Gut microbiota, vitamin A deficiency and autism spectrum disorder: an interconnected trio - a systematic review.

Accumulating evidence proves that children with autism have gastrointestinal problems. However, a significant difference in gut microbiota (GM) exists between autistic and non-autistic children. These changes in the GM may stem from several factors. Recently, researchers focused on nutritional factors, especially vitamin deficiency. Thus, our systematic review investigates the connections among autism, GM alterations, and vitamin A deficiency (VAD), by analyzing studies sourced from PubMed and Embase databases spanning from 2010 to 2022. Adhering to PRISMA guidelines, we meticulously selected 19 pertinent studies that established links between autism and GM changes or between autism and VAD. Our findings uniformly point to significant alterations in the GM of individuals with autism, indicating these changes as promising biomarkers for the disorder. Despite the consistent association of GM alterations with autism, our analysis revealed no notable differences in GM composition between individuals with autism and those experiencing VAD. This suggests that VAD, especially when encountered early in life, might play a role in the onset of autism. Furthermore, our review underscores a distinct correlation between reduced levels of retinoic acid in children with autism, a disparity that could relate to the severity of autism symptoms. The implications of our findings are twofold: they not only reinforce the significance of GM alterations as potential diagnostic markers but also spotlight the critical need for further research into nutritional interventions. Specifically, vitamin A supplementation emerges as a promising avenue for alleviating autism symptoms, warranting deeper investigation into its therapeutic potential.

Use of multiple micronutrient supplementation integrated into routine antenatal care: A discussion of research priorities.

Optimal maternal nutrition, including adequate intake and status of essential micronutrients, is important for the health of women and developing infants. Currently, the World Health Organization (WHO) Antenatal care recommendations for a positive pregnancy experience recommend daily iron and folic acid (IFA) supplementation as the standard of care. The use of multiple micronutrient supplements (MMSs) is recommended in the context of rigorous research as more evidence was needed regarding the impact of switching from IFA supplements to MMS, including evaluation of critical clinical maternal and perinatal outcomes, acceptability, feasibility, sustainability, equity and cost-effectiveness. WHO convened a technical consultation of key stakeholders to discuss research priorities with the objective of providing guidance and clarity to donors, implementers and researchers about this recommendation. The overarching principles of the research agenda include the use of clinical indicators and impact measures that are applicable across studies and settings and the inclusion of outcomes that are important to women. Future studies should consider using standardized protocols based on current best practices to measure critical outcomes such as gestational age (GA) and birthweight (BW) in studies. As GA and BW are influenced by multiple factors, more research is needed to understand the biological impact pathways, and how initiation and considerations for timing of MMS influence these outcomes. A set of core clinical indicators was agreed upon during the technical consultation. For implementation research, the Evidence-to-Decision framework was used as a resource for discussing components of implementation research. The implementation research questions, key indicators and performance measures will depend on country-specific context and bottlenecks that require further research and improved solutions to enable the successful implementation of iron-containing supplements.

Qualitative evaluation of a package of implementation strategies codesigned to support the introduction of multiple micronutrient supplementation (MMS) for pregnant women in Bamako, Mali.

Mali national policy recommends that women take iron and folic acid supplements (IFA) from the time of the first antenatal care (ANC) visit, throughout pregnancy and during the first 3 months after delivery. In 2020, the World Health Organization (WHO) updated their ANC guidelines to recommend the United Nations International Multiple Micronutrient Antenatal Preparation (UNIMMAP) formulation of multiple micronutrient supplements (MMS) in the context of rigorous research, including implementation research. In Bamako, Mali, a codesign process was used to tailor antenatal care MMS packaging and counselling materials aimed at optimizing delivery and uptake of and adherence to MMS. This paper presents the codesign process along with the results of a post-intervention qualitative assessment to evaluate the behaviour change intervention. At the conclusion of the intervention, we conducted semistructured qualitative interviews with 24 women who had received the intervention and six pharmacy managers from the six health centres participating in the study. We conducted two focus groups with midwives who had delivered the intervention and two group discussions with family members of women who had received the intervention. Respondent perspectives reveal an easy experience transitioning from previously used IFA. Women and providers concur that the intervention counselling materials and visual aids were instrumental in influencing the perceived benefit and uptake of MMS. Family members play an influential role in pregnant women's decision-making regarding MMS uptake. MMS and the associated implementation strategies developed through the codesign process were found to be a highly acceptable intervention.

