Maternal Supplementation for Prevention and Treatment of Vitamin D Deficiency in Exclusively Breastfed Infants

Abstract

Current research links newborn and infant vitamin D deficiency with various clinical outcomes, including rickets, failure to thrive, type 1 diabetes, and other immune-related diseases. Breastfed infants are often at a greater risk of developing deficiency due to their mothers' low vitamin D status. Human milk reflects the vitamin D status of the mother and often contains inadequate levels of 25-hydroxyvitamin D for infant nutrition. In 2008 the American Academy of Pediatrics (AAP) recommended 400 IU of vitamin D supplementation of all infants. However, research has indicated low levels of compliance of vitamin D supplementation of breastfed infants and a high incidence of vitamin D deficiency in the United States. Many breastfeeding advocates believe that the AAP's recommendations undermine breastfeeding, implying that human milk is inadequate for infant nutrition. Lactating mothers are also reluctant to add any supplements to their breastmilk. The literature review will examine the effectiveness and safety of maternal vitamin D supplementation for prevention and/or treatment of vitamin D deficiency in breastfed infants and lactating mothers. This method of prevention and intervention provides pediatric providers and certified lactation consultants with an alternative approach for education, counseling, promotion of breastfeeding, and treatment to improve maternal and infant health.

Introduction

The incidence of vitamin D deficiency among infants, children, adolescents, and adults in the United States remains high in spite of the serious health consequences, which are preventable through supplementation. The American Academy of Pediatrics (AAP) introduced new guidelines for oral infant supplementation of vitamin D₃ in 2008. Emphasizing the crucial role that vitamin D plays in an infant's growth, development, formation of innate immunity, and prevention of diseases such as diabetes and cancers, the Academy recommended 400 IU daily for breastfeeding infants and infants receiving <1 L of formula/day.¹ The Canadian Paediatric Society recommended 400 IU daily of oral vitamin D₃ supplementation for infants, increasing the dosage for higher-risk populations to 800 IU daily from October through April.²

These guidelines for infant supplementation may undermine breastfeeding promotion by decreasing maternal confidence and implying that human milk is an inadequate source of complete nutrition for infants, despite data indicating that vitamin D content in human milk is sufficient when the mother's levels are sufficient.³ Supporting this assumption, 36.4% of 44 pediatricians surveyed in Seattle, WA, chose not to recommend vitamin D supplements to breastfed infants with legitimate concern that parents would switch to formula.⁴

The antirachitic activity (ARA) in human milk varies according to the season, amount of sun exposure, or vitamin D₂ or D₃ intake of the mother. Approximately 20% of maternal circulating vitamin D and 25-hydroxyvitamin D [25(OH)D] is transferred through the mother's milk. Research indicates that adequate maternal supplementation increased milk ARA significantly (p < 0.0003) and is as effective in increasing the infant's 25(OH)D levels as supplementing the infant with 400 IU daily.⁵

In addition, evidence indicates that a high percentage of breastfeeding mothers do not supplement their infants in spite of the AAP's recommendations.^1,4,6 Interviewing 1,140 breastfeeding mothers, Taylor et al.⁴ noted only 15.9% of the 1,140 exclusively breastfed infants received any vitamin D supplements. Parents' choices to supplement or not were highly related to their physician's recommendations. Many exclusively breastfeeding mothers did not supplement with vitamin D, believing their breastmilk was sufficient to provide their infant's nutritional needs. In addition, they voiced concern over the issue of adding anything artificial to their infant's diet. Henderson³ noted that the risks of infant vitamin D supplementation are currently unclear, but may include allergic reactions to the ingredients, such as corn oil, aspiration pneumonia, accidental overdose, and changes in intestinal flora and pH that may compromise the immune benefits of human milk.

Evidence demonstrates that adequate prenatal vitamin D supplementation effectively and safely prevents and treats maternal and infant vitamin D deficiency. This literature review provides evidence-based practice guidelines for pediatric providers and lactation consultants involved in health promotion of breastfeeding infants and their mothers.

Physiology of Vitamin D

Healthcare providers and researchers often refer to vitamin D as the sunshine vitamin, emphasizing the primary source for vitamin D is from exposure to solar ultraviolet (UV) B rays. Natural food sources of vitamin D, including oily fish, cod liver oil, liver, and egg yolks, do not provide adequate amounts of vitamin D. Fortified foods such as milk, yogurt, margarine, and orange juice are also inadequate sources of vitamin D.⁷ Infant formula contains 400 IU of vitamin D₃/L, providing adequate vitamin D once an infant's intake is 1 L daily. Vitamin D supplements include plant-based vitamin D₂ (ergocalciferol) and vitamin D₃ (cholecalciferol), derived from lanolin in sheep's wool. Experts recommend vitamin D₃ as the preferred supplement because it is more readily available for increasing serum 25(OH)D levels.⁸

UVB rays photolyse 7-dehydrocholesterol into previtamin D₃ with a thermal reaction in the skin to convert to vitamin D₃ (cholecalciferol), which is hydroxylated in the liver to 25(OH)D, the primary circulating, yet biologically inert, form of vitamin D. Serum 25(OH)D levels indicate the overall vitamin D status for a diagnosis of vitamin D sufficiency, insufficiency, or deficiency. Further hydroxylation occurs in several organs (including the kidney, heart, brain, prostate, breast, and gonads) and in immune cells, osteoblasts, and β-islet pancreatic cells, converting 25(OH)D to 1,25-dihydroxyvitamin D [1,25(OH)₂D] (calcitriol), the biologically active form of vitamin D. The parathyroid hormone (PTH) and phosphorus regulate the activation of vitamin D in the kidneys. Calcitriol enters cells by passive diffusion, binding to the vitamin D receptors (VDRs) and initiating gene transcription.^9,10

