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ORIGINAL RESEARCH |
From the Departments of Pediatrics, Obstetrics and Gynecology, and Preventive Medicine, University of Tennessee, Memphis, Memphis, Tennessee; EMMES Corporation, Potomac, Maryland; and the Division of Epidemiology, Statistics, and Prevention Research, National Institute of Child Health and Human Development, Bethesda, Maryland.
Address reprint requests to: Winston W. K. Koo, MBBS, FRACP Department of Pediatrics Hutzel Hospital 4707 Saint Antoine Boulevard Detroit, MI 48201 E-mail: wkoo{at}wayne.edu
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Abstract |
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Methods: Healthy mothers with early ultrasound confirmation of dates and singleton pregnancies were enrolled in a double-masked study and randomized before 22 weeks’ gestation to 2 g/day of elemental calcium or placebo until delivery. Maternal dietary intake at randomization and at 32–33 weeks’ gestation was recorded with 24-hour dietary recalls. Dual-energy x-ray absorptiometry measurements of the whole body and lumbar spine of the neonates were performed before hospital discharge.
Results: The infants of 256 women (128 per group) had dual-energy x-ray absorptiometry measurements during the first week of life. There were no significant differences between treatment groups in gestational age, birth weight, or length of the infants, or in the total-body or lumbar spine bone mineral content. However, when bone mineral content was analyzed by treatment group within quintiles of maternal dietary calcium intake, total body bone mineral content (mean ± standard error of the mean) was significantly greater in infants born to calcium-supplemented mothers (64.1 ± 3.2 versus 55.7 ± 2.7 g in the placebo group) in the lowest quintile of dietary calcium intake (less than 600 mg/day). The effect of calcium supplementation remained significant after adjustment for maternal age and maternal body mass index and after normalization for skeletal area and body length of the infant.
Conclusion: Maternal calcium supplementation of up to 2 g/day during the second and third trimesters can increase fetal bone mineralization in women with low dietary calcium intake. However, calcium supplementation in pregnant women with adequate dietary calcium intake is unlikely to result in major improvement in fetal bone mineralization.
Pregnancy is a time of physiologic stress on calcium homeostasis because of the increased demands of the developing fetus and associated maternal tissues. Animal studies have shown that the fetal skeleton is affected by low1 and high2,3 maternal calcium intake. In humans, the effect of maternal calcium intake on the fetal skeleton has not been well defined. Most reports have been of populations with restricted access to food, possibly resulting in concomitant deficiencies of calcium and other nutrients. Frequently, data on dietary intake have been limited. Some studies have examined the effects of supplementation not just with calcium, but also with multiple nutrients including minerals, trace metals, and vitamins, with and without fortification with protein or energy.4–8 There has been no systematic investigation of the effect of maternal calcium intake on the fetal skeleton among women in developed countries where food is plentiful, yet calcium intake is low.9,10 This study was done to test the hypothesis that maternal calcium supplementation during pregnancy will increase mineralization of the fetal skeleton as indicated by changes in dual-energy x-ray absorptiometry measurements.
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Each woman was advised to drink at least six glasses of fluid per day and was instructed not to take analgesics, antacids, or vitamins other than vitamin B6 or iron prescribed by a health care provider. Acetaminophen tablets (Tylenol; McNeil Consumer Products Company, Fort Washington, PA) and a noncalcium antacid (Mylanta; Johnson & Johnson-Merck, Fort Washington, PA) were dispensed as needed. Each woman was given a daily commercial prenatal supplement of 400 IU vitamin D2 and 50 mg elemental calcium in addition to iron, 4000 USP vitamin A, and water-soluble vitamins (Mission Prenatal; Mission Pharmacal Company, San Antonio, TX). A certified dietitian or research nurse conducted a 24-hour recall of dietary intake of each woman at randomization and at 32–33 weeks’ gestation to assess nutrient intake. Nutrient content of the diet was determined from an extensive nutrient database at Tufts University.
Two hundred eighty-nine women in the Memphis component of the Calcium for Preeclampsia Prevention trial were approached for participation in the study of fetal bone mineralization. Thirteen refused consent (six in the treatment group and seven in the placebo group). Dual-energy x-ray absorptiometry scans were not done on eight infants because of one fetal death, one postnatal death from complications of prematurity, unavailability of the dual-energy x-ray absorptiometry instrument for two infants, and technical problems associated with the scans of three infants. One infant was discharged before the scan because of inclement weather. Dual-energy x-ray absorptiometry measurements were delayed beyond the first week after birth for six infants from each group because of illnesses. Four of the six from each group had illnesses associated with prematurity. Dual-energy x-ray absorptiometry measurements within the first week after birth were performed in 256 infants, 128 in each group. The 256 women whose infants were included in the study were older (19.6 ± 0.2 versus 17.3 ± 0.6 years; mean ± standard error of the mean [SEM]), had greater body mass index (BMI) (26.1 ± 0.4 versus 23.2 ± 0.6 kg/m2), and had lower dietary sodium intake (4522 ± 109 versus 4915 ± 596 mg) than the 33 women who were approached but whose infants were excluded from the study.
