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Community and International Nutrition

Maternal Zinc Supplementation Does Not Affect Size at Birth or Pregnancy Duration in Peru^{1 ,2}

Center for Human Nutrition, Department of International Health, The Johns Hopkins School of Hygiene and Public Health, Baltimore, MD 21205 and ^* Instituto de Investigación Nutricional (IIN), Avenida La Universidad, La Molina, Lima, Peru

³To whom correspondence and reprint requests should be addressed.

	ABSTRACT

TOP ABSTRACT INTRODUCTION SUBJECTS AND METHODS RESULTS DISCUSSION REFERENCES

 
To estimate the effect of maternal zinc deficiency on pregnancy outcomes, we conducted a zinc supplementation trial in an urban shantytown in Lima, Peru, a population with habitual low zinc intakes. Beginning at 10–24 wk gestation, 1295 mothers were randomly assigned to receive prenatal supplements containing 60 mg iron and 250 (g folate, with or without 15 mg zinc. Women were followed up monthly during pregnancy. At birth, newborn weight was recorded, and crownheel length, head circumference and other circumferences and skinfold thicknesses were assessed on d 1. At delivery, 1016 remained in the study; duration of pregnancy was known for all women, and birth weight information was available for 957 newborns. No differences were noted in duration of pregnancy (39.4 ± 2.2 vs. 39.5 ± 2.0 wk) or birth weight (3267 ± 461 vs. 3300 ± 498 g) by prenatal supplement type (iron + folate + zinc vs. iron + folate; P > 0.05), and there were no differences in the rates of preterm (<37 wk) or post-term (>42 wk) delivery, low birth weight (<2500 g) or high birth weight (>4000 g). Finally, there were no differences by prenatal supplement type in newborn head circumference, crownheel length, chest circumference, mid-upper arm circumference, calf circumference or skinfold thickness at any of three sites. Adjustment for covariates and confounding factors did not alter these results. Adding zinc to prenatal iron and folate tablets did not affect duration of pregnancy or size at birth in this population.

KEY WORDS: • zinc • humans • pregnancy • birth weight • Peru

	INTRODUCTION

TOP ABSTRACT INTRODUCTION SUBJECTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Zinc is important for healthy pregnancy outcomes (Apgar 1985 , Swanson and King 1987 ). Severe maternal zinc deficiency has been associated with spontaneous abortion and congenital malformations (e.g., anencephaly), whereas milder forms of zinc deficiency have been associated with low birth weight, intrauterine growth retardation and preterm delivery (Jameson 1993 ). These associations reflect the role of zinc in cell metabolism and replication, immunocompetence, prostaglandin synthesis and function, and estrogen-dependent gene expression (Apgar 1985 , Bunce et al. 1994 , Caulfield et al. 1998 , Tamura and Goldenberg 1996 ).

Despite this biologic rationale, the results of experimental studies of maternal zinc supplementation and birth weight have been mixed (Caulfield et al. 1998 ). Of 10 supplementation trials (Cherry et al. 1989 , Garg et al. 1993 , Goldenberg et al. 1995 , Hunt et al. 1983 and 1985 , Jameson 1982 , Kynast and Saling 1986 , Mahomed et al. 1989 , Robertson et al. 1991 , Ross et al. 1985 , Simmer et al. 1991 ), the average birth weights of infants born to zinc-supplemented women ranged from 80 g below to 800 g above those in the control groups, with six of the trials reporting increases in average birth weight of 40–170 g. Most of the studies, however, suffered from methodological flaws, and the estimated differences in birth weight were not statistically significant. In the study with the greatest internal validity, Goldenberg et al. (1995) randomly assigned 580 low income African-American women with low serum zinc at entry into prenatal care to receive 25 mg/d of zinc or placebo. Infants born to zinc-supplemented women weighed 126 g more at birth, were 0.6 cm longer and had 0.4 cm greater head circumference than infants born to mothers receiving the placebo.