Ketogenic diet in children and adolescents: The effects on growth and nutritional status.

The ketogenic diet is known to be a possible adjuvant treatment in several medical conditions, such as in patients with severe or drug-resistant forms of epilepsy. Its use has recently been increasing among adolescents and young adults due to its supposed weight-loss effect, mediated by lipolysis and lowered insulin levels. However, there are still no precise indications on the possible use of ketogenic diets in pediatric age for weight loss. This approach has also recently been proposed for other types of disorder such as inherited metabolic disorders, Prader-Willi syndrome, and some specific types of cancers. Due to its unbalanced ratio of lipids, carbohydrates and proteins, a clinical evaluation of possible side effects with a strict evaluation of growth and nutritional status is essential in all patients following a long-term restrictive diet such as the ketogenic one. The prophylactic use of micronutrients supplementation should be considered before starting any ketogenic diet. Lastly, while there is sufficient literature on possible short-term side effects of ketogenic diets, their possible long-term impact on growth and nutritional status is not yet fully understood, especially when started in pediatric age.

Multiple micronutrient supplementation cost-benefit tool for informing maternal nutrition policy and investment decisions.

Antenatal multiple micronutrient supplementation (MMS) is an intervention that can help reach three of the six global nutrition targets, either directly or indirectly: a reduction in low birth weight, stunting, and anaemia in women of reproductive age. To support global guideline development and national decision-making on investments into maternal nutrition, Nutrition International developed a modelling tool called the MMS cost-benefit tool to help users understand whether antenatal MMS is better value for money than iron and folic acid supplementation (IFAS) during pregnancy. The MMS cost-benefit tool can generate estimates on the potential health impact, budget impact, economic value, cost-effectiveness and benefit-cost ratio of investing in MMS compared to IFAS in LMICs. In the 33 countries with data included in the tool, the MMS cost-benefit tool shows that transitioning is expected to generate substantial health benefits in terms of morbidity and mortality averted and can be very cost-effective in multiple scenarios for these countries. The cost per DALY averted averages at US$ 23.61 and benefit-cost ratio ranges from US$ 41-US$ 1304: $1.0, which suggest MMS is good value for money compared with IFAS. With its user-friendly design, open access availability, and online data-driven analytics, the MMS cost-benefit tool can be a powerful resource for governments and nutrition partners seeking timely and evidence-based analyses to inform policy-decision and investments towards the scale-up of MMS for pregnant women globally.

Body Composition and Cardiometabolic Risk Markers in Children of Women who Took Part in a Randomized Controlled Trial of a Preconceptional Nutritional Intervention in Mumbai, India.

BACKGROUND: Maternal nutrition influences fetal development and may permanently alter ("program") offspring body composition and metabolism, thereby influencing later risk of diabetes and cardiovascular (cardiometabolic) disease. The prevalence of cardiometabolic disease is rising rapidly in India. OBJECTIVES: To test the hypothesis that supplementing low-income Indian women with micronutrient-rich foods preconceptionally and during pregnancy has a beneficial impact on the children's body composition and cardiometabolic risk marker profiles. METHODS: Follow-up of 1255 children aged 5-10 y whose mothers took part in the Mumbai Maternal Nutrition Project [Project "SARAS"; International Standard Randomised Controlled Trial Number (ISRCTN)62811278]. Mothers were randomly assigned to receive a daily micronutrient-rich snack or a control snack of lower micronutrient content, both made from local foods, in addition to normal diet, from before pregnancy until delivery. Children's body composition was assessed using anthropometry and DXA. Their blood pressure, plasma glucose, insulin, and lipid concentrations were measured. Outcomes were compared between allocation groups with and without adjustment for confounding factors. RESULTS: Overall, 15% of children were stunted, 34% were wasted, and 3% were overweight. In the intention-to-treat analysis, there were no differences in body composition or risk markers between children in the intervention and control groups. Among children whose mothers started supplementation ≥3 mo before conception (the "per protocol" sample) the intervention increased adiposity among girls, but not boys. BMI in girls was increased relative to controls by 2% (95% CI: 1, 4; P = 0.01); fat mass index by 10% (95% CI: 3, 18; P = 0.004); and percent fat by 7% (95% CI: 1, 13; P = 0.01) unadjusted, with similar results in adjusted models. CONCLUSIONS: Overall, supplementing women with micronutrient-rich foods from before pregnancy until delivery did not alter body composition or cardiometabolic risk markers in the children. Subgroup analyses showed that, if started ≥3 mo before conception, supplementation may increase adiposity among female children.