Once thought to be located in the small intestine to enable absorption of vitamin D and calcium, VDRs have been found in various cells, including osteoblasts, immune cells (T and B lymphocytes, mononuclear cells), β-islet cells in the pancreas, and several organs (heart, brain, skin, prostate, breast, and gonads). Acting on the VDRs, 1,25(OH)₂D promotes calcium absorption in the intestines, facilitates skeletal mineralization, improves differentiation and apoptosis of cells (possibly inhibiting tumor activity), stimulates production of insulin, increases thyroid-stimulating hormone secretion, strengthens myocardial contractility, and enhances immune function. 1,25(OH)₂D inhibits immune cytokine T helper 1 (Th1) cells, involved in overactive autoimmune responses, maintains dominance of T helper 2 (Th2) cells, which promote healthy cell apoptosis and immune function, and increases white blood cell phagocytosis.^9,10

Risk Factors for Infant Vitamin D Deficiency

Risk factors contributing to vitamin D deficiency in infancy are numerous, including deficient prenatal maternal 25(OH)D levels and exclusive breastfeeding when the lactating mother is deficient. Although infant skin pigmentation affects the amount of sunlight exposure in summer months required for adequate cutaneous synthesis of vitamin D, the AAP and American Dermatologic Association do not recommend any direct UV exposure in the first 6 months of life. For infants and children over 6 months, they recommend use of sunscreen, which completely blocks UVB exposure (necessary for vitamin D synthesis). In addition, many sunscreens provide only partial blockage of UVA rays, causing damage to skin and diminishing its ability to synthesize vitamin D.¹

In order to synthesize an adequate amount of vitamin D₃ through sun exposure, an individual must receive 20–25% of a minimum erythemal dose, or the amount at which mild sunburn would occur. Caucasians require approximately 10–12 minutes of adequate UVB ray exposure of face, hands, arms, and legs for cutaneous synthesis of 10,000–20,000 IU of vitamin D and need two or three exposures a week to maintain adequate vitamin D levels. In contrast, African Americans require 60–70 minutes of the same UVB exposure for equivalent synthesis.¹¹ Latitudes of residence >40° increase the risk of developing vitamin D deficiency because of insufficient levels of UVB rays in winter months for cutaneous synthesis. Cultural and religious practices of veiling and covering women, sunscreen use (≥8 SPF), air pollution, and modern lifestyles with less outdoor activity are additional risk factors.^2,12

Incidence

Numerous studies indicate that vitamin D deficiency is a serious international public health problem for all age groups. The National Health and Nutrition Examination Survey 2001–2004 collected data on 6,275 children and adolescents between 1 and 21 years old in the United States and found 9% had 25(OH)D levels <15 ng/mL (deficient), and 61% had insufficient 25(OH)D levels (15–29 ng/mL). According to the survey, only 4% had taken any vitamin D supplements 1 month prior to the data collection.¹³

The incidence of newborn vitamin D deficiency reflects the high incidence of vitamin D deficiency in women of childbearing years. Basile et al.¹² evaluated 100 cord blood samples in South Carolina (latitude 32°72') and found the newborn mean 25(OH)D was 13.5 ng/mL, clearly in the deficient range. Although the Caucasian infant 25(OH)D mean of 19.5 ng/mL was significantly higher than the African American infant mean of 10.5 ng/mL, data indicated that seasonal variability was significantly higher with Caucasian infants. Of note is tht these women had taken the recommended 400 IU of vitamin D daily as part of their prenatal vitamin (PNV) supplement.

Exclusively breastfed infants of deficient mothers compose a large group of vitamin D-deficient infants. Compounding the problem, current evidence indicates the majority of breastfeeding mothers do not supplement their infants despite the current AAP and Canadian recommendations. A systematic review of research of reported nutritional rickets cases from 1986 to 2003 in the United States showed that 83% of the children diagnosed with rickets were African American and that 96% were breastfed; only 5% of the breastfed infants had received any vitamin D supplementation, despite AAP recommendations at that time of 200 IU of vitamin D supplementation daily for infants.⁶ A 2002–2004 survey of 2,325 Canadian pediatricians examined the incidence, clinical profiles, and geographic distribution of confirmed vitamin D-deficient rickets cases; 98 cases (94%) were breastfed infants, and none of them had been supplemented with the recommended dose of 400 IU of vitamin D daily.^4,14

Definition and Diagnosis of Vitamin D Deficiency

While researchers have defined vitamin D insufficiency and deficiency differently through the years, serum 25(OH)D, PTH, and calcium levels provide a thorough evaluation of vitamin D status and are easily obtained through venipuncture and serum assays. Bowden et al.⁹ defined 25(OH)D levels at 54–94 ng/mL as sufficient, <30–32 ng/mL as insufficient (with changes in PTH and calcium levels), and <10–20 ng/mL as vitamin D deficiency with overt clinical symptoms. Most researchers' definitions are close to these values. Hollis¹⁵ also recommended looking at the key biomarkers, such as PTH, calcium absorption, and bone mineral density, to measure vitamin D sufficiency in children and adults. Radiographic images are a late finding and reveal significant progression of skeletal abnormalities from prolonged vitamin D deficiency.

