role of calcium during pregnancy: maternal and fetal needs

Role of calcium during pregnancy: maternal and fetal needs

Andrea N Hacker, Ellen B Fung, and Janet C King

Although the demand for additional calcium during pregnancy is recognized, thedietary reference intake for calcium was lowered for pregnant women in 1997 toamounts recommended for nonpregnant women (1,000 mg/day), and recently(November 2010) the Institute of Medicine report upheld the 1997 recommendation.It has been frequently reported that women of childbearing age do not consume thedietary reference intake for calcium and that calcium intake in the United Statesvaries among ethnic groups. Women who chronically consume suboptimal amountsof calcium (<500 mg/day) may be at risk for increased bone loss during pregnancy.Women who begin pregnancy with adequate intake may not need additionalcalcium, but women with suboptimal intakes (<500 mg) may need additionalamounts to meet both maternal and fetal bone requirements. The objective ofthis review is to elucidate the changes in calcium metabolism that occur duringpregnancy as well as the effect of maternal calcium intake on both maternal andfetal outcomes.© 2012 International Life Sciences Institute

INTRODUCTION

Although the demand for additional calcium duringpregnancy is recognized, the dietary reference intake(DRI) for calcium was lowered for pregnant women in1997 to amounts recommended for nonpregnantwomen.1 The Institute of Medicine (IOM) committeeconcluded that any calcium deficit not provided by anincreased efficiency in calcium absorption could be sup-plied by mobilizing maternal bone calcium. Based on datafrom one cross-sectional study of postpartum women,2

it was assumed that maternal bone loss to support thedemands of both pregnancy and lactation are recoveredby 1 year postpartum. The most recent IOM report(November 2010) upheld the previous recommendationfor dietary calcium intake during pregnancy.3 Thecommittee based the recommendation on three areas ofevidence: 1) randomized controlled trials of womensupplemented with calcium during pregnancy reveal noevidence that additional calcium has any benefit to themother or fetus, 2) the number of children a woman hasdoes not increase her risk of fracture later in life, and 3)

the physiological changes that occur during pregnancyallow for maternal and fetal needs to be met. The report,which is over 900 pages in length, devoted one page to thealterations observed in calcium metabolism during preg-nancy. The objective of this review is to elucidate thechanges in calcium metabolism that occur during preg-nancy and the effect of maternal calcium intake on bothmaternal and fetal outcomes.

CALCIUM METABOLISM DURING PREGNANCY

The effect of pregnancy on the maternal skeleton haspreoccupied the scientific medical community fordecades. Fetal calcium deposition has been shown to peakat 350 mg/day in the third trimester,4 and maternalcalcium absorption increases to meet that demand, withgreater increases reported among women with lowintakes.5–7 Maternal bone turnover also increases,8–12

although women with low calcium intakes may responddifferently to the additional demand.5 The influence oflow calcium intakes (<500 mg/day) on maternal calciummetabolism will be discussed later in this review.

Affiliations: AN Hacker, EB Fung, and JC King are with the Children’s Hospital Oakland Research Institute, Oakland, California, USA, and theUniversity of California, Davis, Nutritional Biology, Davis, California, USA.

Correspondence: AN Hacker, HEDCO/CHORI, 5700 Martin Luther King Jr. Way, Oakland, CA 94609, USA. E-mail: [email protected]: +1-510-428-3885, Ext. 7386.

Key words: bone, calcium, pregnancy

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Special Article

doi:10.1111/j.1753-4887.2012.00491.xNutrition Reviews® Vol. 70(7):397–409 397

Maternal calcium absorption

Longitudinal studies of calcium metabolism during preg-nancy have concluded that maternal calcium absorptionincreases significantly during the second and third tri-mesters.13 This increase in calcium absorption is directlyrelated to maternal calcium intake. Ritchie et al.5 reportedthat women with a daily average calcium intake of1,171 mg during pregnancy absorbed 57% during thesecond trimester and 72% during the third trimester.Several studies have reported that calcitriol [1,25(OH)2D]levels increase progressively each trimester, thereby influ-encing the increase in calcium absorption.5,13 A study ofBrazilian women consuming low amounts of calciumduring pregnancy (438–514 mg calcium/day) reportedeven higher increases in calcium absorption, i.e., 69%during early pregnancy, increasing to 87% during latepregnancy. However, even with these high rates ofabsorption, maternal and fetal needs may not be met inwomen with chronically low calcium consumption(<500 mg/day).

