Factors affecting the implementation of calcium supplementation strategies during pregnancy to prevent pre-eclampsia: a mixed-methods systematic review.

OBJECTIVES: Daily calcium supplements are recommended for pregnant women from 20 weeks' gestation to prevent pre-eclampsia in populations with low dietary calcium intake. We aimed to improve understanding of barriers and facilitators for calcium supplement intake during pregnancy to prevent pre-eclampsia. DESIGN: Mixed-method systematic review, with confidence assessed using the Grading of Recommendations, Assessment, Development and Evaluations-Confidence in the Evidence from Reviews of Qualitative research approach. DATA SOURCES: MEDLINE and EMBASE (via Ovid), CINAHL and Global Health (via EBSCO) and grey literature databases were searched up to 17 September 2022. ELIGIBILITY CRITERIA: We included primary qualitative, quantitative and mixed-methods studies reporting implementation or use of calcium supplements during pregnancy, excluding calcium fortification and non-primary studies. No restrictions were imposed on settings, language or publication date. DATA EXTRACTION AND SYNTHESIS: Two independent reviewers extracted data and assessed risk of bias. We analysed the qualitative data using thematic synthesis, and quantitative findings were thematically mapped to qualitative findings. We then mapped the results to behavioural change frameworks to identify barriers and facilitators. RESULTS: Eighteen reports from nine studies were included in this review. Women reported barriers to consuming calcium supplements included limited knowledge about calcium supplements and pre-eclampsia, fears and experiences of side effects, varying preferences for tablets, dosing, working schedules, being away from home and taking other supplements. Receiving information regarding pre-eclampsia and safety of calcium supplement use from reliable sources, alternative dosing options, supplement reminders, early antenatal care, free supplements and support from families and communities were reported as facilitators. Healthcare providers felt that consistent messaging about benefits and risks of calcium, training, and ensuring adequate staffing and calcium supply is available would be able to help them in promoting calcium. CONCLUSION: Relevant stakeholders should consider the identified barriers and facilitators when formulating interventions and policies on calcium supplement use. These review findings can inform implementation to ensure effective and equitable provision and scale-up of calcium interventions. PROSPERO REGISTRATION NUMBER: CRD42021239143.

Calcium supplementation to prevent pre-eclampsia: protocol for an individual participant data meta-analysis, network meta-analysis and health economic evaluation.

INTRODUCTION: Low dietary calcium intake is a risk factor for pre-eclampsia, a major contributor to maternal and perinatal mortality and morbidity worldwide. Calcium supplementation can prevent pre-eclampsia in women with low dietary calcium. However, the optimal dose and timing of calcium supplementation are not known. We plan to undertake an individual participant data (IPD) meta-analysis of randomised trials to determine the effects of various calcium supplementation regimens in preventing pre-eclampsia and its complications and rank these by effectiveness. We also aim to evaluate the cost-effectiveness of calcium supplementation to prevent pre-eclampsia. METHODS AND ANALYSIS: We will identify randomised trials on calcium supplementation before and during pregnancy by searching major electronic databases including Embase, CINAHL, MEDLINE, CENTRAL, PubMed, Scopus, AMED, LILACS, POPLINE, AIM, IMSEAR, ClinicalTrials.gov and the WHO International Clinical Trials Registry Platform, without language restrictions, from inception to February 2022. Primary researchers of the identified trials will be invited to join the International Calcium in Pregnancy Collaborative Network and share their IPD. We will check each study's IPD for consistency with the original authors before standardising and harmonising the data. We will perform a series of one-stage and two-stage IPD random-effect meta-analyses to obtain the summary intervention effects on pre-eclampsia with 95% CIs and summary treatment-covariate interactions (maternal risk status, dietary intake, timing of intervention, daily dose of calcium prescribed and total intake of calcium). Heterogeneity will be summarised using tau2, I2 and 95% prediction intervals for effect in a new study. Sensitivity analysis to explore robustness of statistical and clinical assumptions will be carried out. Minor study effects (potential publication bias) will be investigated using funnel plots. A decision analytical model for use in low-income and middle-income countries will assess the cost-effectiveness of calcium supplementation to prevent pre-eclampsia. ETHICS AND DISSEMINATION: No ethical approvals are required. We will store the data in a secure repository in an anonymised format. The results will be published in peer-reviewed journals. PROSPERO REGISTRATION NUMBER: CRD42021231276.

