Review article: Vitamin D metabolism during pregnancy

Bone, 7, 331-336 (1986) Printed in the USA. All rights reserved.

Copyright

8756-3282186 $3.00 + .OO 0 1986 Pergamon Journals Ltd.

Review Article: Vitamin D Metabolism during Pregnancy SK.

PAULSON

Department Address

and

H.F. DELUCA

of Biochemistry,

for correspondence

University of Wisconsin-Madison, and reprints:

College of Agricultural

and L/fe Sciences,

Madison,

Wisconsin,

USA.

Susan K. Paulson. Searle Research and Development, Division of G.D. Searle & Co., 4901

Searle Parkway, Skokie, IL 60077, USA

Abstract

The requirements of the fetus for a growing skeleton place great demands on maternal mineral stores such that hormonal adjustments occur in the pregnant animal to prevent calcium depletion. Pregnancy is accompanied by alterations in the calcium-regulating hormones, including the vitamin D endocrine system. The present review focuses on current knowledge concerning vitamin D metabolism during pregnancy.

Vitamin D metabolism is altered in the pregnant animal, presumably in response to fetal demands for calcium. Circulating levels of 1,25dihydroxyvitamin D are elevated in the pregnant animal. The stimulus of this increase and the hydroxylase(s) (placental or renal) responsible are unknown. Maternal plasma 25hydroxyvitamin D levels have been reported to be both unchanged and decreased during pregnancy but very much dependent upon exposure to ultraviolet light and vitamin D supplementation. The major vitamin D metabolites (25hydroxyvitamin D, 24,25dihydroxyvitamin D, and 1,2Bdihydroxyvitamin D) circulate in fetal plasma but generally at lower concentrations than in the mother (exception is the sheep). All of these metabolites are able to cross the placenta. The fetal kidney and placenta both have 25-hydroxyvitamin Dl (Y- and 24-hydroxylase activity. However, the relative contribution of mother, fetus, and placenta to fetal vitamin D metabolism has yet to be fully determined.

Key Words: Vitamin D and Reproduction-Vitarhin Pregnancy-Placenta-Embryonic

Vitamin

D

Studies about the metabolism of vitamin D itself during pregnancy are limited. Vitamin D circulates in the plasma of pregnant women who supplement their diet with 400 IU/ day of ergocalciferol at approximately 1 ng/ml (Hollis and Pittard, 1984). This value is less than that found in normal adults (Shepard et al., 1979). Vitamin D3 levels are higher in white mothers than in black mothers (Hollis and Pittard, 1984). This is most likely due to limited synthesis of vitamin D in the skin of black women. These two groups of women when supplemented with the same preparation of ergocalciferol have equivalent levels of vitamin D2 in their plasma. Ultraviolet light is necessary for the production of vitamin D from 7-dehydrocholesterol in skin. Since the fetus is not exposed to ultraviolet light, fetal vitamin D must come from the mother. The placental transport of vitamin D, has been demonstrated using radioisotopes in the sheep (Ross et al., 1979) and rat (Haddad et al., 1971; Weisman et al., 1976). However, it is interesting that the vitamin is not detectable by current methodology in neonatal bovine (Goff et al., 1982) porcine (Goff et al., 1984) or human (Hollis and Pittard, 1984 plasma).

D and

Development.

Vitamin D, the prohormone, enters an organism from either dietary sources or from synthesis in the skin following exposure to ultraviolet light. Bound to a specific vitamin Dbinding globulin, the prohormone is transported to the liver, where it is rapidly converted to 25hydroxyvitamin D [25(OH)D]. 25(OH)D is the major circulating form of the parent vitamin, and plasma 25(OH)D concentration is the best Indicator of the vitamin D nutritional status of an organism. Also bound to the specific vitamin D-binding globulin, 25(OH)D is transported to the kidney in nonpregnant animals, where it is metabolized to either of two major metabolites: 24,25-dihydroxyvitamin D [24,25(OH),D], a metabolite of no known function, and 1,25-dihydroxyvitamin D [I ,25(OH),D], the biologically active hormone. The synthesis of 1,25(OH),D is tightly regulated according to the mineral needs of the body. The vitamin D endocrine system acts to maintain normal calcium and phosphate homeostasis by increasing intestinal calcium and phosphate absorption and bone mineral mobilization.

