Feasibility and effect of life skills building education and multiple micronutrient supplements versus the standard of care on anemia among non-pregnant adolescent and young Pakistani women (15–24years): a prospective, population-based cluster-randomized trial

Feasibility and effect of life skills building education and multiple micronutrient supplements... Background: Adolescence is a critical period for physical and psychological growth and development, and vitamin and mineral requirements are correspondingly increased. Health and health behaviours correspond strongly from adolescence to adulthood. Developing a preconception care package for adolescent and young women in resource-limited settings could serve to empower them to make informed decisions about their nutrition, health, and well-being, as well as function as a platform for the delivery of basic nutrition-related interventions to address undernutrition. Methods: In this population-based two-arm, cluster-randomized, controlled trial of life skills building education (provided bi-monthly) and multiple micronutrient supplementation (provided twice-weekly; UNIMMAP composition) , we aim to evaluate the effectiveness of the intervention on the prevention of anemia (hemoglobin concentration < 12 g/dL) among adolescent and young women (15–24 years) in Matiari district, Pakistan compared to the standard of care. Several secondary objectives related to nutrition (anthropometry [height, weight, middle upper arm circumference (MUAC)], nutritional status [iron, vitamin A, vitamin D]); general health (morbidity, mortality); and empowerment (age at marriage, completion of the 10th grade, use of personal hygienic materials during menstruation) will also be assessed. Participants will be enrolled in the study for a maximum of 2 years. (Continued on next page) * Correspondence: zulfiqar.bhutta@aku.edu Centre for Global Child Health, The Hospital for Sick Children, Toronto, ON M6S 1S6, Canada Department of Nutritional Sciences, University of Toronto, Toronto, ON, Canada Full list of author information is available at the end of the article © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Baxter et al. Reproductive Health (2018) 15:103 Page 2 of 9 (Continued from previous page) Discussion: Empowering adolescent and young women with the appropriate knowledge to make informed and healthy decisions will be key to sustained behavioural change throughout the life-course. Although multiple micronutrient deficiencies are known to exist among adolescent and young women in low-resource settings, recommendations on preconception multiple micronutrient supplementation do not exist at this time. This study is expected to offer insight into providing an intervention that includes both education and supplements to non- pregnant adolescent and young women for a prolonged duration of time within the existing public health programmatic context. Trial registration: This study is part of the Matiari emPowerment and Preconception Supplementation (MaPPS) Trial. The MaPPS Trial was registered retrospectively on clinicaltrials.gov (Identifier: NCT03287882) on September 19, 2017. Keywords: Adolescence, Young adult, Nutrition, Micronutrients, Education, Preconception, Anemia, Empowerment Plain English summary and child mortality [3], and contribute to 23% of the bur- In low- and middle-income countries many adolescent den of disease arising from pregnancy and childbirth [4]. and young women do not consume enough healthy and When an adolescent becomes pregnant in a resource- nutrient-rich foods to meet their daily needs. Data show limited setting, her access to education generally that adolescent and young women in these places are stops as a result; yet, educating girls is very effective also more likely to become pregnant. If a woman is in raising overall economic productivity, lowering in- undernourished when she becomes pregnant, it can have fant and maternal mortality, improving nutrition, a negative effect on her health, pregnancy, and infant. One and promoting health [5]. Collectively, this makes deter- way to improve adolescent and young women’shealthbe- mining interventions to improve health outcomes from fore they become pregnant is to provide a program that adolescence of public health importance [2]. aims to help them make healthy decisions and improve Nutritional deficiencies are risk factors known to exist their nutrition. This is often called preconception care. In from adolescence, and have important consequences for this study in rural Pakistan, we have designed a future maternal and newborn health. During adolescence, culturally-appropriate preconception care package that in- vitamin and mineral requirements are incrementally in- cludes life skills building education, to help study partici- creased to support one’s ongoing physical development and pants make better decisions about their health and educate the nutritional strain of menstruation [6]. Given the limited them about their rights, and multiple micronutrient supple- intake of animal products, fruits, vegetables, and fortified ments, since they have limited access to foods with the foods in low- and middle-income countries, undernutrition micronutrients that they need. Study participants (15– can be widely prevalent [7]. Deficiencies in multiple micro- 24 years) are enrolled for 2 years, and we will assess several nutrients (MMN) are of particular concern given their dir- factors about their nutrition, health, and well-being over ect effects, such as iron deficiency anemia and iodine this time. The main effect we aim to determine is how deficiency disorders, and their indirect effects, like in- many participants have anemia among those who receive creased risk of serious infectious disease [6]. The burden the preconception care package compared to those who do of undernutrition and its downstream consequences could not receive it. Ultimately, we hope that what we learn in be prevented throughout the life course by using appro- this study will lead us to make recommendations about pol- priate nutrition-specific and nutrition-sensitive interven- icies around preconception care for adolescent and young tions, such as MMN supplementation and the women so that they can live healthier lives and make empowerment of women to make informed decisions, re- healthier decisions. spectively [5]. Since health and health behaviours correspond strongly from adolescence to adulthood, habits acquired during Background adolescence could have significant implications later in life Within the Sustainable Development Goals, promoting [2]. As such, developing a preconception care package for strategies to ensure the survival, health, and well-being of adolescent and young women could serve to empower adolescent girls, women, and their offspring has been rec- them to make informed decisions about their health and ognized as an essential component to ending poverty [1]. well-being [8], and function as a platform for the delivery Adolescence, in particular, is considered a neglected yet of basic nutrition-related interventions to address under- critical period for physical and psychological growth and nutrition [9]. Incorporating a life skills building education development, given the transition from childhood to repro- (LSBE) element will be important to sustainable and profi- ductive adulthood [2]. Pregnancies to adolescents are asso- cient uptake in improving their own general health, ciated with a higher risk of complications and maternal Baxter et al. Reproductive Health (2018) 15:103 Page 3 of 9 pregnancy outcomes, and future health of their children These relate to nutrition (anthropometry [height, weight, [8]. However, at this time there is limited understanding as middle upper arm circumference (MUAC)], nutritional to what health information should be provided and how status [iron, vitamin A, vitamin D]); general health (e.g., within preconception care. morbidity, mortality); and empowerment (age at mar- We hypothesize that the programmatic provision of riage, completion of the 10th grade, and use of personal LSBE and MMN supplements to non-pregnant adoles- hygienic materials during menstruation). cent and young women 15–24 years of age in a population-based setting in rural Pakistan will improve Setting and participants selected nutrition, health, and empowerment-related This trial will be conducted in rural settings within outcomes compared to those who receive the standard Matiari district in Sindh province, Pakistan. Briefly, the of care. For those who receive the intervention, we ex- nutritional status of adolescent girls in Pakistan is poor, pect that there will be a decrease in the prevalence of with 51 and 20% experiencing anemia and iron defi- anemia. Conducting this trial within the context of the ciency anemia, respectively [12]. An urban/rural divide existing public health setting will allow us to assess the is suggested to impact adolescent nutritional status [13], effectiveness of the intervention, and offer important with adolescents living in rural settings having particu- insight around how to achieve coverage in the trial larly limited dietary diversity [14]. The intervention is setting. situated within Pakistan’s existing Lady Health Worker (LHW) Programme. Each LHW is affiliated with a health Methods facility and visit the homes in her catchment area The Matiari emPowerment and Preconception Supplemen- monthly