![[Feedback]](/icons/banner/feedbackACT.gif){kind=icon}
![[For Subscribers]](/icons/banner/subscriberACT.gif){kind=icon}
![[Archive]](/icons/banner/archiveACT.gif){kind=icon}
![[Search]](/icons/banner/searchACT.gif){kind=icon}
![[Contents]](/icons/banner/tocACT.gif){kind=icon}
|
|
|
|
|
||
Institute of Nutrition and Food Technology, Universidad de Chile, Macul 5540, Santiago, Chile
2 To whom correspondence should be addressed. E-mail: ccastd{at}uec.inta.uchile.cl.
 |
ABSTRACT |
|---|
 TOP ABSTRACT LITERATURE CITED |
|---|
KEY WORDS: • zinc • pregnancy • outcome • low birth weight
Zinc deficiency during pregnancy may affect normal embryonic and fetal growth in experimental animals, and the length of gestation may also be affected. However, in humans, the results are controversial, possibly because it is difficult to control the many confounding variables in the studies. Significant effects of zinc supplementation on birth weight or pregnancy duration are found only in some studies, whereas most investigations show no effects. The objective of this review is to discuss the effects of zinc supplementation studies during pregnancy on pregnancy outcome both in experimental animals and humans. We also review the evidence for the effects of maternal zinc supplementation during pregnancy on fetal growth and for other effects during the first months of postnatal life.
Zinc deficiency during pregnancy in experimental animals: effects on fetal growth
During the last four decades, multiple studies were performed on experimental animals to demonstrate the effects of zinc deficiency on fetal growth; mainly birth weight was evaluated as the primary outcome (1– 12) (Table 1). These studies in rodents, guinea pigs, ewes and nonhuman primates demonstrate a consistent effect of severe zinc deficiency on weight at birth (1– 3, 7, 8, 10). The effect is less consistent with marginal zinc deficiency: several studies identify no effect on birth weight and a few studies show significantly decreased birth weight (4– 6, 9, 11, 12). The role of timing of zinc deficiency during pregnancy was also studied and reveals a greater effect if zinc deficiency is induced from conception onward (5, 8– 10). In one study, a significant effect of marginal zinc deficiency on male but not female infant birth weight in rhesus monkeys is reported (6), whereas in two other studies, no effects on pregnancy outcome are found (9, 11, 13).
|
Several studies in humans analyze the effects of zinc supplementation on pregnancy outcome in different communities in both developed and developing countries (14– 27) (Table 2). The apparent risk of zinc deficiency in such communities is not evaluated in many of these studies, although there may be epidemiological evidence of zinc deficiency along with many other nutrient deficiencies. These studies include underserved communities in the U.S. and the U.K., vulnerable groups in Chile and South Africa and very low-socioeconomic status groups in India, Peru, Bangladesh and Indonesia.
|
Most of these studies analyze the effects of zinc as the only supplement, but this approach does not account for nutrient interactions, and addition of a single nutrient may not be sufficient to improve pregnancy outcome in communities where many nutrient deficiencies (e.g., energy and protein, folic acid, vitamin A, calcium) can also affect the outcome (28). Of the 14 studies listed in Table 2, the effects of zinc as a single supplement are analyzed in 9 studies (16– 21, 23– 26), whereas four of the studies include other nutrients such as vitamin A, folate and iron (14, 15, 22, 27).
If we separate the studies according to socioeconomic level of subjects—those performed in low-socioeconomic groups in countries where there is low prevalence of undernutrition (17, 18, 23), those in transitional communities where conditions are improving yet large segments of the population consume diets low in flesh foods (14, 15, 19, 20, 22, 26) and those performed in very poor communities with a high risk of severe zinc deficiency in conjunction with multiple deficiencies (16, 21, 24, 25, 27)—we find that the positive effect of zinc supplementation on birth weight can be observed in some studies of the second group. How can we interpret these findings? The reason could be that the positive effect can be found only when there is an isolated zinc deficit; however, when multiple deficits exist, no benefit from zinc supplementation is found.
