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Neurodevelopmental effects of prenatal vitamin D in humans: systematic

review and meta-analysis

Article  in  Molecular Psychiatry · January 2019

DOI: 10.1038/s41380-019-0357-9

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 Molecular Psychiatry
https://doi.org/10.1038/s41380-019-0357-9

ARTICLE

Neurodevelopmental effects of prenatal vitamin D in humans:

systematic review and meta-analysis
Azahara M García-Serna1,2 Eva Morales1,2,3
●

Received: 25 October 2018 / Revised: 13 December 2018 / Accepted: 11 January 2019

© Springer Nature Limited 2019

Abstract
Diverse studies have investigated the impact of prenatal exposure to vitamin D levels on brain development; however,
evidence in humans has never been systematically reviewed. This article summarized evidence of the association between
25-hydroxyvitamin D [25(OH)D] levels in maternal blood in pregnancy or newborn blood at birth and neurodevelopmental
outcomes, including cognition, psychomotor performance, language development, behavioral difficulties, attention deficit
and hyperactivity disorder (ADHD), and autistic traits. PubMed, Web of Science and SCOPUS databases were
systematically searched for epidemiologic studies published through May 2018 using keywords. Random-effects meta-
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analyses were conducted. Of 260 identified articles, 25 were included in the present review. Comparing the highest vs. the
lowest category of prenatal 25(OH)D levels, the pooled beta coefficients were 0.95 (95% CI −0.03, 1.93; p = 0.05) for
cognition, and 0.88 (95% CI −0.18, 1.93; p = 0.10) for psychomotor development. The pooled relative risk for ADHD was
0.72 (95% CI, 0.59, 0.89; p = 0.002), and the pooled odds ratio for autism-related traits was 0.42 (95% CI, 0.25, 0.71; p =
0.001). There was little evidence for protective effects of high prenatal 25(OH)D for language development and behavior
difficulties. This meta-analysis provides supporting evidence that increased prenatal exposure to 25(OH)D levels is
associated with improved cognitive development and reduced risk of ADHD and autism-related traits later in life.
Associations represent a potentially high public health burden given the current prevalence of vitamin D deficiency and
insufficiency among childbearing aging and pregnant women.

Introduction countries [1]. Developmental brain impairment is too often

Neurodevelopmental behavioral intellectual disorders (NBID)
encompass neurological diseases or neurodevelopmental dis-
abilities, including mental retardation, cerebral palsy, autism,
attention-deficit hyperactivity disorder (ADHD), dyslexia, and
more subtle cognitive and learning impairments, which
together occur in one out of six children in the industrialized
Supplementary information The online version of this article (https://
doi.org/10.1038/s41380-019-0357-9) contains supplementary
material, which is available to authorized users.
* Eva Morales
embarto@hotmail.com
1
Biomedical Research Institute of Murcia (IMIB-Arrixaca),
Murcia, Spain
2
University of Murcia, Murcia, Spain
3
CIBER Epidemiología y Salud Pública (CIBERESP),
Madrid, Spain
untreatable and frequently permanent through adolescence to
adulthood and might result in reduced intelligence, disruption
in behavior, school failure, and loss of economic attainments
on societies [2]. NBIDs seem to be increasing in prevalence,
indicating to some extent a non-genetic origin; however, non-
genetic influences on these neurodevelopmental disorders are
not well established yet.
During the last decade, there has been an increasing
focus on the impact of low vitamin D availability during
pregnancy on brain development and function. The dis-
covery of the vitamin D receptor in multiple brain regions
of the neonatal and adult central nervous system of several
species including humans was crucial for this research
[3, 4]. Further research has evidenced the importance of
vitamin D for brain developmental mechanisms and func-
tioning, including neuronal differentiation, axonal con-
nectivity, dopamine ontogeny, immunological modulation,
and gene transcription [5, 6].
Literature on the potential impacts of prenatal vitamin D
status on brain development in the offspring has rapidly

