Vitamin D requirements during pregnancy

¹ From the Ethel Austin Martin Program in Human Nutrition, South Dakota State University, Brookings, SD.

² Presented at the conference "Vitamin D and Health in the 21st Century: Bone and Beyond," held in Bethesda, MD, October 9–10, 2003.

³ Supported by NIH grant R01 AR47852.

⁴ Address correspondence to B Specker, Box 2204, EAM Building, South Dakota State University, Brookings, SD 57007. E-mail: bonny_specker{at}sdstate.edu.

ABSTRACT

Adequate vitamin D concentrations during pregnancy are necessary to ensure appropriate maternal responses to the calcium demands of the fetus and neonatal handling of calcium. The purpose of this report is to review studies that investigated maternal and neonatal outcomes of vitamin D deficiency or supplementation during pregnancy. Most studies reported included women at high risk of vitamin D deficiency, because of low vitamin D and calcium intake or decreased ability to synthesize endogenous vitamin D (attributable to lack of sun exposure or to heavily pigmented skin). Overall, vitamin D supplementation in these populations leads to improved neonatal handling of calcium. Results concerning benefits for fetal growth and bone development are inconclusive. There is no evidence of a benefit of supplementation during pregnancy above amounts routinely required to prevent vitamin D deficiency.

Key Words: Vitamin D • pregnancy • supplements • neonates • hypocalcemia • fetal growth

INTRODUCTION

Significant changes in maternal vitamin D and calcium metabolism occur during pregnancy, to provide the calcium needed for fetal bone mineral accretion. Approximately 25-30 g of calcium are transferred to the fetal skeleton by the end of pregnancy, most of which is transferred during the last trimester. It has been estimated that the fetus accumulates up to 250 mg/d calcium during the third trimester (1). The 3 possible calcium sources that may supply the mother with the necessary calcium to support fetal growth include increased intestinal absorption from the diet, increased renal conservation, and increased bone mobilization.

Vitamin D is obtained either through photosynthesis in the skin with exposure to ultraviolet B radiation or through dietary sources. Vitamin D is then transported to the liver and hydroxylated to 25-hydroxyvitamin D [25(OH)D]. Additional hydroxylation of 25(OH)D occurs in the kidney and yields a wide variety of vitamin D metabolites, including 1,25-dihydroxyvitamin D [1,25(OH)₂D]. The active metabolite of vitamin D, 1,25(OH)₂D, increases the efficiency of intestinal calcium absorption, decreases renal calcium excretion, and, in conjunction with parathyroid hormone (PTH), mobilizes calcium from bone. Serum 25(OH)D concentrations are often used as an indicator of vitamin D status; although 25(OH)D is present in serum in nanogram amounts and 1,25(OH)₂D is present in picogram amounts, long-term vitamin D deficiency can result in increased PTH concentrations and decreased serum 1,25(OH)₂D concentrations, leading to osteomalacia.

There are few natural food sources of vitamin D (fatty fish and eggs). In the United States, fluid milk is typically fortified with vitamin D. Maternal vitamin D deficiency is more likely to occur in the winter months, in countries that do not routinely fortify dairy products or other food products with vitamin D, among ethnic groups whose members cover most of their skin, and/or among individuals with heavily pigmented skin. Few randomized, nutritional vitamin D interventions have been conducted during pregnancy, and the importance of maternal vitamin D intake is best illustrated in observational studies of women with poor vitamin D status. Adequate maternal vitamin D status is necessary during pregnancy. To ensure appropriate maternal responses to the calcium demands attributable to the pregnancy and neonatal handling of calcium. Most studies that investigated the effects of vitamin D status on maternal and infant outcomes found effects primarily on neonatal calcium metabolism. A few studies showed that maternal vitamin D deficiency might affect maternal weight gain or fetal growth.