Calcium absorption during pregnancy is mediatedby changes in maternal calcitropic hormones. During thefirst trimester, parathyroid hormone (PTH) levels in Cau-casian women consuming adequate amounts of calciumdecrease to low-normal levels and then increase to thehigher end of normal in the third trimester,14,15 reflectingthe increase in calcium transfer from mother to fetus.Although PTH levels typically do not increase abovenormal during pregnancy, levels of a prohormone, para-thyroid hormone receptor protein (PTHrP), do increasein maternal circulation.16 PTHrP is recognized by PTHreceptors and therefore has PTH-like effects. This pro-hormone is produced by mammary and fetal tissues tostimulate placental calcium transport to the fetus.17

PTHrP may also protect the maternal skeleton from boneresorption17 by increasing both calcium absorption in thesmall intestine and tubular resorption in the kidney.PTHrP may also support mineralization of trabecularand cortical bone in the fetus.15

Other calcitropic hormones affecting maternalcalcium metabolism are both the active [1,25(OH)2D]and the inactive [25(OH)D] forms of vitamin D. Serum25(OH)D levels do not change during pregnancy, but anincrease in 1-a-hydroxylase and additional synthesis inthe placenta allows for an increase in the conversion of25(OH)D to 1,25(OH)2D. Maternal serum 1,25(OH)2Dlevels increase twofold during pregnancy, allowing theintestinal absorption of calcium also to double.5,8 Bothfree and protein-bound forms of calcitriol increaseduring pregnancy,18,19 as do concentrations of vitamin-D-binding protein.20 Due to the corresponding changes invitamin-D-binding protein and 1,25(OH)2D, the index offree 1,25(OH)2D does not increase until the third trimes-

ter,5,19,21 which may explain the large increase in calciumabsorption seen during late pregnancy. Because maternal25(OH)D does cross the placenta and because there is apositive association between maternal serum 25(OH)D,cord blood 25(OH)D, and infant 25(OH)D levels at deliv-ery,17 it is thought that vitamin D plays a role in fetal bonedevelopment. However, there is a paucity of research inthis area, and it is not clear what effect maternal vitamin Dstatus has on maternal and/or fetal bone outcomes. Amore in-depth review of the role of vitamin D duringpregnancy is provided by Dror and Allen.22

Maternal calcium excretion

Physiological hypercalciuria occurs during pregnancy asa result of increased maternal calcium absorption. Inter-estingly, urinary calcium is within normal limits duringfasting but increases postprandially, indicating thatelevated excretion is related to the increase in calciumabsorption.17,23 Urinary calcium excretion has beenshown to increase by as much as 43% between prepreg-nancy and the third trimester, reflecting the 50% increasein the glomerular filtration rate (GFR) that also occursduring pregnancy.5 For women with low dietary calciumintake (<500 mg/day), urinary calcium is more tightlyregulated and urinary excretion is actually significantlyhigher in the first than in the third trimester. Althoughurinary calcium excretion increases during pregnancy,the increase in intestinal calcium absorption is not ame-liorated, and net maternal calcium retention is positivebefore fetal needs are calculated.5,13,24

Maternal bone turnover

Biochemical markers of bone turnover increase graduallyduring pregnancy, with the highest levels measured in thethird trimester.8–12,23 Markers of both bone formation andresorption increase significantly (P < 0.001)8,23 from thefirst to the third trimester, demonstrating the increase inmaternal bone turnover and fetal bone development. Tworesorption markers, carboxy terminal collagen cross-links(CTX) and n-telopetide cross-links (NTX), increasesteadily throughout pregnancy, with the largest increaseoccurring between the second and third trimesters.8,25

Markers of bone formation also increase during preg-nancy but follow a different pattern of change; forexample, procollagen type-1 carboxyterminal propeptideand bone-specific alkaline phosphatase vary little duringthe first trimester but increase significantly (44%)between the second and third trimesters.8

The use of biochemical markers to measure boneturnover during pregnancy has its limitations. Due to thelarge intraindividual variability, interpretation of changesin bone turnover markers during gestation is challenging

Nutrition Reviews® Vol. 70(7):397–409398

unless prepregnancy levels are available for comparison.Serum markers of bone turnover can be falsely decreaseddue to the effects of hemodilution. During pregnancy,maternal plasma volume expands an average of 45% toallow for the increased circulatory needs of the maternalorgans.26 Because of this increased blood volume, mea-surement of serum proteins, hormones, and other bio-chemical markers may be altered and not comparableto nonpregnant measurements. Additionally, urinarymarkers may be distorted by an increase in GFR and renalclearance as well as by altered creatinine excretion.16

Data suggest that, in women with low calciumintakes in late pregnancy (<500 mg/day), serum1,25(OH)2D concentrations rise to boost biochemicalmarkers of bone resorption. Both Californian womenwith adequate calcium intakes and Brazilian women withlow calcium intakes showed increases in 1,25(OH)2Dduring pregnancy, though to a greater or lesser extent,depending upon intake.5 Multiple regression analyses ofthe combined Californian and Brazilian data showed thatserum 1,25(OH)2D in combination with serum 25(OH)Dand parity explained 80% of the variability in boneresorption rates during the third trimester; serum1,25(OH)2D was negatively related to bone resorption,whereas serum 25(OH)D and parity were positivelyrelated (Kimberly O’Brien, unpublished data; 2012).