Zinc supplementation: effects in humans during pregnancy and postnatally
Few studies analyze the postnatal effects of maternal zinc supplementation on infant growth and infectious morbidity. Osendarp et al. (29), in a field study within poor Bangladeshi communities, analyzed the effects of supplementing with 30 mg of zinc/d, starting from 12 to 16 wk of gestation, on growth and morbidity of infants in the first 6 mo of life. The overall low rate of exclusive breastfeeding was 13% at 6 mo of age owing to cultural practices of the mothers. No differences in weight gain (zinc supplemented, 0.58 ± 0.13 kg/mo versus placebo, 0.59 ± 0.13 kg/mo) or length gain (zinc supplemented, 2.5 ± 0.3 cm/mo; placebo, 2.6 ± 0.4 cm/mo) are found between infants of zinc-supplemented mothers and those who received a placebo. Yet a significant effect of maternal zinc supplementation is observed with a reduced risk of acute diarrhea [relative risk (RR), 0.84; 95% confidence interval (CI), 0.72–0.98], dysentery (RR, 0.36; 95% CI, 0.25–0.84) and impetigo (RR, 0.53; 95% CI, 0.34–0.82). Analysis of these outcomes by gestational age and birth weight reveals that the favorable effect is found only in those infants born with low birth weight and those born small for gestational age at term. No significant effects were found in preterm low birth weight infants or those with normal birth weights. This illustrates that effects on the infant can occur even if no effects on fetal growth are apparent.
Zinc supplementation studies in low birth weight infants: effects on growth
Only a few studies analyze the effects of zinc supplementation during the first months of life on growth of infants born prematurely or small for their gestational age. A study by Friel et al. in 1993 (30) on Canadian low birth weight infants (mean gestational age, 29 wk) started at discharge from the hospital (mean, 1 mo of corrected age) and continued until 12 mo of age. The study compares a zinc intake of 2.2 mg of zinc·kg-1·d-1 (supplemented) with 1.1 mg of placebo·kg-1·d-1 (placebo). The report indicates a small but significantly greater height–gain z-score over the study period (supplemented, +0.087 ± 0.087; placebo, -0.027 ± 0.13; P < 0.004); the effect is more significant in girls. Our study, (30), which was performed on Chilean term infants that were born small for gestational age (mean birth weight, 2,300 g; mean length at birth, 47 cm) and were randomly assigned to a 3 mg of zinc/d test group (mean total zinc intake, 1.5–1.8 mg of zinc·kg-1·d-1 at the first stages) or to a placebo group (mean zinc intake, 
0.7 mg of zinc·kg-1·d-1) for 6 mo demonstrates improved growth. Significantly greater weight-for-age and length-for-age z-score gains are found in the supplemented group: the mean weight z-score went from -2 to -0.5, whereas in the placebo group it went from -2 to -1.0. The length-for-age effect is also significant but only in girls. This effect is evident in those who receive whole cow's milk but not those who are breastfed.
A third study by Lira et al. (32) on low birth weight full-term infants in northeast Brazil fails to demonstrate an effect on growth of 1 or 5 mg of zinc/d supplementation during the first 26 wk of life, although an effect is found on weight gain with 5 mg of zinc/d between 17 and 26 wk.
In an interesting field study performed on Indian infants who were born small for their gestational ages, Sazawal et al. (33) found that zinc supplementation during the first months of life decreases the risk of death due to acute diarrhea. A similar protective effect is found if exclusive breastfeeding is present. The studies by Sazawal in India (33), by Castillo-Durán in Chile (31) and by Osendarp in Bangladesh (29) show an apparent greater risk of zinc deficiency in infants born small for gestational age that is associated with effects on growth (29, 31, 33) and risk of acute infectious disease (29, 33). This risk is apparently more evident than that observed in infants born preterm but of normal fetal growth (29).
In summary, the effects of severe zinc deficiency on decreased fetal growth in experimental animals (mainly rats) is well demonstrated, whereas the effects of marginal or moderate zinc deficiency are less consistent. Several studies on humans demonstrate an effect of zinc supplementation on birth weight and duration of pregnancy; however, other studies do not reveal such an effect. The main confounding variables that may explain the difference in effects are the risk of associated nutritional deficits in addition to zinc deficiency and the stage of pregnancy when supplementation is started. Unfortunately, the multiple differences between the studies in terms of design and the difficulty of controlling for confounders limit the interpretation of aggregate data. The time has come to go beyond meta-analysis into meta-planning of multisite studies where, based on a common protocol, the data can be collected and then compiled for a meta-regression analysis of main outcomes that include relevant covariates and confounders assessed in the various studies. This approach requires concerted efforts of researchers, funding agencies and data managers before studies are initiated.
|
FOOTNOTES |
|---|
|
LITERATURE CITED |
|---|
|
TOPABSTRACTLITERATURE CITED |
|---|
1. Apgar, J. (1972) Effects of zinc deficiency deprivation from day 12, 15, or 18 of gestation on parturition in the rat. J. Nutr. 102: 343–348.
