Maternal antenatal multiple micronutrient supplementation for long-term health benefits in children: a systematic review and meta-analysis

Follow-up reports were identified for nine of the trials in the Cochrane review. In total, 88,057 women were recruited. The trials were spread geographically: two in Africa [23, 24], one in the Americas [25], and six in Asia [26‐31]. All sites were rural, with the exception of Nepal Janakpur (urban and rural) and Guinea (semi-urban). Mean ages of mothers were similar and ranged from 21.5 (Nepal Janakpur) to 25.6 years (Indonesia). Mean maternal BMI, measured at recruitment during pregnancy, ranged from 19.3 kg/m² (Nepal Sarlahi) to 24.1 kg/m² (Mexico). Trial characteristics, with results summarized in the way in which they were presented in the trial papers, are shown in Table 1 and have been previously described in detail [20, 32].

Six of the nine trials used the UNIMMAP supplement developed by UNICEF, the United Nations University, and WHO, and were designed to provide the recommended daily allowances. It contained vitamin A 800 μg, thiamine 1.4 mg, riboflavin 1.4 mg, niacin 18 mg, vitamin B6 1.9 mg, folic acid 400 μg, vitamin B12 2.6 μg, vitamin C 70 mg, vitamin D 5 μg, vitamin E 10 mg, copper 2 mg, iodine 150 μg, iron 30 mg, selenium 65 μg, and zinc 15 mg [33]. The Bangladesh JiVitA trial used the same micronutrients as UNIMMAP in similar doses. The supplement used in Nepal Sarlahi contained micronutrients in similar doses (with 60 mg iron), plus magnesium and vitamin K, but no selenium or iodine [34]. The supplement used in Mexico included iron 62.4 mg and magnesium 252 mg, and did not include copper, iodine or selenium [25]. In some cases, a comparison group of iron 60 mg and folic acid 400 μg was not available: Nepal Sarlahi included additional vitamin A [34], Mexico did not include folic acid [25], Indonesia used 30 mg iron [29], and Bangladesh JiVitA used 27 mg iron and 600 μg folate [26]. Supplement constituents are shown in Additional file 1: Table S1. Supplementation was initiated in early to mid-pregnancy, with a range of median commencement gestation across studies of 14 weeks (Table 1).

We found 20 follow-up reports (Table 2 and Additional file 1: Figure S1). We divided the findings into five general categories: mortality [26, 27, 35‐41], anthropometry [35, 38, 39, 41‐44] and body composition [39, 44, 45], cardiovascular [39, 43, 46, 47], cognitive [37, 48‐51], and respiratory [52]. Primary publications from the Bangladesh JiVitA and MINIMat trials included follow-up mortality data and were included in the list of follow-up reports. Meta-analyses were conducted for mortality, weight, height, head circumference and blood pressure outcomes.

Follow-up reports from all trials systematically recorded and reported infant/child mortality as an outcome (Table 3). Meta-analysis showed no difference between intervention and control groups (risk difference, –0.05 per 1000 livebirths; 95 % CI, –5.25 to 5.15; I², 8 %; Fig. 1). No difference by age was seen. Subgroup analysis including trials that used only the UNIMMAP supplement showed a risk difference of 3.41 per 1000 livebirths (95 % CI, –4.45 to 11.26; I², 0 %; Additional file 1: Figure S2). Subgroup analysis for trials that used 60 mg iron in control groups yielded a risk difference of 4.51 per 1000 livebirths (95 % CI, –2.91 to 11.94; I², 0 %), and trials that used approximately 30 mg iron in the control group yielded a risk difference of 0.41 per 1000 livebirths (95 % CI, –14.76 to 15.57; I², 62 %; Additional file 1: Figure S3).

