Multiple Micronutrients Intervention Trial Research Articles

Maternal depression is the predominant persistent risk for child cognitive and social-emotional problems from early childhood to pre-adolescence: A longitudinal cohort study

RationaleBrain development occurs rapidly during early childhood and continues throughout middle childhood. Early and later windows of opportunity exist to alter developmental trajectories. Few studies in low- and middle-income countries have examined the importance of the timing of exposure to risks for poor pre-adolescent cognitive and social-emotional outcomes. MethodsWe assessed 359 children who participated in two follow-up studies of the Supplementation with Multiple Micronutrients Intervention Trial conducted in Indonesia in 2001–2004: at 3.5 years in 2006 and 9–12 years in 2012–2014. Using structural equation models, we examined indicators of early childhood (3.5 y) and pre-adolescent (9–12 y) exposure to risks (child height-for-age z-score [HAZ], hemoglobin [Hb], maternal depressive symptoms [MDS], home environment [HOME]), with two developmental outcomes: cognitive ability and social-emotional problems. We characterized patterns of change by calculating residuals of indicators measured earlier (3.5 y) predicting the same indicators measured later (9–12 y), for example, the residual of 3.5 y MDS predicting 9–12 y MDS (rMDS). ResultsThree early risk indicators (HOME, Hb, and MDS) were indirectly associated with pre-adolescent cognitive scores through early cognitive scores (HOME: 0.15, [95% CI 0.09, 0.21]; Hb: 0.08 [0.04, 0.12], MDS: −0.07 [-0.12, −0.02]). Pre-adolescent cognitive scores were also associated with change in MDS (rMDS: −0.13 [-0.23, −0.02]) and Hb (rHb: 0.10 [0.00, 0.20]) during middle childhood. For pre-adolescent social-emotional problems, both early childhood MDS (0.31 [0.19, 0.44]) and change in MDS during middle childhood (rMDS: 0.48 [0.37, 0.60]) showed strong direct associations with this outcome. ConclusionsOur findings confirm those of previous studies that prevention of risk exposures during early childhood is likely to support long-term child development. It also adds evidence to a previously scarce literature for the middle childhood period. Prevention of maternal depressive symptoms and child anemia during middle childhood should be assessed for effectiveness to support child development.

Maternal biomarker patterns for metabolism and inflammation in pregnancy are influenced by multiple micronutrient supplementation and associated with child biomarker patterns and nutritional status at 9-12 years of age.

Maternal nutritional status influences fetal development and long-term risk for adult non-communicable diseases. However, the underlying mechanisms remain poorly understood. We examined whether biomarkers for metabolism and inflammation during pregnancy were associated with maternal health and with child biomarkers and health at 9–12 years of age in 44 maternal-child dyads from the Supplementation with Multiple Micronutrients Intervention Trial (SUMMIT, ISRCTN34151616) in Lombok, Indonesia. Archived blood for each dyad from maternal enrollment, later in pregnancy, postpartum, and from children at 9–12 years comprised 132 specimens. Multiplex microbead immunoassays were used to quantify vitamin D-binding protein (D), adiponectin (A), retinol-binding protein 4 (R), C-reactive protein (C), and leptin (L). Principal component analysis (PCA) revealed distinct variance patterns, i.e. principal components (PC), for baseline pregnancy, bp.pc1.D↓A↓R↓ and bp.pc2.C↓L↑; combined follow-up during pregnancy and postpartum, dp-pp.pc1.D↑↓A↑R↑↓L↓ and dp-pp.pc2.A↑C↑L↑; and children, ch.pc1.D↑R↑C↑ and ch.pc2.D↓A↑L↑. Maternal multiple micronutrient (MMN) supplementation led to an association of baseline maternal bp.pc2.C↓L↑ with decreased post-supplementation maternal dp-pp.pc2.A↑C↑L↑ (p = 0.022), which was in turn associated with both increased child ch.pc1.D↑R↑C↑ (p = 0.036) and decreased child BMI z-score (BMIZ) (p = 0.022). Further analyses revealed an association between maternal dp-pp.pc1.D↑↓A↑R↑↓L↓ and increased child BMIZ (p = 0.036). Child ch.pc1.D↑R↑C↑ was associated with decreased birth weight (p = 0.036) and increased child BMIZ (p = 0.002). Child ch.pc2.D↓A↑L↑ was associated with increased child BMIZ (p = 0.005), decreased maternal height (p = 0.030) and girls (p = 0.002). A pattern of elevated maternal adiponectin and leptin in pregnancy was associated with increased C-reactive protein, vitamin A, and D binding proteins pattern in children, suggesting biomarkers acting in concert may have qualitative as well as quantitative influence beyond single biomarker effects. Patterns in pregnancy proximal to birth were more associated with child status. In addition, child patterns were more associated with child status, particularly child BMI. MMN supplementation affects maternal biomarker patterns of metabolism and inflammation in pregnancy, and potentially in the child. However, child nutrition conditions after birth may have a greater impact on metabolism and inflammation.

