Vitamin D is an essential fat soluble vitamin and a key modulator of calcium metabolism in children and adults. Because calcium demands increase in the third trimester of pregnancy, vitamin D status becomes crucial for maternal health, fetal skeletal growth, and optimal maternal and fetal outcomes. Vitamin D deficiency is common in pregnant women (5-50%) and in breastfed infants (10-56%), despite the widespread use of prenatal vitamins, because these are inadequate to maintain normal vitamin D levels (≥32 ng/mL). Adverse health outcomes such as preeclampsia, low birthweight, neonatal hypocalcemia, poor postnatal growth, bone fragility, and increased incidence of autoimmune diseases have been linked to low vitamin D levels during pregnancy and infancy. Studies are underway to establish the recommended daily doses of vitamin D in pregnant women. This review discusses vitamin D metabolism and the implications of vitamin D deficiency in pregnancy and lactation.
Vitamin D deficiency has long been associated with poor bone development and has been identified as the cause of rickets. Although the incidence of rickets has declined with the current daily recommendations of vitamin D intake, the prevalence and additional consequences of low serum vitamin D levels have not been recognized until recently. The measurement of serum vitamin D in pregnancy has helped researchers establish the prevalence of vitamin D deficiency and elucidate adverse maternal and fetal outcomes associated with it. Prevention of these diseases and reduction of the risk for childhood illnesses that are linked to early vitamin D deficiency are possible with greater understanding of vitamin D physiologic components, risk factors for vitamin D deficiency, and methods of supplementation to attain optimal levels in pregnant and lactating women.
Vitamin D physiologic components
Vitamin D is a prohormone that is derived from cholesterol. The nutritional forms of vitamin D include D 3 (cholecalciferol), which is generated in the skin of humans and animals, and vitamin D 2 (ergocalciferol), which is derived from plants; both forms can be absorbed in the gut and used by humans. Controversy exists as to whether D 2 or D 3 is more effective in maintaining circulating levels of vitamin D in nonpregnant individuals, and specific data during pregnancy is unknown. In this review when we refer to vitamin D, we imply either vitamin D 2 or D 3 . Vitamin D occurs naturally in fish and some plants but is not found in significant amounts in meat, poultry, dairy products (without fortification), or the most commonly eaten fruits and vegetables. The Food and Nutrition Board’s current recommendation for adequate intake of vitamin D is 200 IU/d for both pregnant and nonpregnant individuals aged 0-50 years. Wild salmon (3.5 oz) provides 600-1000 IU; farmed salmon has approximately 25% of this amount per serving. The same amount of mackerel, sardines, or tuna fish provides 200-300 IU. Cod liver oil (1 tsp) provides 600-1000 IU. One of the few plant sources of vitamin D is shiitake mushrooms, which provide 1600 IU. In the United States, the major dietary sources of vitamin D are fortified foods. For example, 8 ounces of fortified milk, orange juice, or yogurt, 3 ounces of fortified cheese, or a serving of fortified breakfast cereal each provides 100 IU of vitamin D ( Table 1 ). However, the relative contribution of dietary vitamin D is low in humans, compared with endogenous production from sunlight.
| Source of vitamin D | Amount of vitamin D (IU) |
|---|---|
| Cow’s milk, fortified with vitamin D, 8 oz | 98 |
| Soy milk, fortified with vitamin D, 8 oz | 100 |
| Orange juice, fortified, 8 oz | 100 |
| Cereal, fortified, 1 cup | 40-50 |
| Pink salmon, canned, 3 oz | 530 |
| Sardines, canned, 3 oz | 231 |
| Mackerel, 3 oz | 306 |
| Herring, 3 oz | 1,383 |
| Catfish, 3 oz | 425 |
| Tuna, canned in oil, 3 oz | 200 |
| Quaker Nutrition for Women Instant Oatmeal, 1 packet | 154 |
| Egg yolk | 25 |
| Most multivitamins | 400 |
| Tri-Vi-Sol infant supplements, 1 drop | 400 |
| Prenatal vitamins | 400 |
| Over-the-counter vitamin D 3 supplements | 2000 (max) |
| Typical prescribed vitamin D 2 supplements for deficiency | 50,000 (given weekly until replete) |
Exposure to sunlight, especially ultraviolet B (UVB) photons, initiates conversion in the skin of provitamin D 3 to previtamin D 3 , which binds to vitamin D binding protein for transport in the circulation and is rapidly stored in fat or metabolized in the liver. Several hepatic cytochrome P -450 enzymes have been shown to 25-hydroxylate vitamin D compounds. This process is regulated poorly, so serum levels of 25-hydroxy vitamin D (25[OH]D) increase in proportion to vitamin D synthesis and intake, which represents the best indicator of vitamin D status.
The second step in vitamin D activation is the formation of 1α,25 dihydroxyvitamin D (1,25[OH] 2 D or active vitamin D) by 1α-hydroxylase, which occurs mainly in the kidney. Numerous tissues (including placenta, prostate, breast, colon, lung, bone, parathyroid, pancreas, immune system, and vascular wall) express the vitamin D receptor and the 1α-hydroxylase and are able to transform 25(OH)D to its active hormonal form. Locally produced 1,25(OH) 2 D serves as an autocrine/paracrine factor that is fundamental for cell-specific proliferation, differentiation, and function early in life.