25(OH)D Plasma 25(OH)D has been measured during various stages of pregnancy in several species (Table I). In humans the data are controversial. Circulating 25(OH)D in pregnant women has been found to be both lower than (Reiter et al., 1979; Turton et al., 1977; Weisman et al., 1978a) and equal to that in nonpregnant controls (Hillman et al., 1978; Seino et al., 1982; Wieland et al., 1980) but remains constant throughout the three trimesters (Reddy et al., 1983; Reiter et al., 1979). The data are clearer in animal studies, where it is easier to control dietary vitamin D intake and exposure to ultraviolet light. Plasma 25(OH)D levels are lower in pregnant rats (Danan et al., 1980; Halloran et al., 1979) pregnant sheep (Bartlet et al., 1978) and pregnant rabbits (Kubota et al., 1982) when com331

S K Paulson and H F DeLuca

332 Table I. Plasma 25(OH)D levelsa tn nonpregnant

Species Human

Humanb Human Human Huma+ Humanb Huma+ Human Human Humanb Huma+ Human Human Human Human Huma+ Human Human Human Human Human Human

Nonpregnant adult

Race Winter Blacks Whites Summer Blacks Whites Blacks Whites

32 23 23 2 15 19260 20270

Blacks Whites Bedourn Jewrsh Asian NonAsIan

39 * 187 322~31

14? 64 55 75 lndtan 20*90 16 + 1 7c 19 f 66 Black White Saudi upper class Saudi middle class Saudi lower class 66235

25(OH)D, 25(OH)D,

pregnant

adult, pregnant Pregnant adult

and fetalneonatal

Fetal;Neonatal

145 162

Sheep Sheep Prg cow

adult

levels levels

Rats Rats Rabbits

13 14 19 t 17

39 7 43 7 20 19 14 2 69 21 i 18 15z70 202 70 81- 75 25 2 11 5 14 f 31 42 t 79 1632 13 16227 16227 16 + 1 1 22 i- 13 21277 13250 45-50 12266 17 r 49 16 -t 16 28288 27ta7 18 -+ 12 1 70 55 48 40232 26~27 104 2 57.6 11 k-21 73 t 96 8 8 5208

Vitamin D durrng pregnancy

subtects of several species

Reference

HIllman and Haddad, Hillman and Haddad,

8 i- 44 16 ? 1.5 9247 14 +- 31 4 2 3.2 12 * 71 36258 92288

lOi-20 10 t 2.0 17 i 1.4 14 2 60 24 t 16 8238 30+50 10 t 55 13 -t 51

15 254 10567 33 30 3.0 36+-24 12 t 08 lo+-47 2+03 22237 16

1976 1976

Hillman and Haddad, 1976 Htllman and Haddad, 1976 Turton et al 1977 Turton et al., 1977 Bouillon et al 1977 t-rllman et al 1978 Wersman et al 1978a Weisman et al 1978a Btale et al., 1979 Biale et al., 1979 Heckmatt et al., 1979 Heckmatt et al 1979 Kumar et al 1979 Relter et al., 1979 Brooke et al., 1.980 Cockburn et al., 1980 Fleischman et al., 1980 Gertner et al 1980 Stetchen et al. 1980 Bourllon et al 1981 Delvtn et al 1982 Gupta et al 1982 Selno et al 1982 Reddy et al 1983 Bikle et al , 1984 Holl~s and Pittard, 1984 HoIlls and Pittard, 1984 Serenrus et al., 1984 Serenrus et al , 1984 Serenius et al 1984 Bartlet et al 1978 Ross et al 1980 Goff et al., 1984 Goff et al 1982 Halloran et al 1979 Danan et al , 1980 Kubota et al , 1982

a Mean ‘_ SEM (ngiml) b Data expressed as nmolil c Represents first trimester of pregnancy

pared to nonpregnant controls. It has been suggested that Increased metabolism of 25(OH)D to 1,25(OH),D may be the reason for the lower 25(OH)D levels observed in pregnant animals. Circulating levels of 25(OH)D in nonpregnant animals