to carry out community support sessions and tation (MaPPS) Trial is a two-arm, cluster-randomized, disseminate health education messages [15]. LHW-led controlled trial of LSBE and MMN supplementation pro- community sessions have the potential to serve as an vided in a programmatic context to evaluate the impact on important communication channel for adolescents, espe- pre-identified nutrition and health outcomes among adoles- cially those out of school. However, the content of exist- cent and young women, and their infants born within the ing LHW educational materials primarily focuses on context of the trial. Depending on whether participants be- priority groups, including children < 5 years, pregnant come pregnant or not, there are three phases: preconcep- women, and couples eligible for family planning [16]. Al- tion (maximum 24 months in duration); pregnancy though the LHW curriculum includes some material on (approximately 9 months in duration); and postpartum topics important to the health of adolescent girls (e.g., (maximum 12 months in duration). A detailed trial proto- dietary practices, anemia), these materials are not widely col has been developed in accordance with the SPIRIT implemented and not included in community sessions guidelines [10] in a collaboration between the Aga Khan regularly. More detail about the trial setting is described University (AKU; Karachi, Pakistan) and the Hospital for in the parent trial protocol publication ([11] Sick Children (Toronto, Ontario, Canada). This paper ad- unpublished). dresses the methods for ongoing data collection during the preconception phase of the trial among participants Eligibility criteria who do not become pregnant, with the methods for the As the MaPPS Trial is a population-based effectiveness parent trial detailing the pregnancy and postpartum study of LSBE and MMN supplementation from precon- phases appearing elsewhere ([11] unpublished). ception, broad eligibility criteria for participation in the The first participant was enrolled on 30 June 2017; en- preconception phase were established. These include rollment is expected to be ongoing until July 2018; and that the minimum age at enrolment is 15 years and the planned data collection will continue until 2021. maximum age is 23 years; adolescent and young women must also report to be physically able to comply with the Objectives trial intervention. Adolescent and young women are not The primary aim of the preconception phase of the eligible to enrol if they are pregnant, participating in a MaPPS Trial is to evaluate the impact of LSBE (provided different nutrition trial, or intend to leave the study area. bi-monthly) and supplementation with MMN (provided They can be of any marital status. If a participant be- twice-weekly) versus the standard of care (non-regulated comes pregnant, she proceeds to the pregnancy phase of community-based health sessions and no supplements) the MaPPS Trial, as detailed in the parent study publica- on anemia (hemoglobin concentration < 12 g/dL) after tion ([11] unpublished). 2 years among non-pregnant adolescents 15–18.9 years The micronutrient status and dietary intake of a of age at enrolment. There are several secondary objec- sub-sample of adolescent participants 15–18.9 years of tives to further determine the effect of LSBE and MMN age at enrolment will also be monitored within the supplementation compared to the standard of care. MaPPS Trial. Participants recruited to the dietary Baxter et al. Reproductive Health (2018) 15:103 Page 4 of 9 assessment subgroup must also be a part of the micro- be assessed in 200 randomly selected micronutrient sta- nutrient status subgroup. tus subgroup participants per arm (15 women per clus- ter), to further form a dietary status subgroup. Design and sample size The MaPPS Trial is a two-arm, parallel, prospective, Intervention and control cluster-randomized, controlled trial (Fig. 1). A LSBE materials cluster-randomized design was chosen to prevent con- In intervention clusters, enhanced LSBE materials have tamination between the control and intervention arms been developed on topics important to the empower- through supplement sharing. The unit of randomization is ment of adolescent and young women to complement previously defined and mapped health facility clusters. A the existing LHW materials for use in community ses- total of 26 clusters are available to be randomized (i.e., 13 sions. These will be implemented bi-monthly and at- clusters per arm), and more detail around randomization tendance will be recorded. Three topic areas were and allocation concealment are found with the description prioritized: (a) delaying early marriage; (b) practicing ap- of the parent study (Baxter et al., unpublished). PASS 11 propriate personal and menstrual hygiene; and (c) the Software (NCSS, LLC., Kaysville, UT, USA) was used to importance of good nutrition to health. Approximately determine all sample size calculations. 20 min is intended to be spent on each topic at commu- To observe a 20% relative reduction in the prevalence nity sessions. Integrated throughout the 3 topics are of anemia among non-pregnant adolescent participants messages related to continuing one’s education, mental 15–18.9 years at enrolment, a 50% baseline prevalence health (how to cope with stress, anxiety, and when you of anemia [12] was assumed. With icc = 0.0256, k = 0.16, are upset), gender norms and equality, decision-making, accounting for 15% attrition, and probability of type I advocacy, resiliency, participation, communication skills, and type II errors of 0.05 and 0.20, respectively, the facing challenges, agency, conflict resolution, and the number anemic adolescents required per cluster was 66. prevention of violence. This equates to 858 anemic adolescents per arm. To Communication tools have been developed to assist the achieve this reduction in anemia, 1716 adolescents per LHWs in conducting the LSBE-based community ses- arm will be required (3432 total). Given the number of sions. These were designed in coordination with Aahung, adolescent and young women required to be powered to a Karachi-based non-governmental organization that aims see a reduction in the primary outcome of the parent to improve the sexual and reproductive health of girls trial (low birth weight), we aim to enrol 12,712 partici- (www.aahung.org; Karachi, Pakistan). Communication pants 15–24 years per arm (25,424 total). tools include a flipchart with 2 pictorials and discussion To monitor the micronutrient status of a subgroup of prompts per topic for use in sessions; and a brief summary participants 15–18.9 years of age at enrolment, the sam- pamphlet for distribution to participants. The flipcharts ple size calculated for the reduction in anemia preva- are similar to existing LHW tools for leading community lence will be used (i.e., 1716 adolescents per arm). Stata sessions. A team of master trainers is trained on all LSBE software (StataCorp, College Station, TX, USA) has been materials and appropriate communication techniques. used to randomly select 132 adolescents 15–18.9 years The master trainers provide comprehensive and inter- at enrolment from each cluster. Dietary intake will also active training for all intervention LHWs. Refresher Fig. 1 Matiari emPowerment and Preconception Supplementation (MaPPS) Trial flow diagram for participants who do not become pregnant Baxter et al. Reproductive Health (2018) 15:103 Page 5 of 9 training will also be provided on an ongoing basis the next time that they remember, but never to consume throughout the duration of the trial. more than 1 tablet/day. If a participant has any side ef- fects, is concerned, or has questions, she is instructed to Trial supplements and administration contact her LHW and not study personnel since study The MMN supplements provided to participants in the personnel are blinded to whether participants are in the intervention arm of the MaPPS Trial are consistent with control or intervention arm. Participants are also asked the UNICEF/WHO/UNU international multiple micronu- not to take non-trial administered supplements while trient preparation (UNIMMAP), and have been procured they are enrolled in the trial. from the UNICEF Supply Catalogue (https://supply.unice- f.org). Each tablet is 10 mm in diameter and includes vita- Enrolment and consent min A: 800 μg RE; vitamin D: 5 μg; vitamin E: 10 mg; folic Adolescent and young women in LHW-covered areas in acid: 400 μg; vitamin B1 (thiamine): 1.4 mg; vitamin B2 Matiari district were identified in a household listing ex- (riboflavin): 1.4 mg; vitamin B3 (niacin): 18 mg; vitamin ercise. Provisionally eligible participants will be invited B12: 2.6 μg; vitamin B6: 1.9 mg; vitamin C: 70 mg; iron: to participate in MaPPS Trial with their family members 30 mg; zinc: 15 mg; iodine: 150 μg; copper: 2000 μg; selen- and/or husbands present. Data collectors will explain the ium 65 μg (Micronutrient Tabs, Pregnancy; Lomapharm, purpose and voluntary nature of the trial; participation Emmerthal, Germany). All MMN supplements are main- components; and potential benefits and harms prior to tained and stored by the study manager in a locked study obtaining written informed consent. If participants are < office that is temperature controlled. MMN supplements 16 years of age, assent will also be obtained as necessary. are provided to LHWs monthly by a study monitoring It is anticipated