increased in humans. However, to our knowledge, there has
never been a systematic review. Hence, we conducted a
systematic review, accompanied by meta-analyses where
possible, to summarize the existing evidence in humans on
the relationship between prenatal vitamin D status—mea-
sured as circulating 25(OH)D levels in pregnancy or at birth
—and neurodevelopmental outcomes, including cognition,
psychomotor performance, language development, beha-
vior, ADHD, and autistic traits.
Materials and methods
This meta-analysis has been registered in PROSPERO
(Registration number: CRD42018108490) and was under-
taken and reported according to PRISMA guidelines [7].
Search strategy
A literature search was conducted by two independent
reviewers (AMG-S and EM) in MEDLINE (via PubMed),
SCOPUS engine searches and Web of Science databases
through May 2018. The search strategy used the following
keywords: outcome (“cognition” OR “cognitive function”
OR “neurodevelopment” OR “intellectual” OR “intelli-
gence” OR “academic” OR “ADHD” OR “autism spectrum
disorder” OR “ASD” OR “behavioral problems” OR
“emotional problems”) combined keywords for vitamin D
((“1 alpha, 25 dihydroxy 20 epi vitamin d” OR “1,25
dihydroxy 20 epi vitamin d3” OR “vitamin d” OR “1,25
dihydroxyvitamin d3” OR “d3,1,25 dihydroxyvitamin” OR
“25 hydroxyvitamin d2” OR “25 hydroxyvitamin d3” OR
“25(OH)D”) AND (“pregnancy” OR “cord blood”)). Lim-
its: Human, English. We retrieved 114 studies in PubMed,
123 in Web of Science and 170 in SCOPUS databases.
Identification and first screening of the articles were per-
formed using the information available in the title and the
abstract. After that, both reviewers read through the articles
to decide whether they were eligible or not. Doubts
regarding the inclusion or exclusion of studies were
resolved by discussion between the two independent
researchers, and if no agreement was reached then a third
researcher helped to decide.
Study eligibility criteria
The selection criteria were: (a) article written in English; (b)
original research article based on an epidemiologic study
performed in human individuals (abstracts, case reports,
ecological studies, comments, and lab-based studies were
excluded); (c) available information on circulating con-
centration of 25(OH)D in maternal blood during pregnancy or
in newborn blood at birth as exposure; (d) outcome
A. M. García-Serna, E. Morales
assessment included information on the offspring’s neurode-
velopment evaluated by standardized test scores, including
global IQ or general cognition, psychomotor performance,
language development, behavior difficulties, ADHD, or
autistic traits; and (e) available data on the relevant estimates
of effect size including beta coefficient estimates, odds ratio
(OR), relative risk (RR), hazard ratio (HR), and the corre-
sponding 95% confidence intervals (CIs).
Data extraction and quality assessment
For each eligible article the following information was
extracted: the name of the first author, year of publication,
country and latitude where the study was conducted, time at
vitamin D exposure assessment, mean 25(OH)D con-
centration and category levels, age of the offspring at eva-
luation, number of the participants, tool and/or scale used
for the offspring’s neurodevelopment assessment and
domains evaluated, variables adjusted for in the analysis, as
well as estimates for 25(OH)D levels with corresponding
95% CI.
If some studies reported the results at different follow-up
time points, we chose the available data at the longest time
point in order to avoid overrepresentation bias. When sev-
eral estimates were reported within the same study, the most
adjusted model was used for the pooled analysis. Moreover,
when in the same study, vitamin D levels were measured in
both maternal and newborn blood, both estimates were
included in the pooled analysis. Quality of cohort and case-
control studies was assessed by the two independent
reviewers using the criteria defined by the nine-star New-
castle-Ottawa Scale [8].
Data synthesis and statistical analysis
Four main meta-analyses were performed. We investigated
the pooled association size between prenatal vitamin D
levels and cognitive development outcome as the full-scale
IQ of the Wechsler Intelligence Scale for Children (WISC),
the mental development index (MDI) of Bayleys, and the
general cognitive scale of McCarthy according to the design
of the study. For psychomotor outcomes, we included
observational studies that used Bayleys and McCarthy
instruments. All these indices measure global cognitive and
motor development and have a population mean of 100 and
a standard deviation of 15. To evaluate the association
between prenatal vitamin D with ADHD and autistic traits,
the RRs or the ORs and corresponding 95% CIs from
individual studies were transformed to natural logarithms in
order to normalize their distribution, stabilize variances, and
facilitate calculation of standard errors. Weighted estimates
and corresponding CIs for each outcome of interest were
meta-analyzed by using random-effects models.
Neurodevelopmental effects of prenatal vitamin D in humans: systematic review and meta-analysis
Fig. 1 Flow chart of study
search
For all the analyses the lowest category of 25(OH)D
concentration was defined as reference. Heterogeneity among
studies was evaluated by using the Cochran Q test (sig-
nificant level of 0.10) and quantified by using the I2 statistical
parameter. I2 values <25%, 25–50%, 50–75% and >75%
usually represents very low, low, moderate, or high hetero-
geneity, respectively. Sensitivity analysis was conducted by
removing individual studies to assess the robustness of the
pooled estimates, and to detect whether any particular study
accounted for a large proportion of heterogeneity. When
possible, stratified analyses were conducted to assess mod-
ification effects by selected factors, including time at expo-
sure assessment, offspring’s age at health endpoint, and
optimal 25(OH)D blood levels (30 and 20 ng/ml or greater)
vs. all the rest. Publication bias was examined by using
Funnel plot and Egger’s regression asymmetry test with a
significant level of 0.1 [9]. Statistical analyses were per-
formed using the metafor package in R (version 3.1.2) [10].
Results
The research retrieved a total of 408 articles (Fig. 1). After
removing 148 articles duplicated, 260 were screened based
on the title and abstract. Finally, 25 articles met our inclu-
sion criteria [11–35], including nineteen cohort studies, four
case-control studies, and two intervention studies conducted
between 1959 and 2015 (Table 1). Four studies were from
the USA [16, 21, 25, 26]; three each from Australia [13, 14,
28], Sweden [18, 19, 24], and China [22, 23, 35]; two each
from UK [11, 27], Spain [12, 20], Denmark [17, 30] and the
Netherlands [32, 34]; and one each from Vietnam [15],
Republic of Seychelles [29], India [31], and Greece [33].
Most studies measured total 25(OH)D circulating levels as a
biomarker of prenatal vitamin D status, except for four
studies that measured 25(OH)D3 levels [12, 19, 20, 25].
Sixteen studies assessed vitamin D status in maternal
plasma or serum collected during pregnancy [11–15, 17, 20,
21, 23–27, 31, 33] or at delivery [29]; six studies measured
vitamin D levels in cord blood [19, 22, 28, 30, 35] or
peripheral blood [18] of newborns; and three studies mea-
sured vitamin D both in mothers and newborns [16, 32, 34].
Offspring’s neurodevelopmental outcomes were assessed
when they were aged between 6 months and 22 years. The
study size varied between 20 and 509,639 participants.
Studies used different instruments and scales for assessing
neurodevelopmental related traits. Among observational
studies 15 were evaluated as moderate quality, and eight as
high quality (Supplementary Table S1).
Cognitive development or global IQ
Nine studies [11, 12, 15, 16, 21, 22, 27, 28, 33] have
evaluated the influence of prenatal vitamin D status on the
Table 1 Characteristics of studies on prenatal vitamin D status and neurodevelopment
Author year [ref.] Country (city, latitude) Study design (years) Prenatal vitamin D Offspring’s age N Neurodevelopment assessment and Report
assessment: time & at assessment dimensions
levels (ng/mL)