Pathophysiology of Vitamin D Deficiency in Infants

Progression of vitamin D deficiency follows three stages. In the first stage 25(OH)D levels decrease, resulting in hypocalcemia with adequate phosphate levels and increased or unchanged 1,25(OH)₂D levels. As the 25(OH)D levels continue to decline in the second stage, PTH is released to maintain calcium levels through bone demineralization. As the PTH levels increase, calcium levels normalize, serum phosphate levels drop, and skeletal levels of alkaline phosphate slightly increase. In the third stage 25(OH)D levels become severely deficient, and hypocalcemia, hypophosphatemia, elevated alkaline phosphate levels, and overt bone demineralization occurs.¹

Severe vitamin D deficiency in infancy or childhood may develop into rickets, a skeletal consequence of disorganization and defective mineralization of epiphyseal growth plates. Typically diagnosed between ages 6 months to 3 years by history, physical exam, laboratory analysis, and radiographic findings, rickets may present with failure to thrive, short stature, soft skull (craniotabes) with delayed closure of the fontanels, muscle weakness, protruding abdomen, enlarged growth plates of long bones (swelling of the ankle, knee, or wrist), costochondral junction rib swelling (rachitic rosary), abnormal chest shape from diaphragmatic pulling (Harrison's sulcus), late teeth eruption, and delayed motor development. Hypocalcemia may also cause seizures, cardiac abnormalities including prolonged QT syndrome, and potential cardiac failure.^3,16,17

Long-term outcomes of vitamin D deficiency during infancy affect the immune system into adulthood. VDRs are located in tissues and cells throughout the body, including the heart, skin, brain, pancreas, stomach, and gonads. Researchers have identified the role of vitamin D in down-regulating cell hyperproliferation and promoting healthy apoptosis, essential in preventing cancer. In contrast, vitamin D deficiency increases the risk of uncontrolled cell proliferation. Researchers recognized in 1941 that people living in northern latitudes had a higher incidence of common cancers. Garland and Garland¹⁸ cited the association between vitamin D deficiency and cancer in their seminal research published in 1980. In the early 1990s scientists found higher risk for developing breast, colon, and prostate cancer in the northern United States and European countries.¹⁹

Vitamin D deficiency also affects activated macrophages, Th1 cells, Th2 cells, and B lymphocytes. The resulting Th1 dominant immune system leads to autoimmune diseases such as rheumatoid arthritis, type 1 diabetes, psoriasis, preeclampsia in pregnancy, allergies, asthma, and eczema.^19,20 Research from a large, birth-cohort study in Finland (n = 12,055) from 1966 to 1997 has shown that achieving adequate 25(OH)D levels through infant supplementation substantially lowers the risk of developing such autoimmune diseases through down-regulating the associated Th1 response pattern.²¹ For example, the risk of developing type 1 diabetes was reduced by approximately 80% in the infants who received the recommended 2,000 IU of vitamin D daily in cod liver oil.²¹ In addition, the risk of developing pre-eclampsia as a pregnant adult was reduced 50% through adequate infant supplementation.²² These findings were also supported by the cohort study of Bodnar et al.²³

Lucas et al.¹⁰ noted that central nervous system function in young adults appears to be affected by vitamin D status, season of birth, and latitude of residence. Researchers found a relationship among latitude of residence, season of birth, and the incidence of multiple sclerosis. In addition, schizophrenia appears more common among males born in urban areas, in winter or spring, and in dark-skinned immigrants in northwest Europe. Data from the Finnish birth cohort study indicated a decreased risk of schizophrenia in vitamin D-supplemented males.^23a

While research investigating the possible relationship of childhood autism and vitamin D deficiency is more recent, Kauffman²⁴ reported an indicated relationship between autism and winter births, with peaks in March and November. Dark-skinned children from Uganda living in Sweden had a 200 times greater risk of autism than white children of the area. Studies have also found a significantly greater prevalence of autism (p = 0.01) in counties with >69 cm of yearly precipitation in Washington, Oregon, and California.

Prevention and Treatment for Vitamin D Insufficiency and Deficiency in Infants

Lucas et al.¹⁰ have shown prenatal supplementation to be effective in prevention of newborn vitamin D deficiency and improved pregnancy outcomes. Treatment for infants involves either infant supplementation or maternal supplementation of the lactating mother. Both strategies have been effective in increasing the serum 25(OH)D levels for populations in the United States. However, research in the United Arab Emirates has indicated that both maternal and infant supplementation may be necessary in high-risk populations with extremely deficient mothers.²⁵

Infant supplementation, either 400 IU of D₃ daily according to the AAP or up to 800 IU daily for high-risk groups in Canada, involves giving either multivitamin drops or vitamin D₃ drops. Research has indicated safe effective infant supplementation from 400 to 1,426 IU of D₃ daily for treatment of severe deficiency.^2,26 Products for infant supplementation include Bio-D-Mulsion Forte^® (www.bioticsresearch.com) and Just D (www.sunlightvitamins.com), containing 400 IU of D₃/mL in a corn oil base, and various multivitamin preparations with vitamin A, D (400 IU/mL), and C. Multivitamins may contain glycerin, propylene glycol, and/or polysorbate 80.¹

Maternal supplementation has the advantage of treating the mother and infant simultaneously without exposing the infant to foreign substances. Experts recommend use of vitamin D₃ (cholecalciferol), which is made from sheared sheep wool lanolin and chemically altered in a laboratory, compared with plant-derived vitamin D₂.⁸ Vitamin D₃ supplements are available at 400, 800, 2,000, and 50,000 IU per tablet. They are also available in supplements with calcium, magnesium, and zinc or as part of a multivitamin.

