Safety of antenatal vitamin DRoth, DE
Vitamin D supplementation during pregnancy: safety considerations in the design and interpretation of clinical trials
SUPPLEMENTARY INFORMATION – TABLES
Table 1. Human trials of vitamin D supplementation in pregnancy
Maternal [25(OH)D] / Cord Blood [25(OH)D] / Reported Effects of Vitamin D on serum calcium concentration[i]Study / Country / Intervention / Timing / N / Pulse dose (mg) / Daily dose (mg) / Estimated cumulative dose[ii] (mg/kg) / Baseline [25(OH)D] (nmol/L) / Timing of baseline (wks of gestation) / [25(OH)D] (nmol/L)
at delivery / [25(OH)D] (nmol/L) / Cord: maternal ratio of means[iii] / Increased maternal [Ca]? / Increased fetal or infant [Ca]?
Randomized Controlled Trials
Brooke (1980)1 / UK / Vitamin D2, 1000 IU/d / 3rd trim. / 59 / 0 / 0.025 / 0.032 / 20.2 / 28 / 168.0 / 138.0 / 0.82 / Yes / YesPlacebo / 3rd trim. / 67 / 0 / 0 / 0.000 / 20.0 / 28 / 16.2 / 10.2 / 0.63
Mallet (1986)2 / France / Vitamin D2, 1000 IU/d / 3rd trim. / 21 / 0 / 0.025 / 0.035 / 9.4 / 28 / 25.3 / 15.7 / 0.62 / No / No
Vitamin D2, 200,000 IU / 7th mo. / 27 / 5 / 0 / 0.083 / 9.4 / 28 / 26.0 / 18.2 / 0.70
No supplement / 29 / 0 / 0 / 0.000 / 9.4 / 28 / 9.4 / 5.3 / 0.56
Delvin (1986)3 / France / Vitamin D3 1000 IU/d / 3rd trim. / 14 / 0 / 0.025 / 0.000 / 27.5 / 26 / 65.0 / 45.0 / 0.69 / No / Yes
No supplement / 13 / 0 / 0 / 0.000 / 27.5 / 26 / 32.5 / 17.5 / 0.54
Zeghoud (1988)4 / France / Vitamin D3, 100,000 IU / 6th mo. / 37 / 2.5 / 0 / 0.042 / 32.8 / 24 / 37.5 / 16.3 / 0.43 / No / Yes
Vitamin D3, 100,000 IU / 7th mo. / 9 / 2.5 / 0 / 0.042 / 23.9 / 28 / 35.6 / – / –
Placebo / 6th or 7th mo / 32 / 0 / 0 / 0.000 / 25.9 / 24 / 19.4 / 12.6 / 0.65
Marya (1988)5 / India / Vitamin D3 600,000 IU x 2 / 7th & 8th mo. / 100 / 15 / 0 / 0.500 / – / – / – / – / – / Yes / Yes
No supplement / 100 / 0 / 0 / 0.000 / – / – / – / – / –
Yu (2009)6 / UK / Vitamin D2 800 IU/d / 3rd trim. / 60 / 0 / 0.02 / 0.030 / 26.0 / 27 / 42.0 / 26.0 / 0.62 / – / –
Vitamin D2, 200,000 IU / 27th wk. / 60 / 5 / 0 / 0.083 / 26.0 / 27 / 34.0 / 17.0 / 0.50
No supplement / 60 / 0 / 0 / 0.000 / 25.0 / 27 / 27.0 / 25.0 / 0.93
Sahu (2009)7 / India / Vitamin D3, 60,000 IU / 5th month / 35 / 1.5 / 0 / 0.025 / 33.4 / 20 / 30.9 / – / – / No / –
Vitamin D3, 120,000 IU x 2 doses / 5th & 7th months / 35 / 3.0 / 0 / 0.1 / 40.1 / 20 / 53.4 / – / –
No supplement / 14 / 0 / 0 / 0 / 25.8 / 20 / 23.8 / – / –
Non-Randomized Controlled Trials
Cockburn (1980)8 / Scotland / Vitamin D2, 400 IU/d / 2nd & 3rd trim. / 262[iv] / 0 / 0.01 / 0.000 / 39.0 / 24 / 42.8 / 28.0 / 0.65 / No / YesPlacebo / 2nd & 3rd trim. / 459d / 0 / 0 / 0.000 / 32.5 / 24 / 32.5 / 20.0 / 0.62
Marya (1981)9 / India / Vitamin D, 1200 IU/d / 3rd trim. / 25 / 0 / 0.03 / 0.045 / – / – / – / – / – / No / Yes
Vitamin D2 600,000 IU x 2 / 7th & 8th mo. / 25 / 15 / 0 / 0.500 / – / – / – / – / –