MATERNAL VITAMIN D AND CALCIUM HOMEOSTASIS DURING PREGNANCY

Increased intestinal calcium absorption appears to be the primary mechanism for obtaining extra calcium during pregnancy (2). Fractional calcium absorption increases from 35% in the nonpregnant state to 60% during the third trimester of pregnancy (3, 4). Serum concentrations of 1,25(OH)₂D increase 50–100% over the nonpregnant state during the second trimester and by 100% during the third trimester (3, 4). Although serum concentrations of vitamin D-binding protein also increase during pregnancy, concentrations of 1,25(OH)₂D continue to increase during the last trimester without an associated increase in binding protein concentrations, which leads to increases in free 1,25(OH)₂D concentrations (5, 6). Although renal calcium conservation does not occur during pregnancy, calcium absorption has been found to be positively associated with serum 1,25(OH)₂D concentrations in late human gestation (3, 4). The mechanism underlying the increased serum 1,25(OH)₂D concentrations during pregnancy is not clear. PTH, which is usually considered the stimulus for increased renal hydroxylation of 25(OH)D to 1,25(OH)₂D, has not been shown to be increased during pregnancy (3, 4, 7), and it has been speculated that the 1,25(OH)₂D present in the maternal circulation may be of placental origin (8).

MATERNAL CHANGES IN BONE AND BONE MARKERS DURING PREGNANCY

Although there are case reports of pregnancy-associated osteoporosis, this appears to be a pathologic condition that occurs among women with preexisting bone disease or that results from inappropriate calcitropic hormonal responses during pregnancy (9, 10). Ensom et al (11) recently reviewed studies on bone changes that occur during normal pregnancies. Unfortunately, in many studies the final bone measurements were made up to 6 wk after the birth, when lactation-induced bone changes have already begun to occur. Although studies using biochemical markers of bone formation and bone resorption have been conducted to allow better understanding of bone turnover throughout pregnancy (4, 12–14), those studies are difficult to interpret because of changes in renal filtration, hemodilution, and the possibility that the markers are of fetal or placental origin.

Several longitudinal studies that included bone measurements before and after pregnancy showed bone density losses of 2-4%. Decreases in bone density were observed in the spine (12, 15, 16), hip (12, 17), and ultradistal radius (18, 19). One study reported an increase in bone density at cortical sites (16), whereas several other studies reported no changes during pregnancy (3, 4, 20, 21). The percentage postpartum bone gain among women who did not breast-feed their infants was of a magnitude similar to that of the observed bone loss (20, 22–24). Most of the postpartum studies of bone gain did not include nonpostpartum control subjects, and it is possible that the bone gain might be a normal, age-related gain. However, there is evidence that the bone changes observed in the postpartum period are not attributable to normal, age-related bone increases. Laskey et al (24) studied 11 nonlactating postpartum women and 22 nonpostpartum women of similar age and found a significant increase in bone mass among the postpartum women but no change among the nonpostpartum women.

EFFECTS OF MATERNAL VITAMIN D STATUS ON NEONATAL CALCIUM HOMEOSTASIS

In the early 1970s, Purvis et al (25) reported an association between the occurrence of neonatal tetany and the amount of sunlight exposure the mothers had received during the last trimester of pregnancy. Those authors, as well as others (26, 27), speculated that vitamin D-deficient mothers develop secondary hyperparathyroidism, which leads to transitory hypoparathyroidism and hypocalcemia among the neonates. Several investigators subsequently reported that infants of mothers with low vitamin D intake during pregnancy had low serum calcium concentrations in cord blood or during the first week of life (28–30).

Asian (subcontinent) immigrants to the United Kingdom are at increased risk of vitamin D deficiency. Okonofua et al (27) initially reported low serum 25(OH)D and calcium concentrations and higher PTH concentrations in maternal and cord samples obtained from 11 Asian mothers, compared with 10 white mothers, at delivery. These authors later reported the results of a similar but larger study involving 43 Asian women and 55 white women who were monitored throughout their pregnancies. They found that PTH concentrations among both Asian and white mothers increased throughout pregnancy (31). Serum PTH concentrations were inversely associated with serum 25(OH)D concentrations, and Asian mothers had lower 25(OH)D concentrations and higher PTH concentrations than did white mothers. The second study replicated the previous findings of lower serum 25(OH)D concentrations and higher PTH concentrations in cord samples obtained from Asian neonates, compared with white neonates.

Datta et al (32) recently screened 160 pregnant women from ethnic minority groups in South Wales and found that 50% had low serum 25(OH)D concentrations. In contrast to the findings of Okonofua et al (27, 31), Datta et al (32) found PTH concentrations to be within the normal range for 81% of the women with low 25(OH)D concentrations. The women were instructed to begin vitamin D supplementation at 800 IU/d and were rechecked at 36 wk of gestation. If serum 25(OH)D concentrations were still low, then the women were instructed to take 1600 IU/d. Serum 25(OH)D concentrations increased, and 60% of the women who were rechecked at delivery exhibited 25(OH)D concentrations within the normal range. Despite the increase in serum 25(OH)D concentrations, serum PTH concentrations remained unchanged. The authors noted that, although vitamin D supplementation during pregnancy is recommended by the British Department of Health for all ethnic minorities, it is not widely practiced and compliance may be low.