Supplementation of high-dose vitamin D₃ for either the infant or lactating mother requires laboratory follow-up for serum levels of 25(OH)D, calcium, and PTH, as well as urine calcium/creatinine ratios to assess for treatment adequacy and any evidence of toxicity. Additional biomarkers and evidence of skeletal improvements are also important indicators of vitamin D sufficiency. In addition, vitamin D supplementation must be used with caution in patients with renal disease.²⁷

Literature Review: Maternal Supplementation of Breastfeeding Mothers

Current research-based evidence clearly points to the importance of interventions to prevent or treat vitamin D deficiency in exclusively breastfed infants and their mothers for health promotion with far-reaching consequences. Search terms for this literature review included vitamin D, deficiency, insufficiency, breastfeeding, lactation, infants, rickets, human milk, breastmilk, antirachitic, and maternal interventions, using Medline (PubMed), CINAHL, OneSearch, The Cochrane Library, and references of retrieved articles.

Five original research articles were chosen as most current and inclusive to examine the effectiveness and safety of vitamin D₃ supplementation of lactating mothers for prevention or treatment of vitamin D deficiency of breastfed infants and their mothers. This literature review includes four randomized clinical trials (RCTs) done since 2004, including two from the United States and two in the United Arab Emirates. The last article is a 2007 systematic review of RCTs to apply the Food and Nutrition Board (FNB) methodology to determine a new tolerable upper intake level (UL) of oral vitamin D₃ supplementation based on research since the FNB defined the UL of 2,000 IU/day for adults in 1997.

Hollis and Wagner²⁸ examined the effectiveness and safety of high-dose vitamin D₂ supplementation in addition to PNVs with 400 IU of D₃ in relation to the following variables: maternal and infant serum 25(OH)D₂, 25(OH)D₃, and total circulating 25(OH)D levels, serum calcium levels, and human milk ARA. They also monitored maternal urine calcium/creatinine levels to assess for vitamin D toxicity. Maternal blood, urine, and milk samples were taken at 1 (used as control), 2, 3, and 4 months, and infant blood samples were obtained for 25(OH)D levels at 1 (used as control) and 4 months.

Enrolling a convenience sample of 1 month postpartum, exclusively breastfeeding, healthy mother–baby dyads planning to exclusively breastfeed for 3 more months, they designed an RCT of two intervention groups. Each group, consisting of nine participants who completed the study (n = 18), was controlled for age, ethnicity, insurance, number of pregnancies, pregnancy interval, infant sex, birth weight, and gestational age. Interventions for group 1 included maternal oral daily supplementation with 1,600 IU of D₂ in addition to daily PNVs with 400 IU of D₃ (total, 2,000 IU/day). The second group received 3,600 IU of D₂ and 400 IU of D₃ daily (total, 4,000 IU/day). They used high doses of vitamin D₂ as the supplemental variable because it could be traced in infant serum as a direct factor of mother's milk transfer without confounding solar or other food source variables.

Results showed a significantly higher increase in maternal serum 25(OH)D levels (p < 0.01) and directly correlated increase in infant serum 25(OH)D levels (p < 0.003) in the group that received 4,000 IU/day compared with those who received 2,000 IU/day. Human milk ARA in the 4,000 IU/day group increased significantly higher (mean, 40.4–134.6 IU/L; p < 0.0001) than the other group (mean, 35.5–69.7 IU/L; p < 0.0001). In addition, daily intake of vitamin D up to 10 times the daily recommended intake had no adverse events on mothers or infants.

Although sample size and location placed limitations on this research, its value in tracing the direct effect of maternal vitamin D₂ supplementation on vitamin D₂ levels in breastfed infants provided documented evidence of the value of maternal supplementation increasing vitamin D through the breastmilk. The researchers concluded maternal supplementation ≥4,000 IU of oral vitamin D₂ daily appeared safe and effective, increasing maternal and breastfed infant vitamin D levels sufficiently. They also emphasized that limited sun exposure causes increasing incidence of vitamin D deficiency in our society through bypassing the endocrine system's source for rapid production of large quantities of vitamin D (10,000–20,000 IU). Finally, they identified the current recommendation of 400 IU daily for lactating mothers as irrelevant and useless for mother and infant supplementation.

Wagner et al.⁵ expanded their research on the effects of high-dose maternal vitamin D supplementation on 25(OH)D levels of lactating mothers and infants. They compared a control group with mothers receiving 400 IU of D₃ and infants receiving 300 IU of D₃ daily with the intervention group receiving 6,400 IU of D₃ maternal supplementation only for 6 months. The pilot RCT (double-blind, placebo-controlled, block randomization) of exclusively lactating mother–infant dyads from 1 month postpartum to 7 months utilized the “proof of concept design” used by the pharmaceutical industry, enhancing the statistical significance of a small sample. They tested maternal serum calcium, phosphorus, vitamin D₃, and 25(OH)D levels as well as milk vitamin D and 25(OH)D levels. Maternal and infant urine calcium/creatinine levels were measured at baseline (as their own control) and monthly. Researchers checked infant serum levels at baseline and at months 4 and 7. Monthly clinic visits with completed questionnaires were required. A convenience sample of healthy fully lactating mothers planning to exclusively breastfeed for 6 months enrolled in this study. Subjects were compensated with gift cards at monthly visits. Although 19 dyads started, only 10 completed the 6-month study.

Mothers in the control group took a placebo and 400 IU of D₃ in PNVs, and infants received 300 IU of D₃ supplements daily. Mothers in the intervention group took 6,000 IU of D₃ supplements and 400 IU of D₃ PNVs, and infants received placebo supplements. Results showed significantly higher increases in maternal serum 25(OH)D levels for the high-dose-supplemented mothers than those taking 400 IU daily (p < 0.0028). The mean maternal 25(OH)D levels in the 6,400 IU/day group increased from 34 to 58.8 ng/mL, rising quickly within the first month and stabilizing at a mean of 58.8 ng/mL after 3 months. However, the maternal 25(OH)D levels of those receiving 400 IU daily went from 32.2 to 38.425 ng/mL (insufficient).