None / 75 / 0 / 0 / 0.000 / – / – / – / – / –
Non-Controlled Studies
Madelenat (2001)10 / France / Vitamin D2, 80,000 IU / 27th– 32ndwk / 59 / 2 / 0 / 0.033 / 35.5 / 30 / 49[v] / 36.3 / 0.74 / Maybe[vi] / Maybe[vii]Datta (2002)11 / Wales / Vitamin D, 800 IU/d[viii] / Variable / 80 / 0 / 0.02 / 0.000 / 14.5 / – / 28.1 / – / – / – / –
Retrospective Study
Congdon (1983)12 / UK / Vitamin D2, 1000 IU/day / 3rd trim. / 19 / 0 / 0.025 / 0.0375 / – / – / – / 15.2 / – / – / Yes
None / 45 / 0 / 0 / 0 / – / – / – / 5.9 / –
Safety of antenatal vitamin DRoth, DE
Table 2. Effect of antenatal vitamin D supplementation on maternal, fetal, and neonatal serum calcium concentrations, and the incidence of hypocalcemia in published controlled trials.
Study / Vitamin D (IU) / Peri-partum maternal [Ca] (mmol/L)[ix] / Cord [Ca] (mmol/L)[x] / Neonatal [Ca] (mmol/L) / Incidence of Neonatal Hypocalcemia (%)Vitamin D / Control / Vitamin D / Control / Significant difference per authors? / Postnatal day / Vitamin D / Control / Significant difference per authors? / Vitamin D / Control
Brooks 1980 / 1000 IU/day / 2.58 / 2.51 / 2.71 / 2.65 / No / 3 / 2.3 / 2.18 / Yes / 6.3 / 24.6
Cockburn 1980 / 400 IU/day / 2.35 / 2.38 / 2.66 / 2.69 / No / 6 / 2.34 / 2.25 / Yes / 6 / 13[xi]
Marya 1981 / 1,200,000 IU in 2 doses / 2.26 / 2.2 / 2.55 / 2.52 / Yes / – / – / – / – / – / –
1200 IU/day / 2.31 / 2.2 / 2.67 / 2.52 / No / – / – / – / – / – / –
Congdon 1983 / 1000 IU/day / 2.64 / 2.5 / Yes / – / – / – / – / – / –
Mallet 1986 / 200,000 IU in single dose / 2.15 / 2.1 / 2.44 / 2.37 / No / 2 / 2.41 / 2.36 / No / 0 / 3.4
1000 IU/day / 2.15 / 2.1 / 2.41 / 2.37 / No / 2.48 / 2.36 / No / 0 / 3.4
Delvin 1986 / 1000 IU/day / 2.55 / 2.63 / No / 4 / 2.28 / 2.1 / Yes
Zeghoud 1988 / 100,000 IU in single dose in 6th month / 2.2 / 2.2 / 2.53 / 2.51 / No / 5 / 2.49 / 2.35 / Yes, in spring / – / –
100,000 IU in single dose in 7th month / 2.2 / 2.19 / – / – / – / 5 / 2.48 / 2.35 / Yes, in spring / – / –
Marya 1988 / 1,200,000 IU in 2 doses / 2.34 / 2.24 / 2.77 / 2.57 / Yes / – / – / – / – / – / –
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Safety of antenatal vitamin DRoth, DE
Table 3. Published reports of infant/child outcomes following high-dose antenatal vitamin D treatment of hypoparathyroid women.
Study
/ Intervention / Number of pregnancies / Average Daily vitamin D dose (mg/kg/dose) / Approximate cumulative vitamin D dose (mg/kg) /Maternal Status[xii]
/ Infant Outcome[xiii]Greer (1984)13 / Vitamin D2 100,000 IU/day throughout pregnancy / 1 / 0.042 / 11.8 / No clinical adverse effects. [25(OH)D] rose to 1375 nmol/L; serum [Ca] was low-normal at delivery (2.12 mmol/L). / Highest serum [Ca] was 2.85 mmol/L (normal); no clinical signs of hypercalcemia or vitamin D toxicity despite a cord blood [25(OH)D] of 633 nmol/L. BW 2.13 kg.