Paunier et al (28) measured plasma 25(OH)D and calcium concentrations among 40 healthy Swiss mothers and their term infants at delivery, during the winter months. At the time of delivery, maternal vitamin D intake during the last trimester was estimated by recall, and maternal and cord blood concentrations of 25(OH)D and calcium were measured. Infant calcium concentrations were determined on day 4. Three groups were defined on the basis of maternal vitamin D intakes, ie, 16 mothers did not receive vitamin supplements and had mean intakes of 150 IU/d, 8 mothers did not receive vitamin supplements and had mean vitamin D intakes from fortified milk of 150-500 IU/d, and 16 mothers received regular vitamin supplements and had mean intakes of 500-1500 IU/d. Cord 25(OH)D concentrations were correlated with maternal plasma concentrations. Cord and maternal 25(OH)D concentrations were not correlated with maternal vitamin D intake and did not differ among the groups defined on the basis of maternal vitamin D intake. Despite the lack of statistical significance in serum 25(OH)D concentrations, which the authors speculated was attributable to large variations in 25(OH)D concentrations, infant calcium concentrations on day 4 were significantly lower among infants whose mothers consumed <150 IU/d, compared with infants whose mothers consumed >500 IU/d.

Congdon et al (29) measured cord 25(OH)D and calcium concentrations among 45 Asian women who received no vitamin D supplements and 19 Asian women who received 1000 IU/d vitamin D during the last trimester. The authors found higher serum 25(OH)D and calcium concentrations and similar alkaline phosphatase concentrations among infants of mothers who received vitamin D, compared with those who did not. Infant forearm bone mineral content (BMC) results are presented below.

Several randomized trials of vitamin D supplementation during pregnancy have been conducted. In 1980, Cockburn et al (33) reported the results of a quasi-randomized trial of 1139 Scottish women who attended 2 different obstetric wards. Women from one ward were assigned to receive 400 IU/d vitamin D from approximately the 12th week of gestation (n = 506), whereas the women attending the other ward received a placebo containing no vitamin D (n = 633). Plasma 25(OH)D, calcium, and phosphorus concentrations were measured at 24 and 34 wk of gestation, as well as in samples obtained from cord plasma and from the neonate on day 6. Plasma 25(OH)D concentrations were higher among the mothers who received vitamin D, compared with those who received placebo, at 24 wk, 34 wk, and delivery and on day 6 for the infants. Calcium concentrations also were higher on day 6 among the infants whose mothers received vitamin D, compared with those whose mothers did not. The incidence of neonatal hypocalcemia also differed, and this was more apparent among infants fed formula, compared with human milk (Figure 1). Tetanic convulsions occurred in 8 of the 1139 infants (0.7%), and there was no difference in the occurrence of convulsions among infants of mothers who received vitamin D, compared with those who did not, probably because of the small numbers. All infants with convulsions were receiving infant formula with a high phosphorus content.

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FIGURE 1.. Association of maternal vitamin D deficiency with neonatal hypocalcemia, especially among infants receiving formula (high phosphate load). Data from Cockburn et al (33).

 
At approximately the same time, Brooke et al (34) published the results of a double-blind, randomized trial of vitamin D supplementation among pregnant Indian Asian women in the United Kingdom. Fifty-nine women received 1000 IU/d vitamin D beginning at 28–32 wk of gestation, whereas 67 women received placebo. Maternal calcium concentrations, but not cord calcium concentrations, were higher for the vitamin D-supplemented group at delivery, compared with the placebo-treated group. Infant plasma calcium concentrations on days 3 and 6 also were significantly higher in the vitamin D-supplemented group, compared with the control group. Although plasma calcium concentrations on days 3 and 6 were higher among breast-fed infants, compared with formula-fed infants, breast-fed infants were not fully protected against the effects of vitamin D deficiency on hypocalcemia; plasma calcium concentrations were significantly lower on day 6 among breast-fed infants in the control group, compared with breast-fed infants in the vitamin D-supplemented group. Five cases of symptomatic hypocalcemia occurred in the control group, whereas no cases occurred in the treated group. Although there was no difference in birth weights between the 2 groups, there was a larger percentage of small-for-gestational age infants in the placebo-treated group (28.6%), compared with the vitamin D-supplemented group (15.3%). Fontanelle area also was larger among infants of mothers randomized to receive the placebo, compared with vitamin D. Five infants in the control group had symptomatic hypocalcemia, compared with 0 in the treated group, and 6 had craniotabes, compared with 2 in the treated group. All infants with symptomatic hypocalcemia or craniotabes underwent wrist radiographic evaluations, and none showed evidence of rickets.

