Vitamin D replacement in children, adolescents and pregnant women in the Middle East and North Africa: A systematic review and meta-analysis of randomized controlled trials

Abstract

Introduction: Hypovitaminosis D affects one-third to two-thirds of children and pregnant women from the Middle East and North Africa (MENA) region.

Objective: To evaluate in infants, children, adolescents and pregnant women, from the MENA region, the effect of supplementation with different vitamin D doses on the change in 25-hydroxyvitamin D [25(OH)D] level reached, and other skeletal and non-skeletal outcomes.

Methods: This is a systematic review of randomized controlled trials of vitamin D supplementation conducted in the MENA region. We conducted a comprehensive literature search in 7 databases, without language or time restriction, until November 2016. Two reviewers abstracted data from the included studies, independently and in duplicate. We calculated the mean difference (MD) and 95% CI of 25(OH)D level reached when at least 2 studies were eligible in each comparison (low (<800IU), intermediate (800-2000IU) or high (>2000IU) daily dose of vitamin D, or placebo). We pooled data using RevMan version 5.3.

Results: We identified a total of 15 eligible trials: one in infants, 4 in children and adolescents and 10 in pregnant women. In children and adolescents, an intermediate vitamin D dose (1901IU/d), resulted in a mean difference in 25(OH)D level of 13.5 (95% confidence interval (CI) 8.1-18.8) ng/ml, compared to placebo, favoring the intermediate dose (p<0.001). The proportion of children and adolescents reaching a 25(OH)D level≥ 20ng/ml was 74% in the intermediate dose group. In pregnant women, four trials started supplementation at 12-16weeks of gestation and continued until delivery, and six trials started supplementation at 20-28weeks' gestation and stopped it at delivery. The MD in 25(OH)D level reached was 8.6 (95% CI 5.3-11.9) ng/ml (p<0.001) comparing the high dose (3662IU/d) to the intermediate dose (1836IU/d), and 12.3 (95% CI 6.4-18.2) ng/ml (p<0.001), comparing the high dose (3399IU/d) to the low dose (375IU/d). Comparing the intermediate (1832IU/d) to the low dose (301IU/d), the MD in 25(OH)D level achieved was 7.8 (95% CI 4.5-10.8) ng/ml (p<0.001). The proportion of pregnant women reaching a 25(OH)D level≥20ng/ml was 80%-90%, 73% and 27%-43% in the high, intermediate, and low dose groups, respectively. The risk of bias in the included studies, for children, adolescents and pregnant women, ranged from low to high across all doamins.

Conclusion: In children, adolescents and pregnant women from the MENA, an intermediate vitamin D dose of 1000-2000IU daily may be necessary to allow for the majority of the population to reach a desirable 25(OH)D level of 20ng/ml. Further high quality RCTs are required to confirm/refute the beneficial impact of vitamin D supplementation on various clinically important outcomes.

Keywords: Children and adolescents; Meta-analysis; Middle East and North Africa; Pregnant women; Vitamin D.

Figure 1

Flow diagram of the different phases of the systematic review

Figure 2. Risk of bias assessment for included studies

A- Children and adolescents B- Pregnant women A green color and (+) sign represent a low risk of bias; A yellow color and (?) sign represent an unclear risk of bias; A red color and a (−) sign represent a high risk of bias.

Figure 2. Risk of bias assessment for included studies

A- Children and adolescents B- Pregnant women A green color and (+) sign represent a low risk of bias; A yellow color and (?) sign represent an unclear risk of bias; A red color and a (−) sign represent a high risk of bias.

Figure 3. Effect of vitamin D supplementation on 25(OH)D level in children and adolescents

A- Intermediate dose (800–2,000 IU/d) versus placebo comparison Vitamin D equivalent daily doses administered in the intermediate dose group were as follows: El Hajj Fuleihan 2006: 2,000 IU/d; Ghazi 2010: 1,667 IU/d; Mayan 2015: 2,000 IU. B- Low dose (< 800 IU/d) versus placebo comparison Vitamin D equivalent daily doses administered in the intermediate dose group were as follows: El Hajj Fuleihan 2006: 200 IU/d; Neyestani 2013: 200 IU/d.

Figure 4. Effect of vitamin D supplementation on 25(OH)D level in pregnant women

A-Intermediate dose (800–2,000 IU/d) versus low dose (<800 IU/d) comparison Vitamin D supplementation started early second trimester and continued until delivery. Vitamin D equivalent daily doses were as follows: Dawodu 2013: 2,000 IU/d versus 400 IU/d; Soheilykhah 2013: 1,660 IU/d versus 200 IU/d. B- High dose (>2,000 IU/d) versus intermediate dose (800–2,000 IU/d) comparison Vitamin D supplementation started early second trimester and continued until delivery. Vitamin D equivalent daily doses were as follows: Dawodu 2013: 4,000 IU/d versus 2,000 IU/d; Soheilykhah 2013: 3,571 IU/d versus 1,667 IU/d. C- High dose (>2,000 IU/d) versus low dose (<800 IU/d) comparison Vitamin D supplementation started early second trimester and continued until delivery in 2 studies (Dawodu 2013 and Soheilykhah 2013). Vitamin D supplementation started at 20 weeks gestation and continued until 32 weeks gestation in 2 other studies (Karamali 2015 and Samimi 2015). The study by Vaziri et al administered vitamin D supplementation from 26–28 weeks gestation until delivery (Vaziri 2016). Vitamin D equivalent daily doses were as follows: Dawodu 2013: 4,000 IU/d versus 400 IU/d; Karamali 7,540 IU/d versus 400 IU/d; Samimi 2015: 3,971 IU/d versus 400 IU/d; Soheilykhah 2013: 3,571 IU/d versus 200 IU/d; Vaziri 2016: 2345 IU/d versus 431 IU/d; in the latter study, the total vitamin D dose administered included dietary vitamin D.

Figure 5. Effect of vitamin D supplementation on 25(OH)D level in venous cord - high versus intermediate dose comparison

Vitamin D equivalent daily doses were as follows: Dawodu 2013: 4,000 IU/d versus 2,000 IU/d; Shakiba 2013: 1,667 IU/d vs 3,571 IU/d.