By Traci Pantuso, ND, MS
Adjunct Faculty, Research Investigator, Bastyr University, Seattle
Dr. Pantuso reports no financial relationships relevant to this field of study.
- Maternal vitamin D supplementation during pregnancy or during the postpartum period had no significant effect on infant length or other anthropometric outcomes by 1 year of age in a population with prenatal vitamin D deficiency.
- Measurements of 25(OH)D concentration levels in maternal and infant serum and in cord blood were dependent on vitamin D dose.
SYNOPSIS: The Maternal Vitamin D for Infant Growth (MDIG) trial was conducted in Bangladesh to further understand whether prenatal vitamin D with or without postpartum supplementation affects infant growth or other maternal, newborn, and infant outcomes.
SOURCE: Roth DE, Morris SK, Zlotkin S, et al. Vitamin D supplementation in pregnancy and lactation and infant growth. N Engl J Med 2018;379:535-546.
Undernutrition in children in Sub-Saharan Africa and South Asia is a global health problem that is directly related to infant growth.1 Approximately 30% of newborns are small for their age in Bangladesh, with 36% of children younger than 5 years of age stunted (height-for-age z score < -2).2 Vitamin D is involved in bone mineral metabolism and skeletal development; however, the exact mechanism of action has not been fully elucidated.3 Rickets is the result of severe vitamin D deficiency, which leads to secondary hyperparathyroidism, demineralization of the skeleton, and impaired bone elongation.3 In the United States, rickets is still diagnosed in children. The American Academy of Pediatrics (AAP) recommends 400 IU per day of vitamin D for infants who are exclusively or partially breastfed starting in the first few days of life as prevention.4 There is a lack of evidence demonstrating whether of vitamin D supplementation during pregnancy and the postpartum period will improve skeletal linear growth.
Previously, Roth et al conducted a trial demonstrating improvements in linear growth with maternal vitamin D supplementation during the third trimester.5 In this study, they investigated whether supplementation in women during pregnancy and throughout the postpartum period, in a population of women and young infants with high incidence of vitamin D deficiency, would improve infant growth measured using the International Fetal and Newborn Growth Consortium for the 21st Century Project recommendations.6,7
The Maternal Vitamin D for Infant Growth (MDIG) trial was a randomized, double-blind, placebo-controlled study, with five parallel dose groups investigating the effects of vitamin D supplementation. A total of 1,300 healthy pregnant women between 17 and 24 weeks of gestation were enrolled in this study between March 2014 and September 2015 at the Maternal and Child Health Training Institute in Dhaka, Bangladesh. Inclusion criteria for the study included preliminary screening, medical screening by a study physician, and obstetric ultrasound. Exclusion criteria are listed in Table 1.
Table 1: Exclusion Criteria
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- Altered vitamin D metabolism, currently taking vitamin D supplementation to correct vitamin D deficiency, and/or previous enrollment in the MDIG trial during a prior pregnancy
- Hypercalcemia
- Self-reported medical history of medications or conditions that would predispose a woman to vitamin D sensitivity
- Active tuberculosis, sarcoidosis
- Parathyroid disease
- Renal or liver failure, history of renal/ureteral stones
- Use of antiseizure medications
- High-risk pregnancy (hemoglobin < 70 g/L)
- Proteinuria defined as ≥ 300 mg/dL
- Hypertension ≥ 140 mmHg and/or diastolic blood pressure ≥ 90 mmHg
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Vitamin D status was assessed by measuring 25(OH) D concentration in maternal blood, cord blood, and infant blood. The authors also measured parathyroid hormone (PTH) and monitored both pregnant women and infants for hypercalcemia through serum calcium measurements, and calcium:creatinine concentrations of infants at 3 and 6 months of age.
