Table 1. Summary of studies assessing the effect of vitamin D status on child development: characteristics and findings.
| Author, year
(Country) |
Participants | Age at
vitamin D measurement (gestational or in child) |
Age at neuro-
assessment in child |
Study design | Domain (tool) | Definition for vitamin D
status |
25(OH)D
quantification method |
Results |
|---|---|---|---|---|---|---|---|---|
| Vitamin D supplementation randomized controlled trials | ||||||||
| Wicklow, 2016
(Canada) 45 |
55 infants | 3 and 6
months |
6 months | RCT: 3 arms
given 400 IU (n=19), 800 IU (n=18) or 1,200 IU (n=18) vitamin D3/day for 5.5 months |
Motor
(AIMS) |
VDS: >75 nmol/L | LC-MS/MS | Infants given 400 IU of
vitamin D had higher motor scores (percentile scores (SD)= 44.7 (27.7)) compared to those who received 800 IU and 1,200 IU (23.6 (13.9) and 25.6 (17.7) respectively, p <0.05). |
| Studies that measured maternal 25(OH)D levels during pregnancy and neurobehavioural outcomes in children after delivery | ||||||||
| López-Vicente,
2019 (Spain) 46 |
2107
mother-child pairs |
Mean (SD)
13.3 (1 st to 2 nd trimester |
4 time-points:
5,8,14 and18 years |
Cohort | Social competence
Total behavioural problems (CBCL, SDQ) |
VDD: <50 nmol/L
VDI: 50–74.9 nmol/L VDS: ≥75 nmol/L |
HPLC | Maternal 25(OH)D levels
>75 nmol/L associated with improved social competence scores compared to levels <50 nmol/L (β=2.14, 95% CI= 0.47, 3.82). No association with total behavioural problems. |
| Dhamayanti,
2019 (Indonesia) 37 |
141 mother-
child pairs |
11 to 14
weeks (1 st trimester) |
3 time-points: 3,
6 and 12 months |
Cohort | Motor
Cognition (ASQ-3) |
VDD: <25 nmol/L | ELFA | Maternal 25(OH)D levels
<25 nmol/L associated with impaired motor development at 3 and 12 months. No association with cognition. |
| Chawla, 2019
(USA) 47 |
218 mother-
child pairs |
1
st and 2
nd
trimester |
12 to 24 months | Cohort | Behaviour
(ITSEA questionnaire) |
25(OH)D levels were
divided into 4 quartiles (exact values unspecified) |
EIA | Lower maternal quartiles of
25(OH)D associated with less favourable behavioural scores among white and Hispanic, but not black infants. |
| Chi, 2018
(China) 31 |
160 mother-
child pairs |
28 weeks (2
nd
trimester) |
6 months | Cohort | Mental
Psychomotor (BSID-III) |
VDD: <50 nmol/L
VDS: >50 nmol/L |
ECLIA | Maternal 25(OH)D <50
nmol/L associated with lower mental (OR=2.77, 95% CI: 1.44, 5.35, p=0.002) and psychomotor scores (OR=2.08, 95% CI: 1.07, 4.04, p=0.032) |
| McCarthy,
2018 (Ireland) 38 |
734 mother-
child pairs |
Two time-
points: 15 weeks (2 nd trimester) and cord blood |
5 years | Cohort | IQ
Behaviour (KBIT-2, CBCL) |
VDD: <30 nmol/L
VDI: 30–50 nmol/L VDS: ≥ 50 nmol/L |
LC-MS/MS | No association with IQ or
behaviour. |
| Darling, 2017
(UK) 32 |
7065
mother-child pairs |
Median 29·6
(12·7–33·3) (1 st to 3 rd trimester) |
Motor, socio-
development at 6 to 42 months Behaviour at 7 years IQ at 8 years Reading ability at 9 years |
Cohort | Motor
Socio-development and communication Behaviour IQ Reading ability (SDQ, WISC) |
VDD: <50 nmol/L
VDS: >50 nmol/L |
HPLC | Maternal 25(OH)D
<50 nmol/L associated with lower gross-motor (OR=1.20, 95% CI: 1.03, 1.40, p=0.02), fine-motor (OR=1.23, 95% CI: 1.05, 1.44, p=0.01) and social development (OR=1.20, 95% CI: 1.01,1.41, p=0.04). No association with IQ or reading ability. |
| Veena, 2017
(India) 35 |
940 mother-
child pairs |