Specificity Matters: Unpacking Impact Pathways of Individual Interventions within Bundled Packages Helps Interpret the Limited Impacts of a Maternal Nutrition Intervention in India.

BACKGROUND: To address gaps in coverage and quality of nutrition services, Alive & Thrive (A&T) strengthened the delivery of maternal nutrition interventions through government antenatal care (ANC) services in Uttar Pradesh, India. The impact evaluation of the A&T interventions compared intensive ANC (I-ANC) with standard ANC (S-ANC) areas and found modest impacts on micronutrient supplementation, dietary diversity, and weight-gain monitoring. OBJECTIVES: This study examined intervention-specific program impact pathways (PIPs) and identified reasons for limited impacts of the A&T maternal nutrition intervention package. METHODS: We used mixed methods: frontline worker (FLW) surveys (n = ∼500), counseling observations (n = 407), and qualitative in-depth interviews with FLWs, supervisors, and block-level staff (n = 59). We assessed 7 PIP domains: training and materials, knowledge, supportive supervision, supply chains, data use, service delivery, and counseling. RESULTS: Exposure to training improved in both I-ANC and S-ANC areas with more job aids used in I-ANC compared with S-ANC (90% compared with 70%), but gaps remained for training content and refresher trainings. FLWs' knowledge improvement was higher in I-ANC than S-ANC (22-36 percentage points), but knowledge of micronutrient supplement benefits and recommended foods was insufficient (<50%). Most FLWs received supervision (>90%), but supportive supervision was limited by staff vacancies and competing work priorities. Supplies of iron-folic acid and calcium supplements were low in both areas (30-50% stock-outs). Use of monitoring data during review meetings was higher in I-ANC than S-ANC (52% compared with 36%) but was constrained by time, understanding, and data quality. Service provision improved in both I-ANC and S-ANC areas, but counseling on supplement benefits and weight-gain monitoring was low (30-40%). CONCLUSIONS: Systems-strengthening efforts improved maternal nutrition interventions in ANC, but gaps remained. Taking an intervention-specific perspective to the PIP analysis in this package of services was critical to understand how common and specific barriers influenced overall program impact.

Body Composition and Cardiometabolic Risk Markers in Children of Women who Took Part in a Randomized Controlled Trial of a Preconceptional Nutritional Intervention in Mumbai, India.

BACKGROUND: Maternal nutrition influences fetal development and may permanently alter ("program") offspring body composition and metabolism, thereby influencing later risk of diabetes and cardiovascular (cardiometabolic) disease. The prevalence of cardiometabolic disease is rising rapidly in India. OBJECTIVES: To test the hypothesis that supplementing low-income Indian women with micronutrient-rich foods preconceptionally and during pregnancy has a beneficial impact on the children's body composition and cardiometabolic risk marker profiles. METHODS: Follow-up of 1255 children aged 5-10 y whose mothers took part in the Mumbai Maternal Nutrition Project [Project "SARAS"; International Standard Randomised Controlled Trial Number (ISRCTN)62811278]. Mothers were randomly assigned to receive a daily micronutrient-rich snack or a control snack of lower micronutrient content, both made from local foods, in addition to normal diet, from before pregnancy until delivery. Children's body composition was assessed using anthropometry and DXA. Their blood pressure, plasma glucose, insulin, and lipid concentrations were measured. Outcomes were compared between allocation groups with and without adjustment for confounding factors. RESULTS: Overall, 15% of children were stunted, 34% were wasted, and 3% were overweight. In the intention-to-treat analysis, there were no differences in body composition or risk markers between children in the intervention and control groups. Among children whose mothers started supplementation ≥3 mo before conception (the "per protocol" sample) the intervention increased adiposity among girls, but not boys. BMI in girls was increased relative to controls by 2% (95% CI: 1, 4; P = 0.01); fat mass index by 10% (95% CI: 3, 18; P = 0.004); and percent fat by 7% (95% CI: 1, 13; P = 0.01) unadjusted, with similar results in adjusted models. CONCLUSIONS: Overall, supplementing women with micronutrient-rich foods from before pregnancy until delivery did not alter body composition or cardiometabolic risk markers in the children. Subgroup analyses showed that, if started ≥3 mo before conception, supplementation may increase adiposity among female children.