that enrolment will take at least 1 year. team, which is unblinded to the allocation of the interven- tion and not involved in data collection. Participants’ per- Visit schedule sonal supply of MMN supplements are monitored and All visits with study participants will occur at their replenished every month by their respective LHWs. Once homes (Table 1). Upon enrolment in the trial, a ques- provided to participants, MMN supplements are stored in tionnaire designed to collect information on demograph- marked, opaque containers labelled with the participant’s ics; socioeconomic status (SES); reproductive health and ID and supplement batch number and expiry date. history; life skills, empowerment, and social determi- Upon enrolment in the trial, intervention arm LHWs nants of health (SDH)-related factors (Table 2); supple- will visit new participants within 1 month to provide mentation practices; and access to LHWs will be MMN supplements. Participants are asked to consume 1 administered. This questionnaire has been adapted from MMN tablet 2 days/week. To make the incorporation the existing demographic health survey for Pakistan and MMN supplementation into their routine easier, partici- several standardized assessment tools. All participants pants are requested to choose a consistent time on 2 days will also undergo anthropometric (height, weight, in the week that are separate from each other (e.g., Mon- MUAC) and hemoglobin concentration measurement. day and Thursday, or Wednesday and Saturday) on which After 12 months of enrolment in the preconception to take 1 MMN tablet with a glass of water and a meal. phase, all participants’ anthropometric measures (height, Each participant is provided with a 1 month supply of weight, MUAC) will be reassessed. After 24 months, all MMN supplements, plus a spare week in case of unsched- participants will be asked to complete a modified version of uled missed visits. As such, participants receive 10 MMN the baseline questionnaire for ongoing assessment of life tablets per month (4 weeks/month × 2 tablets/week + 2 skills, empowerment, and SDH-related factors; and extra tablets = 10 tablets total). If a participant does not undergo repeat anthropometric (height, weight, MUAC) become pregnant within the context of the trial, she will and hemoglobin concentration measurements. Upon trial take the MMN supplements for up to 24 months (the completion or withdrawal, participants will be asked to maximum duration of the preconception period). complete an exit questionnaire designed to assess their per- Participants are instructed that the MMN supplements ception of their own health and satisfaction with trial are just for them and should be kept away from children. participation. They are asked to ensure that the lid of the supplement Additional measures will be collected from partici- bottle is tightly closed when not in use and stored away pants in the micronutrient status subgroup, including a from light and humidity. It is also explained that some 5 mL blood draw at enrolment and after 24 months; re- people experience mild side effects when they start tak- peat anthropometric assessment (height, weight, MUAC) ing the MMN supplements (e.g., nausea, vomiting, diar- after 6 months; and a modified version of the baseline rhea, stomach pains), but that taking it with food should questionnaire for ongoing assessment of life skills and make side effects less likely to happen. If they miss a empowerment at 12 months. Participants in the dietary dose, participants are instructed to take 1 MMN tablet status subgroup will complete 3 dietary assessments Baxter et al. Reproductive Health (2018) 15:103 Page 6 of 9 Table 1 Preconception phase data collection and measurement Adherence, morbidity, and morbidity monitoring activities There will also be ongoing participant monitoring for Activity Month of participation the duration of the trial (Table 3). All participants will be visited by an independent surveillance team to collect 0 6 12 24 morbidity and self-reported adherence data every Consent X 3 months. These visits will also allow for the observance Demographics and SES X M X and collection of data on non-trial administered nutri- Reproductive health and history X tional supplement consumption. Life skills, empowerment, and SDH X M X Anthropometry X M X X Data collection Hemoglobin X M X Data collection tools have been customized for each type of visit, and data is collected orally given the low literacy Serum ferritin M M M rates in the trial population. Trained study personnel Hepcidin M M M will collect all trial outcome data using questionnaires, Transferrin receptor M M M anthropometric measurements, point-of-care tests, and Infection indicators (CRP, AGP) M M M dietary recall methods. Standardized operating proce- Vitamin A M M M dures have been developed for all measures in an effort Vitamin D M M M to make data collection practices consistent. Extensive training sessions will be provided to study personnel, Household food insecurity X M X employing classroom-based lectures, videos, hands-on Food group consumption survey (1 week) D practice, and mock interviews. 24-h recall D X: all participants; M micronutrient status subgroup participants only; D dietary Questionnaires status subgroup participants only For data collector-conducted visits with participants, (24-h food recall, weekly food group consumption sur- tablets (Samsung Galaxy Tab. A T285; Samsung, vey) over the 3 weeks following enrolment in the trial. Vietnam) will be used to collect questionnaire data. The Dietary assessment days will be non-consecutive and un- tablets run a custom-made data collection application, announced, and include 2 weekdays and 1 weekend day. which includes built-in logic and range checks. LHW monitoring visits will use paper-based questionnaires given the large number of LHWs involved in the trial. LHW visits Dietary assessments will also be paper-based. Because LHWs are required to visit households in their catchment areas monthly, these visits will serve to moni- Anthropometric measurements tor menses, new marriages, and suspected pregnancies To assess adolescent and young women’s anthropomet- throughout the duration of the trial, in addition to their rics, height will be measured using a stadiometer (seca mandated function [15]. All trial-administered supple- 213; seca, Hamburg, Germany); weight using a digital ment provision and consumption will also be recorded floor scale (seca 813); and MUAC using a measuring at these visits. tape (seca 201). All measurements will be conducted in Table 2 Factors relating to life skills, empowerment, and SDH captured within trial questionnaires Domains Includes information pertaining to Evaluation tool Nutrition Household food insecurity Household Food Insecurity Access Scale [17] Health Eating habits Health Behaviour in School-aged Children [18] Body image Physical activity Perception of support Family, peer, and school Multidimensional Scale of Perceived Social Support [19] Decision making Family, food, healthcare, and daily needs Pakistan Demographic Health Survey [20] Psychosocial health Self-efficacy Generalized self-efficacy scale [21] Stress Perceived stress scale [22] Mental health (depression, anxiety, and stress) Depression, Anxiety, and Stress Scale-21 [23] Violence Intimate partner violence Conflict Tactics Scale [24] Exposure to violence Pakistan Demographic Health Survey [20] Baxter et al. Reproductive Health (2018) 15:103 Page 7 of 9 Table 3 Monitoring data collection activities ongoing throughout the trial Measurement Monthly (LHW) Quarterly (Monitoring Team) Adherence by pill count i Adherence by self-reported frequency i Side effects X Supplement acceptability i Morbidity X Mortality X X: all participants; i: intervention group only Adherence by pill count defined as number of tablets apparently consumed/number of possible supplements consumed given the number of days enrolled in the study Adherence options by self-report during preconception include twice weekly, intermittently, or not at all duplicate by 2 data collectors. In the case that 2 mea- Paper-based questionnaire forms are visually checked surements exceed the pre-set allowable differences by field site supervisors for completeness before being (height: < 1.0 cm; weight: < 0.5 kg; MUAC: < 0.5 cm), a sent to the AKU data management unit on a weekly third measurement will be obtained. The average (mean) basis for entry into a database. Double data entry is of acceptable paired measures will be used in analysis. used to reduce data entry errors. All collected data is kept under lock and key, and anonymized through Point-of-care hemoglobin assessment the use of nine-digit participant identification codes. To assess hemoglobin concentration, the HemoCue® Hb Data entered into the database is password protected. 