New research links greater gestational vitamin D in blood and reduced childhood behavioral issues

Background

Vitamin D deficiency is common in pregnancy. Vitamin D plays an important role in the developing brain, and deficiency may impair childhood behavioral development.

Objectives

This study examined the relationship between gestational 25(OH)D concentrations and childhood behavior in the Environmental influences on Child Health Outcomes (ECHO) Program.

Methods

Mother-child dyads from ECHO cohorts with data available on prenatal (first trimester through delivery) or cord blood 25(OH)D and childhood behavioral outcomes were included. Behavior was assessed using the Strengths and Difficulties Questionnaire or the Child Behavior Checklist, and data were harmonized using a crosswalk conversion. Linear mixed-effects models examined associations of 25(OH)D with total, internalizing, and externalizing problem scores while adjusting for important confounders, including age, sex, and socioeconomic and lifestyle factors. The effect modification by maternal race was also assessed.

Results

Early (1.5–5 y) and middle childhood (6–13 y) outcomes were examined in 1688 and 1480 dyads, respectively. Approximately 45% were vitamin D deficient [25(OH)D < 20 ng/mL], with Black women overrepresented in this group. In fully adjusted models, 25(OH)D concentrations in prenatal or cord blood were negatively associated with externalizing behavior T-scores in middle childhood [−0.73 (95% CI: −1.36, −0.10) per 10 ng/mL increase in gestational 25(OH)D]. We found no evidence of effect modification by race. In a sensitivity analysis restricted to those with 25(OH)D assessed in prenatal maternal samples, 25(OH)D was negatively associated with externalizing and total behavioral problems in early childhood.

Conclusions

This study confirmed a high prevalence of vitamin D deficiency in pregnancy, particularly among Black women, and revealed evidence of an association between lower gestational 25(OH)D and childhood behavioral problems. Associations were more apparent in analyses restricted to prenatal rather than cord blood samples. Interventions to correct vitamin D deficiency during pregnancy should be explored as a strategy to improve childhood behavioral outcomes.

Discussion

Overall, this study confirmed a high prevalence of vitamin D deficiency among pregnant individuals in the United States, especially those who self-identified as Black. This study found evidence of an association between gestational vitamin D and childhood behavior. Greater 25(OH)D concentrations, measured in prenatal or cord blood samples, were associated with reduced externalizing behaviors in middle childhood. In a sensitivity analysis restricted to 25(OH)D measurements in prenatal samples (that is, excluding the one cohort with cord blood 25(OH)D data), we additionally found favorable associations of vitamin D with total and externalizing problems in early childhood. This finding suggests that the timing of exposure may be related to susceptibility to insult, and future research should evaluate the possible critical windows of exposure. Relationships of gestational 25(OH)D and childhood behavior did not appear to differ between races. Altogether, these results suggest that greater vitamin D status in pregnancy may confer modest protection against behavioral problems during childhood.

Published findings on the relationship between gestational 25(OH)D with offspring behavioral development are inconsistent. Among the strongest positive findings were those reported by Daraki et al. [6] based on a sample of 487 mother-child dyads in Greece. Children of mothers in the highest 25(OH)D tertile (>20.3 ng/mL) in early- to mid-pregnancy had significantly reduced total behavioral difficulties and externalizing behavior scores at age 4 compared to the lowest tertile (<15.5 ng/mL) [6]. In a sample of 218 dyads, Chawla et al. [7] found that greater 25(OH)D concentrations in the first and second trimesters were significantly associated with more favorable internalizing behavior and dysregulation scores at ages 12–24 mo among children of White mothers. However, associations were less evident among Black or Hispanic mothers [7]. In another small study, Gale et al. [45] reported that greater 25(OH)D concentrations in late pregnancy were associated with more favorable scores on the peer problems scale of the SDQ at age 9 but not with any other scales. Another study found that the odds of high total problem scores at 7 y was ∼24% (95% CI: −4%, 60%) greater in children with lower gestational 25(OH)D exposure (<20 ng/mL) compared with higher (>20 ng/mL) exposure, although this did not reach statistical significance (P = 0.09) [46].

