draw individual slips from the container in a masked fashion until 18 have been selected. These 18 clusters will constitute treatment group 1. The other 54 clusters will be assigned to treatment groups 2 through 4 using the same process. Next, 4 identically sized paper slips will be prepared, one indicating the active supplementation group in pregnancy only, one the active supplementation group post-partum only, one the active supplementation group in both periods, and one the control group in both periods. These slips will be placed in the opaque container and the District Public Health Officer will draw one slip at a time in a masked fashion to assign treatment groups 1 to 4. T Biospecimen Sub-study A random sample of participating women will be selected from each of the 4 groups for inclusion in this sub-study. Blood will be collected 3 times (baseline, ~34 weeks gestation, and 3-4 months post-partum). Breastmilk will be collected twice during lactation, once between months 1 & 2 and again between months 3 & 4. Infant stool will be collected twice during early infancy at the same time a breastmilk collection. Maternal blood will be assessed for hemoglobin and a variety of nutrients. The nutrients to be assessed in breastmilk include vitamins A, E, B6, B12, Riboflavin, Thiamin, Niacin, Choline, Biotin and minerals Iron, Zinc, Copper and Selenium. Macronutrients will include fat, lactose and total protein. The infant intestinal microbiome will be assessed for diversity and specific pathogens. Dietary Intake Sub-Study A random sample of 60 women in each group during pregnancy and again in the post-partum groups will be selected to participate in this dietary intake sub-study. The purpose 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 (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. Clearly, outcomes of pregnancy cannot be affected by nutritional supplementation given only after birth, but infant growth may be affected by supplementation during both time periods. Primary Outcomes: Small-for-gestational-age (SGA) is the primary outcome that we have used to drive the sample size calculations. Over a period of 9 months, we expect that clusters will provide an average of 22.3 (SD = 16.2) pregnancy outcome measures. We used Intergrowth21 standards to estimate the overall proportion of SGA (10th percentile) among 14,468 infants in similar clusters in a previous study; 41.3% were SGA ((k=0.107). In the table below, we show the number of clusters needed (in each group) to detect a 22.5% reduction in SGA with 80% and 90% power using the approach described by Hayes/Moulton, 2009. We have chosen a 22.5% reduction as the minimally important reduction for detection with high power as we believe this level of reduction would be compelling from the perspective of policy makers in countries with similar characteristics to southern Nepal. Sample Size Requirements for Primary Outcome Outcome (Number of Clusters in Each Group) 80% Power 90% Power Primary SGA (10th centile) 27 36 We will include 36 clusters per marginal group in order to achieve 90% power to detect a 22.5% reduction in SGA when comparing the treatment groups that receive supplementation during pregnancy versus those that do not. This number of clusters translates to approximately 803 live births per group (# clusters x mean number of births per cluster). Given 36 clusters per group, we have also estimated the detectable difference (reduction) in the pregnancy supplementation group versus those not supplemented during pregnancy for a number of the secondary outcomes with 80% and 90% power in the table below. Detectable Difference in Secondary Outcomes (Marginal Comparisons) Outcome Detectable Difference Between Groups 80% Power 90% Power Secondary ShGA (10th centile)a 24.3% 27.9% SGA (3rd centile)b 29.2% 33.4% ShGA (3rd centile)c 35.9% 40.9% Mean Birth Weight d 75.3 g 87.1 g Mean Birth Length e 3.7 mm 4.3 mm LAZ at 6 months1 0.25 Z scores 0.20 Z Scores WAZ at 6 months2 0.26 Z scores 0.29 Z scores WLZ at 6 months3 0.20 Z scores 0.24 Z scores Maternal Weight Gain in Pregnancy4 418 g 494 g Maternal Weight at 6 months Post-Partum5 1.16 kg 1.35 kg a ShGA (10th centile expected rate is 30.1% (k=0.135). b SGA (3rd centile) expected rate is 22.1% (k=0.156). c ShGA (3rd centile) expected rate is 14.4% (k=0.138). d Expected mean birth weight is 2708 g (SD=429), (k=0.018). e Expected mean birth length is 47.6 cm (SD=2.2) (k=0.005). 1. Expected mean LAZ at 6 months is -1.04 (k=0.251). 2. Expected mean WAZ at 6 months is -1.63 (k=0.186). 3. Expected mean WLZ at 6 months is -1.23 (k=0.118). 4. Expected mean weight gain in pregnancy is 7.55 kg (SD=3.23 kg), (k=0.027). 5. Expected mean maternal weight at 6 m PP is 44.07 kg (SD=6.21 kg), (k=0.02). While detectable relative differences in ShGA (10th centile) and SGA and ShGA at the 3rd centile will be larger than 20%, at 80% power they remain within a range of plausible outcomes. Increases in continuous measures of birth weight, birth length, Z scores at 6 months, maternal weight gain in pregnancy, and maternal weight at 6 months post-partum are detectable with high power at even moderate mean changes/differences. Note that the primary outcome for assessing the effect of the post-partum supplementation is LAZ score at 6 months. Since we are assuming no interaction between the marginal effects, the detectable difference is 0.20 Z scores with 90% power. Note that the detectable growth secondary outcomes are slightly larger at 0.29 Z scores for WAZ and 0.24 Z scores for WLZ. Biospecimen Composition Sub-study: We used the breastmilk aim to drive this sample size estimate. 90 persons per group will be required 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. 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). We used the average of their estimated intake of energy (kcal) and protein (g) and the associate average standard errors for our calculation. As this sub-study is designed to assess dietary diversion due to the supplement, we used a minimally detectable difference of -15% for energy and protein as an indicator that dietary diversion was occurring. Given these parameters and a 20% increase in sample size to account for the clustered design, 60 persons per group will provide over 90% power for energy intake and approximately 85% power for protein intake. Data Analysis, Phase 3 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) to account for the clustered study design. 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. P-values will not be used. 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. These assays will be conducted by colleagues at the USDA Center at the University of California-Davis. A similar analysis for that proposed for continuous anthropometric outcomes will be used. Volume of breastmilk consumed over a 24 hour period will be calculated by the difference in weights of the infant 24 hours apart divided by the specific gravity of breastmilk. 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 to account for the clustered study design. 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. P-values will not be used. 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. P-values will not be used. 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 are allowed 3 orthogonal contrasts and 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. GEE will be used to adjust for the clustered design. 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 have defered to the IRB of record at George Washington University. This trial will be conducted according to Good Clinical Practice (GCP) guidelines (WHO, 2005). An independent in-country Safety Officer will be appointed from among the faculty at the Institute of Medicine of Tribhuvan 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 (Dr. Subarna K. Khatry) 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. 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