Seven reports described anthropometry (Table 4). No differences were seen in any report at the most recent follow-up for WAZ, HAZ or head circumference, nor in any secondary anthropometric outcomes. Differences were seen at younger ages in two trials. In the Burkina Faso trial, greater mean WAZ (β, 0.13; 95 % CI, 0.04 to 0.23) and length-for-age z score (β, 0.13; 95 % CI, 0.02 to 0.24) were seen in the multiple micronutrient supplement group, and a lower proportion were stunted at 1 year (hazard ratio, 0.73; 95 % CI, 0.60 to 0.87), but there was no difference at 2.5 years of age [35]. In the Nepal Janakpur trial, greater mean WAZ (β, 0.14; 95 % CI, 0.00 to 0.27) was seen in the multiple micronutrient supplement group at a mean of 2.5 years, but there was no difference at 8.5 years (β, 0.05; 95 % CI, –0.09 to 0.19). Small increases were seen in head, chest, hip, and mid-upper arm circumferences at 2.5 years, but were also not present at 8.5 years [39, 43].

Effect modification by maternal BMI or child sex was not found in any report with the exception of the Bangladesh MINIMat trial, in which stunting was greater in boys in the MMN group (Males, 7.8 %; 95 % CI, 2.0 to 13.6; Females, 1.8 %; 95 % CI, –3.8 to 7.3). A test for interaction was not reported.

Meta-analyses for WAZ and HAZ showed no difference between multiple micronutrient and 60 mg iron and folic acid groups. The differences in WAZ and HAZ were 0.02 (95 % CI, –0.03 to 0.07; I², 0 %; Fig. 2) and 0.01 (95 % CI, –0.04 to 0.06; I², 0 %; Fig. 3), respectively. Meta-analysis for head circumference was possible for three trials (Mexico, Bangladesh MINIMat and Nepal Janakpur) and showed no difference (0.11 cm; 95 % CI, –0.03 to 0.26; I², 0 %; Fig. 4). Subgroup analysis including UNIMMAP trials made little difference: WAZ 0.04 (95 % CI, –0.01 to 0.09; I², 0 %), HAZ 0.01 (95 % CI, –0.05 to 0.06; I², 0 %), and head circumference 0.11 cm (95 % CI, –0.05 to 0.26; I², 10 %; Additional file 1: Figure S2).

The Bangladesh MINIMat trial found no difference in biceps, triceps, subscapular or suprailiac skinfold thicknesses. The Nepal Janakpur trial found an increase in triceps skinfold thickness at 2.5 years (0.20 mm; 95 % CI, 0.00 to 0.40 mm) [43], but no difference was found in any skinfold thickness at 8.5 years [39]. The Nepal Sarlahi trial found no difference in triceps or subscapular skinfold thickness at 7.5 years of age. Neither the Bangladesh MINIMat nor the Nepal Janakpur trial found a difference in lean mass or fat mass measured using bio-impedance [39, 45, 53, 54].

Cardiovascular outcomes were only examined in trials from South Asia (Table 4). The Bangladesh MINIMat and Nepal Janakpur trials measured blood pressure, while the Nepal Sarlahi trial investigated metabolic syndrome (blood pressure, HbA_1c, urine microalbumin:creatinine, cholesterol, glucose, insulin, homeostasis model assessment of insulin resistance). The Nepal Janakpur cohort showed a reduction in mean systolic blood pressure of 2.5 mmHg (95 % CI, 0.47 to 4.55) at 2.5 years of age, but no difference at 8.5 years (0.02 mmHg; –1.02 to 1.05) [39, 43]. The Bangladesh MINIMat cohort showed no difference at 4.5 years compared with a control group who received iron 30 mg and folic acid [46]. The Nepal Sarlahi trial found neither a difference in blood pressure at 7.5 years, nor a difference in other cardiovascular risk markers compared with a control group who received iron 60 mg and folic acid [47]. Meta-analysis of the three trials showed no difference in blood pressure: the difference in systolic blood pressure was 0.11 mmHg (95 % CI, –0.41 to 0.63; I², 0 %), and in diastolic pressure 0.47 mmHg (95 % CI, –0.01 to 0.95; I², 0 %; Additional file 1: Figure S4). Subgroup analysis for trials that used iron 60 mg in the control group was similar: systolic blood pressure difference 0.16 mmHg (95 % CI, –0.54 to 0.87; I², 0 %), and diastolic 0.37 mmHg (95 % CI, –0.35 to 1.08; I², 0 %; Additional file 1: Figure S3).