Because of the potential role of zinc in the timing and course of parturition, observed differences in the weights of babies born to zinc-supplemented mothers could be due to the effects of zinc supplementation on the duration of pregnancy, rather than on fetal growth per se. Of the trials presenting relevant data (Cherry et al. 1989 , Garg et al. 1993 , Goldenberg et al. 1995 , Kynast and Saling 1986 , Ross et al. 1985 ), maternal zinc supplementation lengthened the average duration of pregnancy by 0.3–1.0 wk, with three of the trials reporting a lengthening of 0.5 wk. These results indicate a consistent albeit small effect of maternal zinc supplementation on average duration of pregnancy that likely explains most or all of the increases in size at birth described previously.

To examine the effect of maternal zinc supplementation on various aspects of maternal and perinatal health, we conducted a randomized controlled trial of prenatal zinc supplementation in an urban shantytown in Lima, Peru. In these analyses, we examine whether maternal zinc supplementation influenced size at birth and duration of pregnancy.

	SUBJECTS AND METHODS

TOP ABSTRACT INTRODUCTION SUBJECTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Between 1995 and 1997, a double-blind, randomized, controlled trial of prenatal zinc supplementation to improve maternal and infant health was conducted at the Hospital Materno Infantil "Cesar Lopez Silva," in Villa El Salvador, an impoverished shantytown in Lima, Peru. In this area, pregnant women typically consume 7 mg/d of zinc of low-to-moderate bioavailability (Sacco et al. 1999 ), and have lower serum and urinary zinc concentrations during pregnancy than seen in more zinc-replete populations (Caulfield et al. 1999 ).

Women were considered eligible for the study if they were low risk (uncomplicated pregnancy and eligible for vaginal delivery), carrying a singleton fetus and living in coastal Peru for at least 6 mo before becoming pregnant. The protocol was fully explained to the women and signed consent for participation was obtained. The protocol for the study was approved by the institutional review board of the Instituto de Investigación Nutricional (IIN) and the Committee on Human Research at The Johns Hopkins School of Hygiene and Public Health.

Upon entry into prenatal care between 10 and 24 wk gestation, women were randomly assigned within parity (nullipara or multipara) and week of gestation at enrollment (<17 wk vs. 17 wk) strata, to receive a daily supplement containing 60 mg iron (as ferrous sulfate) and 250 µg folate (folic acid), with or without an additional 15 mg zinc (as zinc sulfate). The supplements all had the same brick color and shape. They were produced by a local pharmaceutical company (Instituto Quimioterápico, SA, Lima, Peru) and distributed in coded blister packages. The tablets were distributed monthly during prenatal visits with the recommendation to take one tablet every day, between meals, together with an available juice rich in ascorbic acid, lemonade or water. Neither the health personnel nor the investigators had knowledge of the coding scheme until analyses of these data were largely complete. Supplementation began at 10–24 wk gestation and continued until 4 wk postpartum.

At enrollment, duration of pregnancy was calculated on the basis of maternal reporting of date of last menstrual period (LMP), as well as by clinical indications of pregnancy duration (uterine fundal height, fetal heart tones, ultrasound), and a best estimate of gestational age at enrollment was determined. Date of LMP was available and considered reliable (within ±2 wk of physician estimate) for 87% of women; for 13% of the women, the physician estimated a date of LMP on the basis of clinical indications and maternal interview. Duration of pregnancy was calculated in completed weeks as the difference between the date of delivery and the date of LMP (reported or estimated). There were no differences in the method of calculation of duration of pregnancy by type of prenatal supplement consumed (P > 0.05).

Sociodemographic information was collected via interview at enrollment and updated after delivery. Women were followed up monthly during pregnancy or more frequently if necessary. At enrollment, 28–30 and 37–38 wk gestation, maternal anthropometric measures were taken, as well as venous blood samples to monitor concentrations of serum zinc, serum ferritin and hemoglobin. At birth, a sample of cord-vein blood was taken to determine newborn serum zinc, serum ferritin and hemoglobin concentration.

Compliance with supplementation was monitored monthly through the prenatal care distribution system and biweekly by health workers who interviewed women in their homes and observed the number of tablets remaining in each blisterpack. Brief details on compliance with supplementation are provided. A more complete analysis of the patterns of compliance with supplementation throughout pregnancy, as well as the reported benefits and side effects of supplementation, is forthcoming. Previously, we have shown that women in the zinc treatment group had higher maternal serum and urinary zinc concentrations during pregnancy, and their infants had higher cord serum zinc concentrations at birth (Caulfield et al. 1999 ). Fractional zinc absorption was measured using stable isotopes on a subsample of these women (O'Brien et al. 1997 ) and was found to be comparable to zinc absorption data reported for pregnant women in the U.S. taking iron supplements (Fung et al. 1997 ).