Effect of high dose folic acid supplementation in pregnancy on pre-eclampsia (FACT): double blind, phase III, randomised controlled, international, multicentre trial.

OBJECTIVE: To determine the efficacy of high dose folic acid supplementation for prevention of pre-eclampsia in women with at least one risk factor: pre-existing hypertension, prepregnancy diabetes (type 1 or 2), twin pregnancy, pre-eclampsia in a previous pregnancy, or body mass index ≥35. DESIGN: Randomised, phase III, double blinded international, multicentre clinical trial. SETTING: 70 obstetrical centres in five countries (Argentina, Australia, Canada, Jamaica, and UK). PARTICIPANTS: 2464 pregnant women with at least one high risk factor for pre-eclampsia were randomised between 2011 and 2015 (1144 to the folic acid group and 1157 to the placebo group); 2301 were included in the intention to treat analyses. INTERVENTION: Eligible women were randomised to receive either daily high dose folic acid (four 1.0 mg oral tablets) or placebo from eight weeks of gestation to the end of week 16 of gestation until delivery. Clinicians, participants, adjudicators, and study staff were masked to study treatment allocation. MAIN OUTCOME MEASURE: The primary outcome was pre-eclampsia, defined as hypertension presenting after 20 weeks' gestation with major proteinuria or HELLP syndrome (haemolysis, elevated liver enzymes, low platelets). RESULTS: Pre-eclampsia occurred in 169/1144 (14.8%) women in the folic acid group and 156/1157 (13.5%) in the placebo group (relative risk 1.10, 95% confidence interval 0.90 to 1.34; P=0.37). There was no evidence of differences between the groups for any other adverse maternal or neonatal outcomes. CONCLUSION: Supplementation with 4.0 mg/day folic acid beyond the first trimester does not prevent pre-eclampsia in women at high risk for this condition. TRIAL REGISTRATION: Current Controlled Trials ISRCTN23781770 and ClinicalTrials.gov NCT01355159.

Alternative versus standard packages of antenatal care for low-risk pregnancy.

BACKGROUND: The number of visits for antenatal (prenatal) care developed without evidence of how many visits are necessary. The content of each visit also needs evaluation. OBJECTIVES: To compare the effects of antenatal care programmes with reduced visits for low-risk women with standard care. SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (23 March 2015), reference lists of articles and contacted researchers in the field. SELECTION CRITERIA: Randomised trials comparing a reduced number of antenatal visits, with or without goal-oriented care, versus standard care. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trials for inclusion and risk of bias, extracted data and checked for accuracy. We assessed studies for risk of bias and graded the quality of the evidence. MAIN RESULTS: We included seven trials (more than 60,000 women): four in high-income countries with individual randomisation; three in low- and middle-income countries with cluster randomisation (clinics as the unit of randomisation). Most of the data included in the review came from the three large, well-designed cluster-randomised trials that took place in Argentina, Cuba, Saudi Arabia, Thailand and Zimbabwe. All results have been adjusted for the cluster design effect. All of the trials were at some risk of bias as blinding of women and staff was not feasible with this type of intervention. For primary outcomes, evidence was graded as being of moderate or low quality, with downgrading decisions due to risks of bias and imprecision of effects.The number of visits for standard care varied, with fewer visits in low- and middle- income country trials. In studies in high-income countries, women in the reduced visits groups, on average, attended between 8.2 and 12 times. In low- and middle- income country trials, many women in the reduced visits group attended on fewer than five occasions, although in these trials the content as well as the number of visits was changed, so as to be more 'goal-oriented'.Perinatal mortality was increased for those randomised to reduced visits rather than standard care, and this difference was borderline for statistical significance (risk ratio (RR) 1.14; 95% confidence interval (CI) 1.00 to 1.31; five trials, 56,431 babies; moderate-quality evidence). In the subgroup analysis, for high-income countries the number of deaths was small (32/5108), and there was no clear difference between the groups (RR 0.90; 95% CI 0.45 to 1.80, two trials); for low- and middle-income countries perinatal mortality was significantly higher in the reduced visits group (RR 1.15; 95% CI 1.01 to 1.32, three trials).There was no clear difference between groups for our other primary outcomes: maternal death (RR 1.13, 95%CI 0.50 to 2.57, three cluster-randomised trials, 51,504 women, low-quality evidence); hypertensive disorders of pregnancy (various definitions including pre-eclampsia) (RR 0.95, 95% CI 0.80 to 1.12, six studies, 54,108 women, low-quality evidence); preterm birth (RR 1.02, 95% CI 0.94 to 1.11; seven studies, 53,661 women, moderate-quality evidence); and small-for-gestational age (RR 0.99, 95% CI 0.91 to 1.09, four studies 43,045 babies, moderate-quality evidence).Reduced visits were associated with a reduction in admission to neonatal intensive care that was borderline for significance (RR 0.89; 95% CI 0.79 to 1.02, five studies, 43,048 babies, moderate quality evidence). There were no clear differences between the groups for the other secondary clinical outcomes.Women in all settings were less satisfied with the reduced visits schedule and perceived the gap between visits as too long. Reduced visits may be associated with lower costs. AUTHORS' CONCLUSIONS: In settings with limited resources where the number of visits is already low, reduced visits programmes of antenatal care are associated with an increase in perinatal mortality compared to standard care, although admission to neonatal intensive care may be reduced. Women prefer the standard visits schedule. Where the standard number of visits is low, visits should not be reduced without close monitoring of fetal and neonatal outcome.