are dependent on dietary vrtamin D intake and length of exposure to ultraviolet light. Geographic location, season, supplementation of milk with vitamin D, and customs are major influences on the circulating 25(OH)D levels in pregnant women (Stamp et al., 1977). Plasma 25(OH)D levels in pregnant mothers were found to vary seasonally, being significantly higher in the summer and lower in the winter months (Cockburn et al., 1980; Hillman and Haddad, 1976; MacLennan et al., 1980). Pregnant Beduin women, whose clothing restricts their exposure to ultraviolet light, have significantly lower 25(OH)D levels than pregnant Jewish Sephardi women of the same area (Biale et al., 1979). A survey of plasma 25(OH)D levels in 119 pregnant Saudi Arabian women, whose clothing also restricts their

exposure to ultraviolet light, revealed the mean serum concentration to be extremely low (5.7 ng/ml). However, the women in the survey who were of a higher socioeconomic background and received prenatal care and vitamin D supplementation had higher plasma concentrations of 25(OH)D (7.0 ng/ml). Pregnant Asian women (Brooke et al., 1980. 1981; Heckmatt et al., 1979) and pregnant Asian vegetarian women (Dent and Gupta, 1975) living tn London were found to have low circulating 25(OH)D (Brooke et al., 1980, 1981; Dent and Gupta, 1975; Heckmatt et al., 1979) levels and a tendency to develop osteomalacia (Felton and Stone, 1966). The infants born to these mothers had a higher incidence of neonatal hypocalcemia (Heckmatt et al 1979). One study revealed 25(OH)D to circulate at higher concentrations in white women than In black women (Hollis and Pittard, 1984). Pregnant women from Belgium, France, and Switzerland have lower circulating 25(0H)D than their American counterparts, most likely because of the higher latitutde of Bel-

333

SK. Paulson and H.F. DeLuca: Vitamin D during pregnancy

lowing maternal supplementation with ergocalciferol. The ratio of the concentrations of 1,25(OH),D* and 1 ,25(OH)2D3 does not differ in cord and maternal serum in women supplemented with vitamin D, (Markestad et al., 1984). However, the ratio of 1,25(OH),D, to 1,25(OH)2D3 was significantly higher than the ratio of 25(OH)D2 to 25(OH)D3 in both maternal and cord serum. The reason(s) for the discrepancy is not known but may be due to (1) differences in half-life of the vitamin D, and D3 compounds or (2) differences in the affinities of 25-hydroxylated vitamin De and D, compounds for the renal I-hydroxylase (Markestad et al., 1984).

gium (Bouillon et al., 1981) and lack of vitamin D supplementation in their diet (Bouillon et al., 1981; Delvin et al., 1982; Wieland et al., 1980). Vitamin D supplementation in pregnant women will raise plasma 25(OH)D levels and reduce the incidence of osteomalacia (Brooke et al., 1981; Cockburn et al., 1980). Studies in humans (Bouillon et al., 1981; Brooke et al., 1980; Cockburn et al., 1980; Delvin et al., 1982; Gertner et al., 1980; Gupta et al., 1982; Heckmatt et al., 1979; Hillman and Haddad, 1974; Hillman et al., 1978; Seino et al., 1982; Serenius et al., 1984; Weisman et al., 1978a; Wieland et al., 1980) sheep (Bartlet et al., 1978; Ross et al., 1980), calf (Goff et al., 1982), and piglet (Goff et al., 1984) showed maternal plasma 25(OH)D levels to be higher than and positively correlated with umbilical vein or neonatal plasma 25(OH)D levels. Maternal and umbilical venous cord 25(OH)D levels are equal but not correlated in man (Steichen et al., 1980). In rats, plasma 25(OH)D has been reported to be higher in the fetus than in the mother (Danan et al., 1980). The observation of a positive correlation between maternal and fetal 25(OH)D is that 25(OH)D is of maternal origin. Maternal to fetal transfer of 25(OH)D has been demonstrated both in vivo (Devaskar et al., 1984; Haddad et al., 1971) and in vitro (Moshe et al., 1984), but the rate of maternal to fetal placental transfer of 25(OH)D as it relates to total fetal turnover has yet to be established. Using simultaneous measurements of plasma levels of 25(OH)D and vitamin D-binding protein, along with estimations of the Kd for 25(OH)D, binding to the plasma vitamin D-binding protein, investigators have estimated free 25(OH)D to be higher in cord than maternal sera (Bouillon et al., 1981). These data reveal a maternal to fetal gradient of free 25(OH)D that is opposite to that observed when comparing total 25(OH)D levels. Free hormone may be more available than bound hormone for placental transfer, although this is mere speculation without experimental evidence. As a recent publication emphasized (Bikle et al., 1984), estimations of the Kd of the vitamin D-binding protein for 25(OH)D3 vary 1OOO-fold, so determinations of free 25(OH)D as described may contain considerable error. Vitamins D2 and D, appear to be metabolized similarly by the mother and fetus. Markestad et al. (1984) showed that the ratio of 25(OH)D, to 25(OH)D, was the same in both maternal venous and umbilical venous serum fol-

