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Poor maternal zinc status has been associated with foetal loss, congenital malformations, intra-uterine growth retardation, reduced birth weight, prolonged labour and preterm or post-term deliveries. A meta-analysis completed in 2007 showed that maternal zinc supplementation resulted in a small but significant reduction in preterm birth. The purposes of this analysis are to update that previous review and expand the scope of assessment to include maternal, infant and child health outcomes. Electronic searches were carried out to identify peer-reviewed, randomised controlled trials where daily zinc supplementation was given for at least one trimester of pregnancy. The co-authors applied the study selection criteria, assessed trial quality and abstracted data. A total of 20 independent intervention trials involving more than 11 000 births were identified. The 20 trials took place across five continents between 1977 and 2008. Most studies assessed the zinc effect against a background of other micronutrient supplements, but five were placebo-controlled trials of zinc alone. The provided dose of supplemental zinc ranged from 5 to 50 mg/day. Only the risk of preterm birth reached statistical significance (summary relative risk 0.86 [95% confidence interval 0.75, 0.99]). There was no evidence that supplemental zinc affected any parameter of foetal growth (risk of low birth weight, birth weight, length at birth or head circumference at birth). Six of the 20 trials were graded as high quality. The evidence that maternal zinc supplementation lowers the risk of preterm birth was graded low; evidence for a positive effect on other foetal outcomes was graded as very low. The effect of zinc supplementation on preterm birth, if causal, might reflect a reduction in maternal infection, a primary cause of prematurity. While further study would be needed to explore this possibility in detail, the overall public health benefit of zinc supplementation in pregnancy appears limited.
Zinc plays an important role in many biological functions including protein synthesis, cellular division and nucleic acid metabolism.1 Although severe zinc deficiency is relatively rare in human populations, mild to moderate depletion appears to be quite prevalent. Zinc intake data suggest that the risk of deficiencies is high. Using a model that related reported zinc intakes of pregnant women to the recommended intake, Caulfield estimated that 82% of the pregnant women worldwide have inadequate zinc intakes.2
Studies in rats, mice, pigs and ewes show that severe zinc deficiency increases foetal death due to spontaneous abortions or multiple congenital anomalies.3 Every organ system is affected; malformations of the heart, lungs, brain, urogenital system and skeletal system are especially common. These malformations seem to stem from an abnormal synthesis of nucleic acids and protein, impaired cellular growth and morphogenesis, abnormal tubulin polymerisation, chromosomal defects and excessive lipid peroxidation of cellular membranes. Animal studies show that maternal zinc deficiency has long-term effects on the growth, immunity and metabolic status of the surviving offspring.4,5 For example, maternal zinc depletion reduced the offspring's immune function, a condition that persisted for three generations.6
In humans, women with acrodermatitis enteropathica, an inherited defect in zinc absorption causing severe deficiencies, have poor pregnancy outcomes; foetal losses and congenital malformations are common.7 Poor markers of maternal zinc status have been linked to poor pregnancy outcomes in women without acrodermatitis entheropathica. For example, low maternal serum or leucocytic zinc concentrations has been associated with prolonged labour, preterm labour, postpartum haemorrhage, post-term deliveries, small-for-gestational-age babies, intra-uterine growth retardation or reduced birth weight in some,3,8–10 but not all, studies.11,12 Lack of sensitive biomarkers of zinc status or the presence of other underlying nutritional problems affecting pregnancy outcomes may account for the divergent findings.