The Bangladesh MINIMat, China, and Indonesia trials all assessed subgroups of children: in Bangladesh, children born in a 19-month period, at 7 months of age [48]; in China, in the middle year of the trial up to 1 year of age [49] and at 8.8 years [50]; and in Indonesia, in women assigned to blood tests and whose children were born in a 6-month time period, at 3.5 years of age [37]. The Nepal Sarlahi study administered cognitive, motor and executive function tests at 7–9 years of age. Mean cognitive scores were a little lower for the MMN group compared to iron, folic acid and vitamin A (Universal Nonverbal Intelligence Test score, –2.4; 95 % CI, –4.6 to –0.2). Results of motor and executive function tests were mixed [51]. The Bangladesh MINIMat and China trials found no difference in motor or psychomotor scores [48, 49]. The Indonesia trial found an increase in motor ability in an adjusted analysis expressed as a fraction of the variation of the score (0.19; 95 % CI, 0.02 to 0.37) [37]. The Bangladesh MINIMat follow-up found no difference in problem solving or behaviour [48]. In the China trial, there were no differences at 3 or 6 months, but age-adjusted scores at 1 year were higher for mental development in the MMN supplementation group (1.20 points; 95 % CI, 0.32 to 2.08: equivalent to about 6 days of age) [49]. At 8.8 years of age, there were no differences in cognitive scores compared to folic acid or to iron and folic acid groups [50]. The Indonesia trial follow-up found no difference in visuospatial and visual attention, executive functioning, language ability, or socioemotional development [37].

For completeness, we mention stratified analyses. In the Bangladesh MINIMat trial, stratification by maternal BMI, combining the early and usual food groups together, showed an increase in Psychomotor Development Index in children whose mothers had been allocated to MMN supplements and had BMI < 18.5 kg/m² (0.22 z scores; 0.01 to 0.42; interaction term, P = 0.05) [48]. In Indonesia, MMN supplementation was associated with greater motor ability (β = 0.35 z scores; 95 % CI, 0.01 to 0.69, interaction term, P = 0.04) and visual attention/spatial ability (β = 0.35; 95 % CI, 0.08 to 0.63, interaction term, P = 0.01) in children of undernourished mothers (MUAC, < 23.5 cm). These differences were equivalent to approximately 5 months of age [37].

The Nepal Janakpur trial investigated lung function at 8.5 years of age. Spirometry data were obtained from 836 children, with 793 (95 %) achieving optimal results using American Thoracic Society/European Respiratory Society guidelines [55]. No difference in lung function was found between allocation groups: forced expiratory volume in the first second, –0.01 L (95 % CI, –0.04 to 0.02 L); forced vital capacity, –0.01 L (95 % CI, –0.04 to 0.02 L) [52].

The trials had low risks of bias and were generally considered of high-quality [20]. The degree of loss to follow-up was not substantial, although in some cases only subgroups were followed up. Differential loss to follow-up between intervention and control groups did not appear to be an issue, and neither did selective publication, as most trials reported null findings. The evidence on antenatal MMN supplementation comes from a large sample and a substantial number of trials, many of which were coordinated. The trials considered here were spread geographically, although 13 of the 20 follow-up reports were from South Asia, which may have affected generalizability. Differences between the Nepal and Bangladesh reports emphasize the fact that variation can occur within similar populations.

Antenatal MMN supplementation was initially hypothesized to reduce mortality, but increases in neonatal mortality were suspected in some trials [64]. A meta-analysis did not find a difference in neonatal mortality overall, but raised concerns about increased early neonatal mortality (OR, 1.23; 95 % CI, 0.95 to 1.59). The 2015 Cochrane review found a reduction in stillbirths (0.91; 95 % CI, 0.85 to 0.98, n = 15), and no effect on perinatal (0.97; 95 % CI, 0.84 to 1.12, n = 12) or neonatal mortality (0.98; 95 % CI, 0.90 to 1.07, n = 11) [20]. The reduction in stillbirths is interesting and potentially important [65]. It depended on the analytical weighting (57 %) of the study by West et al. [26] and the use of a fixed effects model, and requires confirmation. A suggestion that MMN supplementation would prevent 43,715 annual child deaths (with 90 % coverage in 34 countries most in need) followed from the Lives Saved Tool model, based on evidence that reductions in the prevalence of SGA are associated with reduced stunting and subsequent child survival [12]. Our analyses did not identify evidence of an effect on child mortality and do not support the assumptions made in the Lives Saved Tool.