Gale et al. UK (Southampton, Cohort (1991–1992) Mothers (32 weeks) 9 years 178 • Wechsler Abbreviated Scale of Mother report
2008 [11] 50ºN) Median (IQR) 25 Intelligence (WASI): Global scale IQ
(OH)D: 25 (15-30.1) Verbal IQ • Strengths and Difficulties
Questionnaire (SDQ): Total difficulties
Hyperactivity Conduct problems
Emotional problems Peer problems
Morales et al. Spain (39-42ºN) Cohort (2003–2008) Mothers (13 weeks) 14 months 1820 • Bayley Scales of Infant Development Psychologist report
2012 [12] Median (IQR) 25 (BSID): Mental development index (MDI)
(OH)D3: 29.6 (21.8 Psychomotor development index (PDI)
37.3)
Whitehouse et al. Australia (Perth, 31ºS) Cohort (1989–1991) Mothers (18 weeks) 2 years Range • Peabody Picture Vocabulary Test— Parental report
2012 [13] IQR 25(OH)D: 18.4- 5 years 412–652 Revised (PPVT-R): Language score •
28.8 8 years Child Behaviour Checklist (CBCL): Total
10 years behaviour Internalizing behaviour
14 years Externalizing behaviour
17 years
Whitehouse et al. Australia (Perth, 31ºS) Cohort (1989–1991) Mothers (18 weeks) From 5 to 17 406 • Autism Spectrum Disorder (ASD) Parental report
2013 [14] IQR 25(OH)D: 18.4- years diagnosis • Autism Spectrum Quotient
28.8 (AQ)
Hanieh et al. Vietnam (Ha Nam, Cohort (2010–2012) Mothers (32 weeks) 6 months 960 • Bayley Scales of Infant Development Psychologist report
2014 [15] 20ºN) 25(OH)D -- (BSID): Mental development index (MDI)
Psychomotor development index (PDI)
Language score Socio-emotional score
Keim et al. USA (--) Case-control (1959–1973) Mothers (≤26 weeks) 8 months 4 years Range • Bayley Scales of Infant Development Psychologist report
2014 [16] Median (IQR) 25 7 years 3146– (BSID): Mental development index (MDI)
(OH)D: 18 (13.6) 3587 Psychomotor development index (PDI) •
Newborns (cord Stanford-Binet Intelligence Scale and the
blood) Wechsler Intelligence Scale for Children
Median (IQR) 25 (WISC): Global IQ • Rating system
(OH)D: 12.8 (11.2) behaviour: Internalizing behaviours
Externalizing behaviours
Strøm et al. Denmark (Aarhus, Cohort (1988-1989) Mothers (>30 weeks) 22 years 850 • Prescription for medication or hospital Population-based registry
2014 [17] 56ºN) Median (P10-P90) admission for: ADHD
25(OH)D:
30.5 (13-54.4)
Fernell et al. Sweden (Gothenburg, Sibling-control study Newborns (peripheral 116 • Autism spectrum disorder (ASD) Clinical report
2015 [18] 57ºN; and Stockholm, (1990–2008) blood) diagnosis
59ºN) 25(OH)D:
Mean (SD) in cases:
A. M. García-Serna, E. Morales
Table 1 (continued)
Author year [ref.] Country (city, latitude) Study design (years) Prenatal vitamin D Offspring’s age N Neurodevelopment assessment and Report
assessment: time & at assessment dimensions
levels (ng/mL)