Dual-energy x-ray absorptiometry scans of the whole body and lumbar spine (first to fourth lumbar vertebrae) were done with a whole-body scanner (Hologic QDR 1000/W Densitometer; Hologic Inc., Bedford, MA) operated in a single-beam mode. All scans were done with the infants on a pediatric platform, with a cotton blanket between the subject and the platform and with each infant swaddled in a cotton blanket during scanning. Blankets were weighed in each case. All infants were scanned without sedation or additional restraint and were directly observed at all times by at least one of the investigators or a research nurse. Repeat scans were done if movement artifact was noted. Scans were analyzed using the software developed in conjunction with the manufacturer (Version V5.64P for the whole body and V4.57Q for the lumbar spine). Each scan was reviewed by one of two investigators (WWKK or JCW) and determined to be technically satisfactory.13 Quality-control scans done on a manufacturer-supplied anthropometric spine phantom showed a long-term coefficient of variation for determining bone mineral content, skeletal area, and bone mineral density of less than 0.31% for all variables. The average annual rate of change for each of these measurements was not significantly different from zero. The lean and fat masses were also part of the whole-body scan. This study was approved by the Institutional Review Board for Human Subjects at the University of Tennessee, Memphis, and written informed consent was obained from each woman.
The primary analysis was to determine whether maternal calcium supplementation was associated with increased bone mineral content of the total body or lumbar spine of newborns. Potential confounding variables for fetal growth and bone mineralization, including women’s baseline daily dietary intake of energy, protein, calcium, magnesium, phosphorus, and sodium; women’s BMI and age at randomization; and percentage of study tablets taken, were screened individually in univariate regression analyses for association with bone mineral content. Maternal BMI, maternal age, and dietary calcium at baseline were found to be positively associated with total-body bone mineral content of the infant, although the association was weak (r2 < .1, P < .10).
To adjust for potential confounding variables that were not balanced across treatment groups, multivariable regression models incorporating the significant confounders from the univariate analysis, along with an indicator for treatment effect (calcium or placebo), were fit to the total-body and lumbar spine dual-energy x-ray absorptiometry measurements. To assess whether the effect of calcium supplementation varied according to maternal dietary calcium intake, we stratified the study subjects into quintiles based on maternal dietary calcium intake at randomization. The effect of calcium supplementation was estimated separately within each quintile, with and without adjustment for maternal BMI and age.
The effect of total daily calcium intake was also analyzed. Total calcium intake was estimated by multiplying the average daily percentage of study tablets consumed by 2000 mg for women who received calcium tablets or by 0 mg for those who received placebo, then adding this quantity to the calcium intake obtained from the average of baseline and 32–33-week 24-hour dietary recall. The Cochran-Armitage test for trend14 was used to determine whether there was a dose effect by decile of total calcium intake (diet and supplement) on total-body bone mineral content or lumbar spine bone mineral content. Multivariable regression analyses were also done to ascertain the independent effect of total calcium intake on bone mineral content, after adjustment for maternal BMI and age.
The same multivariable regression models were used post hoc to determine the significance of the data with total-body bone mineral content measurements divided by skeletal area, length, and lean body mass.
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and 2, respectively. The range of dietary calcium intake and tablet-intake compliance were comparable between the calcium and placebo groups at each quintile of maternal dietary calcium intake. Calcium-supplemented women took 59–68% of their tablets, compared with 55–63% for women in the placebo group.
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). There were also no significant differences in dual-energy x-ray absorptiometry measurements by treatment group (Table 4) after adjustment in a multivariable regression analysis.
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). The calcium treatment effect remained significant (P < .04) after adjustment for baseline characteristics of maternal age and maternal BMI. Similar results were obtained when bone mineral content data were analyzed after dividing by skeletal area, body length, or lean body mass (Table 5). For the lumbar spine dual-energy x-ray absorptiometry measurements, there was no calcium treatment effect compared with placebo in any quintile (data not shown).