Plasma 24,25(0H)2D concentrations during pregnancy have been determined in several species Table II). In rats (Danan et al., 1980; Halloran et al., 1979) and rabbits (Kubota et al., 1982) 24,25(OH),D circulates at lower concentrations in pregnant animals than in nonpregnant controls. In pregnant women, plasma 24,25(OH)2D concentration has been reported to be both lower than (Hillman et al., 1978; Reiter et al., 1979; Weisman et al., 1978a) and equal to (Seino et al., 1982; Wieland et al., 1980) the levels in nonpregnant controls. However, the early purification procedures of the assays used in the former human studies may not have excluded other vitamin D metabolites. Cord 24,25(OH)2D levels in humans are lower than and correlated with maternal values (Delvin et al., 1982; Seino et al., 1982; Weisman et al., 1978; Wieland et al., 1980). Neonatal 24,25(OH)2D levels in calf (Goff et al., 1982) and piglet (Goff et al., 1984) are lower than and also correlated with maternal values. These data can also be interpreted to mean that the mother contributes significantly to fetal metabolism of 24,25(OH),D. Tissue cultures of human placenta and decidua (Weisman et al., 1979) and sheep fetal kedney homogenates (Kooh and Vieth, 1980; Ross et al., 1980) contained 25(OH)D-24-hydroxylase activity. These data indicate that placenta and fetal kidney may also be sources of fetal 24,25(OH),D in these species. In rats, 24,25(OH),D circulates at higher concentrations in the fetus than in the mother (Danan et al., 1980; Hillman and Haddad, 1976). Radioactive 24,25(OH),D, administered to pregnant rats can be detected in fetal tissues, indicating maternal to fetal transfer of the compound (Noff

Table II. Plasma 24,25(OH),D levelsa in nonpregnant adult, pregnant adult, and fetal/neonatal subjects of several species Species Human Human Humanb Human Human Human Pig cow Rabbit Rat

Race

Nonpregnant adult

Blacks Whites

3.9 2 0.37 1.8 t 0.7 3.1 * 0.9 1.5 * 0.68 2.7 2 0.4=

Blacks Whites 24,25(0H),D, levels 24,25(OH),D, levels 4.2 -r- 1.0 12.5

a Mean 2 SEM (ng/ml). b Data expressed as nmolil. c Represents first trimester of pregnancy value

Pregnant adult 2.9 1.5 2.3 3.0 1.9 3.3 1.0 1.6 28.8 0.4 5.2 1.4

? 0.26 * 0.6 ” 1.1 t 0.7 2 1.43 + 0.7 * 0.58 ? 0.61 ” 16.4 t- 0.2 ? 1.5 2 0.2 6.5

Fetal/Neonatal 2.5 1.1 1.5 1.8 1.3

” 2 A 2 2

0.26 0.3 0.5 0.4 0.60

0.4 0.8 7.9 0.4 4.4

* ? + * 2

0.29 0.25 3.8 0.2 0.9

14

Reference Hillman et al., 1978 Weisman et al., 1978a Weisman et al., 1978a Delvin et al.. 1982 Seino et al., 1982 Reddy et al., 1983 Hollis and Pittard, 1984 Hollis and Pittard, 1984 Goff et al., 1984 Goff et al., 1982 Kubota et al., 1982 Danan et al., 1980