The Effect of Maternal Multiple Micronutrient Supplementation on Female Early Infant Mortality Is Fully Mediated by Increased Gestation Duration and Intrauterine Growth.

BACKGROUND: Maternal micronutrient supplementation in pregnancy (MMS) has been shown to improve birth weight among infants in low- and middle-income countries. Recent evidence suggests that the survival benefits of MMS are greater for female infants compared to male infants, but the mechanisms leading to differential effects remain unclear. OBJECTIVE: The objective of this study was to examine the potential mechanisms through which MMS acts on infant mortality among Tanzanian infants. METHODS: We used data collected from pregnant women and newborns in a randomized, double-blind, placebo-controlled trial of MMS conducted in Tanzania to examine mediators of the effect of MMS on 6-wk infant mortality (NCT00197548). Causal mediation analyses with the counterfactual approach were conducted to assess the contributions of MMS on survival via their effects on birth weight, gestational age, weight-for-gestational age, and the joint effect of gestational age and weight-for-gestational age. The weighting method allowed for interaction between gestational age and weight-for-gestational age. RESULTS: Among 7486 newborns, the effect of MMS on 6-wk survival was fully mediated (100%) through the joint effect of gestational age and weight-for-gestational age. MMS was also found to have a significant natural indirect effect through increased birth weight (P-value < 0.001) that explained 75% of the total effect on 6-wk mortality. When analyses were stratified by sex, changes in gestational age and weight-for-gestational age fully mediated the mortality effect among female infants (n = 3570), but these mediators only explained 34% of the effect among males (n = 3833). CONCLUSIONS: The potential sex-specific effects of MMS on mortality may be a result of differences in mechanisms related to birth outcomes. In the context of the Tanzanian trial, the observed effect of MMS on 6-wk mortality for female infants was entirely mediated by increased gestation duration and improved intrauterine growth, while these mechanisms did not appear to be major contributors among male infants.

Multiple micronutrient supplementation improves growth and reduces the risk of anemia among infants in Gaza Strip, Palestine: a prospective randomized community trial.

BACKGROUND: Infants and young children 6-24 months of age are the most nutritionally vulnerable groups, as their needs for vitamins and minerals are high relative to the amount of food they consume. This study determines the effect of Micronutrient Powder Supplementation (MNP) on growth and hemoglobin of infants in Gaza Strip, Palestine. METHOD: This was a two-arm parallel-group randomized controlled trial conducted in two health care clinics of the United Nations Relief and Work Agency (UNRWA) at the Middle Area governorate of Gaza Strip, Palestine. A total of 200 healthy infants aged 6-month-old were recruited and randomized to receive 3 sachets/week of MNP for 12 months alongside with the National Micronutrient Supplement (NMS) (n = 100) or NMS alone (n = 100). Weight, length, blood hemoglobin, and dietary intakes were measured at 6, 9, 12, 15, 18, and 21 (3 months after the end of intervention) months of age. Analysis was by intention to treat. RESULTS: The experimental group had a higher concentration of hemoglobin at 12 and 15 months than did the control group, and a significant difference (p <  0.05) was observed at 15 months only. Significantly greater weight, length, weight-for-age, length-for-age, and weight-for-length z-scores were observed in the experimental group than that in the control group at 12 and 15 months (p <  0.05). The prevalence of anemia (18% vs. 52%) and stunting (1% vs. 11%) were higher in the control than the experimental group, respectively. After controlling for sex, similar findings were reported. CONCLUSIONS: Addition of MNP to the existing NMS program improved the nutritional status of young children. The potential benefits of MNP supplementation on physical growth and hemoglobin should be considered in the existing NMS program. TRIAL REGISTRATION: ISRCTN57594793 ; Date of registration: 20-03-2018 (Retrospectively registered).

Impact of nutrient supplementation on maternal nutrition and child growth and development in Sub-Saharan Africa: the case of small-quantity lipid-based nutrient supplements.