Results of the infant mean 25(OH)D after the interventions revealed no significant difference between infants supplemented with oral vitamin D and those receiving only maternal supplementation. Both groups of infants had increases from baseline 25(OH)D means from 13–14 ng/mL, still insufficient levels, to 33–36 ng/mL at 4 months and 43–48 ng/mL at 7 months. These findings indicated that maternal high-dose (6,400 IU) D₃ supplementation of lactating mothers may be equally effective as infant 300 IU D₃ supplementation in achieving sufficient infant vitamin D outcomes. The high-dose maternal supplementation provides an advantage of treating mother and infant without risks to the infant.

Human milk ARA correlated with the mother's 25(OH)D level. Those taking 400 IU/day had slight increases in breastmilk vitamin D (mean, 45.6–78.6 IU/L), and those taking 6,400 IU/day showed significantly increased ARA (82–873 IU/L) (p < 0.0003). In addition, maternal and infant serum calcium, phosphorus levels, and urine calcium/creatinine ratios remained normal in both groups, indicating no evidence of toxicity.

Although the authors recognized the pilot study's limitations of small sample size and limited diversity, they concluded that high maternal doses of 6,400 IU of D₃ were effective and safe to treat maternal and infant vitamin D insufficiency and deficiency. They noted that maternal supplementation with D₃ proved to be significantly more effective in raising maternal 25(OH)D levels than D₂, which they used in 2004.²⁸ They recommended confirmation of their findings through large-scale, multisite studies with more culturally diverse groups. Emphasizing that current recommended doses of 400 IU of D₃ for lactating mothers are clearly suboptimal for her and her infant, they noted the need for further research to define optimal levels of 25(OH)D for lactating women and infants.

Providing research in the United Arab Emirates, Saadi et al.²⁹ examined the effectiveness and safety of 2,000 IU of D₂ daily versus 60,000 IU of D₂ monthly oral supplementation for nulliparous and lactating women. Vitamin D₃ supplements were not available in the United Arab Emirates. The majority of women wore clothing with veils, allowing little sun exposure. In additio,n research indicated that 40% of mothers did not take any PNVs and historically showed low compliance with vitamin supplementation. Noting the 1–2-month biological half-life of 25(OH)D, the authors hypothesized that a higher monthly dose would be as effective as a daily dose, with better compliance to the monthly regimen.

Designing an open label, parallel-group RCT of a convenience sample of nulliparous and lactating women (n = 178 starting, 17 completing), they divided the two nulliparous and lactating women groups into two intervention arms. The first intervention group received 60,000 IU of D₂ orally once a month at the clinic. The second intervention group was instructed to take oral 2,000 IU of D₂ daily, and pills were counted at the test intervals for compliance. All participants took 600 mg of elemental calcium/day. Researchers measured each participant's serum calcium, 25(OH)D, and PTH and urine calcium creatinine levels at 0, 1, 2, and at 3 months.

Results showed that the lactating women had a significantly lower (p < 0.001) baseline 25(OH)D mean of 19.3 nmol/L (7.7 ng/mL) compared with the nulliparous mean of 25.2 nmol/L (10.1 ng/mL). Although the serum 25(OH)D levels in the lactating women increased significantly in both intervention groups (p < 0.001), the 25(OH)D levels reached ≥50 nmol/L (≥20 ng/mL) in only 35% of the daily dosage group and 20% of the monthly intervention group. The interventions for nulliparous women were similar to the lactating group, raising the 25(OH)D level to ≥50 nmol/L (≥20 ng/mL) in 36% in the daily intervention group and 33% in the monthly group. Saadi et al.²⁹ concluded that the majority of the participants who completed the 3-month interventions continued in a state of vitamin D deficiency despite supplementation at four times the recommended 400 IU/day. Therefore, they recommended further research for safety and effectiveness of high-dose D₂ supplementation and raising the current, ineffective dose for 400 IU daily for nulliparous and lactating women in the United Arab Emirates.

After adjustments for baseline 25(OH)D levels for nulliparous and lactating women, they reported a significantly higher improvement with the daily supplements. They also noted that the lab draws were at the trough of the monthly dosing, possibly altering the values. However, the research of Hollis and Wagner²⁸ indicated that mother's milk transfers primarily vitamin D as opposed to 25(OH)D. It must be noted that monthly doses, with a spike of milk vitamin D levels within 24 hours of maternal dosing and then a rapid decrease of milk vitamin D levels, are significantly less efficacious than daily dosing for maintaining adequate milk vitamin D levels. Despite these findings, they acknowledged that monthly dosing may still be preferred in an extremely noncompliant patient population, versus no supplementation at all.

Discussing limitations of the study, the authors stated they expected the D₂ interventions would be less effective than D₃. Noting the unavailability of D₃ in many countries, they advocated for more research to determine effective and safe D₂ interventions. Reporting three results of calcium/creatinine ratios >1.0 nmol/nmol, they emphasized that none of their participants experienced hypervitaminosis D or hypercalcemia. In addition, they discussed the high dropout rates, use of nonstandard or unverified pill dosages, lack of control groups, or accounting for seasonal variation as other limitations of their research.