In 1981, Marya et al (30) reported the results of a randomized study of 120 women at delivery; 75 had taken no vitamin D supplements, 25 had been given 1200 IU/d vitamin D (with 375 mg/d calcium) during the third trimester of pregnancy, and 20 had been given 600000 IU vitamin D orally in both the seventh and eighth months of pregnancy. It was estimated that the usual daily vitamin D intake among this population was <30 IU/d. The mothers who received the large-dose therapy, as well as their respective cord blood samples, exhibited greater serum calcium and lower serum alkaline phosphatase concentrations, compared with the mothers who did not receive vitamin D or received 1200 IU/d.

The results of another randomized vitamin D supplementation trial, involving 200 Asian Indian women, were reported by Marya et al (35) in 1988. Two hundred women were randomlyassigned to receive either 600000 IU of vitamin D twice during the last trimester (seventh and eighth months of gestation, n = 100) or no supplement (n = 100). Serum calcium concentrations were higher and alkaline phosphatase concentrations were lower for mothers who were treated with vitamin D, compared with those who were not. Similar findings were observed for cord samples. Infants of mothers who received vitamin D had greater intrauterine growth, with greater birth weight, crown-heel length, head circumference, arm circumference, and skinfold thickness, compared with infants of mothers who did not receive vitamin D.

Delvin et al (36) conducted a vitamin D supplementation trial with 34 French women who received minimal to no vitamin D from dietary sources. The supplement-treated women received 1000 IU/d vitamin D from the sixth month of gestation, whereas the other group served as a control group. Cord samples for the vitamin D-supplemented group demonstrated higher concentrations of both 25(OH)D and 1,25(OH)₂D. At 4 d of age, serum 25(OH)D and 1,25(OH)₂D concentrations were higher in the vitamin D-supplemented group, compared with the control group. All infants were breast-fed and, although there was no group difference in cord calcium concentrations, the decline in serum calcium and ionized calcium concentrations during the first 4 d of life was less among infants whose mothers received vitamin D, compared with those who did not. There were no significant group differences in either cord or infant serum PTH concentrations.

A randomized trial was conducted by Mallet et al (37) in northern France, to determine the effects of single-dose and daily vitamin D supplementation during the last trimester of a winter pregnancy. One group acted as a control group (n = 29), one group was treated with 1000 IU/d during the last 3 mo of pregnancy (n = 21), and one group was given a single oral dose of 200000 IU of vitamin D during the seventh month of pregnancy (n = 27). Serum 25(OH)D concentrations in maternal and cord samples did not differ between the 2 supplementation groups but were higher than those in the control group. There were no group differences in maternal or cord serum 1,25(OH)₂D and calcium concentrations or neonatal serum calcium concentrations on days 2 and 6.

The studies described above, as well as one by Reif et al (38), are summarized in Tables 1 and 2. The effects of vitamin D supplementation, as either a daily dose or a single high dose, on maternal serum 25(OH)D and neonatal calcium concentrations are illustrated in Figures 2 and 3.

View this table:
TABLE 1. Summary of studies of the effects of varying doses of maternal vitamin D intake on pregnancy outcomes¹

 

View this table:
TABLE 2. Summary of serum calcium and 25(OH)D concentrations in observational studies and trials with varying maternal vitamin D intake¹

 

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FIGURE 2.. Effects of vitamin D supplementation, among mothers at increased risk of vitamin D deficiency, on maternal serum 25(OH)D concentrations. Data are from Table 2. Connected points are from the same study. The dashed line represents an observational study in which the vitamin D-treated group received 500-1500 IU/d. The open circles are data from a study that used 400 IU/d during the second and third trimesters. All other doses were 1000 IU/d during the third trimester. High-dose vitamin D was 200000 IU administered once during the seventh month of pregnancy.