Maternal Multiple Micronutrient Supplementation Stabilizes Mitochondrial DNA Copy Number in Pregnant Women in Lombok, Indonesia

ABSTRACTBackgroundThe Supplementation with Multiple Micronutrients Intervention Trial (SUMMIT) in Lombok, Indonesia showed that maternal multiple micronutrients (MMN), as compared with iron and folic acid (IFA), reduced fetal loss, early infant mortality, and low birth weight. Mitochondria play a key role during pregnancy by providing maternal metabolic energy for fetal development, but the effects of maternal supplementation during pregnancy on mitochondria are not fully understood.ObjectiveThe aim of this study was to assess the impact of MMN supplementation on maternal mitochondrial DNA copy number (mtDNA-CN).MethodsWe used archived venous blood specimens from pregnant women enrolled in the SUMMIT study. SUMMIT was a cluster-randomized double-blind controlled trial in which midwives were randomly assigned to distribute MMN or IFA to pregnant women. In this study, we selected 108 sets of paired baseline and postsupplementation samples (MMN = 54 and IFA = 54). Maternal mtDNA-CN was determined by real-time quantitative polymerase chain reaction in baseline and postsupplementation specimens. The association between supplementation type and change in mtDNA-CN was performed using rank-based estimation for linear models.ResultsIn both groups, maternal mtDNA-CN at postsupplementation was significantly elevated compared with baseline (P < 0.001). The regression revealed that the MMN group had lower postsupplementation mtDNA-CN than the IFA group (β = −4.63, P = 0.003), especially for women with mtDNA-CN levels above the median at baseline (β = −7.49, P = 0.007). This effect was rapid, and observed within 33 d of initiation of supplementation (β = −7.39, P = 0.017).ConclusionMaternal MMN supplementation rapidly stabilized mtDNA-CN in pregnant women who participated in SUMMIT, indicating improved mitochondrial efficiency. The data provide a mechanistic basis for the beneficial effects of MMN on fetal growth and survival, and support the transition from routine IFA to MMN supplementation.This trial was registered at www.isrctn.com as ISRCTN34151616.

Associations of Nutritional and Social Exposures in Utero, Early, and Later Childhood with Cognitive, Motor, and Social-Emotional Development in Indonesia (OR10-03-19)

ObjectivesTo determine the association of biomedical and socio-environmental risk factors during pregnancy, early, and later childhood with cognitive (IQ), motor, social-emotional (SE), and executive function (EF) at age 3.5 and 9–12 y in Indonesia. MethodsChildren born to pregnant women enrolled in the Supplementation with Multiple Micronutrients Intervention Trial (SUMMIT) in 2001–2004 participated in follow-up studies at age 3.5 y in 2006 and 9–12 y in 2013. We assessed 359 children at both time points for outcomes of IQ, motor, SE and EF. We also assessed predictors of outcomes including biomedical risks (small for gestational age at birth: SGA; height-for-age z-score: HAZ; and child hemoglobin: Hb) and socio-environmental risks (HOME Inventory; maternal depression: MD). We calculated the residuals of earlier risks predicting the later scores, e.g., the residual of SGA at birth predicting HAZ at 3.5 y (rHAZ1), representing the deviation of HAZ at 3.5 y from the child’s expected HAZ based on SGA. In Model 1, we entered SGA, representing in utero exposures. In Model 2, we added indicators at 3.5 y (rHAZ1, Hb, HOME, MD). In Model 3, we added indicators at 9–12 y (rHAZ2, rHb, rHOME, rMD) and the corresponding 3.5 y IQ, motor, SE, or EF scores. ResultsThe coefficients for outcomes at early and later time points (Figure 1) show that SGA was not associated with any scores. Early (3.5 y) childhood rHAZ1 was associated with early IQ, motor, and EF, but was not independently associated with later (9–12 y) IQ, motor, or EF. Later childhood rHAZ2 was not associated with any scores. Early childhood HOME was independently associated with both early and later IQ, motor, and EF, while later childhood rHOME was not associated with any scores. Early Hb was not associated with any scores and later rHb was associated with motor scores only. MD during early childhood and rMD during later childhood were independently associated with later childhood SE. ConclusionsThese findings support the importance of early and continual intervention throughout childhood to support healthy growth and even more importantly maternal mental health and nurturing home environments. This is essential for longer-term IQ, motor, SE, and EF. Funding SourcesGrand Challenges Canada, Allen & Turner Foundations, UNICEF, Centre for Health and Human Development, USAID-Indonesia, USDA NIFA #CA-D-NTR-2493-H. Supporting Tables, Images and/or Graphs▪