301 System (HemoCue; Ängelholm, Sweden) will be used from blood collected via finger prick. Outcome measures To assess the prevalence of anemia, the primary out- 24-h dietary recall come measures is hemoglobin concentration < 12 g/dL. Among participants enrolled in the dietary assessment There are many additional secondary outcomes within subgroup, usual dietary intake will be assessed using an the trial related to health, nutrition, and empowerment interactive 24-h recall method [25] administered by that will be also assessed (see Additional file 1). trained food recall data collectors. Consumed food por- tions will be estimated and identified using a locally de- veloped food kit and food item reference manual [26]. Statistical analysis For the primary outcome, the prevalence of anemia will Blood specimen collection and laboratory analyses be compared by intervention arm, irrespective of precon- Trained phlebotomists (blinded to cluster allocation) will ception supplementation duration or adherence (inten- conduct all blood specimen collection using standard tion-to-treat). The per-protocol analysis will consider sampling procedures developed by the AKU Nutrition Re- those women who complied with the recommend MMN search Lab. At each sampling time point, 5 mL of venous supplementation frequency. Because the prevalence of blood will be collected and stored in trace element-free anemia is high in the trial population, an individual-level vacutainer tubes (royal blue top; Greiner Bio-One, Mon- analysis using generalized estimating equations (GEE) will roe, NC, USA). Two drops of whole blood are immedi- be employed to determine the estimate of the population ately taken from the collection tube to assess hemoglobin average. Clustering will be accounted for within the GEE concentration using the HemoCue® Hb 301 System point analysis. There are several potential determinants which of care test. Samples will be further assessed for markers will be considered as covariates, such as age, parity, adher- of nutritional status (iron [ferritin, transferrin receptor, ence, and SES. Relevant information will be collected at hepcidin], vitamin A [retinol], and vitamin D [25(OH)D]) enrolment and throughout follow-up. Summary estimates and inflammation (c-reactive protein, alpha-1-acid glyco- (e.g., means, proportions, counts) will be reported with protein). More details on blood specimen collection and 95% confidence intervals. Dichotomous outcomes will be assays can be found within the description of the parent compared using risk ratios with 95% confidence intervals, trial (Baxter et al., unpublished). and the difference in continuous variables will be deter- mined by comparing means. P values less than 0.05 will Data management be considered statistically significant. Statistical analyses Data collection tablets are collected from study will be conducted using Stata software. The plan for the personnel on a daily basis so that questionnaire data analysis of secondary objectives and outcome measures can be uploaded to the AKU data management unit. will be presented elsewhere. Baxter et al. Reproductive Health (2018) 15:103 Page 8 of 9 Discussion Additional file In this trial, we aim to assess the effectiveness of providing Additional file 1 Additional tables detailing secondary outcome LSBE and MMN supplementation to non-pregnant ado- measures and cut-points. The additional file includes 3 tables detailing lescent and young women in rural Pakistan from precon- secondary nutritional status, anthropometric, and empowerment out- ception, and compare this intervention with the standard come measures for participants. (DOCX 23 kb) of care on anemia prevalence and other secondary health outcomes. The intervention will be implemented within Abbreviations the existing public health system, which is anticipated to AKU: Aga Khan University; GEE: Generalized estimating equations; LHW: Lady lend to the interpretability of the trial findings and offer health worker; MaPPS Trial: Matiari emPowerment and preconception important insight around how to achieve coverage within supplementation trial; MMN: Multiple micronutrient; MUAC: Middle-upper arm circumference; SES: Socioeconomic status; UNIMMAP: UNICEF/ WHO/ the existing public health program context. This trial is UNU international multiple micronutrient preparation; WHO: World Health distinctive in that it recruits both married and unmarried Organization adolescent and young women, regardless of their intent to become pregnant, and collects measures on several do- Acknowledgements mains of health and nutrition throughout participation. The authors wish to acknowledge the entire MaPPS Trial study team for their The existing WHO guidelines on iron supplementa- contributions to data collection, monitoring, logistics, and general study operation, particularly Qamaruddin Junejo (field supervisor). We would also tion for non-pregnant adolescent and menstruating acknowledge the collaboration of the following groups within District women can be confusing, particularly with respect to dos- Matiari: the District of Health, Lady Health Worker Programme, and Education ing frequency (weekly versus daily) and duration [27, 28]. Department. We appreciate the ongoing assistance and support provided by Imran Ahmed, Arjumand Rizvi, Rasool Bux, and the members of the Data At this time, we know of no guidelines that address pre- Management Unit at AKU; Didar Alam and members of the Nutrition conception MMN supplementation. For adolescents, in Research Lab at AKU for ongoing laboratory coordination and logistics; and particular, preconception care that includes MMN Mir Asghar Ali Khan and Ishrat Abbas for grant and budgetary assistance. supplementation could be of benefit given that they are still developing and anemia can be caused by multiple dif- Funding ferent micronutrient deficiencies beyond iron [29, 30]. In- Financial support to conduct this trial was provided by the Bill & Melinda Gates Foundation and the World Food Programme. Neither funding body cluding a culturally-tailored educational piece aimed had any role in the conduction of the study or the preparation of this at empowering the ability of participants to make in- manuscript. formed decisions about their health, well-being, and nutrition will be key to sustained behavioural change Authors’ contributions throughout the life-course. Similarly, guidelines on ZAB conceived the trial and secured funding. JBB, ZAB, and SBS participated pre-pregnancy nutritional counselling specific to ado- in the initial conceptualization, design, and writing of the study protocol. YW and ZS have contributed ongoing input around the design, study protocol lescents are not known to exist, even though attend- development, and data collection methods. YW, SBS, and ZS have ing to adolescents’ nutritional needs will be important implemented the study in Matiari District. YW oversees field operations. JBB in addressing intergenerational malnutrition, chronic dis- produced the first draft of this manuscript, with input from ZAB, YW, SBS, and ZS. All authors reviewed this manuscript and approved the final version. ease, and poverty [31]. Appropriate preconception care ZAB is the guarantor. could allow that adolescents enter reproductive adulthood with improved health and nutrition status prior to Ethics approval and consent to participate conception. Ethics approval for this trial was obtained from the Aga Khan University Overall, the MaPPS Trial is expected to offer Ethics Review Committee on August 16, 2016 (Number: 4324-Ped-ERC-16); insight into providing an intervention that includes and from the Research Ethics Board at the Hospital for Sick Children on No- vember 17, 2016 (Number: 1000054682). All women enrolled in the trial are both LSBE and MMN supplementation to adolescent and asked for their written consent to participate in the trial and are free to de- young women from preconception and for a prolonged cline or stop their participation at any time without any consequences. duration of time. We anticipate that there would be future follow up of the adolescent and young women in this co- Competing interests hort, so as to understand their long-term reproductive The authors declare that they have no competing interests. and empowerment outcomes, as well as development and disease outcomes. We also intend to investigate the cost-effectiveness of the provision of the described Publisher’sNote Springer Nature remains neutral with regard to jurisdictional claims in intervention. published maps and institutional affiliations. Author details Centre for Global Child Health, The Hospital for Sick Children, Toronto, ON Trial status M6S 1S6, Canada. Department of Nutritional Sciences, University of Toronto, As of May 2018, participants are still being enrolled to 3 Toronto, ON, Canada. Centre of Excellence in Women and Child Health, Aga the trial. Khan University, Stadium Road, Karachi 74800, Pakistan. Baxter et al. Reproductive Health (2018) 15:103 Page 9 of 9 Received: 14 May 2018 Accepted: 24 May 2018 23. Lovibond SH, Lovibond PF. Manual for the Depression Anxiety Stress Scales. Sydney: Psychology Foundation; 1995. 24. Straus MA. Measuring Intrafamily conflict and violence: the conflict tactics (CT) scales. J Marriage Fam. 1979;41:75–88. 25. Gibson RS, Ferguson EL. 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Geneva: World Health Organization; 2011. menstruating women. Geneva: World Health Organization; 2011. 4. UNICEF. Adolescent Health. 2016. https://www.unicef.org/health/index_ 28. WHO. Guideline: Daily Iron supplementation in adult women and 92029.html. Accessed 07 May 2018. adolescent girls. Geneva: World Health Organization; 2016. 5. Bhutta ZA, Lassi ZS, Bergeron G, Koletzko B, Salam R, Diaz A, McLean M, 29. Fishman SM, Christian P, West KP. The role of vitamins in the prevention Black RE, De-Regil LM, Christian P, Prentice AM, Klein JD, Keenan W, Hanson and control of anaemia. Public Health Nutr. 2000;3(2):125–50. M. Delivering an action agenda for nutrition interventions addressing 30. Ramakrishnan U, Grant F, Goldenberg T, Zongrone A, Martorell R. Effect of adolescent girls and young women: priorities for implementation and women’s nutrition before and during early pregnancy on maternal and research. Ann N Y Acad Sci. 2017;1393(1):61–71. infant outcomes: a systematic review. 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Feasibility and effect of life skills building education and multiple micronutrient supplements versus the standard of care on anemia among non-pregnant adolescent and young Pakistani women (15–24years): a prospective, population-based cluster-randomized trial