Several other studies have observed no association of gestational 25(OH)D with behavioral problems in early [16,18,47] or middle childhood [17,47,48], or adolescence [47]. However, these studies have important limitations. For example, both Laird [18] and López-Vicente [17] acknowledged that their study samples had few participants with vitamin D deficiency. Others included homogenous populations composed predominantly of White participants (86%–100%) [16,47,48] and often with limited geographic recruitment [16,47]. These authors recognized limitations to generalizability [16], especially to other non-White populations with a greater burden of vitamin D deficiency. In contrast, the present study examined a racially and ethnically diverse sample in which vitamin D deficiency was prevalent. Methodological differences may also underlie the differences in study conclusions. For example, the null findings reported by Whitehouse et al. [47] were based on a simple bivariate analysis examining the relationship between quartiles of prenatal 25(OH)D and the percentage of children exceeding CBCL clinical thresholds. Categorization of the exposure and outcome variables, along with the lack of control for potential confounders, could have limited the researchers’ ability to detect subtle relationships. Another study reporting null findings based their behavioral assessment on a brief symptom rating completed by a psychologist following a study visit [48]. Although highly trained in this field, psychologists had limited exposure to study participants and, therefore, may report behavioral problems differently than parents, who are the primary respondents for other assessment tools such as the CBCL and SDQ. A sensitivity analysis suggested that for some behavioral outcomes, stronger relationships may be observed for vitamin D exposures assessed within pregnancy rather than at the time of delivery. Importantly, this study included only one cohort with cord blood 25(OH)D data, but other research supports this possibility, including a study by Sammallahti et al. [49] examining 2 prospective cohorts in Finland and the Netherlands. In this study, lower 25(OH)D concentrations in early- to mid-pregnancy, but not in cord blood, were associated with higher infant-negative affectivity [49], an outcome linked with internalizing and externalizing behaviors in childhood [50]. Two of the largest human studies examining this relationship, which reported null findings, utilized 25(OH)D measurements from relatively late in pregnancy, at 26 wk [48] or 29.6 wk [46]. In contrast, reports by Daraki [6] and Chawla [7], which provide the greatest support for the role of vitamin D, analyzed 25(OH)D concentrations in the first and second trimesters. Consistent with these findings, our sensitivity analysis restricted to second trimester exposure showed either similar or strengthened relationships with behavioral outcomes compared with the main analysis.

Early pregnancy is a critical window during which vitamin D performs numerous biological functions critical to early brain development, such as cytokine regulation, neurotransmitter synthesis, antioxidant activity, and the expression of genes involved in neuronal differentiation, structure, and metabolism [51]. In animal models, prenatal vitamin D deficiency has been associated with morphological changes [52] that may result in abnormal behaviors in adulthood [53,54]. However, studies in humans are limited, and specific biological mechanisms remain unclear. Additionally, existing data from human studies have yet to clarify optimal 25(OH)D concentrations for promoting offspring behavioral health. The most recent recommendations for vitamin D intake from the Institute of Medicine were released in 2011 and are based on achieving circulating 25(OH)D concentrations of 20 ng/mL, including in pregnancy [44]. These guidelines were based on skeletal health outcomes; key limitations acknowledged within the report were the lack of data on the role of vitamin D in nonskeletal health outcomes and during pregnancy and lactation [44]. The results of our IPTW analysis suggested that targeting 30 ng/mL may provide greater protection against behavioral problems compared to 20 ng/mL, yet few studies have directly examined this. Many observational studies have not evaluated relative risks for this higher exposure level [6,16,46], but others have documented benefits for mental and psychomotor development among those with 25(OH)D ≥ 30 ng/mL compared to those between 20 and 30 ng/mL [55].

This study had multiple strengths. First, using multi-cohort data from the ECHO program provided a large sample size for this analysis with rich geographic, socioeconomic, and racial diversity. We also maximized our sample size using a newly developed crosswalk conversion between the CBCL and SDQ scores [40]. The parent-reported SDQ and CBCL both have high predictive validity for behavioral problems [56,57] and are often used as a “gold standard” to which other tools are compared [58]. However, a sensitivity analysis suggested that the conversion may not have fully harmonized scores from the 2 instruments. Our study is the first, to our knowledge, to utilize this crosswalk in a large epidemiological investigation, and future research should evaluate its performance in other populations.

This study may also be affected by residual confounding. For example, a recent review pointed out that many investigations of this subject fail to control for other dietary nutrients [37]. We did not include other dietary factors and nutrient supplements in this analysis, as most cohorts did not collect this information. Positive associations of prenatal diet quality with children’s executive functioning were recently reported in a Canadian cohort [59], yet other researchers have seen no clear association between prenatal diet quality and childhood behavior [60]. Additionally, although adequate infant vitamin D status may potentially mitigate the harmful effects of gestational vitamin D deficiency on childhood outcomes, we did not include information on infant feeding or supplementation practices. Future research assessing vitamin D status throughout early life might be especially helpful in encouraging adherence to the recommendation in the United States Dietary Guidelines to provide infants with vitamin D supplements soon after birth [61]. Due to limited data availability, we were unable to assess the potential importance of the season of biospecimen collection, which may influence 25(OH)D concentrations. However, results from Darling et al. [46] indicated a minimal change in effect estimates for the association of maternal 25(OH)D with childhood neurocognitive outcomes when the season of vitamin D measurement was added to models already adjusted for sociodemographic and lifestyle factors. Concentrations of 25(OH)D were measured for each cohort by a different laboratory. Method-related differences in 25(OH)D analyses are well recognized and could have influenced our findings. However, each laboratory performed rigorous quality control procedures, and most participated in measurement standardization protocols. Furthermore, a sensitivity analysis showed no remarkable differences in findings when any single cohort was omitted from the analysis. Finally, 25(OH)D has been shown to exhibit a diurnal rhythm with lower values overnight compared to midday [62], and we were unable to account for this in our models. This may have increased random error in our exposure assessment, possibly biasing our findings toward the null hypothesis.

In conclusion, this study supports the hypothesized association between gestational vitamin D and childhood behavioral outcomes. Vitamin D deficiency is prevalent among pregnant women in the United States, which may increase risks for adverse birth outcomes, neonatal mortality, and impaired neurocognitive development [4,5,63,64]. Interventions to prevent or correct vitamin D deficiency in pregnancy may be warranted to promote childhood health and should be evaluated in future studies.