Infants were weighed at birth to the nearest 10 g by hospital personnel, and the scale was checked for accuracy periodically throughout the study. Crownheel length, and various circumferences (head, chest, mid-upper arm and calf) and skinfold thicknesses (biceps, subscapular and calf) were measured using standard methods (Lohman et al. 1988 ) on d 1 by one trained individual from the project team. For babies born at other hospitals (37%), date of birth, birth weight, length and head circumference were obtained from the records at the hospital of delivery. All other anthropometric indices were obtained when the baby was first brought to the study hospital; 84% of the infants were measured within 2 d after birth. For babies born at home (3%), date of birth, early neonatal weight and other anthropometric measures were obtained when the newborn was brought to the hospital; 68% of these infants were measured within 7 d after birth. There were no differences by prenatal supplement type in where deliveries took place or on what postnatal day neonatal anthropometric measures were taken. Reliability (Himes 1989 ) was assessed during training and on a sample of infants born at the study hospital; it was > 95% for the anthropometric measures, including birth weight, and similar to values reported in the literature for clinical perinatal data (Villar et al. 1989 ).

A total of 1295 women were enrolled initially in the supplementation trial. Of these women, 18 (1%) were found to live in another community and therefore not eligible to participate, 92 women (7%) declined to participate after discussing it with their husband or other family members, 71 (5%) moved out of the study area, 30 (2%) miscarried, and 58 (4%) left the study for other reasons. Further, 10 women (1%) were subsequently determined to have twin pregnancies or to have developed complications of pregnancy, and were no longer eligible for the study. Although all women received prenatal care at the study hospital, not all women delivered there. Of the 1016 women remaining in the study at delivery, 608 (60%) delivered at the study hospital, 377 (37%) delivered at other hospitals in the community or in Lima, and 31 (3%) delivered at home. Overall, duration of pregnancy was known for all 1016 women, with birth weight information available for 957 (94%) deliveries. Birth weight data were available for 602 of 608 (99%) deliveries at the study hospital, for 327 of 377 (87%) deliveries occurring at other area hospitals, and early neonatal weights were available for 28 of 31 (90%) deliveries occurring at home. Overall, information on other anthropometric indices (crownheel length, head circumference, other circumferences and skinfold thicknesses) were available for 91, 90 and 84% of the sample, respectively. Considering an -level of 0.05, and a power of 0.80, this sample size was sufficient to detect differences of 0.4 wk gestation, 85 g birth weight, and of 0.3–0.4 cm crownheel length and head circumference between treatment groups.

To assess comparability of the treatment groups, the characteristics of women in each group at enrollment were compared by t test or chi-square analysis. ANOVA techniques were then used to estimate the effects of zinc supplementation on duration of pregnancy and on neonatal anthropometric characteristics, before and after adjustment for covariates and potentially confounding factors, including methodological factors such as place of delivery, use of estimated vs. reported LMP and postnatal age at anthropometric assessment. For analyses, the skinfold thickness measures were normalized using a natural logarithm transformation. In general, statistical significance was defined as P < 0.05. To examine whether the effects of zinc supplementation on the outcomes varied depending on specific study, maternal or fetal characteristics, we also conducted subgroup analyses. In these analyses, we estimated the effect of zinc supplementation (crude and adjusted) within strata of subgroup variables including duration of time in study, maternal parity, age, body mass index (BMI) and initial serum zinc concentration, percentage of compliance and fetal sex. We also included interaction terms (e.g., zinc x primipara) in the overall regression models. No statistically significant interactions were found (P > 0.15). All data analyses were performed using Statistical Analysis System version 6.12 (SAS Institute, Cary, NC).

	RESULTS

TOP ABSTRACT INTRODUCTION SUBJECTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Selected characteristics of the 1016 participants at enrollment are presented in Table 1 . As shown, there were no differences in the presented variables between the two groups at enrollment, with the exception that the mothers receiving zinc in addition to iron and folate were significantly younger and less likely to have electricity in their homes than those receiving iron and folate alone. Adjustments were made for these differences during subsequent analyses.