Bolen (1973)14 / Vitamin D 50,000-100,000 IU/day from 15 weeks gestation / 1 / 0.031 / 5.5 / Healthy. Serum [Ca] 2.2-2.5 mmol/L / Healthy infant boy born at 38 weeks gestation; BW 3.6 kg. Child followed for 6 years with no evidence of any anomalies.
Goodenday (1971)15 / Vitamin Dat average 107,000 IU/day throughout pregnancy / 15 / 0.045 / 12.6 / Reportedly normal serum [Ca] during pregnancy. / Children examined at ages ranging from 6 weeks to 16 years; none had cardiovascular or craniofacial stigmata of Williams syndrome.
Wright (1969)16 / Vitamin D2 100,000 IU/day throughout pregnancy / 1 / 0.042 / 11.8 / Serum calcium remained between 2.45 - 2.75 mmol/L. / 1st: "normal male infant", BW 4.0 kg; 2nd pregnancy: "normal female infant", with high-normal cord [Ca] (3.0 mmol/L), BW 3.66 kg.
Vitamin D2 150,000 IU/day throughout pregnancy / 1 / 0.0625 / 17.5 / Serum calcium remained normal (2.3 – 2.7 mmol/L) during pregnancy. / "Normal infant" at term; cord plasma [Ca] = 2.9 mmol/L (normal). BW 3.3 kg.
O’Leary (1966)17 / Vitamin D 150,000 IU/day (approx) from 10 weeks gestation / 1 / 0.0625 / 13.1 / Serum [Ca] ranged from 2.1-2.5 mmol/L after treatment initiated. No reported adverse effects. / Healthy male infant born at 39 weeks gestation, with Apgar score of 8/10; BW 4.03 kg. Normal development to 3 years.
Vitamin D 50,000-100,000 IU/day from 8 weeks gestation / 1 / 0.031 / 7.0 / Serum [Ca] maintained between 2.0 – 2.4 mmol/L. No reported adverse effects. / Healthy female infant born; Apgar score 8/10; BW 3.13 kg. No other information.
Graham (1964)18 / Vitamin D2 50,000-200,000 IU/day / 10 / 0.021 - 0.084 / – / Serum [Ca] generally maintained in normal range. No adverse effects described. One spontaneous abortion at 3 months gestation. / All 9 live-born infants were “normal”; “no fetal abnormalities were noted”.
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Safety of antenatal vitamin DRoth, DE
Table 4. Animal models of antenatal vitamin D toxicity
Study / Treatment groups / D2 or D3 / Route[xiv] / Individual doses (mg/kg/ dose) / Cumulative dose[xv] (mg/kg) / Effects of vitamin D on maternal [25(OH)D] or calcium / Effects of vitamin D on fetal/ newborn [25(OH)D] or calcium / Maternal toxicity?[xvi] / Placental, fetal or neonatal toxicity attributed to vitamin D?c / SAS?[xvii] / Craniofacial anomalies?cRats
Ornoy (1968-72)19, 20, 21, 22, 23 / Daily doses of 4000 IU (low), 20,000 IU (med) or 40,000 IU (high) from days 9 to 21 of gestation, vs. controls. / D2 / IG / 0, 0.4,2,
or 4 / 0, 5.2,
26,
or 52 / Elevated [Ca] in high-dose group[xviii] / – / Multi-system adverse effects in high-dose group / Growth restriction and impaired osteogenesis in high-dose group;placental effects in med- and high-dose groups / – / –
Tshibangu (1975)24 / 320,000 IU/kg/day (low) or 480,000 IU/kg/day (med) for 4 days, or 900,000 IU/kg/day (high) for 2 days, compared to ‘no vitamin D’ control. / D2 / IG / 0, 8,
12,
or 22.5 / 0, 32,
45,
or 48 / – / – / Multi-system adverse effects of all doses / Growth restriction and delayed ossification / – / Yes
Ariyuki (1987)25 / 40,000 IU per day for 7 days of gestation, with or without fasting, vs. control / D2 / IG / 0 or 4 / 0 or 28 / – / Poor weight gain. / Growth restriction and delayed ossification. / – / Yes
Norman (2002)26 / ‘Control' (cntrl) average 126 IU/day; 'Low' average 174 IU/day; 'High' average 216 IU/day throughout gestation / D3 / PO / 0.01 (cntrl), 0.015 (low), 0.018 (high) / 0.2 (cntrl), 0.3 (low), or 0.4 (high) / – / Relatively elevated [25(OH)D][xix] / No / Dose-dependent reduction in aortic elastin concentration and aortic contractility / None / –
Rabbits