The efficiency of vitamin D synthesis depends on a variety of factors, most importantly the number of UVB photons that penetrate the epidermis. More time spent indoors and widespread use of sunscreen have resulted in reduced sun exposure and less vitamin D production. Latitude and season of the year also determine both the quantity and quality of UVB radiation. Skin production of vitamin D declines after August and virtually ceases from November until March at latitudes of >42° N (Boston). Other factors, such as aging and increased melanin in dark-skinned people, reduce the efficiency by which sunlight converts provitamin D, thereby decreasing vitamin D synthesis ( Table 2 ). Plasma 25(OH)D levels during the winter therefore depend on vitamin D intake, which is largely from food additives or supplements.
| Factor |
|---|
| Northern latitudes, especially winter or spring |
| Limited sun exposure |
| Regular use of sunscreens |
| African American or dark skin |
| Obesity |
| Extensive clothing cover |
| Aging |
| Malabsorptive syndromes (cystic fibrosis, cholestatic liver disease, inflammatory bowel disease, short gut syndrome) |
As an individual becomes deficient in vitamin D, intestinal calcium and phosphorous absorption decrease; serum ionized calcium levels drop, and synthesis of parathyroid hormone (PTH) is stimulated. Increased plasma PTH maintains serum calcium in the normal range by enhancing renal production of 1,25(OH) 2 D, increasing bone turnover, accelerating bone loss, and promoting tubular calcium reabsorption and phosphate excretion. Increased 1,25(OH) 2 D induces intestinal calcium and phosphorus absorption and stimulates osteoclast activity, thereby increasing calcium and phosphorous availability in the blood ( Figure ).
Vitamin D and calcium metabolism in pregnancy
During pregnancy and lactation, significant changes in maternal vitamin D and calcium metabolism occur to provide the calcium that is needed for fetal bone mineral accretion. During the first trimester, the fetus accumulates 2-3 mg/d in the skeleton; however, this rate of accumulation doubles in the last trimester. The body of a pregnant woman adapts to fetal requirements by increasing calcium absorption in early pregnancy, with maximal absorption in the last trimester. Along with the transfer of calcium to the fetus, the increased intestinal absorption is balanced by enhancing urinary calcium excretion, thereby keeping serum ionized calcium stable throughout pregnancy. In several small studies, 1,25(OH) 2 D levels in plasma increased by 2-fold early in pregnancy, compared with prepregnancy values, reached a maximum in the third trimester, and returned to normal or below normal during lactation. Plasma 25(OH)D levels do not change, unless intake or synthesis changes. The increased 1,25(OH) 2 D synthesis depends on the acceleration of 1α-hydroxylation in the maternal kidneys and possibly increased placental and decidual 1α-hydroxylase activity. The stimulus to increase synthesis of 1,25(OH) 2 D is not clear because serum PTH levels do not change during pregnancy. A potential signal for placental calcium transfer and placental synthesis of active vitamin D is PTH-related peptide (PTHrP), which is produced in fetal parathyroid glands and the placental tissues and increases placental synthesis of active vitamin D. PTHrP potentially might reach the maternal circulation. Acting through the PTH/PTHrP receptor in kidney and bone, PTHrP could mediate the increased 1,25(OH) 2 D and help to regulate calcium and PTH levels during human pregnancy. The profound increase in intestinal calcium absorption cannot be explained solely by the increased 1,25(OH) 2 D because the increased calcium absorption occurs before 1,25(OH) 2 D levels increase and occurs in rodents even in the absence of vitamin D receptor.
Other signals that regulate active calcium homeostasis and vitamin D synthesis during pregnancy include prolactin, placental lactogen, calcitonin, osteoprotegerin, and estrogen. Prolactin increases throughout pregnancy and remains above normal after delivery. Placental lactogen increases throughout pregnancy but returns to prepregnancy values after delivery. Prolactin and placental lactogen’s roles have not been clearly elucidated in calcium metabolism. It is thought that they both contribute to increase calcium absorption from the intestine, decrease urinary calcium excretion, and stimulate production of PTHrP and 1,25(OH) 2 D. Calcitonin increases 2-fold in the second trimester, compared with the first trimester, but then declines slightly at term. It has been hypothesized that the rise in serum calcitonin protects the maternal skeleton from excessive resorption of calcium. Osteoprotegerin levels have also been shown to be higher in the third trimester of pregnancy than the first trimester of pregnancy. The fetal skeleton contains 30 g of calcium, most of which is deposited during the third trimester of pregnancy. It can be inferred that osteoprotegerin, which acts as a decoy receptor for RANK ligand and inhibits osteoclast activity, may also protect the maternal skeleton from excessive resorption of calcium. Lactation is a time of relative estrogen deficiency because of elevated prolactin levels that suppress the release of gonadotropins and, in turn, estrogen and perhaps stimulate the release of PTHrP. Estrogen deficiency leads to bone resorption and suppression of PTH levels. PTHrP levels are elevated and act as a surrogate for PTH, thereby allowing continued absorption of calcium from the urine and bone resorption.
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