Community-based supplementary feeding for promoting the growth of children under five years of age in low and middle income countries.

BACKGROUND: Supplementary feeding is defined as the provision of extra food to children or families beyond the normal ration of their home diets. The impact of food supplementation on child growth merits careful evaluation in view of the reliance of many states and non-governmental organisations on this intervention to improve child health in low and middle income countries (LMIC). This is an update of a Cochrane review first published in 2005. OBJECTIVES: To evaluate the effectiveness of community-based supplementary feeding for promoting the physical growth of children under five years of age in LMIC. SEARCH METHODS: For this updated review  we searched the following databases on 31 January 2011: CENTRAL (The Cochrane Library), MEDLINE (1948 to January week 3, 2011), EMBASE (1980 to week 3, 2011), CINAHL (1937 to 27 January 2011), LILACS (all years), WorldCat for dissertations and theses (all years) and ClinicalTrials.gov (all years). SELECTION CRITERIA: Randomised controlled trials (RCTs) evaluating supplementary feeding in comparison to a control group (no intervention or a placebo such as food with a very low number of nutrients and calories) in children from birth to five years of age in LMIC. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted and analysed the data. MAIN RESULTS: We included eight RCTs (n = 1243 children) that were at relatively high risk of bias. We found high levels of clinical heterogeneity in the participants, interventions and outcome measures across studies. Nevertheless, in order to quantify pooled effects of supplementary feeding, we decided to combine studies according to prespecified characteristics. These were the children's age (younger or older than 24 months), their nutritional status at baseline (stunted or wasted, or not stunted or wasted) and the duration of the intervention (less or more than 12 months). A statistically significant difference of effect was only found for length during the intervention in children aged less than 12 months (two studies; 795 children; mean difference 0.19 cm; 95% confidence interval (CI) 0.07 to 0.31). Based on the summary statistic calculated for each study, the mean difference (MD) between intervention and control groups ranged from 0.48 cm (95% CI 0.07 to 0.89) to 1.3 cm (95% CI 0.03 to 2.57) after 3 and 12 months of intervention, respectively. Data on potential adverse effects were lacking. AUTHORS' CONCLUSIONS: The scarcity of available studies and their heterogeneity makes it difficult to reach any firm conclusions. The review findings suggest supplementary feeding has a negligible impact on child growth; however, the pooled results should be interpreted with great caution because the studies included in the review are clinically diverse. Future studies should address issues of research design, including sample size calculation, to detect meaningful clinical effects and adequate intervention allocation concealment. In the meantime, families and children in need should be provided appropriate feeding, health care and sanitation without waiting for new RCTs to establish a research basis for feeding children. 

Alternative versus standard packages of antenatal care for low-risk pregnancy.