The additional zinc need for human pregnancies estimated from the zinc concentration and the weight of tissues gained is about 100 mg (1540 µmol).13 The additional daily need during the last half of pregnancy when foetal growth is most rapid is about 0.6 mg/day (9.2 µmol/day). Studies of maternal zinc intakes fail to show an increased intake during pregnancy, but the methods for assessing food intake are likely to be too imprecise to detect this small difference.3 It is unclear if homeostatic adjustments in zinc absorption or excretion occurs during pregnancy to improve zinc retention for foetal growth. In pregnant rats, zinc absorption increased almost twofold during the last 3 days of pregnancy to meet foetal needs at that stage of pregnancy.14 Similar changes have not been observed in pregnant women possibly because the relative foetal zinc demand in humans is much less than that of in rats with multiple offspring.3
Recent estimates of about 0.5 million maternal and child deaths annually due to zinc deficiency has raised the concern about the adequacy of zinc intakes among pregnant women in developing countries.15 These women frequently subsist on diets lacking zinc-rich animal source foods. Instead, cereals that are high in phytate, which limits zinc absorption, are the primary source of zinc. Maternal plasma zinc concentrations tend to be reduced slightly either because of marginal intakes or because of chronic infections that reduces plasma zinc concentrations.16 Lower plasma zinc concentrations could reduce placental zinc transport and the foetal zinc supply. Based on these observations, United Nations Childrens Fund (UNICEF) recommended the use of multiple micronutrient supplements including zinc by all pregnant women in developing countries.17 Because supplemental zinc significantly improves the weight and height gain in growing children, it was assumed that maternal zinc supplementation would improve foetal growth.
During the past 30 years, numerous randomised controlled trials of zinc supplementation have been performed. In 2007, a systematic review and meta-analysis of 17 of these trials was published.18 This analysis updates that previous review and expands the scope of assessment to include maternal, infant and child health outcomes.
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Our findings of the effects of zinc supplementation for improving pregnancy and infant outcomes agrees with those published by Mahomed and co-workers in 2007.18 Although we draw conclusions from a larger and not entirely overlapping set of trials, the overall impression regarding the effect of supplemental zinc was unchanged. Using data from 16 trials including 7818 births (963 preterm), we estimated a reduction in the risk of a preterm birth with zinc supplementation (sRR 0.86 [95% CI 0.75, 0.99]). We found no effect, however, on mean gestational age. This may be because there were fewer studies of gestational age than of preterm birth (12 vs. 16 trials), and the measurement errors for determining gestational age may be greater than that classifying the birth as preterm. Several different methods can be used to assess gestational age and most require considerable judgement by the evaluator.91 Whereas classifying a birth as preterm is a binary decision that is easier to make, especially if the infant is very preterm. We found no evidence that the effect on preterm birth was affected by zinc dose. One group79 studied the effect of supplemental zinc (50 mg/day) on the risk of preterm birth in a cohort of women who had a previous preterm delivery. There was a suggestion that supplemental zinc reduced prematurity in this high-risk group, but the sample size (42 women/group) was relatively small.
The steady increase in the incidence of preterm birth during the past decade is troubling. Infants born preterm are at greater risk for mortality and a variety of health and developmental problems.91 Thus, if reflective of a true causal effect, a 14% reduction in preterm birth with zinc supplementation, as estimated from these trials, would be of major public health importance. Several plausible explanations for the positive effect of zinc on preterm births exist. Zinc deficiency alters circulating levels of a number of hormones associated with the onset of labour. For example, lower levels of serum progesterone and prolactin concentrations in zinc-deficient ewes was associated with preterm deliveries.92 Also, systemic and intra-uterine infections are a major cause of preterm birth.91 Zinc is essential for normal immune function.1 Zinc supplementation may reduce the incidence or the severity of maternal infections that, in turn, lower the risk of preterm birth. It has been reported that iron supplementation interferes with zinc absorption in pregnancy.1,45 However, we did not observe substantial differences when the analysis was restricted only to those trials providing supplemental zinc alone vs. only those that provided zinc along with iron and other micronutrients (Figures 10–12).