The 1,300 pregnant women were randomized to one of five parallel groups with weekly supplementation. Baseline characteristics were similar across all groups. The five groups are as follows: 1) placebo group, which received a placebo during the prenatal period and for 26 weeks postpartum; 2) 4,200 IU of vitamin D3 (cholecalciferol) per week with no postpartum treatment; 3) 16,800 IU of vitamin D3 per week with no postpartum treatment; 4) 28,000 IU of vitamin D3 per week with no postpartum treatment; and 5) 28,000 IU of vitamin D3 weekly prenatal treatment with 26 weeks of postpartum treatment. The authors tested the tablets measuring the vitamin D3 concentration. Tablets with different doses were identical in appearance and taste and were administered routinely under direct observation by trial personnel. The participants also received calcium (500 mg/day), iron (66 mg/day), and folic acid (350 mcg/day) throughout the intervention phase. Infants were assessed at 9 and 12 months of age, and visits were conducted either at a clinic or in the home.
Women who participated in the study were between 18 and 40 years of age. At baseline, 64% of women had a vitamin D deficiency, which was defined as a 25-hydroxyvitamin D concentration of < 12 ng/mL. They were dispersed equally among the five groups. Breast-feeding patterns and use of micronutrients were similar across all groups. Adherence to the treatment was high in this study, with 90% of scheduled doses received by more than 90% of women during the prenatal period and by more than 80% of women during the postpartum period. There was no difference in adherence between the groups. A total of 1,164 infants were assessed at 12 months for mean length-for-age z scores. The mean standard deviation length-for-age z score at one year was -1.00 ± 1.04, and the prevalence of stunting was 16%. Stunting is defined as the height or length less than two standard deviations below the standard median for age and sex. The z score is the statistical measurement that demonstrates the number of standard deviations that the infant’s length measurement is from the mean.
The authors found no significant difference in stunting between the five groups. Maternal and infant concentrations of vitamin D serum levels and cord blood were found to be dose-dependent on the vitamin D supplementation level. Vitamin D also demonstrated a dose-dependent decrease in maternal PTH concentrations at delivery. The 28,000 IU vitamin D group with both supplementation during pregnancy and throughout the postpartum period had significantly lower PTH concentrations at six months postpartum than the other groups. To evaluate for vitamin D toxicity, serum calcium is the best-known biomarker and was measured in this study. There were no confirmed cases of hypercalcemia found during pregnancy, indicating that there were no cases of vitamin D toxicity. Eight postpartum women and six infants were found to have asymptomatic hypercalcemia, which was not found to be significantly different across the groups. The authors reported that the 4,200 IU/week vitamin D dose was enough to eliminate maternal vitamin D deficiency in this study.
COMMENTARY
The study authors found that vitamin D supplementation starting between 17 and 24 weeks of gestation and continuing to either delivery or six months’ postpartum did not significantly improve length-for-age z scores during the first year of life. One major study limitation was the initiation of supplementation between weeks 17 and 24 of gestation. The authors of an earlier study demonstrated that vitamin D concentrations may be much more influential earlier in pregnancy and that increased rates of pregnancy and live birth have been found in women with elevated serum concentrations of vitamin D before conception but not at week 8 of gestation.8,9 Another criticism of this study is that the placental machinery for vitamin D metabolism and signaling is activated early in pregnancy but decreases at term. Roth et al did not account for this, because the supplementation initiation was later in pregnancy.
Study strengths included the measurements of maternal and infant vitamin D levels that confirm a dose-dependent increase, the confirmation of the amount of vitamin D in the supplements, and an adequately powered study. The authors also evaluated the incidence of hypercalcemia and found lower levels of PTH in the 28,000 IU group supplemented during pregnancy and the postpartum group.
Currently, the American College of Obstetricians and Gynecologists does not recommend that physicians routinely assess vitamin D levels in women desiring to become pregnant.10 More research needs to be performed to further understand the role of vitamin D in the reproductive system and to determine the efficacy and dose of vitamin D in women desiring to become pregnant. Continuing evidence demonstrates that serum vitamin D levels may not be the best indicator of vitamin D status. Thus, ordering vitamin D serum levels and treating patients with vitamin D supplementation for indications other than bone health may be premature. More research needs to be performed to understand the relationship of vitamin D with pregnancy outcomes and infant health. The findings of this study only demonstrated that vitamin D supplementation initiated between 17 and 24 weeks of gestation did not improve stunting among Bangladeshi infants at birth or 12 months. Additional research from this study may help better explain the authors’ findings.