Using data from their 2007 research,²⁹ Saadi et al.²⁵ investigated the effect of combined maternal and infant supplementation of vitamin D₂ on infant vitamin D status, specifically whether combined supplementation prevented vitamin D deficiency, defined as 25(OH)D levels ≤37.5 nmol/L (≤15 ng/mL). Referring to the research of Hollis and Wagner,²⁸ they chose simultaneous supplementation because the previous study had shown that maternal supplementation did not adequately improve infant vitamin D status. In addition, the vitamin D status of exclusively breastfed infants without supplementation in the United Arab Emirates is approximately half that of unsupplemented, breastfed infants in the United States.³⁰

In addition to testing maternal serum levels of 25(OH)D, calcium, and PTH and urine calcium/creatinine levels at baseline and 1, 2, 3, and 4 months, they measured infant serum 25(OH)D at baseline and after 3 months of supplementation. They also measured breastmilk vitamin D levels at baseline and 8 months after completing the 3-month intervention.

Results indicated that 43 of the 46 infants (94%) were deficient at baseline. Combined maternal and infant supplementation increased the infant mean 25(OH)D levels by 33.2 nmol/L (13.3 ng/mL), from 14 nmol/L (5.6 ng/mL) to 47 nmol/L (19 ng/mL). This resulted in a 64% reduction of vitamin D deficiency (p < 0.0001) without any adverse effects. Even after maternal and infant supplementation with D₂, the mean 25(OH)D of 19 ng/mL remained considerably below the insufficient level of 32 ng/mL. Assessment of breastmilk ARA revealed an increase in levels corresponding to the increased maternal 25(OH)D levels. The mean ARA at baseline was undetectable (<20 IU/L) and increased to a median vitamin D level of 50.9 IU/L after 3 months of supplementation.²⁵

Saadi et al.²⁵ acknowledged limitations of the study, including no control group of infants receiving only infant supplementation, the high dropout rate, no assessment of seasonal variations (although there is abundant sunshine year-round in the United Arab Emirates), and no testing for evidence of infant toxicity. They also recommended further evaluation of effectiveness and safety of higher doses of vitamin D₂ supplementation. Acknowledging extensive research with greater improvement of 25(OH)D levels with D₃ supplementation, they noted vitamin D₃ as the preferred method of supplementation whenever possible.

While determining appropriate levels of high-dose maternal vitamin D supplementation for prevention and treatment of vitamin D deficiency and insufficiency in breastfed infants, researchers must consider the safety of high-dose D₃ supplementation and levels at which toxicity could occur. Current recommendations by the FNB of 2,000 IU of vitamin D₃ daily as the Tolerable UL are based on research prior to 1997. Hathcock et al.³¹ performed a systematic review of 21 RCTs, applying the vigorous FNB risk assessment methodology, which is also used by the Expert Group on Vitamins and Minerals of the United Kingdom and the Scientific Committee on Food of the European Commission, to assess hazard identification, dose–response assessment, and a definition of UL to provide an updated evidence-based no-observed-effect level (NOAEL) of oral vitamin D₃ supplementation.

Inclusion criteria for studies had vitamin D supplementation substantially higher than 1,800 IU/day, RCT design, and adequate sample size and duration. Relevant outcomes included statistically significant serum 25(OH)D changes and/or increased serum and urine calcium levels. They incorporated 17 studies that were appropriate for the FNB risk assessment methodology to calculate the NOAEL of vitamin D.

Hathcock et al.³¹ looked at serum 25(OH)D levels at which hypercalcemia occurred in their literature review. Accordingly, they determined the dose–response relationship at which vitamin D toxicity occurred as indicated by elevated serum calcium levels. Research indicated that 25(OH)D levels of approximately 700 nmol/L (280 ng/mL) appeared to evoke hypercalcemia in healthy adults following extremely large doses of vitamin D₃.

Following the systematic review of RCTs, they selected the research of Heaney et al.³² to define the NOAEL of vitamin D₃ as 10,000 IU/day. Although this study involved men only, other studies conducted with both sexes with higher vitamin D doses showed no safety-related differences according to the participant's gender. This definition was supported by 16 additional RCTs, including research by Hollis and Wagner²⁸ on maternal supplementation for lactating women. The data of Heaney et al.³² indicated no serum calcium changes with serum 25(OH)D levels of 220 nmol/L (88 ng/mL) following daily oral supplements of 250 μg (10,000 IU) of vitamin D₃. Confidence at this level increased in the absence of untoward effects with extremely higher doses of 2,500 μg (100,000 IU), resulting in serum 25(OH)D levels seven times higher than 220 nmol/L (88 ng/mL).

Examining cases of reported vitamin D toxicity, the authors noted most included significantly higher vitamin D dose interventions. They also involved compromised patients with renal insufficiency, Mycobacterium infections, sarcoidosis, other health conditions, or co-treatment with medications such as hydrochlorothiazide. The cases reporting vitamin D toxicity had serum 25(OH)D levels from 700 to >1,600 nmol/L (280 to >641 ng/mL), significantly higher than the 25(OH)D levels (220 IU/L or 88 ng/mL) following the defined NOAEL of 250 μg (10,000 IU) of vitamin D daily.

Considering the factor of sun exposure in relation to vitamin D levels, they noted the maximum cutaneous production of vitamin D, occurring from full-body exposure to UVB rays, would be equivalent to the NOAEL of 250 μg (10,000 IU). Although this amount of exposure is rare, lower exposures stimulate cutaneous vitamin D synthesis to a threshold. Prolonged UVB exposure limits synthesis of 25(OH)D as it destroys the skin's vitamin D. They concluded that long-term sun exposure in the United States and Europe would not likely exceed approximately 125 μg or 5,000 IU daily. Additional sources of vitamin D through fortified foods or dietary supplements would be inconsequential to the recommended NOAEL of daily vitamin D₃.