Increased mitochondrial DNA copy number in maternal peripheral blood is associated with low birth weight in Lombok, Indonesia

Fetal development depends on maternal metabolic energy from mitochondria. We investigated the association of maternal mitochondrial function, represented by mitochondrial DNA copy number (mtDNA-CN) of venous blood, with child birth weight (BW) from 528 randomly selected mothers enrolled in the Supplementation with Multiple Micronutrients Intervention Trial (ISRCTN 34151616). Real-time quantitative PCR of archived blood specimens and regression analysis adjusting for other primary determinants of BW showed that loge mtDNA-CN was inversely associated with BW (β = −204.6, p < 0.001), particularly in the third trimester (β = −376.8, p<0.001). Maternal mtDNA-CN may be a marker for low BW and fetal growth restriction.

Maternal multiple micronutrient supplementation and other biomedical and socioenvironmental influences on children's cognition at age 9-12 years in Indonesia: follow-up of the SUMMIT randomised trial.

Brain and cognitive development during the first 1000 days from conception are affected by multiple biomedical and socioenvironmental determinants including nutrition, health, nurturing, and stimulation. An improved understanding of the long-term influence of these factors is needed to prioritise public health investments to optimise human development. We did a follow-up study of the Supplementation with Multiple Micronutrients Intervention Trial (SUMMIT), a double-blind, cluster-randomised trial of maternal supplementation with multiple micronutrients (MMN) or iron and folic acid (IFA) in Indonesia. Of 27 356 live infants from birth to 3 months of age in 2001-04, we re-enrolled 19 274 (70%) children at age 9-12 years, and randomly selected 2879 from the 18 230 who were attending school at a known location. Of these, 574 children were oversampled from mothers who were anaemic or malnourished at SUMMIT enrolment. We assessed the effects of MMN and associations of biomedical (ie, maternal and child anthropometry and haemoglobin and preterm birth) and socioenvironmental determinants (ie, parental education, socioeconomic status, home environment, and maternal depression) on general intellectual ability, declarative memory, procedural memory, executive function, academic achievement, fine motor dexterity, and socioemotional health. The SUMMIT trial was registered, number ISRCTN34151616. Children of mothers given MMN had a mean score of 0·11 SD (95% CI 0·01-0·20, p=0·0319) higher in procedural memory than those given IFA, equivalent to the increase in scores with half a year of schooling. Children of anaemic mothers in the MMN group scored 0·18 SD (0·06-0·31, p=0·0047) higher in general intellectual ability, similar to the increase with 1 year of schooling. Overall, 18 of 21 tests showed a positive coefficient of MMN versus IFA (p=0·0431) with effect sizes from 0·00-0·18 SD. In multiple regression models, socioenvironmental determinants had coefficients of 0·00-0·43 SD and 22 of 35 tests were significant at the 95% CI level, whereas biomedical coefficients were 0·00-0·10 SD and eight of 56 tests were significant, indicating larger and more consistent impact of socioenvironmental factors (p<0·0001). Maternal MMN had long-term benefits for child cognitive development at 9-12 years of age, thereby supporting its role in early childhood development, and policy change toward MMN. The stronger association of socioenvironmental determinants with improved cognition suggests present reproductive, maternal, neonatal, and child health programmes focused on biomedical determinants might not sufficiently enhance child cognition, and that programmes addressing socioenvironmental determinants are essential to achieve thriving populations. Grand Challenges Canada Saving Brains Program.