Mean (SD) in
controls:
Gustafsson et al. Sweden (Malmö, 55ºN) Case-control (1978–2000) Newborns (cord 5–17 years 404 • Diagnostic and Statistical Manual of Clinical report
2015 [19] blood) Mental Disorders (DSM): ADHD
25(OH)D3 diagnosis
Median in cases: 13
Median in controls:
13.5
Morales et al. Spain (39-43ºN) Cohort (1997–2008) Mothers (13 weeks) 4.8 years 1650 • Diagnostic and Statistical Manual of Psychologist report
2015 [20] Median (IQR) 25 Mental Disorders, fourth edition (ADHD-
(OH)D3: DSM-IV): Total ADHD-like symptoms
29.1 (21.7, 36.8) Inattention symptoms Hyperactivity-
impulsivity symptoms
Tylavsky et al. USA (Shelby County, Cohort (2006–2011) Mothers (2nd 2 years 1020 • Bayley Scales of Infant and Toddler --
2015 [21] 35ºN) trimester) Development: Cognitive scale Receptive
Mean (range) 25 Language Scaled Score Expressive
(OH)D: Language Scaled Score
22.3 (5.9–68.4)
Zhu et al. China (Hefei, 31ºN) Cohort (2008) Newborns (cord 16–18 months 363 • Bayley Scales of Infant Development Certified examiners
2015 [22] blood) (BSID): Mental development index (MDI)
Mean 25(OH)D Psychomotor development index (PDI)
(range):
14.9 (2.2-44.4)
Chen et al. China (-) Case-control (2014–2015) Mothers (1st 3–7 years 136 • Autism spectrum disorder (ASD) DSM- Child psychiatrist/
2016 [23] trimester) V criteria diagnosis neuropediatrician and child
Neurodevelopmental effects of prenatal vitamin D in humans: systematic review and meta-analysis

25(OH)D psychologist
--
Magnusson et al. Sweden (Stockholm, Cohort (2001–2011) Mothers (--) 4–17 years 509,639 • Autism Spectrum Disorder (ASD) National and regional
2016 [24] 59ºN) 25OHD clinical diagnosis registers
--
Stubbs et al. USA (-) Uncontrolled trial Intervention: 5000 IU 18 months 20 • The Modified Checklist for Autism in –
2016 [25] D3/day during 3 years Toddlers (MCHAT) and the Pervasive
pregnancy Developmental Disorder Behavior
Inventory (PDDBI): Autism spectrum
disorder (ASD)
Chawla et al. USA (Durham, 35ºN) Cohort (2009–2012) Mothers (1st–2nd 12–24 months 218 • Infant Toddler Social Emotional Maternal report
2017 [26] trimester) Assessment (ITSEA): Externalizing
Mean (SD) 25(OH) Internalizing Dysregulation Social-
D: emotional competence Autism Spectrum
16.6 (5.7)
Table 1 (continued)
Author year [ref.] Country (city, latitude) Study design (years) Prenatal vitamin D Offspring’s age N Neurodevelopment assessment and Report
assessment: time & at assessment dimensions
levels (ng/mL)