Insulin growth factor-1 (IGF-1) has a stimulatoryeffect on bone turnover during pregnancy; concentra-tions increase with advancing gestational age. Duringearly pregnancy, serum IGF-1 concentration is positivelyassociated with bone resorption, measured by stablecalcium isotope multicompartmental models, particu-larly in women with low calcium intakes (approx.500 mg/day). Various studies have reported increases inIGF-1 of between 34% and 68% during pregnancy.24,27,28

IGF-1 is also a significant predictor of bone resorptionduring the third trimester (P = 0.033).24 During latepregnancy, IGF-1, 1,25(OH)2D, and calcium intaketogether explain 88% of the variability in net bonecalcium balance.24

Determining maternal calcium status

Determining a woman’s calcium status during pregnancyis challenging. Serum calcium and serum albumin fall dueto expanded plasma volume; however, ionized calciumremains normal.17 Regardless, even in the nonpregnantstate, serum calcium is considered to be independent ofdietary calcium intake and thus not a reliable measure ofcalcium status.29

Calcium balance studies are typically used to deter-mine if calcium intake is adequate to meet require-ments, but this technique has limitations. Calciumretention is measured by providing a controlled con-

stant calcium diet and collecting all excrement (urineand feces). While balance studies may elucidate an indi-vidual’s calcium metabolism, they only provide informa-tion regarding current calcium status, not long-termrates of calcium retention.30 In women with adequatecalcium intakes, calcium balance is positive early inpregnancy and becomes either neutral or negative in thethird trimester.5

The measurement of fractional calcium absorption,using stable calcium isotopes, demonstrates both theincrease in intestinal calcium absorption and the hyper-calciuria that occur during pregnancy.5 O’Brien et al.24,31

have reported that, when corrected for estimates of fetalbone calcium deposition, net calcium balance decreasessignificantly between early and late pregnancy (mean-224 � 152 mg, P = 0.02). Net bone calcium balance ispositively associated with dietary calcium intake duringearly pregnancy, late pregnancy, and early lactation.24,31

Additionally, the amount of calcium transferred tothe fetus during pregnancy cannot be truly measured,only extrapolated with calcium kinetic studies usingcalcium balance data. The net calcium balance during thethird trimester of pregnancy in adolescents has beenreported as 126 mg � 152,24 which does not account forestimated fetal calcium accretion of 250–350 mg/day.4,32

The increased rate of fetal bone accretion during the thirdtrimester places women with low (<500 mg/day) calciumintakes at risk of having a negative calcium balance.

CALCIUM AND MATERNAL HEALTH

There are biological limits to a pregnant woman’s capac-ity to increase calcium absorption, and if she does notconsume adequate amounts of dietary calcium, she maybe at increased risk for gestational complications, suchas preeclampsia, and preterm delivery or long-term mor-bidities, such as excessive bone loss.

Preeclampsia and pregnancy-induced hypertension

In the 1980s, it was reported that there is an inverse rela-tionship between calcium intake and pregnancy-inducedhypertension (PIH),33 defined as systolic blood pressureof >140 mmHg and/or diastolic blood pressure of>90 mmHg that has occurred on at least two occasions atleast 4 hours to 1 week apart.34 PIH has been estimated tocomplicate 5% of all pregnancies and 11% of first preg-nancies,35 often resulting in preterm birth.36 Preeclampsiais a condition in which hypertension (as defined above)occurs during the latter half of gestation and is associatedwith an increase in urinary protein. Low calcium intakesduring pregnancy may 1) stimulate PTH secretion,increasing intracellular calcium and smooth muscle

Nutrition Reviews® Vol. 70(7):397–409 399

contractibility, and/or 2) release renin from the kidney,leading to vasoconstriction and retention of sodium andfluid. These physiological changes can lead to the devel-opment of PIH and preeclampsia.

A meta-analysis of the role of calcium supplementa-tion during pregnancy in the prevention of gestationalhypertensive disorders found a 45% reduction in thedevelopment of PIH in women receiving calcium versusplacebo (relative risk [RR] 0.55; 95% confidence interval[CI] 0.36–0.85).37 The World Health Organization con-ducted a calcium supplementation trial (1,500 mg/day orplacebo) during pregnancy in women who habituallyconsumed <600 mg calcium per day.34 Women (n =8,325) began supplementation at 20 weeks of gestationand were monitored until delivery. The primary maternaloutcome was the incidence of preeclampsia and/oreclampsia, with preeclampsia defined as de novo hyper-tension (>140/90 mm Hg) plus new-onset proteinuria,both after gestational week 20, and eclampsia defined as aseizure in a woman with preeclampsia in the absence of aknown or subsequently diagnosed convulsive disorder.The difference in the incidence of preeclampsia betweenthe control group (4.5%) and the calcium group (4.1%)was not significantly different. However, the relative risksof severe gestational hypertension (RR 0.76; 95% CI 0.66–0.89) and eclampsia (1.2% calcium vs. 2.8% placebo,P = 0.04) were both significantly lower in women supple-mented with calcium.