The Relative Association of Bio‐Medical and Socio‐Environmental Risk Factors with School‐Age Child Cognition in Indonesia

Child cognitive, motor, and socio‐emotional development is affected by multiple bio‐medical and socio‐environmental factors. A better understanding of the influence and interplay of these factors is needed to inform the strategic design and integration of child development programs with existing reproductive, maternal, neonatal and child health (RMNCH) programs.We assessed the cognitive, motor, and socio‐emotional function of 2879 9–12‐year‐old children whose mothers had participated in the Supplementation with Multiple Micronutrients Intervention Trial (SUMMIT). In multiple regression models, we assessed the relative effect size of seven bio‐medical risk factors and five socio‐environmental risk factors on each of seven cognitive, motor, and socio‐emotional scores. Six factors were measured before birth, two at birth, and four at school‐age follow‐up.The socio‐environmental factors showed stronger and more consistent associations with school‐age cognitive, motor, and socio‐emotional scores, as compared to the bio‐medical factors. Pre‐term birth, born small for gestation age, maternal anemia, and low maternal mid‐upper arm circumference and height during pregnancy were not significantly associated with any score. Child anemia at follow‐up was significantly associated with fine motor dexterity only. Children whose mothers received multiple micronutrient supplements during pregnancy and postpartum scored higher in procedural memory only. Post‐natal growth in height was significantly associated with general intellectual ability and academic achievement. In contrast, each of the socio‐environmental factors was significantly associated with three to five of the seven scores. Children in low SES households scored significantly lower in general intellectual ability, declarative memory, executive function, academic achievement, and fine motor dexterity. Both maternal and paternal education were associated with general intellectual ability, executive function, and academic achievement, while maternal education was also associated with declarative memory and fine motor dexterity. Nurturing and stimulation from the environment (HOME Inventory score) was significantly associated with general intellectual ability, declarative memory, executive function, academic achievement, and fine motor dexterity. Maternal depression was strongly associated with child socio‐emotional development, and was the only significant predictor of this score. Children of depressed mothers also scored lower in declarative memory.In order to achieve thriving populations, coverage of existing RMNCH interventions to prevent these bio‐medical conditions needs to be improved. Even with improved coverage of existing interventions, additional interventions addressing socio‐environmental risk factors are also needed.Support or Funding InformationFunded by Grand Challenges Canada Saving Brains

Effect of Maternal Multiple Micronutrients Supplementation on the Apgar Score of Indonesian Neonates

IntroductionMaternal multiple micronutrients (MMN) supplementation as compared to iron‐folic acid (IFA) can increase birth weight and decrease infant mortality, but the physiological basis remains unclear. We examined Apgar scores to assess the impact of MMN on the dynamic process of neonatal adaptation after birth.MethodsWe selected 3667 singleton live births from the Supplementation with Multiple Micronutrients Intervention Trial (SUMMIT) of maternal MMN versus IFA (ISRCTN34151616) with Apgar scores at the 1st and 5th minute, after excluding those with midline anomaly, inborn diseases and if not a spontaneous vaginal birth. Mixed effect multiple linear regression models were used to adjust for clustered randomization, covariates and interactions.ResultsOverall, there were no significant differences between Apgar scores of children from the MMN and IFA groups at the 1st (adjusted β ‐0.416, 95% CI ‐0.339‐0.047) or 5th minute (adjusted β 0.077, 95% CI ‐0.097‐0.252), or changes from 1 to 5 minutes (adjusted β 0.003, 95% CI ‐0.065‐0.072), nor were there effects on specific component scores. In subgroup analysis, MMN decreased the 1st minute score for full term and small for gestational (SGA) neonates, and MMN increased improvement from 1 to 5minutes in full term and SGA neonates, and those born of well‐nourished mothers (upper arm circumference &gt; 23.5 cm).DiscussionWe observed certain subgroups of neonates of mothers given MMN tended toward lower 1st minute Apgar scores and greater improvement of Apgar scores from the 1st to 5th minute. MMN supplementation may enhance the dynamic adaptive processes of certain neonates after delivery, thereby improving infant survival.