2. MCKenzie, J., Fosmire, C. & Sandstead, H. (1975) Zinc deficiency during the latter third of pregnancy: effects on fetal rat brain, liver and placenta. J. Nutr. 105: 1466–1475.
3. Apgar, J. (1977) Effects of zinc deficiency and zinc repletion during pregnancy on parturition in two strains of rats. J. Nutr. 107: 1399–1403.
4. Beach, R. S., Gershwin, M. E. & Hurley, L. S. (1982) Reversibility of development retardation following murine fetal deprivation. J. Nutr. 112: 1169–1181.
5. Fairweather, S. & Payne, V. (1984) The effect of iron supplements on pregnancy in rats given a low zinc diet. Br. J. Nutr. 52: 79–86.[Medline]
6. Golub, M. S., Gershwin, M. E., Hurley, L. S., Baly, D. L. & Hendrickx, A. G. (1984) Studies of marginal zinc deprivation in rhesus monkeys. II. Pregnancy outcome. Am. J. Clin. Nutr. 39: 879–887.
7. Apgar, J. & Fitzgerald, J. A. (1985) Effect on the ewe and lamb of low zinc intake throughout pregnancy. J. Anim. Sci. 60: 1530–1538.
8. Fuller, N., Evans, P., Howlett, M. & Bates, C. (1988) The effects of dietary folate and zinc on the outcome of pregnancy and early growth in rats. Br. J. Nutr. 59: 251–259.[Medline]
9. Keen, C. L., Lönnerdal, B., Golub, M. S., Uriu-Hare, J. Y., Olin, K. L., Hendrickx, A. G. & Gershwin, M. E. (1989) Influence of marginal maternal zinc deficiency on pregnancy outcome and infant zinc status in rhesus monkeys. Pediatr. Res. 26: 470–477.[Medline]
10. Apgar, J. & Everett, G. (1991) Low zinc intake affects maintenance of pregnancy in guinea pigs. J. Nutr. 121: 192–200.
11. Keen, C. L., Lönnerdal, B., Golub, M. S., Olin, K. L., Graham, T. W., Uriu-Hare, J. Y., Hendrickx, A. G. & Gershwin, M. E. (1993) Effect of the severity of maternal zinc deficiency on pregnancy outcome and infant zinc status in rhesus monkeys. Pediatr. Res. 33: 233–241.[Medline]
12. Southon, S. & Fairweather, S. (1998) Fetal growth, glucose tolerance and plasma insulin concentration in rats given a marginal zinc diet in the latter stages of pregnancy. Br. J. Nutr. 59: 315–322.
13. Lowe N. M., Woodhouse L. R., Wee J., King J. C. (1999) Short-term zinc kinetics in pregnant rats fed marginal zinc diets. J. Nutr. 129: 1020–1025.
14. Hunt, I. F., Murphy, N. J., Cleaver, A. E., Faraji, B., Swenseid, M. E., Coulson, A. H., Clark, V. A., Bowdy, B. L., Cabalum, M. T. & Cecil Smith, J. (1985) Zinc supplementation during pregnancy: effects on selected constituents and progress and outcome of pregnancy in low-income women of Mexican descent. Am. J. Clin. Nutr. 42: 815–828.
15. Hunt, I. F., Murphy, N. J., Cleaver, A. E., Faraji, B., Swenseid, M. E., Browdy, B. L., Coulson, A. H., Clark, V. A., Settlage, R. H. & Cecil Smith, J. (1985) Zinc supplementation during pregnancy in low income teenagers of Mexican descent: effects on selected blood constituents and on progress and outcome of pregnancy. Am. J. Clin. Nutr. 42: 815–828.
16. Ross, S. M., Nel, E. & Naeye, R. L. (1985) Differing effects of low and high bulk maternal dietary supplements during pregnancy. Early Hum. Dev. 10: 295–302.[Medline]
17. Kynast, G. & Saling, E. (1986) Effect of oral zinc application during pregnancy. Gynecol. Obstet. Invest. 21: 117–123.[Medline]
18. Mahomed, K., James, D. K., Golding, J. & MCCabe, R. (1989) Zinc supplementation during pregnancy: a double blind randomized controlled trial. BMJ 299: 826–830.
19. Cherry, F. F., Sandstead, H. H., Rojas, P., Johnson, L. A. K., Batson, H. K. & Wang, X. B. (1989) Adolescent pregnancy: associations among body weight, zinc nutriture and pregnancy outcome. Am. J. Clin. Nutr. 50: 945–954.