BACKGROUND: The number of visits for antenatal (prenatal) care developed without evidence of how many visits are necessary. The content of each visit also needs evaluation. OBJECTIVES: To compare the effects of antenatal care programmes with reduced visits for low-risk women with standard care. SEARCH STRATEGY: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (April 2010), reference lists of articles and contacted researchers in the field. SELECTION CRITERIA: Randomised trials comparing a reduced number of antenatal visits, with or without goal-oriented care, with standard care. DATA COLLECTION AND ANALYSIS: Two authors assessed trial quality and extracted data independently. MAIN RESULTS: We included seven trials (more than 60,000 women): four in high-income countries with individual randomisation; three in low- and middle-income countries with cluster randomisation (clinics as the unit of randomisation). The number of visits for standard care varied, with fewer visits in low- and middle- income country trials. In studies in high-income countries, women in the reduced visits groups, on average, attended between 8.2 and 12 times. In low- and middle- income country trials, many women in the reduced visits group attended on fewer than five occasions, although in these trials the content as well as the number of visits was changed, so as to be more 'goal oriented'.Perinatal mortality was increased for those randomised to reduced visits rather than standard care, and this difference was borderline for statistical significance (five trials; risk ratio (RR) 1.14; 95% confidence interval (CI) 1.00 to 1.31). In the subgroup analysis, for high-income countries the number of deaths was small (32/5108), and there was no clear difference between the groups (2 trials; RR 0.90; 95% CI 0.45 to 1.80); for low- and middle-income countries perinatal mortality was significantly higher in the reduced visits group (3 trials RR 1.15; 95% CI 1.01 to 1.32). Reduced visits were associated with a reduction in admission to neonatal intensive care that was borderline for significance (RR 0.89; 95% CI 0.79 to 1.02). There were no clear differences between the groups for the other reported clinical outcomes.Women in all settings were less satisfied with the reduced visits schedule and perceived the gap between visits as too long. Reduced visits may be associated with lower costs. AUTHORS' CONCLUSIONS: In settings with limited resources where the number of visits is already low, reduced visits programmes of antenatal care are associated with an increase in perinatal mortality compared to standard care, although admission to neonatal intensive care may be reduced. Women prefer the standard visits schedule. Where the standard number of visits is low, visits should not be reduced without close monitoring of fetal and neonatal outcome.

Effects of calcium supplementation on fetal growth in mothers with deficient calcium intake: a randomised controlled trial.

Calcium supplementation in mothers with low calcium intake has been of interest recently because of its association with optimal fetal growth and improved pre-eclampsia-related outcomes. While the effects of calcium supplementation have demonstrated benefits in prolonging gestation and subsequently improving birthweight, no specific studies have identified the longitudinal effects of supplementation on fetal growth in utero. Data were analysed in the context of the World Health Organization trial of calcium supplementation in calcium-deficient women. Five hundred and ten healthy, primiparous pregnant Argentinean women were randomised (at <20 weeks gestation) to either placebo (n = 230) or calcium supplements (1500 mg calcium/day in 3 divided doses; n = 231). Growth parameters in utero were assessed with serial ultrasound scans. Birthweight, length, head, abdominal and thigh circumferences were recorded at delivery. No differences were found in fetal biometric measurements recorded at 20, 24, 28, 32 and 36 weeks gestation between fetuses of women who were supplemented with calcium and those who were not. Similarly, neonatal characteristics and anthropometric measurements recorded at delivery were comparable in both groups. We conclude that calcium supplementation of 1500 mg calcium/day in pregnant women with low calcium intake does not appear to impact on fetal somatic or skeletal growth.

Effects of calcium supplementation on uteroplacental and fetoplacental blood flow in low-calcium-intake mothers: a randomized controlled trial.

OBJECTIVE: We postulated that calcium supplementation of calcium-deficient pregnant women would lower vascular resistance in uteroplacental and fetoplacental circulations. STUDY DESIGN: Pulsatility index (PI) and resistance index (RI) (uterine and umbilical arteries) and presence of bilateral uterine artery diastolic notching were assessed by Doppler ultrasound between 20-36 weeks' gestation in 510 healthy, nulliparous Argentinean women with deficient calcium intake in a randomized, placebo-controlled, double-blinded trial. RESULTS: Average umbilical and uterine artery RI and PI tended to be lower in the supplemented group at each study week. Differences became statistically significant for umbilical artery RI and PI from 32 and 36 weeks, respectively. Estimated probabilities of bilateral uterine artery diastolic notching trended toward lower values in calcium-supplemented women. CONCLUSION: Calcium supplementation of pregnant women with deficient calcium intake may affect uteroplacental and fetoplacental blood flow by preserving the vasodilation of normal gestation.