S K Paulson and H F DeLuca. Vitamin D during pregnancy

334

and Edelstern, 1978). Both rat fetal kidney (Wersman et al.. 1976) and yolk sac (Danan et al., 1982) have 24.hydroxylase activity but little or no 1-hydroxylase activity. Maternal nephrectomy of the vitamin D-deficient, pregnant rat given 251(0H)[~HlD, intravenously will decrease fetal plasma 24,25(OH)[3H]D, at 6 h but not 36 h after the substrate injection (Gray and Lester, 1981). These data indicate that maternal kidney, fetal kidney, and placenta all can supply the rat fetus with 24,25(OH),D. However. the amount of 24,25(OH),D.each of these tissues contribute to fetal 24,25(OH),D turnover cannot be determined from these studies. 1,25(OH),D 1,25(OH&,D is the most active metabolite of vitamin D tn mobilizing calcium from bone and stimulating intestinal calcium transport and whose circulating levels are regulated according to the mineral needs of the organism. A summary of nonpregnant adult, pregnant adult, and fetal/ neonatal plasma levels of 1 ,25(OH)2D in several species is presented in Table III. Kumar et al. (1979) reported elevated 1,25(OH)*D levels early tn human pregnancy, which rose to a peak at term. This observation has been confirmed by other laboratories in humans (Bouillon et al., 1977; Delvin et al., 1982; Lund and Selnes, 1979; Reddy et al., 1983; Seino et al., 1982; Steichen et al., 1980; Whitehead et al., 1981; Wieland et al., 1980), rats (Halloran et al., 1979; Pike et al.. 1979), and rabbits (Kubota et al, 1982). The mechanrsm for the increase in maternal plasma 1,25(OH)*D concentrations during pregnancy is not known. It has been hypothesized that the low maternal plasma calcium concentration, characteristic of pregnancy (Pitkin, 1975), acts via parathyroid hormone to stimulate 1,25(OH)*D synthesis. In sheep, maternal parathyroidectomy in the third trimester will reduce but not abolish circulating 1,25(OH)*D levels (Ross et al., 1980). Third-trimester plasma parathyroid hormone has been shown to be both elevated (Bouillon and DeMoor, 1973; Cushard et al., 1972; Reddy et al., 1983) and unchanged (Delvin et al., 1982; Gillette et al., 1982; Seino et al., 1982; Steichen et al., 1980; Wieland et al., 1980) from values in control

human subjects. One longitudinal study in humans found PTH to increase with gestational age but not to correlate with the increase in serum 1,25(OH),D (Reddy et al., 1983). The same study found no correlation between the elevated plasma 1,25(OH)*D of pregnancy and Increased levels of prolactin, estrogens, or human placental lactogen. However, another study found increased maternal plasma levels of prolactin to be correlated with the elevated levels of 1,25(OH),D (Lund and Selnes, 1979). The stimulus behind the increase synthesis of 1,25(OH)*D during pregnancy remains to be elucidated. In humans, placental vein 1,25(OH)2D concentrations are lower than and not correlated with maternal values (Delvin et al., 1982; Fleischman et al., 1980; Gertner et al., 1980; Serno et al., 1982; Steichen et al., 1980; Wieland et al., 1980). Neonatal plasma 1,25(OH),D levels in calf (Goff et al 1982) and piglet (Goff et al., 1984) are also lower than and not correlated with maternal values, whereas in the sheep, 1,25(OH),D circulates at higher concentrations in the fetus than in the mother (Ross et al., 1980) and the maternal and fetal levels were significantly correlated. Excepting the sheep, these data may indicate little maternal influence over fetal metabolism of 1,25(OH)2D. Indeed, both placenta and fetal kidney have the capacity to synthesize 1,25(OH),D. Placental 1-hydroxylase activity has been observed in a number of species: (1) vitamin D-deficient rat placental whole homogenates (Tanaka et al.. 1979) and cell cultures (Gray and Lester, 1981), (2) guinea ptg placental homogenates (Fenton and Britton, 1980). and (3) homogenates of human decidua (Weisman et al.. 1979; Delvin et al., 1985) and villous tissue (Whitsett et al., 1981) but not in homogenates of rabbit placenta (Sunaga et al., 1979) or yolk sac from vitamin D-deficient rats (Danan et al.. 1982). Fetal kidney I-hydroxylase activity has been found in rabbit (Sunaga et al., 1979), guinea pig (Fenton and Britton, 1980), and pig (Sommerville et al., 1978) kidney homogenates and in cells isolated from kidney from vitamin D-deficient rats (Gray and Lester, 1981). The human fetus is capable of synthesizing 1,25(OH)*D in vivo, since human fetal arterial levels of 1,25(OH)*D are higher than umbilical vein levels (Wieland