The World Health Organization does not recommend routine vitamin supplementation during pregnancy.11 Although, the role of vitamin D in pregnancy is unclear, we do know that women should maintain a sufficient vitamin D serum levels for bone health.12 From this study, we know that the lower dose of 4,200 IU of vitamin D weekly did replete deficient pregnant women and that even the higher dose of 28,000 IU weekly did not demonstrate toxicity. The role of vitamin D in infant linear growth is not clear from this study because vitamin D supplementation was initiated at 17 to 24 weeks and not earlier in pregnancy. Research into the role of vitamin D in pregnancy, lactation, and infant growth is not well understood. At the very least, clinicians should follow the AAP recommendation that infants receive 400 IU vitamin D per day shortly after birth.
REFERENCES
- Stevens GA, Finucane MM, Paciorek CJ, et al. Trends in mild, moderate, and severe stunting and underweight, and progress towards MDG 1 in 141 developing countries: A systematic analysis of population representative data. Lancet 2012;380:824-834.
- National Institute of Population Research and Training; Mitra and Associates, ICF International. 2013. Bangladesh demographic and health survey 2011. Dhaka, Bangladesh/Calverton, MD: NIPORT, Mitra and Associates, ICF International. Available at: http://dhsprogram.com/pubs/pdf/FR265/FR265.pdf. Accessed April 1, 2019.
- Bikle DD. Vitamin D, metabolism, mechanism of action, and clinical applications. Chem Biol 2014;21:319-329.
- Armstrong C. AAP doubles recommended vitamin D intake in children. Am Fam Phys 2009;80:196-198.
- Roth DE, Perumal N, Al Mahmud A, Baqui AH. Maternal vitamin D3 supplementation during the third trimester of pregnancy: Effects on infant growth in a longitudinal follow-up study in Bangladesh. J Pediatr 2013;163:1605-1611.e3.
- Roth DE, Gernand AD, Morris SK, et al. Maternal vitamin D supplementation during pregnancy and lactation to promote infant growth in Dhaka, Bangladesh (MDIG trial): Study protocol for a randomized controlled trial. Trials 2015;16:300.
- Cheikh Ismail L, Knight HE, Bhutta Z, Chumlea WC; International Fetal and Newborn Growth Consortium for the 21st Century. Anthropometric protocols for the construction of new international fetal and newborn growth standards: The INTERGROWTH-21st Project. BJOG 2013;120(Suppl 2):42-47.
- Mumford SL, Garbose RA, Kim K, et al. Association of preconception serum 25-hydroxyvitamin D concentrations with livebirth and pregnancy loss: A prospective cohort study. Lancet Diabetes Endocrinol 2018;6:725-732.
- Mumford SL, Garbose RA, Kim K, et al. Association of preconception serum 25-hydroxyvitamin D concentrations with livebirth and pregnancy loss: A prospective cohort study. Lancet Diabetes Endocrinol 2018;19:1880-1881.
- ACOG Committee on Obstetric Practice. ACOG Committee Opinion No. 495: Vitamin D: Screening and supplementation during pregnancy. Obstet Gynecol 2011;118:197-198.
- World Health Organization. WHO recommendations on antenatal care for a positive pregnancy experience. 2016. Available at: http://apps.who.int/iris/bitstream/handle/10665/250796/9789241549912-eng.pdf. Accessed April 1, 2019.
- Holick MF, Binkley NC, Bischoff-Ferrari HA, et al. Evaluation and treatment and prevention of vitamin D deficiency: An Endocrine Society clinical practice guideline. J Clin Endocrinol Metab 2011;96:1911-1930.