The long term impact of maternal multiple micronutrient supplementation, infant nutrition and health on visual acuity of 9‐12 year old children in Indonesia

The impact of the prenatal nutrition and neonatal health on visual acuity (VA) remains unknown. We investigated the long term relative impact of maternal multiple micronutrient (MMN) versus iron‐folic acid (IFA) supplementation on VA of 9‐12 years old school children, and explored the long term effects of birth weight, preterm birth, and stunting on VA. We assessed VA of 3,398 children of mothers who had participated in the Supplementation with Multiple Micronutrients Intervention Trial (SUMMIT), a cluster‐randomized trial of MMN versus IFA in Indonesia. Multivariate logistic regression was used to assess whether of MMN, child age, gender, socio‐economic status (SES), preterm birth, birth weight or stunting were related to VA. There was no siginificant long term impact of maternal MMN supplementation on VA in school age children. We found significant effects of birth weight on VA of the left eye (p=0.03) and left eye with pinhole assessments (p=0.01), and effects of stunting on VA of the left eye (p=0.04) and for both eyes (p=0.04), and of SES on VA for the right eye (p=0.04). No significant effects were observed for preterm birth, age and gender. There were no siginificant effects of maternal MMN and IFA supplementation on VA in 9‐12 years old school children, but there were significant effects of birth weight, stunting and SES on VA.

The Long‐Term Impact of Water and Sanitation on Childhood Cognition

Unsafe water and poor sanitation may negatively affect brain development, however few studies have examined the long‐term impact on children's cognitive function.Our objective was to assess the relationship between household access to safe water and toilet facilities during the prenatal period with childhood cognition 9‐12 years later.The Supplementation with Multiple Micronutrients Intervention Trial (SUMMIT), conducted in 2001‐2004 In Indonesia, compared the health effects of a prenatal multiple micronutrient supplement to an iron and folic acid supplement. At baseline, information collected included water supply, sanitation, and maternal education. We assessed cognition in 3687 children of SUMMIT participants at 9‐12 years of age. Children of mothers who had access to safe toilet facilities during pregnancy had higher scores in Digit Span Forward (95%CI 0.008‐0.17, P&lt;0.03), Information (95%CI 0.08‐0.2, P&lt;0.001), Block Design (95%CI 0.01‐0.1, P&lt;0.02), and Word List Memory (95%CI 0.006‐0.17, P&lt;0.03) tests after adjusting for cluster randomization, data collector, maternal education, socio‐economic status and home environment score. Children of mothers with access to safe water during pregnancy had higher Word List Memory scores (95%CI 0.01‐0.19, P&lt;0.02).The finding that safe water and toilet facilities were associated with child cognition even after adjustment for socio‐economic status and maternal education suggests that interventions to improve water and sanitation in early life may have long‐term benefits on child cognitive abilities.

Maternal Multiple Micronutrient Supplements and Child Cognition: A Randomized Trial in Indonesia

We investigated the relative benefit of maternal multiple micronutrient (MMN) supplementation during pregnancy and until 3 months postpartum compared with iron/folic acid supplementation on child development at preschool age (42 months). We assessed 487 children of mothers who participated in the Supplementation with Multiple Micronutrients Intervention Trial, a cluster-randomized trial in Indonesia, on tests adapted and validated in the local context measuring motor, language, visual attention/spatial, executive, and socioemotional abilities. Analysis was according to intention to treat. In children of undernourished mothers (mid-upper arm circumference <23.5 cm), a significant benefit of MMNs was observed on motor ability (B = 0.39 [95% confidence interval (CI): 0.08-0.70]; P = .015) and visual attention/spatial ability (B = 0.37 [95% CI: 0.11-0.62]; P = .004). In children of anemic mothers (hemoglobin concentration <110 g/L), a significant benefit of MMNs on visual attention/spatial ability (B = 0.24 [95% CI: 0.02-0.46]; P = .030) was also observed. No robust effects of maternal MMN supplementation were found in any developmental domain over all children. When pregnant women are undernourished or anemic, provision of MMN supplements can improve the motor and cognitive abilities of their children up to 3.5 years later, particularly for both motor function and visual attention/spatial ability. Maternal MMN but not iron/folic acid supplementation protected children from the detrimental effects of maternal undernutrition on child motor and cognitive development.