 

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FIGURE 3.. Effects of vitamin D supplementation, among mothers at increased risk of vitamin D deficiency, on infant calcium concentrations during the first 1 wk of life. Data are from Table 2. Connected points are from the same study and for the same day after birth. The dashed line represents an observational study in which the vitamin D-treated group received 500-1500 IU/d. The open circles are data from a study that used 400 IU/d during the second and third trimesters. All other doses were 1000 IU/d during the third trimester. High-dose vitamin D was 200000 IU administered once during the seventh month of pregnancy.

 
EFFECTS OF MATERNAL VITAMIN D STATUS ON MATERNAL WEIGHT AND FETAL GROWTH

The majority of studies described above involved populations typically at risk for vitamin D and calcium deficiency and osteomalacia. Although most of the studies described above did not report maternal weight gain during pregnancy (28–30, 33, 36, 37), Brooke et al (34) observed less weight gain in the control group compared with the treated group. Marya et al (35) found no effect of maternal vitamin D supplementation on weight gain. Anorexia and malaise are often associated with vitamin D deficiency, which may explain the poor weight gain among pregnant women with vitamin D deficiency. However, Marya et al (35) speculated that vitamin D, and specifically 1,25(OH)₂D, might have an anabolic effect on growth, which might explain impaired maternal weight gain and fetal growth among mothers with severe deficiency. Of the studies described above, only the 2 studies by Marya et al (30, 35) found a beneficial effect of vitamin D on birth weight, whereas the others did not (29, 34, 37). Studies that investigated the effects of maternal vitamin D status on maternal weight gain and fetal growth are summarized in Table 3.

View this table:
TABLE 3. Summary of the effect of maternal vitamin D status on maternal and infant calcium homeostasis, growth and bone¹

 
EFFECTS OF MATERNAL VITAMIN D STATUS ON FETAL AND NEONATAL BONE DEVELOPMENT

Decreased skeletal mineralization in utero may be manifested as rickets or osteopenia among newborn infants. However, fetal or congenital rickets among newborns is rare. Case reports of congenital rickets among newborn infants of mothers with severe nutritional osteomalacia associated with vitamin D or calcium deficiency have been published (39–41). Reif et al (38), in a case-control study, reported an association between craniotabes, or delayed ossification of the cranial vertex, and maternal and neonatal 25(OH)D concentrations. However, those findings have not been replicated in other observational studies or trials (29, 34).

Although Brooke et al (34) did not find an association between craniotabes and vitamin D status, they did find that infants of mothers who received placebo had larger fontanelles than did infants of mothers treated with vitamin D, which is consistent with impaired ossification of the skull. A study of 256 term infants conducted in China also found possible evidence for a relationship between maternal vitamin D deficiency and impaired fetal bone ossification (42). Neonatal wrist ossification centers were less likely to be found among infants born in the spring than among those born in the fall (2 of 127 infants, compared with 10 of 129 infants; P = 0.05). In addition, among infants born in the fall, 3.8% of those with 25(OH)D concentrations of <11 ng/mL had wrist ossification centers, compared with 13.7% of those with 25(OH)D concentrations of >11 ng/mL (P = 0.04). There was no relationship between the presence of ossification centers and cord 25(OH)D concentrations among infants born in the spring, when only 2 of 127 infants (1.6%) had ossification centers. The authors speculated that maternal vitamin D status might affect fetal bone development and that the low rate of ossification centers in the spring might be attributable to maternal vitamin D deficiency in the preceding winter months. Despite a high rate of low 25(OH)D concentrations in cord blood (57%), no cases of neonatal rickets were observed. Only one study investigated the effect of vitamin D supplementation during pregnancy on neonatal bone mineralization. Congdon et al (29) measured forearm infant BMC values with single-photon absorptiometry and found that BMC values did not differ according to the history of vitamin D supplementation during pregnancy and were not correlated with cord serum 25(OH)D concentrations.

Maternal vitamin D status during pregnancy has been shown to be associated with neonatal calcium homeostasis. There are conflicting reports indicating possible effects of maternal vitamin D status on fetal growth and bone development.