Friedman (1966)27 / Total 1.5 million units in 15 divided doses during pregnancy ('treated') versus control group (only received vitamin D in stock feed) / D2 / IM / 0 or 0.625 / 0 or 9.4 / Lower [Ca][xx] / Higher [Ca][xxi] / Calcification and necrosis of the medial layer of the aorta. / SAS lesions; elevated risk of an abnormal aorta / Yes / –Friedman (1969)28 / Total 750,000 units in 15 divided doses during pregnancy (‘treated’) versus control group (only received vitamin D in stock feed) / D2 / IM / 0 or 0.3125 / 0 or 4.7 / – / – / – / Growth restriction, craniofacial hypoplasia and high mortality. / – / Yes
Chan (1979)29 / 1000 IU (low), 10,000 IU (med) or 100,000 IU (high) every other day for 14 doses compared to placebo group / D2 / IM / 0, 0.00625, 0.0625,
or 0.625 / 0 (placebo), 0.088 (low), 0.88 (med),
8.8 (high) / Elevated [25(OH)D] and [Ca][xxii]. / No effect[xxiii] / Poor weight gain; rare aortic calcification in high-dose group only / SAS lesions; higher fetal loss in high-dose group; no differences in fetal/placental weights among surviving newborns. / Yes, in mod- and high-dose groups / –
Cows
Littledike (1982)30 / 15 – 17.5 million IU within one month prior to calving, vs. controls. / D3 / IM / 0 or 0.91 / 0, 0.91, or1.07 / Elevated [25(OH)D] and [Ca][xxiv] / – / Severe morbidity and mortality / – / – / –
Pigs
Toda (1985)31 / ‘High’ vitamin D(1 sow) versus 'low' vitamin D (1 sow) / – / PO / – / – / – / Elevated [25(OH)D][xxv] / – / Coronary artery histopathology / – / –
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Safety of antenatal vitamin DRoth, DE
Table 5. Clinical findings in studies of antenatal vitamin D toxicity in animal models.
Study / Maternal toxicities / Placental, fetal or neonatal toxicities / Craniofacial anomaliesOrnoy et al. (1968-72)19, 20, 21, 22, 23 / Hyperlipidemia, fatty liver degeneration, aortic medial hypertrophy, renal tubular degeneration, and mild calcifications in the media of the aorta and bronchial cartilage were evident in dams that received the high dose (40,000 IU/day); the lesions were milder than those in non-pregnant rats administered the same vitamin D dose. / Low fetal weight, decreased bone mineral content and delayed ossification occurred in high-dose group; placentae showed decreased weight, calcification, and degeneration in both med- and high-dose groups. / –
Tshibangu et al. (1975)24 / Weight loss occurred at all dose levels except the medium dose administered late in pregnancy, which was associated with slower weight gain than the control group; physical debilitation, widespread metastatic calcifications and early death were common following the medium and high doses administered early but not in either the medium-dose group administered late or the low-dose group. / Fetal growth restriction occurred in all vitamin D-treated groups, but was less pronounced in the group administered the medium dose late in pregnancy; delayed ossification, skeletal malformations, disseminated placental calcifications, and abnormal craniofacial skin plaque occurred in vitamin D groups treated early in pregnancy. / Craniofacial skin plaque termed “carnival fetus” in ~1/3 of pups born to mothers intoxicated early in pregnancy.
Ariyuki et al. (1987)25 / Poor weight gain. / Growth restriction and delayed ossification. / "Carnival fetus" appearance (as described by Tshibangu) in 22-54% of fetuses born to rats administered D2 and fasted, but 0% in rats only given D2 and not fasted.
Norman et al. (2002)26 / All animals were reportedly “healthy”. / Higher vitamin D intake was associated with greater offspring body weight, reduced aortic elastin concentration and reduce aortic contractility compared to control animals; there were no calcifications or inflammatory infiltrates in the aortic media in any rats. / None reported.