The Effect of Maternal Multiple Micronutrient Supplementation on Cognition and Mood during Pregnancy and Postpartum in Indonesia: A Randomized Trial

Maternal caregiving capacity, which is affected in part by cognition and mood, is crucial for the health of mothers and infants. Few interventions aim to improve maternal and infant health through improving such capacity. Multiple micronutrient (MMN) supplementation may improve maternal cognition and mood, since micronutrients are essential for brain function. We assessed mothers who participated in the Supplementation with Multiple Micronutrients Intervention Trial (SUMMIT), a double-blind cluster-randomized trial in Indonesia comparing MMN supplementation to iron and folic acid (IFA) during pregnancy and until three months postpartum. We adapted a set of well-studied tests of cognition, motor dexterity, and mood to the local context and administered them to a random sample of 640 SUMMIT participants after an average of 25 weeks (SD = 9) of supplementation. Analysis was by intention to treat. Controlling for maternal age, education, and socio-economic status, MMN resulted in a benefit of 0.12 SD on overall cognition, compared to IFA (95%CI 0.03–0.22, p = .010), and a benefit of 0.18 SD on reading efficiency (95%CI 0.02–0.35, p = .031). Both effects were found particularly in anemic (hemoglobin<110 g/L; overall cognition: B = 0.20, 0.00–0.41, p = .055; reading: B = 0.40, 0.02–0.77, p = .039) and undernourished (mid-upper arm circumference<23.5 cm; overall cognition: B = 0.33, 0.07–0.59, p = .020; reading: B = 0.65, 0.19–1.12, p = .007) mothers. The benefit of MMN on overall cognition was equivalent to the benefit of one year of education for all mothers, to two years of education for anemic mothers, and to three years of education for undernourished mothers. No effects were found on maternal motor dexterity or mood. This is the first study demonstrating an improvement in maternal cognition with MMN supplementation. This improvement may increase the quality of care mothers provide for their infants, potentially partly mediating effects of maternal MMN supplementation on infant health and survival. The study is registered as an International Standard Randomized Controlled Trial, number ISRCTN34151616. http://www.controlled-trials.com/ISRCTN34151616

Programmatic Effects of a Large-Scale Multiple-Micronutrient Supplementation Trial in Indonesia: Using Community Facilitators as Intermediaries for Behavior Change

Clinical trials can serve as an opportunity gateway for enhanced health benefits to the target population, above and beyond the specific intervention being tested. The Supplementation with Multiple Micronutrients Intervention Trial (SUMMIT), a randomized, controlled clinical trial in Lombok, Indonesia, found that supplementation during pregnancy with multiple micronutrients reduced 90-day infant mortality by nearly 20% as compared with iron-folic acid. This trial was designed as both a program and research trial and used community facilitators to serve as liaisons between the study and the pregnant women. This analysis documents the programmatic impacts of SUMMIT on health-seeking and early infant mortality resulting from community facilitators' field activities. Data on compliance, human resource practices, health-seeking, and health outcomes from the 31,290 SUMMIT enrollees were analyzed. Overall compliance with either iron-folic acid or multiple micronutrients was high in the program, at 85.0%. Early prenatal care visits increased significantly. Sixty-three percent of primiparous women used a skilled birth attendant (SBA); among multiparous women, the rate of use of a SBA rose from 35% for the last birth to 53%. Use of a SBA resulted in a 30% reduction in early infant mortality (RR, 0.70; 95% CI, 0.59 to 0.83; p < .0001), independently of any reductions due to multiple micronutrients. The community facilitators played a central role in improving health-seeking; however, the quality of the community facilitators' performance was associated with the impact of the micronutrient supplement on infant health. In a subsample of community facilitators, better-performing facilitators were found to markedly improve the overall impact of the multiple micronutrients on early infant mortality (RR, 0.67; 95% CI, 0.49 to 0.92; p = .0117). In contrast, infants of women with poorly performing community facilitators were found to derive no additional benefit from the multiple micronutrients (RR, 1.04; 95% CI, 0.64 to 1.72; p = .8568). Systematic enhancements to the quality of implementation of SUMMIT led to significant increases in use of SBAs at delivery, resulting in a 30% reduction in early infant mortality independent of the impact of micronutrient supplementation. Therefore, if women were to consume multiple micronutrients on a regular basis and were to use a SBA at delivery, the risk of early infant mortality could be reduced by nearly 50%. The impacts of community facilitators in effecting changes in women's health behaviors are notable and are applicable to other health programs. Enhancements to program implementation should be driven by evidence, be accountable to the communities the program serves, and be evaluated on the basis of measurable gains in health for women and children.