Blood pressure dynamics during pregnancy and spontaneous preterm birth.

OBJECTIVE: The objective of the study was to examine whether blood pressure in early pregnancy and its rise in the second half of gestation are associated with spontaneous preterm birth in healthy, normotensive, nulliparous women. STUDY DESIGN: We included 5167 women with singleton gestation who participated in the World Health Organization Calcium Supplementation for the Prevention of Preeclampsia Trial. Systolic, diastolic, and mean arterial blood pressure and pulse pressure at baseline (12-19 weeks of gestation) and at the midthird trimester (30-34 weeks) were calculated. Rise in blood pressure was the difference between the midthird trimester and baseline. Preterm birth was defined as early preterm (less than 34 completed weeks) and late preterm birth (34-36 weeks). RESULTS: Women experiencing early or late preterm birth had over 10 mm Hg and 3 mm Hg higher rise, respectively, in systolic, diastolic, and mean arterial blood pressure than women delivering at term. A rise in systolic pressure over 30 mm Hg or diastolic pressure over 15 mm Hg was associated with a statistically significant 2- to 3-fold increase in risk of spontaneous preterm birth. CONCLUSION: An excessive rise in either systolic or diastolic blood pressures from early pregnancy to the midthird trimester is associated with spontaneous preterm birth in a dose-response pattern.

Causes of stillbirths and early neonatal deaths: data from 7993 pregnancies in six developing countries.

OBJECTIVE: To report stillbirth and early neonatal mortality and to quantify the relative importance of different primary obstetric causes of perinatal mortality in 171 perinatal deaths from 7993 pregnancies that ended after 28 weeks in nulliparous women. METHODS: A review of all stillbirths and early newborn deaths reported in the WHO calcium supplementation trial for the prevention of pre-eclampsia conducted at seven WHO collaborating centres in Argentina, Egypt, India, Peru, South Africa and Viet Nam. We used the Baird-Pattinson system to assign primary obstetric causes of death and classified causes of early neonatal death using the International classification of diseases and related health problems, Tenth revision (ICD-10). FINDINGS: Stillbirth rate was 12.5 per 1000 births and early neonatal mortality rate was 9.0 per 1000 live births. Spontaneous preterm delivery and hypertensive disorders were the most common obstetric events leading to perinatal deaths (28.7% and 23.6%, respectively). Prematurity was the main cause of early neonatal deaths (62%). CONCLUSIONS: Advancements in the care of premature infants and prevention of spontaneous preterm labour and hypertensive disorders of pregnancy could lead to a substantial decrease in perinatal mortality in hospital settings in developing countries.

World Health Organization randomized trial of calcium supplementation among low calcium intake pregnant women.

OBJECTIVE: The purpose of this trial was to determine whether calcium supplementation of pregnant women with low calcium intake reduces preeclampsia and preterm delivery. STUDY DESIGN: Randomized placebo-controlled, double-blinded trial in nulliparous normotensive women from populations with dietary calcium < 600 mg/d. Women who were recruited before gestational week 20 received supplements (1.5 g calcium/d or placebo) throughout pregnancy. Primary outcomes were preeclampsia and preterm delivery; secondary outcomes focused on severe morbidity and maternal and neonatal mortality rates. RESULTS: The groups comprised 8325 women who were assigned randomly. Both groups had similar gestational ages, demographic characteristics, and blood pressure levels at entry. Compliance were both 85% and follow-up losses (calcium, 3.4%; placebo, 3.7%). Calcium supplementation was associated with a non-statistically significant small reduction in preeclampsia (4.1% vs 4.5%) that was evident by 35 weeks of gestation (1.2% vs 2.8%; P = .04). Eclampsia (risk ratio, 0.68: 95% CI, 0.48-0.97) and severe gestational hypertension (risk ratio, 0.71; 95% CI, 0.61-0.82) were significantly lower in the calcium group. Overall, there was a reduction in the severe preeclamptic complications index (risk ratio, 0.76; 95% CI, 0.66-0.89; life-table analysis, log rank test; P = .04). The severe maternal morbidity and mortality index was also reduced in the supplementation group (risk ratio, 0.80; 95% CI, 0.70-0.91). Preterm delivery (the neonatal primary outcome) and early preterm delivery tended to be reduced among women who were < or = 20 years of age (risk ratio, 0.82; 95% CI, 0.67-1.01; risk ratio, 0.64; 95% CI, 0.42-0.98, respectively). The neonatal mortality rate was lower (risk ratio, 0.70; 95% CI, 0.56-0.88) in the calcium group. CONCLUSION: A 1.5-g calcium/day supplement did not prevent preeclampsia but did reduce its severity, maternal morbidity, and neonatal mortality, albeit these were secondary outcomes.