Friedman and Roberts (1966)27 / Calcification and necrosis of the medial layer of the aorta. / Among offspring sacrificed at birth: 14/18 (78%) treated versus 23/23 (100%) controls had normal aortae; exaggerated supravalvular plica were found in 11/14 (79%) treated versus 5/23 (22%) controls. Medial degeneration and calcification of the aorta (lesions similar to those seen in the vitamin D-treated mothers) was found in 6 ‘treated’ rabbits at 3 months of age. / SAS-like medial aortic lesions in 6/34 (18%) treated offspring versus 0/35 controls; at birth, lesions involved proliferation of media, without calcification.
Friedman and Mills (1969)28 / – / Within 7 days of birth, 95/110 (86.4%) of offspring in vitamin D group died spontaneously. Offspring of treated animals had lower weights, higher death rates, craniofacial hypoplasia, dental malocclusion, and strabismus. / 70-95% of offspring had a range of cranial, dental, and ocular abnormalities.
Chan et al. (1979)29 / Lower weight gain in all vitamin D-treated groups vs. controls; aortic calcifications occurred in two rabbits from the highest dose group. / Prevalence of supravalvular aortic stenosis: High-dose group: 6/20 (30%) newborns; Med-dose group: 2/11 (18%) newborns; Low-dose: 0/13 newborns; control: 0/27 newborns. / –
Littledike (1982)30 / 10/17 (59%) treated vs. 0% control cows died within 3 weeks of calving; 8 of 10 cows had severe clinical signs of toxicity prior to death, including anorexia, acidosis, respiratory distress, and fever. There was widespread calcification in the cows that died. Notably, non-pregnant cows administered the same doses did not manifest toxicity. / – / –
Toda (1985)31 / – / 2.6% vs. 1.2% "degenerated smooth muscle cells", and 3.9% versus 1.9% "lipid-containing cells", in coronary arteries of piglets born to sows with high versus low vitamin D intake. / –
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Safety of antenatal vitamin DRoth, DE
Table 6. Summary of selected hypothetical mechanisms of maternal or fetal toxicity of high-dose antenatal vitamin D supplementation
Hypothesis / Evidence / Implications for trial designMaternal hypercalcemia due to vitamin D toxicity may lead to maternal and fetal harms. / There is sufficient evidence to predict that a fetus would be harmed by maternal hypercalcemia caused by maternal vitamin D excess. / Antenatal doses should not exceed those believed to be associated with a low risk of hypercalemia in non-pregnant adults: daily doses <10,000 IU (250 mcg/day); or, single doses <300,000 IU (7.5 mg).
Following a large oral dose of vitamin D3, a rapid increase in the maternal serum vitamin D3 concentration may cause toxicity by transiently increasing serum 1,25(OH)2D concentrations / Trials in non-pregnant adults suggest that a transient rise in [1,25(OH)2D] may occur, but doses less than 7.5 mg do not appear to have effects on serum calcium concentrations. There is a lack of published data from pregnant women. / In preliminary studies using large single doses, serum calcium concentrations should be monitored in the first 1 to 3 days following D3 dose administration, as well as throughout the period of supplementation.
Extra-renal (e.g., placental-decidual) vitamin D metabolism during pregnancy may create a state of hypersensitivity to exogenous vitamin D3. / Prospective trials to date do not suggest that pregnancy induces a grossly exaggerated response to oral vitamin D. Animal studies are inconsistent: pregnant rats are relatively resistant to vitamin D toxicity, whereas pregnant cows are relatively susceptible. / Careful biochemical monitoring of trial participants should include measures of calcium homeostasis (i.e., serum calcium and urinary calcium excretion), as these are the most sensitive biomarkers of vitamin D toxicity.
Increases in maternal circulating vitamin D, 25(OH)D or 1,25(OH)2D may cause excessive circulating fetal 25(OH)D or 1,25(OH)2D concentrations, even in the absence of maternal toxicity. / This is an unlikely mechanism, based on animal and human studies that suggest a gradient whereby the fetus has relatively lower concentrations of vitamin D metabolites than in the maternal circulation. / Invasive sampling to measure fetal vitamin D biomarkers is not justified. Rather, maintenance of normal maternal [25(OH)D] concentrations and calcium metabolism should be the priority.