Investigator‐initiated pragmatic trials in developing countries – much needed but much ignored

The last decade has witnessed clinicians in developing countries gaining recognition as investigators for many sponsor initiated multicentre rials. This is indeed a welcome change as it has provided an impetus for investigators in these countries to gear up and meet world standards. This is exemplified by the fact that the Ethics Committees across countries are increasingly becoming compliant with International Conference on Harmonization-Good Clinical Practice (ICH-GCP) guidelines, laboratories are making efforts for Good Laboratory Practice (GLP) accreditation, indigenous clinical trial registries have been set up [1] and programmes to train clinical research co-ordinators/monitors and investigators are being undertaken at various levels. Contributions have also been made by generating informed consent templates [2] and by producing teaching materials for clinical trial participants [3]. However, with the recent upsurge of sponsor initiated clinical trials, investigator initiated clinical trials have taken a back seat. High on the agenda for pharmaceutical company-sponsored clinical trials are new drug development or expanding the indication profile of their drugs. Questions such as comparative efficacy of one drug over another or a medical management with surgical/interventional management, strategies to ease drug dosage schedules, quality of life issues, exploration of alternative systems of medicines are not frequently explored in these trials. These are objectives of concern in investigator-initiated trials and the findings of these trials have important bearing for practice and for making health related policies [4]. Many investigators have the keenness and also the know-how for initiating and conducting such trials. However, the task is not easy if GCP standards are to be maintained. Funds are a major crunch. Government funding agencies/research groups/associations in the west have from a long time realized this need and have sponsored such investigator-initiated trials which have contributed significantly to furthering medical knowledge. Key examples would be the Diabetes Control and Complication Trial (DCCT), the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) and Clinical Antipsychotic Trials of Intervention Effectiveness. There are some examples from the developing countries as well such as Supplementation with Multiple Micronutrients Intervention Trial (SUMMIT) [5], the SPEAR trial to compare chloramphenicol vs ampicillin plus gentamicin for community acquired very severe pneumonia in children in low resource settings [6], the ongoing CORONIS trial to compare various surgical techniques for Caesarean section. Interestingly the funding for such studies has come from agencies such as the World Health Organization, the Fogarty International Center of the National Institute of Health, Center of International Health and Development of Boston University and Johns Hopkins Bloomberg School of Public Health to name a few. This is indeed one of the options for investigators in developing countries but self-reliance should be the ultimate goal. All this would need a great deal of commitment from government aided agencies not only for providing funds for the conduct of the studies, but also for establishing systems for overseeing and ensuring GCP-compliant conduct of these trials. A government agency or scientific societies could play a constructive role in this regard. To start with, investigators who have published pilot trials could be encouraged to evolve their studies into adequately sized (if need be multi-centre) studies. A list of unanswered questions addressing the indigenous needs could be prepared and a list of investigators with proven credentials could be drawn up. For this, investigators with a past track record of conducting and publishing their trials should be chosen. Furthermore, these investigators could be helped to develop final protocols with inputs even from various experts the world over. The trial registration should be ensured. Evaluation of reports of the monitors, data safety monitoring board and audit of the trial could help in paving the way for the conduct of GCP compliant trials. Some problems are indeed expected. There could be concerns about the legal issues such as compensation to the participants in case of injury, insurance of the investigators, staff for ensuring quality control and quality assurance, inter-departmental and inter-institutional collaborations. However, none of these is insurmountable. Successful models are available [7, 8] and benefits could be derived from them to suit the needs of our country. Over a period of time sponsor-initiated trials conducted in developing countries have forayed into the medical literature and created their impact on medical practice. There is no reason why investigator-initiated pragmatic trials should lag behind.

Maternal micronutrient deficiencies in developing countries

In today's Lancet, the Supplementation with Multiple Micronutrients Intervention Trial (SUMMIT) Study Group present important findings from their large trial of maternal multiple micronutrients administered through routine health services in Lombok, Indonesia.1 Although the reported outcomes do not include maternal or newborn morbidity or biochemistry, the trial provides evidence of a reduction in mortality in young infants born to mothers who received the supplements. Whilst the rigorous promotional and support strategy limits the generalisability of this trial, SUMMIT does provide important data on the feasibility of delivering such an intervention through a routine health system.