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Medicine & Public Health; Reproductive Medicine; Public Health; Maternal and Child Health
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Abstract

Background: Adolescence is a critical period for physical and psychological growth and development, and vitamin and mineral requirements are correspondingly increased. Health and health behaviours correspond strongly from adolescence to adulthood. Developing a preconception care package for adolescent and young women in resource-limited settings could serve to empower them to make informed decisions about their nutrition, health, and well-being, as well as function as a platform for the delivery of basic nutrition-related interventions to address undernutrition. Methods: In this population-based two-arm, cluster-randomized, controlled trial of life skills building education (provided bi-monthly) and multiple micronutrient supplementation (provided twice-weekly; UNIMMAP composition) , we aim to evaluate the effectiveness of the intervention on the prevention of anemia (hemoglobin concentration < 12 g/dL) among adolescent and young women (15–24 years) in Matiari district, Pakistan compared to the standard of care. Several secondary objectives related to nutrition (anthropometry [height, weight, middle upper arm circumference (MUAC)], nutritional status [iron, vitamin A, vitamin D]); general health (morbidity, mortality); and empowerment (age at marriage, completion of the 10th grade, use of personal hygienic materials during menstruation) will also be assessed. Participants will be enrolled in the study for a maximum of 2 years. (Continued on next page) * Correspondence: zulfiqar.bhutta@aku.edu Centre for Global Child Health, The Hospital for Sick Children, Toronto, ON M6S 1S6, Canada Department of Nutritional Sciences, University of Toronto, Toronto, ON, Canada Full list of author information is available at the end of the article © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Baxter et al. Reproductive Health (2018) 15:103 Page 2 of 9 (Continued from previous page) Discussion: Empowering adolescent and young women with the appropriate knowledge to make informed and healthy decisions will be key to sustained behavioural change throughout the life-course. Although multiple micronutrient deficiencies are known to exist among adolescent and young women in low-resource settings, recommendations on preconception multiple micronutrient supplementation do not exist at this time. This study is expected to offer insight into providing an intervention that includes both education and supplements to non- pregnant adolescent and young women for a prolonged duration of time within the existing public health programmatic context. Trial registration: This study is part of the Matiari emPowerment and Preconception Supplementation (MaPPS) Trial. The MaPPS Trial was registered retrospectively on clinicaltrials.gov (Identifier: NCT03287882) on September 19, 2017. Keywords: Adolescence, Young adult, Nutrition, Micronutrients, Education, Preconception, Anemia, Empowerment Plain English summary and child mortality [3], and contribute to 23% of the bur- In low- and middle-income countries many adolescent den of disease arising from pregnancy and childbirth [4]. and young women do not consume enough healthy and When an adolescent becomes pregnant in a resource- nutrient-rich foods to meet their daily needs. Data show limited setting, her access to education generally that adolescent and young women in these places are stops as a result; yet, educating girls is very effective also more likely to become pregnant. If a woman is in raising overall economic productivity, lowering in- undernourished when she becomes pregnant, it can have fant and maternal mortality, improving nutrition, a negative effect on her health, pregnancy, and infant. One and promoting health [5]. Collectively, this makes deter- way to improve adolescent and young women’shealthbe- mining interventions to improve health outcomes from fore they become pregnant is to provide a program that adolescence of public health importance [2]. aims to help them make healthy decisions and improve Nutritional deficiencies are risk factors known to exist their nutrition. This is often called preconception care. In from adolescence, and have important consequences for this study in rural Pakistan, we have designed a future maternal and newborn health. During adolescence, culturally-appropriate preconception care package that in- vitamin and mineral requirements are incrementally in- cludes life skills building education, to help study partici- creased to support one’s ongoing physical development and pants make better decisions about their health and educate the nutritional strain of menstruation [6]. Given the limited them about their rights, and multiple micronutrient supple- intake of animal products, fruits, vegetables, and fortified ments, since they have limited access to foods with the foods in low- and middle-income countries, undernutrition micronutrients that they need. Study participants (15– can be widely prevalent [7]. Deficiencies in multiple micro- 24 years) are enrolled for 2 years, and we will assess several nutrients (MMN) are of particular concern given their dir- factors about their nutrition, health, and well-being over ect effects, such as iron deficiency anemia and iodine this time. The main effect we aim to determine is how deficiency disorders, and their indirect effects, like in- many participants have anemia among those who receive creased risk of serious infectious disease [6]. The burden the preconception care package compared to those who do of undernutrition and its downstream consequences could not receive it. Ultimately, we hope that what we learn in be prevented throughout the life course by using appro- this study will lead us to make recommendations about pol- priate nutrition-specific and nutrition-sensitive interven- icies around preconception care for adolescent and young tions, such as MMN supplementation and the women so that they can live healthier lives and make empowerment of women to make informed decisions, re- healthier decisions. spectively [5]. Since health and health behaviours correspond strongly from adolescence to adulthood, habits acquired during Background adolescence could have significant implications later in life Within the Sustainable Development Goals, promoting [2]. As such, developing a preconception care package for strategies to ensure the survival, health, and well-being of adolescent and young women could serve to empower adolescent girls, women, and their offspring has been rec- them to make informed decisions about their health and ognized as an essential component to ending poverty [1]. well-being [8], and function as a platform for the delivery Adolescence, in particular, is considered a neglected yet of basic nutrition-related interventions to address under- critical period for physical and psychological growth and nutrition [9]. Incorporating a life skills building education development, given the transition from childhood to repro- (LSBE) element will be important to sustainable and profi- ductive adulthood [2]. Pregnancies to adolescents are asso- cient uptake in improving their own general health, ciated with a higher risk of complications and maternal Baxter et al. Reproductive Health (2018) 15:103 Page 3 of 9 pregnancy outcomes, and future health of their children These relate to nutrition (anthropometry [height, weight, [8]. However, at this time there is limited understanding as middle upper arm circumference (MUAC)], nutritional to what health information should be provided and how status [iron, vitamin A, vitamin D]); general health (e.g., within preconception care. morbidity, mortality); and empowerment (age at mar- We hypothesize that the programmatic provision of riage, completion of the 10th grade, and use of personal LSBE and MMN supplements to non-pregnant adoles- hygienic materials during menstruation). cent and young women 15–24 years of age in a population-based setting in rural Pakistan will improve Setting and participants selected nutrition, health, and empowerment-related This trial will be conducted in rural settings within outcomes compared to those who receive the standard Matiari district in Sindh province, Pakistan. Briefly, the of care. For those who receive the intervention, we ex- nutritional status of adolescent girls in Pakistan is poor, pect that there will be a decrease in the prevalence of with 51 and 20% experiencing anemia and iron defi- anemia. Conducting this trial within the context of the ciency anemia, respectively [12]. An urban/rural divide existing public health setting will allow us to assess the