Antenatal vitamin D supplementation mimics or provokes features of William syndrome, or other vascular pathology. / Although limited animal studies suggested a dose-dependent risk of aortic lesions and craniofacial anomalies analogous to those seen in children with Williams syndrome, human studies do not support this association, even in the context of very high maternal vitamin D exposures. Effects of vitamin D on other cardiovascular outcomes have not been established. / Consideration could be given to echocardiography to rule-out aortic pathology in newborns, although the risk of effects seems remote. However, long-term follow-up studies of vascular anatomy and function in childhood would be important contributions.
When administered at high doses, vitamin D3 may be metabolized to compounds via pathways other than 25-hydroxylation. / There is no empiric evidence that such metabolites are physiologically produced in non-negligible concentrations or exert toxicity, but molecular mechanisms exist by which non-25-hydroxylated metabolites could exert biological activity relevant to fetal development. / More research is required to understand these pathways. Consideration of these theoretical mechanisms would be warranted if unexplained toxic or teratogenic effects were observed, particularly in the absence of hypercalcemia.
REFERENCES
1.Brooke OG, Brown IR, Bone CD, Carter ND, Cleeve HJ, Maxwell JD, et al. Vitamin D supplements in pregnant Asian women: effects on calcium status and fetal growth. Br Med J 1980; 280(6216): 751-754.
2.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(3): 300-304.
3.Delvin EE, Salle BL, Glorieux FH, Adeleine P, David LS. Vitamin D supplementation during pregnancy: effect on neonatal calcium homeostasis. J Pediatr 1986; 109(2): 328-334.
4.Zeghoud F, Garabedian M, Jardel A, Bernard N, Melchior J. [Administration of a single dose of 100,000 U.I. of vitamin D3 in the pregnant woman in winter. The effect on blood calcium level of the newborn infant]. J Gynecol Obstet Biol Reprod (Paris) 1988; 17(8): 1099-1105.
5.Marya RK, Rathee S, Dua V, Sangwan K. Effect of vitamin D supplementation during pregnancy on foetal growth. Indian J Med Res 1988; 88: 488-492.
6.Yu CK, Sykes L, Sethi M, Teoh TG, Robinson S. Vitamin D deficiency and supplementation during pregnancy. Clin Endocrinol (Oxf) 2009; 70(5): 685-690.
7.Sahu M, Das V, Aggarwal A, Rawat V, Saxena P, Bhatia V. Vitamin D replacement in pregnant women in rural north India: a pilot study. Eur J Clin Nutr 2009; 63(9): 1157-1159.
8.Cockburn F, Belton NR, Purvis RJ, Giles MM, Brown JK, Turner TL, et al. Maternal vitamin D intake and mineral metabolism in mothers and their newborn infants. Br Med J 1980; 281(6232): 11-14.
9.Marya RK, Rathee S, Lata V, Mudgil S. Effects of vitamin D supplementation in pregnancy. Gynecol Obstet Invest 1981; 12(3): 155-161.
10.Madelenat P, Bastian H, Menn S. [Winter supplementation in the 3rd trimester of pregnancy by a dose of 80,000 IU of vitamin D]. J Gynecol Obstet Biol Reprod (Paris) 2001; 30(8): 761-767.
11.Datta S, Alfaham M, Davies DP, Dunstan F, Woodhead S, Evans J, et al. Vitamin D deficiency in pregnant women from a non-European ethnic minority population--an interventional study. BJOG 2002; 109(8): 905-908.
12.Congdon P, Horsman A, Kirby PA, Dibble J, Bashir T. Mineral content of the forearms of babies born to Asian and white mothers. Br Med J (Clin Res Ed) 1983; 286(6373): 1233-1235.
13.Greer FR, Hollis BW, Napoli JL. High concentrations of vitamin D2 in human milk associated with pharmacologic doses of vitamin D2. J Pediatr 1984; 105(1): 61-64.
14.Bolen JW. Hypoparathyroidism in pregnancy. Am J Obstet Gynecol 1973; 117(2): 178-179.
15.Goodenday LS, Gordon GS. No risk from vitamin D in pregnancy. Ann Intern Med 1971; 75(5): 807-808.
16.Wright AD, Joplin GF, Dixon HG. Post-partum hypercalcaemia in treated hypoparathyroidism. Br Med J 1969; 1(5635): 23-25.
17.O'Leary JA, Klainer LM, Neuwirth RS. The management of hypoparathyroidism in pregnancy. Am J Obstet Gynecol 1968; 94(8): 1103-1107.