Overall, follow-up reports did not show differences in anthropometry or body composition. A transient improvement was seen in early life in the Burkina Faso and Nepal Janakpur trials, and there was a suggestion of increased stunting in Bangladesh, but these findings were not replicated in other reports. There was a consistent lack of effect on height. It is conceivable that MMN supplementation could have physiological effects that are not manifest in substantial anthropometric change. For example, transient greater weight in early childhood could have long-term benefits, even if not apparent in the short-term.

Small improvements in mental development were seen in China [49] at 1 year but not at 9 years, cognitive score was lower in Nepal Sarlahi [51], and the Bangladesh MINIMat and Indonesia trials found improvements in subgroups of mothers with poorer nutritional status only [37, 48]. Considering the number and range of tests conducted, antenatal MMN supplements did not appear to lead to a consistent cognitive benefit. When found, differences tended to be small and three of the five reports involved children under 4 years, in whom cognitive tests are less reliable than in older children. Further assessment of these cohorts is warranted.

Comparison of follow-ups did not confirm the impression of transiently lower systolic blood pressure at 2.5 years in the Nepal Janakpur trial, or of improved lung function in children seen in a similar trial of vitamin A supplementation from Nepal Sarlahi [66]. Only one trial considered other cardiovascular risk markers and found no effects.

On the basis of the reports we have reviewed, current evidence does not support changing the recommendation for routine antenatal supplementation from iron and folic acid to MMN formulations. It is possible – even probable – that the trial populations differed in their patterns of micronutrient deficiency. There was little evidence to suggest that this influenced the general findings. Although there is consistent evidence that antenatal MMN supplementation increases birth weight, none of the studies demonstrated convincingly that it benefitted offspring in terms of functional or health outcomes, and the directions and magnitudes of effect were similar for mortality and anthropometric outcomes across the study sites. The findings of the Cochrane review on which recent advocacy for routine antenatal MMN supplementation are based are supported by other meta-analyses that have shown an increase in mean birthweight of 22–54 g and corresponding reductions in low birthweight and SGA. As may be expected, the erosion over time of anthropometric differences observed at birth suggests that infants of women who received antenatal MMN supplements lost an advantage over the first few years. This could be the result of numerous environmental stresses over postnatal life. No other changes in anthropometry, gestation or mortality were found [11, 20, 22, 61‐63]. However, improvement in later health outcomes does not necessarily depend on supplementation causing an increase in birthweight (or organ size). The mechanisms of action are likely to be multifactorial and follow-up reports suggest other mechanisms such as the effect of vitamin A on regulation of fetal lung growth, branching and alveolarisation [67, 68]. We also cannot rule out effects emerging later in life or in the next generation. From an evolutionary perspective, supplementing mothers could potentially benefit the woman herself, the index baby, or future offspring. Antenatal micronutrient supplementation has a role in women with a deficiency-related illness, and possibly in micronutrient deficiency itself, but population supplementation may need to start earlier, either in the first trimester or pre-conception, to include the period of rapid organogenesis and genome-wide epigenetic changes that follow fertilization, and be continued into childhood [16, 69, 70]. The formulations of MMN tested may also not be the optimum ones. We cannot rule out the possibility that combinations other than the ones tested might have positive outcomes. It is possible that additional micronutrients, or different doses, might result in functional benefits.

The annual cost of MMN supplementation in pregnancy (at 90 % coverage) in the 34 LMICs in which it would be most useful is estimated at (International)$ 472 million [12]. If, as our review suggests, initiating antenatal MMN supplementation in early/mid-pregnancy does not lead to the anticipated improvements in childhood function or health – the main current justification for recommending it – the opportunity costs to other programmes that do lead to improvements will need to be considered.

More evidence is needed, especially on cognitive development, cardiovascular risk markers and lung function, to adequately appraise the long-term effects of antenatal MMN supplementation. We recommend follow-up studies in more of the MMN trials. Further research into biological mechanisms by which an early advantage could be attenuated will help in our understanding of the intervention and in designing future trials.

BMI, body mass index; HAZ, height-for-age z score; MMN, multiple micronutrient; SGA, small for gestational age; WAZ, weight-for-age z score; WHO, World Health Organization.