is suggested to impact adolescent nutritional status [13], effectiveness of the intervention, and offer important with adolescents living in rural settings having particu- insight around how to achieve coverage in the trial larly limited dietary diversity [14]. The intervention is setting. situated within Pakistan’s existing Lady Health Worker (LHW) Programme. Each LHW is affiliated with a health Methods facility and visit the homes in her catchment area The Matiari emPowerment and Preconception Supplemen- monthly to carry out community support sessions and tation (MaPPS) Trial is a two-arm, cluster-randomized, disseminate health education messages [15]. LHW-led controlled trial of LSBE and MMN supplementation pro- community sessions have the potential to serve as an vided in a programmatic context to evaluate the impact on important communication channel for adolescents, espe- pre-identified nutrition and health outcomes among adoles- cially those out of school. However, the content of exist- cent and young women, and their infants born within the ing LHW educational materials primarily focuses on context of the trial. Depending on whether participants be- priority groups, including children < 5 years, pregnant come pregnant or not, there are three phases: preconcep- women, and couples eligible for family planning [16]. Al- tion (maximum 24 months in duration); pregnancy though the LHW curriculum includes some material on (approximately 9 months in duration); and postpartum topics important to the health of adolescent girls (e.g., (maximum 12 months in duration). A detailed trial proto- dietary practices, anemia), these materials are not widely col has been developed in accordance with the SPIRIT implemented and not included in community sessions guidelines [10] in a collaboration between the Aga Khan regularly. More detail about the trial setting is described University (AKU; Karachi, Pakistan) and the Hospital for in the parent trial protocol publication ([11] Sick Children (Toronto, Ontario, Canada). This paper ad- unpublished). dresses the methods for ongoing data collection during the preconception phase of the trial among participants Eligibility criteria who do not become pregnant, with the methods for the As the MaPPS Trial is a population-based effectiveness parent trial detailing the pregnancy and postpartum study of LSBE and MMN supplementation from precon- phases appearing elsewhere ([11] unpublished). ception, broad eligibility criteria for participation in the The first participant was enrolled on 30 June 2017; en- preconception phase were established. These include rollment is expected to be ongoing until July 2018; and that the minimum age at enrolment is 15 years and the planned data collection will continue until 2021. maximum age is 23 years; adolescent and young women must also report to be physically able to comply with the Objectives trial intervention. Adolescent and young women are not The primary aim of the preconception phase of the eligible to enrol if they are pregnant, participating in a MaPPS Trial is to evaluate the impact of LSBE (provided different nutrition trial, or intend to leave the study area. bi-monthly) and supplementation with MMN (provided They can be of any marital status. If a participant be- twice-weekly) versus the standard of care (non-regulated comes pregnant, she proceeds to the pregnancy phase of community-based health sessions and no supplements) the MaPPS Trial, as detailed in the parent study publica- on anemia (hemoglobin concentration < 12 g/dL) after tion ([11] unpublished). 2 years among non-pregnant adolescents 15–18.9 years The micronutrient status and dietary intake of a of age at enrolment. There are several secondary objec- sub-sample of adolescent participants 15–18.9 years of tives to further determine the effect of LSBE and MMN age at enrolment will also be monitored within the supplementation compared to the standard of care. MaPPS Trial. Participants recruited to the dietary Baxter et al. Reproductive Health (2018) 15:103 Page 4 of 9 assessment subgroup must also be a part of the micro- be assessed in 200 randomly selected micronutrient sta- nutrient status subgroup. tus subgroup participants per arm (15 women per clus- ter), to further form a dietary status subgroup. Design and sample size The MaPPS Trial is a two-arm, parallel, prospective, Intervention and control cluster-randomized, controlled trial (Fig. 1). A LSBE materials cluster-randomized design was chosen to prevent con- In intervention clusters, enhanced LSBE materials have tamination between the control and intervention arms been developed on topics important to the empower- through supplement sharing. The unit of randomization is ment of adolescent and young women to complement previously defined and mapped health facility clusters. A the existing LHW materials for use in community ses- total of 26 clusters are available to be randomized (i.e., 13 sions. These will be implemented bi-monthly and at- clusters per arm), and more detail around randomization tendance will be recorded. Three topic areas were and allocation concealment are found with the description prioritized: (a) delaying early marriage; (b) practicing ap- of the parent study (Baxter et al., unpublished). PASS 11 propriate personal and menstrual hygiene; and (c) the Software (NCSS, LLC., Kaysville, UT, USA) was used to importance of good nutrition to health. Approximately determine all sample size calculations. 20 min is intended to be spent on each topic at commu- To observe a 20% relative reduction in the prevalence nity sessions. Integrated throughout the 3 topics are of anemia among non-pregnant adolescent participants messages related to continuing one’s education, mental 15–18.9 years at enrolment, a 50% baseline prevalence health (how to cope with stress, anxiety, and when you of anemia [12] was assumed. With icc = 0.0256, k = 0.16, are upset), gender norms and equality, decision-making, accounting for 15% attrition, and probability of type I advocacy, resiliency, participation, communication skills, and type II errors of 0.05 and 0.20, respectively, the facing challenges, agency, conflict resolution, and the number anemic adolescents required per cluster was 66. prevention of violence. This equates to 858 anemic adolescents per arm. To Communication tools have been developed to assist the achieve this reduction in anemia, 1716 adolescents per LHWs in conducting the LSBE-based community ses- arm will be required (3432 total). Given the number of sions. These were designed in coordination with Aahung, adolescent and young women required to be powered to a Karachi-based non-governmental organization that aims see a reduction in the primary outcome of the parent to improve the sexual and reproductive health of girls trial (low birth weight), we aim to enrol 12,712 partici- (www.aahung.org; Karachi, Pakistan). Communication pants 15–24 years per arm (25,424 total). tools include a flipchart with 2 pictorials and discussion To monitor the micronutrient status of a subgroup of prompts per topic for use in sessions; and a brief summary participants 15–18.9 years of age at enrolment, the sam- pamphlet for distribution to participants. The flipcharts ple size calculated for the reduction in anemia preva- are similar to existing LHW tools for leading community lence will be used (i.e., 1716 adolescents per arm). Stata sessions. A team of master trainers is trained on all LSBE software (StataCorp, College Station, TX, USA) has been materials and appropriate communication techniques. used to randomly select 132 adolescents 15–18.9 years The master trainers provide comprehensive and inter- at enrolment from each cluster. Dietary intake will also active training for all intervention LHWs. Refresher Fig. 1 Matiari emPowerment and Preconception Supplementation (MaPPS) Trial flow diagram for participants who do not become pregnant Baxter et al. Reproductive Health (2018) 15:103 Page 5 of 9 training will also be provided on an ongoing basis the next time that they remember, but never to consume throughout the duration of the trial. more than 1 tablet/day. If a participant has any side ef- fects, is concerned, or has questions, she is instructed to Trial supplements and administration contact her LHW and not study personnel since study The MMN supplements provided to participants in the personnel are blinded to whether participants are in the intervention arm of the MaPPS Trial are consistent with control or intervention arm. Participants are also asked the UNICEF/WHO/UNU international multiple micronu- not to take non-trial administered supplements while trient preparation (UNIMMAP), and have been procured they are enrolled in the trial. from the UNICEF Supply Catalogue (https://supply.unice- f.org). Each tablet is 10 mm in diameter and includes vita- Enrolment and consent min A: 800 μg RE; vitamin D: 5 μg; vitamin E: 10 mg; folic Adolescent and young women in LHW-covered areas in acid: 400 μg; vitamin B1 (thiamine): 1.4 mg; vitamin B2 Matiari district were identified in a household listing ex- (riboflavin): 1.4 mg; vitamin B3 (niacin): 18 mg; vitamin ercise. Provisionally eligible participants will be invited B12: 2.6 μg; vitamin B6: 1.9 mg; vitamin C: 70 mg; iron: to participate in MaPPS Trial with their family members 30 mg; zinc: 15 mg; iodine: 150 μg; copper: 2000 μg; selen- and/or husbands present. Data collectors will