18.Graham WP, 3rd, Gordan GS, Loken HF, Blum A, Halden A. Effect of pregnancy and of the menstrual cycle on hypoparathyroidism. J Clin Endocrinol Metab 1964; 24: 512-516.
19.Ornoy A, Menczel J, Nebel L. Alterations in the mineral composition and metabolism of rat fetuses and their placentas induced by maternal hypervitaminosis D2. Isr J Med Sci 1968; 4(4): 827-832.
20.Ornoy A, Nebel L, Menczel Y. Impaired osteogenesis of fetal long bones. Induced by maternal hypervitaminosis D2. Arch Pathol 1969; 87(6): 563-571.
21.Ornoy A, Nebel L. Effects of hypervitaminosis D2 altered by pregnancy in rats: hyperlipidemia and fatty liver degeneration with restrained injuries to the cardiovascular system and other organs. Isr J Med Sci 1970; 6(5): 622-629.
22.Ornoy A, Kaspi T, Nebel L. Persistent defects of bone formation in young rats following maternal hypervitaminosis D 2. Isr J Med Sci 1972; 8(7): 943-949.
23.Nebel L, Ornoy A. Structural alterations in rat placenta following hypervitaminosis D 2. Isr J Med Sci 1971; 7(5): 647-655.
24.Tshibangu K, Oosterwijck K, Doumont-Meyvis M. Effects of massive doses of ergocalciferol plus cholesterol on pregnant rats and their offspring. J Nutr 1975; 105(6): 741-758.
25.Ariyuki F. Growth retardation induced in rat fetuses by maternal fasting and massive doses of ergocalciferol. J Nutr 1987; 117(2): 342-348.
26.Norman P, Moss I, Sian M, Gosling M, Powell J. Maternal and postnatal vitamin D ingestion influences rat aortic structure, function and elastin content. Cardiovasc Res 2002; 55(2): 369-374.
27.Friedman WF, Roberts WC. Vitamin D and the supravalvar aortic stenosis syndrome. The transplacental effects of vitamin D on the aorta of the rabbit. Circulation 1966; 34(1): 77-86.
28.Friedman WF, Mills LF. The relationship between vitamin D and the craniofacial and dental anomalies of the supravalvular aortic stenosis syndrome. Pediatrics 1969; 43(1): 12-18.
29.Chan GM, Buchino JJ, Mehlhorn D, Bove KE, Steichen JJ, Tsang RC. Effect of vitamin D on pregnant rabbits and their offspring. Pediatr Res 1979; 13(2): 121-126.
30.Littledike ET, Horst RL. Vitamin D3 toxicity in dairy cows. J Dairy Sci 1982; 65(5): 749-759.
31.Toda T, Toda Y, Kummerow FA. Coronary arterial lesions in piglets from sows fed moderate excesses of vitamin D. Tohoku J Exp Med 1985; 145(3): 303-310.
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[i] See supplementary on-line Table 2 for detailed summary of calcium concentrations and related outcomes.
[ii] Assumes a 60 kg woman, for purposes of between-study comparisons.
[iii] Calculated, where data were available, as the ratio of the mean cord serum [25(OH)D] to the mean maternal [25(OH)D] at or prior to delivery.
[iv] 506 (vitamin D) and 633 (control) women were reportedly treated, but N represents the maximum number of women for whom serum [Ca] was reported at one timepoint. [25(OH)D] was measured in 80-86 women in each group, depending on the timing.
[v] Highest [25(OH)D] was ~100 nmol/L.
[vi] Effect of supplementation unknown given lack of control group; however, highest [Ca] in any participant at delivery was 2.53 mmol/L (i.e., no maternal hypercalcemia was observed).
[vii] Effect of supplementation unknown given lack of control group; however, the highest venous corrected [Ca] at days 3 – 5 was 2.83 mmol/L. In arterial cord blood specimens, mean corrected [Ca] was 2.87 mmol/L (range 2.30 – 3.45 mmol/L). There were no cases of neonatal hypocalcemia.
[viii] Dose was increased at 36 weeks to 1600 IU/day if [25(OH)D]<20 nmol/L
[ix] Reference range for uncorrected maternal serum [Ca] pre-delivery is 1.98 – 2.46 mmol/L [Larsson A et al. BJOG. 2008; 115(7):874-81.]
[x] Reference range for cord blood serum [Ca] is 2.3 – 3.0 mmolL [Perkins SL et al. Clin Chem. 1993; 39(6):1041-4.]