Micronutrient deficiencies remain common among women and children in Sub-Saharan Africa (SSA); in pregnant/lactating women, the intakes of essential fatty acids may also be low. Enriching home-prepared foods with small-quantity lipid-based nutrient supplements (SQ-LNSs) is a promising new strategy of delivering additional micronutrients, essential fatty acids and good quality protein to women and children. This narrative review aimed to examine the impact of SQ-LNSs supplementation among women and infants and young children in SSA, and to discuss the differential impact of SQ-LNS consumption across different settings. Papers reporting randomized trials conducted in SSA in which apparently healthy women and/or ≥6-mo-old children received SQ-LNSs were identified through electronic and manual searches. Prenatal SQ-LNS consumption reduced the prevalence of low gestational weight gain in Ghana when compared with multiple micronutrients supplementation, and was associated with poorer iron/hemoglobin status when compared with iron-plus-folic acid supplementation. SQ-LNSs received alone or as intervention package improved infant/child growth in two trials in Ghana and one trial each in Burkina Faso, Kenya, Zimbabwe and South Africa, but had no impact on growth in two trials in Malawi. SQ-LNSs supplementation improved motor development in Ghana, Burkina Faso, Malawi, Kenya, and South Africa, but had no impact on language, socio-emotional, and executive functions in Ghana and Malawi and on Griffiths' developmental scores in Malawi. SQ-LNSs may contribute to improving child growth in SSA. More research is needed to determine the iron level in SQ-LNSs effective for improving both maternal hemoglobin/iron status and birth outcomes.

New Evidence Should Inform WHO Guidelines on Multiple Micronutrient Supplementation in Pregnancy.

Recent data from an individual patient data (IPD) meta-analysis of 17 randomized control trials including >100,000 women living in low- and middle-income countries found that multiple micronutrient supplementation (MMS) in pregnancy reduced the risk of low birth weight, preterm birth, and being born small for gestational age. Further, MMS reduced the risk of neonatal and infant mortality for females, and there was no evidence of increased risk among the 26 subgroups examined. The 2016 WHO antenatal care guidelines, which were released before the IPD meta-analysis, did not universally recommend MMS, noting: "There is some evidence of additional benefit … but there is also some evidence of risk." The guidelines suggest that MMS may increase the risk of neonatal mortality based on an exploratory subgroup analysis of 6 randomized trials. However, we identified several issues with this subgroup analysis. In this report we correct and update the subgroup analysis and show that there is no evidence that MMS increases the risk of neonatal mortality. There is growing scientific consensus that MMS containing iron and folic acid (IFA) is superior to IFA alone. The WHO guidelines currently state that "policy-makers in populations with a high prevalence of nutritional deficiencies might consider the benefits of MMN [multiple micronutrient] supplements on maternal health to outweigh the disadvantages, and may choose to give MMN supplements that include iron and folic acid." This equivocal guidance has created confusion about the best course of action for public health programs in low- and middle-income countries. Given the new evidence, WHO should review their statements regarding the potential neonatal mortality risks and re-evaluate the overall potential benefits of implementing MMS as a public health program.

Benefits of multiple micronutrient supplementation in heart failure: A comprehensive review.

BACKGROUND: Multiple micronutrient supplementation has been suggested to have a role on health outcomes in patients with heart failure (HF), but the evidence is inconclusive. OBJECTIVE: To elucidate the role of multiple micronutrient supplementation in heart failure we performed a comprehensive review of the literature. METHODS AND RESULTS: The search in databases included PUBMED (until June 2018) to detect randomized controlled trials (RCTs) and meta-analyzes that investigated the impact of micronutrient supplementation in HF. RESULTS: With more than 2357 titles and abstracts reviewed, we included only the studies suitable for the final review. Whether alone or in combination, micronutrients have been found to improve the health outcomes of patients with HF by improving symptoms, work capacity and left ventricular ejection fraction (LVEF), thus increasing the quality of life in these patients. CONCLUSION: Future studies are needed to document the effects of multiple micronutrient associations in order to include them in nutritional guidelines to increase survival and to improve quality of life in patients with heart failure.

Correcting micronutrient deficiencies before sleeve gastrectomy may be useful in preventing early postoperative micronutrient deficiencies.