28 to 32 (3
rd
trimester) |
9–14 years | Cohort | Cognitive
Memory Language (KABC-II, WISC) |
VDD: <50 nmol/L
VDS: >50 nmol/L |
RIA | No association with
cognitive, memory or language development. |
| Wang, 2017
(China) 33 |
1244
mother-child pairs |
Cord blood | 2 years | Cohort | Motor
Cognitive Behaviour (ASQ) |
VDD: <50 nmol/L
VDI: 50-74.9 nmol/L VDS: ≥75 nmol/L |
LC-MS/MS | No association with motor,
cognitive or behavioural development. |
| Laird, 2017
(Seychelles) 39 |
202 mother-
child pairs |
Maternal
blood samples collected 1 day after delivery |
5 years | Cohort | Cognitive
Behaviour Language (FT, PLS, WSAT, CBCL, KBIT) |
VDS: ≥50 nmol/L
VDI: 30–49.9 nmol/L VDD: <30 nmol/L |
LC-MS/MS | No association with
cognitive, language or behavioural development. |
| Daraki, 2017
(Greece) 40 |
487 mother-
child pairs |
13±2.4 weeks
(1 st trimester) |
4 years | Cohort | Cognitive
Motor Behaviour (MSCA, SDQ) |
Tertiles: <38.4 nmol/l;
38.4–50.7 nmol/l; >50.7 nmol/l. |
CLIA | Maternal 25(OH)D levels
>50.7 nmol/l associated with higher behavioural scores compared to maternal 25(OH)D <38.4 nmol/l. No association with cognitive or motor development. |
| Gould, 2016
(Australia) 41 |
337 mother-
child pairs |
Cord blood | Cognitive, motor,
language, behaviour and socio-emotional at 18 months Language at 4 years |
Cohort | Cognitive
Motor Behaviour Language (BSID-III, DAS II, CELF-P2) |
VDD: <25 nmol/L
VDI: 25–50 nmol/L VDS: >50 nmol/L |
LC-MS/MS | Each 10 nmol/L increase in
cord blood 25(OH)D was associated with an increase in mean language scores of 0.60 points at 18 months (95% CI: 0.04, 1.17, P = 0.04) and 0.68 points at 4 years (95% CI: 0.07, 1.29, P = 0.03). No association with cognition, motor, behaviour or socio-emotional development. |
| Zhu, 2015
(China) 30 |
363 mother-
child pairs |
Cord blood | 16–18 months | Cohort | Mental
Psychomotor (BSID-CR) |
Quintiles: 5.56-20.8, 20.9-
30.9, 31.0-39.8, 39.9-51.0, 51.3-111 nmol/L |
RIA | Cord blood 25(OH)D levels
of 5.56 to 20.8 nmol/L associated with a reduction in mental and psychomotor scores (-7.60 ,95% CI: -12.4, -2.82; P=0.002 and -8.04, 95% CI: 212.9, 23.11; P=0.001 points respectively) compared to the reference category (25(OH)D levels 39.9-51.0 nmol/L). Levels of 51.3 to 111 nmol/L associated with a reduction in psychomotor scores -12.3 (95% CI: 217.9, 26.67; P<0.001) points) compared to the reference category. |
| Tylavsky, 2015
(USA) 34 |
1020
mother-child pairs |
2 nd trimester | 2 years | Cohort | Cognitive
Language (BSID III) |
Categories; <49.9, 50.00-
74.9, ≥75 nmol/L |
EIA | Each 25 nmol/L increase
in maternal 25(OH)D was associated with an increase in scaled receptive language scores of 0.24 points (P = 0.017). No association with scaled cognitive or expressive language scores. |
| Hanieh, 2014
(Vietnam) 36 |
886 mother-
child pairs |
32 weeks (3
rd
trimester) |
6 months | Cohort | Cognitive
Motor Behaviour Language (BSID III) |
VDD: <37.5nmol/L
VDI: ≥37.5-75 nmol/L VDS: ≥75 nmol/L |
LC-MS/MS | Maternal 25(OH)D < 37.5
nmol/L associated with a reduction in language scores (mean difference: 23.48; 95% CI: 25.52,1.44). No association with cognitive, motor, or behaviour development. |
| Keim, 2014
(USA) 28 |
3896
mother-child pairs |
Two time-
points: ≤26 weeks (2 nd trimester) and Cord blood |
Cognitive and
motor at 8 months IQ and behaviour at 4 and 7 years School achievement at 7 years |