CONCLUSIONS

Increased intestinal calcium absorption during pregnancy meets fetal calcium demands. In cases of severe maternal vitamin D deficiency, serum PTH concentrations are increased, 1,25(OH)₂D concentrations are decreased, and osteomalacia may occur. Observational studies and vitamin D supplementation trials among pregnant women at high risk of vitamin D deficiency showed improved neonatal handling of calcium with improved maternal vitamin D status. Results concerning the effects of vitamin D on maternal weight gain and fetal growth in these high-risk populations are conflicting and inconclusive. There is no evidence to indicate a beneficial effect of vitamin D intakes during pregnancy above amounts routinely required to prevent vitamin D deficiency among nonpregnant women.

REFERENCES

1. Widdowson EM. Changes in body composition during growth. In: Davis JA, Dobbings J, eds. Scientific foundations of pediatrics. London: Wm Heinemann Medical Books, 1981:330–42.
2. Kent GN, Price RI, Gutteridge DH, et al. The efficiency of intestinal calcium absorption is increased in late pregnancy but not in established lactation. Calcif Tissue Int 1991;48:293–5.
3. Cross NA, Hillman LS, Allen SH, Krause GF, Vieira NE. Calcium homeostasis and bone metabolism during pregnancy, lactation, and postweaning: a longitudinal study. Am J Clin Nutr 1995;61:514–23.
4. Ritchie LD, Fung EB, Halloran BP, et al. A longitudinal study of calcium homeostasis during human pregnancy and lactation and after resumption of menses. Am J Clin Nutr 1998;67:693–701.
5. Bouillon R, Van Assche FA, Van Baelen H. Influence of the vitamin D-binding protein on the serum concentration of 1,25-dihydroxyvitamin D. J Clin Invest 1981;67:589–96.
6. Bikle DD, Gee E, Halloran B, Haddad JG. Free 1,25-dihydroxyvitamin D levels in serum from normal subjects, pregnant subjects, and subjects with liver disease. J Clin Invest 1984;74:1966–71.
7. Bezerra FF, Laboissiere FP, King JC, Donangelo CM. Pregnancy and lactation affect markers of calcium and bone metabolism differently in adolescent and adult women with low calcium intakes. J Nutr 2002;132:2183–7.
8. Seki K, Makimura N, Mitsui C, Hirata J, Nagata I. Calcium-regulating hormones and osteocalcin levels during pregnancy: a longitudinal study. Am J Obstet Gynecol 1991;164:1248–52.
9. Smith R, Stevenson JC, Winearls CG, Wood CG. Osteoporosis of pregnancy. Lancet 1985;1:1178–80.
10. Khastgir G, Studd JWW, King H, et al. Changes in bone density and biochemical markers of bone turnover in pregnancy-associated osteoporosis. Br J Obstet Gynaecol 1996;103:716–8.
11. Ensom MHH, Liu PY, Stephenson MD. Effect of pregnancy on bone mineral density in healthy women. Obstet Gynecol 2002;57:99–111.
12. Black AJ, Topping J, Durham B, Farquharson RG, Fraser WD. A detailed assessment of alterations in bone turnover, calcium homeostasis and bone density in normal pregnancy. J Bone Miner Res 2000;15:557–63.
13. Yoon BK, Lee JW, Choi DS, Roh CR, Lee JH. Changes in biochemical bone markers during pregnancy and puerperium. J Korean Med Sci 2000;15:189–93.
14. Yamaga A, Taga M, Minaguchi H, Sato H. Changes in bone mass as determined by ultrasound and biochemical markers of bone turnover during pregnancy and puerperium: a longitudinal study. J Clin Endocrinol Metab 1996;81:752–6.
15. Shefras J, Farquharson R. Bone density studies in pregnant women receiving heparin. Eur J Obstet Gynecol Reprod Biol 1996;65:171–4.
16. Naylor KE, Iqbal P, Fledelius C, Fraser RB, Eastell R. The effect of pregnancy on bone density and bone turnover. J Bone Miner Res 2000;15:129–37.
17. Drinkwater BL, Chesnut CH III. Bone density changes during pregnancy and lactation in active women: a longitudinal study. Bone Miner 1991;14:153–60.