explain the ium 65 μg (Micronutrient Tabs, Pregnancy; Lomapharm, purpose and voluntary nature of the trial; participation Emmerthal, Germany). All MMN supplements are main- components; and potential benefits and harms prior to tained and stored by the study manager in a locked study obtaining written informed consent. If participants are < office that is temperature controlled. MMN supplements 16 years of age, assent will also be obtained as necessary. are provided to LHWs monthly by a study monitoring It is anticipated that enrolment will take at least 1 year. team, which is unblinded to the allocation of the interven- tion and not involved in data collection. Participants’ per- Visit schedule sonal supply of MMN supplements are monitored and All visits with study participants will occur at their replenished every month by their respective LHWs. Once homes (Table 1). Upon enrolment in the trial, a ques- provided to participants, MMN supplements are stored in tionnaire designed to collect information on demograph- marked, opaque containers labelled with the participant’s ics; socioeconomic status (SES); reproductive health and ID and supplement batch number and expiry date. history; life skills, empowerment, and social determi- Upon enrolment in the trial, intervention arm LHWs nants of health (SDH)-related factors (Table 2); supple- will visit new participants within 1 month to provide mentation practices; and access to LHWs will be MMN supplements. Participants are asked to consume 1 administered. This questionnaire has been adapted from MMN tablet 2 days/week. To make the incorporation the existing demographic health survey for Pakistan and MMN supplementation into their routine easier, partici- several standardized assessment tools. All participants pants are requested to choose a consistent time on 2 days will also undergo anthropometric (height, weight, in the week that are separate from each other (e.g., Mon- MUAC) and hemoglobin concentration measurement. day and Thursday, or Wednesday and Saturday) on which After 12 months of enrolment in the preconception to take 1 MMN tablet with a glass of water and a meal. phase, all participants’ anthropometric measures (height, Each participant is provided with a 1 month supply of weight, MUAC) will be reassessed. After 24 months, all MMN supplements, plus a spare week in case of unsched- participants will be asked to complete a modified version of uled missed visits. As such, participants receive 10 MMN the baseline questionnaire for ongoing assessment of life tablets per month (4 weeks/month × 2 tablets/week + 2 skills, empowerment, and SDH-related factors; and extra tablets = 10 tablets total). If a participant does not undergo repeat anthropometric (height, weight, MUAC) become pregnant within the context of the trial, she will and hemoglobin concentration measurements. Upon trial take the MMN supplements for up to 24 months (the completion or withdrawal, participants will be asked to maximum duration of the preconception period). complete an exit questionnaire designed to assess their per- Participants are instructed that the MMN supplements ception of their own health and satisfaction with trial are just for them and should be kept away from children. participation. They are asked to ensure that the lid of the supplement Additional measures will be collected from partici- bottle is tightly closed when not in use and stored away pants in the micronutrient status subgroup, including a from light and humidity. It is also explained that some 5 mL blood draw at enrolment and after 24 months; re- people experience mild side effects when they start tak- peat anthropometric assessment (height, weight, MUAC) ing the MMN supplements (e.g., nausea, vomiting, diar- after 6 months; and a modified version of the baseline rhea, stomach pains), but that taking it with food should questionnaire for ongoing assessment of life skills and make side effects less likely to happen. If they miss a empowerment at 12 months. Participants in the dietary dose, participants are instructed to take 1 MMN tablet status subgroup will complete 3 dietary assessments Baxter et al. Reproductive Health (2018) 15:103 Page 6 of 9 Table 1 Preconception phase data collection and measurement Adherence, morbidity, and morbidity monitoring activities There will also be ongoing participant monitoring for Activity Month of participation the duration of the trial (Table 3). All participants will be visited by an independent surveillance team to collect 0 6 12 24 morbidity and self-reported adherence data every Consent X 3 months. These visits will also allow for the observance Demographics and SES X M X and collection of data on non-trial administered nutri- Reproductive health and history X tional supplement consumption. Life skills, empowerment, and SDH X M X Anthropometry X M X X Data collection Hemoglobin X M X Data collection tools have been customized for each type of visit, and data is collected orally given the low literacy Serum ferritin M M M rates in the trial population. Trained study personnel Hepcidin M M M will collect all trial outcome data using questionnaires, Transferrin receptor M M M anthropometric measurements, point-of-care tests, and Infection indicators (CRP, AGP) M M M dietary recall methods. Standardized operating proce- Vitamin A M M M dures have been developed for all measures in an effort Vitamin D M M M to make data collection practices consistent. Extensive training sessions will be provided to study personnel, Household food insecurity X M X employing classroom-based lectures, videos, hands-on Food group consumption survey (1 week) D practice, and mock interviews. 24-h recall D X: all participants; M micronutrient status subgroup participants only; D dietary Questionnaires status subgroup participants only For data collector-conducted visits with participants, (24-h food recall, weekly food group consumption sur- tablets (Samsung Galaxy Tab. A T285; Samsung, vey) over the 3 weeks following enrolment in the trial. Vietnam) will be used to collect questionnaire data. The Dietary assessment days will be non-consecutive and un- tablets run a custom-made data collection application, announced, and include 2 weekdays and 1 weekend day. which includes built-in logic and range checks. LHW monitoring visits will use paper-based questionnaires given the large number of LHWs involved in the trial. LHW visits Dietary assessments will also be paper-based. Because LHWs are required to visit households in their catchment areas monthly, these visits will serve to moni- Anthropometric measurements tor menses, new marriages, and suspected pregnancies To assess adolescent and young women’s anthropomet- throughout the duration of the trial, in addition to their rics, height will be measured using a stadiometer (seca mandated function [15]. All trial-administered supple- 213; seca, Hamburg, Germany); weight using a digital ment provision and consumption will also be recorded floor scale (seca 813); and MUAC using a measuring at these visits. tape (seca 201). All measurements will be conducted in Table 2 Factors relating to life skills, empowerment, and SDH captured within trial questionnaires Domains Includes information pertaining to Evaluation tool Nutrition Household food insecurity Household Food Insecurity Access Scale [17] Health Eating habits Health Behaviour in School-aged Children [18] Body image Physical activity Perception of support Family, peer, and school Multidimensional Scale of Perceived Social Support [19] Decision making Family, food, healthcare, and daily needs Pakistan Demographic Health Survey [20] Psychosocial health Self-efficacy Generalized self-efficacy scale [21] Stress Perceived stress scale [22] Mental health (depression, anxiety, and stress) Depression, Anxiety, and Stress Scale-21 [23] Violence Intimate partner violence Conflict Tactics Scale [24] Exposure to violence Pakistan Demographic Health Survey [20] Baxter et al. Reproductive Health (2018) 15:103 Page 7 of 9 Table 3 Monitoring data collection activities ongoing throughout the trial Measurement Monthly (LHW) Quarterly (Monitoring Team) Adherence by pill count i Adherence by self-reported frequency i Side effects X Supplement acceptability i Morbidity X Mortality X X: all participants; i: intervention group only Adherence by pill count defined as number of tablets apparently consumed/number of possible supplements consumed given the number of days enrolled in the study Adherence options by self-report during preconception include twice weekly, intermittently, or not at all duplicate by 2 data collectors. In the case that 2 mea- Paper-based questionnaire forms are visually checked surements exceed the pre-set allowable differences by field site supervisors for completeness before being (height: < 1.0 cm; weight: < 0.5 kg; MUAC: < 0.5 cm), a sent to the AKU data management unit on a weekly third measurement will be obtained. The average (mean) basis for entry into a database. Double data entry is of acceptable paired measures will be used in analysis. used to reduce data entry errors. All collected data is kept under lock and key, and anonymized through Point-of-care hemoglobin assessment the use of nine-digit participant identification codes. To assess hemoglobin concentration, the HemoCue® Hb Data entered into the database is password protected. 