Cohort | IQ
Motor Behaviour School achievemen (BSID, SBIS, WISC, WRAT) |
Categories: <25, 25–50,
50–75, ≥75 nmol/L |
LC-MS/MS | Each 5 nmol/L increase in
both maternal and cord blood 25(OH)D associated with a slight increase in IQ scores of 0.10 points (95% CI: 0.00, 0.19) at 7 years of age. No association with motor, school achievement or behaviour development. |
| Strøm, 2014
(Denmark) 48 |
798 mother-
child pairs |
30 weeks (2
nd
trimester) |
15–16 years | Cohort | School
achievement (Exam scores) |
VDD: <50 nmol/L
VDS: ≥50–75 nmol/L Optimal levels: ≥75–125 nmol/L |
LC-MS/MS | No association between
maternal 25(OH)D and school achievement. |
| Morales, 2012
(Spain) 29 |
1820
mother-child pairs |
11.6%
assessed in 1 st trimester, 88% in 2 nd trimester and <1% in 3 rd trimester |
11–23 months | Cohort | Mental
Psychomotor (BSID) |
VDD: <50 nmol/L
VDS: >75 nmol/L |
HPLC | Each 25 nmol/L increase
in maternal 25(OH)D associated with 0.79 (95% CI: 0.14 to 1.45) and 0.88 (95% CI: 0.22 to 1.54) points increase in mental and psychomotor scores, respectively. |
| Whitehouse,
2012 (Australia) 49 |
743 mother-
child pairs |
18 weeks (2
nd
trimester) |
2 years | Cohort | Language
Behaviour (CBLC, PPVT-R) |
VDD: <46 nmol/L | EIA | Maternal 25(OH)D
levels <46 nmol/L were associated with impaired language development compared to levels >72 nmol/L (OR=1.97; 95% CI 1.00 to 3.92; P < 0.05). No association with behavioural development. |
| Gale, 2007
(UK) 42 |
178 mother-
child pairs |
28–42 weeks
(3 rd trimester) |
9 years | Cohort | Cognitive
(WASI) |
VDS: >50 nmol/L
VDI: 27.5–50 nmol/L VDD: <27.5 nmol/L |
RIA | No association with
cognitive development. |
| Studies that measured 25(OH)D levels and neurobehavioural outcomes in children | ||||||||
| Tofail, 2019
(Bangladesh) 50 |
205 children | 7 months | 6–8 months | Cross-sectional | Cognitive
Motor Language Behaviour (BSID III, parental reports) |
VDS≥50 nmol/L
VDD<50 nmol/L |
ELISA | Children with VDD had
lower behavioural scores (activity: β ±SE 1.64±0.78; 95% CI 0.10, 3.18; p=0.037) and soothability (2.02±0.70; 0.64, 3.41; p=0.004) compared to the VDS group. No association with cognitive, motor and language development. |
| Yakah, 2019
(Uganda) 51 |
254 children
(3 groups: perinatally HIV-infected (PHIV), exposed- uninfected (HEU), or unexposed- uninfected (HUU)) |
6–10 years | 3 time-points: at
birth, 6 and 12 months |
Cohort | Behaviour
BASC-3 |
VDD: <50 nmol/L
VDI: 50-62 nmol/L VDS: >62 nmol/L |
HPLC-MS/MS | VDD associated with poor
behavioural development in perinatally HIV exposed but uninfected and HIV unexposed uninfected (HUU). |
| Windham,
2019 (USA) 52 |
1189
children (753 cases with developmental disability and 436 controls from the general population) |
New-born
stored blood spots |
4.5– 9 years | Case-control | IQ (Intellectual
disability) |
VDS: ≥ 75nmol/L
VDI: 50–74nmol/L VDD: <50 nmol/L |
LC-MS/MS | No association with IQ. |
| Schmidt, 2019
(USA) 53 |
725 children
(491 cases with developmental disability and 234 controls from the general population) |
New-born
stored blood spots. |
24–60 months | Case-control | Cognitive
(MSEL, VABS) |
VDS: ≥75 nmol/L
VDI: 50–75 nmol/L VDD: <50 nmol/L |
LC-MS/MS | No association with
cognitive development. |
| Tavakolizadeh,
2019 (Iran) 27 |
186 children | 12 months | 12 months | Cross-sectional | Gross motor
(Assessed by paediatrician based on achievement of pre-selected milestones) |