A Cochrane review of 13 trials involving 15,730pregnant women reported that the average risk of preec-lampsia was reduced in those receiving calcium supple-ments (RR 0.45) and that the effect was greatest in womenwith low baseline calcium intakes (RR 0.36).38–41 Thereview concluded that pregnant women consuminglow amounts of calcium could reduce their risk of preec-lampsia by 31% to 65% if they consumed an additional1,000 mg of calcium each day.39 This review also reportedthat the risk of developing PIH could be reduced withcalcium supplementation (RR 0.65; 95% CI 0.53–0.81),especially in women with low baseline dietary calciumintakes (RR 0.44; 95% CI 02.8–0.70)42

Preterm delivery

Calcium supplementation has shown effectiveness inreducing the risk of preterm delivery in women with lowcalcium intakes. Among pregnant women who regularlyconsumed less than 600 mg of calcium per day and weresupplemented with additional calcium (1,500 mg/day),decreases in the risk of preterm delivery, in maternalmorbidity, and in the neonatal mortality index wereobserved.34 The previously mentioned Cochrane reviewreported that women who were chronically low consum-ers of calcium but who took 1,000 mg of calcium

supplement per day also reduced their risk of pretermbirth by 24%.39

Short-term maternal bone changes

Changes in maternal bone mineral content (BMC) andbone mineral density (BMD) resulting from gestationhave been studied using three different imaging tech-niques: dual x-ray absorptiometry (DXA), quantitativeultrasound, and peripheral quantitative computedtomography (pQCT). pQCT is the only technique avail-able for measuring changes in trabecular bone, the type ofbone most likely to be mobilized in the adult skeletonduring pregnancy.43

The majority of studies of gestational bone changeshave used DXA to assess BMD at preconception andagain early in the postpartum period.5,10,25,44–48 Postpartumbone measurements may be confounded by the bone lossthat occurs in early lactation.5,49 One study found reduc-tions in maternal bone, with the biggest changes occur-ring at the lumbar spine and the trochanteric region ofthe hip (3–4.5% loss). 5 These skeletal sites are rich intrabecular bone but inaccessible during pregnancy due tothe confounding effect of the developing fetal skeletonlying over the maternal spine and hip areas. Additionally,DXA scans expose the mother and fetus to radiation,which is an unnecessary risk.

Quantitative ultrasound is able to measure bonewithout the use of ionizing radiation, allowing it to beused during pregnancy, primarily at the calcaneus andphalanges. Evidence has shown that the speed of sound,an indication of the density and structure of the trabecu-lar bone, decreases significantly at the phalanges(P < 0.05)50,51 and the calcaneus (P < 0.001)52 between thefirst and third trimesters. A limitation of quantitativeultrasound is its greater variability in measurement thaneither DXA or pQCT; since pregnancy is a time period inwhich changes in fluid status and body size occur, thevariability in the quantitative ultrasound measurementsmay increase.

To date, Wisser et al.53 are the only investigators touse pQCT to measure gestational changes in trabecularand cortical bone. The measurement was performed atonly one site, the nondominant distal radius. Corticalbone volume and density did not change between the firstand third trimesters of pregnancy, but a significantdecrease was seen in trabecular bone density (mean of-3.1%, with some women losing up to 20.7%). Trabecularbone density is more sensitive to bone turnover, particu-larly that resulting from hormonal changes in women,such as what occurs during gestation.

Calcium supplementation �1,000 mg/day duringgestation has resulted in a reduction in bone turnovermarkers in late pregnancy,54,55 a reduction in risk of


preterm delivery, and reduced maternal morbidity andinfant mortality.34 As previously mentioned, the results ofmaternal calcium supplementation on infant morbidityhave been mixed.56–60 The greatest impact of calciumsupplementation is observed in women who consume<500 mg calcium per day; in these studies, calciumsupplementation is positively associated with infantBMC56 and BMD.57

Liu et al. 61 randomized 36 women to a regular diet(550 mg calcium/day), a regular diet plus 45 g of milkpowder (900 mg calcium/day), or a regular diet plus 45 gof milk powder plus 600 mg of calcium (1,500 mg ofcalcium) from 20 weeks of gestation to 6 weeks postpar-tum. A dose-dependent increase (P < 0.01) in maternalBMD at the lumbar spine and whole body was seen ingroups 2 and 3 compared with group 1 (lumbar spine:0.640 � 0.039, 0.685 � 0.030, and 0.758 � 0.033 ingroups 1, 2, and 3, respectively; whole body: 0.975 �

0.037, 1.014 � 0.050, and 1.047 � 0.060, respectively).This group of Chinese women chronically consumed lowamounts of calcium (550 mg/day) and experienced posi-tive bone changes when additional calcium was added tothe diet. These women may have been in a state of chroniccalcium insufficiency, and the increase in BMD may be anindication of the reversal of this nutrient deficiency.Moreover, at least two-thirds of the supplementation wasvia milk powder, which contains not only calcium butalso protein and potassium, potentially contributing tothe positive effect seen. This study adds to the question ofwhether calcium supplied in food is more beneficial to thebones than calcium supplements alone.

Another study recently addressed the issue ofproviding calcium supplements to pregnant women inthe developing world who had low calcium intakes(<355 mg/day). Gambian women were randomized toreceive placebo or calcium supplement (1,500 mg/day)from week 20 until delivery. Bone density was assessedin the mothers by DXA at 2, 13, and 52 weeks postpar-tum. At 2 weeks postpartum, no differences in BMC orBMD were seen between the calcium and placebogroups. From 2 to 52 weeks postpartum, both groupshad decreases in BMC and BCD at all sites. The lossesseen in the calcium group were greater than those in theplacebo group, but it is not clear if the calcium supple-mentation during pregnancy prompted these additionalbone losses to occur. 5 The authors suggested thatcalcium supplementation may have altered the Gambianmothers’ ability to conserve calcium and led to mobili-zation of maternal bone.

These two studies emphasize the important role thatgenetics and environment play in calcium metabolism.The difference between calcium from food versuscalcium from supplementation is also demonstrated,illustrating the argument that it may not just be calcium

that promotes bone health but the synergistic effect of allof the nutrients in calcium-containing foods. While it isnot known which component – diet, genetics, or environ-ment – is the most influential, it does bring to light thedifficulty of making dietary recommendations for diversepopulations.

Long-term bone changes: parity and fracture risk

It has been reported that parity influences bone lossduring gestation, with greater losses reported in primipa-rous women than in multiparous women.27 Hydroxypro-line, a marker of bone resorption, is excreted 58% more inprimiparous compared with multiparous women.62 Thiscould potentially be an adaptive mechanism in womenwith previous pregnancies, providing protection againstexcessive bone loss.

Parity does not appear to increase later fracture riskin women, with studies showing either a negative63,64 or aneutral65–67 relationship between parity and risk of frac-ture. The Study of Osteoporotic Fractures, a prospectivecohort study in 9,704 women over the age of 65, assessedparity and incidence of fracture.64 Nulliparous womenhad a 44% increase in the risk of hip fracture comparedwith parous women, when adjusted for BMD and bodymass index (hazard ratio 1.44; 95% CI 1.17–1.78). Whenstratifying the women into five groups by parity, the prob-ability of hip fracture decreased as parity increased.Among parous women, the risk of hip fracture decreasedby 9% with each additional birth. Women with childrenmay be more physically active, leading to increasedweight bearing and potentially higher BMD, although theStudy of Osteoporotic Fractures adjusted for BMD andstill reported a negative relationship between parity andfracture risk.64 Research has shown that physical activitydoes reduce the risk of future fracture,68–70 but it is notknown if the relationship between physical activity andfracture risk is also associated with parity. It has beenhypothesized that the weight gain associated with preg-nancy may place an increased load on the maternal hip(femoral neck), increasing bone strength and bone areaand decreasing future fracture risk.45,71

RELATIONSHIP BETWEEN CALCIUM INTAKE DURINGPREGNANCY AND INFANT HEALTH

To date, it is unclear what effect maternal calcium intakehas on the bone mineralization of the developing fetus.Observational studies (Table 1) have found a positiverelationship between maternal dietary calcium intake andfetal or child bone outcomes.59,72 Yet, results from calciumsupplementation trials (Table 2) during pregnancy havereported inconsistent results.49,56


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Calcium transfer from mother to fetus

By the time of parturition, a fetus has formed 98% of itsskeleton, accumulating approximately 30 g of calcium.Calcium is actively transported across the placenta, withthe transfer from mother to fetus beginning by week 12 ofgestation and peaking at week 36.32 Placental calciumtransport is dependent upon transport proteins located inthe syncytiotrophoblast, which forms a barrier betweenthe mother and fetus.73 Ninety-nine percent of the flow ofcalcium is maternal-to-fetal, and this active, one-wayprocess is under way by the third trimester, when themajority of calcium is transferred, with the fetus accumu-lating 250–350 mg/day.17,74,75 A more complete review ofthe proteins involved in the transfer of calcium frommother to fetus is provided by Belkacemi et al.76