301 System (HemoCue; Ängelholm, Sweden) will be used from blood collected via finger prick. Outcome measures To assess the prevalence of anemia, the primary out- 24-h dietary recall come measures is hemoglobin concentration < 12 g/dL. Among participants enrolled in the dietary assessment There are many additional secondary outcomes within subgroup, usual dietary intake will be assessed using an the trial related to health, nutrition, and empowerment interactive 24-h recall method [25] administered by that will be also assessed (see Additional file 1). trained food recall data collectors. Consumed food por- tions will be estimated and identified using a locally de- veloped food kit and food item reference manual [26]. Statistical analysis For the primary outcome, the prevalence of anemia will Blood specimen collection and laboratory analyses be compared by intervention arm, irrespective of precon- Trained phlebotomists (blinded to cluster allocation) will ception supplementation duration or adherence (inten- conduct all blood specimen collection using standard tion-to-treat). The per-protocol analysis will consider sampling procedures developed by the AKU Nutrition Re- those women who complied with the recommend MMN search Lab. At each sampling time point, 5 mL of venous supplementation frequency. Because the prevalence of blood will be collected and stored in trace element-free anemia is high in the trial population, an individual-level vacutainer tubes (royal blue top; Greiner Bio-One, Mon- analysis using generalized estimating equations (GEE) will roe, NC, USA). Two drops of whole blood are immedi- be employed to determine the estimate of the population ately taken from the collection tube to assess hemoglobin average. Clustering will be accounted for within the GEE concentration using the HemoCue® Hb 301 System point analysis. There are several potential determinants which of care test. Samples will be further assessed for markers will be considered as covariates, such as age, parity, adher- of nutritional status (iron [ferritin, transferrin receptor, ence, and SES. Relevant information will be collected at hepcidin], vitamin A [retinol], and vitamin D [25(OH)D]) enrolment and throughout follow-up. Summary estimates and inflammation (c-reactive protein, alpha-1-acid glyco- (e.g., means, proportions, counts) will be reported with protein). More details on blood specimen collection and 95% confidence intervals. Dichotomous outcomes will be assays can be found within the description of the parent compared using risk ratios with 95% confidence intervals, trial (Baxter et al., unpublished). and the difference in continuous variables will be deter- mined by comparing means. P values less than 0.05 will Data management be considered statistically significant. Statistical analyses Data collection tablets are collected from study will be conducted using Stata software. The plan for the personnel on a daily basis so that questionnaire data analysis of secondary objectives and outcome measures can be uploaded to the AKU data management unit. will be presented elsewhere. Baxter et al. Reproductive Health (2018) 15:103 Page 8 of 9 Discussion Additional file In this trial, we aim to assess the effectiveness of providing Additional file 1 Additional tables detailing secondary outcome LSBE and MMN supplementation to non-pregnant ado- measures and cut-points. The additional file includes 3 tables detailing lescent and young women in rural Pakistan from precon- secondary nutritional status, anthropometric, and empowerment out- ception, and compare this intervention with the standard come measures for participants. (DOCX 23 kb) of care on anemia prevalence and other secondary health outcomes. The intervention will be implemented within Abbreviations the existing public health system, which is anticipated to AKU: Aga Khan University; GEE: Generalized estimating equations; LHW: Lady lend to the interpretability of the trial findings and offer health worker; MaPPS Trial: Matiari emPowerment and preconception important insight around how to achieve coverage within supplementation trial; MMN: Multiple micronutrient; MUAC: Middle-upper arm circumference; SES: Socioeconomic status; UNIMMAP: UNICEF/ WHO/ the existing public health program context. This trial is UNU international multiple micronutrient preparation; WHO: World Health distinctive in that it recruits both married and unmarried Organization adolescent and young women, regardless of their intent to become pregnant, and collects measures on several do- Acknowledgements mains of health and nutrition throughout participation. The authors wish to acknowledge the entire MaPPS Trial study team for their The existing WHO guidelines on iron supplementa- contributions to data collection, monitoring, logistics, and general study operation, particularly Qamaruddin Junejo (field supervisor). We would also tion for non-pregnant adolescent and menstruating acknowledge the collaboration of the following groups within District women can be confusing, particularly with respect to dos- Matiari: the District of Health, Lady Health Worker Programme, and Education ing frequency (weekly versus daily) and duration [27, 28]. Department. We appreciate the ongoing assistance and support provided by Imran Ahmed, Arjumand Rizvi, Rasool Bux, and the members of the Data At this time, we know of no guidelines that address pre- Management Unit at AKU; Didar Alam and members of the Nutrition conception MMN supplementation. For adolescents, in Research Lab at AKU for ongoing laboratory coordination and logistics; and particular, preconception care that includes MMN Mir Asghar Ali Khan and Ishrat Abbas for grant and budgetary assistance. supplementation could be of benefit given that they are still developing and anemia can be caused by multiple dif- Funding ferent micronutrient deficiencies beyond iron [29, 30]. In- Financial support to conduct this trial was provided by the Bill & Melinda Gates Foundation and the World Food Programme. Neither funding body cluding a culturally-tailored educational piece aimed had any role in the conduction of the study or the preparation of this at empowering the ability of participants to make in- manuscript. formed decisions about their health, well-being, and nutrition will be key to sustained behavioural change Authors’ contributions throughout the life-course. Similarly, guidelines on ZAB conceived the trial and secured funding. JBB, ZAB, and SBS participated pre-pregnancy nutritional counselling specific to ado- in the initial conceptualization, design, and writing of the study protocol. YW and ZS have contributed ongoing input around the design, study protocol lescents are not known to exist, even though attend- development, and data collection methods. YW, SBS, and ZS have ing to adolescents’ nutritional needs will be important implemented the study in Matiari District. YW oversees field operations. JBB in addressing intergenerational malnutrition, chronic dis- produced the first draft of this manuscript, with input from ZAB, YW, SBS, and ZS. All authors reviewed this manuscript and approved the final version. ease, and poverty [31]. Appropriate preconception care ZAB is the guarantor. could allow that adolescents enter reproductive adulthood with improved health and nutrition status prior to Ethics approval and consent to participate conception. Ethics approval for this trial was obtained from the Aga Khan University Overall, the MaPPS Trial is expected to offer Ethics Review Committee on August 16, 2016 (Number: 4324-Ped-ERC-16); insight into providing an intervention that includes and from the Research Ethics Board at the Hospital for Sick Children on No- vember 17, 2016 (Number: 1000054682). All women enrolled in the trial are both LSBE and MMN supplementation to adolescent and asked for their written consent to participate in the trial and are free to de- young women from preconception and for a prolonged cline or stop their participation at any time without any consequences. duration of time. We anticipate that there would be future follow up of the adolescent and young women in this co- Competing interests hort, so as to understand their long-term reproductive The authors declare that they have no competing interests. and empowerment outcomes, as well as development and disease outcomes. We also intend to investigate the cost-effectiveness of the provision of the described Publisher’sNote Springer Nature remains neutral with regard to jurisdictional claims in intervention. published maps and institutional affiliations. Author details Centre for Global Child Health, The Hospital for Sick Children, Toronto, ON Trial status M6S 1S6, Canada. Department of Nutritional Sciences, University of Toronto, As of May 2018, participants are still being enrolled to 3 Toronto, ON, Canada. Centre of Excellence in Women and Child Health, Aga the trial. Khan University, Stadium Road, Karachi 74800, Pakistan. Baxter et al. Reproductive Health (2018) 15:103 Page 9 of 9 Received: 14 May 2018 Accepted: 24 May 2018 23. Lovibond SH, Lovibond PF. Manual for the Depression Anxiety Stress Scales. Sydney: Psychology Foundation; 1995. 24. Straus MA. Measuring Intrafamily conflict and violence: the conflict tactics (CT) scales. J Marriage Fam. 1979;41:75–88. 25. Gibson RS, Ferguson EL. 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Reproductive HealthSpringer Journals

Published: May 30, 2018

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