In concordance with previously reported findings,18 zinc supplementation did not appear to significantly improve birth weight, birth length or head circumference (Table 1). The overall mean difference in birth weight slightly favoured the intervention; however, this estimate was relatively sensitive to the inclusion of one or two particular study results, which likely influenced the differences observed in subgroup analysis (Figure 11). Despite the imprecision surrounding this summary estimate, it is unlikely that additional trials would be sufficient to shift the balance in favour of a clinically and statistically significant effect of zinc on foetal growth. Many investigators have found a relationship between maternal zinc status and birth weight in observational studies.3,8–10 The inability to show a consistent growth effect in intervention trials could be related to the challenges, such as participant compliance, inherent in improving zinc status in field settings. Nonetheless, there was no indication of a stronger effect when summary results excluded those trials that failed to demonstrate an improvement in maternal serum zinc concentrations (Figures 10–12). Alternatively, supplementation might only be effective among those suffering from zinc deficiency, and therefore, population-level effects might not capture improvements among this subgroup. While data were not available to examine this possibility directly, we did not observe stronger effects in low- and middle-income countries, where zinc deficiency is likely to be common.2
The technique of meta-analysis has been the subject of criticism,93 particularly when summary estimates are considered without a detailed exploration of sources of heterogeneity. These concerns are valid, and we agree that meta-analysis is problematic if intentioned to precisely estimate causal effects. Because of heterogeneity in study designs, study populations and the context of the interventions, CI derived from meta-analysis are artificially narrow. That said, meta-analysis is an extremely useful tool for summarising the results of existing intervention trials in a systematic and objective way, with strengths that outnumber weaknesses.94 While the precision of our numeric estimates may be overstated, we believe that the general impression of our findings – that previous trials have shown little to no impact of maternal zinc supplementation on foetal growth but have suggested a modest reduction in the risk of preterm birth that cannot yet be confirmed – is not driven by inherent bias in our quantitative methods.
Meta-analysis, or any standard literature review for that matter, is necessarily limited to the published evidence. Therefore, any tendency of investigators or journals to selectively publish statistically significant positive results could yield a bias when findings are taken in aggregate. While this type of bias has been well described,95 we did not observe an overwhelming trend towards positive results with decreasing statistical precision of individual trial findings (Web Supplement 3). We did detect a stronger zinc effect when pooling studies graded as low quality vs. those graded as high quality (Figures 10–12). Because the quality grades are subjective, firm conclusions cannot be drawn. Yet, this suggests possible preferential publication of methodologically weaker studies with positive results. Again, despite the prospect of bias in quantitative estimates, our general conclusions were not swayed towards remarkably positive findings.
The results of our meta-analysis and that of Mahomed and co-workers18 suggest that prenatal zinc supplementation does not effect foetal growth. One group measured foetal bone growth by ultrasound during gestation.96 Of the four measurements made, only femur diaphysis length was greater in foetuses of mothers receiving supplemental zinc. However, this outcome differs from the effects of supplemental zinc on growth in pre-pubertal children. A meta-analysis of 33 studies showed a highly significant positive effect on both height and weight increments with greater responses seen in children with low weight-for-age or height-for-age z scores.97 These findings suggest that the impact of zinc, per se, on growth in utero is less than that in a young child. It is unclear why this difference exists. Possibly, zinc is prioritised towards developing the immune system and other organs or tissue functions during the in utero period instead of skeletal growth. Or, maybe the effect of maternal nutrition on the foetal growth trajectory is established before conception or early in pregnancy prior to the usual initiation of zinc supplementation. These findings suggest, however, that stunting is more likely to be improved by providing zinc supplements to the child rather than to the mother during pregnancy.98
The small effects of supplemental zinc on pregnancy outcomes suggest a need to compare the effects of delivering nutrients through supplements vs. other methods, such as food. Early studies showed that improving the quality, or nutrient density, of the mother's diet dramatically improved pregnancy outcomes.99–101 The use of prenatal multiple micronutrient supplements became common in the 1960s to prevent iron deficiency. A recent systematic review found that multiple micronutrient supplements did not reduce maternal anaemia or infant mortality when compared with iron-folate supplementation alone, but did report a statistically significant 9% reduction in the risk of small-for-gestational age births when pooling data across 14 studies in developing countries.102 The relative impacts of supplements vs. food on pregnancy outcomes merits further attention.