Disorder (ASD) symptoms (problem

behaviour and social competence)
Darling et al. UK (Avon, 51ºN) Cohort (1991–1992) Mothers (29 weeks) 6–42 months 7065 • The ALSPAC pre-school development Maternal report
2017 [27] Median (IQR) 25 7–9 years tests: Gross and fine motor skills •
(OH)D: Strengths and Difficulties Questionnaire
24.5 (17.2–33.9) (SDQ): Hyperactivity Emotional Conduct
Peer problems Total behaviour • Wechsler
Intelligence Scale for Children (WISC):
Verbal IQ Performance IQ Global IQ •
Neale Analysis of Reading Ability:
Reading ability (accuracy, comprehension
and speed)
Gould et al. Australia (Adelaide RCT of DHA Newborns (cord 18 months Range • Bayley Scales of Infant Development Psychologist report
2017 [28] 34ºS; Melbourne 37ºS; supplementation in blood) 4 years 299–323 (BSID-III): Mental development index
Sydney 34ºS) pregnancy (2005–2008) Mean (SD) 25(OH) (MDI) Psychomotor development index
D: (PDI) Language development • The
22.4 (11.4) Differential Ability Scales Second Edition
(DAS II): Cognitive scale • The Clinical
Evaluation and Language Fundamentals
Preschool, Second edition (CELF-P2)
Laird et al. Republic of Seychelles Cohort (2001) Mothers (delivery) 5 years 189 • Preschool Language Scale-Revised --
2017 [29] (Mahé, 4.7ºS) Mean (SD) 25(OH) Edition: Total Language Score (PLS-TL) •
D: Child Behavior Checklist (CBCL): Total t
40.5 (10.9) score
Mossin et al. Denmark (Odese, 55ºN) Cohort (2010–2012) Newborns (cord 1.5–5 years 1233 • Child Behavior Checklist (CBCL): Parental report
2017 [30] blood) ADHD score
Median (IQR) 25
(OH)D:
17.6 (12.2–23.7)
Veena et al. India (Mysore, 12ºN) Cohort (1997–1998) Mothers (30 wks.) 9–10 years 468 • Kaufman battery: Verbal fluency Psychologist report
2017 [31] Mean (IQR) 25(OH) 13–14 years 472
D:
15.6 (9.4, 23.3)
Vinkhuyzen The Netherlands Cohort (2002–2006) Mothers (mid- 6 years 3895 • Autism Spectrum Disorder (ASD) Clinical records
et al. 2017 [32] (Rotterdam, 51ºN) gestation) 2870 diagnosis
Mean 25(OH)D:
23.4
Newborn (cord
blood)
Mean 25OHD:
14.4
A. M. García-Serna, E. Morales
Table 1 (continued)
Author year [ref.] Country (city, latitude) Study design (years) Prenatal vitamin D Offspring’s age N Neurodevelopment assessment and Report
assessment: time & at assessment dimensions
levels (ng/mL)

Daraki et al. Greece (Heraklion, Cohort (2006–2007) Mothers (13 weeks) 4 years 487 • McCarthy Scales of Children’s Abilities Maternal report
2018 [33] Creta 35ºN) Mean (SD) 25(OH) (MCSA): Verbal scale General cognitive
D: scale Motor scale • Strengths and
18.5 (6.2) Difficulties Questionnaire (SDQ):
Emotional symptoms Conduct problems
Peer relationship problems Prosocial
behaviour Internalizing symptoms
Externalizing symptoms Total difficulties
score • Attention Deficit Hyperactivity
Disorder (ADHD) test: Hyperactivity-
impulsivity Inattention Total ADHD
symptoms
Vinkhuyzen The Netherlands Cohort (2002–2006) Mothers (mid- 6 years 2866 • Social Responsiveness Scale: Autism- Parental report
et al. 2018 [34] (Rotterdam, 51ºN) gestation) 1712 related traits
25OHD
--
Newborn (cord
blood)
25OHD
--
Wang et al. China (Shanghai, 31ºN) Cohort (2012–2013) Newborns (cord 2 years 552 • Ages and Stages Questionnaire: Gross Parental report
2018 [35] blood) and fine motor skills
Median (IQR):
22.4 (27.3-8.6)
IQR interquantile range, SD standard deviation
Neurodevelopmental effects of prenatal vitamin D in humans: systematic review and meta-analysis
 A. M. García-Serna, E. Morales

Fig. 2 Forest plots for the

association comparing the
highest with the lowest levels of
prenatal 25(OH) D with
increased offspring’s cognitive
development or global IQ (a)
and psychomotor development
(b) scores. Black squares
indicate the coefficient in each
study, with square sizes
inversely proportional to the
standard error of the coefficient.
Horizontal lines represent 95%
CI. The summary estimates
(black diamond) were obtained
by using random-effects model.
(1) Indicates vitamin D
measured in maternal blood and
(2) vitamin D measured in
newborns