Although they recognized their study was the first quantitative review and did not include any research or recommendations for infants and children, Hathcock et al.³¹ recommended that the FNB update the UL for vitamin D based on research since 1997. They emphasized that the current UL curtails current research and food fortification, depriving people in the United States of receiving optimal nutritional benefits of adequate vitamin D supplementation. They also encouraged further research of UL of vitamin D in special populations such as infants and children.

Implications and Recommendations

This literature review indicates maternal supplementation of lactating mothers is an effective and safe method of prevention and treatment of vitamin D deficiency in infants and mothers. The research of Hollis and Wagner²⁸ showed significant increases in maternal and infant serum 25(OH)D levels and the mother's milk ARA with 3,600 IU of D₂ and 400 IU of D₃ maternal supplementation with no adverse events. Maternal supplementation with 1,600 IU of D₂ and 400 IU of D₃ showed significantly less improvement. Noting that vitamin D₂ is less effective than D₃ in raising 25(OH)D levels, they confidently recommended higher-dose supplementation than the current ineffective recommendations of 400 IU daily for lactating mothers.

Building on the laboratory's research in 2004,²⁸ Wagner et al.⁵ examined maternal supplementation with 6,400 IU of vitamin D₃ versus 400 IU of D₃ daily on maternal 25(OH)D levels and breastmilk ARA. Additionally, they compared infant outcomes of maternal supplementation with 6,400 IU of D₃ daily with infant outcomes following infant supplementation of 300 IU of D₃ daily. Maternal 25(OH)D levels were significantly higher with high-dose supplementation, as expected. Regarding the effectiveness of maternal supplementation, they found no significant difference in the 25(OH)D levels of infants receiving only maternal supplementation with those receiving only direct infant supplementation. In addition, they found the vitamin D levels in breastmilk were directly correlated with the mother's 25(OH)D levels, increasing with high-dose supplementation. All measures of maternal and infant calcium levels were within normal limits. This study demonstrated safe and effective maternal supplementation with 6,400 IU daily as adequate to elevate breastfed infant and maternal vitamin D levels with less risk for infants.

In the United Arab Emirates, where only vitamin D₂ was available, Saadi et al.²⁵ found maternal high-dose D₂ supplementation was helpful in raising the maternal 25(OH)D levels, but not as effective as D₃ supplementation. They also found maternal supplementation alone was ineffective in increasing infant 25(OH)D levels to a state of sufficiency, probably because the infant mean baseline status was extremely deficient (nearly half the mean American infant baseline). They recommended evaluating the maternal and infant baseline 25(OH)D means of population groups prior to deciding appropriate supplement interventions.

The systemic review of Hathcock et al.³¹ clearly indicated that the FNB's UL for vitamin D for adults of 2,000 IU daily is outdated, too low, and not supported by recent research. Defining the NOAEL of vitamin D as 10,000 IU/day, Hathcock et al.³¹ supported the safety of high-dose maternal supplementation to improve the vitamin D status of breastfed infants. The evidence-based effectiveness of 6,400 IU daily to increase lactating maternal and infant 25(OH)D levels to a sufficient status and increase breast milk ARA accordingly has been established. This dosage is well under the NOAEL of 10,000 IU daily.

While the AAP recommends infant supplementation with 400 IU of vitamin D daily, this literature review provides an evidence-based, viable alternative for prevention or treatment of infant vitamin D deficiency while simultaneously treating the mother. If a mother refuses to supplement her breastfed infant, she may be more willing to assess her vitamin D status and take supplements to help herself and her infant through her milk. Hale,³³ a respected professional resource for medications and breastmilk, recommended 4,000 IU/day D₃ supplementation for lactating mothers to improve maternal and infant vitamin D status, referring to the research of Hollis and Wagner.²⁸ Pediatric practitioners, lactation consultants, and lay lactation advocates may utilize this information in promoting breastfeeding and breastmilk as the ideal source of nutrition for infants, including adequate vitamin D when the mother's vitamin D status is sufficient.

Current research includes the evaluation of a simple lab test for vitamin D deficiency in infants, further research on the effectiveness and safety of maternal/infant vitamin D supplementation, use of infant vitamin D supplemental liquid forms versus cutaneous strips, prenatal high-dose vitamin D interventions, and determining an optimal vitamin D dose for young women of childbearing age. Further information on current clinical trials is located at clinicaltrials.gov/ct2/show/NCT00697294?term = breastfeeding&rank = 77.

It is important for pediatric healthcare providers and lactation consultants to educate and counsel breastfeeding mothers on the risks of vitamin D deficiency and insufficiency, including the long-term health outcomes for them and their infants. It is imperative that providers inform parents of the alternative methods of vitamin D supplementation. If they are not open to giving their infant vitamin D supplements, their infant could be at risk of short- and long-term consequences of vitamin D deficiency.

Footnotes

Disclosure Statement

No competing financial interests exist.

References

Wagner

, Greer

. Prevention of rickets and vitamin D deficiency in infants, children, and adolescents. Pediatrics, 2008; 122:1142–1152.

Taylor

, Wagner

, Hollis

. Vitamin D supplementation during lactation to support infant and mother. J Am Coll Nutr, 2008; 27:690–701.

Henderson

. Vitamin D and the breastfed infant. J Obstet Gynecol Neonatal Nurs, 2005; 34:367–372.

Taylor

, Geyer

, Feldman

. Use of supplemental vitamin d among infants breastfed for prolonged periods. Pediatrics, 2010; 125:105–111.

Wagner

, Hulsey

, Fanning

et al. High-dose vitamin D3 supplementation in a cohort of breastfeeding mothers and their infants: A 6-month follow-up pilot study. Breastfeed Med, 2006; 1:59–71.