Strong evidence exists that zinc supplements improve the prognosis of children being treated for diarrhoea.98 Of the studies we reviewed, three trials reported a trend towards a decreased incidence of diarrhoea between 6 and 13 months of age with prenatal supplemental zinc.46,80,81 The effect on acute diarrhoea was stronger than that for episodes of persistent diarrhoea. Possibly, prenatal zinc supplementation improved the infant's immune function, which would be consistent with our hypothesis that maternal zinc supplement is prioritised towards the development of immunity rather than growth in the foetus. Previous research suggests that development of the fetal nervous system in utero is influenced by maternal zinc status. For example, the offspring of rhesus monkeys deprived of zinc during the third trimester were not as active and they explored less than control infants.16 Morphological examinations showed that the structure and migration of neuronal cell types were altered in these offspring. In a study of Egyptian women, Kirskey and co-workers noted a positive association between maternal zinc status and newborn behaviour.103 However, prenatal zinc supplementation had no effect in neurocognitive development in Bangladeshi infants at 13 months of age, US children at 5 years of age or Peruvian children at 4.5 years of age.52,59,77 Neurocognitive development was evaluated in three trials reviewed by us.52,59,61 The three groups measured different end-points at different time points and reported three different findings. One group found that the mental and psychomotor development was worse in the zinc group compared with the controls at 13 months of age.52 Another reported an improvement in foetal neurobehaviour as measured by foetal heart rate,61 and the third group found no effects on differential abilities, visual or auditory sequential memory scores, gross motor scale and grooved pegboard scores in the children at 5 years of age.59
Of the 20 studies we evaluated, five groups measured postnatal outcomes – Bangladesh,50,52 Indonesia,60 Nepal,69 Peru70,80 and the US.59 Postnatal growth was evaluated more than any other outcome. Recent discoveries show that the interaction between our genes and their environment in utero has health long-term effects. This phenomenon is called developmental programming. Given the role of zinc in regulating DNA synthesis and gene expression, the foetal zinc environment likely influences the developmental programming of that individual. Some evidence for this association exists. Over 30 years ago, Beach and co-workers showed that maternal zinc deficiency adversely affected immune function in the offspring, which persisted for the next three generations.6 Also, Jou and co-workers recently reported that the offspring of pregnant rats fed diets marginally low in zinc gained excessive weight postnatally and had impaired insulin sensitivity.5 These epigenetic changes are thought to be due to shifts in DNA and histone methylation. It has been known since 1985 that zinc deficiency decreases methylation of those nuclear components.104 In the future, longer-term studies are needed to assess the impact of prenatal zinc supplementation on the health of the child. Neuro-cognitive and immunological function should be assessed in addition to growth.
Given the logistical and financial barriers in completing long-term follow-up of intervention trial participants, it is not surprising that less evidence is available on the impact of maternal zinc supplementation on child health than on foetal growth and preterm birth. The suggestion of a reduction in diarrhoea occurrence among infants merits further attention, although from the trials examining impacts on childhood growth, cognitive development and respiratory illness, little evidence of a benefit has emerged (Figure 2). Future work may be directed towards further assessment of functional outcomes that become apparent during childhood or later in life.
In aggregate, results published to date suggest no harm but uncertain benefits with maternal zinc supplementation in pregnancy. While an imperfect global estimator of causal effects, meta-analysis provides a quantitative summary that is unlikely to obscure a strong benefit merely through bias in our quantitative methods. The specifics of the population and implementation protocol should always be considered when anticipating the impacts, although we did not detect striking patterns when considering subgroups of studies separated by national income, dose of zinc provided or the simultaneous provision of other micronutrients. The suggestion that maternal zinc supplementation might reduce the occurrence of preterm birth or the frequency of diarrhoea in childhood is notable and encouraging, as even small reductions in these events would be significant public health achievements. The decisions to undertake further research or to initiate zinc-based interventions, however, must be made within the context of costs, feasibility and the presence of other potential interventions that might offer a greater probability of success. With much to be learned about the mechanism of action and possible lingering effects into childhood, further studies of maternal zinc supplementation might provide new insight. Yet, balanced with considerable evidence of no improvement in foetal growth, it appears unlikely that zinc supplementation in pregnancy will play a leading role in future advances in maternal and child health.