VDS: >75 nmol/L
VDI: 50– 74 nmol/L VDD: < 50 nmol/L |
ELISA | VDD associated with
impaired gross motor ability compared to VDS (OR=3.9, 95% CI=1.9-8.4, P<0.001). |
| Rahman, 2018
(Kuwait) 54 |
1,370
adolescents |
11–16 years | 11–16 years | Cross-sectional | Cognitive
(RSPM), School achievement (Exam scores) |
VDS: ≥75 nmol/L
VDI: 50–75 nmol/L VDD: <50 nmol/L Severe VDD: <25 nmol/L |
LC-MS/MS | No association with
cognitive development or school achievement. |
| Chowdhury,
2017 (India) 44 |
401 pre-
school children |
6–30 months | 12–36 months | Cohort | Cognitive
Motor Personal- social (ASQ-3) |
VDD: <25 nmol/L | ECLIA | No association with
cognitive, motor or personal social development. |
| Filteau,
2016 (India) 55 |
912 school
children |
5 years | 5 years | Cross-sectional | Gross motor
(ASQ-3) |
VDD: <25 nmol/L
Borderline: 25–50 nmol/L VDS: >50 nmol/L |
RIA | No association with gross
motor development. |
| Trilok-Kumar,
2015 (India) 56 |
904 children | 2 time-points:
6 months, 3–6 years |
3–6 years | Cohort (follow
up of a vitamin D supplementation trial in infancy) |
Gross motor
(ASQ-2) |
VDD: <50 nmol/L | RIA | No association with gross
motor development. |
| Nassar, 2012
(Egypt) 43 |
45 school
children |
School age | School age | Cross-sectional | Cognitive
(WISC, BVRT) |
VDD: <27.5 nmol/L
VDI: 27.5–37.5 nmol/L VDS: 37.5–77.5 nmol/L |
HPLC | VDS associated with
improved cognitive and school achievement compared to VDD. |
| Tolppanen,
2011 (USA) 57 |
1790
adolescents |
12–16.9 years | 12–16.9 years | Cross-sectional | Cognitive
(WISC-R, WRAT) |
Quartiles: 8.7–49.2,
49.4–65.6, 65.9–82.1, 82.4–205.2 nmol/L |
RIA | No association with
cognitive development. |
AIMS, Alberta Infant Motor Scale; ASQ-3, Ages and Stages Questionnaire-3; BASC-3, Behavioural Assessment System for Children; BSID, Bailey scales of infant development; BSID-CR, Bayley Scales of Infant Development-China Revision; BSID-III, Bayley Scales of Infant Development-version 3; BVRT, Benton's Visual Retention Test; CBLC, Child Behaviour checklist; CELF-P2, Clinical Evaluation of Language Fundamentals Preschool; Second Edition; DAS-II, Differential Ability Scales Second Edition; FT, Finger tapping; LC-MS/MS, liquid chromatography-tandem mass spectrometry; RIA, radioimmunoassay; HPLC, high performance liquid chromatography; HPLC-MS/MS, high performance liquid chromatography tandem mass spectrometry; ECLIA, electro-chemiluminesce inmmunoassay; ELISA, enzyme-linked immunosorbent assay; EIA, enzyme immunoassay; CLIA, chemiluminescence immunoassay; PLS, Preschool Language Scale-Revised Edition; MSCA, McCarthy Scales of Children Abilities; WSAT, Woodcock-Johnson Scholastic Achievement Test; KBIT, Kaufman Brief Intelligence Test; RSPM, Raven’s Standard Progressive Matrices; PPVT-R, Peabody Picture Vocabulary Test-Revised; SBIS, Stanford-Binet Intelligence Scale; WASI, Wechsler Abbreviated Scale of Intelligence; WISC, Wechsler Intelligence Scale for Children; WISC-R, Wechsler Intelligence Scale for Children-revised; WRAT, Wide Range Achievement Test; SDQ, Strengths and Difficulties Questionnaire; KABC-II, Kaufman Assessment Battery for Children-2nd edition; MSEL, Mullen Scales of Early Learning; VABS, Vineland Adaptive Behaviour Scales. IU, international units; VDD, vitamin D deficiency; VDI, vitamin D insufficiency; VDS, vitamin D sufficiency; β, Beta coefficient.