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At each quintile of maternal dietary calcium intake, the birth weights of infants born to calcium-supplemented mothers were not significantly different from the birth weights of infants born to mothers who received placebo. However, the same multivariable analyses were done to determine whether the increased total-body bone mineral content of infants born to calcium-supplemented women at the lowest quintile of dietary calcium intake, and the increased total-body bone mineral content of infants born to women with increased total (diet plus supplement) calcium intake, could have been confounded by infant size. We used three alternative measures to account for infant size: bone mineral content/dual-energy x-ray absorptiometry area, bone mineral content/infant length, and bone mineral content/dual-energy x-ray absorptiometry lean mass. The results were consistent with the analyses using bone mineral content alone (Table 5
).
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The statistically significant trend for increasing total-body bone mineral content of neonates with increased calcium intake from all sources is consistent with reports that higher calcium intake results in higher bone mass under other situations, for example in infants,15 children,16 and adults.17 Differences in total-body bone mineral content between the calcium and placebo groups were small except within the lowest quintile of maternal dietary calcium intake (less than 600 mg/day). The consistency in the higher bone mineral measurements, expressed as absolute bone mineral content or after adjustment for skeletal area (ie, as area bone mineral density) or body length, supports the beneficial role of calcium supplementation on fetal bone mineralization at low levels of maternal dietary calcium intake. The trend toward increased total-body bone mineral content after adjustment for lean body mass is consistent with this finding. The vast majority of body calcium is found in bone and is better reflected by skeletal area and body length. The lack of a significant change in lumbar spine bone mineral content from total calcium intake presumably is related to the limits of detection of small increases in the absolute amount of bone mass in the lumbar spine as compared with the larger increases in the whole body.
High sodium intake in both groups is consistent with a high intake of prepared convenience foods. It has been estimated that for every 100 mmol (2300 mg) of sodium excreted, there is approximately 1 mmol (40 mg) loss of urinary calcium in a free-living, normocalciuric healthy population,18 but the increase in urinary calcium excretion with sodium chloride supplementation is accompanied by increased calcium absorption.19,20 There was no increase in nephrolithiasis among the 2295 women in the Calcium for Preeclampsia Prevention study who had supplementation with 2 g of calcium daily.12 It appears unlikely that the slightly higher sodium intake in the placebo group would result in a major difference in fetal bone mineralization compared with the calcium group. We are unable to draw further conclusions because we did not measure serial 24-hour urine sodium excretion, which is a better indicator of dietary sodium intake.21 We also have no information on the different sodium salts ingested, which might affect urinary calcium excretion differently.22 It is theoretically possible that low maternal magnesium intake also might limit improvement in fetal bone mineral status. However, this seems unlikely because decreased bone growth and increased bone resorption reported in animal studies occurred only with severe magnesium deficiency from a dietary magnesium intake of less than 10% of the control diet.23
In animals, very high maternal calcium intake during pregnancy may be detrimental to the fetus. For example, calcium intake at 2.5 times the control diet in ewes can result in fetal osteochondrosis.2 The fetuses of rats given calcium at 2.5 times the control diet showed a decrease in the whole-body content of iron by 34.8%, copper by 12.5%, phosphorus by 2.9%, and magnesium by 2.1%.3 However, there were no significant differences in maternal or perinatal outcomes between the calcium and placebo groups in the Calcium for Preeclampsia Prevention study.12 In our study, the lack of a statistically significant difference in total-body bone mineral content of neonates between the calcium-supplemented and placebo groups (other than at the lowest quintile of maternal dietary calcium intake) suggests that a maternal homeostatic response to high calcium intake probably acts to decrease absorption and retention of calcium. There appears to be no excessive mineral retention in fetuses even at levels of total daily maternal calcium intake exceeding 3000 mg from mid-pregnancy until term.
We conclude that low maternal dietary calcium intake may be critical to fetal bone mineralization even in affluent societies where food is plentiful. Maternal calcium supplementation averaging 1300 mg/day from midpregnancy to term can enhance fetal bone mineralization in women with low calcium intake. The best way to assure normal fetal bone mineralization is through maternal dietary calcium intake because calcium-enriched food sources are also rich in other nutrients critical to bone health.8–10 Calcium supplementation in pregnant women who already have dietary calcium intake in the currently recommended range24 is unlikely to result in major improvement in fetal bone mineral content.
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Received January 29, 1999. Received in revised form March 30, 1999. Accepted April 8, 1999.