Table III. Plasma 1,25(OH),D level9 in nonpregnant adult pregnant adult and fetal.:neonatal subjects of several species

Species

Race

Human Human Human Human Human Humanb Human Human Human Human

Nonpregnant adult 53 i

29 -+ 45 -t 62 -+ 43? 74 -+ 41 2

148

1 14 86 151

ac 11 5

Blacks Whrtes

Prg cow Sheep Rabbit Rat Rat a Mean 5 SEM (pgiml) b Data expressed as pmol!l c Represents frrst trtmester of pregnancy

55?

109 25 100

value

Pregnant adult 87 -t 52 8 60~64 77 r 54 63 f 11 97 r 26 142 2 12 89 i 53 t 81 i 11 82 i- 21 65 i 170 61 -t 27 1 76 i- 29 0 85? 157 58 i 5 102 i 165 90 180

Fetal/Neonatal

25~33 58 2 36 19 2 4 48 2 11 82 i 10 66 2 38 0

24 i 64 24i89 42 2 102 43234 88 i- 12

Reference Kumar et al 1979 Flerschman et al 1980 Gertner et al., 1980 Sterchen et al 1980 Bouillon et al 1981 Delvrn et al 1982 Serno et al 1982 Reddy et al 1983 Brkle et al 1984 Hollis and Pittard, 1984 Hollis and Prttard. 1984 Goff et al 1984 Goff et al 1982 Ross et al 1980 Kubota et al 1982 Hailoran et al 1979 Prke et al 1979

S K Paulson

and H F. DeLuca:

Vitamin

D during

pregnancy

et al., 1980). Bilateral nephrectomy of the pregnant rat, unlike in the nonpregnant animal, will not completely inhibit the in vivo production of 1,25(OH),D (Gray et al., 1979; Lester et al., 1978; Weisman et al., 1978b). Nephrectomy of the sheep fetus will lower its plasma 1,25(OH)2D levels (Ross et al., 1980). These data suggest that fetal kidney and/or placental 1-hydroxylase is functional in vivo. A maternal contribution to fetal 1,25(OH)*D metabolism cannot be eliminated. Radioactive 1,25(OH),D, administered to pregnant monkeys (Schedewie et al., 1981), sheep (Devaskar et al., 1984; Ross et al., 1979), and rats (Noff and Edelstein, 1978) can be detected in fetal tissues. However, rates of 1 ,25(OH)2D transfer across the placenta cannot be assessed from these types of studies. The amount of radioactivity accumulated in the fetus after a bolus dose of tritiated 1,25(OH),D, to the mother will vary according to (1) time of animal sacrifice after dose and (2) rate of 1,25(OH),D turnover in the mother and fetus. Further studies are needed to determine the contribution made by maternal kidney, fetal kidney, and placenta to total fetal 1 ,25(OH)2D supplies. Third trimester free 1 ,25(OH)2D serum concentrations have been calculated by two groups. One group determined that the “free 1,25(OH)2D index” (the molar ratio of plasma 1,25(OH),D and vitamin D-binding protein concentration) increased during the last weeks of pregnancy (Bouillon et al., 1977). Using centrifugal ultrafiltration and equilibrium dialysis, other investigators also found that mean free 1,25(OH)2D increased in the third trimester of pregnancy (Bikle et al., 1984). Total and free 1,25(OH)2D levels were highly correlated in the former but not in the latter study.

Acknowledgement: This work was supported by a Prosram Project Grant No. AM14881 from the Naiidnal Institutes of Health and by the Harry Steenbock Research Fund of the Wisconsin Alumni Research Foundation