View larger version (13K): [in this window] [in a new window]   Figure 1. Percentage of women still to deliver at each completed week of gestation among 1016 women who consumed daily supplements containing iron + folate or iron + folate + zinc beginning at 10 to 24 wk gestation.

View larger version (16K): [in this window] [in a new window]   Figure 2. Distributions of birth weight, crownheel length and head circumference of newborns whose mothers consumed daily supplements containing iron + folate or iron + folate + zinc throughout pregnancy, beginning at 10–24 wk gestation. Represented in the figures are data from 957 newborns for birth weight, 927 newborns for crownheel length and 918 newborns for head circumference.

	DISCUSSION

TOP ABSTRACT INTRODUCTION SUBJECTS AND METHODS RESULTS DISCUSSION REFERENCES

 
The results indicate that the addition of zinc to the prenatal supplements consumed by these women did not affect duration of pregnancy or various anthropometric indices of newborn size and body composition in this Peruvian population.

There are numerous strengths of this study that lend credence to the reported findings. First, the study was conducted in a zinc-deficient population. Usual maternal zinc intakes during pregnancy were estimated on a subsample of women in the study to be on the order of 7 mg/d (Sacco et al. 1999 ). Serum zinc concentrations in these women during pregnancy were lower in early pregnancy and declined more during pregnancy than has been described in better-off populations (Caulfield et al. 1999 ). Further, maternal urinary zinc excretion was reduced throughout pregnancy, and cord serum zinc concentrations in the newborns were lower than reference values for healthy newborns (Caulfield et al. 1999 ). Second, compliance with supplementation was high, and this level of compliance permitted women consuming zinc supplements to have higher serum and urinary zinc concentrations during pregnancy and their neonates to have higher cord zinc concentrations at birth (Caulfield et al. 1999 ). Third, the randomization of women to prenatal supplement type adequately formed equivalent treatment groups at enrollment (Table 1) , and the slight differences observed between groups at enrollment did not affect the findings. Fourth, the outcomes were measured well, and thus bias and random error in duration of pregnancy and newborn anthropometry were not likely to have obscured the findings. In fact, to have affected the results substantially, bias in the assessment of the outcome measures would have had to be substantial and differential by supplement type. Fifth, the loss to follow-up was minimal and thus selection bias was not likely a problem. Sixth, the sample size per group was adequate to detect small differences in average birth weight and duration of pregnancy, effect sizes consistent with differences in fetal growth and duration of pregnancy reported in the literature before the study. It should be added that this is the largest randomized trial completed to date investigating the effect of maternal zinc deficiency on pregnancy outcomes. Seventh, we found no evidence that the effect of zinc supplementation differed depending on maternal or fetal characteristics or methodological aspects of the study, despite using a liberal significance level to detect such interactions. Eighth, the results shown in Figures 1 and 2 indicate almost completely overlapping distributions of the outcome variables by prenatal supplement type. Thus, it is unlikely that our focus on measures of central tendency have obscured important differences between groups at specific moments of the distributions (e.g., at the lower tails).

The results of the study are consistent with the results obtained thus far from the majority of zinc supplementation trials conducted in pregnant women, suggesting no effect of maternal zinc supplementation on duration of pregnancy or size at birth. However, they are in sharp contrast to the study by Goldenberg et al. (1995) , who found substantial increases in average birth weight and head circumference of neonates born to women receiving zinc supplements during pregnancy. Average duration of pregnancy was also increased by 0.5 wk (P = 0.06) with zinc supplementation. Even after adjusting for the small positive effect of zinc supplementation on duration of pregnancy, infant birth weights were still greater in the zinc-supplemented group, suggesting an effect of maternal zinc supplementation on fetal growth per se.