offspring’s global IQ or cognitive development (Supple-
mentary Table S2). The pooled analysis of available data
revealed a borderline positive association between prenatal
25(OH)D levels and offspring’s cognitive development
(Fig. 2a). Comparing the highest vs. the lowest category of
25(OH)D levels, the pooled beta coefficient was 0.95 (95%
CI −0.03, 1.93, p = 0.05). Moderate heterogeneity was
detected across the included studies (I2 = 59%, p = 0.03),
but no publication bias (p = 0.09).
Psychomotor development
Eight studies [12, 15, 16, 22, 27, 28, 33, 35] assessed off-
spring’s psychomotor performance in relation to prenatal
vitamin D status (Supplementary Table S3). The pooled
analysis of available studies using the motor scale of the
Bayley and the McCarthy instruments showed no associa-
tion between prenatal 25(OH)D levels and offspring’s
motor development. The pooled beta coefficient was 0.88
(95% CI −0.18, 1.93, p = 0.10), comparing the highest with
the lowest category of 25(OH)D levels (Fig. 2b). No evi-
dence of significant heterogeneity (I2 = 52%, p = 0.10) and
publication bias (p = 0.20) was found.
Language development
Nine studies [11, 13, 15, 21, 27–29, 31, 33] have examined
prenatal vitamin D in relation to language development (Sup-
plementary Table S4). Four studies have reported higher con-
centrations of prenatal 25(OH)D to be associated with increased
language scores in preschool [15, 21, 28] and school children
[13]. Five studies did not find a relationship with verbal score or
suboptimal language development [11, 27, 29, 31, 33].
Behavioral difficulties
Seven studies [11, 13, 16, 26, 27, 29, 33] examined the
relationship between prenatal vitamin D status and
Neurodevelopmental effects of prenatal vitamin D in humans: systematic review and meta-analysis
offspring’s behavioral problems (Supplementary Table S5).
Overall, five studies failed to find a relation between pre-
natal 25(OH)D levels and behavioral difficulties in off-
spring [11, 13, 16, 27, 29]. Chawla et al. found lower
prenatal 25(OH)D to be associated with slightly higher
internalizing and dysregulation scores among White pre-
schoolers [26]. In addition, preschoolers of mothers in the
high 25(OH)D tertile (>20 ng/ml) in early pregnancy scored
lower in total behavioral difficulties and more specifically
externalizing symptoms [33].
Attention deficit hyperactivity disorder (ADHD)
Four cohort studies [17, 20, 30, 33] and one case-control
study [19] evaluated the impact of prenatal vitamin D on
offspring’s ADHD risk (Supplementary Table S6). Two
studies reported no association between prenatal 25(OH)D
levels and risk of ADHD diagnosis defined as prescription
of psychostimulant medication or physician report [17, 19];
however, three additional studies showed higher levels of
prenatal 25(OH)D concentrations related to reduced
ADHD-like symptoms [20, 30, 33]. Meta-analysis revealed
an inverse association between prenatal 25(OH)D levels and
risk of ADHD in offspring. The pooled RR was 0.72 (95%
CI, 0.59, 0.89, p = 0.002), comparing the highest with the
lowest category of 25(OH)D circulating levels (Fig. 3a). No
heterogeneity (I2 = 0.0%, p = 0.54) and publication bias (p
= 0.25) was detected.
Autism-related traits
Five cohort studies [14, 24, 26, 32, 34], two case-control
studies [18, 23] and one intervention study [25] evaluated
the association of prenatal vitamin D status with autistic
traits or ASD diagnosis (Supplementary Table S7). Higher
prenatal 25(OH)D concentrations were associated with
lower risk of autism-related traits [14, 26, 34] and ASD
diagnosis [18, 23, 24, 32]. Preliminary findings of an
intervention study prescribing vitamin D (5000 IU/day)
during pregnancy to mothers of children with autism
showed a reduction in the recurrence rate of autism in
newborn siblings compared to the reported recurrence rate
in the literature [25]. Meta-analysis showed higher levels of
prenatal 25(OH)D to be associated with a lower risk of
autistic traits. Comparing the highest with the lowest cate-
gory of 25(OH)D circulating levels the pooled OR was 0.42
(95% CI 0.25, 0.71, p = 0.001) (Fig. 3b). A moderate het-
erogeneity was detected across the included studies (I2 =
60%, p = 0.04), but no publication bias (p = 0.84).
Sensitivity analyses suggested that the pooled estimates
or heterogeneity were not substantially modified by
removing the included studies one by one (Supplementary
Table S8). Stratified analyses showed stronger associations
between 25(OH)D concentrations in early-mid pregnancy
and cognition (beta coefficient 1.18, 95% CI −0.16, 2.51, p
= 0.08), psychomotor performance (beta coefficient 1.43,
95% CI −0.65, 3.52, p = 0.18), and risk of autism-related
traits (OR 0.28, 95% CI 0.19, 0.42, p < 0.01) (Table 2).
Discussion
Vitamin D has been shown to influence brain development
and function. To our knowledge, this is the first meta-
analysis of studies aimed to assess the association between
prenatal 25(OH)D concentration and offspring’s neurode-
velopmental outcomes in humans. We showed that higher
prenatal concentrations of 25(OH)D have a positive influ-
ence on the offspring’s cognitive development. Further-
more, in utero exposure to 25(OH)D was inversely
associated with risk of offspring’s ADHD and autism-
related traits. There was a little evidence for protective
effects of high prenatal 25(OH)D levels for language
development and behavioral difficulties. Levels of 25(OH)
D in early-mid gestation might have stronger beneficial
effect on the offspring’s neurodevelopment than in late
gestation.
The results of this meta-analysis are in line with previous
reviews that have suggested a positive relationship between
gestational vitamin D status and offspring’s neurocognitive
development. Although we found a mild influence of pre-
natal 25(OH) circulating concentrations on the offspring’s
cognitive development, this finding should be cautiously
taken into consideration due to the magnitude of the high
prevalence of suboptimal levels of vitamin D worldwide
among childbearing age and pregnant women [36, 37], and
considering that in utero period is a critical period for
human neurodevelopment. In addition, current findings
support previous articles that have hypothesized a protective
role of prenatal 25(OH)D levels on the development of
ADHD and autism-related traits [6, 38, 39].
Potential mechanisms of action of vitamin D for neuro-
developmental protection have been proposed. Vitamin D
may have diverse anti-inflammatory effects on the brain,
including reducing harmful inflammatory cytokines and
neuro-inflammation caused by oxidants and toxins, enhan-
cing DNA repair mechanisms, anti-autoimmune effects,
raises seizure threshold, T-regulatory cells increase, pro-
tection of neural mitochondria, and glutathione up-
regulation [40, 41]. Moreover, vitamin D regulates geneti-
cally serotonin’s rate limiting enzymes, a neurotransmitter
that shapes brain networks during development and plays
critical roles in brain functions [42]. Furthermore, vitamin D
down-regulates peripheral tryptophan hydroxylase TPH1,
while up-regulates central TPH2, resulting into increased
peripheral serotonin and decreased central serotonin that
 A. M. García-Serna, E. Morales