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Wilkinson E M , Forfar J 0 Barrie W J M , McKay G S. and Pocock SJ Maternal vitamin D intake and mineral metabolism in mothers and their newborn infants. Br. Med. J. 261 11-14, 1980 Cushard W G., Creditor M A, Canterbury J M and Reiss E. Physiologic hyperparathyroldism in pregnancy J. C//n Endocrinol Metab 34 767771, 1972. Danan J.L., Delorme A.C and Mathieu H 25.Hydroxyvitamin D, and 1,25dihydroxyvitamin D, 24.hydroxylase in vitamin D target cells of rat yolk sac J Viol Chem. 257 10715-10721, 1982 Danan J.L Delorme A.C., Benassayag C Vallette G and CuislnlerGleizes P.: 25.Hydroxyvltamln D In maternal plasma, fetal plasma and amniotic fluid in the rat. Biochem. Biophys. Res. Commun 95.453-460, 1980. Delvin E.E., Arabian A, Glorieux F.H. and Mamer 0 A In vitro metabolism of 25.hydroxycholecalciferol by Isolated cells from human decldua J. Cbn. Endocrinol. Metab. 60.880-885. 1985. Delvin E.E.. Glorieux F.H.. Salle B.L and Varenne J P Control of vitamin D metabolism in preterm Infants Fetal-maternal relatIonshIps Arch. D/s Ch/ld. 57 754-757, 1982 Dent C E and Gupta M.M.: Plasma 25hydroxyvitamin D levels during pregnancy in Caucasians and In vegetarian and nonvegetarian Asians Lancet 2 1057-1060, 1975. Devaskar U.P.. Ho M , Devaskar SU and Tsang R C 25.Hydroxy- and 1.25-dihydroxyvitamin D, Maternal-fetal relatIonshIp and the transfer of 1.25.dihydroxyvitamin D, across the placenta in an ovine model. Dev Pharmacol. Ther. 7 213-220, 1984 Felton D J C. and Stone W D Osteomalacia in Asian immigrants during pregnancy Br. Med. J. 1:1521-1522. 1966 Fenton E. and Brltton H.G 25-Hydroxycholecalciferol 1-hydroxylase activity In the kidney of the fetal, neonatal and adult guinea pig BIO/. Neonate 37:254-256, 1980 Fleischman A R , Rosen J.F., Cole J., Smith C M and DeLuca H F. Maternal and fetal serum 1,25-dlhydroxyvltamlri D levels at term J. Pediatr. 97 640-642. 1980. Gertner J M , Glassman M.S.. Coustan D R. and Goodman D B P: Fetomaternal vitamin D relationships at term. J. Pedfatr. 97:637-639, 1980 Gillette M E lnsogna K L.. Lewis A.M and Baran D T Influence of pregnancy on immunoreactive parathyrotd hormone levels Calcff. T/sue Int. 34-9-12, 1982. Goff J.P Horst R L. and Littledike ET Effect of the maternal vitamin D status at parturition on the vitamin D status of the neonatal calf J. Nutr. 112~1387-1393, 1982 Goff J P , Horst R L. and LIttledike E T : Effect of sow vitamin D status at parturition on the vitamin D status of neonatal plglets J Nutr. 114.163169, 1984. Gray T K and Lester G E.: Vitamin D metabolism in the pregnant rat. In Hormonal Control of Calcium Metaboksm. D V Cohn, R V Talmage. and J L. Matthews, eds Excerpta Medlca, Amsterdam, 1981. pp 236-242 Gray T.K Lester G E and Lorenc R S Evidence for extrarenal 1-hydroxylation of 25.hydroxyvltamln D, in pregnancy Science 204:131 I-1313, 1979. Gupta M M., Kuppuswamy G and Subramanian A R. Transplacental transfer of 25.hydroxycholecalciferol Post. Med. J. 56.408-410. 1982 Haddad J.G., Boisseau V. and Avioll L.V.. Placental transfer of vitamin D, and 25.hydroxycholecalciferol in the rat J. Lab. C/in. Med. 77 90& 915,197l. Halloran B.P., Barthell E N. and DeLuca H F Vitamin D metabolism during pregnancy and lactation in the rat Proc. Nat/ Acad Sci. USA 76:5549-5553, 1979 Heckmatt J L , Peacock M.. Davies A E., McMurray J. and Isherwood D M Plasma 25.hydroxyvitamln D In pregnant Asian women and their babies. Lancet 2.546-548, 1979 Hillman LS and Haddad J.G Human perlnatal vitamin D metabolism I 25.hydroxyvitamln D in maternal and cord blood J. Pediatr 64.742749, 1974. Hillman L.S and Haddad J G. Perinatal vitamin D metabolism Ill Factors influencing late gestational human serum 25.hydroxyvltamln D Am J. Obstet. Gynecol 125196-200, 1976 Hillman L S , Slatopolsky E and Haddad J G Pennatal vltamln D metabolism. IV. Maternal and cord serum 24,25-dlhydroxyvitamln D concentratlons. J. C/in. Endocrinol. Metab. 37.1073-1077. 1978 Hollis B.W. and Pittard W.B Evaluationof the toal fetomaternal vitamin D

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S K Paulson

and H.F

DeLuca.