Infant growth

The effect of maternal calcium intake on infant growthremains unclear. Calcium intake during pregnancy mayhave a positive effect, but the research has provided con-flicting results.58,77,78 A positive relationship betweenmaternal calcium intake and infant length or mid-upperarm circumference has been shown,77,78 but the resultshave not been reproduced in other studies.60,78 The litera-ture also reports inconsistent findings of positive rela-tionships between maternal calcium intake and newbornweight and infant total body calcium.60,77

Bone outcomes in offspring

Observational studies that have assessed maternal diethave found a positive relationship between maternaldietary calcium intake and bone outcomes of off-spring.59,72 Measurement of fetal femur length by ultra-sound has been used as a method to assess fetal bonedevelopment. In 2003, Chang et al. 59 assessed dairy intakein 350 pregnant African-American adolescents and mea-sured fetal femur length at 20 and 34 weeks of gestation.Servings of dairy, but not calcium intake, were assessed inthe women. Dairy intake had a significant positive effecton fetal femur growth, and fetal femur length was signifi-cantly lower in the lowest dairy intake group (<2servings/day) compared with the highest dairy intakegroup (>3 servings/day).

Two studies report that low-calcium-consuming(approx. 500 mg/day) women assigned to calciumsupplements (300, 600, or 2,000 mg/day) during preg-nancy had infants with higher bone density; the greatestbenefit was seen in women consuming the lowest amountof calcium at baseline.56,57 However, calcium supplemen-tation (1,500 mg/day) in pregnant Gambian women(week 20 of gestation to delivery) who chronically con-

sumed approx. 350 mg of calcium per day had no effecton infant bone density measured using single photonabsorptiometry (2, 13, and 52 weeks post delivery).79 Inthe later part of the study, DXA showed a trend of slightlylower BMC in infants born to the calcium-supplementedmothers (total calcium intake approx. 1,850 mg/day).79

Interpreting the effect of maternal calcium intake duringpregnancy on infant bone density measured during thepostpartum period is challenging. Infant bone densitymeasured soon after birth (2 weeks postpartum) may bereflective of the fetal environment, while measurementsmade in later infancy (�13 weeks postpartum) may bereflective of infant nutritional intake. However, thecurrent calcium DRI (1,000 mg/day) has not been testedduring pregnancy to see how it may affect infant BMCand BMD as measured by both DXA and pQCT. Addi-tionally, the fetus may respond differently to calcium-richfoods versus calcium supplement pills.

Fetal bone metabolism appears to be influenced bymaternal metabolism; however, there may also be inde-pendent regulation by the fetus. Serum maternal and cordblood markers of bone turnover are highly correlated(P = 0.01, r = 0.18 for osteocalcin, and P = 0.04, r = 0.15for crosslaps), and the amounts of osteocalcin, bone-specific alkaline phosphatase, and CTX found in cordblood are higher than what is found in maternal serum.12

Leptin and IGF-1 may also impact fetal growth and bonemass, with fetal cord blood levels having a positive rela-tionship with infant bone mass.80,81 Both leptin and IGF-1are produced by the fetus and influence fetal osteoblastdifferentiation, but it is not known to what extent mater-nal lifestyle influences these factors.

Developmental origins of osteoporosis

The environment of the fetus during development mayplay an important role in the risk of future growth delayand health impairment.15,82 Maternal dietary intake, espe-cially calcium and vitamin D status, may influence futurebone development.72,83 A longitudinal study followed 198mother-child pairs from 15 weeks of gestation through 9years of age. Maternal diet was assessed during pregnancyand categorized into dietary patterns. A positive correla-tion was found between women consuming higherintakes of calcium (median daily calcium intake in topquartile, 1,287 mg) during pregnancy and a child’s wholebody bone area, BMC, and areal bone at 9 years of age,84

demonstrating the potential effect of maternal nutritionon bone development later in life. The researchers alsoreported the role of maternal vitamin D status on thechildren’s bone mass. Mean maternal 25(OH)D was53.8 nmol/L (range, 33.0–77.5 nmol/L) at 24 weeks ofgestation and was predictive of childhood bone mass(lumbar spine BMC, P = 0.03; areal BMD, P = 0.0267).83


Although a link between maternal calcium intake andvitamin D status and offspring bone mass at 9 years ofage has been reported, it is also important to considerthe influence that the child’s lifestyle85–87 plays in bonedevelopment.