Micronutrient deficiencies (MD) shortly after sleeve gastrectomy (SG) are frequent and patients with obesity often show MD preoperatively. Our aim was to assess whether the correction of MD before SG could play a role in preventing early postoperative MD. Eighty patients (58 females, 22 males) who underwent SG were evaluated retrospectively. Patients were divided according to whether they had received preoperative MD correction (Group A, n = 42; 30 females, 12 males) or not (Group B, n = 38; 28 females, 10 males). Micronutrient status was assessed preoperatively, at 3 and 12-months after SG in both groups. After SG, Group A and Group B patients received the same multivitamin supplement and followed the same diet. Nutrient intake of all patients was evaluated by food frequency questionnaires. Before SG, patients of Group A had no MD, whereas patients of Group B were mostly deficient in vitamin B12 (10.5%, 3 women, 1 man), folate (15.8%, 5 women, 1 man), 25-vitamin D (39.5%, 10 women, 5 men), iron (26.3%, 8 women, 2 men), and zinc (7.9%, 2 women, 1 men). At 3- and 12-month follow-up, no patient in group A had developed new MD, whereas all patients of Group B continued to be deficient in one or more micronutrient, despite systematic postoperative supplementation. No statistical differences (p<0.05) in estimated nutrient intake were observed in either group. Based on our findings, we are able to support the hypothesis that pre-SG correction of MD may be useful in preventing early post-SG MD.

Rethinking integrated nutrition-health strategies to address micronutrient deficiencies in children under five in Mozambique.

In Mozambique, about two thirds of children 6-59 months of age are affected by vitamin A deficiency and anaemia. The objective of this case study is to provide programme considerations for planning, implementing, monitoring, and evaluating vitamin A and iron deficiency interventions within the context of lessons learned to date for vitamin A supplementation, micronutrient powders (MNPs), and food-based strategies. For 15 years, the Mozambique Ministry of Health implemented twice-yearly vitamin A supplementation through both campaigns and routine health services. Yet coverage in 2017 (55%) was not much higher than in 2003 (44%). Reaching every district/reaching every child, a strategy adapted from the field of immunization, was used to achieve equitable coverage of vitamin A and for microplanning of outreach services in health facilities, with support from the Maternal and Child Survival Program. In Mozambique, a free or subsidized distribution model for MNPs has been rolled out, yet integration of MNPs into infant and young child feeding programming (i.e., cooking demonstrations) is needed to reinforce "the who, what, and why" of MNPs through culturally sensitive behaviour change communication. Food-based strategies to promote dietary diversity, such as through complementary feeding recipes, are also critical. To harmonize efforts, the Mozambique government should consider the development of a national strategy for the prevention and control of micronutrient malnutrition, with clear monitoring and evaluation targets. Ongoing monitoring of the prevalence of micronutrient deficiencies and coverage of implemented micronutrient interventions is needed to make evidence-based decisions to drive nutrition-health programming.

Effects of a micronutrient supplementation combined with a phosphodiesterase type 5 inhibitor on sperm quantitative and qualitative parameters, percentage of mature spermatozoa and sperm capacity to undergo hyperactivation: A randomised controlled trial.

The main objective of this study was to evaluate the effects of a micronutrient supplementation (MS) combined with avanafil on sperm function. Oligoasthenospermic men (n = 217) were treated daily for 90 days with either an MS (45 men, Group A), l-carnitine (44 men, Group B), MS plus avanafil (43 men, Group C) or avanafil (43 men, Group D); another group of 42 men with oligoasthenospermia (Group E) received no treatment. Sperm parameters were evaluated before and after the end of treatment in each Group A, B, C and D respectively. The same sperm parameters were measured in each participant of Group E before and at the 90-day experimental period. Within Groups A, C or D, the total percentage of motile spermatozoa, the hypoosmotic swelling test (HOST) result and the percentage of hyperactivated spermatozoa after incubation under conditions known to induce sperm capacitation were significantly greater after MS or MS plus avanafil treatment, or avanafil treatment than before the respective treatment. We suggest that MS or MS plus avanafil combined administration or avanafil alone improves sperm membrane permeability with an overall result improvement in sperm motility, outcome of HOST and increase in the percentage of hyperactivated spermatozoa.