20. Simmer, K., Lort-Phillips, L., James, C. & Thompson, R. P. H. (1991) A double-blind trial of zinc supplementation in pregnancy. Eur. J. Clin. Nutr. 45: 139–144.
21. Garg, H. K., Singhal, K. C. & Arshad, Z. (1993) A study of the effect of oral zinc supplementation during pregnancy on pregnancy outcome. Indian J. Physiol. Pharmacol. 37: 276–284.[Medline]
22. Goldenberg, R. L., Tamura, T., Neggers, Y., Copper, R. L., Johnston, K. E., DuBard, M. B. & Hauth, J. C. (1995) The effect of zinc supplementation on pregnancy outcome. J. Am. Med. Assoc. 274: 463–468.[Abstract]
23. Jonsson, B., Hauge, B., Larsen, M. F. & Hald, F. (1996) Zinc supplementation during pregnancy: a double blind randomized controlled trial. Acta Obstet. Gynecol. Scand. 75: 725–729.[Medline]
24. Caulfield, L. E., Zavaleta, N., Figueroa, A. & Leon, Z. (1999) Maternal zinc supplementation does not affect size at birth or pregnancy duration in Peru. J. Nutr. 129: 1563–1568.
25. Osendarp, S. J. M., van Raaij, J. M. A., Arifeen, S. E., Wahed, M. A., Baqui, A. H. & Fuchs, G. J. (2000) A randomized, placebo-controlled trial of the effect of zinc supplementation during pregnancy on pregnancy outcome in Bangladeshi urban poor. Am. J. Clin. Nutr. 71: 114–119.
26. Castillo-Durán, C., Marín, V. B., Alcázar, L. S., Iturralde, H. & Ruz, M. (2001) Controlled trial of zinc supplementation in Chilean pregnant adolescents. Nutr. Res. 21: 715–724.
27. Dijkhuizen, M. A. & Wieringa, F. T. (2001) Vitamin A, iron and zinc deficiency in Indonesia. Micronutrient interactions and effects of supplementation. PhD thesis, Wageningen University, The Netherlands.
28. Ramakrishnan, U., Manrekar, R., Rivera, J., Gonzáles-Cossio, T. & Martorell, R. (1999) Micronutrients and pregnancy outcome. A review of the literature. Nutr. Res. 19: 103–159.
29. Osendarp, S. J. M., van Raaij, J. M. A., Darmstadt, G. L., Baqui, A. H., Hautvast, J. G. A. J. & Fuchs, G. J. (2001) Zinc supplementation during pregnancy and effects on growth and morbidity in low birthweight infants: a randomized placebo controlled trial. Lancet 357: 1080–1085.[Medline]
30. Friel, J. K., Andrews, W. L., Matthew, J. D., Long, D. R., Cornel, A. M., Cox, M., McKim, E. & Zerbe, G. O. (1993) Zinc supplementation in very-low-birth-weight infants. J. Pediatr. Gastroenterol. Nutr. 17: 97–104.[Medline]
31. Castillo-Durán, C., Rodríguez, A., Venegas, G. V., Alvarez, P. & Icaza, P. (1995) Zinc supplementation and growth of infants born small-for-gestational age. J. Pediatr. 127: 206–211.[Medline]
32. Lira, P. I., Ashworth, A. & Morris, S. S. (1998) Effect of zinc supplementation on the morbidity, immune function, and growth of low-birth-weight, full term infants in northeast Brazil. Am. J. Clin. Nutr. 68(suppl. 2): 418S–423S.[Abstract]
33. Sazawal, S., Black, R. E., Menon, V. P., Dinghra, P., Caulfield, L. E., Dhingera, U. & Bagati, A. (2001) Zinc supplementation in infants born small for gestational age reduces mortality: a prospective, randomized, controlled trial. Pediatrics 108: 1280–1286.
This article has been cited by other articles:
|
|
 |
|
  S. Premji, T. Fenton, and R. Sauve Does Amount of Protein in Formula Matter for Low-Birthweight Infants? A Cochrane Systematic Review JPEN J Parenter Enteral Nutr, November 1, 2006; 30(6): 507 - 514. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. B. Andree, J. Kim, C. P. Kirschke, J. P. Gregg, H. Paik, H. Joung, L. Woodhouse, J. C. King, and L. Huang Investigation of Lymphocyte Gene Expression for Use as Biomarkers for Zinc Status in Humans J. Nutr., July 1, 2004; 134(7): 1716 - 1723. [Abstract] [Full Text]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