Strategies to prevent and treat preeclampsia: evidence from randomized controlled trials.

Preeclampsia-eclampsia is a major cause of morbidity and mortality in mothers, fetuses, and neonates worldwide, most devastating in developing nations. Its cause is still uncertain, and many controversies exist concerning its management. The World Health Organization is aware of this and is coordinating a series of systematic reviews that focus on the etiology and the best strategies for the screening, prevention, and treatment of preeclampsia. This article summarizes results from systematic reviews of randomized trials to prevent and manage preeclampsia. There is a prophylactic role of modest magnitude for low-dose aspirin but the number to treat (90 women) to avoid one case of preeclampsia still is considered high. Antioxidant and calcium supplement trials remain to be completed before firm conclusions can be rendered on their efficacy for prevention. Magnesium sulfate is effective in preventing and treating eclampsia, while severe hypertension (with or without proteinuria) requires drug therapy, but there appears to be no benefits to treating mild to moderate hypertension without proteinuria in pregnancy. Finally, our review focuses on the quality of data reviewed, suggesting the need for better evidence, and discusses the use of systematic reviews as a strategy to focus future research on this important area of reproductive medicine.

Nutritional interventions during pregnancy for the prevention or treatment of maternal morbidity and preterm delivery: an overview of randomized controlled trials.

This overview assesses the effectiveness of nutritional interventions to prevent or treat maternal morbidity, mortality and preterm delivery. Cochrane systematic reviews and other up-to-date systematic reviews and individual randomized controlled trials were sought. Searches were carried out up to July 2002. Iron and folate supplements reduce anemia and should be included in antenatal care programs. Calcium supplementation to women at high risk of hypertension during pregnancy or low calcium intake reduced the incidence of both preeclampsia and hypertension. Fish oil and vitamins E and C are promising for preventing preeclampsia and preterm delivery and need further testing. Vitamin A and beta-carotene reduced maternal mortality in a large trial; ongoing trials should provide further evaluation. No specific nutrient supplementation was identified for reducing preterm delivery. Nutritional advice, magnesium, fish oil and zinc supplementation appear promising and should be tested alone or together in methodologically sound randomized controlled trials. Anema in pregnancy can be prevented and treated effectively. Considering the multifactorial etiology of the other conditions evaluated, it is unlikely that any specific nutrient on its own, blanket interventions or magic bullets will prevent or treat preeclampsia, hemorrhage, obstructed labor, infections, preterm delivery or death during pregnancy. The few promising interventions for specific outcomes should be tested or reconsidered when results of ongoing trials become available. Until then, women and their families should receive support to improve their diets as a general health rule, which is a basic human right.

Nutritional interventions during pregnancy for the prevention or treatment of impaired fetal growth: an overview of randomized controlled trials.

This paper reviews the efficacy of nutrition interventions to prevent or treat impaired fetal growth. Searches were made for Cochrane systematic reviews and randomized controlled trials published before October 2002. Balanced protein energy supplementation reduced the risk of small for gestational age (SGA) by 30% (95%CI: 20% to 43%) while one trial conducted in New York, U.S., reported a negative effect of high protein supplementation on SGA (RR 1.58; 95%CI: 1.03-2.41). Calcium supplementation protected against low birth weight (RR 0.83; 95%CI: 0.71-0.98). Micronutrient supplements did not affect birth weight, except for magnesium supplementation, which reduced the risk of SGA by 30%. This finding, however, needs or be interpreted with caution because of methodological issues in the data analysis. Programmatic recommendations can be made only for intervening with balanced protein energy supplements, especially in population with a high prevalence of undernutrition. Research is needed to determine the efficacy of multiple micronutrient supplementation and the effect of single micronutrients supplementation on specific growth outcomes such as fetal organ and bone growth. In addition, the public health relevance of these outcomes and their relation to morbidity need to be evaluated.