Weisberg

, Scanlon

, Li

et al. Nutritional rickets among children in the United States: Review of cases reported between 1986 and 2003. Am J Clin Nutr, 2004; 80,6 Suppl:1697S–1705S.

Goldstein

. The epidemic of vitamin D deficiency. J Pediatr Nurs, 2009; 24:345–346.

Houghton

, Vieth

. The case against ergocalciferol (vitamin D2) as a vitamin supplement. Am J Clin Nutr, 2006; 84:694–697.

Bowden

, Robinson

, Carr

et al. Prevalence of vitamin D deficiency and insufficiency in children with osteopenia or osteoporosis referred to a pediatric metabolic bone clinic. Pediatrics, 2008; 121:e1585–e1590.

10.

Lucas

, Ponsonby

, Pasco

et al. Future health implications of prenatal and early-life vitamin D status. Nutr Rev, 2008; 66:710–720.

11.

Holick

. Sunlight and Vitamin D. Sunlight and vitamin D for bone health and prevention of autoimmune diseases, cancers, and cardiovascular disease. Am J Clin Nutr, 2004; 80,6 Suppl:1678S–1688S.

12.

Basile

, Taylor

, Wagner

et al. The effect of high-dose vitamin D supplementation on serum vitamin D levels and milk calcium concentration in lactating women and their infants. Breastfeed Med, 2006; 1:27–35.

13.

Kumar

, Muntner

, Kaskel

et al. Prevalence and associations of 25-hydroxyvitamin D deficiency in US children: NHANES 2001–2004. Pediatrics, 2009; 124:e362–e370.

14.

Ward

, Gaboury

, Ladhani

et al. Vitamin D-deficiency rickets among children in Canada. CMAJ, 2007; 177:161–166.

15.

Hollis

. Circulating 25-hydroxyvitamin D levels indicative of vitamin D sufficiency: Implications for establishing a new effective dietary intake recommendation for vitamin D. J Nutr, 2005; 135:317–322.

16.

Lerch

, Meissner

. Interventions for the prevention of nutritional rickets in term born children. Cochrane Database Syst Rev, 2007; 4:CD006164.

17.

Maiya

, Sullivan

, Allgrove

et al. Hypocalcaemia and vitamin D deficiency: An important, but preventable, cause of life-threatening infant heart failure. Heart, 2008; 94:581–584.

18.

Garland

, Garland

. Do sunlight and vitamin D reduce the likelihood of colon cancer? Int J Epidemiol, 1980; 9:227–231.

19.

Holick

. Vitamin D: Importance in the prevention of cancers, type 1 diabetes, heart disease, and osteoporosis. Am J Clin Nutr, 2004; 79:362–371.

20.

Litonjua

. Childhood asthma may be a consequence of vitamin D deficiency. Curr Opin Allergy Clin Immunol, 2009; 9:202–207.

21.

Hyppönen

, Läärä

, Reunanen

et al. Intake of vitamin D and risk of type 1 diabetes: A birth-cohort study. Lancet, 2001; 358:1500–1503.

22.

Hyppönen

, Hartikainen

, Sovio

et al.

Does vitamin D supplementation in infancy reduce the risk of pre-eclampsia?

Eur J Clin Nutr, 2007; 61:1136–1139.

23.

Bodnar

, Catov

, Simhan

et al. Maternal vitamin D deficiency increases the risk of preeclampsia. J Clin Endocrinol Metab, 2007; 92:3517–3522.

24.

McGrath

, Saari

, Hakko

et al. Vitamin D supplementation during the first year of life and risk of schizophrenia: A Finnish birth cohort study. Schizophr Res, 2004; 67:237–245.

25.

Kauffman

. Benefits of vitamin D supplementation. J Am Physicians Surgeons, 2009; 14:38.

26.

Saadi

, Dawodu

, Afandi

et al. Effect of combined maternal and infant vitamin D supplementation on vitamin D status of exclusively breastfed infants. Matern Child Nutr, 2009; 5:25–32.

27.

Wagner

, Howard

, Hulsey

et al. Circulating 25-hydroxyvitamin D levels in fully breastfed infants on oral vitamin D supplementation. Int J Endocrinol, 2010; 2010:235035.

28.

Dawson-Hughes

. Pregnancy and lactation risks: Vitamin D3 (cholecalciferol): Drug information. Dresner

UpToDate^®. UpToDateWaltham, MA, 2010. www.uptodateonline.com. 2010 March 6.

29.

Hollis

, Wagner

. Vitamin D requirements during lactation: High-dose maternal supplementation as therapy to prevent hypovitaminosis D for both the mother and the nursing infant. Am J Clin Nutr, 2004; 80,6 Suppl:1752S–1758S.

30.

Saadi

, Dawodu

, Afandi

et al. Efficacy of daily and monthly high-dose calciferol in vitamin D-deficient nulliparous and lactating women. Am J Clin Nutr, 2007; 85:1565–1567.

31.

Dawodu

, Agarwal

, Hossain

et al. Hypovitaminosis D and vitamin D deficiency in exclusively breastfeeding infants and their mothers in summer: A justification for vitamin D supplementation of breastfeeding in infants. J Pediatr, 2003; 142:169–173.

32.

Hathcock

, Shao

, Vieth

et al. Risk assessment for vitamin D. Am J Clin Nutr, 2007; 85:6–18.

33.

Heaney

, Davies

, Chen

et al. Human serum 25-hydroxycholecalciferol response to extended oral dosing with cholecalciferol. Am J Clin Nutr, 2003; 77:204–210.

34.

Hale

. Medications and Mother's Milk, 13^th. Hale Publishing: Amarillo, TX, 2008.