Maternal use of supplements containing folic acid within the period from 4 weeks before to 8 weeks after conception was associated with a substantially reduced risk of severe language delay in children at age 3 years. We found no association, however, between maternal use of folic acid supplements and significant delay in gross motor skills at age 3 years. The specificity provides some reassurance that there is not confounding by an unmeasured factor. Such a factor might be expected to relate to both language and motor delay.
To our knowledge, no previous prospective observational study has examined the relation of prenatal folic acid supplements to severe language delay in children. A recent case-control study,22
based on maternal recall of supplement use several years later, found that use of folic acid supplements in early pregnancy was associated with a reduced risk of autism spectrum disorder. In addition, some prospective studies have reported that folic acid supplementation started before 12 weeks after conception was associated with fewer child cognitive or behavioral difficulties,23-26
but these studies were too small to examine severe language delay as an outcome. Although it is a rare condition, severe language delay (as defined herein) has profound social and clinical significance. In childhood, it is associated with intellectual disability, neurodevelopmental disorders such as autism, and difficulty achieving literacy.27
Follow-up studies suggest that, even when there is not an associated intellectual disability, impairment tends to persist into adulthood and is associated with poor literacy.27
A major strength of our study was the prospective design, in which pregnant women were followed up from week 17 of pregnancy. Women responded to detailed questions regarding dietary supplement use over 4-week periods, referring to the ingredient lists on the supplement containers. The precision of these data and the large sample size made it possible to differentiate associations with folic acid from associations with other supplements. We achieved this by using 4 mutually exclusive categories of exposure to prenatal supplements, while retaining adequate statistical power to study a rare outcome.
Another strength of our study was that it was conducted in a country, Norway, that does not fortify food with folic acid. In this population, folic acid supplements eclipse dietary sources of folate.18,28,29
A previous study of a sub-sample of 2934 randomly drawn pregnancies in the MoBa cohort found a strong correlation between maternal report of folic acid use up to week 17 and plasma folate levels at week 17 of pregnancy.28
Because randomized trials that involve withholding usual-care folic acid supplementation are no longer ethical, observational studies must be relied on to examine the implications for child health. Concerns about adverse effects of folic acid supplements on other domains of child30
health magnify the public health implications. For example, studies have suggested, but not proven, that folic acid supplements may be linked to asthma and atopy in children.32
The results from this observational study, on the other hand, are strongly suggestive of beneficial effects on child health, but we caution that this study alone is not a sufficient basis for causal inference or policy recommendations.
One central concern is that observational studies of dietary supplements are vulnerable to confounding by behaviors related to health consciousness and socioeconomic circumstances.33
For several reasons, however, we believe it is unlikely that such confounding explains our main results. First, with respect to prenatal folic acid supplements, prospective observational studies5
were successful in identifying their relationship to neural tube defects, later validated in randomized controlled trials.1,2
Perhaps supplement use is more likely to be accurately reported in the health-conscious context of early pregnancy and with a short period of recall required. Second, the magnitude of the association was large, even after adjustment for well-measured potential confounders. Third, the pattern of our results argues against confounding. Exposure to supplements not containing folic acid was not associated with the risk of severe language delay in children. Exposure to folic acid in combination with other supplements (eg, omega-3 fatty acids) showed the same association with severe language delay as exposure to folic acid supplements alone. Moreover, women in 2 of the exposure categories, other supplements, but no folic acid and folic acid only, did not differ appreciably in maternal education levels; however, their children did differ in the risk of language delay. In addition, we found an association for folic acid among women who started these supplements in weeks 5 to 8 after conception. This is not a particularly health-conscious behavior, because folic acid supplements must be taken before week 4 after conception to prevent neural tube defects.
Another central concern is selection bias. To examine the potential for selection bias related to participation in MoBa, we had previously compared 8 exposure-outcome associations in this cohort with the associations in the Medical Birth Registry of Norway and found no evidence of selection bias.28,34
In this study, we explored the potential for selection bias related to return of the age 3 years questionnaire. Maternal education and folic acid use were associated with the probability of returning the questionnaire, but these associations were found to be independent rather than synergistic, limiting the potential for any resulting selection bias.
In some corollary analyses, the associations we observed were suggestive but not definitive. These results serve to sharpen the challenges for future research. With respect to the relevant period of exposure, the results conform with our a priori hypothesis that folic acid supplements up to week 8 would most likely be associated with a reduced risk of severe language delay. The women who started folic acid supplements after 8 weeks, however, were small in number and not readily comparable with women who started earlier. With respect to a broader spectrum of language delay, we found a statistically robust association with moderate language delay, but it was of a smaller magnitude than for severe language delay. Children with moderate language delay at age 3 years are somewhat heterogeneous, in that a significant number of them will catch up with their peers by age 5 years.12
One possibility is that a stronger association will be found when the age 5 years MoBa data are available, by excluding children who simply had a different pace of development and had caught up by age 5 years.
In addition, the data available thus far do not permit us to investigate the mechanisms by which folic acid supplements might have a protective effect. The archived biological specimens of the MoBa cohort provide a platform, however, for future research to interrogate genetic, epigenetic, and/or other mechanisms.35
One intriguing possibility, supported by some animal data,36
is that folic acid supplements may facilitate reversal or compensation of the epigenetic effects of other early prenatal exposures that disrupt neurodevelopment. Similarly, as suggested by findings on neural tube defects, folic acid may help compensate for genetic variants that confer vulnerability.37
In summary, in this large prospective pregnancy cohort in Norway, use of folic acid supplements in the period 4 weeks before to 8 weeks after conception was associated with a reduced risk of the child having severe language delay at age 3 years. If in future research this relationship were shown to be causal, it would have important implications for understanding the biological processes underlying disrupted neurodevelopment, for the prevention of neurodevelopmental disorders, and for policies of folic acid supplementation for women of reproductive age.