How do the two studies differ? Both studies were conducted in low income populations, but the population studied by Goldenberg et al. (1995) consisted of African-American women from Alabama with average BMI of 28 kg/m2 at enrollment into the study on average at 19 wk gestation, whereas we studied Peruvian women of mestizo origin with average BMI of 24 kg/m2 at enrollment on average at 16 wk gestation. The usual zinc intakes of the Alabama women were 13 mg/d (Goldenberg et al. 1995 ) and were presumably of moderate-to-high bioavailability, whereas the usual zinc intakes of the Peruvian women were on the order of 7 mg/d and were of low-to-moderate bioavailability (Sacco et al. 1999 ). The Peruvian women had slightly higher zinc concentrations at enrollment than Alabama women (10.5 vs. 9.7 (mol/L); however, the 3-wk earlier average duration of pregnancy at enrollment in our study explains this difference. The higher BMI and higher usual zinc intakes would likely favor higher average birth weights in Alabama; however, the pregnancy outcomes in the non zinc-supplemented group in Alabama were more variable, with Alabama infants delivering >1 wk earlier on average (38.3 ± 3.5 and 39.5 ± 2.0 wk in Alabama and Peru, respectively) and weighing >200 g less on average (3088 ± 728 and 3300 ± 498 g in Alabama and Peru, respectively) than infants born in Peru. The women in Alabama received tablets containing 25 mg zinc or placebo in addition to a prenatal multivitamin/mineral supplement (i.e., two tablets), and no instructions were given regarding how to take the supplements. Although not known, the prenatal supplements taken by these women likely contained 60–120 mg iron and 250-1000 µg folate (as well as other nutrients), and presumably they were taken together. In contrast, we added 15 mg zinc to prenatal supplements containing 60 mg iron and 250 µg folate, and instructed women to take the supplement at midmorning with a vitamin C–containing drink. As discussed elsewhere (Caulfield et al. 1999 ), the responsiveness of maternal serum zinc concentration to zinc supplementation was lower among the Peruvian women in absolute terms, but was similar to that observed among Alabama women when calculated per mg/d of supplemental zinc. If the results presented by Goldenberg et al. (1995) are not due to chance, then three possible explanations for the difference in results obtained between the two studies come to mind. First, higher doses of zinc (combined with diet) may be required to affect fetal growth. Second, in addition to zinc, iron and folate, other nutrients must be provided for zinc to affect fetal growth. Third, the efficacy of zinc may be sensitive to as yet not understood factors that differ between these two populations. Finally, although the results produced by Goldenberg et al. (1995) argue against this point, it may be true that in some populations, improvements in maternal zinc nutriture must occur before pregnancy or early in pregnancy to affect these types of pregnancy outcomes.

Although maternal prenatal zinc supplementation did not lengthen duration of pregnancy or increase size at birth in this population, maternal zinc supplementation during pregnancy did improve various indices of neurobehavioral development as assessed with electronic fetal monitoring (Merialdi et al. 1999 ). At 36 wk gestation, fetuses of zinc-supplemented mothers had more variable heart rates and an increased range of fetal heart rate; they were more likely to show heart rate accelerations and less likely to show periods of low heart rate variability than fetuses of mothers who did not receive zinc. Further, fetuses of zinc-supplemented mothers showed an increased number of total movement bouts, increased fetal activity level (time spent moving), and an increased number of large movements. These differences are consistent with a positive effect of maternal zinc supplementation on fetal neurobehavioral development, according to normal developmental trends. The implications of these findings for postnatal development are currently under investigation, as are the potential benefits of maternal zinc supplementation to other obstetric outcomes and infant health. Thus, in this and similar populations, maternal zinc supplementation during pregnancy may have an important role to play in improving maternal, fetal and infant well-being, without necessarily affecting parameters of fetal growth or duration of pregnancy.

	ACKNOWLEDGMENTS

 
The authors thank Gladys Yucra, Jose Luis Delgado, and the rest of the personnel of Hospital Cesar Lopez Silva in Villa El Salvador, Lima, Peru for their cooperation and active participation in the project, as well as the Departmental Health Unit of the Ministry of Health (UDES–Lima Sur) for allowing us to work within their health care system. We would also like to express our thanks and appreciation to the mothers and babies who participated in this project.

	FOOTNOTES

 
¹ Presented in part at The International Nutrition Congress, July 27–August 1, 1997, Montreal, Canada (Caulfield, L. E., Zavaleta, N. & Lembcke, J. The effect of maternal zinc supplementation on pregnancy outcome in Peru.).

² Supported by DAN-5116-A-00–8051-00 and HRN-A-00–97-00015–00, cooperative agreements between USAID/OHN and The Johns Hopkins University.

Manuscript received January 7, 1999. Initial review completed March 3, 1999. Revision accepted May 5, 1999.

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