Fig. 3 Forest plots for the

association comparing the
highest with the lowest levels of
prenatal 25(OH) D with reduced
risk of attention deficit and
hyperactivity disorder (ADHD)
(a) and autism-related traits (b).
Black squares indicate the RR or
the OR in each study, with
square sizes inversely
proportional to the standard
error of the estimate. Horizontal
lines represent 95% CI. The
summary estimates (black
diamond) were obtained by
using random-effects model. (1)
Indicates vitamin D measured in
maternal blood and (2) vitamin
D measured in newborns

characterizes ASD [43, 44]. Vitamin D status might also
affect the expression of tyrosine hydroxylase, the rate-
limiting enzyme for synthesis of dopamine [45]. The
polymorphism in this enzyme’s gene has been associated
with ADHD in animal models [46]. In addition, neonatal
rats maternally deprived of vitamin D showed decreased
dopamine turnover [47].
Although based on a few number of studies, stronger
estimates were found when analyzing studies assessing
25(OH)D circulating concentrations in early-mid gesta-
tion (first and second trimester) compared to late gesta-
tion or birth. These results suggest that protective effects
of vitamin D may occur during prenatal early develop-
ment when brain structures begin to form and are thus
Neurodevelopmental effects of prenatal vitamin D in humans: systematic review and meta-analysis
Table 2 Associations between prenatal 25(OH)D status and offspring’s neurodevelopmental outcomes stratified according to selected variables
Outcome Variable
Global IQ or general cognition Overall
Time at exposure assessment
Early/mid-pregnancy
Late pregnancy or birth
Age at outcome assessment
≤24 months
>24 months
≥30 vs. <20 or <10 ng/ml
Psychomotor performance Overall
Time at exposure assessment
Early/mid-pregnancy
Late pregnancy or birth
Age at outcome assessment
≤12 months
>12 months
≥30 vs. <20 or <10ng/ml
ADHD Overall
Time at exposure assessment
Early/mid-pregnancy
Late pregnancy or birth
Age at outcome assessment
Preschool age
After preschool age
>20 vs. <20 or <10 ng/ml
Autism-related traits Overall
a
Time at exposure assessment
Early/mid-pregnancy
Late pregnancy or birth
Age at outcome assessment
From birth to 7 years
From birth to 17 years
≥20 vs. <10 ng/ml b
Early/Mid pregnancy includes studies measuring 25(OH)D concentrations in maternal blood collected at first or second trimester of pregnancy.
Late pregnancy or birth includes studies measuring 25(OH)D concentrations in maternal blood collected at third trimester of pregnancy or in
newborn blood collected at birth
a
Magnusson et al. was excluded because information on time at exposure assessment was not specified
b
Including Chen et al. comparing >22.9 vs. <15.8 ng/ml
more vulnerable to damaging influences [48, 49]. Given
the low number of included studies these results should
be interpreted with caution. Moreover, we cannot
exclude the possibility that these results could be a
consequence of changes in 25(OH)D measurements over
pregnancy given that some studies have described an
increase in 25(OH)D in maternal blood during the last
n Estimate (95% CI) Heterogeneity test
Beta (95% CI)
8 0.95 (−0.03, 1.93) I2 = 59%, P = 0.03
4 1.18 (−0.16, 2.51) I2 = 65%, P = 0.02
4 0.70 (−0.99, 2.40) I2 = 44%, P = 0.17
4 0.92 (−0.57, 2.41) I2 = 56%, P = 0.07
4 1.07 (−0.45, 2.59) I2 = 53%, P = 0.09
6 0.86 (−0.22, 1.95) I2 = 67%, P= 0.02
6 0.88 (−0.18, 1.93) I2 = 52%, P = 0.10
3 1.43 (−0.65, 3.52) I2 = 74%, P = 0.01
3 0.72 (−0.23, 1.67) I2 = 0.0%, P = 0.92
3 0.26 (−0.52, 1.05) I2 = 30%, P = 0.37
3 2.21 (0.63, 3.78) I2 = 0.0%, P = 0.46
4 0.69 (−0.38, 1.76) I2 = 58%, P = 0.10
RR (95% CI)
5 0.72 (0.59, 0.89) I2 = 0.0%, P = 0.54
2 0.72 (0.56, 0.92) I2 = 0.0%, P = 0.38
3 0.71 (0.47, 1.08) I2 = 23%, P = 0.31
2 0.69 (0.55, 0.87) I2 = 0.0%, P = 0.54
3 0.79 (0.44, 1.43) I2 = 19%, P = 0.27
3 0.58 (0.41, 0.82) I2 = 0.0%, P = 0.87
OR (95% CI)
5 0.42 (0.25, 0.71) I2 = 60%, P = 0.04
3 0.28 (0.19, 0.42) I2 = 0.0%, P = 0.47
1 1.06 (0.41, 2.76) –
3 0.44 (0.20, 0.99) I2 = 73%, P = 0.03
2 0.40 (0.14, 1.10) I2 = 52%, P = 0.15
3 0.44 (0.20, 0.99) I2 = 73%, P = 0.03
trimester [50], while other studies have not [51, 52].
Anyway, we do not expect that these changes should be
differential between cases and controls. Current evidence
is limited to establish the optimal levels of prenatal 25
(OH)D circulating concentrations to improve offspring’s
neurodevelopment. These two important issues warrant
further investigation.