Studies measuring BMD in female monozygotic anddizygotic twins have reported that genetic factors deter-mine between 77% and 80% of the variance.88,89 Currentgenetic markers are able to explain only a small propor-tion of the variation in individual bone mass or fracturerisk.90 Several genes may affect bone density, but eachonly contributes a modest effect.91,92

Fetal programming refers to a critical period duringgestation when a system is plastic and sensitive to theenvironment. Environmental stressors during intrauter-ine growth may increase the sensitivity of the growthplate to growth hormone (GH), resulting in reducedpeak skeletal size.15,82 GH stimulates chondrocytes in thegrowth plate to secrete IGF-1, leading to bone growth. Asingle-nucleotide polymorphism has been found on theGH gene, GH1-A5157G, and is associated with lowerbasal GH levels,93 which are negatively associated withBMD.94 The GH/IGF-1 axis may also be involved in therelationship between weight at 1 year of age and adultbone area at the spine and hip.95–97 An association has alsobeen observed between reduced maternal height, weight,smoking status during pregnancy, and reduced wholebody BMC of children at 9 years of age.83 The intrauterinemechanism that influences future skeletal developmenthas not been elucidated and is an area of further research.

DIETARY REFERENCE INTAKES FOR CALCIUM INTAKEDURING PREGNANCY

Amid controversy, the updated DRIs for calcium(1,000 mg/day) and vitamin D (600 IU/day) werereleased in November 2010. Calcium recommendationswere changed from Adequate Intakes (AIs) to Recom-mended Dietary Allowances (RDAs), reflecting the addi-tional research that has been conducted since theprevious report in 1997. However, neither the amount ofthe RDA nor the Tolerable Upper Level (UL) of calciumchanged for pregnant women. The IOM reported that theevidence supported a role for calcium and vitamin D inbone health but not in other health conditions.3

Average calcium intake

It has been frequently reported that women of childbear-ing age do not consume the RDA of calcium (1,000 mg/day)49,56,77,98–101 and that calcium intake in the UnitedStates varies between ethnic groups. National dietarysurveys have reported that the median calcium intake ofwomen of reproductive age is 467 mg/day for African-

American women and 642 mg/day for Caucasianwomen.102,103 Others report that multiethnic women aged19–50 years consume only 50–70% of the RDA of cal-cium.104 It is estimated that up to 75% of African-Americans are lactose intolerant, which may explain thelow dairy and dietary calcium intake.105 Dairy foodsprovide over 75% of the calcium consumed in theAmerican diet, yet among African-Americans, thisproportion is only 25%.102 Some have suggested thatcalcium intake increases during pregnancy, withstudies (Table 1) reporting intakes of 1,154–1,671 mg/day.84,100,106,107 Ritchie et al.5 reported prepregnancycalcium intakes of 1,054 � 262 mg/day, which increasedsignificantly (P < 0.05) to 1,350 � 319 mg/day during thethird trimester.

Women who chronically consume low amounts ofcalcium (<500 mg/day) may be at risk for increased boneturnover during pregnancy.8,31 Dietary calcium intake hasa negative correlation with bone resorption markers(CTX, r = -0.47, P < 0.03; NTX, r = -0.41, P < 0.05).8

High calcium intake is associated with improved calciumbalance, perhaps providing a protective effect againstbone loss during pregnancy.31 Zeni et al. 8 reported that,as dietary calcium intake increased in women with pre-viously low intakes, production of 1-a-hydroxlyase wasupregulated to increase activation of 1,25(OH)2D, result-ing in increased calcium absorption. This increase incalcium absorption decreased markers of bone resorp-tion. Women with higher dietary calcium intake(mean 1,015 mg/day) had lower NTX levels (r = -0.015,P < 0.005), suggesting that bone resorption during latepregnancy can be attenuated by increased calciumintake.106

Increase demands during gestation

Adolescence is a critical period for peak bone mass devel-opment; therefore, it has been thought that pregnancyduring adolescence will place an adverse burden on thedeveloping maternal and fetal skeletons. Bezerra et al.23

found that adolescents have elevated bone resorptionduring pregnancy, but less than what is typically observedin adult pregnant women. Additionally, the rate of boneformation does not increase in pregnant adolescents as itdoes in pregnant adults. These differences in rates of boneresorption and formation, as measured by bone markers,indicate that bone turnover and calcium metabolism isdifferent in pregnant females who have a developing skel-eton. Additionally, calcium absorption, measured duringthe third trimester in pregnant adolescents, averaged53%,31 not notably different than absorption rates in preg-nant adults.5 However, most adolescent females have notreached peak bone mass and are therefore at risk of notmeeting their peak rate of bone accretion31 Sowers et al.27


measured bone mass at the os calcis in both adolescentsand adults who were pregnant. Ultrasound measure-ments were made at 16 weeks of gestation and at 6 weekspostpartum. Bone mass was lost in all women, but ado-lescents had a significantly greater loss than the adultpregnant women. Since it was not reported if the womenwere nursing or formula feeding, the effect of lactation onbone loss was not considered.