Adherence-Specific Social Support Enhances Adherence to Calcium Supplementation Regimens among Pregnant Women.

Background: WHO guidelines recommend integrating calcium supplementation into antenatal care (ANC) alongside iron and folic acid (IFA) to reduce maternal mortality. However, supplementation programs face multiple barriers, and strategies to improve adherence are needed. An adherence partner is someone whom pregnant women ask to support adherence at home.Objectives: This study 1) assessed adherence partner acceptability, feasibility, and associations with calcium and IFA supplement adherence and 2) examined relations between social support and adherence.Methods: This secondary analysis is from a trial integrating calcium supplementation into ANC in Kenya. ANC providers were trained on calcium and IFA supplementation and counseling, provided with behavior change materials, and given adequate supplement supplies. Pregnant women from 16 government health facilities were recruited (n = 1036); sociodemographic and adherence data were collected at baseline and at 4- to 6-wk follow-up visits. Adherence was measured with pill counts and self-reports. Culturally adapted scales measured social support in general and specific to adherence. Mixed-effects regression analyses were used to examine factors associated with adherence partners, social support, and adherence.Results: Most participants received information about adherence partners (91%) and had a partner at follow-up (89%). Participants with adherence partners reported higher adherence support (OR: 2.10; 95% CI: 1.32, 3.34). Mean ± SD adherence was high for calcium (88.3% ± 20.7%) and IFA (86.1% ± 20.9%). Adherence support was positively associated with calcium adherence at follow-up by using pill counts (OR: 2.2; 95% CI: 1.1, 2.6) and self-report data (OR: 1.9; 95% CI: 1.2, 2.9), but there was not a direct relation between adherence partners and adherence.Conclusions: Adherence support enhanced adherence to calcium supplements. The adherence partner strategy was highly acceptable and feasible but warrants further study. This research demonstrates the importance of adherence support and suggests that interventions to increase household-level support for antenatal micronutrient supplementation may be needed to implement the WHO guidelines. This trial was registered at clinicaltrials.gov as NCT02238704.

A Simplified Regimen Compared with WHO Guidelines Decreases Antenatal Calcium Supplement Intake for Prevention of Preeclampsia in a Cluster-Randomized Noninferiority Trial in Rural Kenya.

Background: To prevent preeclampsia, the WHO recommends antenatal calcium supplementation in populations with inadequate habitual intake. The WHO recommends 1500-2000 mg Ca/d with iron-folic acid (IFA) taken separately, a complex pill-taking regimen. Objective: The objective of this study was to test the hypothesis that simpler regimens with lower daily dosages would lead to higher adherence and similar supplement intake.Methods: In the Micronutrient Initiative Calcium Supplementation study, we compared the mean daily supplement intake associated with 2 dosing regimens with the use of a parallel, cluster-randomized noninferiority trial implemented in 16 primary health care facilities in rural Kenya. The standard regimen was 3 × 500 mg Ca/d in 3 pill-taking events, and the low-dose regimen was 2 × 500 mg Ca/d in 2 pill-taking events; both regimens included a 200 IU cholecalciferol and calcium pill and a separate IFA pill. We enrolled 990 pregnant women between 16 and 30 wk of gestation. The primary outcome was supplemental calcium intake measured by pill counts 4 and 8 wk after recruitment. We carried out intention-to-treat analyses with the use of mixed-effect models, with regimen as the fixed effect and health care facilities as a random effect, by using a noninferiority margin of 125 mg Ca/d.Results: Women in facilities assigned to the standard regimen consumed a mean of 1198 mg Ca/d, whereas those assigned to the low-dose regimen consumed 810 mg Ca/d. The difference in intake was 388 mg Ca/d (95% CI = 341, 434 mg Ca/d), exceeding the prespecified margin of 125 mg Ca/d. The overall adherence rate was 80% and did not differ between study arms.Conclusions: Contrary to our expectation, a simpler, lower-dose regimen led to significantly lower supplement intake than the regimen recommended by the WHO. Further studies are needed to precisely characterize the dose-response relation of calcium supplementation and preeclampsia risk and to examine cost effectiveness of lower and simpler regimens in program settings. This trial was registered at clinicaltrials.gov as NCT02238704.