The main strength of this study is that we investigated a
wide range of neurodevelopmental outcomes, which adds
exceptional value to this meta-analysis. Moreover, we
obtained de novo data from some primary studies [21, 27],
which provided additional information for this analysis. The
present study is based on objectively assessed 25(OH)D
circulating concentrations in maternal and newborn blood
that reflect both diet and sun exposure. Maternal and cord
blood 25(OH)D levels are highly correlated. Cord blood 25
(OH)D concentrations are 75–90% of maternal concentra-
tions at delivery [50, 53].
Several limitations should be acknowledged beyond
common limitations to meta-analyses. First, moderate het-
erogeneity across studies was detected. Different issues
could generate this heterogeneity, including different study
population and location, sample size, duration of follow-up,
source of blood sample, unadjusted seasonal variation, and
adjustment for different covariates. Moreover, instruments
and definitions of neurodevelopmental outcomes were not
completely homogeneous across primary studies (especially
for language development and behavioral difficulties that
could not be meta-analyzed), and in some studies infor-
mation was obtained from parental report. Random-effects
models were run to deal with the heterogeneity. Second,
most studies relied on a single assessment of 25(OH)D
concentration to reflect prenatal vitamin D status during the
entire period, which may not adequately capture long-term
effects and introduce measurement error and exposure
misclassification. Thus, potential misclassification cannot
be ruled out. Third, given the trajectory of the different
components of brain development [54] potential effects of
postnatal vitamin D on specific neurodevelopmental traits
could have been overlooked, as some individuals may have
persistent pattern of vitamin D status that extends post-
natally. Further investigations are warranted to assess
whether infant and child vitamin D status may partly
explain some of the association found in this paper between
prenatal 25(OH)D levels and offspring’s neurodevelopment.
Finally, present estimations might be biased by limitations
in the primary studies.
Our meta-analysis provides supporting evidence that
higher prenatal 25(OH)D circulating concentrations may
have positive effects on offspring’s neurodevelopmental
outcomes, including improved cognitive development and
reduced risk of ADHD and autism-related traits. Although
findings should be interpreted with caution because the
available evidence consists mostly of observational studies
and is susceptible to several potential sources of bias, given
the current prevalence of vitamin D deficiency and insuf-
ficiency among childbearing aging and pregnant women,
observed associations represent a potentially high public
health burden.
A. M. García-Serna, E. Morales
Acknowledgements AMG-S was funded by a predoctoral contract
(FI17/00086) and EM was funded by a Miguel Servet Grant Fellow-
ship (MS14/00046) both awarded by the Spanish Instituto de Salud
Carlos III (ISCIII), Ministry of Economy and Competitiveness, and
Fondos FEDER.
Compliance with ethical standards
Conflict of interest The authors declare that they have no conflict of
interest.
Publisher’s note: Springer Nature remains neutral with regard to
jurisdictional claims in published maps and institutional affiliations.
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