Vitamin

D dunng

pregnancy

Matsuda S Shtmotsufr T , Yabuuchr H , Morimoro S and Onshl T Serum calcrum regulatrng hormones rn the pertnatal penod Caiclf Tissue Int. 34 131- 135, 1982 Serenrus F Elrdnssy A and Dandonsa P Vitamrn D nutntron in pregnant women at term and rn newly born babies In Saudi Arabia. J C/in Pathol 37 4444447, 1984 Shepard R M Horst R L Hamstra A J and DeLuca H F Determlnatron of vltamrn D and its metabolrtes in plasma for normal and anephrlc man Bochem J 182:55-69. 1979 Sommervrlle B A Fox J and Care A D The In vrtro metabolrsm of 25hydroxycholecalciferol by prg krdney Effect of low dretary levels of calcium and phosphorus Br J Nufr 40:159%162. 1978 Slamp T C B Haddad J G and Twrgg C A Comparison of oral 25.hydroxycholecalcrferol, vrtamtn D and ultraviolet lrghl as determinants of circulatrng 25.hydroxyvitamrn D Lancer 1 1341-1343, 1977 Sterchen J J Tsang R C Gratton T L Hamstra A and DeLuca H F VItamrn D homeostasis in the perrnatal period-1,25(OH),D in maternal, cord and neonatal blood N. Engl. J. Med 302:315-319. 1980 Sunaga S Horurchr N , Takahashr N Okuyama K and Suda T The site of 1 25.drhydroxyvctamin D, productron in pregnancy Biochem Biophys Res Commun 90.948-955, 1979 Tanaka Y Halloran B ,, Schnoes H K and DeL;ca H F In vitro productton of 1.25.dthydroxyvrtamin D, by rat placental tissue Proc. Nafi. Acad SC/ USA 76 5033-5035. 1979 Turton C W G Stanley P Stamp T C.B and Maxwell J D Altered vltamrn D metabolrsm In pregnancy Lancet 1 2222224, 1977 Welsman Y Saplr R Harell A and Edelstein S Maternal-perrnatal interrelatronshrps of vrtamrn D metabolism In rats BIoch/m Biophys Acta 428 388 -395. 1976 Wersman Y Occhrprntr, Knox G Rerter E and Root A Concentratrons oi 24.25.drhydroxyvitam~n D and 25hydroxyvrtamrn D In parred maternalcord sera Am. J. Obstet Gynecol. 130 704-707, 1978a Wersman Y Vargas A Duckett G Reiter E and Root A W Synthesis of 1 25.drhydroxyvrtamrn D in the nephrectomized pregnant rat Endow nology 103 1992-1996, 1978b Wetsman Y Harell A, Edelstetn S Davrd M Spirer 2 and Golander A 1.25.Dlhydroxyvitamrn D, and 24,25-dihydroxyvrtamrf D, In vitro synthess by human decrdua and placenta Naiure 281 317-319, 1979 WhItehead M Lane G Young 0 Campbell S Abe-Yasekera G Hillyard C Maclntyre I Phang K G and Stevenson J.C InterrelatIons of calm clum~regulat~ng hormones during normal pregnancy Br Med J 283 lo-12 1981 Whltsett J A, Ho M Tsang R C Norman E J and Adams K G Synthesis of 1 25dthydroxyvltamin D3 by human placenta rn vrtro J C/in. Endocrfnoi Metab 53484-488 1981 Wreland P Frscher J A, Trechsel U Roth H -R Vetter K , Schnerder H and Huch A Perinatal paralhyrord hormone. vrtamrn D metabolrtes and calcrtonrn In man Am J Physrol 239.E3855E390 1980

Received October

29. 1985 Rewed February 24, 1986 Accepted. Apnl3. 1986