Maternal Supplementation with Small-Quantity Lipid-Based Nutrient Supplements Compared with Multiple Micronutrients, but Not with Iron and Folic Acid, Reduces the Prevalence of Low Gestational Weight Gain in Semi-Urban Ghana: A Randomized Controlled Trial.

Background: It is unclear whether maternal supplementation with small-quantity lipid-based nutrient supplements (SQ-LNSs; 118 kcal/d) affects maternal weight.Objective: We compared several secondary anthropometric measures between 3 groups of women in the iLiNS (International Lipid-based Nutrient Supplements)-DYAD trial in Ghana.Methods: Women (n = 1320; <20 wk of gestation) were randomly assigned to receive 60 mg Fe + 400 µg folic acid/d (IFA), 18 vitamins and minerals/d [multiple micronutrients (MMNs)], or 20 g SQ-LNSs with 22 micronutrients/d (LNS) during pregnancy and a placebo (200 mg Ca/d), MMNs, or SQ-LNSs, respectively, for 6 mo postpartum. Weight, midupper arm circumference (MUAC), and triceps skinfold (TSF) thickness at 36 wk of gestation and 6 mo postpartum were analyzed, as were changes from estimated prepregnancy values. We assessed the adequacy of estimated gestational weight gain (GWG) by using Institute of Medicine (IOM) and International Fetal and Newborn Growth Standards for the 21st Century (INTERGROWTH-21st) guidelines.Results: The estimated prepregnancy prevalence of overweight or obesity was 38.5%. By 36 wk of gestation, women (n = 1015) had a mean ± SD weight gain of 7.4 ± 3.7 kg and changes of -1.0 ± 1.7 cm in MUAC and -2.8 ± 4.1 mm in TSF thickness. The LNS group had a lower prevalence of inadequate GWG on the basis of IOM guidelines (57.4%) than the MMN (67.2%) but not the IFA (63.1%) groups (P = 0.030), whereas the prevalence of adequate (26.9% overall) and excessive (10.4% overall) GWG did not differ by group. The percentages of normal-weight women (in kg/m2: 18.5 < body mass index < 25.0; n = 754) whose GWG was less than the third centile of the INTERGROWTH-21st standards were 23.0%, 28.7%, and 28.5% for the LNS, MMN, and IFA groups, respectively (P = 0.36). At 6 mo postpartum, the prevalence of overweight or obesity was 45.3%, and the risk of becoming overweight or obese did not differ by group.Conclusion: SQ-LNS supplementation is one potential strategy to address the high prevalence of inadequate GWG in women in settings similar to Ghana, without increasing the risk of excessive GWG. This trial was registered at clinicaltrials.gov as NCT00970866.

Multi-micronutrient supplementation during pregnancy for prevention of maternal anaemia and adverse birth outcomes in a high-altitude area: a prospective cohort study in rural Tibet of China.

Anaemia during pregnancy, characterised by Hb <110 g/l, is a specific risk factor for adverse maternal and perinatal outcomes in developing countries. The objective of this study was to determine the effectiveness of daily antenatal supplementation with multiple micronutrients (MMN) compared with folic acid (FA) on the occurrence of anaemia among pregnant women and their infants' health in a high-altitude area. A prospective cohort study was carried out in two rural counties in Tibet from 2007 to 2012. A total of 1149 eligible pregnant women were allocated daily supplementation with FA in one county and MMN containing a recommended allowance of twenty-three vitamins and minerals in another county starting ≤24 weeks of gestation and continuing until delivery. Compared with the FA group, prenatal supplementation with MMN was significantly associated with reduced odds of anaemia in the third trimester. This was demonstrated in the primary outcome, with an adjusted OR (AOR) of 0·63; 95 % CI 0·45, 0·88 and P=0·007 and also reduced odds of preterm delivery (AOR: 0·31; 95 % CI 0·15, 0·61; P=0·001). There was no difference between MMN and FA groups in mean birth weight (adjusted mean difference: 36·78; 95 % CI -19·42, 92·98 g; P=0·200), whereas MMN supplementation significantly reduced the odds of low-birth weight (LBW) babies (AOR: 0·58; 95 % CI 0·36, 0·91; P=0·019). In conclusion, the antenatal MMN supplementation in rural Tibet is associated with a reduction of maternal anaemia in the third trimester, and may potentially decrease the risk of preterm delivery and LBW babies.