18. Bjorklund K, Naessen T, Nordstrom ML, Bergstrom S. Pregnancy-related back and pelvic pain and changes in bone density. Acta Obstet Gynecol Scand 1999;78:681–5.
19. Kolthoff N, Eiken P, Kristensen B, Nielsen SP. Bone mineral changes during pregnancy and lactation: a longitudinal cohort study. Clin Sci 1998;94:405–12.
20. Matsumoto I, Kosha S, Noguchi S, et al. Changes in bone mineral density in pregnant and postpartum women. J Obstet Gynaecol 1995;21:419–25.
21. Sowers M, Crutchfield M, Jannausch M, Updike S, Corton G. A prospective evaluation of bone mineral change in pregnancy. Obstet Gynecol 1991;77:841–5.
22. Polatti F, Capuzzo E, Viazzo F, Collconi R, Klersy C. Bone mineral changes during and after lactation. Obstet Gynecol 1999;94:52–6.
23. Kalkwarf HJ, Specker BL, Bianchi DC, Ranz J, Ho M. The effect of calcium supplementation on bone density during lactation and after weaning. N Engl J Med 1997;337:523–8.
24. Laskey MA, Prentice A, Hanratty LA, et al. Bone changes after 3 mo of lactation: influence of calcium intake, breast-milk output, and vitamin D-receptor genotype. Am J Clin Nutr 1998;67:685–92.
25. Purvis RJ, MacKay GS, Cockburn F, et al. Enamel hypoplasia of the teeth associated with neonatal tetany: a manifestation of maternal vitamin D deficiency. Lancet 1973;2:811–4.
26. Daaboul J, Sanderson S, Kristensen K, Kitson H. Vitamin D deficiency in pregnant and breast-feeding women and their infants. J Perinatol 1997;17:10–4.
27. Okonofua F, Menon RK, Houlder S, et al. Parathyroid hormone and neonatal calcium homeostasis: evidence for secondary hyperparathyroidism in the Asian neonate. Metabolism 1986;35:803–6.
28. Paunier L, Lacourt G, Pilloud P, Schlaeppi P, Sizonenko PC. 25-Hydroxyvitamin D and calcium levels in maternal, cord and infant serum in relation to maternal vitamin D intake. Helv Paediatr Acta 1978;33:95–103.
29. Congdon P, Horsman A, Kirby PA, Dibble J, Bashir T. Mineral content of the forearms of babies born to Asian and white mothers. BMJ 1983;286:1234–5.
30. Marya RK, Rathee S, Lata V, Mudgil S. Effects of vitamin D supplementation in pregnancy. Gynecol Obstet Invest 1981;12:155–61.
31. Okonofua F, Menon RK, Houlder S, et al. Calcium, vitamin D and parathyroid hormone relationships in pregnant Caucasian and Asian women and their neonates. Ann Clin Biochem 1987;24:22–8.
32. Datta S, Alfaham M, Davies DP, et al. Vitamin D deficiency in pregnant women from a non-European ethnic minority population: an interventional study. Br J Obstetr Gynaecol 2002;109:905–8.
33. Cockburn F, Belton NR, Purvis RJ, et al. Maternal vitamin D intake and mineral metabolism in mothers and their newborn infants. Br Med J 1980;231:1–10.
34. Brooke DG, Brown IRF, Bone CDM, et al. Vitamin D supplements in pregnant Asian women: effects on calcium status and fetal growth. Br Med J 1980;280:751–4.
35. Marya RK, Rathee S, Dua V, Sangwan K. Effect of vitamin D supplementation during pregnancy on foetal growth. Indian J Med Res 1988;88:488–92.
36. Delvin EE, Salle BL, Glorieux FH, Adeleine P, David LS. Vitamin D supplementation during pregnancy: effect on neonatal calcium homeostasis. J Pediatr 1986;109:328–34.
37. Mallet E, Gugi B, Brunelle P, Henocq A, Basuyau JP, Lemeur H. Vitamin D supplementation in pregnancy: a controlled trial of two methods. Obstet Gynecol 1986;68:300–4.
38. Reif S, Katzir Y, Eisenberg Z, Weisman Y. Serum 25-hydroxyvitamin D levels in congenital craniotabes. Acta Paediatr Scand 1988;77:167–8.
39. Zhou H. Rickets in China. In: Glorieux FH, ed. Rickets. New York: Raven Press, 1991:253.
40. Russell JGB, Hill LF. True fetal rickets. Br Radiol 1974;47:732–4.
41. Moncrief M, Fadahunsi TO. Congenital rickets due to maternal vitamin D deficiency. Arch Dis Child 1974;49:810–1.
42. Specker B, Ho M, Oestreich A, et al. Prospective study of vitamin D supplementation and rickets in China. J Pediatr 1992;120:733–9.