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2. Corbellini CN, Krook L, Nathanielsz PW, Kallfelz FA. Osteochrondrosis in fetuses of ewes overfed calcium. Calcif Tissue Int 1991; 48:37–45.[Medline]
3. Shackelford ME, Collins TF, Black TN, Ames MJ, Dolan S, Sheikh NS, et al. Mineral interactions in rats fed AIN-76A diets with excess calcium. Food Chem Toxicol 1994;32:255–63.[Medline]
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5. Raman L, Rajalakshmi K, Krishnamachari KAVR, Sastry JG. Effect of calcium supplementation to undernourished mothers during pregnancy on the bone density of the neonates. Am J Clin Nutr 1978;31:466–9.
6. Brooke OG, Brown IR, Bone CD, Carter ND, Cleeve HJ, Maxwell JD, et al. Vitamin D supplements in pregnant Asian women: Effects on calcium status and fetal growth. BMJ 1980;280:751–4.
7. Himes JH, Caulfield LE, Reynaldo M, Delgado H. Maternal supplementation and bone growth in infancy. Paediatr Perinat Epidemiol 1990;4:436–47.[Medline]
8. Winkvist A, Habicht JP, Rasmussen KM. Linking maternal and infant benefits of a nutritional supplement during pregnancy and lactation. Am J Clin Nutr 1998;68:656–61.[Abstract]
9. Interagency Board for Nutrition Monitoring and Related Research. Selected findings from the National Nutrition Monitoring and Related Research Program. In: Ervin B, Reed D, eds. Nutrition monitoring in the United States. Chartbook I. Hyattsville, Maryland: Public Health Service, 1993.
10. Miller GD, Groziak SM, DiRienzo D. Age considerations in nutrient needs for bone health. J Am Coll Nutr 1996;15:553–5.[Abstract]
11. Levine RJ, Esterlitz JR, Raymond EG, DerSimonian R, Hauth JC, Curet LB, et al. Trial of Calcium for Preeclampsia Prevention (CPEP): Rationale, design, and methods. Control Clin Trials 1996; 17:442–69.[Medline]
12. Levine RJ, Hauth JC, Curet LB, Sibai BM, Catalano PM, Morris CD, et al. Trial of calcium to prevent preeclampsia. N Engl J Med 1997;337:69–76.
13. Koo WWK, Walters J, Bush AJ. Technical considerations of dual energy x-ray absorptiometry-based bone mineral measurements for pediatric studies. J Bone Miner Res 1995;10:1998–2004.[Medline]
14. Armitage P. Tests for linear trends in proportions and frequencies. Biometrics 1955;11:375–86.
15. Koo WWK, Steichen JJ. Osteopenia and rickets of prematurity. In: Polin R, Fox W, eds. Fetal and neonatal physiology. 2nd ed. Philadelphia; WB Saunders, 1998:2335–49.
16. Johnston CC Jr, Miller JZ, Slemenda CW, Reister TK, Hui S, Christian JC, et al. Calcium supplementation and increases in bone mineral density in children. N Engl J Med 1992;327:82–7.[Abstract]
17. Nieves JW, Komar L, Cosman F, Lindsay R. Calcium potentiates the effect of estrogen and calcitonin on bone mass: Review and analysis. Am J Clin Nutr 1998;67:18–24.[Abstract]
18. Nord BEC, Need A, Morris HA, Horowitz M. The nature and significance of the relationship between urinary sodium and urinary calcium in women. J Nutr 1993;123:1615–22.
19. Meyer WJ, Transbol I, Bartter FC, Delea C. Control of calcium absorption: Effect of sodium chloride loading and depletion. Metabolism 1976;25:989–93.[Medline]
20. Breslau NA, McGuire JL, Zerwekh JE, Pak CYC. The role of dietary sodium on renal excretion and intestinal absorption of calcium and on vitamin D metabolism. J Clin Endocrinol Metab 1982;55:369–73.[Abstract]
21. Luft FC, Fineberg NS, Sloan RN. Estimating dietary sodium intake in individuals receiving a randomly fluctuating intake. Hypertension 1982;4:805–8.
22. Massey LK, Whiting SJ. Dietary salt, urinary calcium, and bone loss. J Bone Miner Res 1996;11:731–6.[Medline]
23. Rude RK, Kirchen ME, Gruber HE, Stasky AA, Meyer MH. Magnesium deficiency induces bone loss in the rat. Miner Electrolyte Metab 1998;24:314–20.[Medline]
24. Standing Committee on the Scientific Evaluation of Dietary Reference Intakes, Food and Nutrition Board, Institute of Medicine. Dietary reference intakes for calcium, phosphorus, magnesium, vitamin D, and fluoride. Washington DC: National Academy Press, 1997.
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