Short time intervals between pregnancies may con-stitute another increased demand on the maternal skel-eton. Thus far, no significant effect of birth interval orlength of lactation on risk of fracture has beenobserved,108–110 nor has an increased risk of fracture beenreported in women who became pregnant while lactat-ing.108 It is not known how a pregnancy with multiplefetuses affects maternal bone health. Multiple births areoccurring more frequently as fertility treatments becomemore common.111 However, there is a paucity of researchfocused on how this additional stress affects maternalcalcium metabolism and/or bone turnover.

Women are also having children later in life. Thebirth rate for women in their forties has more thandoubled since 1981 and has increased more than 70%since 1990. The number of births to women aged 50–54years increased 18% in 2006.112 Women with their lastbirth in the age interval 30–33 years have the smallest riskof hip fracture (OR 0.34; 95% CI 0.16–0.75), and womenwith their last birth at � 38 years of age have an increasedrisk of hip fracture (OR 0.86; 95% CI 0.44–1.66).109 Thisincreased risk of hip fracture in women whose last birth isat an older age (� 38 years) may be attributable todecreased estrogen levels in women near the end of theirreproductive life stage. Low estrogen levels increaseRANKL (receptor activator of nuclear kappa B ligand),which stimulates osteoclast recruitment and activation,resulting in greater bone resorption than formation.113

Decreased bone formation due to decreased estrogenlevels and increased demand for fetal needs may be whywomen who give birth after age 38 are at an increased riskfor hip fracture.

Calcium toxicity

The UL for any essential nutrient represents the safeupper boundary that individuals may consume on aregular basis without significant comorbidity; however, itshould not be an amount that people strive to consume.3

Excess calcium from dietary intake alone is difficult toachieve. Typically, overconsumption of calcium is linkedto an excess intake of dietary supplements. The IOMreport states that “the potential indicators for the adverseoutcomes of excessive calcium intake are not character-ized by a robust data set that clearly provides a basis for adose-response relationship. The measures available are

confounded by a range of variables including otherdietary factors and pre-existing disease conditions,” illus-trating the difficulty in setting a UL.

Excess calcium intake may cause hypercalcemiaand/or hypercalciuria. Hypercalcemia occurs whenserum calcium levels are 10.5 mg/dL or greater. It can becaused by excessive intakes of calcium or vitamin D butmore commonly is caused by primary hyperparathyroid-ism or a malignancy.3 Hypercalciuria is present whenurinary excretion of calcium exceeds 250 mg/day inwomen, which frequently occurs during pregnancy as aconsequence of increased intestinal absorption andincreased GFR.3 Hypercalcemia and hypercalciuria cancause renal insufficiency (GFR < 60 mL/min114), vascularand soft tissue calcification, and nephrolithiasis. As aresult of the hypercalciuria that occurs naturally duringpregnancy, pregnant women are at an increased risk fordeveloping kidney stones.3,115 Yet, because there isminimal data showing an increased risk of nephrolithi-asis during pregnancy, the UL for pregnant women aged19–50 years is 2,500 mg/day, similar to that for nonpreg-nant, nonlactating women.

PUBLIC HEALTH IMPLICATIONS

It is firmly established that calcium plays an essential rolein both the development and maintenance of bonehealth. Given that osteoporosis is actually a condition ofchildhood that presents in older age, the importance ofcalcium intake throughout the lifespan cannot be over-looked. With evidence suggesting that maternal calciumintake can affect the bone development of the fetus andpotentially program future skeletal growth, it is essentialthat women of child-bearing age are educated on theimportance of meeting their calcium requirements.Women of child-bearing age will meet their own needsand those of their infants if they regularly consumeadequate amounts of calcium (1,000 mg/day). Additionalcalcium supplementation during pregnancy appears tohave the greatest impact in women who chronicallyconsume <500 mg calcium/day, demonstrating theimportance of adequate calcium intake before pregnancybegins.

CONCLUSION

Women who begin pregnancy with adequate intakes of atleast 1,000 mg calcium/day may not need additionalcalcium, but women with suboptimal intakes (<500 mg)may need additional amounts to meet both maternal andfetal bone requirements. The relationship between infantBMD, BMC, IGF-1 levels, and cord blood leptin levelssuggests that fetal metabolism influences fetal bone devel-


opment. Areas of future research include comparing theeffects of supplemental and food-based calcium inwomen with chronically low calcium intakes to deter-mine the effect on both maternal and infant bone out-comes and whether there are ethnic differences incalcium metabolism during pregnancy.

Acknowledgments

Declaration of interest. The authors have no relevantinterests to declare.

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2. Kalkwarf HJ, Specker BL, Heubi JE, et al. Intestinal calcium absorption of womenduring lactation and after weaning. Am J Clin Nutr. 1996;63:526–531.

3. Institute of Medicine, Committee to Review Dietary Reference Intakes forVitamin D and Calcium. Dietary Reference Intakes for Calcium and Vitamin D.Washington, DC: National Academies Press; 2011.

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role of calcium during pregnancy: maternal and fetal needs

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